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1.  Burden of chronic kidney disease in resource-limited settings from Peru: a population-based study 
BMC Nephrology  2015;16:114.
The silent progression of chronic kidney diseases (CKD) and its association with other chronic diseases, and high treatment costs make it a great public health concern worldwide. The population burden of CKD in Peru has yet to be fully described.
We completed a cross sectional study of CKD prevalence among 404 participants (total study population median age 54.8 years, 50.2 % male) from two sites, highly-urbanized Lima and less urbanized Tumbes, who were enrolled in the population-based CRONICAS Cohort Study of cardiopulmonary health in Peru. Factors potentially associated with the presence of CKD were explored using Poisson regression, a statistical methodology used to determine prevalence ratios.
In total, 68 participants (16.8 %, 95 % CI 13.5–20.9 %) met criteria for CKD: 60 (14.9%) with proteinuria, four (1%) with eGFR <60mL/min/1.73m2 , and four (1%) with both. CKD prevalence was higher in Lima (20.7 %, 95 % CI 15.8–27.1) than Tumbes (12.9 %, 95 % CI 9.0–18.5). Among participants with CKD, the prevalence of diabetes and hypertension was 19.1 % and 42.7 %, respectively. After multivariable adjustment, CKD was associated with older age, female sex, greater wealth tertile (although all wealth strata were below the poverty line), residence in Lima, and presence of diabetes and hypertension.
The high prevalence rates of CKD identified in Lima and Tumbes are similar to estimates from high-income settings. These findings highlight the need to identify occult CKD and implement strategies to prevent disease progression and secondary morbidity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12882-015-0104-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4512019  PMID: 26205002
Chronic kidney disease; Prevalence; Chronic diseases
2.  A review of the global burden, novel diagnostics, therapeutics, and vaccine targets for cryptosporidium 
Cryptosporidium spp are well recognised as causes of diarrhoeal disease during waterborne epidemics and in immunocompromised hosts. Studies have also drawn attention to an underestimated global burden and suggest major gaps in optimum diagnosis, treatment, and immunisation. Cryptosporidiosis is increasingly identified as an important cause of morbidity and mortality worldwide. Studies in low-resource settings and high-income countries have confirmed the importance of cryptosporidium as a cause of diarrhoea and childhood malnutrition. Diagnostic tests for cryptosporidium infection are suboptimum, necessitating specialised tests that are often insensitive. Antigen-detection and PCR improve sensitivity, and multiplexed antigen detection and molecular assays are underused. Therapy has some effect in healthy hosts and no proven efficacy in patients with AIDS. Use of cryptosporidium genomes has helped to identify promising therapeutic targets, and drugs are in development, but methods to assess the efficacy in vitro and in animals are not well standardised. Partial immunity after exposure suggests the potential for successful vaccines, and several are in development; however, surrogates of protection are not well defined. Improved methods for propagation and genetic manipulation of the organism would be significant advances.
PMCID: PMC4401121  PMID: 25278220
3.  Indoor Particulate Matter Concentration, Water Boiling Time, and Fuel Use of Selected Alternative Cookstoves in a Home-Like Setting in Rural Nepal 
Alternative cookstoves are designed to improve biomass fuel combustion efficiency to reduce the amount of fuel used and lower emission of air pollutants. The Nepal Cookstove Trial (NCT) studies effects of alternative cookstoves on family health. Our study measured indoor particulate matter concentration (PM2.5), boiling time, and fuel use of cookstoves during a water-boiling test in a house-like setting in rural Nepal. Study I was designed to select a stove to be used in the NCT; Study II evaluated stoves used in the NCT. In Study I, mean indoor PM2.5 using wood fuel was 4584 μg/m3, 1657 μg/m3, and 2414 μg/m3 for the traditional, alternative mud brick stove (AMBS-I) and Envirofit G-series, respectively. The AMBS-I reduced PM2.5 concentration but increased boiling time compared to the traditional stove (p-values < 0.001). Unlike AMBS-I, Envirofit G-series did not significantly increase overall fuel consumption. In Phase II, the manufacturer altered Envirofit stove (MAES) and Nepal Nutrition Intervention Project Sarlahi (NNIPS) altered Envirofit stove (NAES), produced lower mean PM2.5, 1573 μg/m3 and 1341 μg/m3, respectively, relative to AMBS-II 3488 μg/m3 for wood tests. The liquid propane gas stove had the lowest mean PM2.5 concentrations, with measurements indistinguishable from background levels. Results from Study I and II showed significant reduction in PM2.5 for all alternative stoves in a controlled setting. In study I, the AMBS-I stove required more fuel than the traditional stove. In contrast, in study II, the MAES and NAES stoves required statistically less fuel than the AMBS-II. Reductions and increases in fuel use should be interpreted with caution because the composition of fuels was not standardized—an issue which may have implications for generalizability of other findings as well. Boiling times for alternative stoves in Study I were significantly longer than the traditional stove—a trade-off that may have implications for acceptability of the stoves among end users. These extended cooking times may increase cumulative exposure during cooking events where emission rates are lower; these differences must be carefully considered in the evaluation of alternative stove designs.
PMCID: PMC4515674  PMID: 26198238
alternative cookstove performance; airborne particulate concentration; PM; indoor air pollution; biomass fuel use; water boiling test
5.  Prevalence of chronic obstructive pulmonary disease and variation in risk factors across four geographically diverse resource-limited settings in Peru 
Respiratory Research  2015;16(1):40.
It is unclear how geographic and social diversity affects the prevalence of chronic obstructive pulmonary disease (COPD). We sought to characterize the prevalence of COPD and identify risk factors across four settings in Peru with varying degrees of urbanization, altitude, and biomass fuel use.
We collected sociodemographics, clinical history, and post-bronchodilator spirometry in a randomly selected, age-, sex- and site-stratified, population-based sample of 2,957 adults aged ≥35 years (median age was 54.8 years and 49.3% were men) from four resource-poor settings: Lima, Tumbes, urban and rural Puno. We defined COPD as a post-bronchodilator FEV1/FVC < 70%.
Overall prevalence of COPD was 6.0% (95% CI 5.1%–6.8%) but with marked variation across sites: 3.6% in semi-urban Tumbes, 6.1% in urban Puno, 6.2% in Lima, and 9.9% in rural Puno (p < 0.001). Population attributable risks (PARs) of COPD due to smoking ≥10 pack-years were less than 10% for all sites, consistent with a low prevalence of daily smoking (3.3%). Rather, we found that PARs of COPD varied by setting. In Lima, for example, the highest PARs were attributed to post-treatment tuberculosis (16% and 22% for men and women, respectively). In rural Puno, daily biomass fuel for cooking among women was associated with COPD (prevalence ratio 2.22, 95% CI 1.02–4.81) and the PAR of COPD due to daily exposure to biomass fuel smoke was 55%.
The burden of COPD in Peru was not uniform and, unlike other settings, was not predominantly explained by tobacco smoking. This study emphasizes the role of biomass fuel use, and highlights pulmonary tuberculosis as an often neglected risk factor in endemic areas.
PMCID: PMC4389577  PMID: 25889777
COPD; Peru; Respiratory disease; Chronic disease; Risk factors; Population studies; Biomass fuels
6.  The 1997–1998 El Niño as an unforgettable phenomenon in northern Peru: a qualitative study 
Disasters  2014;38(2):351-374.
During the 1997–98 El Niño Southern Oscillation (ENSO), Tumbes, Peru received 16 times the annual average rainfall. We explored how Tumbes residents perceived the ENSO’s impact on basic necessities, transport, healthcare, jobs and migration. Forty-five individuals from five rural communities, including those that were isolated and not isolated from the rest of Tumbes during this ENSO, participated in five focus groups and six individuals constructed nutrition diaries. When asked about events in the past twenty years, participants considered the El Niño as a major negative event. Negative effects that were ameliorated quickly were decreased access to transport and healthcare and increased infectious diseases. Residents needed more time to rebuild housing, recover agriculture, livestock and income stability, and return to eating sufficient animal protein. Although large-scale assistance minimized the ENSO’s effects, residents needed more timely support. Residents’ perspectives on their risks to flooding should be considered to generate effective assistance.
PMCID: PMC4317261  PMID: 24601921
El Niño Southern Oscillation; Climate change; Floods; Peru; Qualitative
7.  Establishment of a prospective cohort of mechanically ventilated patients in five intensive care units in Lima, Peru: protocol and organisational characteristics of participating centres 
BMJ Open  2015;5(1):e005803.
Mechanical ventilation is a cornerstone in the management of critically ill patients worldwide; however, less is known about the clinical management of mechanically ventilated patients in low and middle income countries where limitation of resources including equipment, staff and access to medical information may play an important role in defining patient-centred outcomes. We present the design of a prospective, longitudinal study of mechanically ventilated patients in Peru that aims to describe a large cohort of mechanically ventilated patients and identify practices that, if modified, could result in improved patient-centred outcomes and lower costs.
Methods and analysis
Five Peruvian intensive care units (ICUs) and the Medical ICU at the Johns Hopkins Hospital were selected for this study. Eligible patients were those who underwent at least 24 h of invasive mechanical ventilation within the first 48 h of admission into the ICU. Information on ventilator settings, clinical management and treatment were collected daily for up to 28 days or until the patient was discharged from the unit. Vital status was assessed at 90 days post enrolment. A subset of participants who survived until hospital discharge were asked to participate in an ancillary study to assess vital status, and physical and mental health at 6, 12, 24 and 60 months after hospitalisation, Primary outcomes include 90-day mortality, time on mechanical ventilation, hospital and ICU lengths of stay, and prevalence of acute respiratory distress syndrome. In subsequent analyses, we aim to identify interventions and standardised care strategies that can be tailored to resource-limited settings and that result in improved patient-centred outcomes and lower costs.
Ethics and dissemination
We obtained ethics approval from each of the four participating hospitals in Lima, Peru, and at the Johns Hopkins School of Medicine, Baltimore, USA. Results will be disseminated as several separate publications in different international journals.
PMCID: PMC4298097  PMID: 25596196
8.  Designs of two randomized, community-based trials to assess the impact of alternative cookstove installation on respiratory illness among young children and reproductive outcomes in rural Nepal 
BMC Public Health  2014;14:1271.
Acute lower respiratory infections (ALRI) are a leading cause of death among children. Low birthweight is prevalent in South Asia and associated with increased risks of mortality, and morbidity, high levels of indoor household air pollution caused by open burning of biomass fuels are common and associated with high rates of ALRI and low birthweight. Alternative stove designs that burn biomass fuel more efficiently have been proposed as one method for reducing these high exposures and lowering rates of these disorders. We designed two randomized trials to test this hypothesis.
We conducted a pair of community-based, randomized trials of alternative cookstove installation in a rural district in southern Nepal. Phase one was a cluster randomized, modified step-wedge design using an alternative biomass stove with a chimney. A pre-installation period of morbidity assessment and household environmental assessment was conducted for six months in all households. This was followed by a one year step-wedge phase with 12 monthly steps for clusters of households to receive the alternative stove. The timing of alternative stove introduction was randomized. This step-wedge phase was followed in all households by another six month follow-up phase. Eligibility criteria for phase one included household informed consent, the presence of a married woman of reproductive age (15–30 yrs) or a child < 36 months. Children were followed until 36 months of age or the end of the trial. Pregnancies were identified and followed until completion or end of the trial. Phase two was an individually randomized trial of the same alternative biomass stove versus liquid propane gas stove in a subset of households that participated in phase one. Follow-up for phase two was 12 months following stove installation. Eligibility criteria included the same components as phase one except children were only enrolled for morbidity follow-up if they were less than 24 months.
The primary outcomes included: incidence of ALRI in children and birthweight.
We presented the design and methods of two randomized trials of alternative cookstoves on rates of ALRI and birthweight.
Trial registration (NCT00786877, Nov. 5, 2008).
PMCID: PMC4301623  PMID: 25511324
Pneumonia; ALRI; Birthweight; Biomass fuel; Household air pollution; Improved cookstoves; Randomized trials
Critical care medicine  2010;38(9):1882-1889.
Better understanding of the pathophysiology of critical illness has led to an increase in clinical trials designed to improve the clinical care and outcomes of patients with life threatening illness. Knowledge of basic principles of clinical trial design and interpretation will assist the clinician in better applying the results of these studies into clinical practice.
Data Sources
We review selected clinical trials to highlight important design features that will improve understanding of the results of critical care clinical trials.
Main Results
Trial design features such as patient selection, sample size calculation, and primary outcome measure may influence the results of a critical care clinical study. In conjunction with trial design knowledge, understanding the size of the anticipated treatment effect, the importance of any clinical endpoint achieved, and whether patients in the trial are representative of typical patients with the illness will assist the reader in determining whether the results should be applied to usual clinical practice.
Better understanding of important aspects of trial design and interpretation, such as whether patients enrolled in both intervention arms were comparable and whether the primary outcome of the trial is clinically important, will assist the reader in determining whether to apply the findings from the clinical study into clinical practice.
PMCID: PMC4247355  PMID: 20639755
Clinical Trial; Critical Care; Adult; Outcomes
10.  Critical Illness Outcome Study: An Observational Study on Protocols and Mortality in Intensive Care Units 
Many individual Intensive Care Unit (ICU) characteristics have been associated with patient outcomes, including staffing, expertise, continuity and team structure. Separately, many aspects of clinical care in ICUs have been operationalized through the development of complex treatment protocols. The United State Critical Illness and Injury Trials Group-Critical Illness Outcomes Study (USCIITG-CIOS) was designed to determine whether the extent of protocol availability and use in ICUs is associated with hospital survival in a large cohort of United States ICUs. Here, we describe the study protocol and analysis plan approved by the USCIITG-CIOS Steering Committee.
USCIITG-CIOS is a prospective, observational, ecological multi-centered “cohort” study of mixed ICUs in the U.S. The data collected include organizational information for the ICU (e.g., protocol availability and utilization, multi-disciplinary staffing assessment) and patient level information (e.g. demographics, acute and chronic medical conditions). The primary outcome is all-cause hospital mortality, with the objective being to determine whether there is an association between protocol number and hospital mortality for ICU patients. USCIITG-CIOS is powered to detect a 3% difference in crude hospital mortality between high and low protocol use ICUs, dichotomized according to protocol number at the median. The analysis will utilize regression modeling to adjust for outcome clustering by ICU, with secondary linear analysis of protocol number and mortality and a variety of a priori planned ancillary studies. There are presently 60 ICUs participating in USCIITG-CIOS to enroll approximately 6,000 study subjects.
USCIITG-CIOS is a large multicentric study examining the effect of ICU protocol use on patient outcomes. The primary results of this study will inform our understanding of the relationship between protocol availability, use, and patient outcomes in the ICU. Moreover, given the shortage of intensivists worldwide, the results of USCIITG-CIOS can be used to promote more effective ICU and care team design and will impact the delivery of intensive care services beyond individual practitioners.
Trial Registration Identifier NCT01109719
PMCID: PMC4242589  PMID: 25429244
ICU; Critical Care; Outcomes; Protocols; ICU organization
11.  Diarrhea in Early Childhood: Short-term Association With Weight and Long-term Association With Length 
American Journal of Epidemiology  2013;178(7):1129-1138.
The short-term association between diarrhea and weight is well-accepted, but the long-term association between diarrhea and growth is less clear. Using data from 7 cohort studies (Peru, 1985–1987; Peru, 1989–1991; Peru, 1995–1998; Brazil, 1989–1998; Guinea-Bissau, 1987–1990; Guinea-Bissau, 1996–1997; and Bangladesh, 1993–1996), we evaluated the lagged relationship between diarrhea and growth in the first 2 years of life. Our analysis included 1,007 children with 597,638 child-days of diarrhea surveillance and 15,629 anthropometric measurements. We calculated the associations between varying diarrhea burdens during lagged 30-day periods and length at 24 months of age. The cumulative association between the average diarrhea burden and length at age 24 months was −0.38 cm (95% confidence interval: −0.59, −0.17). Diarrhea during the 30 days prior to anthropometric measurement was consistently associated with lower weight at most ages, but there was little indication of a short-term association with length. Diarrhea was associated with a small but measurable decrease in linear growth over the long term. These findings support a focus on prevention of diarrhea as part of an overall public health strategy for improving child health and nutrition; however, more research is needed to explore catch-up growth and potential confounders.
PMCID: PMC3783094  PMID: 23966558
child health; diarrhea; malnutrition; stunting; wasting
12.  Behavioral Attitudes and Preferences in Cooking Practices with Traditional Open-Fire Stoves in Peru, Nepal, and Kenya: Implications for Improved Cookstove Interventions 
Global efforts are underway to develop and promote improved cookstoves which may reduce the negative health and environmental effects of burning solid fuels on health and the environment. Behavioral studies have considered cookstove user practices, needs and preferences in the design and implementation of cookstove projects; however, these studies have not examined the implications of the traditional stove use and design across multiple resource-poor settings in the implementation and promotion of improved cookstove projects that utilize a single, standardized stove design. We conducted in-depth interviews and direct observations of meal preparation and traditional, open-fire stove use of 137 women aged 20–49 years in Kenya, Peru and Nepal prior in the four-month period preceding installation of an improved cookstove as part of a field intervention trial. Despite general similarities in cooking practices across sites, we identified locally distinct practices and norms regarding traditional stove use and desired stove improvements. Traditional stoves are designed to accommodate specific cooking styles, types of fuel, and available resources for maintenance and renovation. The tailored stoves allow users to cook and repair their stoves easily. Women in each setting expressed their desire for a new stove, but they articulated distinct specific alterations that would meet their needs and preferences. Improved cookstove designs need to consider the diversity of values and needs held by potential users, presenting a significant challenge in identifying a “one size fits all” improved cookstove design. Our data show that a single stove design for use with locally available biomass fuels will not meet the cooking demands and resources available across the three sites. Moreover, locally produced or adapted improved cookstoves may be needed to meet the cooking needs of diverse populations while addressing health and environmental concerns of traditional stoves.
PMCID: PMC4210980  PMID: 25286166
cookstove; household air pollution; resource-limited settings; behavior analysis; adoption; qualitative research; formative research; technology
13.  Beyond birth-weight: early growth and adolescent blood pressure in a Peruvian population 
PeerJ  2014;2:e381.
Background. Longitudinal investigations into the origins of adult essential hypertension have found elevated blood pressure in children to accurately track into adulthood, however the direct causes of essential hypertension in adolescence and adulthood remains unclear.
Methods. We revisited 152 Peruvian adolescents from a birth cohort tracked from 0 to 30 months of age, and evaluated growth via monthly anthropometric measurements between 1995 and 1998, and obtained anthropometric and blood pressure measurements 11–14 years later. We used multivariable regression models to study the effects of infantile and childhood growth trends on blood pressure and central obesity in early adolescence.
Results. In regression models adjusted for interim changes in weight and height, each 0.1 SD increase in weight for length from 0 to 5 months of age, and 1 SD increase from 6 to 30 months of age, was associated with decreased adolescent systolic blood pressure by 1.3 mm Hg (95% CI −2.4 to −0.1) and 2.5 mm Hg (95% CI −4.9 to 0.0), and decreased waist circumference by 0.6 (95% CI −1.1 to 0.0) and 1.2 cm (95% CI −2.3 to −0.1), respectively. Growth in infancy and early childhood was not significantly associated with adolescent waist-to-hip ratio.
Conclusions. Rapid compensatory growth in early life has been posited to increase the risk of long-term cardiovascular morbidities such that nutritional interventions may do more harm than good. However, we found increased weight growth during infancy and early childhood to be associated with decreased systolic blood pressure and central adiposity in adolescence.
PMCID: PMC4081287  PMID: 25024902
Developmental origins; Lifecourse; Hypertension; Blood pressure; Obesity; Growth and development; Child development; Cohort studies; Peru
14.  Effects of the 1997–1998 El Niño Episode on Community Rates of Diarrhea 
American journal of public health  2012;102(7):e63-e69.
To improve our understanding of climate variability and diarrheal disease at the community level and inform predictions for future climate change scenarios, we examined whether the El Niño climate pattern is associated with increased rates of diarrhea among Peruvian children.
We analyzed daily surveillance data for 367 children aged 0 to 12 years from 2 cohorts in a peri-urban shantytown in Lima, Peru, 1995 through 1998. We stratified diarrheal incidence by 6-month age categories, season, and El Niño, and modeled between-subject heterogeneity with random effects Poisson models.
Spring diarrheal incidence increased by 55% during El Niño compared with before El Niño. This increase was most acute among children older than 60 months, for whom the risk of a diarrheal episode during the El Niño spring was nearly 100% greater (relative risk = 1.96; 95% confidence interval = 1.24, 3.09).
El Niño–associated climate variability affects community rates of diarrhea, particularly during the cooler seasons and among older children. Public health officials should develop preventive strategies for future El Niño episodes to mitigate the increased risk of diarrheal disease in vulnerable communities.
PMCID: PMC3478018  PMID: 22594750
15.  Humidity and Gravimetric Equivalency Adjustments for Nephelometer-Based Particulate Matter Measurements of Emissions from Solid Biomass Fuel Use in Cookstoves 
Great uncertainty exists around indoor biomass burning exposure-disease relationships due to lack of detailed exposure data in large health outcome studies. Passive nephelometers can be used to estimate high particulate matter (PM) concentrations during cooking in low resource environments. Since passive nephelometers do not have a collection filter they are not subject to sampler overload. Nephelometric concentration readings can be biased due to particle growth in high humid environments and differences in compositional and size dependent aerosol characteristics. This paper explores relative humidity (RH) and gravimetric equivalency adjustment approaches to be used for the pDR-1000 used to assess indoor PM concentrations for a cookstove intervention trial in Nepal. Three approaches to humidity adjustment performed equivalently (similar root mean squared error). For gravimetric conversion, the new linear regression equation with log-transformed variables performed better than the traditional linear equation. In addition, gravimetric conversion equations utilizing a spline or quadratic term were examined. We propose a humidity adjustment equation encompassing the entire RH range instead of adjusting for RH above an arbitrary 60% threshold. Furthermore, we propose new integrated RH and gravimetric conversion methods because they have one response variable (gravimetric PM2.5 concentration), do not contain an RH threshold, and is straightforward.
PMCID: PMC4078586  PMID: 24950062
nephelometer; particulate matter; humidity adjustment; gravimetric equivalent; pDR; low resource environment; biomass burning; cookstove; indoor air quality
16.  Multilevel competing risks in the evaluation of nosocomial infections: time to move on from proportional hazards and even from hazards altogether 
Critical Care  2014;18(3):146.
A competing risk is an event (for example, death in the ICU) that hinders the occurrence of an event of interest (for example, nosocomial infection in the ICU) and it is a common issue in many critical care studies. Not accounting for a competing event may affect how results related to a primary event of interest are interpreted. In the previous issue of Critical Care, Wolkewitz and colleagues extended traditional models for competing risks to include random effects as a means to quantify heterogeneity among ICUs. Reported results from their analyses based on cause-specific hazards and on sub-hazards of the cumulative incidence function were indicative of lack of proportionality of these hazards over time. Here, we argue that proportionality of hazards can be problematic in competing-risk problems and analyses must consider time by covariate interactions as a default. Moreover, since hazards in competing risks make it difficult to disentangle the effects of frequency and timing of the competing events, their interpretation can be murky. Use of mixtures of flexible and succinct parametric time-to-event models for competing risks permits disentanglement of the frequency and timing at the price of requiring stronger data and a higher number of parameters. We used data from a clinical trial on fluid management strategies for patients with acute respiratory distress syndrome to support our recommendations.
PMCID: PMC4057054  PMID: 25042281
17.  Early anthropometric indices predict short stature and overweight status in a cohort of Peruvians in early adolescence 
While childhood malnutrition is associated with increased morbidity and mortality, less well understood is how early childhood growth influences height and body composition later in life. We revisited 152 Peruvian children who participated in a birth cohort study between 1995 and 1998, and obtained anthropometric and bioimpedance measurements 11 to 14 years later. We used multivariable regression models to study the effects of childhood anthropometric indices on height and body composition in early adolescence. Each standard deviation decrease in length-for-age at birth was associated with a decrease in adolescent height-for-age of 0.7 SD in both boys and girls (all p<0.001) and 9.7 greater odds of stunting (95% CI 3.3 to 28.6). Each SD decrease in length-for-age in the first 30 months of life was associated with a decrease in adolescent height-for-age of 0.4 in boys and 0.6 standard deviation in girls (all p<0.001) and with 5.8 greater odds of stunting (95% CI 2.6 to 13.5). The effect of weight gain during early childhood on weight in early adolescence was more complex to understand. Weight-for-length at birth and rate of change in weight-for-length in early childhood were positively associated with age- and sex-adjusted body mass index and a greater risk of being overweight in early adolescence. Linear growth retardation in early childhood is a strong determinant of adolescent stature, indicating that, in developing countries, growth failure in height during early childhood persists through early adolescence. Interventions addressing linear growth retardation in childhood are likely to improve adolescent stature and related-health outcomes in adulthood.
PMCID: PMC4013683  PMID: 22552904
Stunting; obesity; development origins
18.  Helicobacter pylori Infection in Infants and Toddlers in South America: Concordance between [13C]Urea Breath Test and Monoclonal H. pylori Stool Antigen Test 
Journal of Clinical Microbiology  2013;51(11):3735-3740.
Accurate noninvasive tests for diagnosing Helicobacter pylori infection in very young children are strongly required. We investigated the agreement between the [13C]urea breath test ([13C]UBT) and a monoclonal ELISA (HpSA) for detection of H. pylori antigen in stool. From October 2007 to July 2011, we enrolled 414 infants (123 from Brazil and 291 from Peru) of ages 6 to 30 months. Breath and stool samples were obtained at intervals of at least 3 months from Brazilian (n = 415) and Peruvian (n = 908) infants. [13C]UBT and stool test results concurred with each other in 1,255 (94.86%) cases (kappa coefficient = 0.90; 95% confidence interval [CI] = 0.87 to 0.92). In the H. pylori-positive group, delta-over-baseline (DOB) and optical density (OD) values were positively correlated (r = 0.62; P < 0.001). The positivity of the tests was higher (P < 0.001; odds ratio [OR] = 6.01; 95% CI = 4.50 to 8.04) in Peru (546/878; 62.2%) than in Brazil (81/377; 21.5%) and increased with increasing age in Brazil (P = 0.02), whereas in Peru it decreased with increasing age (P < 0.001). The disagreement between the test results was associated with birth in Brazil and female gender but not with age and diarrhea. Our results suggest that both [13C]UBT and the stool monoclonal test are reliable for diagnosing H. pylori infection in very young children, which will facilitate robust epidemiological studies in infants and toddlers.
PMCID: PMC3889760  PMID: 24006009
19.  Lung ultrasound for the diagnosis of pneumonia in adults: a systematic review and meta-analysis 
Respiratory Research  2014;15(1):50.
Guidelines do not currently recommend the use of lung ultrasound (LUS) as an alternative to chest X-ray (CXR) or chest computerized tomography (CT) scan for the diagnosis of pneumonia. We conducted a meta-analysis to summarize existing evidence of the diagnostic accuracy of LUS for pneumonia in adults.
We conducted a systematic search of published studies comparing the diagnostic accuracy of LUS against a referent CXR or chest CT scan and/or clinical criteria for pneumonia in adults aged ≥18 years. Eligible studies were required to have a CXR and/or chest CT scan at the time of evaluation. We manually extracted descriptive and quantitative information from eligible studies, and calculated pooled sensitivity and specificity using the Mantel-Haenszel method and pooled positive and negative likelihood ratios (LR) using the DerSimonian-Laird method. We assessed for heterogeneity using the Q and I2 statistics.
Our initial search strategy yielded 2726 articles, of which 45 (1.7%) were manually selected for review and 10 (0.4%) were eligible for analyses. These 10 studies provided a combined sample size of 1172 participants. Six studies enrolled adult patients who were either hospitalized or admitted to Emergency Departments with suspicion of pneumonia and 4 studies enrolled critically-ill adult patients. LUS was performed by highly-skilled sonographers in seven studies, by trained physicians in two, and one did not mention level of training. All studies were conducted in high-income settings. LUS took a maximum of 13 minutes to conduct. Nine studies used a 3.5-5 MHz micro-convex transducer and one used a 5–9 MHz convex probe. Pooled sensitivity and specificity for the diagnosis of pneumonia using LUS were 94% (95% CI, 92%-96%) and 96% (94%-97%), respectively; pooled positive and negative LRs were 16.8 (7.7-37.0) and 0.07 (0.05-0.10), respectively; and, the area-under-the-ROC curve was 0.99 (0.98-0.99).
Our meta-analysis supports that LUS, when conducted by highly-skilled sonographers, performs well for the diagnosis of pneumonia. General practitioners and Emergency Medicine physicians should be encouraged to learn LUS since it appears to be an established diagnostic tool in the hands of experienced physicians.
PMCID: PMC4005846  PMID: 24758612
Lung ultrasound; Pneumonia; Meta-analysis
20.  Molecular Determinants of Lung Development 
Development of the pulmonary system is essential for terrestrial life. The molecular pathways that regulate this complex process are beginning to be defined, and such knowledge is critical to our understanding of congenital and acquired lung diseases. A recent workshop was convened by the National Heart, Lung, and Blood Institute to discuss the developmental principles that regulate the formation of the pulmonary system. Emerging evidence suggests that key developmental pathways not only regulate proper formation of the pulmonary system but are also reactivated upon postnatal injury and repair and in the pathogenesis of human lung diseases. Molecular understanding of early lung development has also led to new advances in areas such as generation of lung epithelium from pluripotent stem cells. The workshop was organized into four different topics, including early lung cell fate and morphogenesis, mechanisms of lung cell differentiation, tissue interactions in lung development, and environmental impact on early lung development. Critical points were raised, including the importance of epigenetic regulation of lung gene expression, the dearth of knowledge on important mesenchymal lineages within the lung, and the interaction between the developing pulmonary and cardiovascular system. This manuscript describes the summary of the discussion along with general recommendations to overcome the gaps in knowledge in lung developmental biology.
PMCID: PMC3955361  PMID: 23607856
lung development; lung cell fate; lung cell differentiation; tissue interaction; environmental impact
21.  A cross-sectional study of determinants of indoor environmental exposures in households with and without chronic exposure to biomass fuel smoke 
Environmental Health  2014;13:21.
Burning biomass fuels indoors for cooking is associated with high concentrations of particulate matter (PM) and carbon monoxide (CO). More efficient biomass-burning stoves and chimneys for ventilation have been proposed as solutions to reduce indoor pollution. We sought to quantify indoor PM and CO exposures in urban and rural households and determine factors associated with higher exposures. A secondary objective was to identify chronic vs. acute changes in cardiopulmonary biomarkers associated with exposure to biomass smoke.
We conducted a census survey followed by a cross-sectional study of indoor environmental exposures and cardiopulmonary biomarkers in the main household cook in Puno, Peru. We measured 24-hour indoor PM and CO concentrations in 86 households. We also measured PM2.5 and PM10 concentrations gravimetrically for 24 hours in urban households and during cook times in rural households, and generated a calibration equation using PM2.5 measurements.
In a census of 4903 households, 93% vs. 16% of rural vs. urban households used an open-fire stove; 22% of rural households had a homemade chimney; and <3% of rural households participated in a national program encouraging installation of a chimney. Median 24-hour indoor PM2.5 and CO concentrations were 130 vs. 22 μg/m3 and 5.8 vs. 0.4 ppm (all p<0.001) in rural vs. urban households. Having a chimney did not significantly reduce median concentrations in 24-hour indoor PM2.5 (119 vs. 137 μg/m3; p=0.40) or CO (4.6 vs. 7.2 ppm; p=0.23) among rural households with and without chimneys. Having a chimney did not significantly reduce median cook-time PM2.5 (360 vs. 298 μg/m3, p=0.45) or cook-time CO concentrations (15.2 vs. 9.4 ppm, p=0.23). Having a thatched roof (p=0.007) and hours spent cooking (p=0.02) were associated with higher 24-hour average PM concentrations. Rural participants had higher median exhaled CO (10 vs. 6 ppm; p=0.01) and exhaled carboxyhemoglobin (1.6% vs. 1.0%; p=0.04) than urban participants.
Indoor air concentrations associated with biomass smoke were six-fold greater in rural vs. urban households. Having a homemade chimney did not reduce environmental exposures significantly. Measures of exhaled CO provide useful cardiopulmonary biomarkers for chronic exposure to biomass smoke.
PMCID: PMC3978088  PMID: 24655424
Biomass smoke; Biomass fuel; Cookstoves; Biomarkers; Exhaled carbon monoxide; Environmental exposure
22.  Measuring socioeconomic status in multicountry studies: results from the eight-country MAL-ED study 
There is no standardized approach to comparing socioeconomic status (SES) across multiple sites in epidemiological studies. This is particularly problematic when cross-country comparisons are of interest. We sought to develop a simple measure of SES that would perform well across diverse, resource-limited settings.
A cross-sectional study was conducted with 800 children aged 24 to 60 months across eight resource-limited settings. Parents were asked to respond to a household SES questionnaire, and the height of each child was measured. A statistical analysis was done in two phases. First, the best approach for selecting and weighting household assets as a proxy for wealth was identified. We compared four approaches to measuring wealth: maternal education, principal components analysis, Multidimensional Poverty Index, and a novel variable selection approach based on the use of random forests. Second, the selected wealth measure was combined with other relevant variables to form a more complete measure of household SES. We used child height-for-age Z-score (HAZ) as the outcome of interest.
Mean age of study children was 41 months, 52% were boys, and 42% were stunted. Using cross-validation, we found that random forests yielded the lowest prediction error when selecting assets as a measure of household wealth. The final SES index included access to improved water and sanitation, eight selected assets, maternal education, and household income (the WAMI index). A 25% difference in the WAMI index was positively associated with a difference of 0.38 standard deviations in HAZ (95% CI 0.22 to 0.55).
Statistical learning methods such as random forests provide an alternative to principal components analysis in the development of SES scores. Results from this multicountry study demonstrate the validity of a simplified SES index. With further validation, this simplified index may provide a standard approach for SES adjustment across resource-limited settings.
PMCID: PMC4234146  PMID: 24656134
Socioeconomic status; Child growth; Classification; Measurement
23.  Molecular Determinants of Lung Development 
Development of the pulmonary system is essential for terrestrial life. The molecular pathways that regulate this complex process are beginning to be defined, and such knowledge is critical to our understanding of congenital and acquired lung diseases. A recent workshop was convened by the National Heart, Lung, and Blood Institute to discuss the developmental principles that regulate the formation of the pulmonary system. Emerging evidence suggests that key developmental pathways not only regulate proper formation of the pulmonary system but are also reactivated upon postnatal injury and repair and in the pathogenesis of human lung diseases. Molecular understanding of early lung development has also led to new advances in areas such as generation of lung epithelium from pluripotent stem cells. The workshop was organized into four different topics, including early lung cell fate and morphogenesis, mechanisms of lung cell differentiation, tissue interactions in lung development, and environmental impact on early lung development. Critical points were raised, including the importance of epigenetic regulation of lung gene expression, the dearth of knowledge on important mesenchymal lineages within the lung, and the interaction between the developing pulmonary and cardiovascular system. This manuscript describes the summary of the discussion along with general recommendations to overcome the gaps in knowledge in lung developmental biology.
PMCID: PMC3955361  PMID: 23607856
lung development; lung cell fate; lung cell differentiation; tissue interaction; environmental impact
24.  A cross-sectional study of differences in 6-min walk distance in healthy adults residing at high altitude versus sea level 
We sought to determine if adult residents living at high altitude have developed sufficient adaptation to a hypoxic environment to match the functional capacity of a similar population at sea level. To test this hypothesis, we compared the 6-min walk test distance (6MWD) in 334 residents living at sea level vs. at high altitude.
We enrolled 168 healthy adults aged ≥35 years residing at sea level in Lima and 166 individuals residing at 3,825 m above sea level in Puno, Peru. Participants completed a 6-min walk test, answered a sociodemographics and clinical questionnaire, underwent spirometry, and a blood test.
Average age was 54.0 vs. 53.8 years, 48% vs. 43% were male, average height was 155 vs. 158 cm, average blood oxygen saturation was 98% vs. 90%, and average resting heart rate was 67 vs. 72 beats/min in Lima vs. Puno. In multivariable regression, participants in Puno walked 47.6 m less (95% CI -81.7 to -13.6 m; p < 0.01) than those in Lima. Other variables besides age and height that were associated with 6MWD include change in heart rate (4.0 m per beats/min increase above resting heart rate; p < 0.001) and percent body fat (-1.4 m per % increase; p = 0.02).
The 6-min walk test predicted a lowered functional capacity among Andean high altitude vs. sea level natives at their altitude of residence, which could be explained by an incomplete adaptation or a protective mechanism favoring neuro- and cardioprotection over psychomotor activity.
PMCID: PMC3909455  PMID: 24484777
Six-minute walk test; High altitude adaptation; Hypoxia; Functional capacity
25.  Multiple Norovirus Infections in a Birth Cohort in a Peruvian Periurban Community 
Serial norovirus infections with multiple genotypes were found among a Peruvian birth cohort early in infancy. Protection against the subsequent infection was genotype specific, suggesting that norovirus vaccines may need to target multiple genotypes.
Background. Human noroviruses are among the most common enteropathogens globally, and are a leading cause of infant diarrhea in developing countries. However, data measuring the impact of norovirus at the community level are sparse.
Methods. We followed a birth cohort of children to estimate norovirus infection and diarrhea incidence in a Peruvian community. Stool samples from diarrheal episodes and randomly selected nondiarrheal samples were tested by polymerase chain reaction for norovirus genogroup and genotype. Excretion duration and rotavirus coinfection were evaluated in a subset of episodes.
Results. Two hundred twenty and 189 children were followed to 1 and 2 years of age, respectively. By 1 year, 80% (95% confidence interval [CI], 75%–85%) experienced at least 1 norovirus infection and by 2 years, 71% (95% CI, 65%–77%) had at least 1 episode of norovirus-associated diarrhea. Genogroup II (GII) infections were 3 times more frequent than genogroup 1 (GI) infections. Eighteen genotypes were found; GII genotype 4 accounted for 41%. Median excretion duration was 34.5 days for GII vs 8.5 days for GI infection (P = .0006). Repeat infections by the same genogroup were common, but repeat infections by the same genotype were rare. Mean length-for-age z score at 12 months was lower among children with prior norovirus infection compared to uninfected children (coefficient: −0.33 [95% CI, −.65 to −.01]; P = .04); the effect persisted at 24 months.
Conclusions. Norovirus infection occurs early in life and children experience serial infections with multiple genotypes, suggesting genotype-specific immunity. An effective vaccine would have a substantial impact on morbidity, but may need to target multiple genotypes.
PMCID: PMC3905757  PMID: 24300042
norovirus; infant diarrhea; gastroenteritis; birth cohort; natural infection

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