Urine output as one of the most important features in differentiating in-hospital death among patients receiving extracorporeal membrane oxygenation: a random forest approach.

BACKGROUND: It is common to support cardiovascular function in critically ill patients with extracorporeal membrane oxygenation (ECMO). The purpose of this study was to identify patients receiving ECMO with a considerable risk of dying in hospital using machine learning algorithms. METHODS: A total of 1342 adult patients on ECMO support were randomly assigned to the training and test groups. The discriminatory power (DP) for predicting in-hospital mortality was tested using both random forest (RF) and logistic regression (LR) algorithms. RESULTS: Urine output on the first day of ECMO implantation was found to be one of the most predictive features that were related to in-hospital death in both RF and LR models. For those with oliguria, the hazard ratio for 1 year mortality was 1.445 (p < 0.001, 95% CI 1.265-1.650). CONCLUSIONS: Oliguria within the first 24 h was deemed especially significant in differentiating in-hospital death and 1 year mortality.

Reconstructing population exposures to acrylamide from human monitoring data using a pharmacokinetic framework.

BACKGROUND: Acrylamide toxicity involves several metabolic pathways. Thus, a panel of blood and urinary biomarkers for the evaluation of acrylamide exposure was deemed appropriate. OBJECTIVE: The study was designed to evaluate daily acrylamide exposure in US adults via hemoglobin adducts and urinary metabolites using a pharmacokinetic framework. METHODS: A cohort of 2798 subjects aged 20-79 was selected from the National Health and Nutrition Examination Survey (NHANES, 2013-2016) for analysis. Three acrylamide biomarkers including hemoglobin adducts of acrylamide in blood and two urine metabolites, N-Acetyl-S-(2-carbamoylethyl)cysteine (AAMA) and N-Acetyl-S-(2-carbamoyl-2-hydroxyethyl)-l-cysteine (GAMA) were used to estimate daily acrylamide exposure using validated pharmacokinetic prediction models. Multivariate regression models were also used to examine key factors in determining estimated acrylamide intake. RESULTS: The estimated daily acrylamide exposure varied across the sampled population. Estimated acrylamide daily exposure was comparable among the three different biomarkers (median: 0.4-0.7 µg/kg/d). Cigarette smoking emerged as the leading contributor to the acquired acrylamide dose. Smokers had the highest estimated acrylamide intake (1.20-1.49 µg/kg/d) followed by passive smokers (0.47-0.61) and non-smokers (0.45-0.59). Several covariates, particularly, body mass index and race/ethnicity, played roles in determining estimated exposures. DISCUSSION: Estimated daily acrylamide exposures among US adults using multiple acrylamide biomarkers were similar to populations reported elsewhere providing additional support for using the current approach in assessing acrylamide exposure. This analysis assumes that the biomarkers used indicate intake of acrylamide into the body, which is consistent with the substantial known exposures due to diet and smoking. Although this study did not explicitly evaluate background exposure arising from analytical or internal biochemical factors, these findings suggest that the use of multiple biomarkers may reduce uncertainties regarding the ability of any single biomarker to accurately represent actual systemic exposures to the agent. This study also highlights the value of integrating a pharmacokinetic approach into exposure assessments.

Vitamin D status in relation to inflammatory risk and albuminuria associated with polycyclic aromatic hydrocarbon exposure in the US population.

Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with both systematic inflammation and renal dysfunction. Reports have suggested that anti-inflammatory properties of vitamin D may provide protection against renal injury. This cross-sectional study tested the hypothesis that serum 25-hydroxyvitamin D [25(OH)D] moderates the inflammation and albuminuria associated with PAH exposure. Data were obtained from 5,982 subjects aged 20-79 years in the National Health and Nutrition Examination Survey (2001-2010). PAH exposure was estimated by urinary PAH metabolites. Inflammation was defined as serum C-reactive protein (CRP) > 3 mg/L and albuminuria as urinary albumin-to-creatinine ratio > 30 mg/g. The results found that greater PAH exposure was linked with inflammation and albuminuria. Individuals with PAH exposure also tended to have lower 25(OH)D and lower vitamin D was associated with both elevated CRP (Odds ratio [OR] = 1.28, 95% confidence interval [CI] = 1.07-1.54) and urinary albumin (1.35, 95%CI = 1.03-1.77) for any given PAH exposure. Those with lower serum 25(OH)D-to-urinary PAH ratios were likewise at a greater risk of elevated CRP and albuminuria. The findings support prior suggestions that exposure to PAHs is associated with inflammation and albuminuria but suggests further that the risk is higher when vitamin D is lower. Thus, nutritional status becomes an important variable in PAH risk assessment.

Risk stratification and cost-effectiveness analysis of adult patients receiving extracorporeal membrane oxygenation.

RATIONALE, AIMS, AND OBJECTIVES: A more effective allocation of critical care resources is important as the cost of intensive care increases. A model has been developed to predict the probability of in-hospital death among patients who received extracorporeal membrane oxygenation (ECMO). Cost-effectiveness analyses (CEA) were performed regarding the relationship between hospitalization expenses and predicted survival outcomes. METHODS: Adult patients who received ECMO in a medical center in Taiwan (2005-2016) were included. A logistic regression model was applied to a spectrum of clinical measures obtained before and during ECMO institutions to identify the risk variables for in-hospital mortality. CEA were reported as a predictive risk in quintiles and defined as the cost of each quality-adjusted life-year (QALY). The distribution of the cost-effectiveness ratio (CER) was measured by the ellipse and acceptability curve methods. RESULTS: A total of 919 patients (659 males, mean age: 53.7 years) were enrolled. Ten variables emerged as significant predictors of in-hospital death. The area under the receiver operating characteristic curve was 0.75 (95% confidence interval: 0.72-0.79). In-hospital and total follow-up times were 40,366 and 660,205 person-days, respectively. The total in-hospital expense was $31,818,701 USD and the total effectiveness was 1687.3 QALY. For the lowest to the highest risk quintile, the mean mortality risks were 0.30, 0.48, 0.61, 0.75, and 0.88, and mean adjusted CER were $24,230, $43,042, $54,929, $84,973, and $149,095 per QALY, respectively. CONCLUSIONS: The efficient allocation of limited and costly resources is most important when one is forced to decide between groups of critically ill patients. The current analyses of ECMO outcomes should assist in identifying candidates with the greatest prospect for survival while avoiding futile treatments.

Evaluation of lead body burden in US adolescents.

The objective was to examine key determinants in the body burden of lead in adolescents as lead poisoning remains a major public health challenge. Data from 2,925 teenagers aged 12-18 older in the National Health and Nutrition Examination Survey (NHANES), 1999-2012 were analyzed. Lead in both blood and urine was significantly correlated among individuals. Despite higher blood lead in males, urinary lead measures corrected for dilution were similar between male and female adolescents. Thus, the urine-to-blood ratio was approximately 30% lower in male than female adolescents, suggesting that differences in renal disposal contributed to the greater body burden for young males. Differences in urinary lead disposal appear to be a key determinant in lead accumulation and thus, the degree of lead poisoning. Direct renal studies should be conducted to determine mechanisms and potential solutions.

Analysis of mortality risk following receipt of implantable cardioverter defibrillators in patients with and without heart failure.

BACKGROUND: Patients covered by the Taiwan National Health Insurance (NHI) program are eligible to receive an implantable cardioverter defibrillator (ICD) if diagnosed with heart failure (HF) or were at high risk of sudden cardiac death. The study was designed to evaluate the prognoses for ICD recipients with respect to contributory risks. METHODS: ICD recipients (N=2138) from Taiwan's NHI database, for the 11-year period 2004-2014 were identified and assigned to no heart failure (NHF, n=978) or heart failure groups (HF, n=1160). The mortality rates were reported and survival trends were compared between groups. RESULTS: The mean age of these patients was 61.8±15.2 years and 69% were men. The HF group was older (65 vs. 58 years) and had significantly more comorbidities. Pharmaceutical and medical resource utilization was also uniformly higher within the HF group. The 30-day (1.8%) and 1-year (18.4%) mortality rates among the HF patients were 3-4 times higher than in the NHF group (log rank p=0.006 and p<0.001, respectively). A coexistent major diseases score was consistently associated with a progressive mortality risk in ICD recipients overall. CONCLUSIONS: Of those receiving ICDs, the prognosis for HF patients is poorer than for those in the NHF group which most likely reflects the fact that the HF patients were generally older with more complicated medical conditions as evident by the association between multiple major organ dysfunction and an increased risk of death.

Survival analysis of extracorporeal membrane oxygenation in neonatal and pediatric patients - A nationwide cohort study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) provides short-term cardiopulmonary support for patients with acute cardiac and respiratory failure. This study reported the survival rate for pediatric patients from Taiwan's national cohort. METHODS: Patients under the age of 18 who received ECMO from January 1, 2002 to December 31, 2012 were identified from the Taiwan National Health Insurance Research Database. The underlying etiology for ECMO use was categorized into post-operative (n = 410), cardiac (245), pulmonary (146) groups, and others (120). A Cox regression model was used to determine hazard ratios and to compare 30-day and 1-year survival rates using post-operative group as a reference. RESULTS: The average age of all 921 patients was 4.83 ± 5.84 years, and 59.1% were male. The overall mortality rate was 29.2% at 1 month, and 46.9% at 1 year. The cardiac origin group, consisting mostly of congenital heart disease without surgical intervention, myocarditis, and heart failure had a better outcome with an adjusted hazard ratio of 0.69 (95% CI 0.49-0.96, p = 0.008) at 30 days and 0.50 (95% CI 0.38-0.66, p < 0.001) at 1 year, as compared to the post-operative group. CONCLUSION: In contrast to the widespread use of ECMO in respiratory distress syndrome in western countries, pediatric ECMO in Taiwan was more often applied to patients with underlying cardiovascular diseases. Mortality rates varied according to age groups and various etiologies. The results of this large pediatric cohort provides a different prospective in critical care outcomes in medical environments where ECMO is more widely available.

Cardioprotection by intermittent hypoxia conditioning: evidence, mechanisms, and therapeutic potential.

The calibrated application of limited-duration, cyclic, moderately intense hypoxia-reoxygenation increases cardiac resistance to ischemia-reperfusion stress. These intermittent hypoxic conditioning (IHC) programs consistently produce striking reductions in myocardial infarction and ventricular tachyarrhythmias after coronary artery occlusion and reperfusion and, in many cases, improve contractile function and coronary blood flow. These IHC protocols are fundamentally different from those used to simulate sleep apnea, a recognized cardiovascular risk factor. In clinical studies, IHC improved exercise capacity and decreased arrhythmias in patients with coronary artery or pulmonary disease and produced robust, persistent, antihypertensive effects in patients with essential hypertension. The protection afforded by IHC develops gradually and depends on ß-adrenergic, δ-opioidergic, and reactive oxygen-nitrogen signaling pathways that use protein kinases and adaptive transcription factors. In summary, adaptation to intermittent hypoxia offers a practical, largely unrecognized means of protecting myocardium from impending ischemia. The myocardial and perhaps broader systemic protection provided by IHC clearly merits further evaluation as a discrete intervention and as a potential complement to conventional pharmaceutical and surgical interventions.

Metabolic syndrome is associated with an increased incidence of subclinical hypothyroidism - A Cohort Study.

Prior cross-sectional analyses have demonstrated an association between subclinical hypothyroidism and metabolic syndrome and selected components. However, the temporal relation between metabolic syndrome and declining thyroid function remains unclear. In a prospective study, an unselected cohort of 66,822 participants with and without metabolic syndrome were followed. A proportional hazards regression model was used to estimate hazard ratios (HRs) and 95% CIs for hypothyroidism. Exploratory analyses for the relation between components of metabolic syndrome and declining thyroid function were also undertaken. During an average follow-up of 4.2 years, the incident rates for subclinical hypothyroidism were substantially higher in participants who began the study with metabolic syndrome compared with metabolically normal controls. After controlling for risk factors, patients with metabolic syndrome were at a 21% excess risk of developing subclinical hypothyroidism (adjusted HR 1.21; 95% CI 1.03-1.42). When individual components were analyzed, an increased risk of subclinical hypothyroidism was associated with high blood pressure (1.24; 1.04-1.48) and high serum triglycerides (1.18; 1.00-1.39), with a trend of increasing risk as participants had additional more components. Individuals with metabolic syndrome are at a greater risk for developing subclinical hypothyroidism, while its mechanisms and temporal consequences of this observation remain to be determined.

δ-Opioid receptors: Pivotal role in intermittent hypoxia-augmentation of cardiac parasympathetic control and plasticity.

BACKGROUND: Intermittent hypoxia training (IHT) produces robust myocardial protection against ischemia-reperfusion induced infarction and arrhythmias. Blockade of this cardioprotection by antagonism of either ß1-adrenergic or δ-opioid receptors (δ-OR) suggests autonomic and/or opioidergic adaptations. PURPOSE: To test the hypothesis that IHT shifts cardiac autonomic balance toward greater cholinergic and opioidergic influence. METHODS: Mongrel dogs completed 20d IHT, non-hypoxic sham training, or IHT with the δ-OR antagonist naltrindole (200µg/kgsc). The vagolytic effect of the δ-OR agonist met-enkephalin-arg-phe delivered by sinoatrial microdialysis was evaluated following IHT. Sinoatrial, atrial and left ventricular biopsies were analyzed for changes in δ-OR, the neurotrophic monosialoganglioside, GM-1, and cholinergic and adrenergic markers. RESULTS: IHT enhanced vagal bradycardia vs. sham dogs (P<0.05), and blunted the δ2-OR mediated vagolytic effect of met-enkephalin-arg-phe. The GM-1 labeled fibers overlapped strongly with cholinergic markers, and IHT increased the intensity of both signals (P<0.05). IHT increased low and high intensity vesicular acetylcholine transporter labeling of sinoatrial nodal fibers (P<0.05) suggesting an increase in parasympathetic arborization. IHT reduced select δ-OR labeled fibers in both the atria and sinoatrial node (P<0.05) consistent with moderation of the vagolytic δ2-OR signaling described above. Furthermore, blockade of δ-OR signaling with naltrindole during IHT increased the protein content of δ-OR (atria and ventricle) and vesicular acetylcholine transporter (atria) vs. sham and untreated IHT groups. IHT also reduced the sympathetic marker, tyrosine hydroxylase in ventricle (P<0.05). SUMMARY: IHT shifts cardiac autonomic balance in favor of parasympathetic control via adaptations in opioidergic, ganglioside, and adrenergic systems.

No increased risk of hospitalization for heart failure for patients treated with dipeptidyl peptidase-4 inhibitors in Taiwan.

BACKGROUND: Saxagliptin has been reported to be associated with an increased risk of hospitalization for heart failure (HF). The objective of this study was to test whether the increased risk is drug specific or a class effect for dipeptidyl peptidase-4 (DPP-4) inhibitors. METHODS: Diabetic patients prescribed sitagliptin, saxagliptin, and vildagliptin between 2011 and 2013 were identified from Taiwan's National Health Insurance (NHI) claims database. The outcome of interest was the first hospitalization for HF. The patients were followed for one year from drug initiation to outcome occurrence, death, or study termination (December 31, 2013). A Cox proportional hazards regression model was used to calculate the hazard ratios (HR) and their 95% confidence intervals, using sitagliptin as the reference group. RESULTS: A total of 239,669 patients, including 159,330 sitagliptin, 38,561 saxagliptin, and 41,778 vildagliptin initiators, were included in the analysis. With a follow-up period ranging from 269days (vildagliptin) to 313days (sitagliptin), the crude incidence rate of HF was 2.77, 2.63, and 1.91 per 100 person-years for sitagliptin, saxagliptin, and vildagliptin, respectively. Saxagliptin had a similar risk (HR: 0.98, 95% CI: 0.91-1.06) to sitagliptin, while vildagliptin was associated with a lower risk of HF (HR: 0.85, 95% CI: 0.78-0.93). Auxiliary analyses using acarbose (n=130,800) as a reference group consistently showed no increased risk of HF associated with DDP-4 inhibitors. CONCLUSION: Three DPP-4 inhibitors studied seem to be safe regarding the risk of HF, while the reduced risk of vildagliptin might be a spurious association or a chance finding.

Survival Analysis After Extracorporeal Membrane Oxygenation in Critically Ill Adults: A Nationwide Cohort Study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) provides circulatory and respiratory support for patients with severe acute cardiopulmonary failure. The objective of this study was to examine the survival outcomes for patients who received ECMO. METHODS AND RESULTS: Adult patients who received ECMO from September 1, 2002, to December 31, 2012, were identified from the Taiwan National Health Insurance Database associated with coronary artery bypass graft surgery, myocardial infarction/cardiogenic shock, injury, and infection/septic shock. A Cox regression model was used to determine hazard ratios and to compare 30-day and 1-year survival rates with the myocardial infarction/cardiogenic shock group used as the reference. The mean±SD age of the 4227-patient cohort was 57±17 years, and 72% were male. The overall mortalities were 59.8% and 76.5% at 1 month and 1 year. Survival statistics deteriorated sharply when ECMO was required for >3 days. Acute (30-day) survival was more favorable in the infection/septic shock (n=1076; hazard ratio, 0.61; 95% confidence interval, 0.55-0.67), coronary artery bypass graft surgery (n=1077; hazard ratio, 0.68; 95% confidence interval, 0.61-0.75), and injury (n=369, hazard ratio, 0.82; 95% confidence interval, 0.70-0.95) groups. The extended survival rapidly approached an asymptote near 20% for the infection/septic shock, myocardial infarction/cardiogenic shock (n=1705), and coronary artery bypass graft surgery groups. The pattern of survival for the injury group was somewhat better, exceeding 30% at year-end. CONCLUSIONS: Regardless of initial pathology, patients requiring ECMO were critically ill with similar guarded prognoses. Those in the trauma group had somewhat better outcomes. Determining the efficacy and cost-effectiveness of ECMO should be a critical future goal.

δ-Opioid receptor (DOR) signaling and reactive oxygen species (ROS) mediate intermittent hypoxia induced protection of canine myocardium.

Intermittent, normobaric hypoxia confers robust cardioprotection against ischemia-induced myocardial infarction and lethal ventricular arrhythmias. δ-Opioid receptor (DOR) signaling and reactive oxygen species (ROS) have been implicated in cardioprotective phenomena, but their roles in intermittent hypoxia are unknown. This study examined the contributions of DOR and ROS in mediating intermittent hypoxia-induced cardioprotection. Mongrel dogs completed a 20 day program consisting of 5-8 daily, 5-10 min cycles of moderate, normobaric hypoxia (FIO2 0.095-0.10), with intervening 4 min room air exposures. Subsets of dogs received the DOR antagonist naltrindole (200 µg/kg, sc) or antioxidant N-acetylcysteine (250 mg/kg, po) before each hypoxia session. Twenty-four hours after the last session, the left anterior descending coronary artery was occluded for 60 min and then reperfused for 5 h. Arrhythmias detected by electrocardiography were scored according to the Lambeth II conventions. Left ventricles were sectioned and stained with 2,3,5-triphenyl-tetrazolium-chloride, and infarct sizes were expressed as percentages of the area at risk (IS/AAR). Intermittent hypoxia sharply decreased IS/AAR from 41 ± 5 % (n = 12) to 1.8 ± 0.9 % (n = 9; P < 0.001) and arrhythmia score from 4.1 ± 0.3 to 0.7 ± 0.2 (P < 0.001) vs. non-hypoxic controls. Naltrindole (n = 6) abrogated the cardioprotection with IS/AAR 35 ± 5 % and arrhythmia score 3.7 ± 0.7 (P < 0.001 vs. untreated intermittent hypoxia). N-acetylcysteine (n = 6) interfered to a similar degree, with IS/AAR 42 ± 3 % and arrhythmia score 4.7 ± 0.3 (P < 0.001 vs. untreated intermittent hypoxia). Without the intervening reoxygenations, hypoxia (n = 4) was not cardioprotective (IS/AAR 50 ± 8 %; arrhythmia score 4.5 ± 0.5; P < 0.001 vs. intermittent hypoxia). Thus DOR, ROS and cyclic reoxygenation were obligatory participants in the gradually evolving cardioprotection produced by intermittent hypoxia.

Fetal Growth, Obesity, and Atopic Disorders in Adolescence: a Retrospective Birth Cohort Study.

BACKGROUND: Developmental status at birth and subsequent obesity have been implicated in the development of childhood atopic dermatitis (AD) and allergic rhinitis (AR). METHODS: The current study analysed the cohort data of 74 688 junior high school students from a national retrospective birth cohort study in Taiwan. A random 10% sample was selected from singleton livebirths with complete data on the analytical variables of interest. Atopic disorders, including AD and AR, were assessed by questionnaires (International Study of Asthma and Allergies in Childhood). Logistic regression analyses were applied with adjustments for related risk factors. RESULTS: Among subjects mainly 13-15 years of age, the estimated prevalence was 7.6% for AD and 22.4% for AR. While the role of fetal growth in allergic disorders was less evident, the risk of developing AD and AR were both influenced by a combination of fetal growth status and adolescent body mass index (BMI). Compared with those with normal fetal growth and school-aged BMI, the risk of developing AD increased 64% among adolescents with both restricted fetal growth and high BMI (odds ratio 1.64, 95% confidence interval 1.37, 1.97). The risk for this combination was higher than that for either restricted fetal growth or high BMI alone. Nevertheless, the overall interaction between BMI and fetal growth status on atopic disorders did not reach statistical significance. CONCLUSIONS: Excessive weight gain could be an important risk factor related to developing atopic dermatitis and allergic rhinitis during adolescence, especially among infants born small for gestational age.

Risk of Intracranial Hemorrhage From Statin Use in Asians: A Nationwide Cohort Study.

BACKGROUND: Reports of statin usage and increased risk of intracranial hemorrhage (ICH) have been inconsistent. This study examined potential associations between statin usage and the risk of ICH in subjects without a previous history of stroke. METHODS AND RESULTS: Patients initiating statin therapy between 2005 and 2009 without a previous history of ischemic or hemorrhagic stroke were identified from Taiwan's National Health Insurance database. Participants were stratified by advanced age (≥70 years), sex, and diagnosed hypertension. The outcome of interest was hospital admission for ICH (International Classification of Diseases, Ninth Revision, Clinical Modification codes 430, 431, 432). Cox regression models were applied to estimate the hazard ratio of ICH. The cumulative statin dosage stratified by quartile and adjusted for baseline disease risk score served as the primary variable using the lowest quartile of cumulative dosage as a reference. There were 1 096 547 statin initiators with an average follow-up of 3.3 years. The adjusted hazard ratio for ICH between the highest and the lowest quartile was nonsignificant at 1.06 with a 95% confidence interval spanning 1.00 (0.94-1.19). Similar nonsignificant results were found in sensitivity analyses using different outcome definitions or model adjustments, reinforcing the robustness of the study findings. Subgroup analysis identified an excess of ICH frequency in patients without diagnosed hypertension (adjusted hazard ratio 1.36 [1.11-1.67]). CONCLUSIONS: In general, no association was observed between cumulative statin use and the risk of ICH among subjects without a previous history of stroke. An increased risk was identified among the nonhypertensive cohort, but this finding should be interpreted with caution.

Different Angiotensin-converting enzyme inhibitors and the associations with overall and cause-specific mortalities in patients with hypertension.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors have been widely used in the treatment of hypertension, but the comparative effectiveness in reducing mortality among different drugs is seldom reported. METHODS: We identified hypertensive patients who started captopril, enalapril, lisinopril, fosinopril, perindopril, ramipril, or imidapril therapy from Taiwan's National Health Insurance database between 1 January 2004 and 31 December 2009. Overall and cause-specific mortalities were ascertained through a linkage to Taiwan's National Death Registry. Patients were followed from the initiation of ACE inhibitors to death, disenrollment, or study termination (31 December 2010). A Cox proportional hazard regression model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI), using ramipril as the reference group. RESULTS: A total of 989,489 hypertensive patients were included, with a mean follow-up ranging from 3.5 years for imidapril to 4.5 years for enalapril. Captopril initiators had the highest overall mortality rate (117.8 per 1,000,000 person-days) as compared to other ACE inhibitors (54.3-79.4 per 1,000,000 person-days). Patients who started captopril therapy had a significantly increased risk of overall mortality (HR: 1.28, 95% CI: 1.24-1.31) when compared with ramipril. Enalapril (HR: 1.08, 95% CI: 1.05-1.11) and fosinopril (HR: 1.08, 95% CI: 1.05-1.12) were also associated with a modestly increased risk. No difference in mortality was found for lisinopril, perindopril, and imidapril, as compared with ramipril. CONCLUSIONS: There are differences in the mortality risk associated with different ACE inhibitors. However, potential residual confounding effects might still exist.

Low birth weight and environmental tobacco smoke increases the risk of wheezing in adolescents: a retrospective cohort study.

BACKGROUND: Low birth weight (LBW) and environmental tobacco smoke (ETS) exposure are each associated with wheezing in children. This study was designed to examine the combined association of LBW and ETS with wheezing. METHODS: A retrospective birth cohort analysis linked with a national survey of allergic disorders among 1,018,031 junior high school students in Taiwan (1995-1996) was analyzed. The reported incidence of wheezing (yes or no) and ETS exposure (4 categories: 0, 1-20, 21-40 and greater than or equal to 41 household cigarettes per day) were obtained from validated questionnaires. Multiple logistic regression models were used to assess the associations of interest. RESULTS: There were 844,003 (83%) subjects analyzed after the exclusion criteria. LBW was associated with an increased risk of reporting ever wheezing (odds ratio [OR] = 1.08, 95% confidence interval [CI] = 1.01-1.16), current wheezing (OR = 1.09, 95% CI = 1.00-1.20) and wheezing with exercise (OR = 1.11, 95% CI = 1.02-1.21) within the smoke-free cohort. Higher ETS exposure correlated to a higher risk of wheezing (ever, current and with exercise). With ETS exposure, adolescents from the lowest birth weight cohorts were more likely to report wheezing (ever, current and with exercise). CONCLUSIONS: ETS and LBW each has been related to increasing public health risk for respiratory symptoms among adolescents. Furthermore, LBW may aggravate the risk among those exposed to ETS. LBW, ETS and associated respiratory impairments may deserve special attention as part of a comprehensive environmental health risk assessment directed toward prevention and intervention.

Low serum zinc is associated with elevated risk of cadmium nephrotoxicity.

BACKGROUND: Despite animal evidence suggests that zinc modulates cadmium nephrotoxicity, limited human data are available. OBJECTIVE: To test the hypothesis that low serum zinc concentrations may increase the risk of cadmium-mediated renal dysfunction in humans. METHODS: Data from 1545 subjects aged 20 or older in the National Health and Nutrition Examination Survey (NHANES), 2011-2012 were analyzed. Renal function was defined as impaired when estimated glomerular filtration rate (eGFR) fell below 60 ml/min/1.73 m(2) and/or the urinary albumin-to-creatinine ratio surpassed 2.5 in men and 3.5mg/mmol in women. RESULTS: Within the study cohort, 117 subjects had reduced eGFR and 214 had elevated urinary albumin. After adjusting for potential confounders, subjects with elevated blood cadmium (>0.53 µg/L) were more likely to have a reduced eGFR (odds ratio [OR]=2.21, 95% confidence interval [CI]: 1.09-4.50) and a higher urinary albumin (OR=2.04, 95% CI: 1.13-3.69) than their low cadmium (<0.18 µg/L) peers. In addition, for any given cadmium exposure, low serum zinc is associated with elevated risk of reduced eGFR (OR=3.38, 95% CI: 1.39-8.28). A similar increase in the odds ratio was observed between declining serum zinc and albuminuria but failed to reach statistical significance. Those with lower serum zinc/blood cadmium ratios were likewise at a greater risk of renal dysfunction (p<0.01). CONCLUSIONS: This study results suggest that low serum zinc concentrations are associated with an increased risk of cadmium nephrotoxicity. Elevated cadmium exposure is global public health issue and the assessment of zinc nutritional status may be an important covariate in determining its effective renal toxicity.

Association of body burden of mercury with liver function test status in the U.S. population.

The majority of mercury (Hg) exposure in the US population is from consumption of fish contaminated with methylmercury (MeHg). Since inorganic Hg is the predominant form excreted in the feces and urine, hepatic biotransformation is a critical step in its normal clearance. This study was set to test the hypothesis that compromised liver function is associated with body burden of Hg as indirectly reflected by Hg sampled in blood and urine. From the National Health and Nutrition Examination Survey (NHANES, 2003-2008), 3769 adults aged 20 years and above were selected for analysis. Hepatic function was inferred from the three standard serum liver-related enzyme activities, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (GGT). Multivariate regression models were used to examine the associations of interest. Although urinary Hg was significantly correlated with serum Hg, the blood-urinary Hg relationship was influenced by liver function, which is also a function of demographic and lifestyle factors (e.g., gender). Although the results were only marginally significant for examined enzymes (p=0.06-0.08), urinary Hg tended to be lower among subjects with elevated liver enzymes, as compared to those with normal enzyme measurements. Conversely, MeHg generally represents a higher fraction of the total circulating Hg among those with elevated liver enzyme levels, especially among participants with elevations in all three enzymes (p=0.01). In conclusion, this population-based study identified an association between liver function, serum Hg and urinary Hg. Urinalysis may not be the optimal approach to monitor Hg elimination toxicokinetics or Hg exposure, since the majority of Hg excretion is fecal and the fidelity of urinary excretion may depend on healthy liver function. Future prospective studies are warranted to expand these findings.

Examining the association of olmesartan and other angiotensin receptor blockers with overall and cause-specific mortality.

Concerns about an increased cardiovascular risk with the angiotensin receptor blocker, olmesartan, prompted the current study to examine associations between olmesartan and other angiotensin receptor blockers with overall and cause-specific mortalities. We collected patients who started to use losartan, valsartan, irbesartan, candesartan, telmisartan, and olmesartan between January 1, 2004, and December 31, 2009, from Taiwan's National Health Insurance claims database. Prescribed drug types, dosage, and other clinical information were collected. Overall mortality and cause-specific mortality were ascertained through linkages with Taiwan's National Death Registry. Two follow-up analyses, labeled intention-to-treat and as-treated, were conducted. A Cox proportional hazard regression model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) using losartan as the reference group. A total of 690 463 subjects were included, with a mean follow-up ranging from a low of 2.8 years for olmesartan to a high of 4.1 years for irbesartan. Subjects who began with valsartan had a modest but significantly increased risk of overall mortality (HR, 1.04; 95% CI, 1.02-1.06) compared with losartan. Irbesartan (HR, 0.96; 95% CI, 0.94-0.99), candesartan (HR, 0.95; 95% CI, 0.92-0.99), telmisartan (HR, 0.93; 95% CI, 0.90-0.96), and olmesartan (HR, 0.93; 95% CI, 0.88-0.97) were associated with a slightly lower overall mortality risk than losartan. The analysis indicates that the differences in mortality risk among individual angiotensin receptor blockers were only marginal and thus less likely to be clinically important. Although uncontrolled confounding might still exist, olmesartan does not seem to increase cardiovascular risk compared with losartan.