Search

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.

We estimate the amount of 37 Ar produced in natural xenon via cosmic-ray-induced spallation, an inevitable consequence of the transportation and storage of xenon on the Earth’s surface. We then calculate the resulting 37 Ar concentration in a 10-tonne payload (similar to that of the LUX-ZEPLIN experiment) assuming a representative schedule of xenon purification, storage, and delivery to the underground facility. Using the spallation model by Silberberg and Tsao, the sea-level production rate of 37 Ar in natural xenon is estimated to be 0.024 atoms / kg / day . Assuming the xenon is successively purified to remove radioactive contaminants in 1-tonne batches at a rate of 1 tonne / month , the average 37 Ar activity after 10 tons are purified and transported underground is 0.058 − 0.090 μ Bq / kg , depending on the degree of argon removal during above-ground purification. Such cosmogenic 37 Ar will appear as a noticeable background in the early science data, while decaying with a 35-day half-life. This newly noticed production mechanism of 37 Ar should be considered when planning for future liquid-xenon-based experiments.

The projected sensitivity of the LUX-ZEPLIN (LZ) experiment to two-neutrino and neutrinoless double β decay of 134 Xe is presented. LZ is a 10-tonne xenon time-projection chamber optimized for the detection of dark matter particles and is expected to start operating in 2021 at Sanford Underground Research Facility, USA. Its large mass of natural xenon provides an exceptional opportunity to search for the double β decay of 134 Xe , for which xenon detectors enriched in 136 Xe are less effective. For the two-neutrino decay mode, LZ is predicted to exclude values of the half-life up to 1.7 × 10 24 years at 90% confidence level (CL) and has a three-sigma observation potential of 8.7 × 10 23 years, approaching the predictions of nuclear models. For the neutrinoless decay mode LZ, is projected to exclude values of the half-life up to 7.3 × 10 24 years at 90% CL.

LUX-ZEPLIN is a dark matter detector expected to obtain world-leading sensitivity to weakly-interacting massive particles interacting via nuclear recoils with a ∼7-tonne xenon target mass. This paper presents sensitivity projections to several low-energy signals of the complementary electron recoil signal type: 1) an effective neutrino magnetic moment, and 2) an effective neutrino millicharge, both for pp-chain solar neutrinos, 3) an axion flux generated by the Sun, 4) axionlike particles forming the Galactic dark matter, 5) hidden photons, 6) mirror dark matter, and 7) leptophilic dark matter. World-leading sensitivities are expected in each case, a result of the large 5.6 t 1000 d exposure and low expected rate of electron-recoil backgrounds in the

Mathematical modelling is increasingly used to inform budgeting and strategic decision-making by national TB programmes. Despite the importance of these decisions, there is currently no mechanism to review and confirm the appropriateness of modelling analyses. We have developed a benchmarking, reporting, and review (BRR) approach and accompanying tools to allow constructive review of country-level TB modelling applications. This approach has been piloted in five modelling applications and the results of this study have been used to revise and finalise the approach. The BRR approach consists of 1) quantitative benchmarks against which model assumptions and results can be compared, 2) standardised reporting templates and review criteria, and 3) a multi-stage review process providing feedback to modellers during the application, as well as a summary evaluation after completion. During the pilot, use of the tools prompted important changes in the approaches taken to modelling. The pilot also identified issues beyond the scope of a review mechanism, such as a lack of empirical evidence and capacity constraints. This approach provides independent evaluation of the appropriateness of modelling decisions during the course of an application, allowing meaningful changes to be made before results are used to inform decision-making. The use of these tools can improve the quality and transparency of country-level TB modelling applications.

The LUX-ZEPLIN (LZ) experiment will enable a neutrinoless double β decay search in parallel to the main science goal of discovering dark matter particle interactions. We report the expected LZ sensitivity to 136 Xe neutrinoless double β decay, taking advantage of the significant ( > 600 kg) 136 Xe mass contained within the active volume of LZ without isotopic enrichment. After 1000 live-days, the median exclusion sensitivity to the half-life of 136 Xe is projected to be 1.06 × 10 26 years (90% confidence level), similar to existing constraints. We also report the expected sensitivity of a possible subsequent dedicated exposure using 90% enrichment with 136 Xe at 1.06 × 10 27 years.

Objectives Acceptance and mindfulness‐based interventions (A/MBIs) are recommended for people with mental health conditions. Although there is a growing evidence base supporting the effectiveness of different A/MBIs for mental health conditions, the economic case for these interventions has not been fully explored. The aim of this systematic review was to identify and appraise all available economic evidence of A/MBIs for the management of mental health conditions. Methods Eight electronic bibliographic databases (MEDLINE, MEDLINE In‐Process & Other Non‐Indexed Citations, EMBASE, Web of Science, NHS Economic Evaluation Database (EED), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA) database, and EconLit) were searched for relevant economic evaluations published from each database's inception date until November 2017. Study selection, quality assessment, and data extraction were carried out according to published guidelines. Results Ten relevant economic evaluations presented in 11 papers were identified. Seven of the included studies were full economic evaluations (i.e., costs and effects assessed), and three studies were partial economic evaluations (i.e., only costs were considered in the analysis). The A/MBIs that had been subjected to economic evaluation were acceptance and commitment therapy (ACT), dialectical behaviour therapy (DBT), mindfulness‐based cognitive therapy (MBCT), and mindfulness‐based stress reduction (MBSR). In terms of clinical presentations, the evaluation of cost‐effectiveness of A/MBIs has been more focused on depression and emotional unstable personality disorder with three and four economic evaluations, respectively. Three out of seven full economic evaluations observed that A/MBIs were cost‐effective for the management of mental health conditions. Nevertheless, the heterogeneity of included populations, interventions, and economic evaluation study types limits the extent to which firm conclusions can currently be made. Conclusion This first substantive review of economic evaluations of A/MBIs indicates that more research is needed before firm conclusions can be reached on the cost‐effectiveness of A/MBIs for mental health conditions. Practitioner points The findings of the review provide information that may be relevant to mental health service commissioners and decision‐makers as all economic evidence available on acceptance and mindfulness‐based interventions for mental health conditions is summarized. Evidence relating to the cost‐effectiveness and cost‐saving potential of acceptance and mindfulness‐based interventions is focused mainly on depression and emotional unstable personality disorder to date. Heterogeneity in the specific forms of acceptance and mindfulness‐based interventions may limit generalizability of the findings. The number of health economic evaluations relating to acceptance and mindfulness‐based interventions remains relatively small. Further research in this area is required.

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.

Introduction Macaques play a central role in human tuberculosis(TB) vaccine development. Immune and challenge responses differ across macaque and human subpopulations. We determined which macaque subpopulations best predicted immune responses in different human subpopulations, using novel immunostimulation/immunodynamic modelling methods in a proof of concept study. Methods Data on IFN-γ secreting CD4+ T cells over time after recent BCG vaccination were available for 55 humans and 81 macaques. Human population covariates were: baseline BCG vaccination status, time since BCG vaccination, gender and monocyte/lymphocyte cell count ratio. The macaque population covariate was colony of origin. A two-compartment mathematical model describing the dynamics of the post-BCG IFN-γ T cell response was calibrated to these data using nonlinear mixed effects methods. The model was calibrated to macaque and human data separately. The association between subpopulations and BCG immune response in each species was assessed. Which macaque subpopulations best predicted immune responses in different human subpopulations was identified using Bayesian Information Criteria. Results Macaque colony and human baseline-BCG status were significantly (p Conclusion The work suggests that the immune responses of different human populations may be best modelled by different macaque colonies, and demonstrates the potential utility of immunostimulation/immunodynamic modelling to accelerate TB vaccine development.

Several infectious diseases of global importance-e.g., HIV infection and tuberculosis (TB)-require prolonged treatment with combination antimicrobial regimens typically involving high-potency core agents coupled with additional companion drugs that protect against the de novo emergence of mutations conferring resistance to the core agents. Often, the most effective (or least toxic) companion agents are reused in sequential (first-line, second-line, etc.) regimens. We used a multistrain model of Mycobacterium tuberculosis transmission in Southeast Asia to investigate how this practice might facilitate the emergence of extensive drug resistance, i.e., resistance to multiple core agents. We calibrated this model to regional TB and drug resistance data using an approximate Bayesian computational approach. We report the proportion of data-consistent simulations in which the prevalence of pre-extensively drug-resistant (pre-XDR) TB-defined as resistance to both first-line and second-line core agents (rifampin and fluoroquinolones)-exceeds predefined acceptability thresholds (1 to 2 cases per 100,000 population by 2035). The use of pyrazinamide (the most effective companion agent) in both first-line and second-line regimens increased the proportion of simulations in which the prevalence exceeded the pre-XDR acceptability threshold by 7-fold compared to a scenario in which patients with pyrazinamide-resistant TB received an alternative drug. Model parameters related to the emergence and transmission of pyrazinamide-resistant TB and resistance amplification were among those that were the most strongly correlated with the projected pre-XDR prevalence, indicating that pyrazinamide resistance acquired during first-line treatment subsequently promotes amplification to pre-XDR TB under pyrazinamide-containing second-line treatment. These findings suggest that the appropriate use of companion drugs may be critical to preventing the emergence of strains resistant to multiple core agents.

On July 9, 2014, Aeras and the Max Planck Institute for Infection Biology convened a workshop entitled "Whole Mycobacteria Cell Vaccines for Tuberculosis" at the Max Planck Institute for Infection Biology on the grounds of the Charité Hospital in Berlin, Germany, close to the laboratory where, in 1882, Robert Koch first identified Mycobacterium tuberculosis (Mtb) as the pathogen responsible for tuberculosis (TB). The purpose of the meeting was to discuss progress in the development of TB vaccines based on whole mycobacteria cells. Live whole cell TB vaccines discussed at this meeting were derived from Mtb itself, from Bacille Calmette-Guérin (BCG), the only licensed vaccine against TB, which was genetically modified to reduce pathogenicity and increase immunogenicity, or from commensal non-tuberculous mycobacteria. Inactivated whole cell TB and non-tuberculous mycobacterial vaccines, intended as immunotherapy or as safer immunization alternatives for HIV+ individuals, also were discussed. Workshop participants agreed that TB vaccine development is significantly hampered by imperfect animal models, unknown immune correlates of protection and the absence of a human challenge model. Although a more effective TB vaccine is needed to replace or enhance the limited effectiveness of BCG in all age groups, members of the workshop concurred that an effective vaccine would have the greatest impact on TB control when administered to adolescents and adults, and that use of whole mycobacteria cells as TB vaccine candidates merits greater support, particularly given the limited understanding of the specific Mtb antigens necessary to generate an immune response capable of preventing Mtb infection and/or disease.

In an attempt to address inequalities and inequities in mental health provision in low and middle-income countries the WHO commenced the Mental Health Gap Action Programme (mhGAP) in 2008. Four years on from the commencement of this programme of work, the WHO has recently adopted the Comprehensive Mental Health Action Plan 2013-2020. This article will critically appraise the strategic direction that the WHO has adopted to address mental health difficulties across the globe. This will include a consideration of the role that the biomedical model of mental health difficulties has had on global strategy. Concerns will be raised that an over-reliance on scaling up medical resources has led to a strengthening of psychiatric hospital-based care, and insufficient emphasis being placed on social and cultural determinants of human distress. We also argue that consensus scientific opinion garnered from consortia of psychiatric ‘experts’ drawn mainly from Europe and North America may not have universal relevance or applicability, and may have served to silence and subjugate local experience and expertise across the globe. In light of the criticisms that have been made of the research that has been conducted into understanding mental health problems in the global south, the article also explores ways in which the evidence-base can be made more relevant and more valid. An important issue that will be highlighted is the apparent lack of reciprocity that exists in the impetus for change in how mental health problems are understood and addressed in low and middle-income countries compared to high-income countries. Whereas there is much focus on the need for change in low and middle-income countries, there is comparatively little critical reflection on practices in high-income countries in the global mental health discourse. We advocate for the development of mental health services that are sensitive to the socio-cultural context in which the services are applied. Despite the appeal of global strategies to promote mental health, it may be that very local solutions are required. The article concludes with some reflections on the strategic objectives identified in the Comprehensive Mental Health Action Plan 2013-2020 and how this work can be progressed in the future.

Existing approaches to tuberculosis (TB) control have been no more than partially successful in areas with high human immunodeficiency virus (HIV) prevalence. In the context of increasingly constrained resources, mathematical modelling can augment understanding and support policy for implementing those strategies that are most likely to bring public health and economic benefits. In this paper, we present an overview of past and recent contributions of TB modelling in this key area, and suggest a way forward through a modelling research agenda that supports a more effective response to the TB-HIV epidemic, based on expert discussions at a meeting convened by the TB Modelling and Analysis Consortium. The research agenda identified high-priority areas for future modelling efforts, including 1) the difficult diagnosis and high mortality of TB-HIV; 2) the high risk of disease progression; 3) TB health systems in high HIV prevalence settings; 4) uncertainty in the natural progression of TB-HIV; and 5) combined interventions for TB-HIV. Efficient and rapid progress towards completion of this modelling agenda will require co-ordination between the modelling community and key stakeholders, including advocates, health policy makers, donors and national or regional finance officials. A continuing dialogue will ensure that new results are effectively communicated and new policy-relevant questions are addressed swiftly.