Cardiac safety assessment with motion field imaging analysis of human iPS cell-derived cardiomyocytes is improved by an integrated evaluation with cardiac ion channel profiling.

We validated a motion field imaging (MFI) assay with human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) as a model to assess multiple cardiac liabilities by comparing the guinea-pig Langendorff heart with hiPS-CMs using 4 reference compounds and 9 internal compounds. We investigated repolarization duration, beating rate (BR), conduction speed, contractility, and inhibitory profile of three cardiac ion channels: hERG, Cav1.2, and Nav1.5. For repolarization, the contraction-relaxation duration (CRDc) of hiPS-CMs was generally consistent with the QTc interval of Langendorff heart. However, 2 internal compounds shortened CRDc despite QTc prolongation in Langendorff heart. Cardiac ion channel profiling revealed that hiPS-CMs could not be used to detect QTc prolongation when the value of Cav1.2 IC50 / hERG IC50 for a compound was between 1 and 10, whereas hiPS-CMs showed responses largely consistent with Langendorff heart when Cav1.2 IC50 / hERG IC50 was below 1 or above 10. The accuracy of hiPS-CMs for the BR was not high, mainly because the BR of hiPS-CMs was increased by an inhibition of Cav1.2. The hiPS-CMs were highly sensitive to conduction speed and contractility, able to detect QRS widening caused by Nav1.5-inhibition, as well as decreased LVdP/dtmax caused by the inhibition of Cav1.2 and/or Nav1.5. In conclusion, the MFI assay with hiPS-CMs would be useful for evaluating multiple cardiac liabilities. The ion channel profile helps to interpret the results of MFI assay and correctly evaluate cardiac risks. Therefore, an integrated cardiac safety assessment with MFI and ion channel profiling is recommended.

Exposure-response analysis of drug-induced QT interval prolongation in telemetered monkeys for translational prediction to human.

INTRODUCTION: The preclinical in vivo assay for QT prolongation is critical for predicting torsadogenic risk, but still difficult to extrapolate to humans. This study ran preclinical tests in cynomolgus monkeys on seven QT reference drugs containing the drugs used in the IQ-CSRC clinical trial and applied exposure-response (ER) analysis to the data to investigate the potential for translational information on the QT effect. METHODS: In each of six participating facilities in the J-ICET project, telemetered monkeys were monitored for 24 h following administration of vehicle or 3 doses of test drugs, and pharmacokinetic profiles at the same doses were evaluated separately. An individual rate-corrected QT interval (QTca) was derived and the vehicle-adjusted change in QTca from baseline (∆∆QTca) was calculated. Then the relationship of concentration to QT effect was evaluated by ER analysis. RESULTS: For QT-positive drugs in the IQ-CSRC study (dofetilide, dolasetron, moxifloxacin, ondansetron, and quinine) and levofloxacin, the slope of the total concentration-QTca effect was significantly positive, and the QT-prolonging effect, taken as the upper bound of the confidence interval for predicted ∆∆QTca, was confirmed to exceed 10 ms. The ER slope of the negative drug levocetirizine was not significantly positive and the QTca effect was below 10 ms at observed peak exposure. DISCUSSION: Preclinical QT assessment in cynomolgus monkeys combined with ER analysis could identify the small QT effect induced by several QT drugs consistently with the outcomes in humans. Thus, the ER method should be regarded as useful for translational prediction of QT effects in humans.

Conduction and contraction properties of human iPS cell-derived cardiomyocytes: analysis by motion field imaging compared with the guinea-pig isolated heart model.

We used motion field imaging to characterize the conduction and contraction of a sheet of cardiomyocytes derived from human induced pluripotent stem cells (hiPS-CMs). A hiPS-CMs sheet of 2.8 mm × 2.8 mm allowed us to simultaneously measure the conduction and the contraction properties in the same cells. Pharmacological responses in the hiPS-CMs of four typical cardiac functional modulators, Na+ channel blocker (lidocaine), Ca2+ channel blocker (diltiazem), gap-junction inhibitor (carbenoxolone), and ß-adrenergic stimulator (isoproterenol), were investigated, and the results were compared to those found using the isolated guinea-pig heart model perfused by the Langendorff method. The conduction speed of excitation waves in hiPS-CMs was decreased by lidocaine, diltiazem, and carbenoxolone, and increased by isoproterenol, and these results were in accordance with the changes in the conduction parameters of electrocardiogram (QRS duration, PR interval, and P duration) in the Langendorff guinea-pig heart model. The maximum speeds for contraction and relaxation, which respectively represent the contraction and relaxation kinetics of hiPS-CMs, were decreased by lidocaine and diltiazem, and increased by isoproterenol. These results also corresponded to alterations in the contractile and relaxation parameters found by measuring left ventricular pressure (LVdP/dtmax and LVdP/dtmin) in the Langendorff guinea-pig heart model. From these lines of evidence, it was suggested that hiPS-CMs enable us to evaluate the cardiac toxicities associated with conduction disturbance or contractile dysfunction, and thereby would be useful as an integrated assessment of cardiac function.

Implementing Impact Evaluations of Malaria Control Interventions: Process, Lessons Learned, and Recommendations.

As funding for malaria control increased considerably over the past 10 years resulting in the expanded coverage of malaria control interventions, so did the need to measure the impact of these investments on malaria morbidity and mortality. Members of the Roll Back Malaria (RBM) Partnership undertook impact evaluations of malaria control programs at a time when there was little guidance in terms of the process for conducting an impact evaluation of a national-level malaria control program. The President's Malaria Initiative (PMI), as a member of the RBM Partnership, has provided financial and technical support for impact evaluations in 13 countries to date. On the basis of these experiences, PMI and its partners have developed a streamlined process for conducting the evaluations with a set of lessons learned and recommendations. Chief among these are: to ensure country ownership and involvement in the evaluations; to engage stakeholders throughout the process; to coordinate evaluations among interested partners to avoid duplication of efforts; to tailor the evaluation to the particular country context; to develop a standard methodology for the evaluations and a streamlined process for completion within a reasonable time; and to develop tailored dissemination products on the evaluation for a broad range of stakeholders. These key lessons learned and resulting recommendations will guide future impact evaluations of malaria control programs and other health programs.

Framework for Evaluating the Health Impact of the Scale-Up of Malaria Control Interventions on All-Cause Child Mortality in Sub-Saharan Africa.

Concerted efforts from national and international partners have scaled up malaria control interventions, including insecticide-treated nets, indoor residual spraying, diagnostics, prompt and effective treatment of malaria cases, and intermittent preventive treatment during pregnancy in sub-Saharan Africa (SSA). This scale-up warrants an assessment of its health impact to guide future efforts and investments; however, measuring malaria-specific mortality and the overall impact of malaria control interventions remains challenging. In 2007, Roll Back Malaria's Monitoring and Evaluation Reference Group proposed a theoretical framework for evaluating the impact of full-coverage malaria control interventions on morbidity and mortality in high-burden SSA countries. Recently, several evaluations have contributed new ideas and lessons to strengthen this plausibility design. This paper harnesses that new evaluation experience to expand the framework, with additional features, such as stratification, to examine subgroups most likely to experience improvement if control programs are working; the use of a national platform framework; and analysis of complete birth histories from national household surveys. The refined framework has shown that, despite persisting data challenges, combining multiple sources of data, considering potential contributions from both fundamental and proximate contextual factors, and conducting subnational analyses allows identification of the plausible contributions of malaria control interventions on malaria morbidity and mortality.

Availability and Quality of Size Estimations of Female Sex Workers, Men Who Have Sex with Men, People Who Inject Drugs and Transgender Women in Low- and Middle-Income Countries.

OBJECTIVE: To assess the availability and quality of population size estimations of female sex workers (FSW), men who have sex with men (MSM), people who inject drug (PWID) and transgender women. METHODS: Size estimation data since 2010 were retrieved from global reporting databases, Global Fund grant application documents, and the peer-reviewed and grey literature. Overall quality and availability were assessed against a defined set of criteria, including estimation methods, geographic coverage, and extrapolation approaches. Estimates were compositely categorized into 'nationally adequate', 'nationally inadequate but locally adequate', 'documented but inadequate methods', 'undocumented or untimely' and 'no data.' FINDINGS: Of 140 countries assessed, 41 did not report any estimates since 2010. Among 99 countries with at least one estimate, 38 were categorized as having nationally adequate estimates and 30 as having nationally inadequate but locally adequate estimates. Multiplier, capture-recapture, census and enumeration, and programmatic mapping were the most commonly used methods. Most countries relied on only one estimate for a given population while about half of all reports included national estimates. A variety of approaches were applied to extrapolate from sites-level numbers to national estimates in two-thirds of countries. CONCLUSIONS: Size estimates for FSW, MSM, PWID and transgender women are increasingly available but quality varies widely. The different approaches present challenges for data use in design, implementation and evaluation of programs for these populations in half of the countries assessed. Guidance should be further developed to recommend: a) applying multiple estimation methods; b) estimating size for a minimum number of sites; and, c) documenting extrapolation approaches.

Estimating the clinical risk of hypertension from VEGF signal inhibitors by a non-clinical approach using telemetered rats.

Anti-angiogenic drugs that target Vascular Endothelial Growth Factor (VEGF) signaling pathways caused hypertension as an adverse effect in clinical studies. Since the hypertension may limit the benefit provided for patients, the demand for non-clinical research that predicts the clinical risk of the hypertension has risen greatly. To clarify whether non-clinical research using rats can appropriately estimate the clinical risk of hypertension caused by VEGF signal inhibitors, we investigated the hemodynamic effects and pharmacokinetics (PK) of the VEGF signal inhibitors cediranib (0.1, 3, and 10 mg/kg), sunitinib (5, 10, and 40 mg/kg), and sorafenib (0.1, 1, and 5 mg/kg) in telemetered rats and examined the correlation between the non-clinical and the clinical hypertensive effect. The VEGF signal inhibitors significantly elevated blood pressure (BP) in rats within a few days of the initiation of dosing, and levels recovered after dosing ended. The trend of the hypertension was similar to that in clinical studies. We found that the AUC at which BP significantly increased by approximately 10 mmHg in rats was comparable to the clinical AUC at which moderate to severe hypertension occurred. These results represent correlations between the non-clinical and the clinical hypertensive effect of VEGF signal inhibitors, suggesting that non-clinical research using telemetered rats would be an effective approach to predict the clinical risk of hypertension caused by VEGF signal inhibitors.

Saving lives in health: global estimates and country measurement.

Daniel Low-Beer and colleagues provide a response from The Global Fund on the PLOS Medicine article by David McCoy and colleagues critiquing their lives saved assessment models. Please see later in the article for the Editors' Summary.

Innovative community-based approaches doubled tuberculosis case notification and improve treatment outcome in Southern Ethiopia.

BACKGROUND: TB Control Programmes rely on passive case-finding to detect cases. TB notification remains low in Ethiopia despite major expansion of health services. Poor rural communities face many barriers to service access. METHODS AND FINDINGS: A community-based intervention package was implemented in Sidama zone, Ethiopia. The package included advocacy, training, engaging stakeholders and communities and active case-finding by female Health Extension Workers (HEWs) at village level. HEWs conducted house-to-house visits, identified individuals with a cough for two or more weeks, with or without other symptoms, collected sputum, prepared smears and supervised treatment. Supervisors transported smears for microscopy, started treatment, screened contacts and initiated Isoniazid preventive therapy (IPT) for children. Outcomes were compared with the pre-implementation period and a control zone. Qualitative research was conducted to understand community and provider perceptions and experiences. HEWs screened 49,857 symptomatic individuals (60% women) from October 2010 to December 2011. 2,262 (4·5%) had smear-positive TB (53% women). Case notification increased from 64 to 127/100,000 population/year resulting in 5,090 PTB+ and 7,071 cases of all forms of TB. Of 8,005 contacts visited, 1,949 were symptomatic, 1,290 symptomatic were tested and 69 diagnosed with TB. 1,080 children received IPT. Treatment success for smear-positive TB increased from 77% to 93% and treatment default decreased from 11% to 3%. Service users and providers found the intervention package highly acceptable. CONCLUSIONS: Community-based interventions made TB diagnostic and treatment services more accessible to the poor, women, elderly and children, doubling the notification rate and improving treatment outcome. This approach could improve TB diagnosis and treatment in other high burden settings.

Involvement of the autonomic nervous system in diurnal variation of corrected QT intervals in common marmosets.

Our previous study has shown that the corrected QT (QTc) interval of the electrocardiogram is longer during the dark period than during the light period in telemetered common marmosets. In the present study, we investigated the involvement of sympathetic and parasympathetic nervous activities in the changes of QTc interval associated with the light-dark cycle.Telemetry transmitters were implanted in six common marmosets to continuously record the electrocardiogram. The QT intervals obtained were corrected for the RR interval by applying individual probabilistic QT-rate correction formulae. Power spectral analysis of heart rate variability was performed to quantify each autonomic nervous function. Changes in QTc intervals and autonomic nervous tones were associated with the light-dark cycle. Parasympathetic nervous activity and QTc intervals significantly increased by approximately 10 ms during the dark period.Atropine, a muscarinic receptor antagonist, suppressed the increased parasympathetic tone and QTc prolongation during the dark period. In contrast, propranolol, a ß-adrenoceptor antagonist, decreased the sympathetic activity and increased QTc intervals during the light period. These results suggest that the parasympathetic nerve functions prolong QTc intervals during the dark period, while the sympathetic nerve functions shorten them during the light period in common marmosets.

Adoption of rapid diagnostic tests for the diagnosis of malaria, a preliminary analysis of the Global Fund program data, 2005 to 2010.

INTRODUCTION: The World Health Organization Guidelines for the Treatment of Malaria, in 2006 and 2010, recommend parasitological confirmation of malaria before commencing treatment. Although microscopy has been the mainstay of malaria diagnostics, the magnitude of diagnostic scale up required to follow the Guidelines suggests that rapid diagnostic tests (RDTs) will be a large component. This study analyzes the adoption of rapid diagnostic testing in malaria programs supported by the Global Fund to fight AIDS, Tuberculosis and Malaria (Global Fund), the leading international funder of malaria control globally. METHODS AND FINDINGS: We analyzed, for the period 2005 to 2010, Global Fund programmatic data for 81 countries on the quantity of RDTs planned; actual quantities of RDTs and artemisinin-based combination treatments (ACTs) procured in 2009 and 2010; RDT-related activities including RDTs distributed, RDTs used, total diagnostic tests including RDTs and microscopy performed, health facilities equipped with RDTs; personnel trained to perform rapid diagnostic malaria test; and grant budgets allocated to malaria diagnosis. In 2010, diagnosis accounted for 5.2% of malaria grant budget. From 2005 to 2010, the procurement plans include148 million RDTs through 96 malaria grants in 81 countries. Around 115 million parasitological tests, including RDTs, had reportedly been performed from 2005 to 2010. Over this period, 123,132 health facilities were equipped with RDTs and 137,140 health personnel had been trained to perform RDT examinations. In 2009 and 2010, 41 million RDTs and 136 million ACTs were purchased. The ratio of procured RDTs to ACTs was 0.26 in 2009 and 0.34 in 2010. CONCLUSIONS/SIGNIFICANCE: Global Fund financing has enabled 81 malaria-endemic countries to adopt WHO guidelines by investing in RDTs for malaria diagnosis, thereby helping improve case management of acute febrile illness in children. However, roll-out of parasitological diagnosis lags behind the roll-out of ACT-based treatment, and will require prioritization of investments.

Simplifying ART cohort monitoring: can pharmacy stocks provide accurate estimates of patients retained on antiretroviral therapy in Malawi?

BACKGROUND: Routine monitoring of patients on antiretroviral therapy (ART) is crucial for measuring program success and accurate drug forecasting. However, compiling data from patient registers to measure retention in ART is labour-intensive. To address this challenge, we conducted a pilot study in Malawi to assess whether patient ART retention could be determined using pharmacy records as compared to estimates of retention based on standardized paper- or electronic based cohort reports. METHODS: Twelve ART facilities were included in the study: six used paper-based registers and six used electronic data systems. One ART facility implemented an electronic data system in quarter three and was included as a paper-based system facility in quarter two only. Routine patient retention cohort reports, paper or electronic, were collected from facilities for both quarter two [April-June] and quarter three [July-September], 2010. Pharmacy stock data were also collected from the 12 ART facilities over the same period. Numbers of ART continuation bottles recorded on pharmacy stock cards at the beginning and end of each quarter were documented. These pharmacy data were used to calculate the total bottles dispensed to patients in each quarter with intent to estimate the number of patients retained on ART. Information for time required to determine ART retention was gathered through interviews with clinicians tasked with compiling the data. RESULTS: Among ART clinics with paper-based systems, three of six facilities in quarter two and four of five facilities in quarter three had similar numbers of patients retained on ART comparing cohort reports to pharmacy stock records. In ART clinics with electronic systems, five of six facilities in quarter two and five of seven facilities in quarter three had similar numbers of patients retained on ART when comparing retention numbers from electronically generated cohort reports to pharmacy stock records. Among paper-based facilities, an average of 13 4 hours was needed to calculate patient retention for cohort reporting using patient registers as compared to 2.25 hours using pharmacy stock cards. CONCLUSION: The numbers of patients retained on ART as estimated using pharmacy stock records were largely similar to estimates based on either paper registers or electronic data system. Furthermore, less time and staff effort was needed to estimate ART patient retention using pharmacy stock records versus paper-based registers. Reinforcing ARV stock management may improve the precision of estimates.

Global fund financing of tuberculosis services delivery in prisons.

INTRODUCTION: Despite concerted efforts to scale up tuberculosis control with large amounts of international financing in the last 2 decades, tuberculosis continues to be a social issue affecting the world's most marginalized and disadvantaged communities. This includes prisoners, estimated at about 10 million globally, for whom tuberculosis is a leading cause of mortality and morbidity. The Global Fund to Fight AIDS, Tuberculosis and Malaria has emerged as the single largest international donor for tuberculosis control, including funding support in delivering tuberculosis treatment for the confined population. METHODS: The Global Fund grants database, with an aggregate approved investment of $21.7 billion in 150 countries by the end of 2010, was reviewed to identify tuberculosis and human immunodeficiency virus/tuberculosis grants and activities that monitored the delivery of tuberculosis treatment and support activities in penitentiary settings. The distribution and trend of number of countries with tuberculosis prison support was mapped by year, geographic region, tuberculosis or multidrug-resistant tuberculosis burden, and prison population rate. We examined the types of grant recipients managing program delivery, their performance, and the nature and range of services provided. RESULTS: Fifty-three of the 105 countries (50%) with Global Fund-supported tuberculosis programs delivered services within prison settings. Thirty-two percent (73 of 228) of tuberculosis grants, representing $558 million of all disbursements of Global Fund tuberculosis support by the end of 2010, included output indicators related to tuberculosis services delivered in prisons. Nearly two-thirds (64%) of these grants were implemented by governments, with the remaining by civil society and other partners. In terms of services, half (36 of 73) of grants provided diagnosis and treatment and an additional 27% provided screening and monitoring of tuberculosis for prisoners. The range of services tracked was limited in scope and scale, with 69% offering only 1 type of service and less than one-fifth offering 2 types of service. CONCLUSIONS: This study is a preliminary attempt to examine Global Fund investments in the fight against tuberculosis in prison settings. Tuberculosis services delivered in prisons have increased in the last decade, but systematic information on funding levels and gaps, services provided, and cost-effective delivery models for delivering tuberculosis services in prisons are lacking.

Long-term costs and health impact of continued global fund support for antiretroviral therapy.

BACKGROUND: By the end of 2011 Global Fund investments will be supporting 3.5 million people on antiretroviral therapy (ART) in 104 low- and middle-income countries. We estimated the cost and health impact of continuing treatment for these patients through 2020. METHODS AND FINDINGS: Survival on first-line and second-line ART regimens is estimated based on annual retention rates reported by national AIDS programs. Costs per patient-year were calculated from country-reported ARV procurement prices, and expenditures on laboratory tests, health care utilization and end-of-life care from in-depth costing studies. Of the 3.5 million ART patients in 2011, 2.3 million will still need treatment in 2020. The annual cost of maintaining ART falls from $1.9 billion in 2011 to $1.7 billion in 2020, as a result of a declining number of surviving patients partially offset by increasing costs as more patients migrate to second-line therapy. The Global Fund is expected to continue being a major contributor to meeting this financial need, alongside other international funders and domestic resources. Costs would be $150 million less in 2020 with an annual 5% decline in first-line ARV prices and $150-370 million less with a 5%-12% annual decline in second-line prices, but $200 million higher in 2020 with phase out of stavudine (d4T), or $200 million higher with increased migration to second-line regimens expected if all countries routinely adopted viral load monitoring. Deaths postponed by ART correspond to 830,000 life-years saved in 2011, increasing to around 2.3 million life-years every year between 2015 and 2020. CONCLUSIONS: Annual patient-level direct costs of supporting a patient cohort remain fairly stable over 2011-2020, if current antiretroviral prices and delivery costs are maintained. Second-line antiretroviral prices are a major cost driver, underscoring the importance of investing in treatment quality to improve retention on first-line regimens.

Scaling up towards international targets for AIDS, tuberculosis, and malaria: contribution of global fund-supported programs in 2011-2015.

OBJECTIVE: The paper projects the contribution to 2011-2015 international targets of three major pandemics by programs in 140 countries funded by the Global Fund to Fight AIDS, Tuberculosis and Malaria, the largest external financier of tuberculosis and malaria programs and a major external funder of HIV programs in low and middle income countries. DESIGN: Estimates, using past trends, for the period 2011-2015 of the number of persons receiving antiretroviral (ARV) treatment, tuberculosis case detection using the internationally approved DOTS strategy, and insecticide-treated nets (ITNs) to be delivered by programs in low and middle income countries supported by the Global Fund compared to international targets established by UNAIDS, Stop TB Partnership, Roll Back Malaria Partnership and the World Health Organisation. RESULTS: Global Fund-supported programs are projected to provide ARV treatment to 5.5-5.8 million people, providing 30%-31% of the 2015 international target. Investments in tuberculosis and malaria control will enable reaching in 2015 60%-63% of the international target for tuberculosis case detection and 30%-35% of the ITN distribution target in sub-Saharan Africa. CONCLUSION: Global Fund investments will substantially contribute to the achievement by 2015 of international targets for HIV, TB and malaria. However, additional large scale international and domestic financing is needed if these targets are to be reached by 2015.

Global Fund financing of public-private mix approaches for delivery of tuberculosis care.

OBJECTIVES: To map the extent and scope of public-private mix (PPM) interventions in tuberculosis (TB) control programmes supported by the Global Fund. METHODS: We reviewed the Global Fund's official documents and data to analyse the distribution, characteristics and budgets of PPM approaches within Global Fund supported TB grants in recipient countries between 2003 and 2008. We supplemented this analysis with data on contribution of PPM to TB case notifications in 14 countries reported to World Health Organization in 2009, for the preparation of the global TB control report. RESULTS: Fifty-eight of 93 countries and multi-country recipients of Global Fund-supported TB grants had PPM activities in 2008. Engagement with 'for-profit' private sector was more prevalent in South Asia while involvement of prison health services has been common in Eastern Europe and central Asia. In the Middle East and North Africa, involving non-governmental organizations seemed to be the focus. Average and median spending on PPM within grants was 10% and 5% respectively, ranging from 0.03% to 69% of the total grant budget. In China, India, Nigeria and the Philippines, PPM contributed to detecting more than 25% TB cases while maintaining high treatment success rates. CONCLUSION: In spite of evidence of cost-effectiveness, PPM constitutes only a modest part of overall TB control activities. Scaling up PPM across countries could contribute to expanding access to TB care, increasing case detection, improving treatment outcomes and help achieve the global TB control targets.

Reductions in malaria and anaemia case and death burden at hospitals following scale-up of malaria control in Zanzibar, 1999-2008.

BACKGROUND: In Zanzibar, the Ministry of Health and partners accelerated malaria control from September 2003 onwards. The impact of the scale-up of insecticide-treated nets (ITN), indoor-residual spraying (IRS) and artemisinin-combination therapy (ACT) combined on malaria burden was assessed at six out of seven in-patient health facilities. METHODS: Numbers of outpatient and inpatient cases and deaths were compared between 2008 and the pre-intervention period 1999-2003. Reductions were estimated by segmented log-linear regression, adjusting the effect size for time trends during the pre-intervention period. RESULTS: In 2008, for all age groups combined, malaria deaths had fallen by an estimated 90% (95% confidence interval 55-98%)(p < 0.025), malaria in-patient cases by 78% (48-90%), and parasitologically-confirmed malaria out-patient cases by 99.5% (92-99.9%). Anaemia in-patient cases decreased by 87% (57-96%); anaemia deaths and out-patient cases declined without reaching statistical significance due to small numbers. Reductions were similar for children under-five and older ages. Among under-fives, the proportion of all-cause deaths due to malaria fell from 46% in 1999-2003 to 12% in 2008 (p < 0.01) and that for anaemia from 26% to 4% (p < 0.01). Cases and deaths due to other causes fluctuated or increased over 1999-2008, without consistent difference in the trend before and after 2003. CONCLUSIONS: Scaling-up effective malaria interventions reduced malaria-related burden at health facilities by over 75% within 5 years. In high-malaria settings, intensified malaria control can substantially contribute to reaching the Millennium Development Goal 4 target of reducing under-five mortality by two-thirds between 1990 and 2015.

Sexual and reproductive health activities in HIV programmes: can we monitor progress?

BACKGROUND: Resource allocation and integration of services have been of interest recently to achieve health-related Millennium Development Goals. This paper analyses the extent to which countries receiving funding in HIV were able to invest in activities in the area of sexual and reproductive health (SRH). METHODS: The authors screened the Global Fund grants data with an aggregate investment of US$16 billion in 140 countries to identify indicators revealing typical SRH services. The analysis focused on the 'Top Ten' internationally agreed indicators and used international guidelines and frameworks to define services for SRH and opportunities for 'linkage' between HIV and SRH services. RESULTS: As of December 2008, 238 of all HIV grants (n = 252) from 133 countries included 1620 service delivery indicators related to SRH. The budgets amounted to US$9.1 billion with US$5.9 billion committed and US$4 billion disbursed. Services included (1) prevention of mother to child transmission for 445,000 HIV-positive pregnant women, (2) 5.7 million care and support services, (3) 1.2 billion condoms delivered, (4) 4.4 million episodes of sexually transmitted infections treated, (5) 61 million counselling and testing encounters, and (6) 11.6 million behavioural change communication (BCC) outreach services for people at high risk and 64.5 million BCC activities for the general population, including youth. Information on the linkage and integration of SRH-HIV services was limited. CONCLUSION: Around 94% of HIV programmes supported SRH-related activities. However, there is a need to systematically capture data on SRH-HIV service integration to understand the benefits of linking these services.

Accurate detection of drug-induced delayed ventricular repolarization with a suitable correction formula in Langendorff guinea pig heart.

The aims of this study were to determine a suitable method to correct the ventricular repolarization period against the RR interval in isolated perfused Langendorff guinea pig heart and to clarify the reliability of this model using several drugs. QT and RR intervals from an electrocardiogram and the epicardial monophasic action potential duration (MAP(90)) were measured. Two drugs clinically known to be QT-prolonging (E-4031, moxifloxacin) and two known to be non-QT-prolonging (verapamil, zatebradine) were used for the study. To determine a method of correcting the ventricular repolarization period against RR interval, heart rates were slowed with 0.3 µM zatebradine, a specific bradycardiac agent, and then accelerated with atrial pacing to obtain a wide range of MAP(90)/RR relationships. An exponential rate-correction model elicited the most appropriate algorithm for the relationship among the four models tested. Based on linear regression analysis, the exponential showed superior dissociation of corrected MAP(90)s against RR intervals than generic Bazett's and Fridericia's formulae. E-4031 and moxifloxacin prolonged the corrected QT (QTc) intervals and MAP(90) under atrial pacing at a cycle length of 0.25 sec (MAP(90(pacing))) dose-dependently; verapamil and zatebradine failed to prolong them, indicating that the reliability of this model was excellent. MAP(90(pacing)) prolongation by moxifloxacin, the positive compound in the clinical "Thorough QT/QTc Study", was seen at around QTc-prolonging concentrations in clinic, suggesting that the sensitivity would be appropriate for QT evaluation. We therefore concluded that the isolated guinea pig heart model is sufficiently sensitive and useful for assessing the potential QT prolongation of drugs.

Asia can afford universal access for AIDS prevention and treatment.

This paper draws on published reports, data from the Global Fund to Fight AIDS, Tuberculosis, and Malaria and the Asian Development Bank, and analysis by the Commission on AIDS in Asia to estimate financial resources required to achieve universal access for HIV in low-income and middle-income countries of Asia. It explores optimal use of available resources to mount effective response to AIDS in Asia against an uncertain economic climate. Although there is global commitment to tackle the HIV pandemic, available financing falls short of minimum requirements to achieve universal access to prevention and treatment. To support essential HIV priorities in Asia, the Commission on AIDS in Asia estimated annual resource needs to be US$ 3.1 billion. Yet, in 2007, according to one study, estimated total public spending on AIDS in 14 major Asian countries was only US$ 0.9 billion. Hence, scarce resources need to be carefully applied to address the concentrated HIV epidemics in Asia and achieve universal coverage by prioritizing investment in high-impact interventions to maximally avert new infections and deaths, intensifying multisectoral efforts through catalytic financing that mainstreams HIV interventions into existing services, particularly for low-impact prevention programs, and ensuring countries with growing economies mobilize increased amounts of domestic funding to match international financing.