Optima TB: A tool to help optimally allocate tuberculosis spending.

Approximately 85% of tuberculosis (TB) related deaths occur in low- and middle-income countries where health resources are scarce. Effective priority setting is required to maximise the impact of limited budgets. The Optima TB tool has been developed to support analytical capacity and inform evidence-based priority setting processes for TB health benefits package design. This paper outlines the Optima TB framework and how it was applied in Belarus, an upper-middle income country in Eastern Europe with a relatively high burden of TB. Optima TB is a population-based disease transmission model, with programmatic cost functions and an optimisation algorithm. Modelled populations include age-differentiated general populations and higher-risk populations such as people living with HIV. Populations and prospective interventions are defined in consultation with local stakeholders. In partnership with the latter, demographic, epidemiological, programmatic, as well as cost and spending data for these populations and interventions are then collated. An optimisation analysis of TB spending was conducted in Belarus, using program objectives and constraints defined in collaboration with local stakeholders, which included experts, decision makers, funders and organisations involved in service delivery, support and technical assistance. These analyses show that it is possible to improve health impact by redistributing current TB spending in Belarus. Specifically, shifting funding from inpatient- to outpatient-focused care models, and from mass screening to active case finding strategies, could reduce TB prevalence and mortality by up to 45% and 50%, respectively, by 2035. In addition, an optimised allocation of TB spending could lead to a reduction in drug-resistant TB infections by 40% over this period. This would support progress towards national TB targets without additional financial resources. The case study in Belarus demonstrates how reallocations of spending across existing and new interventions could have a substantial impact on TB outcomes. This highlights the potential for Optima TB and similar modelling tools to support evidence-based priority setting.

A New Method for Estimating the Incidence of Infectious Diseases.

Ambitious World Health Organization targets for disease elimination require monitoring of epidemics using routine health data in settings of decreasing and low incidence. We evaluated 2 methods commonly applied to routine testing results to estimate incidence rates that assume a uniform probability of infection between consecutive negative and positive tests based on 1) the midpoint of this interval and 2) a randomly selected point in this interval. We compared these with an approximation of the Poisson binomial distribution, which assigns partial incidence to time periods based on the uniform probability of occurrence in these intervals. We assessed bias, variance, and convergence of estimates using simulations of Weibull-distributed failure times with systematically varied baseline incidence and varying trend. We considered results for quarterly, half-yearly, and yearly incidence estimation frequencies. We applied the methods to assess human immunodeficiency virus (HIV) incidence in HIV-negative patients from the Treatment With Antiretrovirals and Their Impact on Positive and Negative Men (TAIPAN) Study, an Australian study of HIV incidence in men who have sex with men, between 2012 and 2018. The Poisson binomial method had reduced bias and variance at low levels of incidence and for increased estimation frequency, with increased consistency of estimation. Application of methods to real-world assessment of HIV incidence found decreased variance in Poisson binomial model estimates, with observed incidence declining to levels where simulation results had indicated bias in midpoint and random-point methods.

Sustainable HIV treatment in Africa through viral-load-informed differentiated care.

There are inefficiencies in current approaches to monitoring patients on antiretroviral therapy in sub-Saharan Africa. Patients typically attend clinics every 1 to 3 months for clinical assessment. The clinic costs are comparable with the costs of the drugs themselves and CD4 counts are measured every 6 months, but patients are rarely switched to second-line therapies. To ensure sustainability of treatment programmes, a transition to more cost-effective delivery of antiretroviral therapy is needed. In contrast to the CD4 count, measurement of the level of HIV RNA in plasma (the viral load) provides a direct measure of the current treatment effect. Viral-load-informed differentiated care is a means of tailoring care so that those with suppressed viral load visit the clinic less frequently and attention is focussed on those with unsuppressed viral load to promote adherence and timely switching to a second-line regimen. The most feasible approach to measuring viral load in many countries is to collect dried blood spot samples for testing in regional laboratories; however, there have been concerns over the sensitivity and specificity of this approach to define treatment failure and the delay in returning results to the clinic. We use modelling to synthesize evidence and evaluate the cost-effectiveness of viral-load-informed differentiated care, accounting for limitations of dried blood sample testing. We find that viral-load-informed differentiated care using dried blood sample testing is cost-effective and is a recommended strategy for patient monitoring, although further empirical evidence as the approach is rolled out would be of value. We also explore the potential benefits of point-of-care viral load tests that may become available in the future.

A Systematic Review of Interventions Used to Increase Blood Donor Compliance with Deferral Criteria.

BACKGROUND AND OBJECTIVES: Pre-donation screening of potential blood donors is critical for ensuring the safety of the donor blood supply, and donor deferral as a result of risk factors is practised worldwide. This systematic review was conducted in the context of an expert review convened by the Australian Red Cross Lifeblood in 2013 to consider Lifeblood's injecting drug use (IDU)-related policies and aimed to identify studies assessing interventions to improve compliance with deferral criteria in blood donation settings. MATERIALS AND METHODS: MEDLINE/PubMed, OVID Medline, OVID Embase, LILACS, and the Cochrane Library (CENTRAL and DARE) databases were searched for studies conducted within blood donation settings that examined interventions to increase blood donor compliance with deferral criteria. Observational and experimental studies from all geographical areas were considered. RESULTS: Ten studies were identified that tested at least one intervention to improve blood donor compliance with deferral criteria, including computerized interviews or questionnaires, direct and indirect oral questioning, educational materials, and a combination of a tickbox questionnaire and a personal donor interview. High-quality evidence from a single study was provided for the effectiveness of a computerized interview in improving detection of HIV risk behaviour. Low-quality evidence for the effectiveness of computerized interviews was provided by 3 additional studies. Two studies reported a moderate effect of direct questioning in increasing donor deferral, but the quality of the evidence was low. CONCLUSION: This review identified several interventions to improve donor compliance that have been tested in blood donation settings and provided evidence for the effectiveness of computerized interviews in improving detection of risk factors.

Population-level diagnosis and care cascade for chlamydia in Australia.

OBJECTIVES: Key strategies to control chlamydia include testing, treatment, partner management and re-testing. We developed a diagnosis and care cascade for chlamydia to highlight gaps in control strategies nationally and to inform efforts to optimise control programmes. METHODS: The Australian Chlamydia Cascade was organised into four steps: (1) annual number of new chlamydia infections (including re-infections); (2) annual number of chlamydia diagnoses; (3) annual number of diagnoses treated; (4) annual number of diagnoses followed by a re-test for chlamydia within 42-180 days of diagnosis. For 2016, we estimated the number of infections among young men and women aged 15-29 years in each of these steps using a combination of mathematical modelling, national notification data, sentinel surveillance data and previous research studies. RESULTS: Among young people in Australia, there were an estimated 248 580 (range, 240 690-256 470) new chlamydia infections in 2016 (96 470 in women; 152 100 in men) of which 70 164 were diagnosed (28.2% overall: women 43.4%, men 18.6%). Of the chlamydia infections diagnosed, 65 490 (range, 59 640-70 160) were treated (93.3% across all populations), but only 11 330 (range, 7660-16 285) diagnoses were followed by a re-test within 42-180 days (17.3% overall: women 20.6%, men 12.5%) of diagnosis. CONCLUSIONS: The greatest gaps in the Australian Chlamydia Cascade for young people were in the diagnosis and re-testing steps, with 72% of infections undiagnosed and 83% of those diagnosed not re-tested: both were especially low among men. Treatment rates were also lower than recommended by guidelines. Our cascade highlights the need for enhanced strategies to improve treatment and re-testing coverage such as short message service reminders, point-of-care and postal test kits.

Australia needs to increase testing to achieve hepatitis C elimination.

OBJECTIVES: To assess progress in Australia toward the 2030 WHO hepatitis C elimination targets two years after the introduction of highly effective direct-acting antiviral (DAA) treatments. DESIGN: Analysis of quarterly data on government-subsidised hepatitis C RNA testing and hepatitis C treatment in Australia, January 2013 - June 2018. Changes in testing and treatment levels associated with DAA availability were assessed in an autoregressive integrated moving average (ARIMA) statistical model, and the impact by 2030 of different levels of testing and treatment were estimated using a mathematical model. MAJOR OUTCOME MEASURES: Hepatitis C prevalence among people who inject drugs; annual hepatitis C incidence relative to 2015 levels; projections for the hepatitis C care cascade in 2030. RESULTS: The mean annual number of treatments initiated for people with hepatitis C increased from 6747 during 2013-2015 (before the introduction of DAAs) to 28 022 during 2016-18; the mean annual number of diagnostic RNA tests increased from 17 385 to 23 819. If current trends in testing and treatment continue (ie, 2018 testing numbers are maintained but treatment numbers decline by 50%), it is projected that by 2030 only 72% of infected people would be treated (by 2025 all people diagnosed with hepatitis C would be treated). The incidence of hepatitis C in 2030 would be 59% lower than in 2015, well short of the WHO target of an 80% reduction. The identification and testing of people exposed to hepatitis C must be increased by at least 50% for Australia to reach the WHO elimination targets. CONCLUSION: Hepatitis C elimination programs in Australia should focus on increasing testing rates and linkage with care to maintain adequate levels of treatment.

Sex differences in vascular reactivity of coronary artery bypass graft conduits.

Females have increase in-hospital mortality and poorer outcomes following coronary artery bypass grafting (CABG). Biological differences in the reactivity of the graft conduits to circulating catecholamine may contribute to this sex difference. This study examined sex differences in the vasoconstrictor responses of internal mammary artery (IMA) and saphenous vein (SV) conduits to phenylephrine (PE) and endothelin-1 (ET-1). Functional IMA and SV were obtained from 78 male and 50 female patients undergoing CABG (67.7 ± 11 and 69 ± 10 years, respectively) and subjected to the following experimental conditions. (1) Concentration response curves for PE and ET-1 were generated in an intact IMA and SV and endothelium denuded IMA segments, (2) in the presence of the nitric oxide synthase inhibitor (L-NAME) or the cyclooxygenase inhibitor (indomethacin) in an endothelium-intact IMA and (3) the activity state (abundance and phosphorylation) of the α1-adrenergic receptor was investigated using Phos-tag™ western blot analysis. (1) Compared to male, female IMA and SV were hypersensitive to PE but not ET-1 (p < 0.05). The female IMA hypersensitivity response to PE was abolished following endothelial denudation, (2) persisted in the presence of L-NAME but was abolished in the presence of indomethacin and (3) there was no sex differences in the abundance and phosphorylation of the α1-adrenergic receptor in IMA. Female IMA and SV graft conduits are hypersensitive to α1-adrenergic stimuli. This endothelial cyclooxygenase pathway-mediated hypersensitivity may produce excessive IMA and SV graft constriction in females administered catecholamines and could contribute to their poorer CABG outcomes.

The case for a universal hepatitis C vaccine to achieve hepatitis C elimination.

BACKGROUND: The introduction of highly effective direct-acting antiviral (DAA) therapy for hepatitis C has led to calls to eliminate it as a public health threat through treatment-as-prevention. Recent studies suggest it is possible to develop a vaccine to prevent hepatitis C. Using a mathematical model, we examined the potential impact of a hepatitis C vaccine on the feasibility and cost of achieving the global WHO elimination target of an 80% reduction in incidence by 2030 in the era of DAA treatment. METHODS: The model was calibrated to 167 countries and included two population groups (people who inject drugs (PWID) and the general community), features of the care cascade, and the coverage of health systems to deliver services. Projections were made for 2018-2030. RESULTS: The optimal incidence reduction strategy was to implement test and treat programmes among PWID, and in settings with high levels of community transmission undertake screening and treatment of the general population. With a vaccine available, the optimal strategy was to include vaccination within test and treat programmes, in addition to vaccinating adolescents in settings with high levels of community transmission. Of the 167 countries modelled, between 0 and 48 could achieve an 80% reduction in incidence without a vaccine. This increased to 15-113 countries if a 75% efficacious vaccine with a 10-year duration of protection were available. If a vaccination course cost US$200, vaccine use reduced the cost of elimination for 66 countries (40%) by an aggregate of US$7.4 (US$6.6-8.2) billion. For a US$50 per course vaccine, this increased to a US$9.8 (US$8.7-10.8) billion cost reduction across 78 countries (47%). CONCLUSIONS: These findings strongly support the case for hepatitis C vaccine development as an urgent public health need, to ensure hepatitis C elimination is achievable and at substantially reduced costs for a majority of countries.

Optimal allocation of HIV resources among geographical regions.

BACKGROUND: Health resources are limited, which means spending should be focused on the people, places and programs that matter most. Choosing the mix of programs to maximize a health outcome is termed allocative efficiency. Here, we extend the methodology of allocative efficiency to answer the question of how resources should be distributed among different geographic regions. METHODS: We describe a novel geographical optimization algorithm, which has been implemented as an extension to the Optima HIV model. This algorithm identifies an optimal funding of services and programs across regions, such as multiple countries or multiple districts within a country. The algorithm consists of three steps: (1) calibrating the model to each region, (2) determining the optimal allocation for each region across a range of different budget levels, and (3) finding the budget level in each region that minimizes the outcome (such as reducing new HIV infections and/or HIV-related deaths), subject to the constraint of fixed total budget across all regions. As a case study, we applied this method to determine an illustrative allocation of HIV program funding across three representative oblasts (regions) in Ukraine (Mykolayiv, Poltava, and Zhytomyr) to minimize the number of new HIV infections. RESULTS: Geographical optimization was found to identify solutions with better outcomes than would be possible by considering region-specific allocations alone. In the case of Ukraine, prior to optimization (i.e. with status quo spending), a total of 244,000 HIV-related disability-adjusted life years (DALYs) were estimated to occur from 2016 to 2030 across the three oblasts. With optimization within (but not between) oblasts, this was estimated to be reduced to 181,000. With geographical optimization (i.e., allowing reallocation of funds between oblasts), this was estimated to be further reduced to 173,000. CONCLUSIONS: With the increasing availability of region- and even facility-level data, geographical optimization is likely to play an increasingly important role in health economic decision making. Although the largest gains are typically due to reallocating resources to the most effective interventions, especially treatment, further gains can be achieved by optimally reallocating resources between regions. Finally, the methods described here are not restricted to geographical optimization, and can be applied to other problems where competing resources need to be allocated with constraints, such as between diseases.

Estimating the syphilis epidemic among gay, bisexual and other men who have sex with men in Australia following changes in HIV care and prevention.

Background Syphilis control remains a challenge in many high-income countries, including Australia, where diagnoses are concentrated among gay, bisexual men and other men who have sex with men (GBM). The aim of this study is to project the syphilis epidemic among GBM under a range of scenarios. METHODS: A dynamic coinfection model of HIV and syphilis transmission among GBM in Victoria, Australia, was parametrised to test data from clinics in Melbourne and syphilis case notifications in Victoria. Projected outcomes were new syphilis infections between 2018 and 2025 under seven testing and behaviour change scenarios. RESULTS: Among HIV-negative GBM, the model estimated that increasing syphilis testing coverage (69% - 75%) and frequency (~8-monthly - 6-monthly) could prevent 5% and 13% of syphilis cases respectively between 2018 and 2025 compared to the status quo. Among HIV-positive GBM, less syphilis testing due to changes in HIV care increased syphilis cases by 29% between 2018 and 2025 compared to the status quo. Under a scenario of 20% HIV pre-exposure prophylaxis (PrEP) coverage among HIV-negative GBM (and associated increased serodiscordant sex, reduced condom use and increased syphilis testing), syphilis cases were estimated to decrease by 6% among HIV-negative GBM and by 3% among HIV-positive GBM compared to the status quo, driven by increased testing among PrEP users. CONCLUSION: The present study findings support syphilis control policies focusing on increased testing among GBM. Current Australian PrEP guidelines of quarterly syphilis testing are likely to negate any increases in syphilis due to risk compensation occurring with PrEP scale-up.

Achieving 90-90-90 Human Immunodeficiency Virus (HIV) Targets Will Not Be Enough to Achieve the HIV Incidence Reduction Target in Australia.

Background: We estimated the human immunodeficiency virus (HIV) incidence reduction in Australia that would correspond to achieving the United Nations Program on HIV and AIDS (UNAIDS) 90-90-90 targets by 2020 and extended targets of 95-95-95 by 2030. This was done in combination with various scale-ups of HIV testing, primary prevention, and preexposure prophylaxis (PrEP) among high-risk men who have sex with men (MSM). These projections were evaluated against the target of achieving a 90% reduction in HIV incidence by 2030 compared with 2010 levels. Methods: A mathematical model. Results: Achieving 90-90-90 by 2020 was estimated to reduce incidence by 10% from 2010 levels. Achieving 95-95-95 by 2030 was estimated to reduce incidence by 17% from 2010 levels, with the first "95" being achievable by testing low- and high-risk MSM 2 and 4 times per year, respectively. This was improved to a 34% reduction by including a 5-year scale-up of PrEP to 30% coverage among high-risk MSM and to 45% by also increasing MSM condom use from 42% to 60%. However, even with 95-95-95, 2 and 4 tests per year for low- and high-risk MSM, 100% high-risk MSM PrEP coverage, and 100% MSM condom use, only an 80% reduction in incidence was possible by 2030. Conclusions: Many countries, particularly those with low HIV prevalence, will struggle to achieve a 90% reduction in HIV incidence by 2030, even if UNAIDS targets are met. Most will require substantially higher levels of prevention coverage and higher testing frequencies to reach this target.

Implications of population-level immunity for the emergence of artemisinin-resistant malaria: a mathematical model.

BACKGROUND: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong Subregion, an area of relatively low transmission, but has yet to be reported in Africa. A population-based mathematical model was used to investigate the relationship between P. falciparum prevalence, exposure-acquired immunity and time-to-emergence of artemisinin resistance. The possible implication for the emergence of resistance across Africa was assessed. METHODS: The model included human and mosquito populations, two strains of malaria ("wild-type", "mutant"), three levels of human exposure-acquired immunity (none, low, high) with two types of immunity for each level (sporozoite/liver stage immunity and blood-stage/gametocyte immunity) and drug pressure based on per-capita treatment numbers. RESULTS: The model predicted that artemisinin-resistant strains may circulate up to 10 years longer in high compared to low P. falciparum prevalence areas before resistance is confirmed. Decreased time-to-resistance in low prevalence areas was explained by low genetic diversity and immunity, which resulted in increased probability of selection and spread of artemisinin-resistant strains. Artemisinin resistance was estimated to be established by 2020 in areas of Africa with low (< 10%) P. falciparum prevalence, but not for 5 or 10 years later in moderate (10-25%) or high (> 25%) prevalence areas, respectively. CONCLUSIONS: Areas of low transmission and low immunity give rise to a more rapid expansion of artemisinin-resistant parasites, corroborating historical observations of anti-malarial resistance emergence. Populations where control strategies are in place that reduce malaria transmission, and hence immunity, may be prone to a rapid emergence and spread of artemisinin-resistant strains and thus should be carefully monitored.

Optima Nutrition: an allocative efficiency tool to reduce childhood stunting by better targeting of nutrition-related interventions.

BACKGROUND: Child stunting due to chronic malnutrition is a major problem in low- and middle-income countries due, in part, to inadequate nutrition-related practices and insufficient access to services. Limited budgets for nutritional interventions mean that available resources must be targeted in the most cost-effective manner to have the greatest impact. Quantitative tools can help guide budget allocation decisions. METHODS: The Optima approach is an established framework to conduct resource allocation optimization analyses. We applied this approach to develop a new tool, 'Optima Nutrition', for conducting allocative efficiency analyses that address childhood stunting. At the core of the Optima approach is an epidemiological model for assessing the burden of disease; we use an adapted version of the Lives Saved Tool (LiST). Six nutritional interventions have been included in the first release of the tool: antenatal micronutrient supplementation, balanced energy-protein supplementation, exclusive breastfeeding promotion, promotion of improved infant and young child feeding (IYCF) practices, public provision of complementary foods, and vitamin A supplementation. To demonstrate the use of this tool, we applied it to evaluate the optimal allocation of resources in 7 districts in Bangladesh, using both publicly available data (such as through DHS) and data from a complementary costing study. RESULTS: Optima Nutrition can be used to estimate how to target resources to improve nutrition outcomes. Specifically, for the Bangladesh example, despite only limited nutrition-related funding available (an estimated $0.75 per person in need per year), even without any extra resources, better targeting of investments in nutrition programming could increase the cumulative number of children living without stunting by 1.3 million (an extra 5%) by 2030 compared to the current resource allocation. To minimize stunting, priority interventions should include promotion of improved IYCF practices as well as vitamin A supplementation. Once these programs are adequately funded, the public provision of complementary foods should be funded as the next priority. Programmatic efforts should give greatest emphasis to the regions of Dhaka and Chittagong, which have the greatest number of stunted children. CONCLUSIONS: A resource optimization tool can provide important guidance for targeting nutrition investments to achieve greater impact.

Correction to: Optima nutrition: an allocative efficiency tool to reduce childhood stunting by better targeting of nutrition-related interventions.

It has been highlighted that the original manuscript [1] contains a typesetting error in the name of Meera Shekar. This had been incorrectly captured as Meera Shekhar in the original article which has since been updated.

Maximizing the impact of malaria funding through allocative efficiency: using the right interventions in the right locations.

BACKGROUND: The high burden of malaria and limited funding means there is a necessity to maximize the allocative efficiency of malaria control programmes. Quantitative tools are urgently needed to guide budget allocation decisions. METHODS: A geospatial epidemic model was coupled with costing data and an optimization algorithm to estimate the optimal allocation of budgeted and projected funds across all malaria intervention approaches. Interventions included long-lasting insecticide-treated nets (LLINs), indoor residual spraying (IRS), intermittent presumptive treatment during pregnancy (IPTp), seasonal mass chemoprevention in children (SMC), larval source management (LSM), mass drug administration (MDA), and behavioural change communication (BCC). The model was applied to six geopolitical regions of Nigeria in isolation and also the nation as a whole to minimize incidence and malaria-attributable mortality. RESULTS: Allocative efficiency gains could avert approximately 84,000 deaths or 15.7 million cases of malaria in Nigeria over 5 years. With an additional US$300 million available, approximately 134,000 deaths or 37.3 million cases of malaria could be prevented over 5 years. Priority funding should go to LLINs, IPTp and BCC programmes, and SMC should be expanded in seasonal areas. To minimize mortality, treatment expansion is critical and prioritized over some LLIN funding, while to minimize incidence, LLIN funding remained a priority. For areas with lower rainfall, LSM is prioritized over IRS but MDA is not recommended unless all other programmes are established. CONCLUSIONS: Substantial reductions in malaria morbidity and mortality can be made by optimal targeting of investments to the right malaria interventions in the right areas.

Projecting the epidemiological effect, cost-effectiveness and transmission of HIV drug resistance in Vietnam associated with viral load monitoring strategies.

OBJECTIVES: The objective of this study was to investigate the potential epidemiological impact of viral load (VL) monitoring and its cost-effectiveness in Vietnam, where transmitted HIV drug resistance (TDR) prevalence has increased from <5% to 5%-15% in the past decade. METHODS: Using a population-based mathematical model driven by data from Vietnam, we simulated scenarios of various combinations of VL testing coverage, VL thresholds for second-line ART initiation and availability of HIV drug-resistance tests. We assessed the cost per disability-adjusted life year (DALY) averted for each scenario. RESULTS: Projecting expected ART scale-up levels, to approximately double the number of people on ART by 2030, will lead to an estimated 18 510 cases (95% CI: 9120-34 600 cases) of TDR and 55 180 cases (95% CI: 40 540-65 900 cases) of acquired drug resistance (ADR) in the absence of VL monitoring. This projection corresponds to a TDR prevalence of 16% (95% CI: 11%-24%) and ADR of 18% (95% CI: 15%-20%). Annual or biennial VL monitoring with 30% coverage is expected to relieve 12%-31% of TDR (2260-5860 cases), 25%-59% of ADR (9620-22 650 cases), 2%-6% of HIV-related deaths (360-880 cases) and 19 270-51 400 DALYs during 2015-30. The 30% coverage of VL monitoring is estimated to cost US$4848-5154 per DALY averted. The projected additional cost for implementing this strategy is US$105-268 million over 2015-30. CONCLUSIONS: Our study suggests that a programmatically achievable 30% coverage of VL monitoring can have considerable benefits for individuals and leads to population health benefits by reducing the overall national burden of HIV drug resistance. It is marginally cost-effective according to common willingness-to-pay thresholds.

Australian trachoma surveillance annual report, 2013.

Australia remains the only developed country to have endemic levels of trachoma (a prevalence of 5% or greater among children) in some regions. Endemic trachoma in Australia is found predominantly in remote and very remote Aboriginal communities. The Australian Government funds the National Trachoma Surveillance and Reporting Unit to collate, analyse and report trachoma prevalence data and document trachoma control strategies in Australia through an annual surveillance report. This report presents data collected in 2013. Data are collected from Aboriginal and Torres Strait Island communities designated at-risk for endemic trachoma within New South Wales, the Northern Territory, South Australia and Western Australia. The World Health Organization grading criteria were used to diagnose cases of trachoma in Aboriginal children, with jurisdictions focusing screening activities on the 5-9 years age group; but some children in the 1-4 and 10-14 years age groups were also screened. The prevalence of trachoma within a community was used to guide treatment strategies as a public health response. Aboriginal adults aged 40 years or over were screened for trichiasis. Screening coverage for the estimated population of children aged 5-9 years and adults aged 40 years or over in at-risk communities required to be screened in 2013 was 84% and 30%, respectively. There was a 4% prevalence of trachoma among children aged 5-9 years who were screened. Of communities screened, 50% were found to have no cases of active trachoma and 33% were found to have endemic levels of trachoma. Treatment was required in 75 at-risk communities screened. Treatment coverage for active cases and their contacts varied between jurisdictions from 79% to 100%. Trichiasis prevalence was 1% within the screened communities.

Structural and stoichiometric determinants of Ca2+ release-activated Ca2+ (CRAC) channel Ca2+-dependent inactivation.

Depletion of intracellular Ca(2+) stores in mammalian cells results in Ca(2+) entry across the plasma membrane mediated primarily by Ca(2+) release-activated Ca(2+) (CRAC) channels. Ca(2+) influx through these channels is required for the maintenance of homeostasis and Ca(2+) signaling in most cell types. One of the main features of native CRAC channels is fast Ca(2+)-dependent inactivation (FCDI), where Ca(2+) entering through the channel binds to a site near its intracellular mouth and causes a conformational change, closing the channel and limiting further Ca(2+) entry. Early studies suggested that FCDI of CRAC channels was mediated by calmodulin. However, since the discovery of STIM1 and Orai1 proteins as the basic molecular components of the CRAC channel, it has become apparent that FCDI is a more complex phenomenon. Data obtained using heterologous overexpression of STIM1 and Orai1 suggest that, in addition to calmodulin, several cytoplasmic domains of STIM1 and Orai1 and the selectivity filter within the channel pore are required for FCDI. The stoichiometry of STIM1 binding to Orai1 also has emerged as an important determinant of FCDI. Consequently, STIM1 protein expression levels have the potential to be an endogenous regulator of CRAC channel Ca(2+) influx. This review discusses the current understanding of the molecular mechanisms governing the FCDI of CRAC channels, including an evaluation of further experiments that may delineate whether STIM1 and/or Orai1 protein expression is endogenously regulated to modulate CRAC channel function, or may be dysregulated in some pathophysiological states.

A new approach to estimating trends in chlamydia incidence.

OBJECTIVES: Directly measuring disease incidence in a population is difficult and not feasible to do routinely. We describe the development and application of a new method for estimating at a population level the number of incident genital chlamydia infections, and the corresponding incidence rates, by age and sex using routine surveillance data. METHODS: A Bayesian statistical approach was developed to calibrate the parameters of a decision-pathway tree against national data on numbers of notifications and tests conducted (2001-2013). Independent beta probability density functions were adopted for priors on the time-independent parameters; the shapes of these beta parameters were chosen to match prior estimates sourced from peer-reviewed literature or expert opinion. To best facilitate the calibration, multivariate Gaussian priors on (the logistic transforms of) the time-dependent parameters were adopted, using the Matérn covariance function to favour small changes over consecutive years and across adjacent age cohorts. The model outcomes were validated by comparing them with other independent empirical epidemiological measures, that is, prevalence and incidence as reported by other studies. RESULTS: Model-based estimates suggest that the total number of people acquiring chlamydia per year in Australia has increased by ∼120% over 12 years. Nationally, an estimated 356 000 people acquired chlamydia in 2013, which is 4.3 times the number of reported diagnoses. This corresponded to a chlamydia annual incidence estimate of 1.54% in 2013, increased from 0.81% in 2001 (∼90% increase). CONCLUSIONS: We developed a statistical method which uses routine surveillance (notifications and testing) data to produce estimates of the extent and trends in chlamydia incidence.