Estimating Percentile-Specific Causal Effects: A Case Study of Micronutrient Supplementation, Birth Weight, and Infant Mortality

In developing countries, higher infant mortality is partially caused by poor maternal and fetal nutrition. Clinical trials of micronutrient supplementation are aimed at reducing the risk of infant mortality by increasing birth weight. Because infant mortality is greatest among the low birth weight infants (LBW) (• 2500 grams), an effective intervention may need to increase the birth weight among the smallest babies. Although it has been demonstrated that supplementation increases the birth weight in a trial conducted in Nepal, there is inconclusive evidence that the supplementation improves their survival. It has been hypothesized that a potential benefit of the treatment on survival among the LBW is partly compensated by a null or even harmful effects among the largest infants. Thus, two key scientific questions are whether the effect of the treatment on survival differs across the birth weight distribution (e.g. is largest among the LBW), and whether the effect of the treatment on survival is mediated wholly or in part by increases in birth weight. Motivated by a community trial in Nepal, this paper defines population and causal parameters for estimating the treatment effects on birth weight and on survival as functions of the percentiles of the birth weight distribution. We develop a model with potential outcomes and implement principal stratification for estimating and comparing the causal effects of the treatment on mortality in sub-populations of babies defined by their birth weights. We use a Bayesian approach with data augmentation to approximate the posterior distributions of the parameters taking into account uncertainty associated with the imputation of the counterfactuals. This approach is particularly suitable for exploring the sensitivity of the results to modelling assumptions and other prior beliefs. Our analysis shows that the average causal effect of the treatment on birth weight is equal to 68 grams (95% posterior regions 25 to 110) and that this causal effect is largest among the LBW. Posterior inferences about average causal effects of the treatment on birth weight are robust to modelling assumptions. However inferences about causal effects for babies at the tails of the birth weight distribution can be highly sensitive to the unverifiable assumption about the correlation between the observed and the counterfactuals birth weights. Among the LBW infants who have a large causal effect of the treatment on birth weight, we found that a baby receiving the treatment has 5% to 7% less chance of death if the same baby had received the control. Among the LBW,we found weak evidence supporting an additional beneficial effect of the treatment on mortality independent of birth weight

Does the Effect of Micronutrient Supplementation on Neonatal Survival Vary with Respect to the Percentiles of the Birth Weight Distribution?

Scientific Background: In developing countries, higher infant mortality is partially caused by poor maternal and fetal nutrition. Clinical trials of micronutrient supplementation are aimed at reducing the risk of infant mortality by increasing birth weight. Because infant mortality is greatest among the low birth weight infants (LBW) (less than or equal to 2500 grams), an effective intervention might be needed to increase birth weight among the smallest babies. Although it has been demonstrated that supplementation increases the birth weight in a trial conducted in Nepal, there is inconclusive evidence that the supplementation improves their survival. It has been hypothesized that a potential benefit of the treatment on survival among the LBW infants is partly compensated by a null or even harmful effects among the largest infants. Exploratory analyses have suggested that the treatment effect on birth weight might vary with respect to the percentiles of the birth weight distribution. Data: The methods in this paper are motivated by a double-blind randomized community trial in rural Nepal (Christian et al. 2003a,b). The investigators implemented an intervention program to evaluate benefits of the following micronutrient supplementations: folic acid and vitamin A (F+A); folic acid, iron, and vitamin A (F+I+A); folic acid, iron, zinc, and vitamin A (F+I+Z+A); multiple nutrients and vitamin A (M+A). Each micronutrient supplement was administered weekly to 1000 pregnant women, who ultimately delivered approximately 800 live-born infants. The team measured the birth weight within 72 hours of delivery and then followed the infants for one year to determine whether or not they survived. In addition, they measured several characteristics of the mother (maternal age, parity, maternal height, arm circumference) and of the infant (weight, length, head and chest circumference). In this case study we focus on the supplementations F + I + A and M + A as compared to vitamin A only and we address the following scientific questions: 1. Is there an overall effect of the treatments on birth weight? Does this effect vary with the percentiles of the birth weight distribution; in particular, is it largest among the LBW infants? 2. Is there an overall effect of the treatments on survival? Does this effect vary with the percentiles of the birth weight distribution; in particular, is it largest among the LBW infants? 3. Do these percentile-specific effects on birth weight and survival differ by micronutrients? Statistical Approach: The data analysis is challenged by measurement error and informative missing data in birth weight and survival. In community-based interventions in developing countries, most births occur in the home without assistance from trained birth attendants. Approximately 88% of the babies are measured within 72 hours of the delivery. The remaining 12% are measured between the 72 and the 2000 hours approximately. Hence, weights are obtained at varying times following birth and therefore they are imprecise measures of the true weight at birth . In addition, a high proportion of deaths of young infants occur in the first few hours after birth. If there is a delay in reaching the mother and infant, then many of these infants would be weighed because they have already died. For example in the F +1+ A group, approximately 7% of the birth weight measurements are missing and among this 7%, approximately 34% of the babies have died right within 24 hours of the delivery. These babies are likely to have been of lower birth weight than those who survived to be weighed, and therefore, these missing birth weights due to death are likely to be informative. In this paper we develop a measurement error model with counterfactual variables that address the scientific questions for this birth weight-mortality case study. Our approach integrates Bayesian methods and data augmentation (Tanner and Wong, 1987; Tanner, 1991; Albert and Chib, 1993; Chib and Greenberg, 1998) with a counterfactual model and principal stratification (Rubin, 1978; Holland, 1986; Frangakis and Rubin, 2002). We calculate marginal posterior distributions of the treatment effects on birth weight and infant mortality that are allowed to vary with the percentiles of the birth weight distributions. We compare our posterior inferences with two simpler approaches. The first still relies on a Bayesian approach but ignores the uncertainty in the imputation and prediction of the birth weight and does account for the mother\u27s covariates. The second is a simpler re-sampling approach that imputes the missing birth weights (Rubin, 1987). Results and Public Health Impact: First we found that both F+I+A and M+A increase birth weight. However, the F+I+A increases birth weight mainly among the LBW infants, whereas M + A increases birth weight across the entire birth weight distribution compared to vitamin A only. The F+I+A reduces the risk of infant mortality, whereas the M+A slightly increases the risk of early infant mortality, especially among the larger infants. Currently recommendations exist to supplement pregnant women in developing countries. This case study provides critical information toward the evaluation and planning of these public health interventions

Structure of the carbon layers deposited on the toroidal pump limiter of Tore Supra

International audienceScanning and transmission electron microscopy analyses have been performed for tiles extracted from the toroidal pump limiter of Tore Supra for erosion- and deposition-dominated zones. Deposit thicknesses have been estimated for the plasma-facing top and the gap side lateral surfaces. Deposit thickness profiles have been measured inside gaps, showing that deposition mainly occurs in the first millimetre and that both poloidal and toroidal gap deposition is asymmetric. Quantitative information on the deposit volume and on D-retention are thus obtained from these measurements. Carbon probed at the tile top surfaces is mainly amorphous carbon, due either to the amorphization induced by ion bombardment in the erosion dominated zone, or to deposit formation processes in the deposition-dominated zones. Deposits are tip-shaped and are oriented, which should give information on transport processes

Dataset associated with "Unequal airborne exposure burden to toxic metals is associated with race, ethnicity, and segregation"

This dataset contains annual and county-level mean concentrations and mass proportions of fine particulate metals (aggregated from the EPA's CSN/IMPROVE networks), associated minimum detectable limit for each monitor, as well as racial and ethnic demographic population data. This dataset is aggregated from publicly available air pollutant data from the EPA (http://views.cira.colostate.edu/fed/QueryWizard/Default.aspx) and the US Census Bureau (https://data.census.gov/cedsci/). This dataset is used to examine the association of racial residential segregation with fine particulate metal concentrations. The time period ranges from year 2009 to 2019.- Columns labeled "XX_concentration" report the annual and county-level mean concentration in ug m-3 - Columns labeled 'XX_content" report the mass proportion of fine particulate metals relative to PM2.5 mass - Columns labeled "XX_mdl" report the minimum detectable limit for that species at that monitor. In the case of more than one monitor in the county, this column reports the average. - Columns labeled "DI_XX" report the dissimilarity index for the racial/ethnic group using the non-Hispanic White population as the reference population (see associated manuscript for details), where "NHB" corresponds to non-Hispanic Black and "native_amer" to "Native American". - Columns labeled "XX_pop_county" report the county population of the respective racial/ethnic group. These groupings reflect the identification made by individuals in US Census Bureau data. "NHW" refers to "non-Hispanic White". - "CountyFIPS" refers to the county FIPS code. - "Latitude" and "Longitude" reflect the coordinates of the monitor in degrees. In the case of more than one monitor per county, these columns averages.Communities of color have been exposed to a disproportionate burden of air pollution across the United States for decades. Yet, the inequality in exposure to known toxic elements of air pollution is unclear. Here, we find that populations living in racially segregated communities are exposed to a form of fine particulate matter with over three times higher mass proportions of known toxic and carcinogenic metals. While concentrations of total fine particulate matter are two times higher in racially segregated communities, concentrations of metals from anthropogenic sources are nearly ten times higher. Populations living in racially segregated communities have been disproportionately exposed to these environmental stressors throughout the past decade. We find evidence, however, that these disproportionate exposures may be abated though targeted regulatory action. For example, recent regulations on marine fuel oil not only reduced vanadium concentrations in coastal cities, but also sharply lessened differences in vanadium exposure by segregation.This work was supported financially by grants from the Health Effects Institute under grant number 4953- RFA14-3/16-4 awarded to FD, National Institute of Health under grant numbers DP2MD012722 and P50MD010428 awarded to FD, National Institute of Health and National Institute of Environmental Health Sciences under grant number R01 ES028033 awarded to FD, National Institute of Health and Columbia University under grant number 1R01ES030616 awarded to FD, the National Institute On Minority Health And Health Disparities of the National Institutes of Health under award number R01MD012769 awarded to MLB and FD, the Environmental Protection Agency under grant number 83587201-0 awarded to FD and grant number RD83587101 awarded to MLB, The Climate Change Solutions Fund, and the Harvard Star Friedman Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Environmental Protection Agency

Regional and global contributions of air pollution to risk of death from COVID-19.

AIMS: The risk of mortality from the coronavirus disease that emerged in 2019 (COVID-19) is increased by comorbidity from cardiovascular and pulmonary diseases. Air pollution also causes excess mortality from these conditions. Analysis of the first severe acute respiratory syndrome coronavirus (SARS-CoV-1) outcomes in 2003, and preliminary investigations of those for SARS-CoV-2 since 2019, provide evidence that the incidence and severity are related to ambient air pollution. We estimated the fraction of COVID-19 mortality that is attributable to the long-term exposure to ambient fine particulate air pollution. METHODS AND RESULTS: We characterized global exposure to fine particulates based on satellite data, and calculated the anthropogenic fraction with an atmospheric chemistry model. The degree to which air pollution influences COVID-19 mortality was derived from epidemiological data in the USA and China. We estimate that particulate air pollution contributed ∼15% (95% confidence interval 7-33%) to COVID-19 mortality worldwide, 27% (13 - 46%) in East Asia, 19% (8-41%) in Europe, and 17% (6-39%) in North America. Globally, ∼50-60% of the attributable, anthropogenic fraction is related to fossil fuel use, up to 70-80% in Europe, West Asia, and North America. CONCLUSION: Our results suggest that air pollution is an important cofactor increasing the risk of mortality from COVID-19. This provides extra motivation for combining ambitious policies to reduce air pollution with measures to control the transmission of COVID-19

Prime Focus Spectrograph - Subaru's future -

The Prime Focus Spectrograph (PFS) of the Subaru Measurement of Images and Redshifts (SuMIRe) project has been endorsed by Japanese community as one of the main future instruments of the Subaru 8.2-meter telescope at Mauna Kea, Hawaii. This optical/near-infrared multi-fiber spectrograph targets cosmology with galaxy surveys, Galactic archaeology, and studies of galaxy/AGN evolution. Taking advantage of Subaru's wide field of view, which is further extended with the recently completed Wide Field Corrector, PFS will enable us to carry out multi-fiber spectroscopy of 2400 targets within 1.3 degree diameter. A microlens is attached at each fiber entrance for F-ratio transformation into a larger one so that difficulties of spectrograph design are eased. Fibers are accurately placed onto target positions by positioners, each of which consists of two stages of piezo-electric rotary motors, through iterations by using back-illuminated fiber position measurements with a wide-field metrology camera. Fibers then carry light to a set of four identical fast-Schmidt spectrographs with three color arms each: the wavelength ranges from 0.38 {\mu}m to 1.3 {\mu}m will be simultaneously observed with an average resolving power of 3000. Before and during the era of extremely large telescopes, PFS will provide the unique capability of obtaining spectra of 2400 cosmological/astrophysical targets simultaneously with an 8-10 meter class telescope. The PFS collaboration, led by IPMU, consists of USP/LNA in Brazil, Caltech/JPL, Princeton, & JHU in USA, LAM in France, ASIAA in Taiwan, and NAOJ/Subaru.Comment: 13 pages, 11 figures, submitted to "Ground-based and Airborne Instrumentation for Astronomy IV, Ian S. McLean, Suzanne K. Ramsay, Hideki Takami, Editors, Proc. SPIE 8446 (2012)

Impact of proton pump inhibitors on efficacy of antiplatelet strategies with ticagrelor or aspirin after percutaneous coronary intervention:Insights from the GLOBAL LEADERS trial

BACKGROUND Several studies have suggested that proton pump inhibitors (PPIs) may reduce the antiplatelet effects of clopidogrel and/or aspirin, possibly leading to cardiovascular events. AIMS We aimed to investigate the association between PPI and clinical outcomes in patients treated with ticagrelor monotherapy or conventional antiplatelet therapy after percutaneous coronary intervention (PCI). METHODS This is a subanalysis of the randomized GLOBAL LEADERS trial, comparing the experimental antiplatelet arm (23-month ticagrelor monotherapy following 1-month dual antiplatelet therapy [DAPT]) with the reference arm (12-month aspirin monotherapy following 12-month DAPT) after PCI. Patient-oriented composite endpoints (POCEs: all-cause mortality, myocardial infarction, stroke, or repeat revascularization) and its components were assessed stratified by PPI use as a time-dependent covariate in patients with the experiment or reference antiplatelet arm. RESULTS Among 15,839 patients, 2115 patients (13.5%) experienced POCE at 2 years. In the reference arm, the use of PPIs was independently associated with POCE (hazard ratio [HR]: 1.27; 95% confidence interval [CI]: 1.12-1.44) and its individual components, whereas it was not in the experimental arm (HR: 1.04; 95% CI: 0.92-1.19; pinteraction  = 0.035). During the second-year follow-up, patients taking aspirin with PPIs had a significantly higher risk of POCE compared to those on aspirin without PPIs (HR: 1.57; 95% CI: 1.27-1.94), whereas the risk did not differ significantly irrespective of PPI in ticagrelor monotherapy group (HR: 1.03; 95% CI: 0.83-1.28; pinteraction  = 0.008). CONCLUSIONS In contrast to conventional antiplatelet strategy, there were no evidence suggesting the interaction between ticagrelor monotherapy and PPIs on increased cardiovascular events, which should be confirmed in further studies. CLINICAL TRIAL REGISTRATION URL: https://clinicaltrials.gov

Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial

Background: ORTHO-1 is a European, multicentric, first in human clinical trial to prove safety and feasibility after surgical implantation of commercially available biphasic calcium phosphate bioceramic granules associated during surgery with autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSC) under good manufacturing practices, in patients with long bone pseudarthrosis. Methods: Twenty-eight patients with femur, tibia or humerus diaphyseal or metaphyso-diaphyseal non-unions were recruited and surgically treated in France, Germany, Italy and Spain with 100 or 200 million BM-hMSC/mL associated with 5–10 cc of bioceramic granules. Patients were followed up during one year. The investigational advanced therapy medicinal product (ATMP) was expanded under the same protocol in all four countries, and approved by each National Competent Authority. Findings: With safety as primary end-point, no severe adverse event was reported as related to the BM-hMSC. With feasibility as secondary end-point, the participating production centres manufactured the BM-hMSC as planned. The ATMP combined to the bioceramic was surgically delivered to the non-unions, and 26/28 treated patients were found radiologically healed at one year (3 out of 4 cortices with bone bridging). Interpretation: Safety and feasibility were clinically proven for surgical implantation of expanded autologous BM-hMSC with bioceramic. Funding: EU-FP7-HEALTH-2009, REBORNE Project (GA: 241876).The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/FP7-HEALTH-2009); REBORNE Project (GA: 241876

Isolation and characterisation of human gingival margin-derived STRO-1/MACS+ and MACS− cell populations

Recently, gingival margin-derived stem/progenitor cells isolated via STRO-1/magnetic activated cell sorting (MACS) showed remarkable periodontal regenerative potential in vivo. As a second-stage investigation, the present study's aim was to perform in vitro characterisation and comparison of the stem/progenitor cell characteristics of sorted STRO-1-positive (MACS+) and STRO-1-negative (MACS−) cell populations from the human free gingival margin. Cells were isolated from the free gingiva using a minimally invasive technique and were magnetically sorted using anti-STRO-1 antibodies. Subsequently, the MACS+ and MACS− cell fractions were characterized by flow cytometry for expression of CD14, CD34, CD45, CD73, CD90, CD105, CD146/MUC18 and STRO-1. Colony-forming unit (CFU) and multilineage differentiation potential were assayed for both cell fractions. Mineralisation marker expression was examined using real-time polymerase chain reaction (PCR). MACS+ and MACS− cell fractions showed plastic adherence. MACS+ cells, in contrast to MACS− cells, showed all of the predefined mesenchymal stem/progenitor cell characteristics and a significantly higher number of CFUs (P<0.01). More than 95% of MACS+ cells expressed CD105, CD90 and CD73; lacked the haematopoietic markers CD45, CD34 and CD14, and expressed STRO-1 and CD146/MUC18. MACS− cells showed a different surface marker expression profile, with almost no expression of CD14 or STRO-1, and more than 95% of these cells expressed CD73, CD90 and CD146/MUC18, as well as the haematopoietic markers CD34 and CD45 and CD105. MACS+ cells could be differentiated along osteoblastic, adipocytic and chondroblastic lineages. In contrast, MACS− cells demonstrated slight osteogenic potential. Unstimulated MACS+ cells showed significantly higher expression of collagen I (P<0.05) and collagen III (P<0.01), whereas MACS− cells demonstrated higher expression of osteonectin (P<0.05; Mann–Whitney). The present study is the first to compare gingival MACS+ and MACS− cell populations demonstrating that MACS+ cells, in contrast to MACS− cells, harbour stem/progenitor cell characteristics. This study also validates the effectiveness of the STRO-1/MACS+ technique for the isolation of gingival stem/progenitor cells. Human free gingival margin-derived STRO-1/MACS+ cells are a unique renewable source of multipotent stem/progenitor cells