Constrained Dynamic Matrix Control under International Electrotechnical Commission Standard 61499 and the Open Platform Communications Unified Architecture.

This paper focuses on the implementation of a constrained Dynamic Matrix Control (DMC) approach within the level processes of the FESTO™ MPS-PA Compact Workstation plant in the context of the Industrial Internet of Things (IIoT) paradigm. The goal is to develop an industrial control application with decentralized logic that optimizes the operation of the plant while adhering to specific constraints. The implementation is carried out using the IEC-61499 standard and the OPC-UA protocol, enabling seamless communication between devices and systems. The authors utilize the 4diac-IDE and 4diac-FORTE as the development and runtime environments, respectively, to enable the execution of the control application on low-cost devices. The Beagle Bone Black (BBB) card is used for data acquisition and actuator control. Three types of constraints are considered: control increment (Δu(k)), output (ym(k)), and control (u(k)) constraints, to prevent unnecessary stress on the actuator and avoid damage to the plant. The QP algorithm is employed to optimize the objective function and address these constraints effectively. By integrating advanced control strategies into industrial processes in the IIoT paradigm and implementing them on low-cost devices, this paper demonstrates the feasibility and effectiveness of improving system performance, resource utilization, and overall productivity while considering system limitations and constraints.

Personal and household PM2.5 and black carbon exposure measures and respiratory symptoms in 8 low- and middle-income countries.

BACKGROUND: Household air pollution (HAP) from cooking with solid fuels has been associated with adverse respiratory effects, but most studies use surveys of fuel use to define HAP exposure, rather than on actual air pollution exposure measurements. OBJECTIVE: To examine associations between household and personal fine particulate matter (PM2.5) and black carbon (BC) measures and respiratory symptoms. METHODS: As part of the Prospective Urban and Rural Epidemiology Air Pollution study, we analyzed 48-h household and personal PM2.5 and BC measurements for 870 individuals using different cooking fuels from 62 communities in 8 countries (Bangladesh, Chile, China, Colombia, India, Pakistan, Tanzania, and Zimbabwe). Self-reported respiratory symptoms were collected after monitoring. Associations between PM2.5 and BC exposures and respiratory symptoms were examined using logistic regression models, controlling for individual, household, and community covariates. RESULTS: The median (interquartile range) of household and personal PM2.5 was 73.5 (119.1) and 65.3 (91.5) µg/m3, and for household and personal BC was 3.4 (8.3) and 2.5 (4.9) x10-5 m-1, respectively. We observed associations between household PM2.5 and wheeze (OR: 1.25; 95%CI: 1.07, 1.46), cough (OR: 1.22; 95%CI: 1.06, 1.39), and sputum (OR: 1.26; 95%CI: 1.10, 1.44), as well as exposure to household BC and wheeze (OR: 1.20; 95%CI: 1.03, 1.39) and sputum (OR: 1.20; 95%CI: 1.05, 1.36), per IQR increase. We observed associations between personal PM2.5 and wheeze (OR: 1.23; 95%CI: 1.00, 1.50) and sputum (OR: 1.19; 95%CI: 1.00, 1.41). For household PM2.5 and BC, associations were generally stronger for females compared to males. Models using an indicator variable of solid versus clean fuels resulted in larger OR estimates with less precision. CONCLUSIONS: We used measurements of household and personal air pollution for individuals using different cooking fuels and documented strong associations with respiratory symptoms.

Variations between women and men in risk factors, treatments, cardiovascular disease incidence, and death in 27 high-income, middle-income, and low-income countries (PURE): a prospective cohort study.

BACKGROUND: Some studies, mainly from high-income countries (HICs), report that women receive less care (investigations and treatments) for cardiovascular disease than do men and might have a higher risk of death. However, very few studies systematically report risk factors, use of primary or secondary prevention medications, incidence of cardiovascular disease, or death in populations drawn from the community. Given that most cardiovascular disease occurs in low-income and middle-income countries (LMICs), there is a need for comprehensive information comparing treatments and outcomes between women and men in HICs, middle-income countries, and low-income countries from community-based population studies. METHODS: In the Prospective Urban Rural Epidemiological study (PURE), individuals aged 35-70 years from urban and rural communities in 27 countries were considered for inclusion. We recorded information on participants' sociodemographic characteristics, risk factors, medication use, cardiac investigations, and interventions. 168 490 participants who enrolled in the first two of the three phases of PURE were followed up prospectively for incident cardiovascular disease and death. FINDINGS: From Jan 6, 2005 to May 6, 2019, 202 072 individuals were recruited to the study. The mean age of women included in the study was 50·8 (SD 9·9) years compared with 51·7 (10) years for men. Participants were followed up for a median of 9·5 (IQR 8·5-10·9) years. Women had a lower cardiovascular disease risk factor burden using two different risk scores (INTERHEART and Framingham). Primary prevention strategies, such as adoption of several healthy lifestyle behaviours and use of proven medicines, were more frequent in women than men. Incidence of cardiovascular disease (4·1 [95% CI 4·0-4·2] for women vs 6·4 [6·2-6·6] for men per 1000 person-years; adjusted hazard ratio [aHR] 0·75 [95% CI 0·72-0·79]) and all-cause death (4·5 [95% CI 4·4-4·7] for women vs 7·4 [7·2-7·7] for men per 1000 person-years; aHR 0·62 [95% CI 0·60-0·65]) were also lower in women. By contrast, secondary prevention treatments, cardiac investigations, and coronary revascularisation were less frequent in women than men with coronary artery disease in all groups of countries. Despite this, women had lower risk of recurrent cardiovascular disease events (20·0 [95% CI 18·2-21·7] versus 27·7 [95% CI 25·6-29·8] per 1000 person-years in men, adjusted hazard ratio 0·73 [95% CI 0·64-0·83]) and women had lower 30-day mortality after a new cardiovascular disease event compared with men (22% in women versus 28% in men; p<0·0001). Differences between women and men in treatments and outcomes were more marked in LMICs with little differences in HICs in those with or without previous cardiovascular disease. INTERPRETATION: Treatments for cardiovascular disease are more common in women than men in primary prevention, but the reverse is seen in secondary prevention. However, consistently better outcomes are observed in women than in men, both in those with and without previous cardiovascular disease. Improving cardiovascular disease prevention and treatment, especially in LMICs, should be vigorously pursued in both women and men. FUNDING: Full funding sources are listed at the end of the paper (see Acknowledgments).

Sex Differences in Cardiovascular Disease Risk Factor Prevalence, Morbidity, and Mortality in Colombia: Findings from the Prospective Urban Rural Epidemiology (PURE) Study.

Background: Controversies exist on whether the presence of cardiovascular risk factors and their association with major cardiovascular events (MACE) is different between men and women. Most of the evidence comes from high-income countries, hindering extrapolation of sociocultural and demographic factors of other regions. Objective: To evaluate sex differences in the prevalence of cardiovascular risk factors and the incidence of MACE and diabetes in Colombian adults. Methods: We performed a survival analysis from women and men aged 35-70 belonging to the Prospective Urban Rural Epidemiology-Colombia prospective study. Incidence rates for MACE composite (myocardial infarction, stroke, heart failure, death) and each outcome and diabetes were calculated. Kaplan-Meier curves and log-rank tests were performed. The association between demographic, behavioral, and metabolic variables with MACE and diabetes were evaluated with Cox proportional hazards models. Results: 7,552 participants (50±9.7 years) were included; 64% were women. Women had higher hypertension prevalence, body mass index, levels of total cholesterol, LDL-c, and HDL-c but lower triglycerides levels. Women were more sedentary but fewer smokers or active alcohol consumers and had higher educational levels. After 12-year mean follow-up (SD 2.3), the incidence rate of MACE composite was higher in men [4.2 (3.6-4.9) vs. 3.2 (2.8-3.7) cases per 1000 person-years]. Diabetes had the greatest association with MACE (HR = 2.63 95%CI:1.85;3.76), followed by hypertension (HR = 1.75 95%CI:1.30;2.35), low relative grip strength (HR = 1.53 95%CI:1.15;2.02), smoking (HR = 1.47 95%CI: 1.11;1.93), low physical activity (HR = 1.42 95%CI: 1.03;1.96). When evaluating risk factors by sex, only an increased waist-to-hip ratio was more strongly associated with MACE in men (p-interaction <0.05). Conclusions: The composite MACE outcome was higher in men despite having a lower overall burden of risk factors. The risk factors contribution was similar, leading us to reconsider the need to carrying out differentiated cardiovascular risk prevention and management campaigns, at least in our region.

External validation and comparison of six cardiovascular risk prediction models in the Prospective Urban Rural Epidemiology (PURE)-Colombia study.

AIMS: To external validate the SCORE2, AHA/ACC Pooled Cohort Equation (PCE), Framingham Risk Score (FRS), Non-Laboratory INTERHEART Risk Score (NL-IHRS), Globorisk-LAC, and WHO prediction models and compare their discrimination and calibration capacity. METHODS: Validation in individuals aged 40-69 years with at least 10 years follow-up and without baseline use of statins or cardiovascular diseases from the Prospective Urban Rural Epidemiology prospective cohort study (PURE)-Colombia. For discrimination, the C-statistic, and Receiver Operating Characteristic curves with the integrated area under the curve (AUCi) were used and compared. For calibration, the smoothed time-to-event method was used, choosing a recalibration factor based on the integrated calibration index (ICI). In the NL-IHRS, linear regressions were used. RESULTS: In 3,802 participants (59.1% women), baseline risk ranged from 4.8% (SCORE2 women) to 55.7% (NL-IHRS). After a mean follow-up of 13.2 years, 234 events were reported (4.8 cases per 1000 person-years). The C-statistic ranged between 0.637 (0.601-0.672) in NL-IHRS and 0.767 (0.657-0.877) in AHA/ACC PCE. Discrimination was similar between AUCi. In women, higher overprediction was observed in the Globorisk-LAC (61%) and WHO (59%). In men, higher overprediction was observed in FRS (72%) and AHA/ACC PCE (71%). Overestimations were corrected after multiplying by a factor derived from the ICI. CONCLUSIONS: Six prediction models had a similar discrimination capacity, supporting their use after multiplying by a correction factor. If blood tests are unavailable, NL-IHRS is a reasonable option. Our results suggest that these models could be used in other countries of Latin America after correcting the overestimations with a multiplying factor.

Detecting people at high risk of cardiovascular disease and implementing preventive interventions in this population is a key strategy in primary prevention. Recently, new risk calculation tools have been developed, but before their application and routine use in populations different from those where it was developed, it's necessary to validate them. The recommendations for predicting cardiovascular risk in Colombia's guidelines are based on studies with noteworthy limitations. This study involving 3,802 healthy individuals in Colombia supports the recommendation of using these prediction models. The estimation result should be multiplied by a correction factor, because most of the prediction models overestimate cardiovascular risk. For example, the correction factors suggested in women for AHA/ACC PCE and SCORE2 are 0.54 and 0.75, respectively. In men, the correction factors suggested in AHA/ACC PCE and SCORE2 are 0.28 and 0.61, respectively. Therefore, the present study with a contemporary population provides additional evidence to update these recommendations in Colombia and perhaps in Latin America.

Physical Activity and Obesity Risk in Adults in Colombia: The Prospective Urban Rural Epidemiology (PURE) Study.

PURPOSE: This study aimed to investigate longitudinal associations between physical activity levels and obesity in adults in Colombia, where participation in large amounts of light-intensity physical activity is a necessity for many people. METHODS: Participation in moderate- and vigorous-intensity physical activity was assessed from 2005 to 2009, and obesity was assessed from 2011 to 2019 in men and women from the Prospective Urban Rural Epidemiology (PURE) study. Total physical activity level was categorized as low (<600 MET·min·wk -1 ), medium (600-3000 MET·min·wk -1 ), or high (>3000 MET·min·wk -1 ; 600 MET·min·wk -1 is equivalent to 150 min of moderate activity or 75 min of vigorous activity per week). Obesity was defined as body mass index ≥30 kg·m -2 . Analyses were adjusted for age, sex, smoking, socioeconomic status, diet, alcohol, sedentary time, and sleep. RESULTS: The main analysis included 3086 men and women aged 51 ± 9 yr at baseline (mean ± SD). Compared with the low physical activity group, the odds ratio (95% confidence interval) for obesity was 0.67 (0.53-0.85) in the medium physical activity group and 0.78 (0.62-0.98) in the high physical activity group after adjustment for potential confounders. Smoking is probably a major confounder, and it is noteworthy that similar associations were observed in participants who reported never smoking. CONCLUSIONS: The PURE study is the only prospective cohort study in Colombia. The present analysis is important because it suggests that even the busy people of Colombia could substantially reduce their risk of obesity by participating in moderate- and vigorous-intensity physical activity.

Waist circumference cut-off points to identify major cardiovascular events and incident diabetes in Latin America: findings from the prospective Urban rural epidemiology study Colombia.

Background: Abdominal obesity (AO) indirectly represents visceral adiposity and can be assessed by waist circumference (WC) measurement. In Latin America, cut-off points for the diagnosis of AO are based on Asian population data. We aim to establish the WC cut-off points to predict major cardiovascular events (MACE) and incident diabetes. Methods: We analyzed data from the cohort PURE study in Colombia. WC cut-off points were defined according to the maximum Youden index. Multivariate logistic regression was used to obtain associations between WC and MACE, diabetes, and cumulative incidence of outcomes visualized using Kaplan-Meier curves. Results: After a mean follow-up of 12 years, 6,580 individuals with a mean age of 50.7 ± 9.7 years were included; 64.2% were women, and 53.5% were from rural areas. The mean WC was 85.2 ± 11.6 cm and 88.3 ± 11.1 cm in women and men, respectively. There were 635 cases of the MACE composite plus incident diabetes (5.25 events per 1,000 person-years). Using a cut-off value of 88.85 cm in men (sensitivity = 0.565) and 85.65 cm in women (sensitivity = 0.558) resulted in the highest value for the prediction of the main outcome. These values were associated with a 1.76 and 1.41-fold increased risk of presenting the composite outcome in men and women, respectively. Conclusions: We defined WC cut-off points of 89 cm in men and 86 cm in women to identify the elevated risk of MACE and incident diabetes. Therefore, we suggest using these values in cardiovascular risk assessment in Latin America.

Coronary collateral growth--back to the future.

The coronary collateral circulation is critically important as an adaptation of the heart to prevent the damage from ischemic insults. In their native state, collaterals in the heart would be classified as part of the microcirculation, existing as arterial-arterial anastomotic connections in the range of 30 to 100 µM in diameter. However, these vessels also show a propensity to remodel into components of the macrocirculation and can become arteries larger than 1000 µM in diameter. This process of outward remodeling is critically important in the adaptation of the heart to ischemia because the resistance to blood flow is inversely related to the fourth power of the diameter of the vessel. Thus, an expansion of a vessel from 100 to 1000 µM would reduce resistance (in this part of the circuit) to a negligible amount and enable delivery of flow to the region at risk. Our goal in this review is to highlight the voids in understanding this adaptation to ischemia-the growth of the coronary collateral circulation. In doing so we discuss the controversies and unknown aspects of the causal factors that stimulate growth of the collateral circulation, the role of genetics, and the role of endogenous stem and progenitor cells in the context of the normal, physiological situation and under more pathological conditions of ischemic heart disease or with some of the underlying risk factors, e.g., diabetes. The major conclusion of this review is that there are many gaps in our knowledge of coronary collateral growth and this knowledge is critical before the potential of stimulating collateralization in the hearts of patients can be realized. This article is part of a Special Issue entitled "Coronary Blood Flow".

miR-145 is differentially regulated by TGF-ß1 and ischaemia and targets Disabled-2 expression and wnt/ß-catenin activity.

The effect of wnt/ß-catenin signalling in the response to acute myocardial infarction (AMI) remains controversial. The membrane receptor adaptor protein Disabled-2 (Dab2) is a tumour suppressor protein and has a critical role in stem cell specification. We recently demonstrated that down-regulation of Dab2 regulates cardiac protein expression and wnt/ß-catenin activity in mesenchymal stem cells (MSC) in response to transforming growth factor-ß(1) (TGF-ß(1)). Although Dab2 expression has been shown to have effects in stem cells and tumour suppression, the molecular mechanisms regulating this expression are still undefined. We identified putative binding sites for miR-145 in the 3'-UTR of Dab2. In MSC in culture, we observed that TGF-ß(1) treatment led to rapid and sustained up-regulation of pri-miR-145. Through gain and loss of function studies we demonstrate that miR-145 up-regulation was required for the down-regulation of Dab2 and increased ß-catenin activity in response to TGF-ß(1). To begin to define how Dab2 might regulate wnt/ß-catenin in the heart following AMI, we quantified myocardial Dab2 as a function of time after left anterior descending ligation. There was no significant Dab2 expression in sham-operated myocardium. Following AMI, Dab2 levels were rapidly up-regulated in cardiac myocytes in the infarct border zone. The increase in cardiac myocyte Dab2 expression correlated with the rapid and sustained down-regulation of myocardial pri-miR-145 expression following AMI. Our data demonstrate a novel and critical role for miR-145 expression as a regulator of Dab2 expression and ß-catenin activity in response to TGF-ß(1) and hypoxia.

Optical mapping of cryoinjured rat myocardium grafted with mesenchymal stem cells.

Mesenchymal stem cells (MSCs) have been shown to improve cardiac electrophysiology when administered in the setting of acute myocardial infarction. However, the electrophysiological phenotype of MSCs in situ is not clear. We hypothesize that MSCs delivered intramyocardially to cryoinjured myocardium can engraft, but will not actively generate, action potentials. Cryoinjury-induced scar was created on the left ventricular epicardial surface of adult rat hearts. Within 30 min, hearts were injected with saline (sham, n = 11) or bone marrow-derived MSCs (2 × 10(6)) labeled with 1,1'-dioctadecyl-3,3,3,3'-tetramethylindocarbocyanine percholate (DiI; n = 16). At 3 wk, optical mapping and cell isolation were used to measure optical action potentials and calcium transients, respectively. Histological analysis confirmed subepicardial scar thickness and the presence of DiI-positive cells that express connexin-43. Optical action potential amplitude within the scar at MSC-positive sites (53.8 ± 14.3%) was larger compared with sites devoid of MSCs (35.3 ± 14.2%, P < 0.05) and sites within the scar of shams (33.5 ± 6.9%, P < 0.05). Evidence of simultaneous action potential upstroke, the loss of action potential activity following ablation of adjacent viable myocardium, and no rapid calcium transient response in isolated DiI+ cells suggest that the electrophysiological influence of engrafted MSCs is electrotonic. MSCs can engraft when directly injected into a cryoinjury and are associated with evidence of action potential activity. However, our results suggest that this activity is not due to generation of action potentials, but rather passive influence coupled from neighboring viable myocardium.

Insulin Resistance Markers to Detect Nonalcoholic Fatty Liver Disease in a Male Hispanic Population.

Background: Nonalcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver disease and is closely associated with cardiometabolic disorders, being insulin resistance (IR) the common pathogenic mechanism. The triglycerides/glucose (TyG) index and triglycerides/HDL-c (TG/HDL) ratio are markers correlated with IR. We compared the capacity of these two indexes, alongside IR, to detect NAFLD. Methods: In a cross-sectional cohort study, we examined 263 active military personnel from the Colombian Air Force, aged between 29 and 54 years. Anthropometric measurements and biochemical determinations (glycemia, lipid profile, and insulin) were obtained, and ultrasound studies were performed to evaluate the presence of NAFLD. HOMA-IR index was calculated as (fasting insulin (µIU/mL) × fasting glucose (mmol/L)/22.5), the TyG index as Ln (triglycerides (mg/dL) × fasting glucose (mg/dL)/2), and the TG/HDL ratio as (triglycerides (mg/dL)/HDL-c (mg/dL)). Results: NAFLD ultrasound criteria were met in 70 individuals (26.6%). Subjects with NAFLD had significantly higher values of HOMA-IR (2.55 ± 1.36 vs. 1.51 ± 0.91), TyG (9.17 ± 0.53 vs. 8.7 ± 0.51), and TG/HDL (6.6 ± 4.54 vs. 3.52 ± 2.32) compared to those without NAFLD (p < 0.001). A TyG cutoff point of 8.92 showed an AUC of 0.731, while cutoff points of 3.83 for TG/HDL and 1.68 for HOMA-IR showed an AUC of 0.766 and 0.781, respectively. Conclusion: Our study shows that novel and lower-cost markers of IR are useful for detecting NALFD, with a performance comparable to the HOMA-IR index. These markers should be used as the first step when screening patients for NAFLD.

Ethnic Differences in the Prevalence of Hypertension in Colombia: Association With Education Level.

BACKGROUND: A higher prevalence of hypertension is reported among Afro-descendants compared with other ethnic groups in high-income countries; however, there is a paucity of information in low- and medium-income countries. METHODS: We evaluated 3,745 adults from 3 ethnic groups (552 White, 2,746 Mestizos, 447 Afro-descendants) enrolled in the prospective population-based cohort study (PURE)-Colombia. We assessed associations between anthropometric, socioeconomic, behavioral factors, and hypertension. RESULTS: The overall prevalence of hypertension was 39.2% and was higher in Afro-descendants (46.3%) than in Mestizos (37.6%) and Whites (41.5%), differences that were due to the higher prevalence in Afro-descendant women. Hypertension was associated with older age, increased body mass index, waist circumference and waist-to-hip ratio, independent of ethnicity. Low education was associated with hypertension in all ethnic groups, and particularly in Afro-descendants, for whom it was the factor with the strongest association with prevalence. Notably, 70% of Afro-descendants had a low level of education, compared with 52% of Whites-26% of Whites were university graduates while only 7% of Afro-descendants were. We did not find that education level alone had a mediator effect, suggesting that it is not a causal risk factor for hypertension but is an indicator of socioeconomic status, itself an important determinant of hypertension prevalence. CONCLUSIONS: We found that a higher prevalence of hypertension in Colombian Afro-descendants than other ethnic groups. This was principally associated with their lower mean educational level, an indicator of lower socioeconomic status.

A randomized clinical trial of lipid metabolism modulation with fenofibrate for acute coronavirus disease 2019.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cytotoxicity may involve inhibition of peroxisome proliferator-activated receptor alpha. Fenofibrate activates peroxisome proliferator-activated receptor alpha and inhibits SARS-CoV-2 replication in vitro. Whether fenofibrate can be used to treat coronavirus disease 2019 (COVID-19) infection in humans remains unknown. Here, we randomly assigned inpatients and outpatients with COVID-19 within 14 d of symptom onset to 145 mg of oral fenofibrate nanocrystal formulation versus placebo for 10 d, in a double-blinded fashion. The primary endpoint was a severity score whereby participants were ranked across hierarchical tiers incorporating time to death, mechanical ventilation duration, oxygenation, hospitalization and symptom severity and duration. In total, 701 participants were randomized to fenofibrate (n = 351) or placebo (n = 350). The mean age of participants was 49 ± 16 years, 330 (47%) were female, mean body mass index was 28 ± 6 kg/m2 and 102 (15%) had diabetes. Death occurred in 41 participants. Compared with placebo, fenofibrate had no effect on the primary endpoint. The median (interquartile range) rank in the placebo arm was 347 (172, 453) versus 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in secondary and exploratory endpoints, including all-cause death, across arms. There were 61 (17%) adverse events in the placebo arm compared with 46 (13%) in the fenofibrate arm, with slightly higher incidence of gastrointestinal side effects in the fenofibrate group. Overall, among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes ( NCT04517396 ).

Measuring and predicting personal and household Black Carbon levels from 88 communities in eight countries.

Black Carbon (BC) is an important component of household air pollution (HAP) in low- and middle- income countries (LMICs), but levels and drivers of exposure are poorly understood. As part of the Prospective Urban and Rural Epidemiological (PURE) study, we analyzed 48-hour BC measurements for 1187 individual and 2242 household samples from 88 communities in 8 LMICs (Bangladesh, Chile, China, Colombia, India, Pakistan, Tanzania, and Zimbabwe). Light absorbance (10-5 m-1) of collected PM2.5 filters, a proxy for BC concentrations, was calculated via an image-based reflectance method. Surveys of household/personal characteristics and behaviors were collected after monitoring. The geometric mean (GM) of personal and household BC measures was 2.4 (3.3) and 3.5 (3.9)·10-5 m-1, respectively. The correlation between BC and PM2.5 was r = 0.76 for personal and r = 0.82 for household measures. A gradient of increasing BC concentrations was observed for cooking fuels: BC increased 53% (95%CI: 30, 79) for coal, 142% (95%CI: 117, 169) for wood, and 190% (95%CI: 149, 238) for other biomass, compared to gas. Each hour of cooking was associated with an increase in household (5%, 95%CI: 3, 7) and personal (5%, 95%CI: 2, 8) BC; having a window in the kitchen was associated with a decrease in household (-38%, 95%CI: -45, -30) and personal (-31%, 95%CI: -44, -15) BC; and cooking on a mud stove, compared to a clean stove, was associated with an increase in household (125%, 95%CI: 96, 160) and personal (117%, 95%CI: 71, 117) BC. Male participants only had slightly lower personal BC (-0.6%, 95%CI: -1, 0.0) compared to females. In multivariate models, we were able to explain 46-60% of household BC variation and 33-54% of personal BC variation. These data and models provide new information on exposure to BC in LMICs, which can be incorporated into future exposure assessments, health research, and policy surrounding HAP and BC.

A Randomized Trial of Lipid Metabolism Modulation with Fenofibrate for Acute Coronavirus Disease 2019.

Background Abnormal cellular lipid metabolism appears to underlie SARS-CoV-2 cytotoxicity and may involve inhibition of peroxisome proliferator activated receptor alpha (PPARα). Fenofibrate, a PPAR-α activator, modulates cellular lipid metabolism. Fenofibric acid has also been shown to affect the dimerization of angiotensin-converting enzyme 2, the cellular receptor for SARS-CoV-2. Fenofibrate and fenofibric acid have been shown to inhibit SARS-CoV-2 replication in cell culture systems in vitro . Methods We randomly assigned 701 participants with COVID-19 within 14 days of symptom onset to 145 mg of fenofibrate (nanocrystal formulation with dose adjustment for renal function or dose-equivalent preparations of micronized fenofibrate or fenofibric acid) vs. placebo for 10 days, in a double-blinded fashion. The primary endpoint was a ranked severity score in which participants were ranked across hierarchical tiers incorporating time to death, duration of mechanical ventilation, oxygenation parameters, subsequent hospitalizations and symptom severity and duration. ClinicalTrials.gov registration: NCT04517396. Findings: Mean age of participants was 49 ± 16 years, 330 (47%) were female, mean BMI was 28 ± 6 kg/m 2 , and 102 (15%) had diabetes mellitus. A total of 41 deaths occurred. Compared with placebo, fenofibrate administration had no effect on the primary endpoint. The median (interquartile range [IQR]) rank in the placebo arm was 347 (172, 453) vs. 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in various secondary and exploratory endpoints, including all-cause death, across randomization arms. These results were highly consistent across pre-specified sensitivity and subgroup analyses. Conclusion Among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes.

Quantitative intracellular magnetic nanoparticle uptake measured by live cell magnetophoresis.

Superparamagnetic iron oxide (SPIO) particles have been used successfully as an intracellular contrast agent for nuclear MRI cell tracking in vivo. We present a method of detecting intracellular SPIO colloid uptake in live cells using cell magnetophoresis, with potential applications in measuring intracellular MRI contrast uptake. The method was evaluated by measuring shifts in mean and distribution of the cell magnetophoretic mobility, and the concomitant changes in population frequency of the magnetically positive cells when compared to the unmanipulated negative control. Seven different transfection agent (TA) -SPIO complexes based on dendrimer, lipid, and polyethylenimine compounds were used as test standards, in combination with 3 different cell types: mesenchymal stem cells, cardiac fibroblasts, and cultured KG-1a hematopoietic stem cells. Transfectol (TRA) -SPIO incubation resulted in the highest frequency of magnetically positive cells (>90%), and Fugene 6 (FUG) -SPIO incubation the lowest, below that when using SPIO alone. A highly regular process of cell magnetophoresis was amenable to intracellular iron mass calculations. The results were consistent in all the cell types studied and with other reports. The cell magnetophoresis depends on the presence of high-spin iron species and is therefore expected to be directly related to the cell MRI contrast level.

Role of SDF-1:CXCR4 in Impaired Post-Myocardial Infarction Cardiac Repair in Diabetes.

Diabetes is a risk factor for worse outcomes following acute myocardial infarction (AMI). In this study, we tested the hypothesis that SDF-1:CXCR4 expression is compromised in post-AMI in diabetes, and that reversal of this defect can reverse the adverse effects of diabetes. Mesenchymal stem cells (MSC) isolated from green fluorescent protein (GFP) transgenic mice (control MSC) were induced to overexpress stromal cell-derived factor-1 (SDF-1). SDF-1 expression in control MSC and SDF-1-overexpressing MSC (SDF-1:MSC) were quantified using enzyme-linked immunosorbent assay (ELISA). AMI was induced on db/db and control mice. Mice were randomly selected to receive infusion of control MSC, SDF-1:MSC, or saline into the border zone after AMI. Serial echocardiography was used to assess cardiac function. SDF-1 and CXCR4 mRNA expression in the infarct zone of db/db mice and control mice were quantified. Compared to control mice, SDF-1 levels were decreased 82%, 91%, and 45% at baseline, 1 day and 3 days post-AMI in db/db mice, respectively. CXCR4 levels are increased 233% at baseline and 54% 5 days post-AMI in db/db mice. Administration of control MSC led to a significant improvement in ejection fraction (EF) in control mice but not in db/db mice 21 days after AMI. In contrast, administration of SDF-1:MSC produced a significant improvement in EF in both control mice and db/db mice 21 days after AMI. The SDF-1:CXCR4 axis is compromised in diabetes, which appears to augment the deleterious consequences of AMI. Over-express of SDF-1 expression in diabetes rescues cardiac function post AMI. Our results suggest that modulation of SDF-1 may improve post-AMI cardiac repair in diabetes. Stem Cells Translational Medicine 2018;7:115-124.

Plasma Levels of Myonectin But Not Myostatin or Fibroblast-Derived Growth Factor 21 Are Associated with Insulin Resistance in Adult Humans without Diabetes Mellitus.

BACKGROUND: Myokines are a group of protein mediators produced by skeletal muscle under stress or physical exertion. Even though their discovery and effects in cell culture and animal models of disease have elicited great enthusiasm, very little is known about their role in human metabolism. We assessed whether plasma concentrations of three known myokines [myonectin, myostatin, and fibroblast-derived growth factor 21 (FGF-21)] would be associated with direct and indirect indicators of insulin resistance (IR) in individuals who did not have a diagnosis of diabetes. METHODS: We studied 81 adults of both sexes comprising a wide range of body adiposity and insulin sensitivity. All participants underwent a thorough clinical assessment and a 5-point oral glucose tolerance test with calculation of multiple IR and insulin sensitivity indices. Twenty-one of them additionally underwent a hyperinsulinemic-euglycemic clamp with determination of steady-state whole-body insulin-stimulated glucose disposal ("M"). We compared plasma myokine concentrations across quartiles of IR indices and clinical IR surrogates, and explored the correlation of each myokine with the M-value. RESULTS: Plasma myonectin levels increased monotonically across quartiles of the incremental area under the insulin curve (higher values indicate more IR) (p-trend = 0.021) and decreased monotonically across quartiles of the insulin sensitivity index (ISI - higher values indicate less IR) (p-trend = 0.012). After multivariate adjustment for other relevant determinants of IR (body mass index, age, and sex), the negative association of myonectin with ISI persisted (standardized beta = -0.235, p = 0.023). Myostatin was not associated with any clinical IR indicator or direct IR index measure. In multivariate analyses, FGF-21 showed a trend toward a positive correlation with glucose disposal that did not reach statistical significance (standardized beta = 0.476, p = 0.091). CONCLUSION: The secretion of myonectin may constitute an attempt at a compensatory mechanism against IR in humans.

A Novel Role for CAMKK1 in the Regulation of the Mesenchymal Stem Cell Secretome.

Transplantation of adult stem cells into myocardial tissue after acute myocardial infarction (AMI), has been shown to improve tissue recovery and prevent progression to ischemic cardiomyopathy. Studies suggest that the effects of mesenchymal stem cells (MSC) are due to paracrine factors released by MSC, as the benefits of MSC can be achieved through delivery of conditioned media (CM) alone. We previously demonstrated that downregulation of Dab2 enhances MSC cardiac protein expression and improves cardiac function after AMI following MSC engraftment. In order to define the molecular mechanisms that regulate MSC secretome, we analyzed gene arrays in MSC following downregulation of Dab2 via TGFß1 pretreatment or transfection with Dab2:siRNA or miR-145. We identified 23 genes whose expressions were significantly changed in all three conditions. Among these genes, we have initially focused our validation and functional work on calcium/calmodulin-dependent protein kinase kinase-1 (CAMKK1). We quantified the effects of CAMKK1 overexpression in MSC following injection of CM after AMI. Injections of CM from MSC with CAMKK1 over-expression correlated with an increase in vascular density (CAMKK1 CM: 2,794.95 ± 44.2 versus Control: 1,290.69 ± 2.8 vessels/mm2 ) and decreased scar formation (CAMKK1 CM 50% ± 3.2% versus Control: 28% ± 1.4%), as well as improved cardiac function. Direct overexpression of CAMKK1 in infarcted tissue using a CAMKK1-encoding plasmid significantly improved ejection fraction (CAMKK1: 83.2% ± 5.4% versus saline: 51.7% ± 5.8%. Baseline: 91.3% ± 4.3%) and decreased infarct size after AMI. Our data identify a novel role for CAMKK1 as regulator of the MSC secretome and demonstrate that direct overexpression of CAMKK1 in infarcted cardiac tissue, results in therapeutic beneficial effects. Stem Cells Translational Medicine 2017;6:1759-1766.