Journal: PLoS Med

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Abstract

Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication Bias.

Clarke R, Bennett DA, Parish S, Verhoef P, ... Peto R, for the MTHFR Studies Collaborative Group
Background: Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so "Mendelian randomization" studies using this variant as an instrumental variable could help test causality. Methods and findings: Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T. These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied. In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98-1.07; p = 0.28) overall, and 1.01 (0.95-1.07) in unsupplemented low-folate populations. By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 1.15 (1.09-1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets. Within the meta-analysis of published studies, the OR was 1.12 (1.04-1.21) in the 14 larger studies (those with variance of log OR<0.05; total 13,119 cases) and 1.18 (1.09-1.28) in the 72 smaller ones (total 15,498 cases). Conclusions: The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD. The discrepant overall result from previously published studies reflects publication bias or methodological problems. Please see later in the article for the Editors\' Summary.

PLoS Med: 23 Feb 2012; 9:e1001177
Clarke R, Bennett DA, Parish S, Verhoef P, ... Peto R, for the MTHFR Studies Collaborative Group
PLoS Med: 23 Feb 2012; 9:e1001177 | PMID: 22363213
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Abstract

Rotating Night Shift Work and Risk of Type 2 Diabetes: Two Prospective Cohort Studies in Women.

Pan A, Schernhammer ES, Sun Q, Hu FB
Background: Rotating night shift work disrupts circadian rhythms and has been associated with obesity, metabolic syndrome, and glucose dysregulation. However, its association with type 2 diabetes remains unclear. Therefore, we aimed to evaluate this association in two cohorts of US women. Methods and findings: We followed 69,269 women aged 42-67 in Nurses\' Health Study I (NHS I, 1988-2008), and 107,915 women aged 25-42 in NHS II (1989-2007) without diabetes, cardiovascular disease, and cancer at baseline. Participants were asked how long they had worked rotating night shifts (defined as at least three nights/month in addition to days and evenings in that month) at baseline. This information was updated every 2-4 years in NHS II. Self-reported type 2 diabetes was confirmed by a validated supplementary questionnaire. We documented 6,165 (NHS I) and 3,961 (NHS II) incident type 2 diabetes cases during the 18-20 years of follow-up. In the Cox proportional models adjusted for diabetes risk factors, duration of shift work was monotonically associated with an increased risk of type 2 diabetes in both cohorts. Compared with women who reported no shift work, the pooled hazard ratios (95% confidence intervals) for participants with 1-2, 3-9, 10-19, and ≥20 years of shift work were 1.05 (1.00-1.11), 1.20 (1.14-1.26), 1.40 (1.30-1.51), and 1.58 (1.43-1.74, p-value for trend <0.001), respectively. Further adjustment for updated body mass index attenuated the association, and the pooled hazard ratios were 1.03 (0.98-1.08), 1.06 (1.01-1.11), 1.10 (1.02-1.18), and 1.24 (1.13-1.37, p-value for trend <0.001). Conclusions: Our results suggest that an extended period of rotating night shift work is associated with a modestly increased risk of type 2 diabetes in women, which appears to be partly mediated through body weight. Proper screening and intervention strategies in rotating night shift workers are needed for prevention of diabetes. Please see later in the article for the Editors\' Summary.

PLoS Med: 13 Dec 2011; 8:e1001141
Pan A, Schernhammer ES, Sun Q, Hu FB
PLoS Med: 13 Dec 2011; 8:e1001141 | PMID: 22162955
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Abstract

Risk Factors for Severe Outcomes following 2009 Influenza A (H1N1) Infection: A Global Pooled Analysis.

Van Kerkhove MD, Vandemaele KA, Shinde V, Jaramillo-Gutierrez G, ... Mounts AW, on behalf of the WHO Working Group for Risk Factors for Severe H1N1pdm Infection
Background: Since the start of the 2009 influenza A pandemic (H1N1pdm), the World Health Organization and its member states have gathered information to characterize the clinical severity of H1N1pdm infection and to assist policy makers to determine risk groups for targeted control measures. Methods and findings: Data were collected on approximately 70,000 laboratory-confirmed hospitalized H1N1pdm patients, 9,700 patients admitted to intensive care units (ICUs), and 2,500 deaths reported between 1 April 2009 and 1 January 2010 from 19 countries or administrative regions-Argentina, Australia, Canada, Chile, China, France, Germany, Hong Kong SAR, Japan, Madagascar, Mexico, the Netherlands, New Zealand, Singapore, South Africa, Spain, Thailand, the United States, and the United Kingdom-to characterize and compare the distribution of risk factors among H1N1pdm patients at three levels of severity: hospitalizations, ICU admissions, and deaths. The median age of patients increased with severity of disease. The highest per capita risk of hospitalization was among patients <5 y and 5-14 y (relative risk [RR] = 3.3 and 3.2, respectively, compared to the general population), whereas the highest risk of death per capita was in the age groups 50-64 y and ≥65 y (RR = 1.5 and 1.6, respectively, compared to the general population). Similarly, the ratio of H1N1pdm deaths to hospitalizations increased with age and was the highest in the ≥65-y-old age group, indicating that while infection rates have been observed to be very low in the oldest age group, risk of death in those over the age of 64 y who became infected was higher than in younger groups. The proportion of H1N1pdm patients with one or more reported chronic conditions increased with severity (median = 31.1%, 52.3%, and 61.8% of hospitalized, ICU-admitted, and fatal H1N1pdm cases, respectively). With the exception of the risk factors asthma, pregnancy, and obesity, the proportion of patients with each risk factor increased with severity level. For all levels of severity, pregnant women in their third trimester consistently accounted for the majority of the total of pregnant women. Our findings suggest that morbid obesity might be a risk factor for ICU admission and fatal outcome (RR = 36.3). Conclusions: Our results demonstrate that risk factors for severe H1N1pdm infection are similar to those for seasonal influenza, with some notable differences, such as younger age groups and obesity, and reinforce the need to identify and protect groups at highest risk of severe outcomes. Please see later in the article for the Editors\' Summary.

PLoS Med: 13 Jul 2011; 8:e1001053
Van Kerkhove MD, Vandemaele KA, Shinde V, Jaramillo-Gutierrez G, ... Mounts AW, on behalf of the WHO Working Group for Risk Factors for Severe H1N1pdm Infection
PLoS Med: 13 Jul 2011; 8:e1001053 | PMID: 21750667
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Abstract

CD4 Cell Count and the Risk of AIDS or Death in HIV-Infected Adults on Combination Antiretroviral Therapy with a Suppressed Viral Load: A Longitudinal Cohort Study from COHERE.

The Opportunistic Infections Project Team of the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord
Background: Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load. Methods and findings: Using data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger), we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements <50 copies/µl and ending with either a measurement >500 copies/µl, the first of two consecutive measurements between 50-500 copies/µl, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell count and a new AIDS event or death or death alone. 75,336 patients contributed 104,265 suppression episodes and were suppressed while on cART for a median 2.7 years. The mortality rate was 4.8 per 1,000 years of viral suppression. A higher CD4 cell count was always associated with a reduced risk of a new AIDS event or death; with a hazard ratio per 100 cells/µl (95% CI) of: 0.35 (0.30-0.40) for counts <200 cells/µl, 0.81 (0.71-0.92) for counts 200 to <350 cells/µl, 0.74 (0.66-0.83) for counts 350 to <500 cells/µl, and 0.96 (0.92-0.99) for counts ≥500 cells/µl. A higher CD4 cell count became even more beneficial over time for patients with CD4 cell counts <200 cells/µl. Conclusions: Despite the low mortality rate, the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression. A higher CD4 cell count was associated with the greatest benefit for patients with a CD4 cell count <200 cells/µl but still some slight benefit for those with a CD4 cell count ≥500 cells/µl. Please see later in the article for the Editors\' Summary.

PLoS Med: 25 Mar 2012; 9:e1001194
The Opportunistic Infections Project Team of the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord
PLoS Med: 25 Mar 2012; 9:e1001194 | PMID: 22448150
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Abstract

A Research Agenda for Malaria Eradication: Vector Control.

The malERA Consultative Group on Vector Control
Different challenges are presented by the variety of malaria transmission environments present in the world today. In each setting, improved control for reduction of morbidity is a necessary first step towards the long-range goal of malaria eradication and a priority for regions where the disease burden is high. For many geographic areas where transmission rates are low to moderate, sustained and well-managed application of currently available tools may be sufficient to achieve local elimination. The research needs for these areas will be to sustain and perhaps improve the effectiveness of currently available tools. For other low-to-moderate transmission regions, notably areas where the vectors exhibit behaviours such as outdoor feeding and resting that are not well targeted by current strategies, new interventions that target predictable features of the biology/ecologies of the local vectors will be required. To achieve elimination in areas where high levels of transmission are sustained by very efficient vector species, radically new interventions that significantly reduce the vectorial capacity of wild populations will be needed. Ideally, such interventions should be implemented with a one-time application with a long-lasting impact, such as genetic modification of the vectorial capacity of the wild vector population.

PLoS Med: 11 Feb 2011; 8:e1000401
The malERA Consultative Group on Vector Control
PLoS Med: 11 Feb 2011; 8:e1000401 | PMID: 21311587
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Abstract

Triple-Antiretroviral Prophylaxis to Prevent Mother-To-Child HIV Transmission through Breastfeeding-The Kisumu Breastfeeding Study, Kenya: A Clinical Trial.

Thomas TK, Masaba R, Borkowf CB, Ndivo R, ... Fowler MG, for the KiBS Study Team
Background: Effective strategies are needed for the prevention of mother-to-child HIV transmission (PMTCT) in resource-limited settings. The Kisumu Breastfeeding Study was a single-arm open label trial conducted between July 2003 and February 2009. The overall aim was to investigate whether a maternal triple-antiretroviral regimen that was designed to maximally suppress viral load in late pregnancy and the first 6 mo of lactation was a safe, well-tolerated, and effective PMTCT intervention. Methods and findings: HIV-infected pregnant women took zidovudine, lamivudine, and either nevirapine or nelfinavir from 34-36 weeks\' gestation to 6 mo post partum. Infants received single-dose nevirapine at birth. Women were advised to breastfeed exclusively and wean rapidly just before 6 mo. Using Kaplan-Meier methods we estimated HIV-transmission and death rates from delivery to 24 mo. We compared HIV-transmission rates among subgroups defined by maternal risk factors, including baseline CD4 cell count and viral load. Among 487 live-born, singleton, or first-born infants, cumulative HIV-transmission rates at birth, 6 weeks, and 6, 12, and 24 mo were 2.5%, 4.2%, 5.0%, 5.7%, and 7.0%, respectively. The 24-mo HIV-transmission rates stratified by baseline maternal CD4 cell count <500 and ≥500 cells/mm(3) were 8.4% (95% confidence interval [CI] 5.8%-12.0%) and 4.1% (1.8%-8.8%), respectively (p = 0.06); the corresponding rates stratified by baseline maternal viral load <10,000 and ≥10,000 copies/ml were 3.0% (1.1%-7.8%) and 8.7% (6.1%-12.3%), respectively (p = 0.01). None of the 12 maternal and 51 infant deaths (including two second-born infants) were attributed to antiretrovirals. The cumulative HIV-transmission or death rate at 24 mo was 15.7% (95% CI 12.7%-19.4%). Conclusions: This trial shows that a maternal triple-antiretroviral regimen from late pregnancy through 6 months of breastfeeding for PMTCT is safe and feasible in a resource-limited setting. These findings are consistent with those from other trials using maternal triple-antiretroviral regimens during breastfeeding in comparable settings. Trial registration: ClinicalTrials.gov NCT00146380 Please see later in the article for the Editors\' Summary.

PLoS Med: 06 Apr 2011; 8:e1001015
Thomas TK, Masaba R, Borkowf CB, Ndivo R, ... Fowler MG, for the KiBS Study Team
PLoS Med: 06 Apr 2011; 8:e1001015 | PMID: 21468300
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Abstract

Hospital Performance, the Local Economy, and the Local Workforce: Findings from a US National Longitudinal Study.

Blustein J, Borden WB, Valentine M
Background: Pay-for-performance is an increasingly popular approach to improving health care quality, and the US government will soon implement pay-for-performance in hospitals nationwide. Yet hospital capacity to perform (and improve performance) likely depends on local resources. In this study, we quantify the association between hospital performance and local economic and human resources, and describe possible implications of pay-for-performance for socioeconomic equity. Methods and findings: We applied county-level measures of local economic and workforce resources to a national sample of US hospitals (n = 2,705), during the period 2004-2007. We analyzed performance for two common cardiac conditions (acute myocardial infarction [AMI] and heart failure [HF]), using process-of-care measures from the Hospital Quality Alliance [HQA], and isolated temporal trends and the contributions of individual resource dimensions on performance, using multivariable mixed models. Performance scores were translated into net scores for hospitals using the Performance Assessment Model, which has been suggested as a basis for reimbursement under Medicare\'s "Value-Based Purchasing" program. Our analyses showed that hospital performance is substantially associated with local economic and workforce resources. For example, for HF in 2004, hospitals located in counties with longstanding poverty had mean HQA composite scores of 73.0, compared with a mean of 84.1 for hospitals in counties without longstanding poverty (p<0.001). Hospitals located in counties in the lowest quartile with respect to college graduates in the workforce had mean HQA composite scores of 76.7, compared with a mean of 86.2 for hospitals in the highest quartile (p<0.001). Performance on AMI measures showed similar patterns. Performance improved generally over the study period. Nevertheless, by 2007-4 years after public reporting began-hospitals in locationally disadvantaged areas still lagged behind their locationally advantaged counterparts. This lag translated into substantially lower net scores under the Performance Assessment Model for hospital reimbursement. Conclusions: Hospital performance on clinical process measures is associated with the quantity and quality of local economic and human resources. Medicare\'s hospital pay-for-performance program may exacerbate inequalities across regions, if implemented as currently proposed. Policymakers in the US and beyond may need to take into consideration the balance between greater efficiency through pay-for-performance and socioeconomic equity. Please see later in the article for the Editors\' Summary.

PLoS Med: 08 Jul 2010; 7:e1000297
Blustein J, Borden WB, Valentine M
PLoS Med: 08 Jul 2010; 7:e1000297 | PMID: 20613863
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Abstract

A Research Agenda for Malaria Eradication: Health Systems and Operational Research.

The malERA Consultative Group on Health Systems and Operational Research
Health systems research and development is needed to support the global malaria eradication agenda. In this paper, we (the malERA Consultative Group on Health Systems and Operational Research) focus on the health systems needs of the elimination phase of malaria eradication and consider groupings of countries at different stages along the pathway to elimination. We examine the difference between the last attempt at eradication of malaria and more recent initiatives, and consider the changing health system challenges as countries make progress towards elimination. We review recent technological and theoretical developments related to health systems and the renewed commitment to strengthening health systems for universal access and greater equity. Finally, we identify a number of needs for research and development, including tools for analyzing and improving effective coverage and strengthening decision making and discuss the relevance of these needs at all levels of the health system from the community to the international level.

PLoS Med: 11 Feb 2011; 8:e1000397
The malERA Consultative Group on Health Systems and Operational Research
PLoS Med: 11 Feb 2011; 8:e1000397 | PMID: 21311588
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Abstract

Preventing Acute Malnutrition among Young Children in Crises: A Prospective Intervention Study in Niger.

Langendorf C, Roederer T, de Pee S, Brown D, ... Manzo ML, Grais RF
Finding the most appropriate strategy for the prevention of moderate acute malnutrition (MAM) and severe acute malnutrition (SAM) in young children is essential in countries like Niger with annual "hunger gaps." Options for large-scale prevention include distribution of supplementary foods, such as fortified-blended foods or lipid-based nutrient supplements (LNSs) with or without household support (cash or food transfer). To date, there has been no direct controlled comparison between these strategies leading to debate concerning their effectiveness. We compared the effectiveness of seven preventive strategies-including distribution of nutritious supplementary foods, with or without additional household support (family food ration or cash transfer), and cash transfer only-on the incidence of SAM and MAM among children aged 6-23 months over a 5-month period, partly overlapping the hunger gap, in Maradi region, Niger. We hypothesized that distributions of supplementary foods would more effectively reduce the incidence of acute malnutrition than distributions of household support by cash transfer.

PLoS Med: 02 Sep 2014; 11:e1001714
Langendorf C, Roederer T, de Pee S, Brown D, ... Manzo ML, Grais RF
PLoS Med: 02 Sep 2014; 11:e1001714 | PMID: 25180584
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Abstract

A Research Agenda for Malaria Eradication: Vaccines.

The malERA Consultative Group on Vaccines
Vaccines could be a crucial component of efforts to eradicate malaria. Current attempts to develop malaria vaccines are primarily focused on Plasmodium falciparum and are directed towards reducing morbidity and mortality. Continued support for these efforts is essential, but if malaria vaccines are to be used as part of a repertoire of tools for elimination or eradication of malaria, they will need to have an impact on malaria transmission. We introduce the concept of "vaccines that interrupt malaria transmission" (VIMT), which includes not only "classical" transmission-blocking vaccines that target the sexual and mosquito stages but also pre-erythrocytic and asexual stage vaccines that have an effect on transmission. VIMT may also include vaccines that target the vector to disrupt parasite development in the mosquito. Importantly, if eradication is to be achieved, malaria vaccine development efforts will need to target other malaria parasite species, especially Plasmodium vivax, where novel therapeutic vaccines against hypnozoites or preventive vaccines with effect against multiple stages could have enormous impact. A target product profile (TPP) for VIMT is proposed and a research agenda to address current knowledge gaps and develop tools necessary for design and development of VIMT is presented.

PLoS Med: 11 Feb 2011; 8:e1000398
The malERA Consultative Group on Vaccines
PLoS Med: 11 Feb 2011; 8:e1000398 | PMID: 21311586
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Abstract

Major Radiodiagnostic Imaging in Pregnancy and the Risk of Childhood Malignancy: A Population-Based Cohort Study in Ontario.

Ray JG, Schull MJ, Urquia ML, You JJ, Guttmann A, Vermeulen MJ
Background: The association between fetal exposure to major radiodiagnostic testing in pregnancy-computed tomography (CT) and radionuclide imaging-and the risk of childhood cancer is not established. Methods and findings: We completed a population-based study of 1.8 million maternal-child pairs in the province of Ontario, from 1991 to 2008. We used Ontario\'s universal health care-linked administrative databases to identify all term obstetrical deliveries and newborn records, inpatient and outpatient major radiodiagnostic services, as well as all children with a malignancy after birth. There were 5,590 mothers exposed to major radiodiagnostic testing in pregnancy (3.0 per 1,000) and 1,829,927 mothers not exposed. The rate of radiodiagnostic testing increased from 1.1 to 6.3 per 1,000 pregnancies over the study period; about 73% of tests were CT scans. After a median duration of follow-up of 8.9 years, four childhood cancers arose in the exposed group (1.13 per 10,000 person-years) and 2,539 cancers in the unexposed group (1.56 per 10,000 person-years), a crude hazard ratio of 0.69 (95% confidence interval 0.26-1.82). After adjusting for maternal age, income quintile, urban status, and maternal cancer, as well as infant sex, chromosomal or congenital anomalies, and major radiodiagnostic test exposure after birth, the risk was essentially unchanged (hazard ratio 0.68, 95% confidence interval 0.25-1.80). Conclusions: Although major radiodiagnostic testing is now performed in about 1 in 160 pregnancies in Ontario, the absolute annual risk of childhood malignancy following exposure in utero remains about 1 in 10,000. Since the upper confidence limit of the relative risk of malignancy may be as high as 1.8 times that of an unexposed pregnancy, we cannot exclude the possibility that fetal exposure to CT or radionuclide imaging is carcinogenic. Please see later in the article for the Editors\' Summary.

PLoS Med: 14 Sep 2010; 7
Ray JG, Schull MJ, Urquia ML, You JJ, Guttmann A, Vermeulen MJ
PLoS Med: 14 Sep 2010; 7 | PMID: 20838660
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Pregnancy and Infant Outcomes among HIV-Infected Women Taking Long-Term ART with and without Tenofovir in the DART Trial.

Gibb DM, Kizito H, Russell EC, Chidziva E, ... Musoke P, on behalf of the DART trial team
Background: Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)-recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure. Methods and findings: Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models. 382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0-4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths (≥22 wk), and 137 (35%) terminations/miscarriages (<22 wk). Of 226 live-births, seven (3%) infants died <2 wk from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero tenofovir exposure (p>0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12-38) months. From mothers\' ART, 62/9/111 infants had no/20%-89%/≥90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/182(40%) infants were breast-fed for median 94 (IQR 75-212) days. Overall, 14 infants died at median (IQR) age 9 (3-23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p>0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens. Conclusions: Overall 1-year 5% infant mortality was similar to the 2%-4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children. Trial registration: www.controlled-trials.comISRCTN13968779 Please see later in the article for the Editors\' Summary.

PLoS Med: 21 May 2012; 9:e1001217
Gibb DM, Kizito H, Russell EC, Chidziva E, ... Musoke P, on behalf of the DART trial team
PLoS Med: 21 May 2012; 9:e1001217 | PMID: 22615543
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Neonatal Mortality Levels for 193 Countries in 2009 with Trends since 1990: A Systematic Analysis of Progress, Projections, and Priorities.

Oestergaard MZ, Inoue M, Yoshida S, Mahanani WR, ... Mathers CD, on behalf of the United Nations Inter-agency Group for Child Mortality Estimation and the Child Health Epidemiology Reference Group
Background: Historically, the main focus of studies of childhood mortality has been the infant and under-five mortality rates. Neonatal mortality (deaths <28 days of age) has received limited attention, although such deaths account for about 41% of all child deaths. To better assess progress, we developed annual estimates for neonatal mortality rates (NMRs) and neonatal deaths for 193 countries for the period 1990-2009 with forecasts into the future. Methods and findings: We compiled a database of mortality in neonates and children (<5 years) comprising 3,551 country-years of information. Reliable civil registration data from 1990 to 2009 were available for 38 countries. A statistical model was developed to estimate NMRs for the remaining 155 countries, 17 of which had no national data. Country consultation was undertaken to identify data inputs and review estimates. In 2009, an estimated 3.3 million babies died in the first month of life-compared with 4.6 million neonatal deaths in 1990-and more than half of all neonatal deaths occurred in five countries of the world (44% of global livebirths): India 27.8% (19.6% of global livebirths), Nigeria 7.2% (4.5%), Pakistan 6.9% (4.0%), China 6.4% (13.4%), and Democratic Republic of the Congo 4.6% (2.1%). Between 1990 and 2009, the global NMR declined by 28% from 33.2 deaths per 1,000 livebirths to 23.9. The proportion of child deaths that are in the neonatal period increased in all regions of the world, and globally is now 41%. While NMRs were halved in some regions of the world, Africa\'s NMR only dropped 17.6% (43.6 to 35.9). Conclusions: Neonatal mortality has declined in all world regions. Progress has been slowest in the regions with high NMRs. Global health programs need to address neonatal deaths more effectively if Millennium Development Goal 4 (two-thirds reduction in child mortality) is to be achieved. Please see later in the article for the Editors\' Summary.

PLoS Med: 15 Sep 2011; 8:e1001080
Oestergaard MZ, Inoue M, Yoshida S, Mahanani WR, ... Mathers CD, on behalf of the United Nations Inter-agency Group for Child Mortality Estimation and the Child Health Epidemiology Reference Group
PLoS Med: 15 Sep 2011; 8:e1001080 | PMID: 21918640
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Estimating the Number of Paediatric Fevers Associated with Malaria Infection Presenting to Africa\'s Public Health Sector in 2007.

Gething PW, Kirui VC, Alegana VA, Okiro EA, Noor AM, Snow RW
Background: As international efforts to increase the coverage of artemisinin-based combination therapy in public health sectors gather pace, concerns have been raised regarding their continued indiscriminate presumptive use for treating all childhood fevers. The availability of rapid-diagnostic tests to support practical and reliable parasitological diagnosis provides an opportunity to improve the rational treatment of febrile children across Africa. However, the cost effectiveness of diagnosis-based treatment polices will depend on the presumed numbers of fevers harbouring infection. Here we compute the number of fevers likely to present to public health facilities in Africa and the estimated number of these fevers likely to be infected with Plasmodium falciparum malaria parasites. Methods and findings: We assembled first administrative-unit level data on paediatric fever prevalence, treatment-seeking rates, and child populations. These data were combined in a geographical information system model that also incorporated an adjustment procedure for urban versus rural areas to produce spatially distributed estimates of fever burden amongst African children and the subset likely to present to public sector clinics. A second data assembly was used to estimate plausible ranges for the proportion of paediatric fevers seen at clinics positive for P. falciparum in different endemicity settings. We estimated that, of the 656 million fevers in African 0-4 y olds in 2007, 182 million (28%) were likely to have sought treatment in a public sector clinic of which 78 million (43%) were likely to have been infected with P. falciparum (range 60-103 million). Conclusions: Spatial estimates of childhood fevers and care-seeking rates can be combined with a relational risk model of infection prevalence in the community to estimate the degree of parasitemia in those fevers reaching public health facilities. This quantification provides an important baseline comparison of malarial and nonmalarial fevers in different endemicity settings that can contribute to ongoing scientific and policy debates about optimum clinical and financial strategies for the introduction of new diagnostics. These models are made publicly available with the publication of this paper. Please see later in the article for the Editors\' Summary.

PLoS Med: 13 Jul 2010; 7:e1000301
Gething PW, Kirui VC, Alegana VA, Okiro EA, Noor AM, Snow RW
PLoS Med: 13 Jul 2010; 7:e1000301 | PMID: 20625548
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Prescription Medicines and the Risk of Road Traffic Crashes: A French Registry-Based Study.

Orriols L, Delorme B, Gadegbeku B, Tricotel A, ... Lagarde E, on behalf of the CESIR research group
Background: In recent decades, increased attention has been focused on the impact of disabilities and medicinal drug use on road safety. The aim of our study was to investigate the association between prescription medicines and the risk of road traffic crashes, and estimate the attributable fraction. Methods and findings: WE EXTRACTED AND MATCHED DATA FROM THREE FRENCH NATIONWIDE DATABASES: the national health care insurance database, police reports, and the national police database of injurious crashes. Drivers identified by their national health care number involved in an injurious crash in France, between July 2005 and May 2008, were included in the study. Medicines were grouped according to the four risk levels of the French classification system (from 0 [no risk] to 3 [high risk]). We included 72,685 drivers involved in injurious crashes. Users of level 2 (odds ratio [OR]  = 1.31 [1.24-1.40]) and level 3 (OR  = 1.25 [1.12-1.40]) prescription medicines were at higher risk of being responsible for a crash. The association remained after adjustment for the presence of a long-term chronic disease. The fraction of road traffic crashes attributable to levels 2 and 3 medications was 3.3% [2.7%-3.9%]. A within-person case-crossover analysis showed that drivers were more likely to be exposed to level 3 medications on the crash day than on a control day, 30 days earlier (OR  = 1.15 [1.05-1.27]). Conclusion: The use of prescription medicines is associated with a substantial number of road traffic crashes in France. In light of the results, warning messages appear to be relevant for level 2 and 3 medications and questionable for level 1 medications. A follow-up study is needed to evaluate the impact of the warning labeling system on road traffic crash prevention. Please see later in the article for the Editors\' Summary.

PLoS Med: 02 Dec 2010; 7:e1000366
Orriols L, Delorme B, Gadegbeku B, Tricotel A, ... Lagarde E, on behalf of the CESIR research group
PLoS Med: 02 Dec 2010; 7:e1000366 | PMID: 21125020
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Abstract

Evaluation of Coseasonality of Influenza and Invasive Pneumococcal Disease: Results from Prospective Surveillance.

Kuster SP, Tuite AR, Kwong JC, McGeer A, the Toronto Invasive Bacterial Diseases Network, Fisman DN
Background: The wintertime co-occurrence of peaks in influenza and invasive pneumococcal disease (IPD) is well documented, but how and whether wintertime peaks caused by these two pathogens are causally related is still uncertain. We aimed to investigate the relationship between influenza infection and IPD in Ontario, Canada, using several complementary methodological tools. Methods and findings: We evaluated a total number of 38,501 positive influenza tests in Central Ontario and 6,191 episodes of IPD in the Toronto/Peel area, Ontario, Canada, between 1 January 1995 and 3 October 2009, reported through population-based surveillance. We assessed the relationship between the seasonal wave forms for influenza and IPD using fast Fourier transforms in order to examine the relationship between these two pathogens over yearly timescales. We also used three complementary statistical methods (time-series methods, negative binomial regression, and case-crossover methods) to evaluate the short-term effect of influenza dynamics on pneumococcal risk. Annual periodicity with wintertime peaks could be demonstrated for IPD, whereas periodicity for influenza was less regular. As for long-term effects, phase and amplitude terms of pneumococcal and influenza seasonal sine waves were not correlated and meta-analysis confirmed significant heterogeneity of influenza, but not pneumococcal phase terms. In contrast, influenza was shown to Granger-cause pneumococcal disease. A short-term association between IPD and influenza could be demonstrated for 1-week lags in both case-crossover (odds ratio [95% confidence interval] for one case of IPD per 100 influenza cases  = 1.10 [1.02-1.18]) and negative binomial regression analysis (incidence rate ratio [95% confidence interval] for one case of IPD per 100 influenza cases  = 1.09 [1.05-1.14]). Conclusions: Our data support the hypothesis that influenza influences bacterial disease incidence by enhancing short-term risk of invasion in colonized individuals. The absence of correlation between seasonal waveforms, on the other hand, suggests that bacterial disease transmission is affected to a lesser extent. Please see later in the article for the Editors\' Summary.

PLoS Med: 20 Jun 2011; 8:e1001042
Kuster SP, Tuite AR, Kwong JC, McGeer A, the Toronto Invasive Bacterial Diseases Network, Fisman DN
PLoS Med: 20 Jun 2011; 8:e1001042 | PMID: 21687693
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Abstract

The role of research in viral disease eradication and elimination programs: lessons for malaria eradication.

Breman JG, de Quadros CA, Dowdle WR, Foege WH, ... John TJ, Levine MM
By examining the role research has played in eradication or regional elimination initiatives for three viral diseases-smallpox, poliomyelitis, and measles-we derive nine cross-cutting lessons applicable to malaria eradication. In these initiatives, some types of research commenced as the programs began and proceeded in parallel. Basic laboratory, clinical, and field research all contributed notably to progress made in the viral programs. For each program, vaccine was the lynchpin intervention, but as the programs progressed, research was required to improve vaccine formulations, delivery methods, and immunization schedules. Surveillance was fundamental to all three programs, whilst polio eradication also required improved diagnostic methods to identify asymptomatic infections. Molecular characterization of pathogen isolates strengthened surveillance and allowed insights into the geographic source of infections and their spread. Anthropologic, sociologic, and behavioural research were needed to address cultural and religious beliefs to expand community acceptance. The last phases of elimination and eradication became increasingly difficult, as a nil incidence was approached. Any eradication initiative for malaria must incorporate flexible research agendas that can adapt to changing epidemiologic contingencies and allow planning for posteradication scenarios.

PLoS Med: 11 Feb 2011; 8:e1000405
Breman JG, de Quadros CA, Dowdle WR, Foege WH, ... John TJ, Levine MM
PLoS Med: 11 Feb 2011; 8:e1000405 | PMID: 21311582
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Abstract

A Randomised Controlled Trial of Ion-Exchange Water Softeners for the Treatment of Eczema in Children.

Thomas KS, Dean T, O\'Leary C, Sach TH, ... Williams HC, the SWET Trial Team
Background: Epidemiological studies and anecdotal reports suggest a possible link between household use of hard water and atopic eczema. We sought to test whether installation of an ion-exchange water softener in the home can improve eczema in children. Methods and findings: This was an observer-blind randomised trial involving 336 children (aged 6 months to 16 years) with moderate/severe atopic eczema. All lived in hard water areas (≥200 mg/l calcium carbonate). Participants were randomised to either installation of an ion-exchange water softener plus usual eczema care, or usual eczema care alone. The primary outcome was change in eczema severity (Six Area Six Sign Atopic Dermatitis Score, SASSAD) at 12 weeks, measured by research nurses who were blinded to treatment allocation. Analysis was based on the intent-to-treat population. Eczema severity improved for both groups during the trial. The mean change in SASSAD at 12 weeks was -5.0 (20% improvement) for the water softener group and -5.7 (22% improvement) for the usual care group (mean difference 0.66, 95% confidence interval -1.37 to 2.69, p = 0.53). No between-group differences were noted in the use of topical corticosteroids or calcineurin inhibitors. Conclusions: Water softeners provided no additional benefit to usual care in this study population. Small but statistically significant differences were found in some secondary outcomes as reported by parents, but it is likely that such improvements were the result of response bias, since participants were aware of their treatment allocation. A detailed report for this trial is also available at http://www.hta.ac.uk. Trial registration: Current Controlled Trials ISRCTN71423189 Please see later in the article for the Editors\' Summary.

PLoS Med: 01 Mar 2011; 8:e1000395
Thomas KS, Dean T, O'Leary C, Sach TH, ... Williams HC, the SWET Trial Team
PLoS Med: 01 Mar 2011; 8:e1000395 | PMID: 21358807
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Abstract

HIV Treatment as Prevention: Natural Experiments Highlight Limits of Antiretroviral Treatment as HIV Prevention.

Wilson DP
There is growing enthusiasm for increasing coverage of antiretroviral treatment among HIV-infected people for the purposes of preventing ongoing transmission. Treatment as prevention will face a number of barriers when implemented in real world populations, which will likely lead to the effectiveness of this strategy being lower than proposed by optimistic modelling scenarios or ideal clinical trial settings. Some settings, as part of their prevention and treatment strategies, have already attained rates of HIV testing and use of antiretroviral therapy-with high levels of viral suppression-that many countries would aspire to as targets for a treatment-as-prevention strategy. This review examines a number of these "natural experiments", namely, British Columbia, San Francisco, France, and Australia, to provide commentary on whether treatment as prevention has worked in real world populations. This review suggests that the population-level impact of this strategy is likely to be considerably less than as inferred from ideal conditions.

PLoS Med: 17 Jul 2012; 9:e1001231
Wilson DP
PLoS Med: 17 Jul 2012; 9:e1001231 | PMID: 22807656
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Abstract

Impact Evaluation of a System-Wide Chronic Disease Management Program on Health Service Utilisation: A Propensity-Matched Cohort Study.

Billot L, Corcoran K, McDonald A, Powell-Davies G, Feyer AM
The New South Wales Health (NSW Health) Chronic Disease Management Program (CDMP) delivers interventions to adults at risk of hospitalisation for five target chronic conditions that respond well to ambulatory care: diabetes, hypertension, chronic obstructive pulmonary disease, congestive heart failure, and coronary artery disease. The intervention consists of two main components: (1) care coordination across sectors (acute, ambulatory, and community care from both public and private sectors) and clinical specialties, facilitated by program care coordinators, and (2) health coaching including management of lifestyle risk factors and medications and self-management. These components were broadly prescribed by the head office of NSW Health, which funded the program, and were implemented by regional health services (local health districts) in ways that best suited their own history, environment, workforce, and patient need. We used a propensity-matched cohort study to evaluate health service utilisation after enrolment in the CDMP.

PLoS Med: 07 Jun 2016; 13:e1002035
Billot L, Corcoran K, McDonald A, Powell-Davies G, Feyer AM
PLoS Med: 07 Jun 2016; 13:e1002035 | PMID: 27270663
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Abstract

HIV Treatment as Prevention: Issues in Economic Evaluation.

Bärnighausen T, Salomon JA, Sangrujee N
Meyer-Rath and Over assert in another article in the July 2012 PLoS Medicine Collection, "Investigating the Impact of Treatment on New HIV Infections", that economic evaluations of antiretroviral therapy (ART) in currently existing programs and in HIV treatment as prevention (TasP) programs should use cost functions that capture cost dependence on a number of factors, such as scale and scope of delivery, health states, ART regimens, health workers\' experience, patients\' time on treatment, and the distribution of delivery across public and private sectors. We argue that for particular evaluation purposes (e.g., to establish the social value of TasP) and from particular perspectives (e.g., national health policy makers) less detailed cost functions may be sufficient. We then extend the discussion of economic evaluation of TasP, describing why ART outcomes and costs assessed in currently existing programs are unlikely to be generalizable to TasP programs for several fundamental reasons. First, to achieve frequent, widespread HIV testing and high uptake of ART immediately following an HIV diagnosis, TasP programs will require components that are not present in current ART programs and whose costs are not included in current estimates. Second, the early initiation of ART under TasP will change not only patients\' disease courses and treatment experiences-which can affect behaviors that determine clinical treatment success, such as ART adherence and retention-but also quality of life and economic outcomes for HIV-infected individuals. Third, the preventive effects of TasP are likely to alter the composition of the HIV-infected population over time, changing its biological and behavioral characteristics and leading to different costs and outcomes for ART.

PLoS Med: 16 Jul 2012; 9:e1001263
Bärnighausen T, Salomon JA, Sangrujee N
PLoS Med: 16 Jul 2012; 9:e1001263 | PMID: 22802743
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Abstract

A Research Agenda for Malaria Eradication: Cross-Cutting Issues for Eradication.

The malERA Consultative Group on Integration Strategies
Discipline-specific Malaria Eradication Research Agenda (malERA) Consultative Groups have recognized several cross-cutting issues that must be addressed to prevent repetition of some of the mistakes of past malaria elimination campaigns in future programs. Integrated research is required to develop a decision-making framework for the switch from malaria control to elimination. Similarly, a strong economic case is needed for the very long-term financial support that is essential for elimination. Another cross-cutting priority is the development of improved measures of intensity of transmission, especially at low and nonrandom levels. Because sustained malaria elimination is dependent on a functioning health system, a further key cross-cutting research question is to determine how inputs for malaria can strengthen health systems, information systems, and overall health outcomes. Implementation of elimination programs must also be accompanied by capacity building and training to allow the assessment of the impact of new combinations of interventions, new roles for different individuals, and the operational research that is needed to facilitate program expansion. Finally, because community engagement, knowledge management, communication, political, and multisectoral support are critical but poorly understood success factors for malaria elimination, integrated research into these issues is vital.

PLoS Med: 01 Feb 2011; 8:e1000404
The malERA Consultative Group on Integration Strategies
PLoS Med: 01 Feb 2011; 8:e1000404 | PMID: 21283603
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Abstract

Planned Vaginal Birth or Elective Repeat Caesarean: Patient Preference Restricted Cohort with Nested Randomised Trial.

Crowther CA, Dodd JM, Hiller JE, Haslam RR, Robinson JS, on behalf of the Birth After Caesarean Study Group
Background: Uncertainty exists about benefits and harms of a planned vaginal birth after caesarean (VBAC) compared with elective repeat caesarean (ERC). We conducted a prospective restricted cohort study consisting of a patient preference cohort study, and a small nested randomised trial to compare benefits and risks of a planned ERC with planned VBAC. Methods and findings: 2,345 women with one prior caesarean, eligible for VBAC at term, were recruited from 14 Australian maternity hospitals. Women were assigned by patient preference (n = 2,323) or randomisation (n = 22) to planned VBAC (1,225 patient preference, 12 randomised) or planned ERC (1,098 patient preference, ten randomised). The primary outcome was risk of fetal death or death of liveborn infant before discharge or serious infant outcome. Data were analysed for the 2,345 women (100%) and infants enrolled. The risk of fetal death or liveborn infant death prior to discharge or serious infant outcome was significantly lower for infants born in the planned ERC group compared with infants in the planned VBAC group (0.9% versus 2.4%; relative risk [RR] 0.39; 95% CI 0.19-0.80; number needed to treat to benefit 66; 95% CI 40-200). Fewer women in the planned ERC group compared with women in the planned VBAC had a major haemorrhage (blood loss ≥1,500 ml and/or blood transfusion), (0.8% [9/1,108] versus 2.3% [29/1,237]; RR 0.37; 95% CI 0.17-0.80). Conclusions: Among women with one prior caesarean, planned ERC compared with planned VBAC was associated with a lower risk of fetal and infant death or serious infant outcome. The risk of major maternal haemorrhage was reduced with no increase in maternal or perinatal complications to time of hospital discharge. Women, clinicians, and policy makers can use this information to develop health advice and make decisions about care for women who have had a previous caesarean. Trial registration: Current Controlled Trials ISRCTN53974531 Please see later in the article for the Editors\' Summary.

PLoS Med: 18 Mar 2012; 9:e1001192
Crowther CA, Dodd JM, Hiller JE, Haslam RR, Robinson JS, on behalf of the Birth After Caesarean Study Group
PLoS Med: 18 Mar 2012; 9:e1001192 | PMID: 22427749
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Abstract

HIV Treatment as Prevention: Optimising the Impact of Expanded HIV Treatment Programmes.

Delva W, Eaton JW, Meng F, Fraser C, ... Boily MC, Hallett TB
Until now, decisions about how to allocate ART have largely been based on maximising the therapeutic benefit of ART for patients. Since the results of the HPTN 052 study showed efficacy of antiretroviral therapy (ART) in preventing HIV transmission, there has been increased interest in the benefits of ART not only as treatment, but also in prevention. Resources for expanding ART in the short term may be limited, so the question is how to generate the most prevention benefit from realistic potential increases in the availability of ART. Although not a formal systematic review, here we review different ways in which access to ART could be expanded by prioritising access to particular groups based on clinical or behavioural factors. For each group we consider (i) the clinical and epidemiological benefits, (ii) the potential feasibility, acceptability, and equity, and (iii) the affordability and cost-effectiveness of prioritising ART access for that group. In re-evaluating the allocation of ART in light of the new data about ART preventing transmission, the goal should be to create policies that maximise epidemiological and clinical benefit while still being feasible, affordable, acceptable, and equitable.

PLoS Med: 16 Jul 2012; 9:e1001258
Delva W, Eaton JW, Meng F, Fraser C, ... Boily MC, Hallett TB
PLoS Med: 16 Jul 2012; 9:e1001258 | PMID: 22802738
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Abstract

HIV Treatment as Prevention: Principles of Good HIV Epidemiology Modelling for Public Health Decision-Making in All Modes of Prevention and Evaluation.

Delva W, Wilson DP, Abu-Raddad L, Gorgens M, ... Hallett TB, Welte A
Public health responses to HIV epidemics have long relied on epidemiological modelling analyses to help prospectively project and retrospectively estimate the impact, cost-effectiveness, affordability, and investment returns of interventions, and to help plan the design of evaluations. But translating model output into policy decisions and implementation on the ground is challenged by the differences in background and expectations of modellers and decision-makers. As part of the PLoS Medicine Collection "Investigating the Impact of Treatment on New HIV Infections"-which focuses on the contribution of modelling to current issues in HIV prevention-we present here principles of "best practice" for the construction, reporting, and interpretation of HIV epidemiological models for public health decision-making on all aspects of HIV. Aimed at both those who conduct modelling research and those who use modelling results, we hope that the principles described here will become a shared resource that facilitates constructive discussions about the policy implications that emerge from HIV epidemiology modelling results, and that promotes joint understanding between modellers and decision-makers about when modelling is useful as a tool in quantifying HIV epidemiological outcomes and improving prevention programming.

PLoS Med: 16 Jul 2012; 9:e1001239
Delva W, Wilson DP, Abu-Raddad L, Gorgens M, ... Hallett TB, Welte A
PLoS Med: 16 Jul 2012; 9:e1001239 | PMID: 22802729
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Abstract

Some lessons for the future from the global malaria eradication programme (1955-1969).

Nájera JA, González-Silva M, Alonso PL
Encouraged by the early success of using dichloro-diphenyl-trichloroethane (DDT) against malaria, the World Health Organization (WHO) embarked on the Global Malaria Eradication Program (GMEP) in 1955. Fourteen years later, the campaign was discontinued when it was recognised that eradication was not achievable with the available means in many areas, although the long-term goal remained unchanged. During the GMEP, malaria was permanently eliminated from many regions. In other areas, however, substantial gains were lost in resurgences, sometimes of epidemic proportions. During the 1970s and 1980s, because of economic and financial crises, international support for malaria control declined rapidly, but in the past decade, following increasing demands from endemic countries and promising results from scaling up of control activities, interest in malaria elimination and the long-term goal of eradication has received international political and financial support. In 2007, there was a renewed call for malaria eradication and a consultative process to define a research and development agenda for malaria eradication (malERA) was established. Lessons learned from the GMEP (1955-1969) highlight the fact that no single strategy can be applicable everywhere and that a long-term commitment with a flexible strategy that includes community involvement, integration with health systems, and the development of agile surveillance systems is needed.

PLoS Med: 11 Feb 2011; 8:e1000412
Nájera JA, González-Silva M, Alonso PL
PLoS Med: 11 Feb 2011; 8:e1000412 | PMID: 21311585
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Abstract

A Research Agenda for Malaria Eradication: Monitoring, Evaluation, and Surveillance.

The malERA Consultative Group on Monitoring, Evaluation, and Surveillance
Monitoring, evaluation, and surveillance measure how well public health programs operate over time and achieve their goals. As countries approach malaria elimination, these activities will need to shift from measuring reductions in morbidity and mortality, to detecting infections (with or without symptoms) and measuring transmission. Thus, the monitoring and evaluation and surveillance research and development agenda needs to develop the tools and strategies that will replace passive surveillance of morbidity with active and prompt detection of infection, including confirmation of interruption of transmission by detecting present and past infections, particularly in mobile populations. The capacity to assess trends and respond without delay will need to be developed, so that surveillance itself becomes an intervention. Research is also needed to develop sensitive field tests that can detect low levels of parasitaemia, together with strategies for their implementation. Other areas to explore include the rigorous evaluation of the utility of more detailed maps of disease and infection incidence and prevalence, the development of new maps to inform programmatic responses and the use of surveillance technologies based on cell phone or real-time internet Web-based reporting. Because any new strategies for monitoring and evaluation and surveillance for eradication have major implications for program implementation, research is also needed to test systems of delivery for acceptability, feasibility, efficiency, cost-effectiveness, and community engagement. Finally, there is a clear need to systematically review the information from past elimination efforts for malaria and other infectious diseases.

PLoS Med: 11 Feb 2011; 8:e1000400
The malERA Consultative Group on Monitoring, Evaluation, and Surveillance
PLoS Med: 11 Feb 2011; 8:e1000400 | PMID: 21311581
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Abstract

Child mortality estimation: accelerated progress in reducing global child mortality, 1990-2010.

Hill K, You D, Inoue M, Oestergaard MZ, Technical Advisory Group of the United Nations Inter-agency Group for Child Mortality Estimation
Monitoring development indicators has become a central interest of international agencies and countries for tracking progress towards the Millennium Development Goals. In this review, which also provides an introduction to a collection of articles, we describe the methodology used by the United Nations Inter-agency Group for Child Mortality Estimation to track country-specific changes in the key indicator for Millennium Development Goal 4 (MDG 4), the decline of the under-five mortality rate (the probability of dying between birth and age five, also denoted in the literature as U5MR and (5)q(0)). We review how relevant data from civil registration, sample registration, population censuses, and household surveys are compiled and assessed for United Nations member states, and how time series regression models are fitted to all points of acceptable quality to establish the trends in U5MR from which infant and neonatal mortality rates are generally derived. The application of this methodology indicates that, between 1990 and 2010, the global U5MR fell from 88 to 57 deaths per 1,000 live births, and the annual number of under-five deaths fell from 12.0 to 7.6 million. Although the annual rate of reduction in the U5MR accelerated from 1.9% for the period 1990-2000 to 2.5% for the period 2000-2010, it remains well below the 4.4% annual rate of reduction required to achieve the MDG 4 goal of a two-thirds reduction in U5MR from its 1990 value by 2015. Thus, despite progress in reducing child mortality worldwide, and an encouraging increase in the pace of decline over the last two decades, MDG 4 will not be met without greatly increasing efforts to reduce child deaths.

PLoS Med: 05 Sep 2012; 9:e1001303
Hill K, You D, Inoue M, Oestergaard MZ, Technical Advisory Group of the United Nations Inter-agency Group for Child Mortality Estimation
PLoS Med: 05 Sep 2012; 9:e1001303 | PMID: 22952441
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Abstract

Promotional Tone in Reviews of Menopausal Hormone Therapy After the Women\'s Health Initiative: An Analysis of Published Articles.

Fugh-Berman A, McDonald CP, Bell AM, Bethards EC, Scialli AR
Even after the Women\'s Health Initiative (WHI) found that the risks of menopausal hormone therapy (hormone therapy) outweighed benefit for asymptomatic women, about half of gynecologists in the United States continued to believe that hormones benefited women\'s health. The pharmaceutical industry has supported publication of articles in medical journals for marketing purposes. It is unknown whether author relationships with industry affect promotional tone in articles on hormone therapy. The goal of this study was to determine whether promotional tone could be identified in narrative review articles regarding menopausal hormone therapy and whether articles identified as promotional were more likely to have been authored by those with conflicts of interest with manufacturers of menopausal hormone therapy.

PLoS Med: 22 Mar 2011; 8:e1000425
Fugh-Berman A, McDonald CP, Bell AM, Bethards EC, Scialli AR
PLoS Med: 22 Mar 2011; 8:e1000425 | PMID: 21423581
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Abstract

HIV Treatment as Prevention: Modelling the Cost of Antiretroviral Treatment-State of the Art and Future Directions.

Meyer-Rath G, Over M
Policy discussions about the feasibility of massively scaling up antiretroviral therapy (ART) to reduce HIV transmission and incidence hinge on accurately projecting the cost of such scale-up in comparison to the benefits from reduced HIV incidence and mortality. We review the available literature on modelled estimates of the cost of providing ART to different populations around the world, and suggest alternative methods of characterising cost when modelling several decades into the future. In past economic analyses of ART provision, costs were often assumed to vary by disease stage and treatment regimen, but for treatment as prevention, in particular, most analyses assume a uniform cost per patient. This approach disregards variables that can affect unit cost, such as differences in factor prices (i.e., the prices of supplies and services) and the scale and scope of operations (i.e., the sizes and types of facilities providing ART). We discuss several of these variables, and then present a worked example of a flexible cost function used to determine the effect of scale on the cost of a proposed scale-up of treatment as prevention in South Africa. Adjusting previously estimated costs of universal testing and treatment in South Africa for diseconomies of small scale, i.e., more patients being treated in smaller facilities, adds 42% to the expected future cost of the intervention.

PLoS Med: 16 Jul 2012; 9:e1001247
Meyer-Rath G, Over M
PLoS Med: 16 Jul 2012; 9:e1001247 | PMID: 22802731
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Abstract

A Research Agenda for Malaria Eradication: Basic Science and Enabling Technologies.

The malERA Consultative Group on Basic Science and Enabling Technologies
Today\'s malaria control efforts are limited by our incomplete understanding of the biology of Plasmodium and of the complex relationships between human populations and the multiple species of mosquito and parasite. Research priorities include the development of in vitro culture systems for the complete life cycle of P. falciparum and P. vivax and the development of an appropriate liver culture system to study hepatic stages. In addition, genetic technologies for the manipulation of Plasmodium need to be improved, the entire parasite metabolome needs to be characterized to identify new druggable targets, and improved information systems for monitoring the changes in epidemiology, pathology, and host-parasite-vector interactions as a result of intensified control need to be established to bridge the gap between bench, preclinical, clinical, and population-based sciences.

PLoS Med: 11 Feb 2011; 8:e1000399
The malERA Consultative Group on Basic Science and Enabling Technologies
PLoS Med: 11 Feb 2011; 8:e1000399 | PMID: 21311584
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Abstract

HIV Treatment as Prevention: The Utility and Limitations of Ecological Observation.

Smith MK, Powers KA, Muessig KE, Miller WC, Cohen MS
Results from several observational studies of HIV-discordant couples and a randomized controlled trial (HIV Prevention Trials Network 052) show that antiretroviral therapy (ART) can greatly reduce heterosexual HIV transmission in stable HIV-discordant couples. However, such data do not prove that ART will reduce HIV incidence at the population level. Observational investigations using ecological measures have been used to support the implementation of HIV treatment for the specific purpose of preventing transmission at the population level. Many of these studies note ecological associations between measures of increased ART uptake and decreased HIV transmission. Given the urgency of implementing HIV prevention measures, ecological studies must de facto be used to inform current strategies. However, the hypothesis that widespread ART can eliminate HIV infection may have raised expectations beyond what we may be able to achieve. Here we review and discuss the construct of the exposure and outcome measures and analysis methods used in ecological studies. By examining the strengths and weaknesses of ecological analyses, we aim to aid understanding of the findings from these studies to inform future policy decisions regarding the use of ART for HIV prevention.

PLoS Med: 16 Jul 2012; 9:e1001260
Smith MK, Powers KA, Muessig KE, Miller WC, Cohen MS
PLoS Med: 16 Jul 2012; 9:e1001260 | PMID: 22802740
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A Research Agenda for Malaria Eradication: Diagnoses and Diagnostics.

The malERA Consultative Group on Diagnoses and Diagnostics
Many of malaria\'s signs and symptoms are indistinguishable from those of other febrile diseases. Detection of the presence of Plasmodium parasites is essential, therefore, to guide case management. Improved diagnostic tools are required to enable targeted treatment of infected individuals. In addition, field-ready diagnostic tools for mass screening and surveillance that can detect asymptomatic infections of very low parasite densities are needed to monitor transmission reduction and ensure elimination. Antibody-based tests for infection and novel methods based on biomarkers need further development and validation, as do methods for the detection and treatment of Plasmodium vivax. Current rapid diagnostic tests targeting P. vivax are generally less effective than those targeting Plasmodium falciparum. Moreover, because current drugs for radical cure may cause serious side effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, more information is needed on the distribution of G6PD-deficiency variants as well as tests to identify at-risk individuals. Finally, in an environment of very low or absent malaria transmission, sustaining interest in elimination and maintaining resources will become increasingly important. Thus, research is required into the context in which malaria diagnostic tests are used, into diagnostics for other febrile diseases, and into the integration of these tests into health systems.

PLoS Med: 11 Feb 2011; 8:e1000396
The malERA Consultative Group on Diagnoses and Diagnostics
PLoS Med: 11 Feb 2011; 8:e1000396 | PMID: 21311583
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Abstract

Child Mortality Estimation: Methods Used to Adjust for Bias due to AIDS in Estimating Trends in Under-Five Mortality.

Walker N, Hill K, Zhao F
In most low- and middle-income countries, child mortality is estimated from data provided by mothers concerning the survival of their children using methods that assume no correlation between the mortality risks of the mothers and those of their children. This assumption is not valid for populations with generalized HIV epidemics, however, and in this review, we show how the United Nations Inter-agency Group for Child Mortality Estimation (UN IGME) uses a cohort component projection model to correct for AIDS-related biases in the data used to estimate trends in under-five mortality. In this model, births in a given year are identified as occurring to HIV-positive or HIV-negative mothers, the lives of the infants and mothers are projected forward using survivorship probabilities to estimate survivors at the time of a given survey, and the extent to which excess mortality of children goes unreported because of the deaths of HIV-infected mothers prior to the survey is calculated. Estimates from the survey for past periods can then be adjusted for the estimated bias. The extent of the AIDS-related bias depends crucially on the dynamics of the HIV epidemic, on the length of time before the survey that the estimates are made for, and on the underlying non-AIDS child mortality. This simple methodology (which does not take into account the use of effective antiretroviral interventions) gives results qualitatively similar to those of other studies.

PLoS Med: 05 Sep 2012; 9:e1001298
Walker N, Hill K, Zhao F
PLoS Med: 05 Sep 2012; 9:e1001298 | PMID: 22952437
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Abstract

Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings.

Campbell TB, Smeaton LM, Kumarasamy N, Flanigan T, ... Hakim JG, PEARLS study team of the ACTG
Background: Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world. Methods and findings: 1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; p = 0.007). Conclusion: EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen. Trial registration: www.ClinicalTrials.govNCT00084136 Please see later in the article for the Editors\' Summary.

PLoS Med: 30 Aug 2012; 9:e1001290
Campbell TB, Smeaton LM, Kumarasamy N, Flanigan T, ... Hakim JG, PEARLS study team of the ACTG
PLoS Med: 30 Aug 2012; 9:e1001290 | PMID: 22936892
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Long-Term Risk of Incident Type 2 Diabetes and Measures of Overall and Regional Obesity: The EPIC-InterAct Case-Cohort Study.

The InterAct Consortium
Background: Waist circumference (WC) is a simple and reliable measure of fat distribution that may add to the prediction of type 2 diabetes (T2D), but previous studies have been too small to reliably quantify the relative and absolute risk of future diabetes by WC at different levels of body mass index (BMI). Methods and findings: The prospective InterAct case-cohort study was conducted in 26 centres in eight European countries and consists of 12,403 incident T2D cases and a stratified subcohort of 16,154 individuals from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. We used Prentice-weighted Cox regression and random effects meta-analysis methods to estimate hazard ratios for T2D. Kaplan-Meier estimates of the cumulative incidence of T2D were calculated. BMI and WC were each independently associated with T2D, with WC being a stronger risk factor in women than in men. Risk increased across groups defined by BMI and WC; compared to low normal weight individuals (BMI 18.5-22.4 kg/m(2)) with a low WC (<94/80 cm in men/women), the hazard ratio of T2D was 22.0 (95% confidence interval 14.3; 33.8) in men and 31.8 (25.2; 40.2) in women with grade 2 obesity (BMI≥35 kg/m(2)) and a high WC (>102/88 cm). Among the large group of overweight individuals, WC measurement was highly informative and facilitated the identification of a subgroup of overweight people with high WC whose 10-y T2D cumulative incidence (men, 70 per 1,000 person-years; women, 44 per 1,000 person-years) was comparable to that of the obese group (50-103 per 1,000 person-years in men and 28-74 per 1,000 person-years in women). Conclusions: WC is independently and strongly associated with T2D, particularly in women, and should be more widely measured for risk stratification. If targeted measurement is necessary for reasons of resource scarcity, measuring WC in overweight individuals may be an effective strategy, since it identifies a high-risk subgroup of individuals who could benefit from individualised preventive action. Please see later in the article for the Editors\' Summary.

PLoS Med: 07 Jun 2012; 9:e1001230
The InterAct Consortium
PLoS Med: 07 Jun 2012; 9:e1001230 | PMID: 22679397
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Abstract

The Case against a Smoker\'s License.

Collin J
Background TO THE DEBATE: Tobacco continues to kill millions of people around the world each year and its use is increasing in some countries, which makes the need for new, creative, and radical efforts to achieve the tobacco control endgame vitally important. One such effort is discussed in this PLOS Medicine Debate, where Simon Chapman presents his proposal for a "smoker\'s license" and Jeff Collin argues against. Chapman sets out a case for introducing a smart card license for smokers designed to limit access to tobacco products and encourage cessation. Key elements of the smoker\'s license include smokers setting daily limits, financial incentives for permanent license surrender, and a test of health risk knowledge for commencing smokers. Collin argues against the proposal, saying that it would shift focus away from the real vector of the epidemic-the tobacco industry-and that by focusing on individuals it would censure victims, increase stigmatization of smokers, and marginalize the poor.

PLoS Med: 14 Nov 2012; 9:e1001343
Collin J
PLoS Med: 14 Nov 2012; 9:e1001343 | PMID: 23152727
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Abstract

The Case for a Smoker\'s License.

Chapman S
Background TO THE DEBATE: Tobacco continues to kill millions of people around the world each year and its use is increasing in some countries, which makes the need for new, creative, and radical efforts to achieve the tobacco control endgame vitally important. One such effort is discussed in this PLOS Medicine Debate, where Simon Chapman presents his proposal for a "smoker\'s license" and Jeff Collin argues against. Chapman sets out a case for introducing a smart card license for smokers designed to limit access to tobacco products and encourage cessation. Key elements of the smoker\'s license include smokers setting daily limits, financial incentives for permanent license surrender, and a test of health risk knowledge for commencing smokers. Collin argues against the proposal, saying that it would shift focus away from the real vector of the epidemic-the tobacco industry-and that by focusing on individuals it would censure victims, increase stigmatization of smokers, and marginalize the poor.

PLoS Med: 14 Nov 2012; 9:e1001342
Chapman S
PLoS Med: 14 Nov 2012; 9:e1001342 | PMID: 23152726
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Abstract

Child mortality estimation: a global overview of infant and child mortality age patterns in light of new empirical data.

Guillot M, Gerland P, Pelletier F, Saabneh A
The under-five mortality rate (the probability of dying between birth and age 5 y, also denoted in the literature as U5MR and (5)q(0)) is a key indicator of child health, but it conceals important information about how this mortality is distributed by age. One important distinction is what amount of the under-five mortality occurs below age 1 y ((1)q(0)) versus at age 1 y and above ((4)q(1)). However, in many country settings, this distinction is often difficult to establish because of various types of data errors. As a result, it is common practice to resort to model age patterns to estimate (1)q(0) and (4)q(1) on the basis of an observed value of (5)q(0). The most commonly used model age patterns for this purpose are the Coale and Demeny and the United Nations systems. Since the development of these models, many additional sources of data for under-five mortality have become available, making possible a general evaluation of age patterns of infant and child mortality. In this paper, we do a systematic comparison of empirical values of (1)q(0) and (4)q(1) against model age patterns, and discuss whether observed deviations are due to data errors, or whether they reflect true epidemiological patterns not addressed in existing model life tables.

PLoS Med: 05 Sep 2012; 9:e1001299
Guillot M, Gerland P, Pelletier F, Saabneh A
PLoS Med: 05 Sep 2012; 9:e1001299 | PMID: 22952438
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Abstract

Ovarian Cancer and Body Size: Individual Participant Meta-Analysis Including 25,157 Women with Ovarian Cancer from 47 Epidemiological Studies.

Collaborative Group on Epidemiological Studies of Ovarian Cancer
Background: Only about half the studies that have collected information on the relevance of women\'s height and body mass index to their risk of developing ovarian cancer have published their results, and findings are inconsistent. Here, we bring together the worldwide evidence, published and unpublished, and describe these relationships. Methods and findings: Individual data on 25,157 women with ovarian cancer and 81,311 women without ovarian cancer from 47 epidemiological studies were collected, checked, and analysed centrally. Adjusted relative risks of ovarian cancer were calculated, by height and by body mass index. Ovarian cancer risk increased significantly with height and with body mass index, except in studies using hospital controls. For other study designs, the relative risk of ovarian cancer per 5 cm increase in height was 1.07 (95% confidence interval [CI], 1.05-1.09; p<0.001); this relationship did not vary significantly by women\'s age, year of birth, education, age at menarche, parity, menopausal status, smoking, alcohol consumption, having had a hysterectomy, having first degree relatives with ovarian or breast cancer, use of oral contraceptives, or use of menopausal hormone therapy. For body mass index, there was significant heterogeneity (p<0.001) in the findings between ever-users and never-users of menopausal hormone therapy, but not by the 11 other factors listed above. The relative risk for ovarian cancer per 5 kg/m(2) increase in body mass index was 1.10 (95% CI, 1.07-1.13; p<0.001) in never-users and 0.95 (95% CI, 0.92-0.99; p = 0.02) in ever-users of hormone therapy. Conclusions: Ovarian cancer is associated with height and, among never-users of hormone therapy, with body mass index. In high-income countries, both height and body mass index have been increasing in birth cohorts now developing the disease. If all other relevant factors had remained constant, then these increases in height and weight would be associated with a 3% increase in ovarian cancer incidence per decade. Please see later in the article for the Editors\' Summary.

PLoS Med: 17 May 2012; 9:e1001200
Collaborative Group on Epidemiological Studies of Ovarian Cancer
PLoS Med: 17 May 2012; 9:e1001200 | PMID: 22606070
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Abstract

A Research Agenda for Malaria Eradication: Modeling.

The malERA Consultative Group on Modeling
Malaria modeling can inform policy and guide research for malaria elimination and eradication from local implementation to global policy. A research and development agenda for malaria modeling is proposed, to support operations and to enhance the broader eradication research agenda. Models are envisioned as an integral part of research, planning, and evaluation, and modelers should ideally be integrated into multidisciplinary teams to update the models iteratively, communicate their appropriate use, and serve the needs of other research scientists, public health specialists, and government officials. A competitive and collaborative framework will result in policy recommendations from multiple, independently derived models and model systems that share harmonized databases. As planned, modeling results will be produced in five priority areas: (1) strategic planning to determine where and when resources should be optimally allocated to achieve eradication; (2) management plans to minimize the evolution of drug and pesticide resistance; (3) impact assessments of new and needed tools to interrupt transmission; (4) technical feasibility assessments to determine appropriate combinations of tools, an associated set of target intervention coverage levels, and the expected timelines for achieving a set of goals in different socio-ecological settings and different health systems; and (5) operational feasibility assessments to weigh the economic costs, capital investments, and human resource capacities required.

PLoS Med: 01 Feb 2011; 8:e1000403
The malERA Consultative Group on Modeling
PLoS Med: 01 Feb 2011; 8:e1000403 | PMID: 21283605
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HIV Treatment as Prevention: Models, Data, and Questions-Towards Evidence-Based Decision-Making.

The HIV Modelling Consortium Treatment as Prevention Editorial Writing Group
Antiretroviral therapy (ART) for those infected with HIV can prevent onward transmission of infection, but biological efficacy alone is not enough to guide policy decisions about the role of ART in reducing HIV incidence. Epidemiology, economics, demography, statistics, biology, and mathematical modelling will be central in framing key decisions in the optimal use of ART. PLoS Medicine, with the HIV Modelling Consortium, has commissioned a set of articles that examine different aspects of HIV treatment as prevention with a forward-looking research agenda. Interlocking themes across these articles are discussed in this introduction. We hope that this article, and others in the collection, will provide a foundation upon which greater collaborations between disciplines will be formed, and will afford deeper insights into the key factors involved, to help strengthen the support for evidence-based decision-making in HIV prevention.

PLoS Med: 16 Jul 2012; 9:e1001259
The HIV Modelling Consortium Treatment as Prevention Editorial Writing Group
PLoS Med: 16 Jul 2012; 9:e1001259 | PMID: 22802739
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Abstract

Gender Differences in Survival among Adult Patients Starting Antiretroviral Therapy in South Africa: A Multicentre Cohort Study.

Cornell M, Schomaker M, Garone DB, Giddy J, ... Myer L, for the International Epidemiologic Databases to Evaluate AIDS Southern Africa (IeDEA-SA) Collaboration
Background: Increased mortality among men on antiretroviral therapy (ART) has been documented but remains poorly understood. We examined the magnitude of and risk factors for gender differences in mortality on ART. Methods and findings: Analyses included 46,201 ART-naïve adults starting ART between January 2002 and December 2009 in eight ART programmes across South Africa (SA). Patients were followed from initiation of ART to outcome or analysis closure. The primary outcome was mortality; secondary outcomes were loss to follow-up (LTF), virologic suppression, and CD4+ cell count responses. Survival analyses were used to examine the hazard of death on ART by gender. Sensitivity analyses were limited to patients who were virologically suppressed and patients whose CD4+ cell count reached >200 cells/µl. We compared gender differences in mortality among HIV+ patients on ART with mortality in an age-standardised HIV-negative population. Among 46,201 adults (65% female, median age 35 years), during 77,578 person-years of follow-up, men had lower median CD4+ cell counts than women (85 versus 110 cells/µl, p<0.001), were more likely to be classified WHO stage III/IV (86 versus 77%, p<0.001), and had higher mortality in crude (8.5 versus 5.7 deaths/100 person-years, p<0.001) and adjusted analyses (adjusted hazard ratio [AHR] 1.31, 95% CI 1.22-1.41). After 36 months on ART, men were more likely than women to be truly LTF (AHR 1.20, 95% CI 1.12-1.28) but not to die after LTF (AHR 1.04, 95% CI 0.86-1.25). Findings were consistent across all eight programmes. Virologic suppression was similar by gender; women had slightly better immunologic responses than men. Notably, the observed gender differences in mortality on ART were smaller than gender differences in age-standardised death rates in the HIV-negative South African population. Over time, non-HIV mortality appeared to account for an increasing proportion of observed mortality. The analysis was limited by missing data on baseline HIV disease characteristics, and we did not observe directly mortality in HIV-negative populations where the participating cohorts were located. Conclusions: HIV-infected men have higher mortality on ART than women in South African programmes, but these differences are only partly explained by more advanced HIV disease at the time of ART initiation, differential LTF and subsequent mortality, and differences in responses to treatment. The observed differences in mortality on ART may be best explained by background differences in mortality between men and women in the South African population unrelated to the HIV/AIDS epidemic. Please see later in the article for the Editors\' Summary.

PLoS Med: 12 Sep 2012; 9:e1001304
Cornell M, Schomaker M, Garone DB, Giddy J, ... Myer L, for the International Epidemiologic Databases to Evaluate AIDS Southern Africa (IeDEA-SA) Collaboration
PLoS Med: 12 Sep 2012; 9:e1001304 | PMID: 22973181
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Abstract

Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients.

Ahuja SD, Ashkin D, Avendano M, Banerjee R, ... Yim JJ, Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB
Background: Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB. Methods and findings: Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1-6.0]), ofloxacin (aOR: 2.5 [1.6-3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3-2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3-3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7-4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7-4.3]), ofloxacin (aOR: 2.3 [1.3-3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4-2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9-3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4-6.0]). Conclusions: In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment. Please see later in the article for the Editors\' Summary.

PLoS Med: 05 Sep 2012; 9:e1001300
Ahuja SD, Ashkin D, Avendano M, Banerjee R, ... Yim JJ, Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB
PLoS Med: 05 Sep 2012; 9:e1001300 | PMID: 22952439
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Abstract

Nuclear Receptor Expression Defines a Set of Prognostic Biomarkers for Lung Cancer.

Jeong Y, Xie Y, Xiao G, Behrens C, ... Minna JD, Mangelsdorf DJ
Background: The identification of prognostic tumor biomarkers that also would have potential as therapeutic targets, particularly in patients with early stage disease, has been a long sought-after goal in the management and treatment of lung cancer. The nuclear receptor (NR) superfamily, which is composed of 48 transcription factors that govern complex physiologic and pathophysiologic processes, could represent a unique subset of these biomarkers. In fact, many members of this family are the targets of already identified selective receptor modulators, providing a direct link between individual tumor NR quantitation and selection of therapy. The goal of this study, which begins this overall strategy, was to investigate the association between mRNA expression of the NR superfamily and the clinical outcome for patients with lung cancer, and to test whether a tumor NR gene signature provided useful information (over available clinical data) for patients with lung cancer. Methods and findings: Using quantitative real-time PCR to study NR expression in 30 microdissected non-small-cell lung cancers (NSCLCs) and their pair-matched normal lung epithelium, we found great variability in NR expression among patients\' tumor and non-involved lung epithelium, found a strong association between NR expression and clinical outcome, and identified an NR gene signature from both normal and tumor tissues that predicted patient survival time and disease recurrence. The NR signature derived from the initial 30 NSCLC samples was validated in two independent microarray datasets derived from 442 and 117 resected lung adenocarcinomas. The NR gene signature was also validated in 130 squamous cell carcinomas. The prognostic signature in tumors could be distilled to expression of two NRs, short heterodimer partner and progesterone receptor, as single gene predictors of NSCLC patient survival time, including for patients with stage I disease. Of equal interest, the studies of microdissected histologically normal epithelium and matched tumors identified expression in normal (but not tumor) epithelium of NGFIB3 and mineralocorticoid receptor as single gene predictors of good prognosis. Conclusions: NR expression is strongly associated with clinical outcomes for patients with lung cancer, and this expression profile provides a unique prognostic signature for lung cancer patient survival time, particularly for those with early stage disease. This study highlights the potential use of NRs as a rational set of therapeutically tractable genes as theragnostic biomarkers, and specifically identifies short heterodimer partner and progesterone receptor in tumors, and NGFIB3 and MR in non-neoplastic lung epithelium, for future detailed translational study in lung cancer. Please see later in the article for the Editors\' Summary.

PLoS Med: 23 Dec 2010; 7:e1000378
Jeong Y, Xie Y, Xiao G, Behrens C, ... Minna JD, Mangelsdorf DJ
PLoS Med: 23 Dec 2010; 7:e1000378 | PMID: 21179495
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Nevirapine- Versus Lopinavir/Ritonavir-Based Initial Therapy for HIV-1 Infection among Women in Africa: A Randomized Trial.

Lockman S, Hughes M, Sawe F, Zheng Y, ... Currier J, the OCTANE (Optimal Combination Therapy After Nevirapine Exposure) ACTG A5208/OCTANE Study Team
Background: Nevirapine (NVP) is widely used in antiretroviral treatment (ART) of HIV-1 globally. The primary objective of the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r)-based initial ART. Methods and findings: In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, and Zimbabwe), 500 antiretroviral-naïve HIV-infected women with CD4<200 cells/mm(3) were enrolled into a two-arm randomized trial to initiate open-label ART with tenofovir (TDF)/emtricitabine (FTC) once/day plus either NVP (n = 249) or LPV/r (n = 251) twice/day, and followed for ≥48 weeks. The primary endpoint was time from randomization to death or confirmed virologic failure ([VF]) (plasma HIV RNA<1 log(10) below baseline 12 weeks after treatment initiation, or ≥400 copies/ml at or after 24 weeks), with comparison between treatments based on hazard ratios (HRs) in intention-to-treat analysis. Equivalence of randomized treatments was defined as finding the 95% CI for HR for virological failure or death in the range 0.5 to 2.0. Baseline characteristics were (median): age = 34 years, CD4 = 121 cells/mm(3), HIV RNA = 5.2 log(10)copies/ml. Median follow-up = 118 weeks; 29 (6%) women were lost to follow-up. 42 women (37 VFs, five deaths; 17%) in the NVP and 50 (43 VFs, seven deaths; 20%) in the LPV/r arm reached the primary endpoint (HR 0.85, 95% CI 0.56-1.29). During initial assigned treatment, 14% and 16% of women receiving NVP and LPV/r experienced grade 3/4 signs/symptoms and 26% and 22% experienced grade 3/4 laboratory abnormalities. However, 35 (14%) women discontinued NVP because of adverse events, most in the first 8 weeks, versus none for LPV/r (p<0.001). VF, death, or permanent treatment discontinuation occurred in 80 (32%) of NVP and 54 (22%) of LPV/r arms (HR = 1.7, 95% CI 1.2-2.4), with the difference primarily due to more treatment discontinuation in the NVP arm. 13 (45%) of 29 women tested in the NVP versus six (15%) of 40 in the LPV/r arm had any drug resistance mutation at time of VF. Conclusions: Initial ART with NVP+TDF/FTC demonstrated equivalent virologic efficacy but higher rates of treatment discontinuation and new drug resistance compared with LPV/r+TDF/FTC in antiretroviral-naïve women with CD4<200 cells/mm(3). Trial registration: ClinicalTrials.gov NCT00089505 Please see later in the article for the Editors\' Summary.

PLoS Med: 20 Jun 2012; 9:e1001236
Lockman S, Hughes M, Sawe F, Zheng Y, ... Currier J, the OCTANE (Optimal Combination Therapy After Nevirapine Exposure) ACTG A5208/OCTANE Study Team
PLoS Med: 20 Jun 2012; 9:e1001236 | PMID: 22719231
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The Impact of eHealth on the Quality and Safety of Health Care: A Systematic Overview.

Black AD, Car J, Pagliari C, Anandan C, ... Majeed A, Sheikh A
Background: There is considerable international interest in exploiting the potential of digital solutions to enhance the quality and safety of health care. Implementations of transformative eHealth technologies are underway globally, often at very considerable cost. In order to assess the impact of eHealth solutions on the quality and safety of health care, and to inform policy decisions on eHealth deployments, we undertook a systematic review of systematic reviews assessing the effectiveness and consequences of various eHealth technologies on the quality and safety of care. Methods and findings: We developed novel search strategies, conceptual maps of health care quality, safety, and eHealth interventions, and then systematically identified, scrutinised, and synthesised the systematic review literature. Major biomedical databases were searched to identify systematic reviews published between 1997 and 2010. Related theoretical, methodological, and technical material was also reviewed. We identified 53 systematic reviews that focused on assessing the impact of eHealth interventions on the quality and/or safety of health care and 55 supplementary systematic reviews providing relevant supportive information. This systematic review literature was found to be generally of substandard quality with regards to methodology, reporting, and utility. We thematically categorised eHealth technologies into three main areas: (1) storing, managing, and transmission of data; (2) clinical decision support; and (3) facilitating care from a distance. We found that despite support from policymakers, there was relatively little empirical evidence to substantiate many of the claims made in relation to these technologies. Whether the success of those relatively few solutions identified to improve quality and safety would continue if these were deployed beyond the contexts in which they were originally developed, has yet to be established. Importantly, best practice guidelines in effective development and deployment strategies are lacking. Conclusions: There is a large gap between the postulated and empirically demonstrated benefits of eHealth technologies. In addition, there is a lack of robust research on the risks of implementing these technologies and their cost-effectiveness has yet to be demonstrated, despite being frequently promoted by policymakers and "techno-enthusiasts" as if this was a given. In the light of the paucity of evidence in relation to improvements in patient outcomes, as well as the lack of evidence on their cost-effectiveness, it is vital that future eHealth technologies are evaluated against a comprehensive set of measures, ideally throughout all stages of the technology\'s life cycle. Such evaluation should be characterised by careful attention to socio-technical factors to maximise the likelihood of successful implementation and adoption. Please see later in the article for the Editors\' Summary.

PLoS Med: 26 Jan 2011; 8:e1000387
Black AD, Car J, Pagliari C, Anandan C, ... Majeed A, Sheikh A
PLoS Med: 26 Jan 2011; 8:e1000387 | PMID: 21267058
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A research agenda to underpin malaria eradication.

Alonso PL, Brown G, Arevalo-Herrera M, Binka F, ... Slutsker L, Tanner M
The interruption of malaria transmission worldwide is one of the greatest challenges for international health and development communities. The current expert view suggests that, by aggressively scaling up control with currently available tools and strategies, much greater gains could be achieved against malaria, including elimination from a number of countries and regions; however, even with maximal effort we will fall short of global eradication. The Malaria Eradication Research Agenda (malERA) complements the current research agenda-primarily directed towards reducing morbidity and mortality-with one that aims to identify key knowledge gaps and define the strategies and tools that will result in reducing the basic reproduction rate to less than 1, with the ultimate aim of eradication of the parasite from the human population. Sustained commitment from local communities, civil society, policy leaders, and the scientific community, together with a massive effort to build a strong base of researchers from the endemic areas will be critical factors in the success of this new agenda.

PLoS Med: 11 Feb 2011; 8:e1000406
Alonso PL, Brown G, Arevalo-Herrera M, Binka F, ... Slutsker L, Tanner M
PLoS Med: 11 Feb 2011; 8:e1000406 | PMID: 21311579
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HIV Treatment as Prevention: Considerations in the Design, Conduct, and Analysis of Cluster Randomized Controlled Trials of Combination HIV Prevention.

Boily MC, Mâsse B, Alsallaq R, Padian NS, ... Vesga JF, Hallett TB
The rigorous evaluation of the impact of combination HIV prevention packages at the population level will be critical for the future of HIV prevention. In this review, we discuss important considerations for the design and interpretation of cluster randomized controlled trials (C-RCTs) of combination prevention interventions. We focus on three large C-RCTs that will start soon and are designed to test the hypothesis that combination prevention packages, including expanded access to antiretroviral therapy, can substantially reduce HIV incidence. Using a general framework to integrate mathematical modelling analysis into the design, conduct, and analysis of C-RCTs will complement traditional statistical analyses and strengthen the evaluation of the interventions. Importantly, even with combination interventions, it may be challenging to substantially reduce HIV incidence over the 2- to 3-y duration of a C-RCT, unless interventions are scaled up rapidly and key populations are reached. Thus, we propose the innovative use of mathematical modelling to conduct interim analyses, when interim HIV incidence data are not available, to allow the ongoing trials to be modified or adapted to reduce the likelihood of inconclusive outcomes. The preplanned, interactive use of mathematical models during C-RCTs will also provide a valuable opportunity to validate and refine model projections.

PLoS Med: 17 Jul 2012; 9:e1001250
Boily MC, Mâsse B, Alsallaq R, Padian NS, ... Vesga JF, Hallett TB
PLoS Med: 17 Jul 2012; 9:e1001250 | PMID: 22807657
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Strategies for Increasing Recruitment to Randomised Controlled Trials: Systematic Review.

Caldwell PH, Hamilton S, Tan A, Craig JC
Background: Recruitment of participants into randomised controlled trials (RCTs) is critical for successful trial conduct. Although there have been two previous systematic reviews on related topics, the results (which identified specific interventions) were inconclusive and not generalizable. The aim of our study was to evaluate the relative effectiveness of recruitment strategies for participation in RCTs. Methods and findings: A systematic review, using the PRISMA guideline for reporting of systematic reviews, that compared methods of recruiting individual study participants into an actual or mock RCT were included. We searched MEDLINE, Embase, The Cochrane Library, and reference lists of relevant studies. From over 16,000 titles or abstracts reviewed, 396 papers were retrieved and 37 studies were included, in which 18,812 of at least 59,354 people approached agreed to participate in a clinical RCT. Recruitment strategies were broadly divided into four groups: novel trial designs (eight studies), recruiter differences (eight studies), incentives (two studies), and provision of trial information (19 studies). Strategies that increased people\'s awareness of the health problem being studied (e.g., an interactive computer program [relative risk (RR) 1.48, 95% confidence interval (CI) 1.00-2.18], attendance at an education session [RR 1.14, 95% CI 1.01-1.28], addition of a health questionnaire [RR 1.37, 95% CI 1.14-1.66]), or a video about the health condition (RR 1.75, 95% CI 1.11-2.74), and also monetary incentives (RR1.39, 95% CI 1.13-1.64 to RR 1.53, 95% CI 1.28-1.84) improved recruitment. Increasing patients\' understanding of the trial process, recruiter differences, and various methods of randomisation and consent design did not show a difference in recruitment. Consent rates were also higher for nonblinded trial design, but differential loss to follow up between groups may jeopardise the study findings. The study\'s main limitation was the necessity of modifying the search strategy with subsequent search updates because of changes in MEDLINE definitions. The abstracts of previous versions of this systematic review were published in 2002 and 2007. Conclusion: Recruitment strategies that focus on increasing potential participants\' awareness of the health problem being studied, its potential impact on their health, and their engagement in the learning process appeared to increase recruitment to clinical studies. Further trials of recruitment strategies that target engaging participants to increase their awareness of the health problems being studied and the potential impact on their health may confirm this hypothesis. Please see later in the article for the Editors\' Summary.

PLoS Med: 18 Nov 2010; 7:e1000368
Caldwell PH, Hamilton S, Tan A, Craig JC
PLoS Med: 18 Nov 2010; 7:e1000368 | PMID: 21085696
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Abstract

No Treatment versus 24 or 60 Weeks of Antiretroviral Treatment during Primary HIV Infection: The Randomized Primo-SHM Trial.

Grijsen ML, Steingrover R, Wit FW, Jurriaans S, ... Prins JM, on behalf of the Primo-SHM Study Group
Background: The objective of this study was to assess the benefit of temporary combination antiretroviral therapy (cART) during primary HIV infection (PHI). Methods and findings: Adult patients with laboratory evidence of PHI were recruited in 13 HIV treatment centers in the Netherlands and randomly assigned to receive no treatment or 24 or 60 wk of cART (allocation in a 1∶1∶1 ratio); if therapy was clinically indicated, participants were randomized over the two treatment arms (allocation in a 1∶1 ratio). Primary end points were (1) viral set point, defined as the plasma viral load 36 wk after randomization in the no treatment arm and 36 wk after treatment interruption in the treatment arms, and (2) the total time that patients were off therapy, defined as the time between randomization and start of cART in the no treatment arm, and the time between treatment interruption and restart of cART in the treatment arms. cART was (re)started in case of confirmed CD4 cell count <350 cells/mm(3) or symptomatic HIV disease. In total, 173 participants were randomized. The modified intention-to-treat analysis comprised 168 patients: 115 were randomized over the three study arms, and 53 randomized over the two treatment arms. Of the 115 patients randomized over the three study arms, mean viral set point was 4.8 (standard deviation 0.6) log(10) copies/ml in the no treatment arm, and 4.0 (1.0) and 4.3 (0.9) log(10) copies/ml in the 24- and 60-wk treatment arms (between groups: p<0.001). The median total time off therapy in the no treatment arm was 0.7 (95% CI 0.0-1.8) y compared to 3.0 (1.9-4.2) and 1.8 (0.5-3.0) y in the 24- and 60-wk treatment arms (log rank test, p<0.001). In the adjusted Cox analysis, both 24 wk (hazard ratio 0.42 [95% CI 0.25-0.73]) and 60 wk of early treatment (hazard ratio 0.55 [0.32-0.95]) were associated with time to (re)start of cART. Conclusions: In this trial, temporary cART during PHI was found to transiently lower the viral set point and defer the restart of cART during chronic HIV infection. Trial registration: Current Controlled Trials ISRCTN59497461 Please see later in the article for the Editors\' Summary.

PLoS Med: 04 Apr 2012; 9:e1001196
Grijsen ML, Steingrover R, Wit FW, Jurriaans S, ... Prins JM, on behalf of the Primo-SHM Study Group
PLoS Med: 04 Apr 2012; 9:e1001196 | PMID: 22479156
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Abstract

Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials.

Mozaffarian D, Micha R, Wallace S
Background: Reduced saturated fat (SFA) consumption is recommended to reduce coronary heart disease (CHD), but there is an absence of strong supporting evidence from randomized controlled trials (RCTs) of clinical CHD events and few guidelines focus on any specific replacement nutrient. Additionally, some public health groups recommend lowering or limiting polyunsaturated fat (PUFA) consumption, a major potential replacement for SFA. Methods and findings: We systematically investigated and quantified the effects of increased PUFA consumption, as a replacement for SFA, on CHD endpoints in RCTs. RCTs were identified by systematic searches of multiple online databases through June 2009, grey literature sources, hand-searching related articles and citations, and direct contacts with experts to identify potentially unpublished trials. Studies were included if they randomized participants to increased PUFA for at least 1 year without major concomitant interventions, had an appropriate control group, and reported incidence of CHD (myocardial infarction and/or cardiac death). Inclusions/exclusions were adjudicated and data were extracted independently and in duplicate by two investigators and included population characteristics, control and intervention diets, follow-up duration, types of events, risk ratios, and SEs. Pooled effects were calculated using inverse-variance-weighted random effects meta-analysis. From 346 identified abstracts, eight trials met inclusion criteria, totaling 13,614 participants with 1,042 CHD events. Average weighted PUFA consumption was 14.9% energy (range 8.0%-20.7%) in intervention groups versus 5.0% energy (range 4.0%-6.4%) in controls. The overall pooled risk reduction was 19% (RR = 0.81, 95% confidence interval [CI] 0.70-0.95, p = 0.008), corresponding to 10% reduced CHD risk (RR = 0.90, 95% CI = 0.83-0.97) for each 5% energy of increased PUFA, without evidence for statistical heterogeneity (Q-statistic p = 0.13; I(2) = 37%). Meta-regression identified study duration as an independent determinant of risk reduction (p = 0.017), with studies of longer duration showing greater benefits. Conclusions: These findings provide evidence that consuming PUFA in place of SFA reduces CHD events in RCTs. This suggests that rather than trying to lower PUFA consumption, a shift toward greater population PUFA consumption in place of SFA would significantly reduce rates of CHD. Please see later in the article for the Editors\' Summary.

PLoS Med: 30 Mar 2010; 7:e1000252
Mozaffarian D, Micha R, Wallace S
PLoS Med: 30 Mar 2010; 7:e1000252 | PMID: 20351774
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Abstract

Rapid scaling up of insecticide-treated bed net coverage in Africa and its relationship with development assistance for health: a systematic synthesis of supply, distribution, and household survey data.

Flaxman AD, Fullman N, Otten MW, Menon M, ... Murray CJ, Lim SS
Background: Development assistance for health (DAH) targeted at malaria has risen exponentially over the last 10 years, with a large fraction of these resources directed toward the distribution of insecticide-treated bed nets (ITNs). Identifying countries that have been successful in scaling up ITN coverage and understanding the role of DAH is critical for making progress in countries where coverage remains low. Sparse and inconsistent sources of data have prevented robust estimates of the coverage of ITNs over time. METHODS AND PRINCIPAL Findings: We combined data from manufacturer reports of ITN deliveries to countries, National Malaria Control Program (NMCP) reports of ITNs distributed to health facilities and operational partners, and household survey data using Bayesian inference on a deterministic compartmental model of ITN distribution. For 44 countries in Africa, we calculated (1) ITN ownership coverage, defined as the proportion of households that own at least one ITN, and (2) ITN use in children under 5 coverage, defined as the proportion of children under the age of 5 years who slept under an ITN. Using regression, we examined the relationship between cumulative DAH targeted at malaria between 2000 and 2008 and the change in national-level ITN coverage over the same time period. In 1999, assuming that all ITNs are owned and used in populations at risk of malaria, mean coverage of ITN ownership and use in children under 5 among populations at risk of malaria were 2.2% and 1.5%, respectively, and were uniformly low across all 44 countries. In 2003, coverage of ITN ownership and use in children under 5 was 5.1% (95% uncertainty interval 4.6% to 5.7%) and 3.7% (2.9% to 4.9%); in 2006 it was 17.5% (16.4% to 18.8%) and 12.9% (10.8% to 15.4%); and by 2008 it was 32.8% (31.4% to 34.4%) and 26.6% (22.3% to 30.9%), respectively. In 2008, four countries had ITN ownership coverage of 80% or greater; six countries were between 60% and 80%; nine countries were between 40% and 60%; 12 countries were between 20% and 40%; and 13 countries had coverage below 20%. Excluding four outlier countries, each US$1 per capita in malaria DAH was associated with a significant increase in ITN household coverage and ITN use in children under 5 coverage of 5.3 percentage points (3.7 to 6.9) and 4.6 percentage points (2.5 to 6.7), respectively. Conclusions: Rapid increases in ITN coverage have occurred in some of the poorest countries, but coverage remains low in large populations at risk. DAH targeted at malaria can lead to improvements in ITN coverage; inadequate financing may be a reason for lack of progress in some countries. Please see later in the article for the Editors\' Summary.

PLoS Med: 02 Sep 2010; 7
Flaxman AD, Fullman N, Otten MW, Menon M, ... Murray CJ, Lim SS
PLoS Med: 02 Sep 2010; 7 | PMID: 20808957
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Abstract

P2RX7 Purinoceptor: A Therapeutic Target for Ameliorating the Symptoms of Duchenne Muscular Dystrophy.

Sinadinos A, Young CN, Al-Khalidi R, Teti A, ... doRego JC, Górecki DC
Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease, leading to severe disability and death in young men. Death is caused by the progressive degeneration of striated muscles aggravated by sterile inflammation. The pleiotropic effects of the mutant gene also include cognitive and behavioral impairments and low bone density. Current interventions in DMD are palliative only as no treatment improves the long-term outcome. Therefore, approaches with a translational potential should be investigated, and key abnormalities downstream from the absence of the DMD product, dystrophin, appear to be strong therapeutic targets. We and others have demonstrated that DMD mutations alter ATP signaling and have identified P2RX7 purinoceptor up-regulation as being responsible for the death of muscles in the mdx mouse model of DMD and human DMD lymphoblasts. Moreover, the ATP-P2RX7 axis, being a crucial activator of innate immune responses, can contribute to DMD pathology by stimulating chronic inflammation. We investigated whether ablation of P2RX7 attenuates the DMD model mouse phenotype to assess receptor suitability as a therapeutic target.

PLoS Med: 13 Oct 2015; 12:e1001888
Sinadinos A, Young CN, Al-Khalidi R, Teti A, ... doRego JC, Górecki DC
PLoS Med: 13 Oct 2015; 12:e1001888 | PMID: 26461208
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Abstract

Air Pollution and the Microvasculature: A Cross-Sectional Assessment of In Vivo Retinal Images in the Population-Based Multi-Ethnic Study of Atherosclerosis (MESA).

Adar SD, Klein R, Klein BE, Szpiro AA, ... Sampson PD, Kaufman JD
Background: Long- and short-term exposures to air pollution, especially fine particulate matter (PM(2.5)), have been linked to cardiovascular morbidity and mortality. One hypothesized mechanism for these associations involves microvascular effects. Retinal photography provides a novel, in vivo approach to examine the association of air pollution with changes in the human microvasculature. Methods and findings: Chronic and acute associations between residential air pollution concentrations and retinal vessel diameters, expressed as central retinal arteriolar equivalents (CRAE) and central retinal venular equivalents (CRVE), were examined using digital retinal images taken in Multi-Ethnic Study of Atherosclerosis (MESA) participants between 2002 and 2003. Study participants (46 to 87 years of age) were without clinical cardiovascular disease at the baseline examination (2000-2002). Long-term outdoor concentrations of PM(2.5) were estimated at each participant\'s home for the 2 years preceding the clinical exam using a spatio-temporal model. Short-term concentrations were assigned using outdoor measurements on the day preceding the clinical exam. Residential proximity to roadways was also used as an indicator of long-term traffic exposures. All associations were examined using linear regression models adjusted for subject-specific age, sex, race/ethnicity, education, income, smoking status, alcohol use, physical activity, body mass index, family history of cardiovascular disease, diabetes status, serum cholesterol, glucose, blood pressure, emphysema, C-reactive protein, medication use, and fellow vessel diameter. Short-term associations were further controlled for weather and seasonality. Among the 4,607 participants with complete data, CRAE were found to be narrower among persons residing in regions with increased long- and short-term levels of PM(2.5). These relationships were observed in a joint exposure model with -0.8 µm (95% confidence interval [CI] -1.1 to -0.5) and -0.4 µm (95% CI -0.8 to 0.1) decreases in CRAE per interquartile increases in long- (3 µg/m(3)) and short-term (9 µg/m(3)) PM(2.5) levels, respectively. These reductions in CRAE are equivalent to 7- and 3-year increases in age in the same cohort. Similarly, living near a major road was also associated with a -0.7 µm decrease (95% CI -1.4 to 0.1) in CRAE. Although the chronic association with CRAE was largely influenced by differences in exposure between cities, this relationship was generally robust to control for city-level covariates and no significant differences were observed between cities. Wider CRVE were associated with living in areas of higher PM(2.5) concentrations, but these findings were less robust and not supported by the presence of consistent acute associations with PM(2.5). Conclusions: Residing in regions with higher air pollution concentrations and experiencing daily increases in air pollution were each associated with narrower retinal arteriolar diameters in older individuals. These findings support the hypothesis that important vascular phenomena are associated with small increases in short-term or long-term air pollution exposures, even at current exposure levels, and further corroborate reported associations between air pollution and the development and exacerbation of clinical cardiovascular disease. Please see later in the article for the Editors\' Summary.

PLoS Med: 14 Dec 2010; 7:e1000372
Adar SD, Klein R, Klein BE, Szpiro AA, ... Sampson PD, Kaufman JD
PLoS Med: 14 Dec 2010; 7:e1000372 | PMID: 21152417
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Abstract

A Research Agenda for Malaria Eradication: Drugs.

The malERA Consultative Group on Drugs
Antimalarial drugs will be essential tools at all stages of malaria elimination along the path towards eradication, including the early control or "attack" phase to drive down transmission and the later stages of maintaining interruption of transmission, preventing reintroduction of malaria, and eliminating the last residual foci of infection. Drugs will continue to be used to treat acute malaria illness and prevent complications in vulnerable groups, but better drugs are needed for elimination-specific indications such as mass treatment, curing asymptomatic infections, curing relapsing liver stages, and preventing transmission. The ideal malaria eradication drug is a coformulated drug combination suitable for mass administration that can be administered in a single encounter at infrequent intervals and that results in radical cure of all life cycle stages of all five malaria species infecting humans. Short of this optimal goal, highly desirable drugs might have limitations such as targeting only one or two parasite species, the priorities being Plasmodium falciparum and Plasmodium vivax. The malaria research agenda for eradication should include research aimed at developing such drugs and research to develop situation-specific strategies for using both current and future drugs to interrupt malaria transmission.

PLoS Med: 11 Feb 2011; 8:e1000402
The malERA Consultative Group on Drugs
PLoS Med: 11 Feb 2011; 8:e1000402 | PMID: 21311580
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Abstract

Social Relationships and Mortality Risk: A Meta-analytic Review.

Holt-Lunstad J, Smith TB, Layton JB
Background: The quality and quantity of individuals\' social relationships has been linked not only to mental health but also to both morbidity and mortality. ObjectiveS: This meta-analytic review was conducted to determine the extent to which social relationships influence risk for mortality, which aspects of social relationships are most highly predictive, and which factors may moderate the risk. Data extraction: Data were extracted on several participant characteristics, including cause of mortality, initial health status, and pre-existing health conditions, as well as on study characteristics, including length of follow-up and type of assessment of social relationships. Results: Across 148 studies (308,849 participants), the random effects weighted average effect size was OR = 1.50 (95% CI 1.42 to 1.59), indicating a 50% increased likelihood of survival for participants with stronger social relationships. This finding remained consistent across age, sex, initial health status, cause of death, and follow-up period. Significant differences were found across the type of social measurement evaluated (p<0.001); the association was strongest for complex measures of social integration (OR = 1.91; 95% CI 1.63 to 2.23) and lowest for binary indicators of residential status (living alone versus with others) (OR = 1.19; 95% CI 0.99 to 1.44). Conclusions: The influence of social relationships on risk for mortality is comparable with well-established risk factors for mortality. Please see later in the article for the Editors\' Summary.

PLoS Med: 29 Jul 2010; 7:e1000316
Holt-Lunstad J, Smith TB, Layton JB
PLoS Med: 29 Jul 2010; 7:e1000316 | PMID: 20668659
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Abstract

Induction of Labor versus Expectant Management in Women with Preterm Prelabor Rupture of Membranes between 34 and 37 Weeks: A Randomized Controlled Trial.

van der Ham DP, Vijgen SM, Nijhuis JG, van Beek JJ, ... Willekes C, on behalf of the PPROMEXIL trial group
Background: At present, there is insufficient evidence to guide appropriate management of women with preterm prelabor rupture of membranes (PPROM) near term. Methods and findings: We conducted an open-label randomized controlled trial in 60 hospitals in The Netherlands, which included non-laboring women with >24 h of PPROM between 34(+0) and 37(+0) wk of gestation. Participants were randomly allocated in a 1∶1 ratio to induction of labor (IoL) or expectant management (EM) using block randomization. The main outcome was neonatal sepsis. Secondary outcomes included mode of delivery, respiratory distress syndrome (RDS), and chorioamnionitis. Patients and caregivers were not blinded to randomization status. We updated a prior meta-analysis on the effect of both interventions on neonatal sepsis, RDS, and cesarean section rate. From 1 January 2007 to 9 September 2009, 776 patients in 60 hospitals were eligible for the study, of which 536 patients were randomized. Four patients were excluded after randomization. We allocated 266 women (268 neonates) to IoL and 266 women (270 neonates) to EM. Neonatal sepsis occurred in seven (2.6%) newborns of women in the IoL group and in 11 (4.1%) neonates in the EM group (relative risk [RR] 0.64; 95% confidence interval [CI] 0.25 to 1.6). RDS was seen in 21 (7.8%, IoL) versus 17 neonates (6.3%, EM) (RR 1.3; 95% CI 0.67 to 2.3), and a cesarean section was performed in 36 (13%, IoL) versus 37 (14%, EM) women (RR 0.98; 95% CI 0.64 to 1.50). The risk for chorioamnionitis was reduced in the IoL group. No serious adverse events were reported. Updating an existing meta-analysis with our trial results (the only eligible trial for the update) indicated RRs of 1.06 (95% CI 0.64 to 1.76) for neonatal sepsis (eight trials, 1,230 neonates) and 1.27 (95% CI 0.98 to 1.65) for cesarean section (eight trials, 1,222 women) for IoL compared with EM. Conclusions: In women whose pregnancy is complicated by late PPROM, neither our trial nor the updated meta-analysis indicates that IoL substantially improves pregnancy outcomes compared with EM. Trial registration: Current Controlled Trials ISRCTN29313500 Please see later in the article for the Editors\' Summary.

PLoS Med: 29 Apr 2012; 9:e1001208
van der Ham DP, Vijgen SM, Nijhuis JG, van Beek JJ, ... Willekes C, on behalf of the PPROMEXIL trial group
PLoS Med: 29 Apr 2012; 9:e1001208 | PMID: 22545024
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Abstract

Clinical Benefits, Costs, and Cost-Effectiveness of Neonatal Intensive Care in Mexico.

Profit J, Lee D, Zupancic JA, Papile L, ... Gonzalez-Pier E, Salomon JA
Background: Neonatal intensive care improves survival, but is associated with high costs and disability amongst survivors. Recent health reform in Mexico launched a new subsidized insurance program, necessitating informed choices on the different interventions that might be covered by the program, including neonatal intensive care. The purpose of this study was to estimate the clinical outcomes, costs, and cost-effectiveness of neonatal intensive care in Mexico. Methods and findings: A cost-effectiveness analysis was conducted using a decision analytic model of health and economic outcomes following preterm birth. Model parameters governing health outcomes were estimated from Mexican vital registration and hospital discharge databases, supplemented with meta-analyses and systematic reviews from the published literature. Costs were estimated on the basis of data provided by the Ministry of Health in Mexico and World Health Organization price lists, supplemented with published studies from other countries as needed. The model estimated changes in clinical outcomes, life expectancy, disability-free life expectancy, lifetime costs, disability-adjusted life years (DALYs), and incremental cost-effectiveness ratios (ICERs) for neonatal intensive care compared to no intensive care. Uncertainty around the results was characterized using one-way sensitivity analyses and a multivariate probabilistic sensitivity analysis. In the base-case analysis, neonatal intensive care for infants born at 24-26, 27-29, and 30-33 weeks gestational age prolonged life expectancy by 28, 43, and 34 years and averted 9, 15, and 12 DALYs, at incremental costs per infant of US$11,400, US$9,500, and US$3,000, respectively, compared to an alternative of no intensive care. The ICERs of neonatal intensive care at 24-26, 27-29, and 30-33 weeks were US$1,200, US$650, and US$240, per DALY averted, respectively. The findings were robust to variation in parameter values over wide ranges in sensitivity analyses. Conclusions: Incremental cost-effectiveness ratios for neonatal intensive care imply very high value for money on the basis of conventional benchmarks for cost-effectiveness analysis. Please see later in the article for the Editors\' Summary.

PLoS Med: 23 Dec 2010; 7:e1000379
Profit J, Lee D, Zupancic JA, Papile L, ... Gonzalez-Pier E, Salomon JA
PLoS Med: 23 Dec 2010; 7:e1000379 | PMID: 21179496
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Abstract

Measuring Coverage in MNCH: Challenges and Opportunities in the Selection of Coverage Indicators for Global Monitoring.

Requejo JH, Newby H, Bryce J
Global monitoring of intervention coverage is a cornerstone of international efforts to improve reproductive, maternal, newborn, and child health. In this review, we examine the process and implications of selecting a core set of coverage indicators for global monitoring, using as examples the processes used by the Countdown to 2015 for Maternal, Newborn and Child Survival and the Commission on Accountability for Women\'s and Children\'s Health. We describe how the generation of data for global monitoring involves five iterative steps: development of standard indicator definitions and measurement approaches to ensure comparability across countries; collection of high-quality data at the country level; compilation of country data at the global level; organization of global databases; and rounds of data quality checking. Regular and rigorous technical review processes that involve high-level decision makers and experts familiar with indicator measurement are needed to maximize uptake and to ensure that indicators used for global monitoring are selected on the basis of available evidence of intervention effectiveness, feasibility of measurement, and data availability as well as programmatic relevance. Experience from recent initiatives illustrates the challenges of striking this balance as well as strategies for reducing the tensions inherent in the indicator selection process. We conclude that more attention and continued investment need to be directed to global monitoring, to support both the process of global database development and the selection of sets of coverage indicators to promote accountability. The stakes are high, because these indicators can drive policy and program development at the country and global level, and ultimately impact the health of women and children and the communities where they live.

PLoS Med: 12 May 2013; 10:e1001416
Requejo JH, Newby H, Bryce J
PLoS Med: 12 May 2013; 10:e1001416 | PMID: 23667336
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Abstract

Gestational age at delivery and special educational need: retrospective cohort study of 407,503 schoolchildren.

Mackay DF, Smith GC, Dobbie R, Pell JP
Background: Previous studies have demonstrated an association between preterm delivery and increased risk of special educational need (SEN). The aim of our study was to examine the risk of SEN across the full range of gestation. Methods and findings: We conducted a population-based, retrospective study by linking school census data on the 407,503 eligible school-aged children resident in 19 Scottish Local Authority areas (total population 3.8 million) to their routine birth data. SEN was recorded in 17,784 (4.9%) children; 1,565 (8.4%) of those born preterm and 16,219 (4.7%) of those born at term. The risk of SEN increased across the whole range of gestation from 40 to 24 wk: 37-39 wk adjusted odds ratio (OR) 1.16, 95% confidence interval (CI) 1.12-1.20; 33-36 wk adjusted OR 1.53, 95% CI 1.43-1.63; 28-32 wk adjusted OR 2.66, 95% CI 2.38-2.97; 24-27 wk adjusted OR 6.92, 95% CI 5.58-8.58. There was no interaction between elective versus spontaneous delivery. Overall, gestation at delivery accounted for 10% of the adjusted population attributable fraction of SEN. Because of their high frequency, early term deliveries (37-39 wk) accounted for 5.5% of cases of SEN compared with preterm deliveries (<37 wk), which accounted for only 3.6% of cases. Conclusions: Gestation at delivery had a strong, dose-dependent relationship with SEN that was apparent across the whole range of gestation. Because early term delivery is more common than preterm delivery, the former accounts for a higher percentage of SEN cases. Our findings have important implications for clinical practice in relation to the timing of elective delivery. Please see later in the article for the Editors\' Summary.

PLoS Med: 14 Jun 2010; 7:e1000289
Mackay DF, Smith GC, Dobbie R, Pell JP
PLoS Med: 14 Jun 2010; 7:e1000289 | PMID: 20543995
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Abstract

Association of Early Repolarization Pattern on ECG with Risk of Cardiac and All-Cause Mortality: A Population-Based Prospective Cohort Study (MONICA/KORA).

Sinner MF, Reinhard W, Müller M, Beckmann BM, ... Hengstenberg C, Kääb S
Background: Early repolarization pattern (ERP) on electrocardiogram was associated with idiopathic ventricular fibrillation and sudden cardiac arrest in a case-control study and with cardiovascular mortality in a Finnish community-based sample. We sought to determine ERP prevalence and its association with cardiac and all-cause mortality in a large, prospective, population-based case-cohort study (Monitoring of Cardiovascular Diseases and Conditions [MONICA]/KORA [Cooperative Health Research in the Region of Augsburg]) comprised of individuals of Central-European descent. Methods and findings: Electrocardiograms of 1,945 participants aged 35-74 y, representing a source population of 6,213 individuals, were analyzed applying a case-cohort design. Mean follow-up was 18.9 y. Cause of death was ascertained by the 9th revision of the International Classification of Disease (ICD-9) codes as documented in death certificates. ERP-attributable effects on mortality were determined by a weighted Cox proportional hazard model adjusted for covariables. Prevalence of ERP was 13.1% in our study. ERP was associated with cardiac and all-cause mortality, most pronounced in those of younger age and male sex; a clear ERP-age interaction was detected (p = 0.005). Age-stratified analyses showed hazard ratios (HRs) for cardiac mortality of 1.96 (95% confidence interval [CI] 1.05-3.68, p = 0.035) for both sexes and 2.65 (95% CI 1.21-5.83, p = 0.015) for men between 35-54 y. An inferior localization of ERP further increased ERP-attributable cardiac mortality to HRs of 3.15 (95% CI 1.58-6.28, p = 0.001) for both sexes and to 4.27 (95% CI 1.90-9.61, p<0.001) for men between 35-54 y. HRs for all-cause mortality were weaker but reached significance. Conclusions: We found a high prevalence of ERP in our population-based cohort of middle-aged individuals. ERP was associated with about a 2- to 4-fold increased risk of cardiac mortality in individuals between 35 and 54 y. An inferior localization of ERP was associated with a particularly increased risk. Please see later in the article for the Editors\' Summary.

PLoS Med: 29 Jul 2010; 7:e1000314
Sinner MF, Reinhard W, Müller M, Beckmann BM, ... Hengstenberg C, Kääb S
PLoS Med: 29 Jul 2010; 7:e1000314 | PMID: 20668657
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Abstract

Measuring Coverage in MNCH: New Findings, New Strategies, and Recommendations for Action.

Bryce J, Arnold F, Blanc A, Hancioglu A, ... Wardlaw T, CHERG Working Group on Improving Coverage Measurement
Considerable progress has been made in reducing maternal, newborn, and child mortality worldwide, but many more deaths could be prevented if effective interventions were available to all who could benefit from them. Timely, high-quality measurements of intervention coverage-the proportion of a population in need of a health intervention that actually receives it-are essential to support sound decisions about progress and investments in women\'s and children\'s health. The PLOS Medicine "Measuring Coverage in MNCH" Collection of research studies and reviews presents systematic assessments of the validity of health intervention coverage measurement based on household surveys, the primary method for estimating population-level intervention coverage in low- and middle-income countries. In this overview of the Collection, we discuss how and why some of the indicators now being used to track intervention coverage may not provide fully reliable coverage measurements, and how a better understanding of the systematic and random error inherent in these coverage indicators can help in their interpretation and use. We draw together strategies proposed across the Collection for improving coverage measurement, and recommend continued support for high-quality household surveys at national and sub-national levels, supplemented by surveys with lighter tools that can be implemented every 1-2 years and by complementary health-facility-based assessments of service quality. Finally, we stress the importance of learning more about coverage measurement to strengthen the foundation for assessing and improving the progress of maternal, newborn, and child health programs. Please see later in the article for the Editors\' Summary.

PLoS Med: 12 May 2013; 10:e1001423
Bryce J, Arnold F, Blanc A, Hancioglu A, ... Wardlaw T, CHERG Working Group on Improving Coverage Measurement
PLoS Med: 12 May 2013; 10:e1001423 | PMID: 23667340
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Abstract

Measuring Coverage in MNCH: Indicators for Global Tracking of Newborn Care.

Moran AC, Kerber K, Sitrin D, Guenther T, ... Hill Z, Lawn JE
Neonatal mortality accounts for 43% of under-five mortality. Consequently, improving newborn survival is a global priority. However, although there is increasing consensus on the packages and specific interventions that need to be scaled up to reduce neonatal mortality, there is a lack of clarity on the indicators needed to measure progress. In 2008, in an effort to improve newborn survival, the Newborn Indicators Technical Working Group (TWG) was convened by the Saving Newborn Lives program at Save the Children to provide a forum to develop the indicators and standard measurement tools that are needed to measure coverage of key newborn interventions. The TWG, which included evaluation and measurement experts, researchers, individuals from United Nations agencies and non-governmental organizations, and donors, prioritized improved consistency of measurement of postnatal care for women and newborns and of immediate care behaviors and practices for newborns. In addition, the TWG promoted increased data availability through inclusion of additional questions in nationally representative surveys, such as the United States Agency for International Development-supported Demographic and Health Surveys and the United Nations Children\'s Fund-supported Multiple Indicator Cluster Surveys. Several studies have been undertaken that have informed revisions of indicators and survey tools, and global postnatal care coverage indicators have been finalized. Consensus has been achieved on three additional indicators for care of the newborn after birth (drying, delayed bathing, and cutting the cord with a clean instrument), and on testing two further indicators (immediate skin-to-skin care and applications to the umbilical cord). Finally, important measurement gaps have been identified regarding coverage data for evidence-based interventions, such as Kangaroo Mother Care and care seeking for newborn infection.

PLoS Med: 12 May 2013; 10:e1001415
Moran AC, Kerber K, Sitrin D, Guenther T, ... Hill Z, Lawn JE
PLoS Med: 12 May 2013; 10:e1001415 | PMID: 23667335
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Abstract

Measuring Coverage in MNCH: Total Survey Error and the Interpretation of Intervention Coverage Estimates from Household Surveys.

Eisele TP, Rhoda DA, Cutts FT, Keating J, ... Barros AJ, Arnold F
Nationally representative household surveys are increasingly relied upon to measure maternal, newborn, and child health (MNCH) intervention coverage at the population level in low- and middle-income countries. Surveys are the best tool we have for this purpose and are central to national and global decision making. However, all survey point estimates have a certain level of error (total survey error) comprising sampling and non-sampling error, both of which must be considered when interpreting survey results for decision making. In this review, we discuss the importance of considering these errors when interpreting MNCH intervention coverage estimates derived from household surveys, using relevant examples from national surveys to provide context. Sampling error is usually thought of as the precision of a point estimate and is represented by 95% confidence intervals, which are measurable. Confidence intervals can inform judgments about whether estimated parameters are likely to be different from the real value of a parameter. We recommend, therefore, that confidence intervals for key coverage indicators should always be provided in survey reports. By contrast, the direction and magnitude of non-sampling error is almost always unmeasurable, and therefore unknown. Information error and bias are the most common sources of non-sampling error in household survey estimates and we recommend that they should always be carefully considered when interpreting MNCH intervention coverage based on survey data. Overall, we recommend that future research on measuring MNCH intervention coverage should focus on refining and improving survey-based coverage estimates to develop a better understanding of how results should be interpreted and used.

PLoS Med: 12 May 2013; 10:e1001386
Eisele TP, Rhoda DA, Cutts FT, Keating J, ... Barros AJ, Arnold F
PLoS Med: 12 May 2013; 10:e1001386 | PMID: 23667331
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Abstract

Measuring Coverage in MNCH: Determining and Interpreting Inequalities in Coverage of Maternal, Newborn, and Child Health Interventions.

Barros AJ, Victora CG
To monitor progress towards the Millennium Development Goals, it is essential to monitor the coverage of health interventions in subgroups of the population, because national averages can hide important inequalities. In this review, we provide a practical guide to measuring and interpreting inequalities based on surveys carried out in low- and middle-income countries, with a focus on the health of mothers and children. Relevant stratification variables include urban/rural residence, geographic region, and educational level, but breakdowns by wealth status are increasingly popular. For the latter, a classification based on an asset index is the most appropriate for national surveys. The measurement of intervention coverage can be made by single indicators, but the use of combined measures has important advantages, and we advocate two summary measures (the composite coverage index and the co-coverage indicator) for the study of time trends and for cross-country comparisons. We highlight the need for inequality measures that take the whole socioeconomic distribution into account, such as the relative concentration index and the slope index of inequality, although simpler measures such as the ratio and difference between the richest and poorest groups may also be presented for non-technical audiences. Finally, we present a framework for the analysis of time trends in inequalities, arguing that it is essential to study both absolute and relative indicators, and we provide guidance to the joint interpretation of these results.

PLoS Med: 12 May 2013; 10:e1001390
Barros AJ, Victora CG
PLoS Med: 12 May 2013; 10:e1001390 | PMID: 23667332
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Abstract

Measuring Coverage in MNCH: Challenges in Monitoring the Proportion of Young Children with Pneumonia Who Receive Antibiotic Treatment.

Campbell H, El Arifeen S, Hazir T, O\'Kelly J, ... Rudan I, Qazi SA
Pneumonia remains a major cause of child death globally, and improving antibiotic treatment rates is a key control strategy. Progress in improving the global coverage of antibiotic treatment is monitored through large household surveys such as the Demographic and Health Surveys (DHS) and the Multiple Indicator Cluster Surveys (MICS), which estimate antibiotic treatment rates of pneumonia based on two-week recall of pneumonia by caregivers. However, these survey tools identify children with reported symptoms of pneumonia, and because the prevalence of pneumonia over a two-week period in community settings is low, the majority of these children do not have true pneumonia and so do not provide an accurate denominator of pneumonia cases for monitoring antibiotic treatment rates. In this review, we show that the performance of survey tools could be improved by increasing the survey recall period or by improving either overall discriminative power or specificity. However, even at a test specificity of 95% (and a test sensitivity of 80%), the proportion of children with reported symptoms of pneumonia who truly have pneumonia is only 22% (the positive predictive value of the survey tool). Thus, although DHS and MICS survey data on rates of care seeking for children with reported symptoms of pneumonia and other childhood illnesses remain valid and important, DHS and MICS data are not able to give valid estimates of antibiotic treatment rates in children with pneumonia.

PLoS Med: 12 May 2013; 10:e1001421
Campbell H, El Arifeen S, Hazir T, O'Kelly J, ... Rudan I, Qazi SA
PLoS Med: 12 May 2013; 10:e1001421 | PMID: 23667338
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Abstract

Measuring Coverage in MNCH: Evaluation of Community-Based Treatment of Childhood Illnesses through Household Surveys.

Hazel E, Requejo J, David J, Bryce J
Community case management (CCM) is a strategy for training and supporting workers at the community level to provide treatment for the three major childhood diseases-diarrhea, fever (indicative of malaria), and pneumonia-as a complement to facility-based care. Many low- and middle-income countries are now implementing CCM and need to evaluate whether adoption of the strategy is associated with increases in treatment coverage. In this review, we assess the extent to which large-scale, national household surveys can serve as sources of baseline data for evaluating trends in community-based treatment coverage for childhood illnesses. Our examination of the questionnaires used in Demographic and Health Surveys (DHS) and Multiple Indicator Cluster Surveys (MICS) conducted between 2005 and 2010 in five sub-Saharan African countries shows that questions on care seeking that included a locally adapted option for a community-based provider were present in all the DHS surveys and in some MICS surveys. Most of the surveys also assessed whether appropriate treatments were available, but only one survey collected information on the place of treatment for all three illnesses. This absence of baseline data on treatment source in household surveys will limit efforts to evaluate the effects of the introduction of CCM strategies in the study countries. We recommend alternative analysis plans for assessing CCM programs using household survey data that depend on baseline data availability and on the timing of CCM policy implementation.

PLoS Med: 12 May 2013; 10:e1001384
Hazel E, Requejo J, David J, Bryce J
PLoS Med: 12 May 2013; 10:e1001384 | PMID: 23667329
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Abstract

Measuring Coverage in MNCH: Current Indicators for Measuring Coverage of Diarrhea Treatment Interventions and Opportunities for Improvement.

Fischer Walker CL, Fontaine O, Black RE
Diarrhea morbidity and mortality remain important child health problems in low- and middle-income countries. The treatment of diarrhea and accurate measurement of treatment coverage are critical if child mortality is going to continue to decline. In this review, we examine diarrhea treatment coverage indicators collected in two large-scale community-based household surveys-the Demographic and Health Surveys (DHS) and Multiple Indicator Cluster Surveys (MICS). Current surveys do not distinguish between children with mild diarrhea episodes and those at risk for dehydration. Additional disease severity questions may improve the identification of cases of severe diarrhea but research is needed to identify indicators with the highest sensitivity and specificity. We also review the current treatment indicators in these surveys and highlight three areas for improvement and research. First, specific questions on fluids other than oral rehydration salts (ORS) should be eliminated to refocus the treatment of dehydration on ORS and to prevent confusion between prevention and treatment of dehydration. Second, consistency across surveys and throughout translations is needed for questions about the caregiver behavior of "offering" the sick child fluid and food. Third, breastfeeding should be separated from other fluid and food questions to capture the frequency and duration of nursing sessions offered during the illness. Research is also needed to assess the accuracy of the current zinc indicator to determine if caregivers are correctly recalling zinc treatment for current and recent diarrhea episodes.

PLoS Med: 12 May 2013; 10:e1001385
Fischer Walker CL, Fontaine O, Black RE
PLoS Med: 12 May 2013; 10:e1001385 | PMID: 23667330
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Abstract

Measuring Coverage in MNCH: Design, Implementation, and Interpretation Challenges Associated with Tracking Vaccination Coverage Using Household Surveys.

Cutts FT, Izurieta HS, Rhoda DA
Vaccination coverage is an important public health indicator that is measured using administrative reports and/or surveys. The measurement of vaccination coverage in low- and middle-income countries using surveys is susceptible to numerous challenges. These challenges include selection bias and information bias, which cannot be solved by increasing the sample size, and the precision of the coverage estimate, which is determined by the survey sample size and sampling method. Selection bias can result from an inaccurate sampling frame or inappropriate field procedures and, since populations likely to be missed in a vaccination coverage survey are also likely to be missed by vaccination teams, most often inflates coverage estimates. Importantly, the large multi-purpose household surveys that are often used to measure vaccination coverage have invested substantial effort to reduce selection bias. Information bias occurs when a child\'s vaccination status is misclassified due to mistakes on his or her vaccination record, in data transcription, in the way survey questions are presented, or in the guardian\'s recall of vaccination for children without a written record. There has been substantial reliance on the guardian\'s recall in recent surveys, and, worryingly, information bias may become more likely in the future as immunization schedules become more complex and variable. Finally, some surveys assess immunity directly using serological assays. Sero-surveys are important for assessing public health risk, but currently are unable to validate coverage estimates directly. To improve vaccination coverage estimates based on surveys, we recommend that recording tools and practices should be improved and that surveys should incorporate best practices for design, implementation, and analysis.

PLoS Med: 12 May 2013; 10:e1001404
Cutts FT, Izurieta HS, Rhoda DA
PLoS Med: 12 May 2013; 10:e1001404 | PMID: 23667334
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Abstract

Reducing Plasmodium falciparum Malaria Transmission in Africa: A Model-Based Evaluation of Intervention Strategies.

Griffin JT, Hollingsworth TD, Okell LC, Churcher TS, ... Basáñez MG, Ghani AC
Background: Over the past decade malaria intervention coverage has been scaled up across Africa. However, it remains unclear what overall reduction in transmission is achievable using currently available tools. Methods and findings: We developed an individual-based simulation model for Plasmodium falciparum transmission in an African context incorporating the three major vector species (Anopheles gambiae s.s., An. arabiensis, and An. funestus) with parameters obtained by fitting to parasite prevalence data from 34 transmission settings across Africa. We incorporated the effect of the switch to artemisinin-combination therapy (ACT) and increasing coverage of long-lasting insecticide treated nets (LLINs) from the year 2000 onwards. We then explored the impact on transmission of continued roll-out of LLINs, additional rounds of indoor residual spraying (IRS), mass screening and treatment (MSAT), and a future RTS,S/AS01 vaccine in six representative settings with varying transmission intensity (as summarized by the annual entomological inoculation rate, EIR: 1 setting with low, 3 with moderate, and 2 with high EIRs), vector-species combinations, and patterns of seasonality. In all settings we considered a realistic target of 80% coverage of interventions. In the low-transmission setting (EIR approximately 3 ibppy [infectious bites per person per year]), LLINs have the potential to reduce malaria transmission to low levels (<1% parasite prevalence in all age-groups) provided usage levels are high and sustained. In two of the moderate-transmission settings (EIR approximately 43 and 81 ibppy), additional rounds of IRS with DDT coupled with MSAT could drive parasite prevalence below a 1% threshold. However, in the third (EIR = 46) with An. arabiensis prevailing, these interventions are insufficient to reach this threshold. In both high-transmission settings (EIR approximately 586 and 675 ibppy), either unrealistically high coverage levels (>90%) or novel tools and/or substantial social improvements will be required, although considerable reductions in prevalence can be achieved with existing tools and realistic coverage levels. Conclusions: Interventions using current tools can result in major reductions in P. falciparum malaria transmission and the associated disease burden in Africa. Reduction to the 1% parasite prevalence threshold is possible in low- to moderate-transmission settings when vectors are primarily endophilic (indoor-resting), provided a comprehensive and sustained intervention program is achieved through roll-out of interventions. In high-transmission settings and those in which vectors are mainly exophilic (outdoor-resting), additional new tools that target exophagic (outdoor-biting), exophilic, and partly zoophagic mosquitoes will be required. Please see later in the article for the Editors\' Summary.

PLoS Med: 16 Aug 2010; 7
Griffin JT, Hollingsworth TD, Okell LC, Churcher TS, ... Basáñez MG, Ghani AC
PLoS Med: 16 Aug 2010; 7 | PMID: 20711482
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Abstract

Measuring Coverage in MNCH: Tracking Progress in Health for Women and Children Using DHS and MICS Household Surveys.

Hancioglu A, Arnold F
Household surveys are the primary data source of coverage indicators for children and women for most developing countries. Most of this information is generated by two global household survey programmes-the USAID-supported Demographic and Health Surveys (DHS) and the UNICEF-supported Multiple Indicator Cluster Surveys (MICS). In this review, we provide an overview of these two programmes, which cover a wide range of child and maternal health topics and provide estimates of many Millennium Development Goal indicators, as well as estimates of the indicators for the Countdown to 2015 initiative and the Commission on Information and Accountability for Women\'s and Children\'s Health. MICS and DHS collaborate closely and work through interagency processes to ensure that survey tools are harmonized and comparable as far as possible, but we highlight differences between DHS and MICS in the population covered and the reference periods used to measure coverage. These differences need to be considered when comparing estimates of reproductive, maternal, newborn, and child health indicators across countries and over time and we discuss the implications of these differences for coverage measurement. Finally, we discuss the need for survey planners and consumers of survey results to understand the strengths, limitations, and constraints of coverage measurements generated through household surveys, and address some technical issues surrounding sampling and quality control. We conclude that, although much effort has been made to improve coverage measurement in household surveys, continuing efforts are needed, including further research to improve and refine survey methods and analytical techniques.

PLoS Med: 12 May 2013; 10:e1001391
Hancioglu A, Arnold F
PLoS Med: 12 May 2013; 10:e1001391 | PMID: 23667333
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Abstract

Road trauma in teenage male youth with childhood disruptive behavior disorders: a population based analysis.

Redelmeier DA, Chan WK, Lu H
Background: Teenage male drivers contribute to a large number of serious road crashes despite low rates of driving and excellent physical health. We examined the amount of road trauma involving teenage male youth that might be explained by prior disruptive behavior disorders (attention deficit hyperactivity disorder, conduct disorder, oppositional defiant disorder). Methods and findings: We conducted a population-based case-control study of consecutive male youth between age 16 and 19 years hospitalized for road trauma (cases) or appendicitis (controls) in Ontario, Canada over 7 years (April 1, 2002 through March 31, 2009). Using universal health care databases, we identified prior psychiatric diagnoses for each individual during the decade before admission. Overall, a total of 3,421 patients were admitted for road trauma (cases) and 3,812 for appendicitis (controls). A history of disruptive behavior disorders was significantly more frequent among trauma patients than controls (767 of 3,421 versus 664 of 3,812), equal to a one-third increase in the relative risk of road trauma (odds ratio  =  1.37, 95% confidence interval 1.22-1.54, p<0.001). The risk was evident over a range of settings and after adjustment for measured confounders (odds ratio 1.38, 95% confidence interval 1.21-1.56, p<0.001). The risk explained about one-in-20 crashes, was apparent years before the event, extended to those who died, and persisted among those involved as pedestrians. Conclusions: Disruptive behavior disorders explain a significant amount of road trauma in teenage male youth. Programs addressing such disorders should be considered to prevent injuries. Please see later in the article for the Editors\' Summary.

PLoS Med: 02 Dec 2010; 7:e1000369
Redelmeier DA, Chan WK, Lu H
PLoS Med: 02 Dec 2010; 7:e1000369 | PMID: 21125017
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Abstract

Colorectal cancer screening for average-risk north americans: an economic evaluation.

Heitman SJ, Hilsden RJ, Au F, Dowden S, Manns BJ
Background: Colorectal cancer (CRC) fulfills the World Health Organization criteria for mass screening, but screening uptake is low in most countries. CRC screening is resource intensive, and it is unclear if an optimal strategy exists. The objective of this study was to perform an economic evaluation of CRC screening in average risk North American individuals considering all relevant screening modalities and current CRC treatment costs. Methods and findings: An incremental cost-utility analysis using a Markov model was performed comparing guaiac-based fecal occult blood test (FOBT) or fecal immunochemical test (FIT) annually, fecal DNA every 3 years, flexible sigmoidoscopy or computed tomographic colonography every 5 years, and colonoscopy every 10 years. All strategies were also compared to a no screening natural history arm. Given that different FIT assays and collection methods have been previously tested, three distinct FIT testing strategies were considered, on the basis of studies that have reported "low," "mid," and "high" test performance characteristics for detecting adenomas and CRC. Adenoma and CRC prevalence rates were based on a recent systematic review whereas screening adherence, test performance, and CRC treatment costs were based on publicly available data. The outcome measures included lifetime costs, number of cancers, cancer-related deaths, quality-adjusted life-years gained, and incremental cost-utility ratios. Sensitivity and scenario analyses were performed. Annual FIT, assuming mid-range testing characteristics, was more effective and less costly compared to all strategies (including no screening) except FIT-high. Among the lifetimes of 100,000 average-risk patients, the number of cancers could be reduced from 4,857 to 1,782 and the number of CRC deaths from 1,393 to 457, while saving CAN$68 per person. Although screening patients with FIT became more expensive than a strategy of no screening when the test performance of FIT was reduced, or the cost of managing CRC was lowered (e.g., for jurisdictions that do not fund expensive biologic chemotherapeutic regimens), CRC screening with FIT remained economically attractive. Conclusions: CRC screening with FIT reduces the risk of CRC and CRC-related deaths, and lowers health care costs in comparison to no screening and to other existing screening strategies. Health policy decision makers should consider prioritizing funding for CRC screening using FIT. Please see later in the article for the Editors\' Summary.

PLoS Med: 02 Dec 2010; 7:e1000370
Heitman SJ, Hilsden RJ, Au F, Dowden S, Manns BJ
PLoS Med: 02 Dec 2010; 7:e1000370 | PMID: 21124887
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Immediate risk for cardiovascular events and suicide following a prostate cancer diagnosis: prospective cohort study.

Fall K, Fang F, Mucci LA, Ye W, ... Adami HO, Valdimarsdóttir U
Background: Stressful life events have been shown to be associated with altered risk of various health consequences. The aim of the present study was to investigate whether the emotional stress evoked by a prostate cancer diagnosis increases the immediate risks of cardiovascular events and suicide. Methods and findings: We conducted a prospective cohort study by following all men in Sweden who were 30 y or older (n = 4,305,358) for a diagnosis of prostate cancer (n = 168,584) and their subsequent occurrence of cardiovascular events and suicide between January 1, 1961 and December 31, 2004. We used Poisson regression models to calculate relative risks (RRs) and 95% confidence intervals (CIs) of cardiovascular events and suicide among men who had prostate cancer diagnosed within 1 y to men without any cancer diagnosis. The risks of cardiovascular events and suicide were elevated during the first year after prostate cancer diagnosis, particularly during the first week. Before 1987, the RR of fatal cardiovascular events was 11.2 (95% CI 10.4-12.1) during the first week and 1.9 (95% CI 1.9-2.0) during the first year after diagnosis. From 1987, the RR for cardiovascular events, nonfatal and fatal combined, was 2.8 (95% CI 2.5-3.2) during the first week and 1.3 (95% CI 1.3-1.3) during the first year after diagnosis. While the RR of cardiovascular events declined, the RR of suicide was stable over the entire study period: 8.4 (95% CI 1.9-22.7) during the first week and 2.6 (95% CI 2.1-3.0) during the first year after diagnosis. Men 54 y or younger at cancer diagnosis demonstrated the highest RRs of both cardiovascular events and suicide. A limitation of the present study is the lack of tumor stage data, which precluded possibilities of investigating the potential impact of the disease severity on the relationship between a recent diagnosis of prostate cancer and the risks of cardiovascular events and suicide. In addition, we cannot exclude residual confounding as a possible explanation. Conclusions: Men newly diagnosed with prostate cancer are at increased risks for cardiovascular events and suicide. Future studies with detailed disease characteristic data are warranted.

PLoS Med: 17 Dec 2009; 6:e1000197
Fall K, Fang F, Mucci LA, Ye W, ... Adami HO, Valdimarsdóttir U
PLoS Med: 17 Dec 2009; 6:e1000197 | PMID: 20016838
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Complexity in Non-Pharmacological Caregiving Activities at the End of Life: An International Qualitative Study.

Lindqvist O, Tishelman C, Hagelin CL, Clark JB, ... Rasmussen BH, on behalf of OPCARE9
Background: In late-stage palliative cancer care, relief of distress and optimized well-being become primary treatment goals. Great strides have been made in improving and researching pharmacological treatments for symptom relief; however, little systematic knowledge exists about the range of non-pharmacological caregiving activities (NPCAs) staff use in the last days of a patient\'s life. Methods and findings: Within a European Commission Seventh Framework Programme project to optimize research and clinical care in the last days of life for patients with cancer, OPCARE9, we used a free-listing technique to identify the variety of NPCAs performed in the last days of life. Palliative care staff at 16 units in nine countries listed in detail NPCAs they performed over several weeks. In total, 914 statements were analyzed in relation to (a) the character of the statement and (b) the recipient of the NPCA. A substantial portion of NPCAs addressed bodily care and contact with patients and family members, with refraining from bodily care also described as a purposeful caregiving activity. Several forms for communication were described; information and advice was at one end of a continuum, and communicating through nonverbal presence and bodily contact at the other. Rituals surrounding death and dying included not only spiritual/religious issues, but also more subtle existential, legal, and professional rituals. An unexpected and hitherto under-researched area of focus was on creating an aesthetic, safe, and pleasing environment, both at home and in institutional care settings. Conclusions: Based on these data, we argue that palliative care in the last days of life is multifaceted, with physical, psychological, social, spiritual, and existential care interwoven in caregiving activities. Providing for fundamental human needs close to death appears complex and sophisticated; it is necessary to better distinguish nuances in such caregiving to acknowledge, respect, and further develop end-of-life care. Please see later in the article for the Editors\' Summary.

PLoS Med: 19 Feb 2012; 9:e1001173
Lindqvist O, Tishelman C, Hagelin CL, Clark JB, ... Rasmussen BH, on behalf of OPCARE9
PLoS Med: 19 Feb 2012; 9:e1001173 | PMID: 22347815
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Development of a Standardized Screening Rule for Tuberculosis in People Living with HIV in Resource-Constrained Settings: Individual Participant Data Meta-analysis of Observational Studies.

Getahun H, Kittikraisak W, Heilig CM, Corbett EL, ... Date AA, Varma JK
Background: The World Health Organization recommends the screening of all people living with HIV for tuberculosis (TB) disease, followed by TB treatment, or isoniazid preventive therapy (IPT) when TB is excluded. However, the difficulty of reliably excluding TB disease has severely limited TB screening and IPT uptake in resource-limited settings. We conducted an individual participant data meta-analysis of primary studies, aiming to identify a sensitive TB screening rule. Methods and findings: We identified 12 studies that had systematically collected sputum specimens regardless of signs or symptoms, at least one mycobacterial culture, clinical symptoms, and HIV and TB disease status. Bivariate random-effects meta-analysis and the hierarchical summary relative operating characteristic curves were used to evaluate the screening performance of all combinations of variables of interest. TB disease was diagnosed in 557 (5.8%) of 9,626 people living with HIV. The primary analysis included 8,148 people living with HIV who could be evaluated on five symptoms from nine of the 12 studies. The median age was 34 years. The best performing rule was the presence of any one of: current cough (any duration), fever, night sweats, or weight loss. The overall sensitivity of this rule was 78.9% (95% confidence interval [CI] 58.3%-90.9%) and specificity was 49.6% (95% CI 29.2%-70.1%). Its sensitivity increased to 90.1% (95% CI 76.3%-96.2%) among participants selected from clinical settings and to 88.0% (95% CI 76.1%-94.4%) among those who were not previously screened for TB. Negative predictive value was 97.7% (95% CI 97.4%-98.0%) and 90.0% (95% CI 88.6%-91.3%) at 5% and 20% prevalence of TB among people living with HIV, respectively. Abnormal chest radiographic findings increased the sensitivity of the rule by 11.7% (90.6% versus 78.9%) with a reduction of specificity by 10.7% (49.6% versus 38.9%). Conclusions: Absence of all of current cough, fever, night sweats, and weight loss can identify a subset of people living with HIV who have a very low probability of having TB disease. A simplified screening rule using any one of these symptoms can be used in resource-constrained settings to identify people living with HIV in need of further diagnostic assessment for TB. Use of this algorithm should result in earlier TB diagnosis and treatment, and should allow for substantial scale-up of IPT. Please see later in the article for the Editors\' Summary.

PLoS Med: 26 Jan 2011; 8:e1000391
Getahun H, Kittikraisak W, Heilig CM, Corbett EL, ... Date AA, Varma JK
PLoS Med: 26 Jan 2011; 8:e1000391 | PMID: 21267059
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Event Rates, Hospital Utilization, and Costs Associated with Major Complications of Diabetes: A Multicountry Comparative Analysis.

Clarke PM, Glasziou P, Patel A, Chalmers J, ... Salomon JA, on behalf of the ADVANCE Collaborative Group
Background: Diabetes imposes a substantial burden globally in terms of premature mortality, morbidity, and health care costs. Estimates of economic outcomes associated with diabetes are essential inputs to policy analyses aimed at prevention and treatment of diabetes. Our objective was to estimate and compare event rates, hospital utilization, and costs associated with major diabetes-related complications in high-, middle-, and low-income countries. Methods and findings: Incidence and history of diabetes-related complications, hospital admissions, and length of stay were recorded in 11,140 patients with type 2 diabetes participating in the Action in Diabetes and Vascular Disease (ADVANCE) study (mean age at entry 66 y). The probability of hospital utilization and number of days in hospital for major events associated with coronary disease, cerebrovascular disease, congestive heart failure, peripheral vascular disease, and nephropathy were estimated for three regions (Asia, Eastern Europe, and Established Market Economies) using multiple regression analysis. The resulting estimates of days spent in hospital were multiplied by regional estimates of the costs per hospital bed-day from the World Health Organization to compute annual acute and long-term costs associated with the different types of complications. To assist, comparability, costs are reported in international dollars (Int$), which represent a hypothetical currency that allows for the same quantities of goods or services to be purchased regardless of country, standardized on purchasing power in the United States. A cost calculator accompanying this paper enables the estimation of costs for individual countries and translation of these costs into local currency units. The probability of attending a hospital following an event was highest for heart failure (93%-96% across regions) and lowest for nephropathy (15%-26%). The average numbers of days in hospital given at least one admission were greatest for stroke (17-32 d across region) and heart failure (16-31 d) and lowest for nephropathy (12-23 d). Considering regional differences, probabilities of hospitalization were lowest in Asia and highest in Established Market Economies; on the other hand, lengths of stay were highest in Asia and lowest in Established Market Economies. Overall estimated annual hospital costs for patients with none of the specified events or event histories ranged from Int$76 in Asia to Int$296 in Established Market Economies. All complications included in this analysis led to significant increases in hospital costs; coronary events, cerebrovascular events, and heart failure were the most costly, at more than Int$1,800, Int$3,000, and Int$4,000 in Asia, Eastern Europe, and Established Market Economies, respectively. Conclusions: Major complications of diabetes significantly increase hospital use and costs across various settings and are likely to impose a high economic burden on health care systems. Please see later in the article for the Editors\' Summary.

PLoS Med: 26 Feb 2010; 7:e1000236
Clarke PM, Glasziou P, Patel A, Chalmers J, ... Salomon JA, on behalf of the ADVANCE Collaborative Group
PLoS Med: 26 Feb 2010; 7:e1000236 | PMID: 20186272
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Scaling Up the 2010 World Health Organization HIV Treatment Guidelines in Resource-Limited Settings: A Model-Based Analysis.

Walensky RP, Wood R, Ciaranello AL, Paltiel AD, ... Freedberg KA, for the CEPAC-International Investigators
Background: The new 2010 World Health Organization (WHO) HIV treatment guidelines recommend earlier antiretroviral therapy (ART) initiation (CD4<350 cells/µl instead of CD4<200 cells/µl), multiple sequential ART regimens, and replacement of first-line stavudine with tenofovir. This paper considers what to do first in resource-limited settings where immediate implementation of all of the WHO recommendations is not feasible. Methods and findings: We use a mathematical model and local input data to project clinical and economic outcomes in a South African HIV-infected cohort (mean age = 32.8 y, mean CD4 = 375/µl). For the reference strategy, we assume that all patients initiate stavudine-based ART with WHO stage III/IV disease and receive one line of ART (stavudine/WHO/one-line). We rank-in survival, cost-effectiveness, and equity terms-all 12 possible combinations of the following: (1) stavudine replacement with tenofovir, (2) ART initiation (by WHO stage, CD4<200 cells/µl, or CD4<350 cells/µl), and (3) one or two regimens, or lines, of available ART. Projected life expectancy for the reference strategy is 99.0 mo. Considering each of the guideline components separately, 5-y survival is maximized with ART initiation at CD4<350 cells/µl (stavudine/<350/µl/one-line, 87% survival) compared with stavudine/WHO/two-lines (66%) and tenofovir/WHO/one-line (66%). The greatest life expectancies are achieved via the following stepwise programmatic additions: stavudine/<350/µl/one-line (124.3 mo), stavudine/<350/µl/two-lines (177.6 mo), and tenofovir/<350/µl/two-lines (193.6 mo). Three program combinations are economically efficient: stavudine/<350/µl/one-line (cost-effectiveness ratio, US$610/years of life saved [YLS]), tenofovir/<350/µl/one-line (US$1,140/YLS), and tenofovir/<350/µl/two-lines (US$2,370/YLS). Conclusions: In settings where immediate implementation of all of the new WHO treatment guidelines is not feasible, ART initiation at CD4<350 cells/µl provides the greatest short- and long-term survival advantage and is highly cost-effective. Please see later in the article for the Editors\' Summary.

PLoS Med: 06 Jan 2011; 7:e1000382
Walensky RP, Wood R, Ciaranello AL, Paltiel AD, ... Freedberg KA, for the CEPAC-International Investigators
PLoS Med: 06 Jan 2011; 7:e1000382 | PMID: 21209794
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Abstract

Monitoring Intervention Coverage in the Context of Universal Health Coverage.

Boerma T, AbouZahr C, Evans D, Evans T
Monitoring universal health coverage (UHC) focuses on information on health intervention coverage and financial protection. This paper addresses monitoring intervention coverage, related to the full spectrum of UHC, including health promotion and disease prevention, treatment, rehabilitation, and palliation. A comprehensive core set of indicators most relevant to the country situation should be monitored on a regular basis as part of health progress and systems performance assessment for all countries. UHC monitoring should be embedded in a broad results framework for the country health system, but focus on indicators related to the coverage of interventions that most directly reflect the results of UHC investments and strategies in each country. A set of tracer coverage indicators can be selected, divided into two groups-promotion/prevention, and treatment/care-as illustrated in this paper. Disaggregation of the indicators by the main equity stratifiers is critical to monitor progress in all population groups. Targets need to be set in accordance with baselines, historical rate of progress, and measurement considerations. Critical measurement gaps also exist, especially for treatment indicators, covering issues such as mental health, injuries, chronic conditions, surgical interventions, rehabilitation, and palliation. Consequently, further research and proxy indicators need to be used in the interim. Ideally, indicators should include a quality of intervention dimension. For some interventions, use of a single indicator is feasible, such as management of hypertension; but in many areas additional indicators are needed to capture quality of service provision. The monitoring of UHC has significant implications for health information systems. Major data gaps will need to be filled. At a minimum, countries will need to administer regular household health surveys with biological and clinical data collection. Countries will also need to improve the production of reliable, comprehensive, and timely health facility data. Please see later in the article for the Editors\' Summary.

PLoS Med: 21 Sep 2014; 11:e1001728
Boerma T, AbouZahr C, Evans D, Evans T
PLoS Med: 21 Sep 2014; 11:e1001728 | PMID: 25243586
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Abstract

Early emergence of ethnic differences in type 2 diabetes precursors in the UK: the Child Heart and Health Study in England (CHASE Study).

Whincup PH, Nightingale CM, Owen CG, Rudnicka AR, ... Alberti KG, Cook DG
Background: Adults of South Asian origin living in the United Kingdom have high risks of type 2 diabetes and central obesity; raised circulating insulin, triglyceride, and C-reactive protein concentrations; and low HDL-cholesterol when compared with white Europeans. Adults of African-Caribbean origin living in the UK have smaller increases in type 2 diabetes risk, raised circulating insulin and HDL-cholesterol, and low triglyceride and C-reactive protein concentrations. We examined whether corresponding ethnic differences were apparent in childhood. Methods and findings: We performed a cross-sectional survey of 4,796 children aged 9-10 y in three UK cities who had anthropometric measurements (68% response) and provided blood samples (58% response); ethnicity was based on parental definition. In age-adjusted comparisons with white Europeans (n = 1,153), South Asian children (n = 1,306) had higher glycated haemoglobin (HbA1c) (% difference: 2.1, 95% CI 1.6 to 2.7), fasting insulin (% difference 30.0, 95% CI 23.4 to 36.9), triglyceride (% difference 12.9, 95% CI 9.4 to 16.5), and C-reactive protein (% difference 43.3, 95% CI 28.6 to 59.7), and lower HDL-cholesterol (% difference -2.9, 95% CI -4.5 to -1.3). Higher adiposity levels among South Asians (based on skinfolds and bioimpedance) did not account for these patterns. Black African-Caribbean children (n = 1,215) had higher levels of HbA1c, insulin, and C-reactive protein than white Europeans, though the ethnic differences were not as marked as in South Asians. Black African-Caribbean children had higher HDL-cholesterol and lower triglyceride levels than white Europeans; adiposity markers were not increased. Conclusions: Ethnic differences in type 2 diabetes precursors, mostly following adult patterns, are apparent in UK children in the first decade. Some key determinants operate before adult life and may provide scope for early prevention.

PLoS Med: 27 Apr 2010; 7:e1000263
Whincup PH, Nightingale CM, Owen CG, Rudnicka AR, ... Alberti KG, Cook DG
PLoS Med: 27 Apr 2010; 7:e1000263 | PMID: 20421924
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Abstract

Correcting Mortality for Loss to Follow-Up: A Nomogram Applied to Antiretroviral Treatment Programmes in Sub-Saharan Africa.

Egger M, Spycher BD, Sidle J, Weigel R, ... for IeDEA East Africa, West Africa and Southern Africa
Background: The World Health Organization estimates that in sub-Saharan Africa about 4 million HIV-infected patients had started antiretroviral therapy (ART) by the end of 2008. Loss of patients to follow-up and care is an important problem for treatment programmes in this region. As mortality is high in these patients compared to patients remaining in care, ART programmes with high rates of loss to follow-up may substantially underestimate mortality of all patients starting ART. Methods and findings: We developed a nomogram to correct mortality estimates for loss to follow-up, based on the fact that mortality of all patients starting ART in a treatment programme is a weighted average of mortality among patients lost to follow-up and patients remaining in care. The nomogram gives a correction factor based on the percentage of patients lost to follow-up at a given point in time, and the estimated ratio of mortality between patients lost and not lost to follow-up. The mortality observed among patients retained in care is then multiplied by the correction factor to obtain an estimate of programme-level mortality that takes all deaths into account. A web calculator directly calculates the corrected, programme-level mortality with 95% confidence intervals (CIs). We applied the method to 11 ART programmes in sub-Saharan Africa. Patients retained in care had a mortality at 1 year of 1.4% to 12.0%; loss to follow-up ranged from 2.8% to 28.7%; and the correction factor from 1.2 to 8.0. The absolute difference between uncorrected and corrected mortality at 1 year ranged from 1.6% to 9.8%, and was above 5% in four programmes. The largest difference in mortality was in a programme with 28.7% of patients lost to follow-up at 1 year. Conclusions: The amount of bias in mortality estimates can be large in ART programmes with substantial loss to follow-up. Programmes should routinely report mortality among patients retained in care and the proportion of patients lost. A simple nomogram can then be used to estimate mortality among all patients who started ART, for a range of plausible mortality rates among patients lost to follow-up. Please see later in the article for the Editors\' Summary.

PLoS Med: 26 Jan 2011; 8:e1000390
Egger M, Spycher BD, Sidle J, Weigel R, ... for IeDEA East Africa, West Africa and Southern Africa
PLoS Med: 26 Jan 2011; 8:e1000390 | PMID: 21267057
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Abstract

Are patents impeding medical care and innovation?

Gold ER, Kaplan W, Orbinski J, Harland-Logan S, N-Marandi S
Background to the debate: Pharmaceutical and medical device manufacturers argue that the current patent system is crucial for stimulating research and development (R&D), leading to new products that improve medical care. The financial return on their investments that is afforded by patent protection, they claim, is an incentive toward innovation and reinvestment into further R&D. But this view has been challenged in recent years. Many commentators argue that patents are stifling biomedical research, for example by preventing researchers from accessing patented materials or methods they need for their studies. Patents have also been blamed for impeding medical care by raising prices of essential medicines, such as antiretroviral drugs, in poor countries. This debate examines whether and how patents are impeding health care and innovation.

PLoS Med: 06 Jan 2010; 7:e1000208
Gold ER, Kaplan W, Orbinski J, Harland-Logan S, N-Marandi S
PLoS Med: 06 Jan 2010; 7:e1000208 | PMID: 20052274
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Abstract

Effective Coverage: A Metric for Monitoring Universal Health Coverage.

Ng M, Fullman N, Dieleman JL, Flaxman AD, Murray CJ, Lim SS
A major challenge in monitoring universal health coverage (UHC) is identifying an indicator that can adequately capture the multiple components underlying the UHC initiative. Effective coverage, which unites individual and intervention characteristics into a single metric, offers a direct and flexible means to measure health system performance at different levels. We view effective coverage as a relevant and actionable metric for tracking progress towards achieving UHC. In this paper, we review the concept of effective coverage and delineate the three components of the metric - need, use, and quality - using several examples. Further, we explain how the metric can be used for monitoring interventions at both local and global levels. We also discuss the ways that current health information systems can support generating estimates of effective coverage. We conclude by recognizing some of the challenges associated with producing estimates of effective coverage. Despite these challenges, effective coverage is a powerful metric that can provide a more nuanced understanding of whether, and how well, a health system is delivering services to its populations.

PLoS Med: 21 Sep 2014; 11:e1001730
Ng M, Fullman N, Dieleman JL, Flaxman AD, Murray CJ, Lim SS
PLoS Med: 21 Sep 2014; 11:e1001730 | PMID: 25243780
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Abstract

Yellow Fever in Africa: estimating the burden of disease and impact of mass vaccination from outbreak and serological data.

Garske T, Van Kerkhove MD, Yactayo S, Ronveaux O, ... Ferguson NM, Yellow Fever Expert Committee
Yellow fever is a vector-borne disease affecting humans and non-human primates in tropical areas of Africa and South America. While eradication is not feasible due to the wildlife reservoir, large scale vaccination activities in Africa during the 1940s to 1960s reduced yellow fever incidence for several decades. However, after a period of low vaccination coverage, yellow fever has resurged in the continent. Since 2006 there has been substantial funding for large preventive mass vaccination campaigns in the most affected countries in Africa to curb the rising burden of disease and control future outbreaks. Contemporary estimates of the yellow fever disease burden are lacking, and the present study aimed to update the previous estimates on the basis of more recent yellow fever occurrence data and improved estimation methods.

PLoS Med: 06 May 2014; 11:e1001638
Garske T, Van Kerkhove MD, Yactayo S, Ronveaux O, ... Ferguson NM, Yellow Fever Expert Committee
PLoS Med: 06 May 2014; 11:e1001638 | PMID: 24800812
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Abstract

A longitudinal study of medicaid coverage for tobacco dependence treatments in massachusetts and associated decreases in hospitalizations for cardiovascular disease.

Land T, Rigotti NA, Levy DE, Paskowsky M, ... Wetherell L, Keithly L
Insurance coverage of tobacco cessation medications increases their use and reduces smoking prevalence in a population. However, uncertainty about the impact of this coverage on health care utilization and costs is a barrier to the broader adoption of this policy, especially by publicly funded state Medicaid insurance programs. Whether a publicly funded tobacco cessation benefit leads to decreased medical claims for tobacco-related diseases has not been studied. We examined the experience of Massachusetts, whose Medicaid program adopted comprehensive coverage of tobacco cessation medications in July 2006. Over 75,000 Medicaid subscribers used the benefit in the first 2.5 years. On the basis of earlier secondary survey work, it was estimated that smoking prevalence declined among subscribers by 10% during this period.

PLoS Med: 20 Dec 2010; 7:e1000375
Land T, Rigotti NA, Levy DE, Paskowsky M, ... Wetherell L, Keithly L
PLoS Med: 20 Dec 2010; 7:e1000375 | PMID: 21170313
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Abstract

World Health Organization Global Estimates and Regional Comparisons of the Burden of Foodborne Disease in 2010.

Havelaar AH, Kirk MD, Torgerson PR, Gibb HJ, ... Devleesschauwer B, World Health Organization Foodborne Disease Burden Epidemiology Reference Group
Illness and death from diseases caused by contaminated food are a constant threat to public health and a significant impediment to socio-economic development worldwide. To measure the global and regional burden of foodborne disease (FBD), the World Health Organization (WHO) established the Foodborne Disease Burden Epidemiology Reference Group (FERG), which here reports their first estimates of the incidence, mortality, and disease burden due to 31 foodborne hazards. We find that the global burden of FBD is comparable to those of the major infectious diseases, HIV/AIDS, malaria and tuberculosis. The most frequent causes of foodborne illness were diarrheal disease agents, particularly norovirus and Campylobacter spp. Diarrheal disease agents, especially non-typhoidal Salmonella enterica, were also responsible for the majority of deaths due to FBD. Other major causes of FBD deaths were Salmonella Typhi, Taenia solium and hepatitis A virus. The global burden of FBD caused by the 31 hazards in 2010 was 33 million Disability Adjusted Life Years (DALYs); children under five years old bore 40% of this burden. The 14 subregions, defined on the basis of child and adult mortality, had considerably different burdens of FBD, with the greatest falling on the subregions in Africa, followed by the subregions in South-East Asia and the Eastern Mediterranean D subregion. Some hazards, such as non-typhoidal S. enterica, were important causes of FBD in all regions of the world, whereas others, such as certain parasitic helminths, were highly localised. Thus, the burden of FBD is borne particularly by children under five years old-although they represent only 9% of the global population-and people living in low-income regions of the world. These estimates are conservative, i.e., underestimates rather than overestimates; further studies are needed to address the data gaps and limitations of the study. Nevertheless, all stakeholders can contribute to improvements in food safety throughout the food chain by incorporating these estimates into policy development at national and international levels.

PLoS Med: 02 Dec 2015; 12:e1001923
Havelaar AH, Kirk MD, Torgerson PR, Gibb HJ, ... Devleesschauwer B, World Health Organization Foodborne Disease Burden Epidemiology Reference Group
PLoS Med: 02 Dec 2015; 12:e1001923 | PMID: 26633896
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Abstract

Achieving the HIV Prevention Impact of Voluntary Medical Male Circumcision: Lessons and Challenges for Managing Programs.

Sgaier SK, Reed JB, Thomas A, Njeuhmeli E
Voluntary medical male circumcision (VMMC) is capable of reducing the risk of sexual transmission of HIV from females to males by approximately 60%. In 2007, the WHO and the Joint United Nations Programme on HIV/AIDS (UNAIDS) recommended making VMMC part of a comprehensive HIV prevention package in countries with a generalized HIV epidemic and low rates of male circumcision. Modeling studies undertaken in 2009-2011 estimated that circumcising 80% of adult males in 14 priority countries in Eastern and Southern Africa within five years, and sustaining coverage levels thereafter, could avert 3.4 million HIV infections within 15 years and save US$16.5 billion in treatment costs. In response, WHO/UNAIDS launched the Joint Strategic Action Framework for accelerating the scale-up of VMMC for HIV prevention in Southern and Eastern Africa, calling for 80% coverage of adult male circumcision by 2016. While VMMC programs have grown dramatically since inception, they appear unlikely to reach this goal. This review provides an overview of findings from the PLOS Collection "Voluntary Medical Male Circumcision for HIV Prevention: Improving Quality, Efficiency, Cost Effectiveness, and Demand for Services during an Accelerated Scale-up." The use of devices for VMMC is also explored. We propose emphasizing management solutions to help VMMC programs in the priority countries achieve the desired impact of averting the greatest possible number of HIV infections. Our recommendations include advocating for prioritization and funding of VMMC, increasing strategic targeting to achieve the goal of reducing HIV incidence, focusing on programmatic efficiency, exploring the role of new technologies, rethinking demand creation, strengthening data use for decision-making, improving governments\' program management capacity, strategizing for sustainability, and maintaining a flexible scale-up strategy informed by a strong monitoring, learning, and evaluation platform.

PLoS Med: 06 May 2014; 11:e1001641
Sgaier SK, Reed JB, Thomas A, Njeuhmeli E
PLoS Med: 06 May 2014; 11:e1001641 | PMID: 24800840
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Abstract

Effects of women\'s groups practising participatory learning and action on preventive and care-seeking behaviours to reduce neonatal mortality: A meta-analysis of cluster-randomised trials.

Seward N, Neuman M, Colbourn T, Osrin D, ... Tripathy P, Prost A
The World Health Organization recommends participatory learning and action (PLA) in women\'s groups to improve maternal and newborn health, particularly in rural settings with low access to health services. There have been calls to understand the pathways through which this community intervention may affect neonatal mortality. We examined the effect of women\'s groups on key antenatal, delivery, and postnatal behaviours in order to understand pathways to mortality reduction.

PLoS Med: 29 Nov 2017; 14:e1002467
Seward N, Neuman M, Colbourn T, Osrin D, ... Tripathy P, Prost A
PLoS Med: 29 Nov 2017; 14:e1002467 | PMID: 29206833
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Abstract

Voluntary medical male circumcision: translating research into the rapid expansion of services in kenya, 2008-2011.

Mwandi Z, Murphy A, Reed J, Chesang K, ... Knight N, Bock N
Since the World Health Organization and the Joint United Nations Programme on HIV/AIDS recommended implementation of medical male circumcision (MC) as part of HIV prevention in areas with low MC and high HIV prevalence rates in 2007, the government of Kenya has developed a strategy to circumcise 80% of uncircumcised men within five years. To facilitate the quick translation of research to practice, a national MC task force was formed in 2007, a medical MC policy was implemented in early 2008, and Nyanza Province, the region with the highest HIV burden and low rates of circumcision, was prioritized for services under the direction of a provincial voluntary medical male circumcision (VMMC) task force. The government\'s early and continuous engagement with community leaders/elders, politicians, youth, and women\'s groups has led to the rapid endorsement and acceptance of VMMC. In addition, several innovative approaches have helped to optimize VMMC scale-up. Since October 2008, the Kenyan VMMC program has circumcised approximately 290,000 men, mainly in Nyanza Province, an accomplishment made possible through a combination of governmental leadership, a documented implementation strategy, and the adoption of appropriate and innovative approaches. Kenya\'s success provides a model for others planning VMMC scale-up programs.

PLoS Med: 05 Dec 2011; 8:e1001130
Mwandi Z, Murphy A, Reed J, Chesang K, ... Knight N, Bock N
PLoS Med: 05 Dec 2011; 8:e1001130 | PMID: 22140365
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This program is still in alpha version.