Cooking with liquefied petroleum gas or biomass and fetal growth outcomes: a multi-country randomised controlled trial.

BACKGROUND: Household air pollution might lead to fetal growth restriction during pregnancy. We aimed to investigate whether a liquefied petroleum gas (LPG) intervention to reduce personal exposures to household air pollution during pregnancy would alter fetal growth. METHODS: The Household Air Pollution Intervention Network (HAPIN) trial was an open-label randomised controlled trial conducted in ten resource-limited settings across Guatemala, India, Peru, and Rwanda. Pregnant women aged 18-34 years (9-19 weeks of gestation) were randomly assigned in a 1:1 ratio to receive an LPG stove, continuous fuel delivery, and behavioural messaging or to continue usual cooking with biomass for 18 months. We conducted ultrasound assessments at baseline, 24-28 weeks of gestation (the first pregnancy visit), and 32-36 weeks of gestation (the second pregnancy visit), to measure fetal size; we monitored 24 h personal exposures to household air pollutants during these visits; and we weighed children at birth. We conducted intention-to-treat analyses to estimate differences in fetal size between the intervention and control group, and exposure-response analyses to identify associations between household air pollutants and fetal size. This trial is registered with ClinicalTrials.gov (NCT02944682). FINDINGS: Between May 7, 2018, and Feb 29, 2020, we randomly assigned 3200 pregnant women (1593 to the intervention group and 1607 to the control group). The mean gestational age was 14·5 (SD 3·0) weeks and mean maternal age was 25·6 (4·5) years. We obtained ultrasound assessments in 3147 (98·3%) women at baseline, 3052 (95·4%) women at the first pregnancy visit, and 2962 (92·6%) at the second pregnancy visit, through to Aug 25, 2020. Intervention adherence was high (the median proportion of days with biomass stove use was 0·0%, IQR 0·0-1·6) and pregnant women in the intervention group had lower mean exposures to particulate matter with a diameter less than 2·5 µm (PM2·5; 35·0 [SD 37·2] µg/m3vs 103·3 [97·9] µg/m3) than did women in the control group. We did not find differences in averaged post-randomisation Z scores for head circumference (0·30 vs 0·39; p=0·04), abdominal circumference (0·38 vs 0·39; p=0·99), femur length (0·44 vs 0·45; p=0·73), and estimated fetal weight or birthweight (-0·13 vs -0·12; p=0·70) between the intervention and control groups. Personal exposures to household air pollutants were not associated with fetal size. INTERPRETATION: Although an LPG cooking intervention successfully reduced personal exposure to air pollution during pregnancy, it did not affect fetal size. Our findings do not support the use of unvented liquefied petroleum gas stoves as a strategy to increase fetal growth in settings were biomass fuels are used predominantly for cooking. FUNDING: US National Institutes of Health and Bill & Melinda Gates Foundation. TRANSLATIONS: For the Kinyarwanda, Spanish and Tamil translations of the abstract see Supplementary Materials section.

Differences in Cardiometabolic Proteins in Pregnancy Prioritize Relevant Targets of Preeclampsia.

BACKGROUND: Preeclampsia is a hypertensive disorder of pregnancy characterized by widespread vascular inflammation. It occurs frequently in pregnancy, often without known risk factors, and has high rates of maternal and fetal morbidity and mortality. Identification of biomarkers that predict preeclampsia and its cardiovascular sequelae before clinical onset, or even before pregnancy, is a critical unmet need for the prevention of adverse pregnancy outcomes. METHODS: We explored differences in cardiovascular proteomics (Olink Explore 384) in 256 diverse pregnant persons across 2 centers (26% Hispanic, 21% Black). RESULTS: We identified significant differences in plasma abundance of markers associated with angiogenesis, blood pressure, cell adhesion, inflammation, and metabolism between individuals delivering with preeclampsia and controls, some of which have not been widely described previously and are not represented in the preeclampsia placental transcriptome. While we observed a broadly similar pattern in early (<34 weeks) versus late (≥34 weeks) preeclampsia, several proteins related to hemodynamic stress, hemostasis, and immune response appeared to be more highly dysregulated in early preeclampsia relative to late preeclampsia. CONCLUSIONS: These results demonstrate the value of performing targeted proteomics using a panel of cardiovascular biomarkers to identify biomarkers relevant to preeclampsia pathophysiology and highlight the need for larger multiomic studies to define modifiable pathways of surveillance and intervention upstream to preeclampsia diagnosis.

Liquefied Petroleum Gas or Biomass Cooking and Severe Infant Pneumonia.

BACKGROUND: Exposure to household air pollution is a risk factor for severe pneumonia. The effect of replacing biomass cookstoves with liquefied petroleum gas (LPG) cookstoves on the incidence of severe infant pneumonia is uncertain. METHODS: We conducted a randomized, controlled trial involving pregnant women 18 to 34 years of age and between 9 to less than 20 weeks' gestation in India, Guatemala, Peru, and Rwanda from May 2018 through September 2021. The women were assigned to cook with unvented LPG stoves and fuel (intervention group) or to continue cooking with biomass fuel (control group). In each trial group, we monitored adherence to the use of the assigned cookstove and measured 24-hour personal exposure to fine particulate matter (particles with an aerodynamic diameter of ≤2.5 µm [PM2.5]) in the women and their offspring. The trial had four primary outcomes; the primary outcome for which data are presented in the current report was severe pneumonia in the first year of life, as identified through facility surveillance or on verbal autopsy. RESULTS: Among 3200 pregnant women who had undergone randomization, 3195 remained eligible and gave birth to 3061 infants (1536 in the intervention group and 1525 in the control group). High uptake of the intervention led to a reduction in personal exposure to PM2.5 among the children, with a median exposure of 24.2 µg per cubic meter (interquartile range, 17.8 to 36.4) in the intervention group and 66.0 µg per cubic meter (interquartile range, 35.2 to 132.0) in the control group. A total of 175 episodes of severe pneumonia were identified during the first year of life, with an incidence of 5.67 cases per 100 child-years (95% confidence interval [CI], 4.55 to 7.07) in the intervention group and 6.06 cases per 100 child-years (95% CI, 4.81 to 7.62) in the control group (incidence rate ratio, 0.96; 98.75% CI, 0.64 to 1.44; P = 0.81). No severe adverse events were reported to be associated with the intervention, as determined by the trial investigators. CONCLUSIONS: The incidence of severe pneumonia among infants did not differ significantly between those whose mothers were assigned to cook with LPG stoves and fuel and those whose mothers were assigned to continue cooking with biomass stoves. (Funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; HAPIN ClinicalTrials.gov number, NCT02944682.).

Effects of Cooking with Liquefied Petroleum Gas or Biomass on Stunting in Infants.

BACKGROUND: Household air pollution is associated with stunted growth in infants. Whether the replacement of biomass fuel (e.g., wood, dung, or agricultural crop waste) with liquefied petroleum gas (LPG) for cooking can reduce the risk of stunting is unknown. METHODS: We conducted a randomized trial involving 3200 pregnant women 18 to 34 years of age in four low- and middle-income countries. Women at 9 to less than 20 weeks' gestation were randomly assigned to use a free LPG cookstove with continuous free fuel delivery for 18 months (intervention group) or to continue using a biomass cookstove (control group). The length of each infant was measured at 12 months of age, and personal exposures to fine particulate matter (particles with an aerodynamic diameter of ≤2.5 µm) were monitored starting at pregnancy and continuing until the infants were 1 year of age. The primary outcome for which data are presented in the current report - stunting (defined as a length-for-age z score that was more than two standard deviations below the median of a growth standard) at 12 months of age - was one of four primary outcomes of the trial. Intention-to-treat analyses were performed to estimate the relative risk of stunting. RESULTS: Adherence to the intervention was high, and the intervention resulted in lower prenatal and postnatal 24-hour personal exposures to fine particulate matter than the control (mean prenatal exposure, 35.0 µg per cubic meter vs. 103.3 µg per cubic meter; mean postnatal exposure, 37.9 µg per cubic meter vs. 109.2 µg per cubic meter). Among 3061 live births, 1171 (76.2%) of the 1536 infants born to women in the intervention group and 1186 (77.8%) of the 1525 infants born to women in the control group had a valid length measurement at 12 months of age. Stunting occurred in 321 of the 1171 infants included in the analysis (27.4%) of the infants born to women in the intervention group and in 299 of the 1186 infants included in the analysis (25.2%) of those born to women in the control group (relative risk, 1.10; 98.75% confidence interval, 0.94 to 1.29; P = 0.12). CONCLUSIONS: An intervention strategy starting in pregnancy and aimed at mitigating household air pollution by replacing biomass fuel with LPG for cooking did not reduce the risk of stunting in infants. (Funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; HAPIN ClinicalTrials.gov number, NCT02944682.).

Prenatal Low-Dose Aspirin Use Associated with Reduced Incidence of Postpartum Hypertension among Women with Preeclampsia.

OBJECTIVE: Postpartum hypertension (PP-HTN), defined as systolic/diastolic blood pressure (SBP/DBP) ≥140/90, on two occasions at least 4 hours apart after delivery occurs in up to 50% of preeclamptic pregnancies, and is associated with adverse maternal outcomes. Excessive production of antiangiogenic factors (i.e., soluble fms-like tyrosine kinase 1 [sFLT1]) and reduced levels of proangiogenic factors (i.e., placental growth factor [PlGF]) are associated with preeclamptic pregnancies. The aim of this study was to identify clinical risk factors and/or serum biomarkers associated with PP-HTN in preeclampsia. STUDY DESIGN: Preeclamptic women (n = 82, aged ≥18 years) were prospectively enrolled in an observational study. Serial blood pressures were obtained through the labor course and until 48 hours postpartum, and serum was obtained within 24 hours postpartum. Statistical analysis was performed by using Student's two-tailed t-test and Fisher's exact test. RESULTS: Baseline comorbidities and antihypertensive use were similar among those who developed PP-HTN and those who did not. Among preeclamptic patients, 33% developed PP-HTN; these had significantly more severe preeclampsia features versus no PP-HTN (96 vs. 78%, p = 0.05). PP-HTN was associated with higher re-hospitalization rates (26 vs. 6%, p = 0.01). Among those taking low-dose aspirin (ASA) for preeclampsia prophylaxis (n = 12), PP-HTN was significantly less frequent versus those not taking low-dose ASA (0 vs. 22%, p = 0.007). Low-dose ASA use was associated with significantly lower peripartum sFLT1 levels (4,650 ± 2,335 vs. 7,870 ± 6,282 pg/mL, p = 0.03) and sFLT1/PlGF ratio (397 ± 196 vs. 1,527 ± 2,668, p = 0.03). CONCLUSION: One-third of women with preeclampsia develop PP-HTN; these patients have more severe preeclampsia and have higher re-hospitalization rates. Prenatal low-dose ASA use was associated with significantly lower incidence of PP-HTN, reduced levels of antiangiogenic factors, and lower 6-week re-hospitalization rates. These findings, if replicated, may have clinical implications on the use of low-dose ASA during pregnancy to reduce incidence of postpartum HTN. KEY POINTS: · Postpartum hypertension is common in preeclampsia.. · Prenatal aspirin may reduce postpartum hypertension.. · Prenatal aspirin may reduce sFLT1 levels..

Effects of a Liquefied Petroleum Gas Stove Intervention on Gestational Blood Pressure: Intention-to-Treat and Exposure-Response Findings From the HAPIN Trial.

BACKGROUND: Approximately 3 to 4 billion people worldwide are exposed to household air pollution, which has been associated with increased blood pressure (BP) in pregnant women in some studies. METHODS: We recruited 3195 pregnant women in Guatemala, India, Peru, and Rwanda and randomly assigned them to intervention or control groups. The intervention group received a gas stove and fuel during pregnancy, while the controls continued cooking with solid fuels. We measured BP and personal exposure to PM2.5, black carbon and carbon monoxide 3× during gestation. We conducted an intention-to-treat and exposure-response analysis to determine if household air pollution exposure was associated with increased gestational BP. RESULTS: Median 24-hour PM2.5 dropped from 84 to 24 µg/m3 after the intervention; black carbon and carbon monoxide decreased similarly. Intention-to-treat analyses showed an increase in systolic BP and diastolic BP in both arms during gestation, as expected, but the increase was greater in intervention group for both systolic BP (0.69 mm Hg [0.03-1.35]; P=0.04) and diastolic BP (0.62 mm Hg [0.05-1.19]; P=0.03). The exposure-response analyses suggested that higher exposures to household air pollution were associated with moderately higher systolic BP and diastolic BP; however, none of these associations reached conventional statistical significance. CONCLUSIONS: In intention-to-treat, we found higher gestational BP in the intervention group compared with controls, contrary to expected. In exposure-response analyses, we found a slight increase in BP with higher exposure, but it was not statistically significant. Overall, an intervention with gas stoves did not markedly affect gestational BP.

High rates of undiagnosed and uncontrolled hypertension upon a screening campaign in rural Rwanda: a cross-sectional study.

BACKGROUND: Hypertension remains the major risk factor for cardiovascular diseases (CVDs) worldwide with a prevalence and mortality in low- and middle-income countries (LMICs) among the highest. The early detection of hypertension risk factors is a crucial pillar for CVD prevention. DESIGN AND METHOD: This cross-sectional study included 4284 subjects, mean age 46 ± 16SD, 56.4% females and mean BMI 26.6 ± 3.7 SD. Data were collected through a screening campaign in rural area of Kirehe District, Eastern of Rwanda, with the objective to characterize and examine the prevalence of elevated blood pressure (BP) and other CVD risk factors. An adapted tool from the World Health Organization STEPwise Approach was used for data collection. Elevated BP was defined as ≥ 140/90 mm/Hg and elevated blood glucose as blood glucose ≥ 100 mg/dL after a 6-h fast. RESULTS: Of the sampled population, 21.2% (n = 910) had an elevated BP at screening; BP was elevated among individuals not previously known to have HTN in 18.7% (n = 752). Among individuals with a prior diagnosis of HTN, 62.2% (n = 158 of 254) BP was uncontrolled. Age, weight, smoking, alcohol history and waist circumference were associated with BP in both univariate analyses and multivariate analysis. CONCLUSION: High rates of elevated BP identified through a health screening campaign in this Rwandan district were surprising given the rural characteristics of the district and relatively low population age. These data highlight the need to implement an adequate strategy for the prevention, diagnosis, and control of HTN that includes rural areas of Rwanda as part of a multicomponent strategy for CVD prevention.

Effects of a Household Air Pollution Intervention with Liquefied Petroleum Gas on Cardiopulmonary Outcomes in Peru. A Randomized Controlled Trial.

Rationale: Approximately 40% of people worldwide are exposed to household air pollution (HAP) from the burning of biomass fuels. Previous efforts to document health benefits of HAP mitigation have been stymied by an inability to lower emissions to target levels. Objectives: We sought to determine if a household air pollution intervention with liquefied petroleum gas (LPG) improved cardiopulmonary health outcomes in adult women living in a resource-poor setting in Peru. Methods: We conducted a randomized controlled field trial in 180 women aged 25-64 years living in rural Puno, Peru. Intervention women received an LPG stove, continuous fuel delivery for 1 year, education, and behavioral messaging, whereas control women were asked to continue their usual cooking practices. We assessed for stove use adherence using temperature loggers installed in both LPG and biomass stoves of intervention households. Measurements and Main Results: We measured blood pressure, peak expiratory flow (PEF), and respiratory symptoms using the St. George's Respiratory Questionnaire at baseline and at 3-4 visits after randomization. Intervention women used their LPG stove exclusively for 98% of days. We did not find differences in average postrandomization systolic blood pressure (intervention - control 0.7 mm Hg; 95% confidence interval, -2.1 to 3.4), diastolic blood pressure (0.3 mm Hg; -1.5 to 2.0), prebronchodilator peak expiratory flow/height2 (0.14 L/s/m2; -0.02 to 0.29), postbronchodilator peak expiratory flow/height2 (0.11 L/s/m2; -0.05 to 0.27), or St. George's Respiratory Questionnaire total score (-1.4; -3.9 to 1.2) over 1 year in intention-to-treat analysis. There were no reported harms related to the intervention. Conclusions: We did not find evidence of a difference in blood pressure, lung function, or respiratory symptoms during the year-long intervention with LPG. Clinical trial registered with www.clinicaltrials.gov (NCT02994680).

The Spectrum of Pregnancy-Associated Heart Failure Phenotypes: An Echocardiographic Study.

Compare echocardiographic phenotypes of women presenting with peripartum heart failure. A retrospective case-control study of pregnant women (n = 86) presenting with PP-HF symptoms (i.e., dyspnea, PND, orthopnea) and objective examination and laboratory findings (lung congestion, elevated JVP and/or HJR, elevated brain natriuretic peptide [BNP] and pulmonary edema on chest X-ray). Three distinct phenotypes based on echocardiographically-defined LVEF were identified: (a) PP-HF with preserved ejection fraction (PP HFpEF, LVEF: > 50%); (b) PP-HF with midrange ejection fraction (PP HFmrEF, LVEF: 40-50%); c) PP-HF with reduced ejection fraction (PP HFrEF, LVEF: < 40%); these were compared with 17 pregnant subjects without PP-HF symptoms/findings. Most patients were African American (n = 63; 73%), with low prevalence of hypertension (n = 15, 17%) or diabetes mellitus (n = 5, 5%); pre-eclampsia was highly prevalent (n = 52, 60%). Echocardiographically-defined phenotypes (HFpEF, n = 37; HFmrEF, n = 18; HFrEF, n = 31) showed progressively worse abnormalities in LV remodeling (LV enlargement, LV hypertrophy), LV diastolic function, and right ventricular function; the three PP-HF groups had comparable abnormalities in increased left atrial size and estimated peak tricuspid valve regurgitation velocity. Compared to controls, all three groups had significantly increased filling pressures, LV mass index and left atrial volume index. Peripartum women presenting with the clinical syndrome of heart failure exhibit a spectrum of echocardiographic phenotypes. Significant abnormalities in LV structure, diastolic function, LA size, peak TR velocity and RV function were identified in women with preserved and mid-range EFs, suggesting pregnancy-related cardiac pathophysiologic derangements.

Design and Rationale of the HAPIN Study: A Multicountry Randomized Controlled Trial to Assess the Effect of Liquefied Petroleum Gas Stove and Continuous Fuel Distribution.

BACKGROUND: Globally, nearly 3 billion people rely on solid fuels for cooking and heating, the vast majority residing in low- and middle-income countries (LMICs). The resulting household air pollution (HAP) is a leading environmental risk factor, accounting for an estimated 1.6 million premature deaths annually. Previous interventions of cleaner stoves have often failed to reduce exposure to levels that produce meaningful health improvements. There have been no multicountry field trials with liquefied petroleum gas (LPG) stoves, likely the cleanest scalable intervention. OBJECTIVE: This paper describes the design and methods of an ongoing randomized controlled trial (RCT) of LPG stove and fuel distribution in 3,200 households in 4 LMICs (India, Guatemala, Peru, and Rwanda). METHODS: We are enrolling 800 pregnant women at each of the 4 international research centers from households using biomass fuels. We are randomly assigning households to receive LPG stoves, an 18-month supply of free LPG, and behavioral reinforcements to the control arm. The mother is being followed along with her child until the child is 1 year old. Older adult women (40 to <80 years of age) living in the same households are also enrolled and followed during the same period. Primary health outcomes are low birth weight, severe pneumonia incidence, stunting in the child, and high blood pressure (BP) in the older adult woman. Secondary health outcomes are also being assessed. We are assessing stove and fuel use, conducting repeated personal and kitchen exposure assessments of fine particulate matter with aerodynamic diameter ≤2.5µm (PM2.5), carbon monoxide (CO), and black carbon (BC), and collecting dried blood spots (DBS) and urinary samples for biomarker analysis. Enrollment and data collection began in May 2018 and will continue through August 2021. The trial is registered with ClinicalTrials.gov (NCT02944682). CONCLUSIONS: This study will provide evidence to inform national and global policies on scaling up LPG stove use among vulnerable populations. https://doi.org/10.1289/EHP6407.

Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness.

BACKGROUND: Metabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalarial drug chloroquine activates the kinase ataxia telangiectasia mutated (ATM), improves metabolic syndrome and reduces atherosclerosis in mice. To translate this observation to humans, we conducted two clinical trials of chloroquine in people with the metabolic syndrome. METHODS: Eligibility included adults with at least 3 criteria of metabolic syndrome but who did not have diabetes. Subjects were studied in the setting of a single academic health center. The specific hypothesis: chloroquine improves insulin sensitivity and decreases atherosclerosis. In Trial 1, the intervention was chloroquine dose escalations in 3-week intervals followed by hyperinsulinemic euglycemic clamps. Trial 2 was a parallel design randomized clinical trial, and the intervention was chloroquine, 80 mg/day, or placebo for 1 year. The primary outcomes were clamp determined-insulin sensitivity for Trial 1, and carotid intima-media thickness (CIMT) for Trial 2. For Trial 2, subjects were allocated based on a randomization sequence using a protocol in blocks of 8. Participants, care givers, and those assessing outcomes were blinded to group assignment. RESULTS: For Trial 1, 25 patients were studied. Chloroquine increased hepatic insulin sensitivity without affecting glucose disposal, and improved serum lipids. For Trial 2, 116 patients were randomized, 59 to chloroquine (56 analyzed) and 57 to placebo (51 analyzed). Chloroquine had no effect on CIMT or carotid contrast enhancement by MRI, a pre-specified secondary outcome. The pre-specified secondary outcomes of blood pressure, lipids, and activation of JNK (a stress kinase implicated in diabetes and atherosclerosis) were decreased by chloroquine. Adverse events were similar between groups. CONCLUSIONS: These findings suggest that low dose chloroquine, which improves the metabolic syndrome through ATM-dependent mechanisms in mice, modestly improves components of the metabolic syndrome in humans but is unlikely to be clinically useful in this setting.Trial registration ClinicalTrials.gov (NCT00455325, NCT00455403), both posted 03 April 2007.

Determinants of Diuretic Responsiveness and Associated Outcomes During Acute Heart Failure Hospitalization: An Analysis From the NHLBI Heart Failure Network Clinical Trials.

BACKGROUND: Poor response to loop diuretic therapy is a marker of risk during heart failure hospitalization. We sought to describe baseline determinants of diuretic response and to further explore the relationship between this response and clinical outcomes. METHODS AND RESULTS: Patient data from the National Heart, Lung, and Blood Institute Heart Failure Network ROSE-AHF and CARRESS-HF clinical trials were analyzed to determine baseline determinants of diuretic response. Diuretic efficiency (DE) was defined as total 72-hour fluid output per total equivalent loop diuretic dose. Data from DOSE-AHF was then used to determine if these predictors of DE correlated with response to a high- versus low-dose diuretic strategy. At 72 hours, the high-DE group had median fluid output of 9071 ml (interquartile range: 7240-11775) with median furosemide dose of 320 mg (220-480) compared with 8030 ml (6300-9915) and 840 mg (600-1215) respectively for the low DE group. Cystatin C was independently associated with DE (odds ratio 0.36 per 1mg/L increase; 95% confidence interval: 0.24-0.56; P < 0.001). Independently from baseline characteristics, reduced fluid output, weight loss and DE were each associated with increased 60 day mortality. Among patients with estimated glomerular filtration rate below the median, those randomized to a high-dose strategy had improved symptoms compared with those randomized to a low-dose strategy. CONCLUSIONS: Elevated baseline cystatin C, as a biomarker of renal dysfunction, is associated with reduced diuretic response during heart failure hospitalization. Higher loop diuretic doses are required for therapeutic decongestion in patients with renal insufficiency. Poor response identifies a high-risk population.

Effects of a liquefied petroleum gas stove intervention on pollutant exposure and adult cardiopulmonary outcomes (CHAP): study protocol for a randomized controlled trial.

BACKGROUND: Biomass fuel smoke is a leading risk factor for the burden of disease worldwide. International campaigns are promoting the widespread adoption of liquefied petroleum gas (LPG) in resource-limited settings. However, it is unclear if the introduction and use of LPG stoves, in settings where biomass fuels are used daily, reduces pollution concentration exposure, improves health outcomes, or how cultural and social barriers influence the exclusive adoption of LPG stoves. METHODS: We will conduct a randomized controlled, field intervention trial of LPG stoves and fuel distribution in rural Puno, Peru, in which we will enroll 180 female participants aged 25-64 years and follow them for 2 years. After enrollment, we will collect information on sociodemographic characteristics, household characteristics, and cooking practices. During the first year of the study, LPG stoves and fuel tanks will be delivered to the homes of 90 intervention participants. During the second year, participants in the intervention arm will keep their LPG stoves, but the gas supply will stop. Control participants will receive LPG stoves and vouchers to obtain free fuel from distributors at the beginning of the second year, but gas will not be delivered. Starting at baseline, we will collect longitudinal measurements of respiratory symptoms, pulmonary function, blood pressure, endothelial function, carotid artery intima-media thickness, 24-h dietary recalls, exhaled carbon monoxide, quality-of-life indicators, and stove-use behaviors. Environmental exposure assessments will occur six times over the 2-year follow-up period, consisting of 48-h personal exposure and kitchen concentration measurements of fine particulate matter and carbon monoxide, and 48-h kitchen concentrations of nitrogen dioxide for a subset of 100 participants. DISCUSSION: Findings from this study will allow us to better understand behavioral patterns, environmental exposures, and cardiovascular and pulmonary outcomes resulting from the adoption of LPG stoves. If this trial indicates that LPG stoves are a feasible and effective way to reduce household air pollution and improve health, it will provide important information to support widespread adoption of LPG fuel as a strategy to reduce the global burden of disease. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02994680 , Cardiopulmonary Outcomes and Household Air Pollution (CHAP) Trial. Registered on 28 November 2016.

Association between serum concentrations of hypoxia inducible factor responsive proteins and excessive erythrocytosis in high altitude Peru.

Painschab, Matthew S., Gary E. Malpartida, Victor G. Davila-Roman, Robert H. Gilman, Todd M. Kolb, Fabiola Leon-Velarde, J. Jaime Miranda, and William Checkley. Association between serum concentrations of hypoxia inducible factor responsive proteins and excessive erythrocytosis in high altitude Peru. High Alt Med Biol 16:26-33, 2015.-Long-term residence at high altitude is associated with the development of chronic mountain sickness (CMS), which is characterized by excessive erythrocytosis (EE). EE occurs under chronic hypoxia, and a strongly selected mutation in hypoxia-inducible factor 2α (HIF2A) has been found in native Tibetans that correlates with having a normal hemoglobin at high altitude. We sought to evaluate differences in plasma levels of four HIF-responsive proteins in 20 participants with EE (hemoglobin >21 g/dL in men and >19 in women) and in 20 healthy, age- and sex-matched participants without EE living at high altitude in Puno, Peru. We performed ELISA to measure plasma levels of the four HIF-responsive proteins: vascular endothelial growth factor (VEGF), soluble VEGF receptor 1 (sVEGF-R1), endothelin-1, and erythropoietin. As a secondary aim, we evaluated the association between HIF-responsive proteins and echocardiography-estimated pulmonary artery systolic pressure (PASP) in a subset of 26 participants. sVEGF-R1 was higher in participants with vs. without EE (mean 107 pg/mL vs. 90 pg/mL; p=0.007). Although plasma concentrations of endothelin-1, VEGF, and erythropoietin were higher in participants with vs. without EE, they did not achieve statistical significance (all p>0.25). Both sVEGF-R1 (p=0.04) and erythropoietin (p=0.04) were positively associated with PASP after adjustment for age, sex, and BMI. HIF-responsive proteins may play a pathophysiological role in altitude-related, chronic diseases but our results did not show consistent changes in all measured HIF-responsive proteins. Larger studies are needed to evaluate for additional genetic and environmental risk factors.

Prevalence, clinical profile, iron status, and subject-specific traits for excessive erythrocytosis in andean adults living permanently at 3,825 meters above sea level.

BACKGROUND: Excessive erythrocytosis (EE) is a prevalent condition in populations living at high altitudes (> 2,500 m above sea level). Few large population-based studies have explored the association between EE and multiple subject-specific traits including oxygen saturation, iron status indicators, and pulmonary function. METHODS: We enrolled a sex-stratified and age-stratified sample of 1,065 high-altitude residents aged ≥ 35 years from Puno, Peru (3,825 m above sea level) and conducted a standardized questionnaire and physical examination that included spirometry, pulse oximetry, and a blood sample for multiple clinical markers. Our primary objectives were to estimate the prevalence of EE, characterize the clinical profile and iron status indicators of subjects with EE, and describe subject-specific traits associated with EE. RESULTS: Overall prevalence of EE was 4.5% (95% CI, 3.3%-6.0%). Oxygen saturation was significantly lower among EE than non-EE group subjects (85.3% vs 90.1%, P < .001) but no difference was found in iron status indicators between both groups (P > .09 for all values). In multivariable logistic regression, we found that age ≥ 65 years (OR = 2.45, 95% CI, 1.16-5.09), male sex (3.86, 1.78-9.08), having metabolic syndrome (2.66, 1.27-5.75) or being overweight (5.20, 1.95-16.77), pulse oximetry < 85% (14.90, 6.43-34.90), and % predicted FVC < 80% (13.62, 4.40-41.80) were strongly associated with EE. Attributable fractions for EE were greatest for being overweight (26.7%), followed by male sex (21.5%), pulse oximetry < 85% (16.4%), having metabolic syndrome (14.4%), and % predicted FVC < 80% (9.3%). CONCLUSIONS: We found a lower prevalence of EE than in previous reports in the Peruvian Andes. Although the presence of hypoxemia and decreased vital capacity were strongly associated with excessive erythrocytosis, being overweight or having metabolic syndrome were associated with an important fraction of cases in our study population.