Comparison of Costs and Clinical Outcomes Between Hospital and Outpatient Administration of Omalizumab in Patients With Severe Uncontrolled Asthma.

OBJECTIVES: To compare clinical outcomes and costs between two administration strategies of omalizumab treatment. METHOD: We evaluated two cohorts of patients with uncontrolled severe asthma over a 1-year period. Patients received the treatment in the primary care center in Hospital A and conventional hospital administration in Hospital B. RESULTS: We studied 130 patients, 86 in Hospital A and 44 in Hospital B, 30 men (24%) and 100 women (76%), age 50 ± 15 years, FEV1% 67 ± 22%, body mass index (BMI) 28 ± 6 kg/m(2), 639 ± 747 UI IgE/mL, followed for 24 ± 11 months (12-45), Asthma Control Test (ACT) score 12 ± 4 and Asthma Control Questionnaire (ACQ) 3 ± 2. There were no significant pretreatment differences between the groups in hospital admissions and emergency room visits in the previous year, nor in proportion of patients receiving oral steroids. Evaluations were performed at baseline and after 12 months of treatment, revealing significant differences in ACT (P<0.001), ACQ (P<0.001), improvement in FEV1% (P<0.001), reduction in total admissions (P<0.001), days of hospitalization (P<0.001), emergency room visits (P<0.001), cycles and doses of oral steroids (P<0.001) compared to the previous year. Hospitalization costs, emergency room visits, unscheduled visits to primary care and to the pulmonologist were significantly reduced in each hospital and on the whole, but administration and travel costs were 35% lower in the ambulatory strategy adopted in Hospital A. CONCLUSION: The administration of omalizumab in ambulatory health centers achieved the same clinical results as a hospital administration strategy, but with lower costs.

High Ambient Temperatures and Risk of Motor Vehicle Crashes in Catalonia, Spain (2000-2011): A Time-Series Analysis.

BACKGROUND: Experimental studies have shown a decrease in driving performance at high temperatures. The epidemiological evidence for the relationship between heat and motor vehicle crashes is not consistent. OBJECTIVES: We estimated the impact of high ambient temperatures on the daily number of motor vehicle crashes and, in particular, on crashes involving driver performance factors (namely distractions, driver error, fatigue, or sleepiness). METHODS: We performed a time-series analysis linking daily counts of motor vehicle crashes and daily temperature or occurrence of heat waves while controlling for temporal trends. All motor vehicle crashes with victims that occurred during the warm period of the years 2000-2011 in Catalonia (Spain) were included. Temperature data were obtained from 66 weather stations covering the region. Poisson regression models adjusted for precipitation, day of the week, month, year, and holiday periods were fitted to quantify the associations. RESULTS: The study included 118,489 motor vehicle crashes (an average of 64.1 per day). The estimated risk of crashes significantly increased by 2.9% [95% confidence interval (CI): 0.7%, 5.1%] during heat wave days, and this association was stronger (7.7%, 95% CI: 1.2%, 14.6%) when restricted to crashes with driver performance-associated factors. The estimated risk of crashes with driver performance factors significantly increased by 1.1% (95% CI: 0.1%, 2.1%) for each 1 °C increase in maximum temperature. CONCLUSIONS: Motor vehicle crashes involving driver performance-associated factors were increased in association with heat waves and increasing temperature. These findings are relevant for designing preventive plans in a context of global warming.

Role of circulating miRNAs as biomarkers in idiopathic pulmonary arterial hypertension: possible relevance of miR-23a.

Idiopathic pulmonary hypertension (IPAH) is a rare disease characterized by a progressive increase in pulmonary vascular resistance leading to heart failure. MicroRNAs (miRNAs) are small noncoding RNAs that control the expression of genes, including some involved in the progression of IPAH, as studied in animals and lung tissue. These molecules circulate freely in the blood and their expression is associated with the progression of different vascular pathologies. Here, we studied the expression profile of circulating miRNAs in 12 well-characterized IPAH patients using microarrays. We found significant changes in 61 miRNAs, of which the expression of miR23a was correlated with the patients' pulmonary function. We also studied the expression profile of circulating messenger RNA (mRNAs) and found that miR23a controlled 17% of the significantly changed mRNA, including PGC1α, which was recently associated with the progression of IPAH. Finally we found that silencing of miR23a resulted in an increase of the expression of PGC1α, as well as in its well-known regulated genes CYC, SOD, NRF2, and HO1. The results point to the utility of circulating miRNA expression as a biomarker of disease progression.

PGC-1α induction in pulmonary arterial hypertension.

Idiopathic Pulmonary arterial hypertension (IPAH) is characterized by the obstructive remodelling of pulmonary arteries, and a progressive elevation in pulmonary arterial pressure (PAP) with subsequent right-sided heart failure and dead. Hypoxia induces the expression of peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α) which regulates oxidative metabolism and mitochondrial biogenesis. We have analysed the expression of PGC-1α, cytochrome C (CYTC), superoxide dismutase (SOD), the total antioxidant status (TAS) and the activity of glutathione peroxidase (GPX) in blood samples of IPAH patients. Expression of PGC-1α was detected in IPAH patients but not in healthy volunteers. The mRNA levels of SOD were lower in IPAH patients compared to controls (3.93 ± 0.89 fold change). TAS and GPX activity were lower too in patients compared to healthy donors, (0.13 ± 0.027 versus 0.484 ± 0.048 mM and 56.034 ± 10.37 versus 165.46 ± 11.38 nmol/min/mL, resp.). We found a negative correlation between expression levels of PGC-1α and age, PAP and PVR, as well as a positive correlation with CI, PaO(2), mRNA levels of CYTC and SOD, TAS and GPX activity. These results taken together are indicative of the possible role of PGC-1α as a potential biomarker of the progression of IPAH.

Sphingosine-1-phosphate is increased in patients with idiopathic pulmonary fibrosis and mediates epithelial to mesenchymal transition.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterised by the aberrant epithelial to mesenchymal transition (EMT) and myofibroblast accumulation. Sphingosine-1-phosphate (S1P) and sphingosine kinase 1 (SPHK1) have been implicated in lung myofibroblast transition, but their role in EMT and their expression in patients with IPF is unknown. METHODS AND RESULTS: S1P levels were measured in serum (n=27) and bronchoalveolar lavage (BAL; n=15) from patients with IPF and controls (n=30 for serum and n=15 for BAL studies). SPHK1 expression was measured in lung tissue from patients with IPF (n=12) and controls (n=15). Alveolar type II transformation into mesenchymal cells was studied in response to S1P (10(-9)-10(-5) M). The median (IQR) of S1P serum levels was increased in patients with IPF (1.4 (0.4) µM) versus controls (1 (0.26) µM; p<0.0001). BAL S1P levels were increased in patients with IPF (1.12 (0.53) µM) versus controls (0.2 (0.5); p<0.0001) and correlated with diffusion capacity of the lung for carbon monoxide, forced expiratory volume in 1 s and forced vital capacity (Spearman's r=-0.87, -0.72 and -0.68, respectively) in patients with IPF. SPHK1 was upregulated in lung tissue from patients with IPF and correlated with α-smooth muscle actin, vimentin and collagen type I (Spearman's r=0.82, 0.85 and 0.72, respectively). S1P induced EMT in alveolar type II cells by interacting with S1P(2) and S1P(3), as well as by the activation of p-Smad3, RhoA-GTP, oxidative stress and transforming growth factor-ß1 (TGF-ß1) release. Furthermore, TGF-ß1-induced EMT was partially conducted by the S1P/SPHK1 activation, suggesting crosstalk between TGF-ß1 and the S1P/SPHK1 axis. CONCLUSIONS: S1P is elevated in patients with IPF, correlates with the lung function and mediates EMT.

Heat waves and cause-specific mortality at all ages.

BACKGROUND: Mortality has been shown to increase with extremely hot ambient temperatures. Details on the specific cause of mortality can be useful for improving preventive policies. Infants are often identified as a population that is vulnerable to extreme heat conditions; however, information on heat and infant mortality is scarce, with no studies reporting on cause-specific mortality. METHODS: The study includes all deaths in the Catalonia region of Spain during the warm seasons of 1983-2006 (503,389 deaths). We used the case-crossover design to evaluate the association between the occurrence of extremely hot days (days with maximum temperature above the 95th percentile) and mortality. Total mortality and infant mortality were stratified into 66 and 8 causes of death, respectively. RESULTS: Three consecutive hot days increased total daily mortality by 19%. We calculated that 1.6% of all deaths were attributable to heat. About 40% of attributable deaths did not occur during heat-wave periods. The causes of death that were increased included cardiovascular and respiratory diseases, mental and nervous system disorders, infectious and digestive system diseases, diabetes, and some external causes such as suicide. In infants, the effect of heat was observed on the same day and was detected only for conditions originating in the perinatal period (relative risk = 1.53 [95% confidence interval = 1.16-2.02]). Within the perinatal causes, cardiovascular, respiratory, digestive system, and hemorrhagic and hematologic disorders were the causes of death with stronger effects. CONCLUSIONS: Heat contributes to an increase in mortality from several causes. In infants, the first week of life is the most critical window of vulnerability.

Monitoring of heavy metal concentrations in home outdoor air using moss bags.

One monitoring station is insufficient to characterize the high spatial variation of traffic-related heavy metals within cities. We tested moss bags (Hylocomium splendens), deployed in a dense network, for the monitoring of metals in outdoor air and characterized metals' long-term spatial distribution and its determinants in Girona, Spain. Mosses were exposed outside 23 homes for two months; NO2 was monitored for comparison. Metals were not highly correlated with NO2 and showed higher spatial variation than NO2. Regression models explained 61-85% of Cu, Cr, Mo, Pb, Sb, Sn, and Zn and 72% of NO2 variability. Metals were strongly associated with the number of bus lines in the nearest street. Heavy metals are an alternative traffic-marker to NO2 given their toxicological relevance, stronger association with local traffic and higher spatial variability. Monitoring heavy metals with mosses is appealing, particularly for long-term exposure assessment, as mosses can remain on site many months without maintenance.

Local determinants of road traffic noise levels versus determinants of air pollution levels in a Mediterranean city.

BACKGROUND: Both traffic-related noise and air pollution have been associated with cardiovascular disease (CVD). Spatial correlations between these environmental stressors may entail mutual confounding in epidemiological studies investigating their long-term effects. Few studies have investigated their correlation - none in Spain - and results differ among cities. OBJECTIVES: We assessed the contribution of urban land-use and traffic variables to the noise-air pollution correlation in Girona town, where an investigation of the chronic effects of air pollution and noise on CVD takes place (REGICOR-AIR). METHODOLOGY: Outdoor annual mean concentrations of nitrogen dioxide (NO(2)) derived from monthly passive sampler measurements were obtained at 83 residential locations. Long-term average traffic-related noise levels from a validated model were assigned to each residence. Linear regression models were fitted both for NO(2) and noise. RESULTS: The correlation between NO(2) and noise (L(24h)) was 0.62. However, the correlation differed across the urban space, with lower correlations at sites with higher traffic density and in the modern downtown. Traffic density, distance from the location to the sidewalk and building density nearby explained 35.6% and 73.2% of the variability of NO(2) and noise levels, respectively. The correlation between the residuals of the two models suggested the presence of other unmeasured common variables. CONCLUSIONS: The substantial correlation between traffic-related noise and NO(2), endorsed by common determinants, and the dependence of this correlation on complex local characteristics call for careful evaluations of both factors to ultimately assess their cardiovascular effects.

The impact of heat waves on mortality in 9 European cities: results from the EuroHEAT project.

BACKGROUND: The present study aimed at developing a standardized heat wave definition to estimate and compare the impact on mortality by gender, age and death causes in Europe during summers 1990-2004 and 2003, separately, accounting for heat wave duration and intensity. METHODS: Heat waves were defined considering both maximum apparent temperature and minimum temperature and classified by intensity, duration and timing during summer. The effect was estimated as percent increase in daily mortality during heat wave days compared to non heat wave days in people over 65 years. City specific and pooled estimates by gender, age and cause of death were calculated. RESULTS: The effect of heat waves showed great geographical heterogeneity among cities. Considering all years, except 2003, the increase in mortality during heat wave days ranged from + 7.6% in Munich to + 33.6% in Milan. The increase was up to 3-times greater during episodes of long duration and high intensity. Pooled results showed a greater impact in Mediterranean (+ 21.8% for total mortality) than in North Continental (+ 12.4%) cities. The highest effect was observed for respiratory diseases and among women aged 75-84 years. In 2003 the highest impact was observed in cities where heat wave episode was characterized by unusual meteorological conditions. CONCLUSIONS: Climate change scenarios indicate that extreme events are expected to increase in the future even in regions where heat waves are not frequent. Considering our results prevention programs should specifically target the elderly, women and those suffering from chronic respiratory disorders, thus reducing the impact on mortality.

Direct effect of cigarette smoke on human pulmonary artery tension.

The effect of chronic cigarette smoke on pulmonary artery (PA) tension has been studied extensively; nevertheless, the direct effect of cigarette smoke is poorly understood. We investigated the direct effect of cigarette smoke extract (CSE) on PA tension in non-smokers, smokers, and COPD patients in vitro. PA samples from 35 patients who underwent lung resection were examined by measuring isometric tension in response to increasing serotonin concentrations. CSE dose dependently inhibited the response to serotonin in smokers and COPD patients, and to a lesser extent in non-smokers. CSE-induced relaxation was similarly inhibited by the nonspecific nitric oxide synthase (NOS) inhibitor l-NOARG and the specific inducible NOS (iNOS) inhibitor l-NIL, mainly in non-smokers and smokers, and to a lesser extent in COPD patients. Immunostaining of iNOS in PA samples was greater for smokers and COPD patients compared with non-smokers, which explains the lesser effect of CSE on PA tension in non-smokers. Moreover, CSE induced the release of nitrite via iNOS in human PA smooth muscle cells. In conclusion, CSE inhibition of serotonin-induced PA contraction was mediated mainly by iNOS in non-smokers, smokers, and COPD patients, but in different ways, which may be explained by differential iNOS expression in the PA of these patients.

Who is more vulnerable to die from ozone air pollution?

BACKGROUND: Daily increases in ambient ozone have been associated with increased mortality. However, little is known about which subpopulations are more susceptible to death related to ozone. METHODS: We conducted a case-only study in 48 US cities to identify subpopulations particularly vulnerable to ozone air pollution. Mortality and ozone data were obtained for the period 1989-2000 (May through September of each year) for 2,729,640 decedents. For each potential effect modifier, we fitted city-specific logistic regression models and pooled the results across all cities. Additionally, we examined differences in susceptibility factors according to several city characteristics using a meta-regression. RESULTS: For each 10 ppb increase in ozone (average of lags 0 to 2), people aged > or =65 years had a 1.10% (95% confidence interval = 0.44% to 1.77%) additional increase in mortality (compared with younger ages). Other groups that were particularly susceptible were black people (additional 0.53% [0.19% to 0.87%]), women (additional 0.58% [0.18% to 0.98%]), and those with atrial fibrillation (additional 1.66% [0.03% to 3.32%]). Susceptibility factors had a larger effect in cities with lower ozone levels. For instance, the additional increase in ozone-related mortality for the elderly was 1.48% (0.81% to 2.15%) in a city with a mean ozone level of 42 ppb versus 0.45% (-0.27% to 1.19%) in a city with a level of 51 ppb. CONCLUSIONS: We confirmed the susceptibility of the elderly to die of ambient ozone and identified other vulnerable subpopulations including women, blacks, and those with atrial fibrillation. Differences in vulnerability were particularly marked in cities with lower ozone concentrations.

Residential exposure to traffic-related air pollution and survival after heart failure.

BACKGROUND: Although patients with heart failure (HF) have been identified as particularly susceptible to the acute effects of air pollution, the effects of long-term exposure to air pollution on patients with this increasingly prevalent disease are largely unknown. OBJECTIVE: This study was designed to examine the mortality risk associated with residential exposure to traffic-related air pollution among HF patients. METHODS: A total of 1,389 patients hospitalized with acute HF in greater Worcester, Massachusetts, during 2000 were followed for survival through December 2005. We used daily traffic within 100 and 300 m of residence as well as the distance from residence to major roadways and to bus routes as proxies for residential exposure to traffic-related air pollution. We assessed mortality risks for each exposure variable using Cox proportional hazards models adjusted for prognostic factors. RESULTS: After the 5-year follow-up, only 334 (24%) subjects were still alive. An interquartile range increase in daily traffic within 100 m of home was associated with a mortality hazard ratio (HR) of 1.15 [95% confidence interval (CI), 1.05-1.25], whereas for traffic within 300 m this association was 1.09 (95% CI, 1.01-1.19). The mortality risk decreased with increasing distance to bus routes (HR = 0.88; 95% CI, 0.81-0.96) and was larger for those living within 100 m of a major roadway or 50 m of a bus route (HR = 1.30; 95% CI, 1.13-1.49). Adjustment for area-based income and educational level slightly attenuated these associations. CONCLUSIONS: Residential exposure to traffic-related air pollution increases the mortality risk after hospitalization with acute HF. Reducing exposure to traffic-related emissions may improve the long-term prognosis of HF patients.

Diaphragmatic paralysis following minor cervical trauma.

Two asthmatic patients developed unilateral diaphragmatic paralysis from phrenic nerve injury, in one case following cervical chiropractic manipulation and in the other after a motorcycle accident. Both presented with increased dyspnea and orthopnea. Diagnosis, severity, and level of the lesion were established by neurophysiological methods, which are preferred to chest radiography and diaphragmatic ultrasonography. In spite of only partial electrophysiological recovery of the nerve, both patients were asymptomatic 1 year later.

Extreme temperatures and mortality: assessing effect modification by personal characteristics and specific cause of death in a multi-city case-only analysis.

BACKGROUND: Extremes of temperature are associated with short-term increases in daily mortality. OBJECTIVES: We set out to identify subpopulations and mortality causes with increased susceptibility to temperature extremes. METHODS: We conducted a case-only analysis using daily mortality and hourly weather data from 50 U.S. cities for the period 1989-2000, covering a total of 7,789,655 deaths. We used distributions of daily minimum and maximum temperature in each city to define extremely hot days (>/= 99 th percentile) and extremely cold days (

Electrophysiologic evaluation of phrenic nerve and diaphragm function after coronary bypass surgery: prospective study of diabetes and other risk factors.

OBJECTIVE: Phrenic neuropathy after coronary artery bypass grafting has been related to various risk factors with conflicting results. The aim of this study was to assess the incidence, characteristics, and clinical consequences of phrenic neuropathy and the influence of diabetes and other risk factors. METHODS: We conducted an observational, prospective study of parallel groups including 94 consecutive patients subjected to coronary artery bypass grafting, half of them with diabetes and associated polyneuropathy. Electrophysiologic study of phrenic nerve conduction as the reference method, chest radiography, diaphragm ultrasound, and functional respiratory tests were performed 24 to 48 hours before and 7 days after surgery. In those patients showing phrenic neuropathy, explorations were repeated, including needle diaphragmatic electromyography, at 1, 3, 6, 9, 12, 18, and 24 months or until recovery. RESULTS: Fifteen of the 94 patients (16%) had phrenic neuropathy, 9 in the left side, 3 on the right, and 3 bilateral. Nine (60%) of the affected patients had diabetes, but diabetes did not represent a greater risk of neuropathy (relative risk 1.5, 95% confidence interval 0.6-3.9). Multivariate analysis showed no association of phrenic nerve injury with age, sex, ejection fraction, diabetes, use of internal thoracic artery, or number of grafts as risk factors. Phrenic neuropathy did not result in greater morbidity, and most patients recovered in less than 1 year. CONCLUSIONS: None of the risk factors studied, including diabetes, influenced the appearance of phrenic neuropathy, thus indicating a role for nerve damage during surgery. Low morbidity and relatively rapid recovery were observed.

The effect of ozone and PM10 on hospital admissions for pneumonia and chronic obstructive pulmonary disease: a national multicity study.

A case-crossover study was conducted in 36 US cities to evaluate the effect of ozone and particulate matter with an aerodynamic diameter of < or =10 microm (PM10) on respiratory hospital admissions and to identify which city characteristics may explain the heterogeneity in risk estimates. Respiratory hospital admissions and air pollution data were obtained for 1986-1999. In a meta-analysis based on the city-specific regression models, several city characteristics were evaluated as effect modifiers. During the warm season, the 2-day cumulative effect of a 5-ppb increase in ozone was a 0.27% (95% confidence interval (CI): 0.08, 0.47) increase in chronic obstructive pulmonary disease admissions and a 0.41% (95% CI: 0.26, 0.57) increase in pneumonia admissions. Similarly, a 10-microg/m(3) increase in PM10 during the warm season resulted in a 1.47% (95% CI: 0.93, 2.01) increase in chronic obstructive pulmonary disease at lag 1 and a 0.84% (95% CI: 0.50, 1.19) increase in pneumonia at lag 0. Percentage of households with central air conditioning reduced the effect of air pollution, and variability of summer apparent temperature reduced the effect of ozone on chronic obstructive pulmonary disease. The study confirmed, in a large sample of cities, that exposure to ozone and PM10 is associated with respiratory hospital admissions and provided evidence that the effect of air pollution is modified by certain city characteristics.

Palliative treatment of dyspnea with epidural methadone in advanced emphysema.

STUDY OBJECTIVES: This study investigated whether epidural methadone perfusion at the thoracic level can mitigate dyspnea in patients with advanced emphysema. DESIGN: Open-label clinical trial without a control group. SETTING: University hospital. PATIENTS: The inclusion criteria were a diagnosis of emphysema, basal dyspnea index (Mahler scale) < or = 3, FEV(1) < or = 35%, and no indication for pneumoreduction or lung transplantation surgery. INTERVENTIONS: An epidural catheter was inserted at the thoracic level connected to a perfusion pump for administering methadone (6 mg/24 h). Assessments were made at baseline, 1 week, and 1 month after catheter insertion. MEASUREMENTS: Pulmonary function tests were performed, and determinations were made of arterial blood gas levels, respiratory control data, dyspnea quantification by Mahler transitional dyspnea index (TDI), and the Borg scale change with inspiratory resistive loading, 6-min walk (6MW) distance, and health-related quality of life using the Chronic Respiratory Disease Questionnaire. RESULTS: Of the nine patients studied, infection and catheter migration lead to suspension of treatment before the end of the study in two cases. A significant improvement in dyspnea occurred by 1 week: mean TDI, 3.77 (SD, 1.98) [p < 0.01]. After 1 month of treatment, there were significant improvements in the 6MW distance (mean, 35.33 m; SD, 17.03; p < 0.05), health-related quality of life (mean, 1.63; SD, 0.36; p < 0.05), and dyspnea (mean TDI, 5.33; SD, 2.16; p < 0.05). In addition, after 1 month, Paco(2) fell by 6.67 mm Hg (p < 0.05) and rapid shallow breathing index decreased from 38 to 27 (p < 0.05). These changes occurred without any alteration in the subject's ability to perceive or respond to inspiratory loading. CONCLUSION: Epidural methadone perfusion at chest level can effectively palliate dyspnea and improve exercise capacity and quality of life in patients with advanced emphysema, without deterioration in respiratory control or lung function. These data suggest that modulation of spinal cord afferent signaling is an appropriate novel target for dyspnea control in chronic respiratory disease.