Coarse particulate matter air pollution and hospital admissions for cardiovascular and respiratory diseases among Medicare patients

Roger D. Peng, PhD; Howard H. Chang, BS; Michelle L. Bell, PhD; Aidan McDermott, PhD; Scott L. Zeger, PhD; Jonathan M. Samet, MD; Francesca Dominici, PhD

JAMA. 2008;299(18):2172-2179.

Context  Health risks of fine particulate matter of 2.5 µm or less in aerodynamic diameter (PM_2.5) have been studied extensively over the last decade. Evidence concerning the health risks of the coarse fraction of greater than 2.5 µm and 10 µm or less in aerodynamic diameter (PM_10-2.5) is limited.

Objective  To estimate risk of hospital admissions for cardiovascular and respiratory diseases associated with PM_10-2.5 exposure, controlling for PM_2.5.

Design, Setting, and Participants  Using a database assembled for 108 US counties with daily cardiovascular and respiratory disease admission rates, temperature and dew-point temperature, and PM_10-2.5 and PM_2.5 concentrations were calculated with monitoring data as an exposure surrogate from January 1, 1999, through December 31, 2005. Admission rates were constructed from the Medicare National Claims History Files, for a study population of approximately 12 million Medicare enrollees living on average 9 miles (14.4 km) from collocated pairs of PM₁₀ and PM_2.5 monitors.

Main Outcome Measures  Daily counts of county-wide emergency hospital admissions for primary diagnoses of cardiovascular or respiratory disease.

Results  There were 3.7 million cardiovascular disease and 1.4 million respiratory disease admissions. A 10-µg/m³ increase in PM_10-2.5 was associated with a 0.36% (95% posterior interval [PI], 0.05% to 0.68%) increase in cardiovascular disease admissions on the same day. However, when adjusted for PM_2.5, the association was no longer statistically significant (0.25%; 95% PI, –0.11% to 0.60%). A 10-µg/m³ increase in PM_10-2.5 was associated with a nonstatistically significant unadjusted 0.33% (95% PI, –0.21% to 0.86%) increase in respiratory disease admissions and with a 0.26% (95% PI, –0.32% to 0.84%) increase in respiratory disease admissions when adjusted for PM_2.5. The unadjusted associations of PM_2.5 with cardiovascular and respiratory disease admissions were 0.71% (95% PI, 0.45%-0.96%) for same-day exposure and 0.44% (95% PI, 0.06% to 0.82%) for exposure 2 days before hospital admission.

Conclusion  After adjustment for PM_2.5, there were no statistically significant associations between coarse particulates and hospital admissions for cardiovascular and respiratory diseases.

     

Fine particulate air pollution and hospital admission for cardiovascular and respiratory diseases

Context  Evidence on the health risks associated with short-term exposure to fine particles (particulate matter 2.5 µm in aerodynamic diameter [PM_2.5]) is limited. Results from the new national monitoring network for PM_2.5 make possible systematic research on health risks at national and regional scales. Objectives  To estimate risks of cardiovascular and respiratory hospital admissions associated with short-term exposure to PM_2.5 for Medicare enrollees and to explore heterogeneity of the variation of risks across regions. Design, Setting, and Participants  A national database comprising daily time-series data daily for 1999 through 2002 on hospital admission rates (constructed from the Medicare National Claims History Files) for cardiovascular and respiratory outcomes and injuries, ambient PM_2.5 levels, and temperature and dew-point temperature for 204 US urban counties (population >200 000) with 11.5 million Medicare enrollees (aged >65 years) living an average of 5.9 miles from a PM_2.5 monitor. Main Outcome Measures  Daily counts of county-wide hospital admissions for primary diagnosis of cerebrovascular, peripheral, and ischemic heart diseases, heart rhythm, heart failure, chronic obstructive pulmonary disease, and respiratory infection, and injuries as a control outcome. Results  There was a short-term increase in hospital admission rates associated with PM_2.5 for all of the health outcomes except injuries. The largest association was for heart failure, which had a 1.28% (95% confidence interval, 0.78%-1.78%) increase in risk per 10-µg/m³ increase in same-day PM_2.5. Cardiovascular risks tended to be higher in counties located in the Eastern region of the United States, which included the Northeast, the Southeast, the Midwest, and the South. Conclusion  Short-term exposure to PM_2.5 increases the risk for hospital admission for cardiovascular and respiratory diseases.      

Long-term air pollution exposure and acceleration of atherosclerosis and vascular inflammation in an animal model

Context  Recent studies have suggested a link between inhaled particulate matter exposure in urban areas and susceptibility to cardiovascular events; however, the precise mechanisms remain to be determined. Objective  To test the hypothesis that subchronic exposure to environmentally relevant particulate matter, even at low concentrations, potentiates atherosclerosis and alters vasomotor tone in a susceptible disease model. Design, Setting, and Participants  Between July 21, 2004, and January 12, 2005, 28 apolipoprotein E^–/– (apoE^–/–) mice were, based on randomized assignments, fed with normal chow or high-fat chow and exposed to concentrated ambient particles of less than 2.5 µm (PM_2.5) or filtered air (FA) in Tuxedo, NY, for 6 hours per day, 5 days per week for a total of 6 months. Main Outcome Measures  Composite atherosclerotic plaque in the thoracic and abdominal aorta and vasomotor tone changes. Results  In the high-fat chow group, the mean (SD) composite plaque area of PM_2.5 vs FA was 41.5% (9.8%) vs 26.2% (8.6%), respectively (P<.001); and in the normal chow group, the composite plaque area was 19.2% (13.1%) vs 13.2% (8.1%), respectively (P = .15). Lipid content in the aortic arch measured by oil red-O staining revealed a 1.5-fold increase in mice fed the high-fat chow and exposed to PM_2.5 vs FA (30.0 [8.2] vs 20.0 [7.0]; 95% confidence interval [CI], 1.21-1.83; P = .02). Vasoconstrictor responses to phenylephrine and serotonin challenge in the thoracic aorta of mice fed high-fat chow and exposed to PM_2.5 were exaggerated compared with exposure to FA (mean [SE], 134.2% [5.2%] vs 100.9% [2.9%], for phenylephrine, and 156.0% [5.6%] vs 125.1% [7.5%], for serotonin; both P = .03); relaxation to the endothelium-dependent agonist acetylcholine was attenuated (mean [SE] of half-maximal dose for dilation, 8.9 [0.2] x 10^-8 vs 4.3 [0.1] x 10^-8, respectively; P = .04). Mice fed high-fat chow and exposed to PM_2.5 demonstrated marked increases in macrophage infiltration, expression of the inducible isoform of nitric oxide synthase, increased generation of reactive oxygen species, and greater immunostaining for the protein nitration product 3-nitrotyrosine (all P<.001). Conclusion  In an apoE^–/– mouse model, long-term exposure to low concentration of PM_2.5 altered vasomotor tone, induced vascular inflammation, and potentiated atherosclerosis.      

Distribution of and factors associated with serum homocysteine levels in children: Child and Adolescent Trial for Cardiovascular Health

Context  Although evidence suggests that homocysteine is a risk factor for cardiovascular disease in adults, little information exists on homocysteine levels in children. Objectives  To describe the distribution of serum homocysteine concentrations among children and to examine the association between homocysteine levels and several characteristics, including serum levels of folic acid and vitamins B₁₂ and B₆. Design  Cross-sectional analysis. Setting  School-based cohort from California, Louisiana, Minnesota, and Texas. Participants  A total of 3524 US schoolchildren, aged 13 and 14 years, from the Child and Adolescent Trial for Cardiovascular Health (completed in 1994). Measurement was conducted in 1997. Main Outcome Measure  Nonfasting serum total homocysteine concentration. Results  The distribution of homocysteine values ranged from 0.1 to 25.7 µmol/L (median, 4.9 µmol/L). Geometric mean homocysteine concentration was significantly higher in boys (5.22 µmol/L) than girls (4.84 µmol/L); blacks (5.51 µmol/L) than whites (4.96 µmol/L) or Hispanics (4.93 µmol/L); nonusers of multivitamins (5.09 µmol/L) than users (4.82 µmol/L); and smokers (5.19 µmol/L) than nonsmokers (5.00 µmol/L). Serum homocysteine was significantly inversely correlated with serum levels of folic acid (r=-0.36; P=.001), vitamin B₁₂ (r=-0.21; P=.001), and vitamin B₆ (r=-0.18; P=.001). Serum homocysteine was not significantly associated with serum lipid levels or family history of cardiovascular disease and was only weakly related to body mass index and systolic blood pressure. After multivariate adjustment, homocysteine remained independently associated with sex, race, serum folic acid and vitamin B₁₂ levels, and systolic blood pressure. Conclusions  The distribution of homocysteine levels in children is substantially lower than that observed for adults; however, a small percentage of children are still potentially at elevated risk for future cardiovascular disease. Serum folic acid may be an important determinant of homocysteine levels in children.      

Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes

Context  Glycemic disorders, one of the main risk factors for cardiovascular disease, are associated with activation of oxidative stress. Objective  To assess the respective contributions of sustained chronic hyperglycemia and of acute glucose fluctuations to oxidative stress in type 2 diabetes. Design, Setting, and Participants  Case-control study of 21 patients with type 2 diabetes (studied 2003-2005) compared with 21 age- and sex-matched controls (studied in 2001) in Montpellier, France. Main Outcome Measures  Oxidative stress, estimated from 24-hour urinary excretion rates of free 8-iso prostaglandin F₂ (8-iso PGF₂). Assessment of glucose fluctuations was obtained from continuous glucose monitoring system data by calculating the mean amplitude of glycemic excursions (MAGE). Postprandial contribution to glycemic instability was assessed by determining the postprandial increment of glucose level above preprandial values (mean postprandial incremental area under the curve [AUCpp]). Long-term exposure to glucose was estimated from hemoglobin A_1c, from fasting glucose levels, and from mean glucose concentrations over a 24-hour period. Results  Mean (SD) urinary 8-iso PGF₂ excretion rates were higher in the 21 patients with diabetes (482 [206] pg/mg of creatinine) compared with controls (275 [85] pg/mg of creatinine). In univariate analysis, only MAGE (r = 0.86; P<.001) and AUCpp (r = 0.55; P = .009) showed significant correlations with urinary 8-iso PGF₂ excretion rates. Relationships between 8-iso PGF₂ excretion rates and either MAGE or AUCpp remained significant after adjustment for the other markers of diabetic control in multiple linear regression analysis (multiple R² = 0.72 for the model including MAGE and multiple R² = 0.41 for the model including AUCpp). Standardized regression coefficients were 0.830 (P<.001) for MAGE and 0.700 (P = .003) for AUCpp. Conclusions  Glucose fluctuations during postprandial periods and, more generally, during glucose swings exhibited a more specific triggering effect on oxidative stress than chronic sustained hyperglycemia. The present data suggest that interventional trials in type 2 diabetes should target not only hemoglobin A_1c and mean glucose concentrations but also acute glucose swings.      

Potentially inappropriate medication use among elderly home care patients in Europe

Context  Criteria for potentially inappropriate medication use among elderly patients have been used in the past decade in large US epidemiological surveys to identify populations at risk and specifically target risk-management strategies. In contrast, in Europe little information is available about potentially inappropriate medication use and is based on small studies with uncertain generalizability. Objective  To estimate the prevalence and associated factors of potentially inappropriate medication use among elderly home care patients in European countries. Design, Setting, and Participants  Retrospective cross-sectional study of 2707 elderly patients receiving home care (mean [SD] age, 82.2 [ 7.2] years) representatively enrolled in metropolitan areas of the Czech Republic, Denmark, Finland, Iceland, Italy, the Netherlands, Norway, and the United Kingdom. Patients were prospectively assessed between September 2001 and January 2002 using the Minimum Data Set in Home Care instrument. Main Outcome Measures  Prevalence of potentially inappropriate medication use was documented using all expert panels criteria for community-living elderly persons (Beers and McLeod). Patient-related characteristics independently associated with inappropriate medication use were identified with a multiple logistic regression model. Results  Combining all 3 sets of criteria, we found that 19.8% of patients in the total sample used at least 1 inappropriate medication; using older 1997 criteria it was 9.8% to 10.9%. Substantial differences were documented between Eastern Europe (41.1% in the Czech Republic) and Western Europe (mean 15.8%, ranging from 5.8% in Denmark to 26.5% in Italy). Potentially inappropriate medication use was associated with patient’s poor economic situation (adjusted relative risk [RR], 1.96; 95% confidence interval [CI], 1.58-2.36), polypharmacy (RR, 1.91; 95% CI, 1.62- 2.22), anxiolytic drug use (RR, 1.82; 95% CI, 1.51-2.15), and depression (RR, 1.29; 95% CI, 1.06-1.55). Negatively associated factors were age 85 years and older (RR, 0.78; 95% CI, 0.65-0.92) and living alone (RR, 0.76; 95% CI, 0.64-0.89). The odds of potentially inappropriate medication use significantly increased with the number of associated factors (P<.001). Conclusions  Substantial differences in potentially inappropriate medication use exist between European countries and might be a consequence of different regulatory measures, clinical practices, or inequalities in socioeconomic background. Since financial resources and selected patient-related characteristics are associated with such prescribing, specific educational strategies and regulations should reflect these factors to improve prescribing quality in elderly individuals in Europe.      

Nortriptyline and Interpersonal Psychotherapy as Maintenance Therapies for Recurrent Major Depression: A Randomized Controlled Trial in Patients Older Than 59 Years

Context  Elderly patients with major depression are at high risk for recurrence, increased mortality, and chronic disability. Objective  To determine the efficacy of maintenance nortriptyline hydrochloride and interpersonal psychotherapy (IPT) in preventing recurrence of major depressive episodes in patients older than 59 years. Design  A 2x2 randomized, double-blind, placebo-controlled clinical trial, stratified by therapist. Setting  University-based psychiatric research clinic. Patients  Of a total of 187 patients with recurrent nonpsychotic unipolar major depression (average age, 67 years; one third aged 70 years) recruited through clinical referral and media announcements, 107 were fully recovered after open acute and treatment continuation with nortriptyline and IPT. These patients were randomly assigned to 1 of 4 maintenance therapy conditions. Interventions  Monthly medication clinic with nortriptyline hydrochloride (80-120 ng/mL steady-state levels) (n=24); medication clinic with placebo (n=29); monthly maintenance IPT with placebo (n=21); and monthly maintenance IPT with nortriptyline (n=22). Main Outcome Measure  Recurrence of major depressive episode. Results  The time to recurrence of a major depressive episode for all 3 active treatments was significantly better than for placebo. Recurrence rates over 3 years were as follows: nortriptyline and IPT, 20% (95% confidence interval [CI], 4%-36%); nortriptyline and medication clinic visits, 43% (95% CI, 25%-61%); IPT and placebo, 64% (95% CI, 45%-83%); and placebo and medication clinic visits, 90% (95% CI, 79%-100%). Combined treatment with nortriptyline and IPT was superior to IPT and placebo and showed a trend to superior efficacy over nortriptyline monotherapy (Wald ²=3.56; P=.06). Subjects aged 70 years and older had a higher and more rapid rate of recurrence than those aged 60 to 69 years. Conclusion  In geriatric patients with recurrent major depression, maintenance treatment with nortriptyline or IPT is superior to placebo in preventing or delaying recurrence. Combined treatment using both appears to be the optimal clinical strategy in preserving recovery.      

Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. The ARDS Network

Context  Three clinical studies have suggested that ketoconazole, a synthetic imidazole with anti-inflammatory activity, may prevent the development of acute respiratory distress syndrome (ARDS) in critically ill patients. However, the use of ketoconazole as treatment for acute lung injury (ALI) and ARDS has not been previously studied. Objective  To test the efficacy of ketoconazole in reducing mortality and morbidity in patients with ALI or ARDS. Design  Randomized, double-blind, placebo-controlled trial conducted from March 1996 to January 1997. Setting  Twenty-four hospitals associated with 10 network centers in the United States, constituting the ARDS Network. Patients  A total of 234 patients with ALI or ARDS. Intervention  Patients were randomly assigned to receive ketoconazole, 400 mg/d (n=117), or placebo (n=117), initiated within 36 hours of fulfilling study entry criteria and given enterally for up to 21 days. Main Outcome Measures  Primary outcome measures were the proportion of patients alive with unassisted breathing at hospital discharge and the number of days of unassisted breathing (ventilator-free days) during 28 days of follow-up. Secondary outcome measures included the proportion of patients achieving unassisted breathing for 48 hours or more, the number of organ failure–free days, and changes in plasma interleukin 6 (IL-6) and urinary thromboxane A₂ metabolites (thromboxane B₂ [TXB₂] and 11-dehydro-TXB₂). Results  In-hospital mortality (SE) was 34.1% (4.3%) for the placebo group and 35.2% (4.3%) for the ketoconazole group (P=.85). The median number of ventilator-free days within 28 days of randomization was 9 in the placebo group and 10 in the ketoconazole group (P=.89). There were no statistically significant differences in the number of organ failure–free days, pulmonary physiology, or adverse events between treatment groups. The median serum ketoconazole level was 1.25 µg/mL and serum levels greater than 0.5 µg/mL were detected in 96% of patients assayed. Plasma IL-6, urinary TXB₂, and 11-dehydro-TXB₂ levels were unaffected by ketoconazole. Conclusions  In these patients with ALI or ARDS, ketoconazole was safe and bioavailable but did not reduce mortality or duration of mechanical ventilation or improve lung function. These data do not support the use of ketoconazole for the early treatment of ALI or ARDS.      

Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial

Context  Observational studies have reported associations between circulating total homocysteine concentration and risk of cardiovascular disease. Oral administration of folic acid and vitamin B₁₂ can lower plasma total homocysteine levels. Objective  To assess the effect of treatment with folic acid and vitamin B₁₂ and the effect of treatment with vitamin B₆ as secondary prevention in patients with coronary artery disease or aortic valve stenosis. Design, Setting, and Participants  Randomized, double-blind controlled trial conducted in the 2 university hospitals in western Norway in 1999-2006. A total of 3096 adult participants undergoing coronary angiography (20.5% female; mean age, 61.7 years) were randomized. At baseline, 59.3% had double- or triple-vessel disease, 83.7% had stable angina pectoris, and 14.9% had acute coronary syndromes. Interventions  Using a 2 x 2 factorial design, participants were randomly assigned to 1 of 4 groups receiving daily oral treatment with folic acid, 0.8 mg, plus vitamin B₁₂, 0.4 mg, plus vitamin B₆, 40 mg (n = 772); folic acid plus vitamin B₁₂ (n = 772); vitamin B₆ alone (n = 772); or placebo (n = 780). Main Outcome Measures  The primary end point was a composite of all-cause death, nonfatal acute myocardial infarction, acute hospitalization for unstable angina pectoris, and nonfatal thromboembolic stroke. Results  Mean plasma total homocysteine concentration was reduced by 30% after 1 year of treatment in the groups receiving folic acid and vitamin B₁₂. The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention. During a median 38 months of follow-up, the primary end point was experienced by a total of 422 participants (13.7%): 219 participants (14.2%) receiving folic acid/vitamin B₁₂ vs 203 (13.1%) not receiving such treatment (hazard ratio, 1.09; 95% confidence interval, 0.90-1.32; P = .36) and 200 participants (13.0%) receiving vitamin B₆ vs 222 (14.3%) not receiving vitamin B₆ (hazard ratio, 0.90; 95% confidence interval, 0.74-1.09; P = .28). Conclusions  This trial did not find an effect of treatment with folic acid/vitamin B₁₂ or vitamin B₆ on total mortality or cardiovascular events. Our findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease. Trial Registration  clinicaltrials.gov Identifier: NCT00354081      

Effect of calcium carbonate on the absorption of levothyroxine

Context  The effect of calcium carbonate on the absorption of levothyroxine has not been studied systematically. Such a potential drug interaction merits investigation because concurrent treatment with both drugs is common, particularly in postmenopausal women. Objective  To investigate the potential interference of calcium carbonate in the absorption of levothyroxine. Design  Prospective cohort study conducted from November 1998 to June 1999, supplemented with an in vitro study of thyroxine (T₄) binding to calcium carbonate. Setting  Veterans Affairs Medical Center in West Los Angeles, Calif. Patients  Twenty patients (age range, 27-78 years; n=11 men) with hypothyroidism who were taking a stable long-term regimen of levothyroxine were included in the study. All patients had serum free T₄ and thyrotropin values in the normal range before beginning the study. Intervention  Subjects were instructed to take 1200 mg/d of elemental calcium as calcium carbonate, ingested with their levothyroxine, for 3 months. Main Outcome Measures  Levels of free T₄, total T₄, total triiodothyronine (T₃), and thyrotropin, measured in all subjects at baseline (while taking levothyroxine alone), at 2 and 3 months (while taking calcium carbonate and levothyroxine), and 2 months after calcium carbonate discontinuation (while continuing to take levothyroxine). Results  Mean free T₄ and total T₄ levels were significantly reduced during the calcium period and increased after calcium discontinuation. Mean free T₄ levels were 17 pmol/L (1.3 ng/dL) at baseline, 15 pmol/L (1.2 ng/dL) during the calcium period, and 18 pmol/L (1.4 ng/dL) after calcium discontinuation (overall P<.001); mean total T₄ levels were 118 nmol/L (9.2 µg/dL) at baseline, 111 nmol/L (8.6 µg/dL) during the calcium period, and 120 nmol/L (9.3 µg/dL) after calcium discontinuation (overall P=.03). Mean thyrotropin levels increased significantly, from 1.6 mIU/L at baseline to 2.7 mIU/L during the calcium period, and decreased to 1.4 mIU/L after calcium discontinuation (P=.008). Twenty percent of patients had serum thyrotropin levels higher than the normal range during the calcium period; the highest observed level was 7.8 mIU/L. Mean T₃ levels did not change during the calcium period. The in vitro study of T₄ binding to calcium showed that adsorption of T₄ to calcium carbonate occurs at acidic pH levels. Conclusions  This study of 20 patients receiving long-term levothyroxine replacement therapy indicates that calcium carbonate reduces T₄ absorption and increases serum thyrotropin levels. Levothyroxine adsorbs to calcium carbonate in an acidic environment, which may reduce its bioavailability.      

Remissions in maternal depression and child psychopathology: a STAR*D-child report

Context  Children of depressed parents have high rates of anxiety, disruptive, and depressive disorders that begin early, often continue into adulthood, and are impairing. Objective  To determine whether effective treatment with medication of women with major depression is associated with reduction of symptoms and diagnoses in their children. Design  Assessments of children whose depressed mothers were being treated with medication as part of the multicenter Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial conducted (between December 16, 2001 and April 24, 2004) in broadly representative primary and psychiatric outpatient practices. Children were assessed by a team of evaluators not involved in maternal treatment and unaware of maternal outcomes. Study is ongoing with cases followed at 3-month intervals. Setting and Patients  One hundred fifty-one mother-child pairs in 8 primary care and 11 psychiatric outpatient clinics across 7 regional centers in the United States. Children were aged 7 to 17 years. Main Outcome Measures  Child diagnoses based on the Kiddie Schedule for Affective Disorders and Schizophrenia; child symptoms based on the Child Behavior Checklist; child functioning based on the Child Global Assessment Scale in mothers whose depression with treatment remitted with a score of 7 or lower or whose depression did not remit with a score higher than 7 on the Hamilton Rating Scale for Depression. Results  Remission of maternal depression after 3 months of medication treatment was significantly associated with reductions in the children's diagnoses and symptoms. There was an overall 11% decrease in rates of diagnoses in children of mothers whose depression remitted compared with an approximate 8% increase in rates of diagnoses in children of mothers whose depression did not. This rate difference remained statistically significant after controlling for the child's age and sex, and possible confounding factors (P = .01). Of the children with a diagnosis at baseline, remission was reported in 33% of those whose mothers' depression remitted compared with only a 12% remission rate among children of mothers whose depression did not remit. All children of mothers whose depression remitted after treatment and who themselves had no baseline diagnosis for depression remained free of psychiatric diagnoses at 3 months, whereas 17% of the children whose mothers remained depressed acquired a diagnosis. Findings were similar using child symptoms as an outcome. Greater level of maternal response was associated with fewer current diagnoses and symptoms in the children, and a maternal response of at least 50% was required to detect an improvement in the child. Conclusions  Remission of maternal depression has a positive effect on both mothers and their children, whereas mothers who remain depressed may increase the rates of their children's disorders. These findings support the importance of vigorous treatment for depressed mothers in primary care or psychiatric clinics and suggest the utility of evaluating the children, especially children whose mothers continue to be depressed.      

Ozone and short-term mortality in 95 US urban communities, 1987-2000

Context  Ozone has been associated with various adverse health effects, including increased rates of hospital admissions and exacerbation of respiratory illnesses. Although numerous time-series studies have estimated associations between day-to-day variation in ozone levels and mortality counts, results have been inconclusive. Objective  To investigate whether short-term (daily and weekly) exposure to ambient ozone is associated with mortality in the United States. Design and Setting  Using analytical methods and databases developed for the National Morbidity, Mortality, and Air Pollution Study, we estimated a national average relative rate of mortality associated with short-term exposure to ambient ozone for 95 large US urban communities from 1987-2000. We used distributed-lag models for estimating community-specific relative rates of mortality adjusted for time-varying confounders (particulate matter, weather, seasonality, and long-term trends) and hierarchical models for combining relative rates across communities to estimate a national average relative rate, taking into account spatial heterogeneity. Main Outcome Measure  Daily counts of total non–injury-related mortality and cardiovascular and respiratory mortality in 95 large US communities during a 14-year period. Results  A 10-ppb increase in the previous week’s ozone was associated with a 0.52% increase in daily mortality (95% posterior interval [PI], 0.27%-0.77%) and a 0.64% increase in cardiovascular and respiratory mortality (95% PI, 0.31%-0.98%). Effect estimates for aggregate ozone during the previous week were larger than for models considering only a single day’s exposure. Results were robust to adjustment for particulate matter, weather, seasonality, and long-term trends. Conclusions  These results indicate a statistically significant association between short-term changes in ozone and mortality on average for 95 large US urban communities, which include about 40% of the total US population. The findings indicate that this widespread pollutant adversely affects public health.      

Glycemic Control With Diet, Sulfonylurea, Metformin, or Insulin in Patients With Type 2 Diabetes Mellitus: Progressive Requirement for Multiple Therapies (UKPDS 49)

Context  Treatment with diet alone, insulin, sulfonylurea, or metformin is known to improve glycemia in patients with type 2 diabetes mellitus, but which treatment most frequently attains target fasting plasma glucose (FPG) concentration of less than 7.8 mmol/L (140 mg/dL) or glycosylated hemoglobin A_1c(HbA_1c) below 7% is unknown. Objective  To assess how often each therapy can achieve the glycemic control target levels set by the American Diabetes Association. Design  Randomized controlled trial conducted between 1977 and 1997. Patients were recruited between 1977 and 1991 and were followed up every 3 months for 3, 6, and 9 years after enrollment. Setting  Outpatient diabetes clinics in 15 UK hospitals. Patients  A total of 4075 patients newly diagnosed as having type 2 diabetes ranged in age between 25 and 65 years and had a median (interquartile range) FPG concentration of 11.5 (9.0-14.4) mmol/L [207 (162-259) mg/dL], HbA_1c levels of 9.1% (7.5%-10.7%), and a mean (SD) body mass index of 29 (6) kg/m². Interventions  After 3 months on a low-fat, high-carbohydrate, high-fiber diet, patients were randomized to therapy with diet alone, insulin, sulfonylurea, or metformin. Main Outcome Measures  Fasting plasma glucose and HbA_1c levels, and the proportion of patients who achieved target levels below 7% HbA_1c or less than 7.8 mmol/L (140 mg/dL) FPG at 3, 6, or 9 years following diagnosis. Results  The proportion of patients who maintained target glycemic levels declined markedly over 9 years of follow-up. After 9 years of monotherapy with diet, insulin, or sulfonylurea, 8%, 42%, and 24%, respectively, achieved FPG levels of less than 7.8 mmol/L (140 mg/dL) and 9%, 28%, and 24% achieved HbA_1c levels below 7%. In obese patients randomized to metformin, 18% attained FPG levels of less than 7.8 mmol/L (140 mg/dL) and 13% attained HbA_1c levels below 7%. Patients less likely to achieve target levels were younger, more obese, or more hyperglycemic than other patients. Conclusions  Each therapeutic agent, as monotherapy, increased 2- to 3-fold the proportion of patients who attained HbA_1c below 7% compared with diet alone. However, the progressive deterioration of diabetes control was such that after 3 years approximately 50% of patients could attain this goal with monotherapy, and by 9 years this declined to approximately 25%. The majority of patients need multiple therapies to attain these glycemic target levels in the longer term.      

Influence of patient literacy on the effectiveness of a primary care-based diabetes disease management program

Context  Low literacy is an important barrier for patients with diabetes, but interventions to address low literacy have not been well examined. Objective  To examine the role of literacy on the effectiveness of a comprehensive disease management program for patients with diabetes. Design, Setting, and Participants  Analysis of the influence of literacy on glycemic control and systolic blood pressure using data from a randomized controlled trial (conducted from February 2001 through April 2003) of a comprehensive diabetes management program. Participants were 217 patients aged 18 years or older with type 2 diabetes and poor glycemic control (glycosylated hemoglobin [HbA_1c] levels 8.0%) and presenting to a US academic general internal medicine practice. Interventions  All communication to patients was individualized and delivered to enhance comprehension among patients with low literacy. Intervention patients received intensive disease management from a multidisciplinary team. Control patients received an initial management session and continued with usual care. Main Outcome Measures  Achievement of goal HbA_1c levels and systolic blood pressure at 12-month follow-up for control and intervention patients stratified by literacy status. Results  Complete 12-month data were available for 193 patients (89%). Among patients with low literacy, intervention patients were more likely than control patients to achieve goal HbA_1c levels (7.0%) (42% vs 15%, respectively; adjusted odds ratio [OR], 4.6; 95% confidence interval [CI], 1.3 to 17.2; P = .02). Patients with higher literacy had similar odds of achieving goal HbA_1c levels regardless of intervention status (24% vs 23%; adjusted OR, 1.0; 95% CI, 0.4 to 2.5; P = .98). Improvements in systolic blood pressure were similar by literacy status. Conclusions  Literacy may be an important factor for predicting who will benefit from an intervention for diabetes management. A diabetes disease management program that addresses literacy may be particularly beneficial for patients with low literacy, and increasing access to such a program could help reduce health disparities.      

Relationships between poverty and psychopathology: a natural experiment

Context  Social causation (adversity and stress) vs social selection (downward mobility from familial liability to mental illness) are competing theories about the origins of mental illness. Objective  To test the role of social selection vs social causation of childhood psychopathology using a natural experiment. Design  Quasi-experimental, longitudinal study. Population and Setting  A representative population sample of 1420 rural children aged 9 to 13 years at intake were given annual psychiatric assessments for 8 years (1993-2000). One quarter of the sample were American Indian, and the remaining were predominantly white. Halfway through the study, a casino opening on the Indian reservation gave every American Indian an income supplement that increased annually. This increase moved 14% of study families out of poverty, while 53% remained poor, and 32% were never poor. Incomes of non-Indian families were unaffected. Main Outcome Measures  Levels of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, psychiatric symptoms in the never-poor, persistently poor, and ex-poor children were compared for the 4 years before and after the casino opened. Results  Before the casino opened, the persistently poor and ex-poor children had more psychiatric symptoms (4.38 and 4.28, respectively) than the never-poor children (2.75), but after the opening levels among the ex-poor fell to those of the never-poor children, while levels among those who were persistently poor remained high (odds ratio, 1.50; 95% confidence interval, 1.08-2.09; and odds ratio, 0.91; 95% confidence interval, 0.77-1.07, respectively). The effect was specific to symptoms of conduct and oppositional defiant disorders. Anxiety and depression symptoms were unaffected. Similar results were found in non-Indian children whose families moved out of poverty during the same period. Conclusions  An income intervention that moved families out of poverty for reasons that cannot be ascribed to family characteristics had a major effect on some types of children's psychiatric disorders, but not on others. Results support a social causation explanation for conduct and oppositional disorder, but not for anxiety or depression.      

Outcomes of percutaneous coronary interventions performed at centers without and with onsite coronary artery bypass graft surgery

Context  An ongoing debate focuses on whether institutions should perform percutaneous coronary interventions (PCIs) without an onsite coronary artery bypass graft (CABG) surgery program. Objective  To compare patient outcomes following PCI at US institutions performing this procedure without and with onsite cardiac surgery. Design, Setting, and Patients  Medicare hospital (part A) data were used to identify PCIs performed on fee-for-service Medicare enrollees (n = 625 854) aged at least 65 years at acute care facilities between January 1, 1999, and December 1, 2001. Hospitals without and with onsite cardiac surgery were identified based on the presence of claims for CABG surgery. Patients were characterized as undergoing primary/rescue PCI, defined as an emergency procedure performed on the same day of admission for an acute myocardial infarction (MI), vs all other PCIs. Main Outcome Measures  Post-PCI CABG surgery and combined in-hospital and 30-day mortality. Results  A total of 178 hospitals performed PCIs without onsite cardiac surgery and 943 hospitals performed PCIs with onsite cardiac surgery. Patients undergoing PCIs in hospitals without onsite cardiac surgery were similar to those with onsite cardiac surgery with respect to age, sex, race, and measurable comorbidities; however, patients undergoing PCIs in hospitals without onsite cardiac surgery were more likely to have a primary/rescue PCI (22.0% vs 5.6%, P < .001). Patients undergoing PCIs in hospitals without cardiac surgery were more likely to die (6.0% vs 3.3%; adjusted odds ratio [OR], 1.29; 95% confidence interval [CI], 1.14-1.47; P < .001). After accounting for baseline differences, mortality for patients with primary/rescue PCI was similar in institutions without and with cardiac surgery (adjusted OR, 0.93; 95% CI, 0.80-1.08; P = .34). However, for the larger non-primary/rescue PCI population, mortality was higher in hospitals without onsite cardiac surgery (adjusted OR, 1.38; 95% CI, 1.14-1.67; P=.001). This increase in mortality was primarily confined to hospitals performing 50 or less Medicare PCIs per year. Conclusions  Percutaneous coronary interventions in hospitals without onsite cardiac surgery are often performed for reasons other than immediate treatment of an MI and are associated with a higher risk of adverse outcomes. Policies aimed at increasing access to primary/rescue PCI through promoting PCI in hospitals without cardiac surgery may inadvertently lead to an overall increase in mortality related to PCI.      

Surgical site infection and the routine use of perioperative hyperoxia in a general surgical population: a randomized controlled trial

Context  Surgical site infection (SSI) in the general surgical population is a significant public health issue. The use of a high fractional inspired concentration of oxygen (FIO₂) during the perioperative period has been reported to be of benefit in selected patients, but its role as a routine intervention has not been investigated. Objective  To determine whether the routine use of high FIO₂ during the perioperative period alters the incidence of SSI in a general surgical population. Design, Setting, and Patients  Double-blind, randomized controlled trial conducted between September 2001 and May 2003 at a large university hospital in metropolitan New York City of 165 patients undergoing major intra-abdominal surgical procedures under general anesthesia. Interventions  Patients were randomly assigned to receive either 80% oxygen (FIO₂ of 0.80) or 35% oxygen (FIO₂ of 0.35) during surgery and for the first 2 hours after surgery. Main Outcome Measures  Presence of clinically significant SSI in the first 14 days after surgery, as determined by clinical assessment, a management change, and at least 3 prospectively defined objective criteria. Results  The study groups were closely matched in a large number of clinical variables. The overall incidence of SSI was 18.1%. In an intention-to-treat analysis, the incidence of infection was significantly higher in the group receiving FIO₂ of 0.80 than in the group with FIO₂ of 0.35 (25.0% vs 11.3%; P = .02). FIO₂ remained a significant predictor of SSI (P = .03) in multivariate regression analysis. Patients who developed SSI had a significantly longer length of hospitalization after surgery (mean [SD], 13.3 [9.9] vs 6.0 [4.2] days; P<.001). Conclusions  The routine use of high perioperative FIO₂ in a general surgical population does not reduce the overall incidence of SSI and may have predominantly deleterious effects. General surgical patients should continue to receive oxygen with cardiorespiratory physiology as the principal determinant.      

Association between phonocardiographic third and fourth heart sounds and objective measures of left ventricular function

Context  The third (S₃) and fourth (S₄) heart sounds detected by phonocardiography are considered to represent the criterion standards of the gallop sounds, but their test characteristics have not been explored. Objective  To determine the diagnostic test characteristics of the S₃ and S₄ for prediction of left ventricular dysfunction using a computerized heart sound detection algorithm. Design, Setting, and Participants  Prospective study of 90 adult patients undergoing elective left-sided heart catheterization at a single US teaching hospital between August 2003 and June 2004. The mean age was 62 (SD, 13) years (range, 24-90 years) and 61 (68%) were male. Within a 4-hour period, participants underwent computerized heart sound phonocardiographic analysis, cardiac catheterization, transthoracic echocardiography, and blood sampling for assessment of an S₃/S₄, left ventricular end-diastolic pressure (LVEDP), left ventricular ejection fraction (LVEF), and B-type natriuretic peptide (BNP), respectively. Main Outcome Measures  Diagnostic test characteristics of the computerized phonocardiographic S₃ and S₄ using markers of left ventricular function as criterion standards. Results  Mean (SD) LVEDP was significantly elevated (18.4 [6.9] mm Hg vs 12.1 [7.3] mm Hg; P<.001), mean (SD) LVEF was reduced (49.4% [20.2%] vs 63.6% [14.8%]; P<.001), and median (interquartile range) BNP was elevated (330 [98-1155] pg/mL vs 86 [41-192] pg/mL; P<.001) in those with an S₃, S₄, or both compared with patients without a diastolic heart sound. The sensitivities of these heart sounds to detect an elevated LVEDP, reduced LVEF, or elevated BNP were 41%, 52%, and 32% for an S₃, and 46%, 43%, and 40% for an S₄, respectively. For abnormal levels of the same markers of ventricular function, the specificities of the S₃ were 92%, 87%, and 92%, while the specificities of the S₄ were 80%, 72%, and 78%, respectively. Conclusions  Neither the phonocardiographic S₃ nor the S₄ is a sensitive marker of left ventricular dysfunction. The phonocardiographic S₃ is specific for left ventricular dysfunction and appears to be superior to the moderate specificity of the phonocardiographic S₄.      

Respiration during snow burial using an artificial air pocket

Context  Asphyxia is the most common cause of death after avalanche burial. A device that allows a person to breathe air contained in snow by diverting expired carbon dioxide (CO₂) away from a 500-cm³ artificial inspiratory air pocket may improve chances of survival in avalanche burial. Objective  To determine the duration of adequate oxygenation and ventilation during burial in dense snow while breathing with vs without the artificial air pocket device. Design  Field study of physiologic respiratory measures during snow burial with and without the device from December 1998 to March 1999. Study burials were terminated at the subject's request, when oxygen saturation as measured by pulse oximetry (SpO₂) dropped to less than 84%, or after 60 minutes elapsed. Setting  Mountainous outdoor site at 2385 m elevation, with an average barometric pressure of 573 mm Hg. Participants  Six male and 2 female volunteers (mean age, 34.6 years; range, 28-39 years). Main Outcome Measures  Burial time, SpO₂, partial pressure of end-tidal CO₂ (ETCO₂), partial pressure of inspiratory CO₂(PICO₂), respiratory rate, and heart rate at baseline (in open atmosphere) and during snow burial while breathing with the device and without the device but with a 500-cm³ air pocket in the snow. Results  Mean burial time was 58 minutes (range, 45-60 minutes) with the device and 10 minutes (range, 5-14 minutes) without it (P=.001). A mean baseline SpO₂ of 96% (range, 90%-99%) decreased to 90% (range, 77%-96%) in those buried with the device (P=.01) and to 84% (range, 79%-92%) in the control burials (P=.02). Only 1 subject buried with the device, but 6 control subjects buried without the device, decreased SpO₂ to less than 88% (P=.005). A mean baseline ETCO₂ of 32 mm Hg (range, 27-38 mm Hg) increased to 45 mm Hg (range, 32-53 mm Hg) in the burials with the device (P=.02) and to 54 mm Hg (range, 44-63 mm Hg) in the control burials (P=.02). A mean baseline PICO₂ of 2 mm Hg (range, 0-3 mm Hg) increased to 32 mm Hg (range, 20-44 mm Hg) in the burials with the device (P=.01) and to 44 mm Hg (range, 37-50 mm Hg) in the control burials (P=.02). Respiratory and heart rates did not change in burials with the device but significantly increased in control burials. Conclusions  In our study, although hypercapnia developed, breathing with the device during snow burial considerably extended duration of adequate oxygenation compared with breathing with an air pocket in the snow. Further study will be needed to determine whether the device improves survival during avalanche burial.