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The difference method is used in mediation analysis to quantify the extent to which a mediator explains the mechanisms underlying the pathway between an exposure and an outcome. In many health science studies, the exposures are almost never measured without error, which can result in biased effect estimates. This article investigates methods for mediation analysis when a continuous exposure is mismeasured. Under a linear exposure measurement error model, we prove that the bias of indirect effect and mediation proportion can go in either direction but the mediation proportion is usually be less biased when the associations between the exposure and its error‐prone counterpart are similar with and without adjustment for the mediator. We further propose methods to adjust for exposure measurement error with continuous and binary outcomes. The proposed approaches require a main study/validation study design where in the validation study, data are available for characterizing the relationship between the true exposure and its error‐prone counterpart. The proposed approaches are then applied to the Health Professional Follow‐up Study, 1986‐2016, to investigate the impact of body mass index (BMI) as a mediator for mediating the effect of physical activity on the risk of cardiovascular diseases. Our results reveal that physical activity is significantly associated with a lower risk of cardiovascular disease incidence, and approximately half of the total effect of physical activity is mediated by BMI after accounting for exposure measurement error. Extensive simulation studies are conducted to demonstrate the validity and efficiency of the proposed approaches in finite samples. [ABSTRACT FROM AUTHOR]

Mediation analysis is widely used in biomedical research to quantify the extent to which the effect from an exposure on a health outcome is through a mediator and the extent to which the effect is direct. A traditional approach for quantifying mediation is through the difference method. The other popular approach uses a counterfactual framework from which the product method arises. However, there is little prior work to articulate which method is more efficient for estimating 2 key quantities in mediation analysis, the natural indirect effect and mediation proportion. To fill in this gap, we investigated the asymptotic relative efficiency for mediation measure estimators given by the product method and the difference method. We considered 4 data types characterized by continuous and binary mediators and outcomes. Under certain conditions, we show analytically that the product method is equally efficient to the difference method, or more efficient. However, our numerical studies demonstrate that the difference method is usually at least 90% as efficient as the product method under realistic scenarios in epidemiologic research, especially for estimating the mediation proportion. We demonstrate the efficiency results by analyzing the MaxART study (Eswatini, 2014–2017), which aimed to evaluate the effectiveness of the early access to antiretroviral therapy among human immunodeficiency virus–positive patients. [ABSTRACT FROM AUTHOR]

Background: The natural indirect effect (NIE) and mediation proportion (MP) are two measures of primary interest in mediation analysis. The standard approach for mediation analysis is through the product method, which involves a model for the outcome conditional on the mediator and exposure and another model describing the exposure-mediator relationship. The purpose of this article is to comprehensively develop and investigate the finite-sample performance of NIE and MP estimators via the product method.Methods: With four common data types with a continuous/binary outcome and a continuous/binary mediator, we propose closed-form interval estimators for NIE and MP via the theory of multivariate delta method, and evaluate its empirical performance relative to the bootstrap approach. In addition, we have observed that the rare outcome assumption is frequently invoked to approximate the NIE and MP with a binary outcome, although this approximation may lead to non-negligible bias when the outcome is common. We therefore introduce the exact expressions for NIE and MP with a binary outcome without the rare outcome assumption and compare its performance with the approximate estimators.Results: Simulation studies suggest that the proposed interval estimator provides satisfactory coverage when the sample size ≥500 for the scenarios with a continuous outcome and sample size ≥20,000 and number of cases ≥500 for the scenarios with a binary outcome. In the binary outcome scenarios, the approximate estimators based on the rare outcome assumption worked well when outcome prevalence less than 5% but could lead to substantial bias when the outcome is common; in contrast, the exact estimators always perform well under all outcome prevalences considered.Conclusions: Under samples sizes commonly encountered in epidemiology and public health research, the proposed interval estimator is valid for constructing confidence interval. For a binary outcome, the exact estimator without the rare outcome assumption is more robust and stable to estimate NIE and MP. An R package mediateP is developed to implement the methods for point and variance estimation discussed in this paper. [ABSTRACT FROM AUTHOR]

Introduction: The WHO recommends antiretroviral treatment (ART) for all HIV‐positive patients regardless of CD4 count or disease stage, referred to as "Early Access to ART for All" (EAAA). The health systems effects of EAAA implementation are unknown. This trial was implemented in a government‐managed public health system with the aim to examine the "real world" impact of EAAA on care retention and viral suppression. Methods: In this stepped‐wedge randomized controlled trial, 14 public sector health facilities in Eswatini were paired and randomly assigned to stepwise transition from standard of care (SoC) to EAAA. ART‐naïve participants ≥18 years who were not pregnant or breastfeeding were eligible for enrolment. We used Cox proportional hazard models with censoring at clinic transition to estimate the effects of EAAA on retention in care and retention and viral suppression combined. Results: Between September 2014 and August 2017, 3405 participants were enrolled. In SoC and EAAA respectively, 12‐month HIV care retention rates were 80% (95% CI: 77 to 83) and 86% (95% CI: 83 to 88). The 12‐month combined retention and viral suppression endpoint rates were 44% (95% CI: 40 to 48) under SoC compared to 80% (95% CI: 77 to 83) under EAAA. EAAA increased both retention (HR: 1·60, 95% CI: 1·15 to 2·21, p = 0.005) and retention and viral suppression combined (HR: 4.88, 95% CI: 2.96 to 8.05, p < 0.001). We also identified significant gaps in current health systems ability to provide viral load (VL) monitoring with 80% participants in SoC and 66% in EAAA having a missing VL at last contact. Conclusions: The observed improvement in retention in care and on the combined retention and viral suppression provides an important co‐benefit of EAAA to HIV‐positive adults themselves, at least in the short term. Our results from this "real world" health systems trial strongly support EAAA for Eswatini and countries with similar HIV epidemics and health systems. VL monitoring needs to be scaled up for appropriate care management. [ABSTRACT FROM AUTHOR]

Background: In the context of task shifting, a promoted approach to healthcare delivery in resource-poor settings, trained community health workers (CHWs) have been shown to be effective in delivering quality care of malaria for febrile under-5 children. While their effectiveness has been documented, the fidelity of implementation (FOI) has not been adequately studied. By understanding and measuring whether an intervention has been performed with fidelity, researchers and practitioners gain a better understanding of how and why an intervention works, and the extent to which outcomes can be improved. The objective of this study was to assess the FOI of a recommended protocol for malaria care by CHWs in a resource-poor setting in Nigeria.Methods: Thirty-five female CHWs who participated in a 3-day training on home management of malaria among under-5 children were studied. They managed 1,646 children over the implementation period and then underwent evaluation via a one-time hospital-based observation by the trainers. During the evaluation, a pre-tested standard checklist was used to compute performance scores for CHWs; doctors and nurses were selected to serve as the gold standard for comparison. Performance scores (PS) recorded during the evaluation were used to assess adherence and compliance with the recommended treatment protocol.Results: Of the 4 skill domains assessed, adherence was greatest for compliance with malaria treatment recommendations (94%) and lowest for post-treatment initiation counseling of home-based caregivers (69%). The average overall adherence of 83% was comparable to adherence by gold standard comparators. Mean PS was not found to be significantly associated with CHW demographics. Scores for clinical evaluation among those whose occupation was not healthcare-related were significantly lowered by 0.52 [95% CI (1.05-0.01), p = 0.05]. Compliance with the treatment protocol increased by 23% for every unit increase in total PS (p = 0.07) and doubled for every unit increase in scores for post-treatment initiation counseling of caregivers (p = 0.002).Conclusions: Studying intervention fidelity stands to identify the shortcomings of implementation and specific areas to target for improvement in future adoption or implementation. This study concludes that future trainings should emphasize clinical evaluation and post-treatment counseling of caregivers by CHWs to ensure the best outcome for children. [ABSTRACT FROM AUTHOR]

Background: Four of the largest HIV prevention trials have been conducted in sub-Saharan Africa, enrolling hundreds of thousands of participants in catchment areas of millions of people. The trials have focused on community-level interventions to increase diagnosis and initiation of antiretroviral therapy (ART) to improve health and reduce HIV transmission. Universal test-and-treat strategies are deployed to achieve viral suppression thereby reducing risk to uninfected persons, known as treatment as prevention (TasP). Purpose: We review the work that found HIV plasma load to correlate with transmission risk, demonstrated that ART could reduce genital tract viral expression, and showed early treatment to be beneficial for persons living with HIV, and that HIV-uninfected sexual partners were protected from infection. We review the seemingly inconsistent findings of the major TasP trials: the TasP [National Agency for AIDS Research (ANRS) 12249] study in South Africa, the SEARCH trial in Kenya and Uganda, the Botswana Combination Prevention Project Ya Tsie study, and the HIV Prevention Trials Network 071 (PopART) trial in Zambia and South Africa. Findings: All the trials reinforce the critical need to identify approaches to optimize programs and incentivize uptake and engagement in HIV testing and ART-based care in ways that consistently reduce HIV transmission. That other chronic conditions can be screened for and treated in the same infrastructures suggests added value of HIV investments. Conclusions: Implementation challenges are a principal frontier in the global struggle to reduce HIV transmission and mortality using TasP, complementing efforts to find a cure for HIV and an effective, deployable vaccine. [ABSTRACT FROM AUTHOR]

We provide an overview of classical and newer methods for the control of confounding of time-invariant interventions to permit causal inference in public health evaluations. We estimated the causal effect of gender on all-cause mortality in a large HIV care and treatment program supported by the President's Emergency Program for AIDS Relief in Dar es Salaam, Tanzania, between 2004 and 2012. We compared results from multivariable modeling, three propensity score methods, inverse-probability weighting, doubly robust methods, and targeted maximum likelihood estimation. Considerable confounding was evident, and, as expected by theory, all methods considered gave the same result, a statistically significant approximately 20% increased mortality rate in men. In general, there is no clear advantage of any of these methods for causal inference over classical multivariable modeling, from the point of view of either bias reduction or efficiency. Rather, given sufficient data to adequately fit the multivariable model to the data, multivariable modeling will yield causal estimates with the greatest statistical efficiency. All methods can adjust only for well-measured confounders--if there are unmeasured or poorly measured confounders, none of these methods will yield causal estimates. [ABSTRACT FROM AUTHOR]

We evaluated the performance of a semiquantitative food frequency questionnaire (SFFQ), the Automated Self-Administered 24-Hour Dietary Recall (ASA24), and 7-day dietary records (7DDRs), in comparison with biomarkers, in the estimation of nutrient intakes among 627 women in the Women's Lifestyle Validation Study (United States, 2010-2012). Two paper SFFQs, 1 Web-based SFFQ, 4 ASA24s (beta version), 2 7DDRs, 4 24-hour urine samples, 1 doubly labeled water measurement (repeated among 76 participants), and 2 fasting blood samples were collected over a 15-month period. The dietary variables evaluated were energy, energy-adjusted intakes of protein, sodium, potassium, and specific fatty acids, carotenoids, a-tocopherol, retinol, and folate. In general, relative to biomarkers, averaged ASA24s had lower validity than the SFFQ completed at the end of the data-collection year (SFFQ2); SFFQ2 had slightly lower validity than 1 7DDR; the averaged SFFQs had validity similar to that of 1 7DDR; and the averaged 7DDRs had the highest validity. The deattenuated correlation of energy-adjusted protein intake assessed by SFFQ2 with its biomarker was 0.46, similar to its correlation with 7DDRs (deattenuated r = 0.54). These data indicate that the SFFQ2 provides reasonably valid measurements of energy-adjusted intake for most of the nutrients assessed in our study, consistent with earlier conclusions derived using 7DDRs as the comparison method. The ASA24 needs further evaluation for use in large population studies, but an average of 3 days of measurement will not be sufficient for some important nutrients. [ABSTRACT FROM AUTHOR]

We define measures of effect used in public health evaluations, which include the risk difference and the risk ratio, the population-attributable risk, years of life lost or gained, disability-adjusted life years, quality-adjusted life years, and the incremental costeffectiveness ratio. Except for the risk ratio, all of these are absolute effect measures. For constructing externally generalizable absolute measures of effect when there is superior fit of the multiplicative model, we suggest using the multiplicative model to estimate relative risks, which will often be obtained in simple linear formwith no interactions, and then converting these to the desired absolute measure. The externally generalizable absolute measure of effect can be obtained by suitably standardizing to the risk factor distribution of the population to which the results are to be generalized. External generalizability will often be compromised when absolutemeasures are computed from study populations with risk factor distributions different from those of the population to whom the results are to be generalized, even when these risk factors are not confounders of the intervention effect. [ABSTRACT FROM AUTHOR]

Objective To evaluate the service readiness of health facilities in Bangladesh, Haiti, Kenya, Malawi, Namibia, Nepal, Rwanda, Senegal, Uganda and the United Republic of Tanzania. Methods Using existing data from service provision assessments of the health systems of the 10 study countries, we calculated a service readiness index for each of 8443 health facilities. This index represents the percentage availability of 50 items that the World Health Organization considers essential for providing health care. For our analysis we used 37-49 of the items on the list. We used linear regression to assess the independent explanatory power of four national and four facility-level characteristics on reported service readiness. Findings The mean values for the service readiness index were 77% for the 636 hospitals and 52% for the 7807 health centres/clinics. Deficiencies in medications and diagnostic capacity were particularly common. The readiness index varied more between hospitals and health centres/clinics in the same country than between them. There was weak correlation between national factors related to health financing and the readiness index. Conclusion Most health facilities in our study countries were insufficiently equipped to provide basic clinical care. If countries are to bolster health-system capacity towards achieving universal coverage, more attention needs to be given to within-country inequities. [ABSTRACT FROM AUTHOR]

We provide an overview of the relative merits of ratio measures (relative risks, risk ratios, and rate ratios) compared with difference measures (risk and rate differences). We discuss evidence that the multiplicative model often fits the data well, so that rarely are interactions with other risk factors for the outcome observed when one uses a logistic, relative risk, or Cox regression model to estimate the intervention effect. As a consequence, additive models, which estimate the risk or rate difference, will often exhibit interactions. Under these circumstances, absolute measures of effect, such as years of life lost, disability- or quality-adjusted years of life lost, and number needed to treat, will not be externally generalizable to populations other than those with similar risk factor distributions as the population in which the intervention effect was estimated. Nevertheless, these absolute measures are often of the greatest importance in public health decision-making. When studies of high-risk study populations are used to more efficiently estimate effects, these populations will not be representative of the general population's risk factor distribution. The relative homogeneity of ratio versus absolute measures will thus have important implications for the generalizability of results across populations. [ABSTRACT FROM AUTHOR]

The authors evaluated the validity of a 152-item semiquantitative food frequency questionnaire (SFFQ) by comparing it with two 7-day dietary records (7DDRs) or up to 4 automated self-administered 24-hour recalls (ASA24s) over a 1-year period in the women's Lifestyle Validation Study (2010-2012), conducted among subgroups of the Nurses' Health Studies. Intakes of energy and 44 nutrients were assessed using the 3 methods among 632 US women. Compared with the 7DDRs, SFFQ responses tended to underestimate sodium intake but overestimate intakes of energy, macronutrients, and several nutrients in fruits and vegetables, such as carotenoids. Spearman correlation coefficients between energy-adjusted intakes from 7DDRs and the SFFQ completed at the end of the data-collection period ranged from 0.36 for lauric acid to 0.77 for alcohol (mean r = 0.53). Correlations of the end-period SFFQ were weaker when ASA24s were used as the comparison method (mean r = 0.43). After adjustment for within-person variation in the comparison method, the correlations of the final SFFQ were similar with 7DDRs (mean r = 0.63) and ASA24s (mean r = 0.62). These data indicate that this SFFQ provided reasonably valid estimates for intakes of a wide variety of dietary variables and that use of multiple 24-hour recalls or 7DDRs as a comparison method provided similar conclusions if day-to-day variation was taken into account. [ABSTRACT FROM AUTHOR]

Counterfactual frameworks and statistical methods for supporting causal inference are powerful tools to clarify scientific questions and guide analyses in public health research. Counterfactual accounts of causation contrast what would happen to a population’s health under alternative exposure scenarios. A long-standing debate in counterfactual theory relates to whether sex, race, and biological characteristics, including obesity, should be evaluated as causes, given that these variables do not directly correspond to clearly defined interventions. We argue that sex, race, and biological characteristics are important health determinants. Quantifying the overall health effects of these variables is often a natural starting point for disparities research. Subsequent assessments of biological or social pathways mediating those effects can facilitate the development of interventions designed to reduce disparities. [ABSTRACT FROM AUTHOR]

We examined the proportions of multiple types of breast cancers in the population that were attributable to established risk factors, focusing on behaviors that are modifiable at menopause. We estimated the full and partial population attributable risk percentages (PAR%) by combining the relative risks and the observed prevalence rates of the risk factors of interest. A total of 8,421 cases of invasive breast cancer developed in postmenopausal women (n = 121,700) in the Nurses' Health Study from 1980-2010. We included the following modifiable risk factors in our analyses: weight change since age 18 years, alcohol consumption, physical activity level, breastfeeding, and menopausal hormone therapy use. Additionally, the following nonmodifiable factors were included: age, age at menarche, height, a combination of parity and age at first birth, body mass index at age 18 years, family history of breast cancer, and prior benign breast disease. When we considered all risk factors (and controlled for age), the PAR% for invasive breast cancers was 70.0% (95% confidence interval: 55.0, 80.7). When considering only modifiable factors, we found that changing the risk factor profile to the lowest weight gain, no alcohol consumption, high physical activity level, breastfeeding, and no menopausal hormone therapy use was associated with a PAR% of 34.6% (95% confidence interval: 22.7, 45.4). The PAR% for modifiable factors was higher for estrogen receptor-positive breast cancers (PAR% = 39.7%) than for estrogen receptor-negative breast cancers (PAR% = 27.9%). Risk factors that are modifiable at menopause account for more than one-third of postmenopausal breast cancers; therefore, a substantial proportion of breast cancer in the United States is preventable. [ABSTRACT FROM AUTHOR]

The article discusses the 40th anniversary of the Nurses' Health Study (NHS) as of 2016 in relation to the author's views about public health interventions and methods for eliminating bias that is attributable to measurement error and misclassification. Controversies involving longitudinal cohort studies that use food frequency questionnaires to assess dietary intake over time are examined, along with various American epidemiological research methodologies.

In public health evaluations, confounding bias in the estimate of the intervention effect will typically threaten the validity of the findings. It is a common misperception that the only way to avoid this bias is to measure detailed, high-quality data on potential confounders for every intervention participant, but this strategy for adjusting for confounding bias is often infeasible. Rather than ignoring confounding altogether, the twophase design and analysis--in which detailed high-quality confounding data are obtained among a small subsample--can be considered. We describe the two-stage design and analysis approach, and illustrate its use in the evaluation of an intervention conducted in Dar es Salaam, Tanzania, of an enhanced community health worker program to improve antenatal care uptake. [ABSTRACT FROM AUTHOR]

In a stepped wedge design (SWD), an intervention is rolled out in a staggered manner over time, in groups of experimental units, so that by the end, all units experience the intervention. For example, in the MaxART study, the date at which to offer universal antiretroviral therapy to otherwise ineligible clients is being randomly assigned in nine "steps" of four months duration so that after three years, all 14 facilities in northern and central Swaziland will be offering early treatment. In the common alternative, the cluster randomized trial (CRT), experimental units are randomly allocated on a single common start date to the interventions to be compared. Often, the SWD is more feasible than the CRT, both for practical and ethical reasons, but takes longer to complete. The SWD permits both within- and between- unit comparisons, while the CRT only allows between-unit comparisons. Thus, confounding bias with respect to time-invariant factors tends to be lower in an SWD than a CRT, but the SWD cannot as readily control for confounding by time-varying factors. SWDs have generally more statistical power than CRTs, especially as the intraunit correlation and the number of participants within unit increases. Software for both designs are available, although for a more limited set of SWD scenarios. [ABSTRACT FROM AUTHOR]

A fundamental goal of epidemiologic research is to investigate the relationship between exposures and disease risk. Cases of the disease are often considered a single outcome and assumed to share a common etiology. However, evidence indicates that many human diseases arise and evolve through a range of heterogeneous molecular pathologic processes, influenced by diverse exposures. Pathogenic heterogeneity has been considered in various neoplasms such as colorectal, lung, prostate, and breast cancers, leukemia and lymphoma, and non-neoplastic diseases, including obesity, type II diabetes, glaucoma, stroke, cardiovascular disease, autism, and autoimmune disease. In this article, we discuss analytic options for studying disease subtype heterogeneity, emphasizing methods for evaluating whether the association of a potential risk factor with disease varies by disease subtype. Methods are described for scenarios where disease subtypes are categorical and ordinal and for cohort studies, matched and unmatched case-control studies, and case-case study designs. For illustration, we apply the methods to a molecular pathological epidemiology study of alcohol intake and colon cancer risk by tumor LINE-1 methylation subtypes. User-friendly software to implement the methods is publicly available. [ABSTRACT FROM AUTHOR]

In the first contribution to a new section in AJPH that will address critical methodological issues in evaluations of public health interventions, I will discuss topics in study design and analysis, covering the most innovative emerging methodologies and providing an overview of best practices. The methods considered are motivated by public health evaluations, both domestic and global. In this first contribution, I also define implementation science, program evaluation, impact evaluation, and cost-effectiveness research, disciplines that have tremendous methodological and substantive overlap with evaluation of public health interventions-- the focus of this section. [ABSTRACT FROM AUTHOR]

Background Intakes of magnesium, potassium, and calcium have been inversely associated with the incidence of hypertension, a known risk factor for stroke. However, only a few studies have examined intakes of these cations in relation to risk of stroke. Aim The aim of this study was to investigate whether high intake of magnesium, potassium, and calcium is associated with reduced stroke risk among men. Methods We prospectively examined the associations between intakes of magnesium, potassium, and calcium from diet and supplements, and the risk of incident stroke among 42 669 men in the Health Professionals Follow-up Study, aged 40 to 75 years and free of diagnosed cardiovascular disease and cancer at baseline in 1986. We calculated the hazard ratio of total, ischemic, and haemorrhagic strokes by quintiles of each cation intake, and of a combined dietary score of all three cations, using multivariate Cox proportional hazard models. Results During 24 years of follow-up, 1547 total stroke events were documented. In multivariate analyses, the relative risks and 95% confidence intervals of total stroke for men in the highest vs. lowest quintile were 0·87 (95% confidence interval, 0·74-1·02; P, trend = 0·04) for dietary magnesium, 0·89 (95% confidence interval, 0·76-1·05; P, trend = 0·10) for dietary potassium, and 0·89 (95% confidence interval, 0·75-1·04; P, trend = 0·25) for dietary calcium intake. The relative risk of total stroke for men in the highest vs. lowest quintile was 0·74 (95% confidence interval, 0·59-0·93; P, trend = 0·003) for supplemental magnesium, 0·66 (95% confidence interval, 0·50-0·86; P, trend = 0·002) for supplemental potassium, and 1·01 (95% confidence interval, 0·84-1·20; P, trend = 0·83) for supplemental calcium intake. For total intake (dietary and supplemental), the relative risk of total stroke for men in the highest vs. lowest quintile was 0·83 (95% confidence interval, 0·70-0·99; P, trend = 0·04) for magnesium, 0·88 (95% confidence interval, 0·75-4; P, trend = 6) for potassium, and 3 (95% confidence interval, 79-09; P, trend = 84) for calcium. Men in the highest quintile for a combined dietary score of all three cations had a multivariate relative risk of 0·79 (95% confidence interval, 0·67-0·92; P, trend = 0·008) for total stroke, compared with those in the lowest. Conclusions A diet rich in magnesium, potassium, and calcium may contribute to reduced risk of stroke among men. Because of significant collinearity, the independent contribution of each cation is difficult to define. [ABSTRACT FROM AUTHOR]

Objectives were to examine the growth patterns of preterm and growth‐restricted infants and to evaluate the associations of prematurity and intrauterine growth restriction (IUGR) with risk of stunting, wasting and underweight. Data from a cohort of HIV‐negative pregnant women–infant pairs were collected prospectively in Tanzania. Small for gestational age [SGA, birthweight (BW) <10th percentile] was used as proxy for IUGR. Anthropometry was measured monthly until 18 months. Length‐for‐age (LAZ), weight‐for‐length (WLZ), and weight‐for‐age (WAZ) z‐scores were calculated using the 2006 World Health Organization (WHO) Child Growth Standards. Stunting, wasting and underweight were defined as binary outcomes using a cut‐off of <−2 SD of the respective z‐scores. Multivariate Cox proportional hazard models were used to assess the associations between preterm and SGA to time to stunting, wasting and underweight. The study included 6664 singletons. Preterm and appropriate for gestational age (AGA) infants had slightly better nutritional status than term‐SGA infants and despite some catch‐up growth, preterm‐SGA infants had the poorest nutritional status. The gap in LAZ and WAZ z‐scores among the groups remained similar throughout the follow‐up. Compared with term‐AGA babies, relative risk (RR) of stunting among preterm‐AGA babies was 2.13 (95% confidence interval (CI) 1.93–2.36), RR among term‐SGA was 2.21 (95% CI 2.02–2.41) and the highest risk was among the babies who were both preterm and SGA (RR = 7.58, 95% CI 5.41–10.64). Similar magnitude of RR of underweight was observed among the three groups. Preterm and SGA infants should be closely monitored for growth failure. Intervention to reduce preterm and SGA birth may lower risk of undernutrition in resource‐limited settings. [ABSTRACT FROM AUTHOR]

Background: The International Agency for Research on Cancer (IARC) recently declared air pollution carcinogenic to humans. However, no study of air pollution and lung cancer to date has incorporated adjustment for exposure measurement error, and few have examined specific histological subtypes. Objectives: Our aim was to assess the association of air pollution and incident lung cancer in the Netherlands Cohort Study on Diet and Cancer and the impact of measurement error on these associations. Methods: The cohort was followed from 1986 through 2003, and 3,355 incident cases were identified. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals, for long-term exposures to nitrogen dioxide (NO2), black smoke (BS), PM2.5 (particulate matter with diameter ≤ 2.5 μm), and measures of roadway proximity and traffic volume, adjusted for potential confounders. Information from a previous validation study was used to correct the effect estimates for measurement error. Results: We observed elevated risks of incident lung cancer with exposure to BS [hazard ratio (HR) = 1.16; 95% CI: 1.02, 1.32, per 10 μg/m3], NO2 (HR = 1.29; 95% CI: 1.08, 1.54, per 30 μg/m3), PM2.5 (HR = 1.17; 95% CI: 0.93, 1.47, per 10 μg/m3), and with measures of traffic at the baseline address. The exposures were positively associated with all lung cancer subtypes. After adjustment for measurement error, the HRs increased and the 95% CIs widened [HR = 1.19 (95% CI: 1.02, 1.39) for BS and HR = 1.37 (95% CI: 0.86, 2.17) for PM2.5]. Conclusions: These findings add support to a growing body of literature on the effects of air pollution on lung cancer. In addition, they highlight variation in measurement error by pollutant and support the implementation of measurement error corrections when possible. [ABSTRACT FROM AUTHOR]

Background: Few studies have described time-based trends of clinical and demographic characteristics of children enrolling in HIV and AIDS care and treatment services. We present findings of a study that explored time-based trends of baseline characteristics among children enrolling into 26 public HIV care facilities in Dar es Salaam, Tanzania. Methods: Children enrolled between October 2004 and September 2011 was included in these analyses. The year of enrollment was used as the primary predictor of interest, and log linear and linear regressions model were used to analyze dichotomous and continuous variables respectively. P-values under 0.05 were considered significant. Results: Among the 6,579 children enrolled, the proportion with advanced disease at enrollment increased from 35% to 58%, mean age increasing from 5.0 to 6.2 years (p < 0.0001), proportion of children less than 2 years decreased from 35% to 29%. While the median hemoglobin concentration rose from 9.1 g/dl to 10.3 g/dl (P <0.0001), proportion with a history of past TB dropped from 25% to 12.8% (P < 0.0001). Over time, health centers and dispensaries enrolled more children as compared to hospitals (P < 0.0001). Temeke district, which has the lowest socioeconomic status among the three districts in Dar es Salaam, had a significant increase in enrollment from 22% to 25% (P = 0.02). Conclusion: We found that as time progressed, children were enrolled in care and treatment services at an older age sicker status as evidenced by increase in mean age and more advanced disease stage at first contact with providers. We recommend more efforts be focused on scaling up early HIV infant diagnosis and enrollment to HIV care and treatment. [ABSTRACT FROM AUTHOR]

HIV and malaria infections occur in the same individuals, particularly in sub-Saharan Africa. We examined whether daily multivitamin supplementation (vitamins B complex, C, and E) or vitamin A supplementation altered malaria incidence in HIV-infected women of reproductive age.HIV-infected pregnant Tanzanian women recruited into the study were randomly assigned to daily multivitamins (B complex, C, and E), vitamin A alone, both multivitamins and vitamin A, or placebo. Women received malaria prophylaxis during pregnancy and were followed monthly during the prenatal and postpartum periods. Malaria was defined in 2 ways: presumptive diagnosis based on a physician's or nurse's clinical judgment, which in many cases led to laboratory investigations, and periodic examination of blood smears for malaria parasites.Multivitamin supplementation compared with no multivitamins significantly lowered women's risk of presumptively diagnosed clinical malaria (relative risk: 0.78, 95% confidence interval: 0.67 to 0.92), although multivitamins increased their risk of any malaria parasitemia (relative risk: 1.24, 95% confidence interval: 1.02 to 1.50). Vitamin A supplementation did not change malaria incidence during the study.Multivitamin supplements have been previously shown to reduce HIV disease progression among HIV-infected women, and consistent with that, these supplements protected against development of symptomatic malaria. The clinical significance of increased risk of malaria parasitemia among supplemented women deserves further research, however. Preventive measures for malaria are warranted as part of an integrated approach to the care of HIV-infected individuals exposed to malaria. [ABSTRACT FROM AUTHOR]

We assembled a prospective cohort of 3144 human immunodeficiency virus (HIV) infected children aged <15 years initiating antiretroviral therapy (ART) in Dar es Salaam, Tanzania. The prospective relationships of baseline covariates with growth were examined using linear regression models. ART led to improvement in mean weight-for-age (WAZ), height/length-for-age (HAZ) and weight-for-length or body mass index (WLZ/BMIZ) scores. However, normal HAZ values were not attained over an average follow-up of 17.2 months. After 6 months of ART, underweight (P < 0.001), low CD4 count or percent (P < 0.001), stavudine containing regimens (P = 0.05) and advanced WHO disease stage (P < 0.001) at ART initiation were associated with better WAZ scores. Age >5 years on the other hand was associated with less increase in WAZ score after 6 months of ART (P < 0.001). These findings suggest that although ART improved the growth of the HIV-infected children in Tanzania, adjunct nutritional interventions may be needed to ensure that the growth of these children is optimized to the greatest extent possible. [ABSTRACT FROM PUBLISHER]

Background: Improving the carbohydrate quality of the diet by replacing the common cereal staple white rice (WR) with brown rice (BR) could have beneficial effects on reducing the risk for diabetes and related complications. Hence we aimed to compare the effects of BR, WR, and BR with legumes (BRL) diets on 24-h glycemic and insulinemic responses among overweight Asian Indians. Subjects and Methods: Fifteen overweight (body mass index, ≥23 kg/m2) Asian Indians without diabetes who were 25-45 years old participated in a randomized crossover study. Test meals (nonisocaloric, ad libitum) were identical except for the type of rice and the addition of legumes (50 g/day) and were provided for 5 consecutive days. Glucose profiles were assessed using the Medtronic MiniMed (Northridge, CA) iPro™2 continuous glucose monitoring device. The mean positive change from baseline glucose concentration was calculated as the daily incremental area under the curve (IAUC) on each test day for 5 days and averaged. Fasting serum insulin was measured prior to and at the end of each test diet. Results: The percentage difference in 5-day average IAUC was 19.8% lower in the BR group than in the WR group ( P=0.004). BRL further decreased the glycemic response (22.9% lower compared with WR ( P=0.02). The 5-day percentage change in fasting insulin was 57% lower ( P=0.0001) for the BR group and 54% lower for the BRL group compared with the 5-day percentage change observed in the WR group. The glycemic and insulinemic responses to the BR and BRL diets were not significantly different. Conclusions: Consumption of BR in place of WR can help reduce 24-h glucose and fasting insulin responses among overweight Asian Indians. [ABSTRACT FROM AUTHOR]

Background: Pulmonary tuberculosis and anemia are both prevalent in Tanzania. There is limited and inconsistent literature on the association between anemia and sputum conversion following tuberculosis treatment. Methods: Newly diagnosed sputum smear positive pulmonary tuberculosis patients aged ≥15 years initiating on standard anti tuberculosis therapy were recruited from 14 of 54 tuberculosis clinics in Dar es Salaam. Patients were receiving medication according to the recommended short course Directly Observed Therapy (DOT) strategy and were followed up prospectively until completion of treatment (six months). Patients were evaluated before initiation of TB treatment by performing the following; clinical history, physical examination, complete blood counts, serum biochemistry and sputum microscopy. Sputum smears were re-examined at two months of anti-tuberculosis therapy for presence of acid fast bacilli. Anemia was defined as hemoglobin <13 g/dl (males) or <12 g/dl (females). Log-binomial regression was used to assess the association between anemia and sputum conversion at two months. Results: Of the 1245 patients included in the study, 86% were anemic and 7% were sputum smear positive at two months of anti-tuberculosis therapy. Anemic patients were three times more likely to have sputum positive smear as compared to non-anemic patients at two months (RR = 3.05; 95% CI 1.11–8.40) p = 0.03. The risk for sputum positive smear results increased with severity of anemia (P for trend <0.01). Conclusion: Baseline anemia is associated with increased risk for persistent positive sputum smears at two months of tuberculosis treatment. Future studies should evaluate the mechanisms for TB-associated anemia as well as the role of intervention for anemia among TB patients. [ABSTRACT FROM AUTHOR]

Background Exposure measurement error is a concern in long-term PM2.5 health studies using ambient concentrations as exposures. We assessed error magnitude by estimating calibration coefficients as the association between personal PM2.5 exposures from validation studies and typically available surrogate exposures. Methods Daily personal and ambient PM2.5, and when available sulfate, measurements were compiled from nine cities, over 2 to 12 days. True exposure was defined as personal exposure to PM2.5 of ambient origin. Since PM2.5 of ambient origin could only be determined for five cities, personal exposure to total PM2.5 was also considered. Surrogate exposures were estimated as ambient PM2.5 at the nearest monitor or predicted outside subjects' homes. We estimated calibration coefficients by regressing true on surrogate exposures in random effects models. Results When monthly-averaged personal PM2.5 of ambient origin was used as the true exposure, calibration coefficients equaled 0.31 (95%CI:0.14, 0.47) for nearest monitor and 0.54 (95%CI:0.42, 0.65) for outdoor home predictions. Between-city heterogeneity was not found for outdoor home PM2.5 for either true exposure. Heterogeneity was significant for nearest monitor PM2.5, for both true exposures, but not after adjusting for city-average motor vehicle number for total personal PM2.5. Conclusions Calibration coefficients were <1, consistent with previously reported chronic health risks using nearest monitor exposures being under-estimated when ambient concentrations are the exposure of interest. Calibration coefficients were closer to 1 for outdoor home predictions, likely reflecting less spatial error. Further research is needed to determine how our findings can be incorporated in future health studies. [ABSTRACT FROM AUTHOR]

Background Our objectives were to examine the associations of neonatal and infant mortality with preterm birth and intrauterine growth restriction ( IUGR), and to estimate the partial population attributable risk per cent ( pPAR%) of neonatal and infant mortality due to preterm birth and IUGR. Methods Participants were HIV-negative pregnant women and their infants enrolled in Dar es Salaam, Tanzania. Gestational age calculated from date of last menstrual period was used to define preterm, and small for gestational age ( SGA) was used as proxy for IUGR. Survival of infants was ascertained at monthly follow-up visits. Cox proportional hazard models were used to estimate the associations of preterm and SGA with neonatal and infant mortality. Results Study included 7225 singletons, of whom 15% were preterm and 21% were SGA; majority of preterm or SGA babies had birthweight ≥2500 g. Compared to term and appropriately sized babies ( AGA), relative risks ( RR) of neonatal mortality among preterm- AGA was 2.6 [95% CI 1.8, 3.9], RR among term- SGA was 2.3 [95% CI 1.6, 3.3], and the highest risk was among the preterm- SGA babies ( RR 15.1 [95% CI 8.2, 27.7]). Risk associated with preterm was elevated throughout the infancy, and risk associated with SGA was elevated during the neonatal period only. The pPAR% of neonatal mortality for preterm was 22% [95% CI 17%, 26%] and for SGA it was 26% [95% CI 16%, 36%]. Conclusions Preterm and SGA birth substantially increased the risk of mortality. Interventions for prevention and management of these conditions are likely to reduce of infant mortality in Tanzania. [ABSTRACT FROM AUTHOR]

In the context of observational longitudinal studies, we explored the values of the number of participants and the number of repeated measurements that maximize the power to detect the hypothesized effect, given the total cost of the study. We considered two different models, one that assumes a transient effect of exposure and one that assumes a cumulative effect. Results were derived for a continuous response variable, whose covariance structure was assumed to be damped exponential, and a binary time-varying exposure. Under certain assumptions, we derived simple formulas for the approximate solution to the problem in the particular case in which the response covariance structure is assumed to be compound symmetry. Results showed the importance of the exposure intraclass correlation in determining the optimal combination of the number of participants and the number of repeated measurements, and therefore the optimized power. Thus, incorrectly assuming a time-invariant exposure leads to inefficient designs. We also analyzed the sensitivity of results to dropout, mis-specification of the response correlation structure, allowing a time-varying exposure prevalence and potential confounding impact. We illustrated some of these results in a real study. In addition, we provide software to perform all the calculations required to explore the combination of the number of participants and the number of repeated measurements. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

We prospectively determined the association between undernutrition and incidence of acute respiratory infections (ARIs) among 711 children born to HIV-infected women. Overall, underweight was associated with a 58% increased risk of ARI. Similarly, wasting (54%), very low birth weight (88%) and child HIV infection (62%) were significantly associated with increased risk of ARI during the first 2 years. Breastfeeding was associated with 52% reduction in risk of ARI only during the first 12 months of life. Among HIV-exposed, but uninfected, children, underweight, wasting and stunting were associated with 73%, 61% and 33% increased risk of ARI, respectively. Very low birthweight and advanced maternal disease stage were also associated with increased risk of ARI. Similar results were observed among HIV-infected children, except for stunting and very low birth weight. Prevention of child undernutrition could have major impact in reducing child ARI morbidity in settings of high HIV prevalence. [ABSTRACT FROM PUBLISHER]

Background Estrogen receptor–negative (ER−) breast cancer has few known or modifiable risk factors. Because ER− tumors account for only 15% to 20% of breast cancers, large pooled analyses are necessary to evaluate precisely the suspected inverse association between fruit and vegetable intake and risk of ER− breast cancer. Methods Among 993 466 women followed for 11 to 20 years in 20 cohort studies, we documented 19 869 estrogen receptor positive (ER+) and 4821 ER− breast cancers. We calculated study-specific multivariable relative risks (RRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression analyses and then combined them using a random-effects model. All statistical tests were two-sided. Results Total fruit and vegetable intake was statistically significantly inversely associated with risk of ER− breast cancer but not with risk of breast cancer overall or of ER+ tumors. The inverse association for ER− tumors was observed primarily for vegetable consumption. The pooled relative risks comparing the highest vs lowest quintile of total vegetable consumption were 0.82 (95% CI = 0.74 to 0.90) for ER− breast cancer and 1.04 (95% CI = 0.97 to 1.11) for ER+ breast cancer (Pcommon-effects by ER status < .001). Total fruit consumption was non-statistically significantly associated with risk of ER− breast cancer (pooled multivariable RR comparing the highest vs lowest quintile = 0.94, 95% CI = 0.85 to 1.04). Conclusions We observed no association between total fruit and vegetable intake and risk of overall breast cancer. However, vegetable consumption was inversely associated with risk of ER− breast cancer in our large pooled analyses. [ABSTRACT FROM PUBLISHER]

Fruit and vegetable intake may protect against pancreatic cancer, since fruits and vegetables are rich in potentially cancer-preventive nutrients. Most case-control studies have found inverse associations between fruit and vegetable intake and pancreatic cancer risk, although bias due to reporting error cannot be ruled out. In most prospective studies, inverse associations have been weaker and imprecise because of small numbers of cases. The authors examined fruit and vegetable intake in relation to pancreatic cancer risk in a pooled analysis of 14 prospective studies from North America, Europe, and Australia (study periods between 1980 and 2005). Relative risks and 2-sided 95% confidence intervals were estimated separately for the 14 studies using the Cox proportional hazards model and were then pooled using a random-effects model. Of 862,584 men and women followed for 7−20 years, 2,212 developed pancreatic cancer. The pooled multivariate relative risks of pancreatic cancer per 100-g/day increase in intake were 1.01 (95% confidence interval (CI): 0.99, 1.03) for total fruits and vegetables, 1.01 (95% CI: 0.99, 1.03) for total fruits, and 1.02 (95% CI: 0.99, 1.06) for total vegetables. Associations were similar for men and women separately and across studies. These results suggest that fruit and vegetable intake during adulthood is not associated with a reduced pancreatic cancer risk. [ABSTRACT FROM AUTHOR]

Prenatal iron supplementation may improve pregnancy outcomes and decrease the risk of child mortality. However, little is known about the importance of post-natal maternal iron status for child health and survival, particularly in the context of HIV infection. We examined the association of maternal anaemia and hypochromic microcytosis, an erythrocyte morphology consistent with iron deficiency, with child health and survival in the first two to five years of life. Repeated measures of maternal anaemia and hypochromic microcytosis from 840 HIV-positive women enrolled in a clinical trial of vitamin supplementation were prospectively related to child mortality, HIV infection and CD4 T-cell count. Median duration of follow-up for the endpoints of child mortality, HIV infection and CD4 cell count was 58, 17 and 23 months, respectively. Maternal anaemia and hypochromic microcytosis were associated with greater risk of child mortality [hazard ratio (HR) for severe anaemia = 2.58, 95% confidence interval (CI): 1.66-4.01, P trend < 0.0001; HR for severe hypochromic microcytosis = 2.36, 95% CI: 1.27-4.38, P trend = 0.001]. Maternal anaemia was not significantly associated with greater risk of child HIV infection (HR for severe anaemia = 1.46, 95% CI: 0.91, 2.33, P trend = 0.08) but predicted lower CD4 T-cell counts among HIV-uninfected children (difference in CD4 T-cell count/ µL for severe anaemia: −93, 95% CI: −204-17, P trend = 0.02). The potential child health risks associated with maternal anaemia and iron deficiency may not be limited to the prenatal period. Efforts to reduce maternal anaemia and iron deficiency during pregnancy may need to be expanded to include the post-partum period. [ABSTRACT FROM AUTHOR]

Objective To determine whether human immunodeficiency virus (HIV) infection is associated with increased risk of malaria incidence and recurrence in children. Methods Newborn infants of HIV-infected mothers were enrolled at 6 weeks and followed for 2 years. HIV status was assessed by enzyme-linked immunosorbant assay and confirmed by HIV DNA polymerase chain reaction. Malaria was defined as (1) physician-diagnosed clinical malaria; (2) probable malaria, in which laboratory testing is requested for parasitemia; and (3) blood smear–confirmed malaria. Cox proportional hazards models estimated hazard ratios (HRs) for development of first and second malaria episodes, and generalized estimating equation models estimated malaria rate differences per 100-child-years in relation to time-updated HIV status. Results Child HIV infection was associated with clinical (HR, 1.34; 95% confidence interval [CI], 1.12–1.61), probable (HR, 1.47; 95% CI, 1.19–1.81), and confirmed (HR, 1.67; 95% CI, 1.18–2.36) malaria episodes. Per 100 child-years, HIV-infected children experienced 88 (95% CI, 65–113), 36 (95% CI, 19–53), and 20 (95% CI, 9–31) more episodes of clinical, probable, and confirmed malaria episodes, respectively, than HIV-uninfected children. Among children with ≥1 malaria episodes, those with HIV infection developed second clinical (HR, 1.28; 95% CI, 1.04–1.57), probable (HR, 1.60; 95% CI, 1.26–2.14), and confirmed (HR, 2.27; 95% CI, 1.06–3.89) malaria sooner than HIV-uninfected children. Conclusions HIV infection is a risk factor for the development of malaria. Proactive malaria disease prevention and treatment is warranted for all children, particularly those with HIV infection in settings of coendemicity. [ABSTRACT FROM PUBLISHER]

Endogenous estrogens and estrogen metabolism are hypothesized to be associated with premenopausal breast cancer risk but evidence is limited. We examined 15 urinary estrogens/estrogen metabolites and breast cancer risk among premenopausal women in a case-control study nested within the Nurses' Health Study II (NHSII). From 1996 to 1999, urine was collected from 18,521 women during the mid-luteal menstrual phase. Breast cancer cases (N=247) diagnosed between collection and June 2005 were matched to two controls each (N = 485). Urinary estrogen metabolites were measured by liquid chromatography-tandem mass spectrometry and adjusted for creatinine level. Relative risks (RR) and 95% confidence intervals (CI) were estimated by multivariate conditional logistic regression. Higher urinary estrone and estradiol levels were strongly significantly associated with lower risk (top vs. bottom quartile RR: estrone = 0.52; 95% CI, 0.30-0.88; estradiol = 0.51; 95% CI, 0.30-0.86). Generally inverse, although nonsignificant, patterns also were observed with 2- and 4-hydroxylation pathway estrogen metabolites. Inverse associations generally were not observed with 16-pathway estrogen metabolites and a significant positive association was observed with 17-epiestriol (top vs. bottom quartile RR = 1.74; 95% CI, 1.08-2.81; Ptrend = 0.01). In addition, there was a significant increased risk with higher 16-pathway/parent estrogen metabolite ratio (comparable RR = 1.61; 95% CI, 0.99-2.62; Ptrend = 0.04). Other pathway ratios were not significantly associated with risk except parent estrogen metabolites/non-parent estrogen metabolites (comparable RR = 0.58; 95% CI, 0.35-0.96; Ptrend = 0.03). These data suggest that most mid-luteal urinary estrogen metabolite concentrations are not positively associated with breast cancer risk among premenopausal women. The inverse associations with parent estrogen metabolites and the parent estrogen metabolite/non-parent estrogen metabolite ratio suggest that women with higher urinary excretion of parent estrogens are at lower risk. [ABSTRACT FROM AUTHOR]

Background: Few studies have directly assessed the association of secondhand smoke (SHS) with cardiovascular disease-related inflammatory markers, and the findings are inconsistent. Objectives: We assessed the association between SHS exposure and the inflammatory markers high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and soluble intercellular adhesion molecule-1 (sICAM-1) in 199nonsmoking U.S. trucking industry workers. Methods: Participants provided blood samples either by mail (blood drawn at local health care provider near home) or at the work site (blood drawn by research staff on-site) and completed a health and work history questionnaire at the time of blood draw. Exposure to SHS was measured by plasma cotinine concentrations. We used multivariate regression analyses to assess the associations between levels of cotinine and inflammatory markers. Results: The median cotinine level was 0.10 ng/mL (interquartile range, 0.04-0.23 ng/mL). The odds ratios of elevated hs-CRP (above highest CRP tertile, 1.5 mg/L) were 2.85 [95% confidence interval (CI), 1.03-7.89] for the high-cotinine group (> 0.215 ng/mL) and 2.80 (95% CI, 1.11-7.10) for the moderate-cotinine group (0.05-0.215 ng/mL), compared with the low-cotinine group (< 0.05 ng/mL), adjusting for age, sex, race, educational level, obesity, previous smoking history, job title, and medical history. Plasma cotinine levels were not associated with IL 6 or sICAM 1. Conclusions: SHS exposure, as assessed by plasma cotinine, was positively associated with hs CRP in this group of blue-collar workers. The strength of the association with hs-CRP depended on the cut points selected for analysis. [ABSTRACT FROM AUTHOR]

BACKGROUND: The etiology of autism is unknown, although perinatal and neonatal exposures have been the focus of epidemiologic research for over 40 years. OBJECTIVE: To provide the first review and meta-analysis of the association between perinatal and neonatal factors and autism risk. METHODS: PubMed, Embase, and Psyclnfo databases were searched for studies that examined the association between perinatal and neonatal factors and autism through March 2007. Forty studies were eligible for the meta-analysis. For each exposure, a summary effect estimate was calculated using a random-effects model. Heterogeneity in effect estimates across studies was examined, and, if found, a meta- regression was conducted to identify measured methodological factors that could explain between-study variability. RESULTS: Over 60 perinatal and neonatal factors were examined. Factors associated with autism risk in the meta-analysis were abnormal presentation, umbilical-cord complications, fetal distress, birth injury or trauma, multiple birth, maternal hemorrhage, summer birth, low birth weight, small for gestational age, congenital malformation, low 5-minute Apgar score, feeding difficulties, meconium aspiration, neonatal anemia, ABO or Rh incompatibility, and hyperbilirubmemia. Factors not associated with autism risk included anesthesia, assisted vaginal delivery, postterm birth, high birth weight, and head circumference. CONCLUSIONS: There is insufficient evidence to implicate any 1 perinatal or neonatal factor in autism etiology, although there is some evidence to suggest that exposure to a broad class of conditions reflecting general compromises to perinatal and neonatal health may increase the risk. Methodological variations were likely sources of heterogeneity of risk factor effects across studies. [ABSTRACT FROM AUTHOR]

Background. Poor nutritional status is associated with immunologic impairment and adverse health outcomes among adults infected with human immunodeficiency virus (HIV).Methods. We investigated body mass index (BMI), middle upper arm circumference (MUAC), and hemoglobin (Hgb) concentrations at initiation of antiretroviral therapy (ART) in 18,271 HIV-infected Tanzanian adults and their changes in the first 3 months of ART, in relation to the subsequent risk of death.Results. Lower BMI, MUAC, and Hgb concentrations at ART initiation were strongly associated with a higher risk of death within 3 months. Among patients who survived >3 months after ART initiation, those with a decrease in weight, MUAC, or Hgb concentrations by 3 months had a higher risk of death during the first year. After 1 year, only a decrease in MUAC by 3 months after ART initiation was associated with a higher risk of death. Weight loss was associated with a higher risk of death across all levels of baseline BMI, with the highest risk observed among patients with BMI <17 kg/m2 (relative risk, 7.9; 95% confidence interval, 4.4–14.4).Conclusions. Poor nutritional status at ART initiation and decreased nutritional status in the first 3 months of ART were strong independent predictors of mortality. The role of nutritional interventions as adjunct therapies to ART merits further investigation. [ABSTRACT FROM PUBLISHER]

ObjectiveWe examined the relationships between exclusive breast-feeding and the risks of respiratory, diarrhoea and nutritional morbidities during the first 2 years of life among children born to women infected with HIV-1.DesignWe prospectively determined the incidence of respiratory illnesses, diarrhoea, fever, hospitalizations, outpatient visits and nutritional morbidities. Generalized estimating equations were used to estimate the relative risks for morbidity episodes and Cox proportional hazards models to estimate the incidence rate ratios of nutritional morbidities.SettingDar es Salaam, Tanzania.SubjectsThe sample consisted of 666 children born to HIV-infected women.ResultsThe 666 children were followed for 2 years. Exclusive breast-feeding was associated with lower risk for cough (rate ratio (RR) = 0·49, 95 % CI 0·41, 0·60, P < 0·0001), cough and fever (RR = 0·44, 95 % CI 0·32, 0·60, P < 0·0001) and cough and difficulty breathing or refusal to feed (RR = 0·31, 95 % CI 0·18, 0·55, P < 0·0001). Exclusive breast-feeding was also associated with lower risk of acute diarrhoea, watery diarrhoea, dysentery, fever and outpatient visits during the first 6 months of life, but showed no effect at 6–24 months of life. Exclusive breast-feeding did not significantly reduce the risks of nutritional morbidities during the first 2 years of life.ConclusionsExclusive breast-feeding is strongly associated with reductions in the risk of respiratory and diarrhoea morbidities during the first 6 months of life among children born to HIV-infected women. [ABSTRACT FROM AUTHOR]

Objective: To systematically review randomized controlled trials comparing the effect of supplementation with multiple micronutrients versus iron and folie acid on pregnancy outcomes in developing countries. Methods: MEDLINE and EMBASE were searched. Outcomes of interest were birth weight, low birth weight, small size for gestational age, perinatal mortality and neonatal mortality. Pooled relative risks (RRs) were estimated by random effects models. Sources of heterogeneity were explored through subgroup meta-analyses and meta-regression. Findings: Multiple micronutrlent supplementation was more effective than iron and folie acid supplementation at reducing the risk of low birth weight (RR:0.86, 95% confidence interval, CI:0.79-0.93) and of small size for gestational age (RR:0.85; 95% CI: 0.78- 0.93). Mlcronutrient supplementation had no overall effect on perinatal mortality (RR: 1.05; 95% CI: 0.90-1.22), although substantial heterogeneity was evident {R = 58%; Pfor heterogeneity = 0.008). Subgroup and meta-regression analyses suggested that micronutrient supplementation was associated with a lower risk of perinatal mortality in trials in which > 50% of mothers had formal education (RR: 0.93; 95% CI: 0.82-1.06) or in which supplementation was initiated after a mean of 20 weeks of gestation (RR:0.88; 95% CI: 0.80-0.97). Conclusion: Maternal education or gestational age at initiation of supplementation may have contributed to the observed heterogeneous effects on perinatal mortality. The safety, efficacy and effective delivery of maternal micronutrient supplementation require further research. [ABSTRACT FROM AUTHOR]

Repeat-biomarker measurement error models accounting for systematic correlated within-person error can be used to estimate the correlation coefficient (ρ) and deattenuation factor (λ), used in measurement error correction. These models account for correlated errors in the food frequency questionnaire (FFQ) and the 24-hour diet recall and random within-person variation in the biomarkers. Failure to account for within-person variation in biomarkers can exaggerate correlated errors between FFQs and 24-hour diet recalls. For 2 validation studies, ρ and λ were calculated for total energy and protein density. In the Automated Multiple-Pass Method Validation Study (n = 471), doubly labeled water (DLW) and urinary nitrogen (UN) were measured twice in 52 adults approximately 16 months apart (2002—2003), yielding intraclass correlation coefficients of 0.43 for energy (DLW) and 0.54 for protein density (UN/DLW). The deattenuated correlation coefficient for protein density was 0.51 for correlation between the FFQ and the 24-hour diet recall and 0.49 for correlation between the FFQ and the biomarker. Use of repeat-biomarker measurement error models resulted in a ρ of 0.42. These models were similarly applied to the Observing Protein and Energy Nutrition Study (1999—2000). In conclusion, within-person variation in biomarkers can be substantial, and to adequately assess the impact of correlated subject-specific error, this variation should be assessed in validation studies of FFQs. [ABSTRACT FROM AUTHOR]

Background: Although child abuse is associated with obesity, it is not known whether early abuse increases risk of type 2 diabetes. Purpose: To investigate associations of child and adolescent abuse with adult diabetes. Methods: Proportional hazards models were used to examine associations of lifetime abuse reported in 2001 with risk of diabetes from 1989 to 2005 among 67,853 women in the Nurses'' Health Study II. Data were analyzed in 2009. Results: Child or teen physical abuse was reported by 54% and sexual abuse by 34% of participants. Models were adjusted for age, race, body type at age 5 years, and parental education and history of diabetes. Compared to women who reported no physical abuse, the hazards ratio (HR) was 1.03 (95% CI=0.91, 1.17) for mild physical abuse; 1.26 (1.14, 1.40) for moderate physical abuse; and 1.54 (1.34, 1.77) for severe physical abuse. Compared with women reporting no sexual abuse in childhood or adolescence, the HR was 1.16 (95% CI=1.05, 1.29) for unwanted sexual touching; 1.34 (1.13, 1.59) for one episode of forced sexual activity; and 1.69 (1.45, 1.97) for repeated forced sex. Adult BMI accounted for 60% (95% CI=32%, 87%) of the association of child and adolescent physical abuse and 64% (95% CI=38%, 91%) of the association of sexual abuse with diabetes. Conclusions: Moderate to severe physical and sexual abuse in childhood and adolescence have dose–response associations with risk of type 2 diabetes among adult women. This excess risk is partially explained by the higher BMI of women with a history of early abuse. [Copyright &y& Elsevier]

The article comments on the paper about relation between correlation and causation by Charles Spearman. According to the author, the human mind played a key role in linking correlation with causation deterministically. She adds that correlation demonstrates its ability to quantify the strength of a causal relationship despite the absence of evidence of its effectivity. She also asserts the key role of correlation in scientific discovery and innovation.

The article presents a study on the effects of white rice and brown rice consumption on risk of type 2 diabetes mellitus. Diet, lifestyle and disease status of subjects were ascertained and updated. It is found that higher intake of white rice correlates with a higher risk of type 2 diabetes while high brown rice consumption is associated with lower risk. It is concluded that replacing whole grains such as brown rice for white rice may reduce type 2 diabetes risks.

Uncertainty in assessment of individual exposure levels leads to bias, often, but not always, toward the null in estimates of health effects, and to underestimation of the variability of the estimates, leading to anticonservative p-values. In the absence of data on the uncertainty in individual exposure estimates, sensitivity analysis, also known as uncertainty analysis and bias analysis, is available. Hypothesized values of key parameters of the model relating the observed exposure to the true exposure are used to assess the resulting amount of bias in point and interval estimates. In general, the relative risk estimates can vary from zero to infinity as the hypothesized values of key parameters of the measurement error model vary. Thus, we recommend that exposure validation data be used to empirically adjust point and interval estimates of health effects for measurement error. The remainder of this review gives an overview of available methods for doing so. Just as we routinely adjust for confounding, we can and should routinely adjust for measurement error. [ABSTRACT FROM AUTHOR]

Uncertainty in assessment of individual exposure levels leads to bias, often, but not always, toward the null in estimates of health effects, and to underestimation of the variability of the estimates, leading to anticonservative p-values. In the absence of data on the uncertainty in individual exposure estimates, sensitivity analysis, also known as uncertainty analysis and bias analysis, is available. Hypothesized values of key parameters of the model relating the observed exposure to the true exposure are used to assess the resulting amount of bias in point and interval estimates. In general, the relative risk estimates can vary from zero to infinity as the hypothesized values of key parameters of the measurement error model vary. Thus, we recommend that exposure validation data be used to empirically adjust point and interval estimates of health effects for measurement error. The remainder of this review gives an overview of available methods for doing so. Just as we routinely adjust for confounding, we can and should routinely adjust for measurement error. [ABSTRACT FROM AUTHOR]

Objective To determine risk factors and estimate their population-level contribution to hepatitis C virus (HCV) burden. Methods Established and potentially modifiable risk factors were estimated using partial population attributable risk ( PARp) in a cohort of new injecting drug users (IDUs) in Sydney, Australia. Results A total of 204 hepatitis C seronegative IDUs were recruited through street-based outreach, methadone clinics and needle and syringe programmes (NSPs) and followed-up at 3–6-monthly intervals. A total of 61 HCV seroconversions were observed during the follow-up [overall incidence rate of 45.8 per 100 person-years (95% confidence interval: 35.6–58.8)]. Overall, five potentially modifiable risk factors (sharing needles/syringes, sharing other injecting equipment, assisted injecting, frequency of injection and not being in drug treatment) accounted for approximately 50% of HCV cases observed. Conclusion While sharing needles/syringes or other injecting equipment were associated most strongly with increased risk of HCV infection, the PARp associated with these behaviours was relatively modest (12%) because they are relatively low-prevalence behaviours. Our analyses suggest that more HCV infection could be avoided by changing more common, but less strongly associated behaviours such as assisted injecting or daily injecting. Results suggest that to have a very substantial effect on HCV, a range of risk factors need modifying. The most efficient use of scarce resources in reducing HCV infections will require complex balancing between the PAR for a given risk factor(s), the efficacy of interventions to actually modify the risk factor, and the cost of these interventions. [ABSTRACT FROM AUTHOR]

Background: Results of several case-control studies suggest that high consumption of meat (all meat, red meat, or processed meat) is associated with an increased risk of renal cell cancer, but only a few prospective studies have examined the associations of intakes of meat, fat, and protein with renal cell cancer. Methods: We conducted a pooled analysis of 13 prospective studies that included 530469 women and 244483 men and had follow-up times of up to 7-20 years to examine associations between meat, fat, and protein intakes and the risk of renal cell cancer. All participants had completed a validated food frequency questionnaire at study entry. Using the primary data from each study, we calculated the study-specific relative risks (RRs) for renal cell cancer by using Cox proportional hazards models and then pooled these RRs by using a random-effects model. All statistical tests were two-sided. Results: A total of 1478 incident cases of renal cell cancer were identified (709 in women and 769 in men). We observed statistically significant positive associations or trends in pooled age-adjusted models for intakes of total fat, saturated fat, monounsaturated fat, polyunsaturated fat, cholesterol, total protein, and animal protein. However, these associations were attenuated and no longer statistically significant after adjusting for body mass index, fruit and vegetable intake, and alcohol intake. For example, the pooled age-adjusted RR of renal cell cancer for the highest vs the lowest quintile of intake for total fat was 1.30 (95% confidence interval [Cl] = 1.08 to 1.56; Ptrend = .001) and for total protein was 1.17 (95% Cl = 0.99 to 1.38; Ptrend = .02). By comparison, the pooled multivariable RR for the highest vs the lowest quintile of total fat intake was 1.10 (95% Cl = 0.92 to 1.32; Ptrend = .31) and of total protein intake was 1.06 (95% Cl = 0.89 to 1.26; Ptrend = .37). Intakes of red meat, processed meat, poultry, or seafood were not associated with the risk of renal cell cancer. Conclusions: Intakes of fat and protein or their subtypes, red meat, processed meat, poultry, and seafood are not associated with risk of renal cell cancer. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the total body bone mineral density (total BMD) of HIV-infected men and women. It states that total BMD was measured using the whole-body dual-energy absorptiometry (DXA) while the medical and behavioral histories of the patients were collected. Findings show that low body weight and catabolic steroid use may accelerate bone loss while tenofovir and didanosine may cause a harmful effect on BMD.