Reduced Quality of Life in Survivors of Acute Respiratory Distress Syndrome Compared With Critically Ill Control Patients

Context  Health-related quality of life (HRQL) is reduced in patients who survive acute respiratory distress (ARDS), but whether this decline in HRQL is caused by ARDS or other aspects of the patient's illness or injury is unknown. Objective  To determine if there are differences in the HRQL of ARDS survivors and comparably ill or injured controls without ARDS. Design  Prospective, matched, parallel cohort study. Setting  A 411-bed municipal medical and regional level I trauma center. Patients  Seventy-three pairs of ARDS survivors and severity-matched controls with the clinical risk factors for ARDS of sepsis and trauma admitted between January 1, 1994, and July 30, 1996. Main Outcome Measures  The HRQL of ARDS survivors and controls, assessed by generic and pulmonary disease–specific HRQL instruments (Medical Outcomes Study 36-Item Short Form Health Survey, Standard Form [SF-36] and St George's Respiratory Questionnaire [SGRQ], respectively). Results  Clinically meaningful and statistically significant reductions in HRQL scores of ARDS survivors (n=73) were seen in 7 of 8 SF-36 domains and 3 of 3 SGRQ domains compared with matched controls (P<.001 for all reductions). The largest decrements in the HRQL were seen in physical function and pulmonary symptoms and limitations. Analysis of trauma-matched pairs (n=46) revealed significant reductions in 7 of 8 SF-36 domains (P.02) and 3 of 3 SGRQ domains (P.003). Analysis of sepsis-matched pairs (n=27) revealed significant reductions in 6 of 8 SF-36 domains (P.05) and 3 of 3 SGRQ domains (P.002). Conclusions  Survivors of ARDS have a clinically significant reduction in HRQL that appears to be caused exclusively by ARDS and its sequelae. Reductions were primarily noted in physical functioning and pulmonary disease–specific domains.      

Association of apolipoprotein E genotypes with lipid levels and coronary risk

Context  Previous reviews of associations of apolipoprotein E (apoE) genotype and coronary disease have been dominated by smaller studies that are liable to biases. Objective  To reassess associations of apoE genotypes with circulating lipid levels and with coronary risk. Data Sources  We conducted an updated meta-analysis including both published and previously unreported studies, using MEDLINE, EMBASE, BIOSIS, Science Citation Index, and the Chinese National Knowledge Infrastructure Database published between January 1970 and January 2007, reference lists of articles retrieved, and a registry of relevant studies. Study Selection  Eighty-two studies of lipid levels (86 067 healthy participants) and 121 studies of coronary outcomes (37 850 cases and 82 727 controls) were identified, with prespecified principal focus on studies with at least 1000 healthy participants for lipids and those with at least 500 coronary outcomes. Data Extraction  Information on genotype frequencies, lipid levels, coronary outcomes, and laboratory and population characteristics were recorded independently by 2 investigators and/or supplied by study investigators. Results  In the most extreme comparison, people with the 2/2 genotype had 1.14 mmol/L (95% confidence interval [CI], 0.87-1.40 mmol/L [44.0 mg/dL; 95% CI; 33.6-51.1 mg/dL]) or about 31% (95% CI, 23%-38%) lower mean low-density lipoprotein cholesterol (LDL-C) values than those with the 4/4 genotype. There were approximately linear relationships of apoE genotypes (when ordered 2/2, 2/3, 2/4, 3/3, 3/4, 4/4) with LDL-C and with coronary risk. The relationship with high-density lipoprotein cholesterol was inverse and shallow and that with triglycerides was nonlinear and largely confined to the 2/2 genotype. Compared with 3/3, the odds ratio for coronary disease was 0.80 (95% CI, 0.70-0.90) in 2 carriers and was 1.06 (95% CI, 0.99-1.13) in 4 carriers. Conclusions  There are approximately linear relationships of apoE genotypes with both LDL-C levels and coronary risk. Compared with individuals with the 3/3 genotype, 2 carriers have a 20% lower risk of coronary heart disease and 4 carriers have a slightly higher risk.      

Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial

Context  Implantable cardioverter defibrillator (ICD) therapy is effective but is associated with high-voltage shocks that are painful. Objective  To determine whether amiodarone plus -blocker or sotalol are better than -blocker alone for prevention of ICD shocks. Design, Setting, and Patients  A randomized controlled trial with blinded adjudication of events of 412 patients from 39 outpatient ICD clinical centers located in Canada, Germany, United States, England, Sweden, and Austria, conducted from January 13, 2001, to September 28, 2004. Patients were eligible if they had received an ICD within 21 days for inducible or spontaneously occurring ventricular tachycardia or fibrillation. Intervention  Patients were randomized to treatment for 1 year with amiodarone plus -blocker, sotalol alone, or -blocker alone. Main Outcome Measure  Primary outcome was ICD shock for any reason. Results  Shocks occurred in 41 patients (38.5%) assigned to -blocker alone, 26 (24.3%) assigned to sotalol, and 12 (10.3%) assigned to amiodarone plus -blocker. A reduction in the risk of shock was observed with use of either amiodarone plus -blocker or sotalol vs -blocker alone (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.28-0.68; P<.001). Amiodarone plus -blocker significantly reduced the risk of shock compared with -blocker alone (HR, 0.27; 95% CI, 0.14-0.52; P<.001) and sotalol (HR, 0.43; 95% CI, 0.22-0.85; P = .02). There was a trend for sotalol to reduce shocks compared with -blocker alone (HR, 0.61; 95% CI, 0.37-1.01; P = .055). The rates of study drug discontinuation at 1 year were 18.2% for amiodarone, 23.5% for sotalol, and 5.3% for -blocker alone. Adverse pulmonary and thyroid events and symptomatic bradycardia were more common among patients randomized to amiodarone. Conclusions  Despite use of advanced ICD technology and treatment with a -blocker, shocks occur commonly in the first year after ICD implant. Amiodarone plus -blocker is effective for preventing these shocks and is more effective than sotalol but has an increased risk of drug-related adverse effects. Clinical Trials Registration  ClinicalTrials.gov Identifier: NCT00257959      

Efficacy of Rofecoxib, Celecoxib, and Acetaminophen in Osteoarthritis of the Knee: A Randomized Trial

Context  Osteoarthritis (OA) is often treated with nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, or specific inhibitors of cyclooxygenase 2 (COX-2). Objective  To assess the relative therapeutic efficacy of rofecoxib, celecoxib, and acetaminophen in adults with OA. Design and Setting  Randomized, parallel-group, double-blind trial, conducted from June 1999 to February 2000, in 29 clinical centers in the United States. Patients  Three hundred eighty-two patients aged at least 40 years who had OA of the knee that was previously treated with NSAIDs or acetaminophen. Interventions  Patients were randomly assigned to receive rofecoxib, 12.5 mg/d (n = 96); rofecoxib, 25 mg/d (n = 95); celecoxib, 200 mg/d (n = 97); or acetaminophen, 4000 mg/d (n = 94) for 6 weeks. Main Outcome Measures  Assessments over days 1 to 6 and over 6 weeks included pain on walking, night pain, pain at rest, and morning stiffness as measured on a Western Ontario McMaster Universities Osteoarthritis Index (100-mm visual analog scale [VAS]) and global response to therapy compared among 4 treatment groups. Results  79% of patients completed the study. More patients treated with acetaminophen discontinued early due to lack of efficacy than patients treated with COX-2 inhibitors (31% vs 18%-19%). Efficacy assessed in the first 6 days of therapy showed greatest response to rofecoxib, 25 mg/d, followed by rofecoxib, 12.5 mg/d, celecoxib, and acetaminophen, respectively, in terms of relief of pain on walking (-32.2, - 29.0, - 26.4, and -20.6 mm change on the VAS; P.04 for all others vs acetaminophen; P = .05 for 25-mg rofecoxib vs celecoxib), rest pain (-21.8, - 18.6, - 15.5, and - 12.5 mm; P.02 for either dose of rofecoxib vs acetaminophen and P = .02 for rofecoxib, 25 mg/d, vs celecoxib), night pain (-25.2, - 22.0, - 18.7, and - 18.8 mm; P = .04 for rofecoxib, 25 mg/d, vs both acetaminophen and celecoxib), and morning stiffness (-30.4, - 28.4, - 25.7, and - 20.9 mm; P.02 for either dose of rofecoxib vs acetaminophen). Over 6 weeks, rofecoxib, 25 mg/d, provided greatest response for night pain (P<.002 vs celecoxib and P = .006 vs acetaminophen and P = .02 vs rofecoxib, 12.5 mg/d), composite pain subscale (P.03 vs all other treatments), stiffness subscale (P.04 vs celecoxib and acetaminophen), and physical function subscale (P = .001 vs acetaminophen). Global responses over 6 weeks showed a similar pattern (good or excellent response at week 6: 60%, 56%, 46%, and 39%, respectively; P.03 for rofecoxib, 25 mg/d, vs celecoxib and acetaminophen; P = .02 for rofecoxib, 12.5 mg/d, vs acetaminophen). All treatments were generally safe and well tolerated. Conclusion  Rofecoxib, 25 mg/d, provided efficacy advantages over acetaminophen, 4000 mg/d, celecoxib, 200 mg/d, and rofecoxib, 12.5 mg, for symptomatic knee OA.      

Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study

Context  Sleep-disordered breathing (SDB) and sleep apnea have been linked to hypertension in previous studies, but most of these studies used surrogate information to define SDB (eg, snoring) and were based on small clinic populations, or both. Objective  To assess the association between SDB and hypertension in a large cohort of middle-aged and older persons. Design and Setting  Cross-sectional analyses of participants in the Sleep Heart Health Study, a community-based multicenter study conducted between November 1995 and January 1998. Participants  A total of 6132 subjects recruited from ongoing population-based studies (aged 40 years; 52.8% female). Main Outcome Measures  Apnea-hypopnea index (AHI, the average number of apneas plus hypopneas per hour of sleep, with hypopnea defined as a 30% reduction in airflow or thoracoabdominal excursion accompanied by a 4% drop in oxyhemoglobin saturation), obtained by unattended home polysomnography. Other measures include arousal index; percentage of sleep time below 90% oxygen saturation; history of snoring; and presence of hypertension, defined as resting blood pressure of at least 140/90 mm Hg or use of antihypertensive medication. Results  Mean systolic and diastolic blood pressure and prevalence of hypertension increased significantly with increasing SDB measures, although some of this association was explained by body mass index (BMI). After adjusting for demographics and anthropometric variables (including BMI, neck circumference, and waist-to-hip ratio), as well as for alcohol intake and smoking, the odds ratio for hypertension, comparing the highest category of AHI (30 per hour) with the lowest category (<1.5 per hour), was 1.37 (95% confidence interval [CI], 1.03-1.83; P for trend=.005). The corresponding estimate comparing the highest and lowest categories of percentage of sleep time below 90% oxygen saturation (12% vs <0.05%) was 1.46 (95% CI, 1.12-1.88; P for trend <.001). In stratified analyses, associations of hypertension with either measure of SDB were seen in both sexes, older and younger ages, all ethnic groups, and among normal-weight and overweight individuals. Weaker and nonsignificant associations were observed for the arousal index or self-reported history of habitual snoring. Conclusion  Our findings from the largest cross-sectional study to date indicate that SDB is associated with systemic hypertension in middle-aged and older individuals of different sexes and ethnic backgrounds.      

Beta2-adrenergic receptor genotype and survival among patients receiving beta-blocker therapy after an acute coronary syndrome

Context  Previous data support an association between polymorphisms of the ₁- and ₂-adrenergic receptors (ADRB1 and ADRB2) and surrogate end points of response to -adrenergic blocker therapy. However, no associations between these polymorphisms and mortality have been demonstrated. Objective  To evaluate the effect of ADRB1 Arg389Gly (1165 CG), Ser49Gly (145 AG), and ADRB2 Gly16Arg (46 GA), Gln27Glu (79 CG) genotypes on survival among patients discharged with prescribed -blockers after an acute coronary syndrome (ACS). Design, Setting, and Patients  Prospective cohort study of 735 ACS patients admitted to 2 Kansas City, Mo, medical centers between March 2001 and October 2002; 597 patients were discharged with -blocker therapy. Main Outcome Measure  Multivariable-adjusted time to all-cause 3-year mortality. Results  There were 84 deaths during follow-up. There was a significant association between ADRB2 genotype and 3-year mortality among patients prescribed -blocker therapy. For the 79 CG polymorphism, Kaplan-Meier 3-year mortality rates were 16% (35 deaths), 11% (27 deaths), and 6% (4 deaths) for the CC, CG, and GG genotypes, respectively (P = .03; adjusted hazard ratios [AHRs], 0.51 [95% confidence interval {CI}, 0.30-0.87] for CG vs CC and 0.24 (95% CI, 0.09-0.68) for GG vs CC, P = .004). For the ADRB2 46 GA polymorphism, 3-year Kaplan-Meier mortality estimates were 10% (17 deaths), 10% (28 deaths), and 20% (20 deaths) for the GG, GA, and AA genotypes, respectively (P = .005; AHRs, 0.48 [95% CI, 0.27-0.86] for GA vs AA and 0.44 [95% CI, 0.22-0.85] for GG vs AA, P = .02). No mortality difference between genotypes was found among patients not discharged with -blocker therapy for either the 79 CG or 46 GA polymorphisms (P = .98 and P = .49, respectively). The ADRB2 diplotype and compound genotypes were predictive of survival in patients treated with -blockers (P = .04 and P = .002; AHRs, 5.36 [95% CI, 1.83-15.69] and 2.41 [95% CI, 0.86-6.74] for 46 A homozygous and composite heterozygous vs 79 G homozygous, respectively). No association of the ADRB1 variants with mortality was observed in either the -blocker or no -blocker groups. Conclusions  Patients prescribed -blocker therapy after an ACS have differential survival associated with their ADRB2 genotypes. Further assessment of the benefits of -blocker therapy in high-risk genotype groups may be warranted.      

Prevalence and trends in obesity among US adults, 1999-2000

Context  The prevalence of obesity and overweight increased in the United States between 1978 and 1991. More recent reports have suggested continued increases but are based on self-reported data. Objective  To examine trends and prevalences of overweight (body mass index [BMI] 25) and obesity (BMI 30), using measured height and weight data. Design, Setting, and Participants  Survey of 4115 adult men and women conducted in 1999 and 2000 as part of the National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of the US population. Main Outcome Measure  Age-adjusted prevalence of overweight, obesity, and extreme obesity compared with prior surveys, and sex-, age-, and race/ethnicity–specific estimates. Results  The age-adjusted prevalence of obesity was 30.5% in 1999-2000 compared with 22.9% in NHANES III (1988-1994; P<.001). The prevalence of overweight also increased during this period from 55.9% to 64.5% (P<.001). Extreme obesity (BMI 40) also increased significantly in the population, from 2.9% to 4.7% (P = .002). Although not all changes were statistically significant, increases occurred for both men and women in all age groups and for non-Hispanic whites, non-Hispanic blacks, and Mexican Americans. Racial/ethnic groups did not differ significantly in the prevalence of obesity or overweight for men. Among women, obesity and overweight prevalences were highest among non-Hispanic black women. More than half of non-Hispanic black women aged 40 years or older were obese and more than 80% were overweight. Conclusions  The increases in the prevalences of obesity and overweight previously observed continued in 1999-2000. The potential health benefits from reduction in overweight and obesity are of considerable public health importance.      

Vitamin A Intake and Hip Fractures Among Postmenopausal Women

Context  Ingestion of toxic amounts of vitamin A affects bone remodeling and can have adverse skeletal effects in animals. The possibility has been raised that long-term high vitamin A intake could contribute to fracture risk in humans. Objective  To assess the relationship between high vitamin A intake from foods and supplements and risk of hip fracture among postmenopausal women. Design  Prospective analysis begun in 1980 with 18 years of follow-up within the Nurses' Health Study. Setting  General community of registered nurses within 11 US states. Participants  A total of 72 337 postmenopausal women aged 34 to 77 years. Main Outcome Measures  Incident hip fractures resulting from low or moderate trauma, analyzed by quintiles of vitamin A intake and by use of multivitamins and vitamin A supplements, assessed at baseline and updated during follow-up. Results  From 1980 to 1998, 603 incident hip fractures resulting from low or moderate trauma were identified. After controlling for confounding factors, women in the highest quintile of total vitamin A intake (3000 µg/d of retinol equivalents [RE]) had a significantly elevated relative risk (RR) of hip fracture (RR, 1.48; 95% confidence interval [CI], 1.05-2.07; P for trend = .003) compared with women in the lowest quintile of intake (<1250 µg/d of RE). This increased risk was attributable primarily to retinol (RR, 1.89; 95% CI, 1.33-2.68; P for trend <.001 comparing 2000 µg/d vs <500 µg/d). The association of high retinol intake with hip fracture was attenuated among women using postmenopausal estrogens. Beta carotene did not contribute significantly to fracture risk (RR, 1.22; 95% CI, 0.90-1.66; P for trend = .10 comparing 6300 µg/d vs <2550 µg/d). Women currently taking a specific vitamin A supplement had a nonsignificant 40% increased risk of hip fracture (RR, 1.40; 95% CI, 0.99-1.99) compared with those not taking that supplement, and, among women not taking supplemental vitamin A, retinol from food was significantly associated with fracture risk (RR, 1.69; 95% CI, 1.05-2.74; P for trend = .05 comparing 1000 µg/d vs <400 µg/d). Conclusions  Long-term intake of a diet high in retinol may promote the development of osteoporotic hip fractures in women. The amounts of retinol in fortified foods and vitamin supplements may need to be reassessed.      

Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers

Context  Data on the efficacy of -blockers in the 3 most common genetic long QT syndrome (LQTS) loci are limited. Objective  To describe and assess outcome in a large systematically genotyped population of -blocker–treated LQTS patients. Design, Setting, and Patients  Consecutive LQTS-genotyped patients (n = 335) in Italy treated with -blockers for an average of 5 years. Main Outcome Measures  Cardiac events (syncope, ventricular tachycardia/torsades de pointes, cardiac arrest, and sudden cardiac death) while patients received -blocker therapy according to genotype. Results  Cardiac events among patients receiving -blocker therapy occurred in 19 of 187 (10%) LQT1 patients, 27 of 120 (23%) LQT2 patients, and 9 of 28 (32%) LQT3 patients (P<.001). The risk of cardiac events was higher among LQT2 (adjusted relative risk, 2.81; 95% confidence interval [CI], 1.50-5.27; P = .001) and LQT3 (adjusted relative risk, 4.00; 95% CI, 2.45-8.03; P<.001) patients than among LQT1 patients, suggesting inadequate protection from -blocker therapy. Other important predictors of risk were a QT interval corrected for heart rate that was more than 500 ms in patients receiving therapy (adjusted relative risk, 2.01; 95% CI, 1.16-3.51; P = .01) and occurrence of a first cardiac event before the age of 7 years (adjusted RR, 4.34; 95% CI, 2.35-8.03; P<.001). Conclusion  Among patients with genetic LQTS treated with -blockers, there is a high rate of cardiac events, particularly among patients with LQT2 and LQT3 genotypes.      

Apolipoprotein E and progression of chronic kidney disease

Context  Apolipoprotein E (APOE) genetic variation has been implicated in diabetic nephropathy with the 2 allele increasing and the 4 allele decreasing risk. APOE allelic associations with chronic kidney disease beyond diabetic nephropathy are unknown, with no studies reported in high-risk African American populations. Objective  To quantify the risk of chronic kidney disease progression associated with APOE in a population-based study including white, African American, diabetic, and nondiabetic individuals. Design, Setting, and Participants  Prospective follow-up (through January 1, 2003) of Atherosclerosis Risk in Communities (ARIC) study participants, including 3859 African American and 10 661 white adults aged 45 to 64 years without severe renal dysfunction at baseline in 1987-1989, sampled from 4 US communities. Main Outcome Measures  Incident chronic kidney disease progression, defined as hospitalization or death with kidney disease or increase in serum creatinine level of 0.4 mg/dL (35 µmol/L) or more above baseline, examined by APOE genotypes and alleles. Results  During median follow-up of 14 years, chronic kidney disease progression developed in 1060 individuals (incidence per 1000 person-years: 5.5 overall; 8.8 in African Americans and 4.4 in whites). Adjusting for major chronic kidney disease risk factors, 2 moderately increased and 4 decreased risk of disease progression (likelihood ratio test, P = .03). Further adjustment for low- and high-density lipoprotein cholesterol and triglycerides did not attenuate relative risks (RRs) (2: 1.08 [95% CI, 0.93-1.25] and 4: 0.85 [95% CI, 0.75-0.95] compared with 3; likelihood ratio test, P = .008). 4 decreased risk of end-stage renal disease (RR, 0.60 [95% CI, 0.43-0.84]). 2 was associated with a decline in renal function (RR, 1.25 [95% CI, 1.02-1.53]), though not with events, such as hospitalizations or end-stage renal disease. Risks were similar stratified by race, sex, diabetes, and hypertension (all P values for interaction >.05). Excess risk of chronic kidney disease in African Americans was not explained by APOE alleles. Conclusions  APOE variation predicts chronic kidney disease progression, independent of diabetes, race, lipid, and nonlipid risk factors. Our study suggests that nonlipid-mediated pathways, such as cellular mechanisms of kidney remodeling, may be involved in the association of APOE alleles and progression of chronic kidney disease.      

Discrepancy between the tuberculin skin test and the whole-blood interferon gamma assay for the diagnosis of latent tuberculosis infection in an intermediate tuberculosis-burden country

Context  A recently developed whole-blood interferon (IFN-) assay based on stimulation with the Mycobacterium tuberculosis–specific antigens early secreted antigenic target 6 and culture filtrate protein 10 shows promise for the diagnosis of latent tuberculosis (TB) infection. Objective  To compare the tuberculin skin test (TST) and the whole-blood IFN- assay in the diagnosis of latent TB infection according to the intensity of exposure. Design and Setting  A prospective comparison between the whole-blood IFN- assay and the TST using a 2-TU dose of purified protein derivative RT23 in a population with intermediate TB burden was conducted sequentially between February 1, 2004, and February 28, 2005, in a Korean tertiary referral hospital. Participants  Of 273 participants, 220 (95.7%) had received BCG vaccine. Participants were grouped according to their risk of infection: group 1, no identifiable risk of M tuberculosis infection (n = 99); group 2, recent casual contacts (n = 72); group 3, recent close contacts (n = 48); group 4, bacteriologically or pathologically confirmed TB patients (n = 54). Main Outcome Measures  Levels of agreement between the TST and the IFN- assay and the likelihood of infection in the various groups. Results  For the TST with a 10-mm induration cutoff, the positive response rate in group 1 was 51%; group 2, 60%; group 3, 71%, and group 4, 78%. For the IFN- assay, the positive response rate in group 1 was 4%; group 2, 10%; group 3, 44%; and group 4, 81%. The overall agreement between the TST and the IFN- assay in healthy volunteers was = 0.16. The odds of a positive test result per unit increase in exposure across the 4 groups increased by a factor of 5.31 (95% confidence interval [CI], 3.62-7.79) for the IFN- assay and by a factor of 1.52 (95% CI, 1.20-1.91) for the TST (P<.001). Using a 15-mm induration cutoff for the TST did not make a substantial difference to the test results. Conclusion  The IFN- assay is a better indicator of the risk of M tuberculosis infection than TST in a BCG-vaccinated population.      

Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial

Context  The expression and release of tissue factor is a major trigger for the activation of coagulation in patients with sepsis. Tissue factor pathway inhibitor (TFPI) forms a complex with tissue factor and blood protease factors leading to inhibition of thrombin generation and fibrin formation. Objectives  To determine if administration of tifacogin (recombinant TFPI) provides mortality benefit in patients with severe sepsis and elevated international normalized ratio (INR) and to assess tifacogin safety in severe sepsis, including patients with low INR. Design and Setting  A randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial conducted from March 21, 2000, through September 27, 2001, in 245 hospitals in 17 countries in North America, Europe, and Israel. Patients  The primary efficacy population consisted of 1754 patients (=" BORDER="0">18 years) with severe sepsis and a high INR (=" BORDER="0">1.2) randomly assigned to intravenous infusion of either tifacogin (0.025 mg/kg per hour for 96 hours, n = 880) or placebo (arginine citrate buffer, n = 874), and 201 patients with a low INR (<1.2) randomly assigned to receive the same dose of either tifacogin or placebo. Main Outcome Measure  All-cause 28-day mortality. Results  Overall mortality at 28 days in the tifacogin-treated group (n = 880) vs the placebo group (n = 874) for high INR was 34.2% vs 33.9%, respectively (P = .88, Pearson ² test; P = .75, logistic regression model). None of the protocol-specified secondary end points differed between the tifacogin vs placebo groups. An analysis on the first 722 patients demonstrated a mortality rate of 38.9% for placebo vs 29.1% for tifacogin (P = .006, Pearson ² test). Tifacogin significantly attenuated prothrombin fragment 1.2 and thrombin:antithrombin complex levels (P<.001, 2-sample t test) in patients with high and low INR. Overall mortality was lower in the tifacogin response in patients with low INR (12%; n = 83) vs placebo (22.9%; n = 118) (P = .051, Pearson ² test; P = .03, logistic regression model). There was an increase in serious adverse events with bleeding in the tifacogin group in both cohorts (6.5% tifacogin and 4.8% placebo for high INR; 6.0% tifacogin and 3.3% placebo for low INR). Conclusions  Treatment with tifacogin had no effect on all-cause mortality in patients with severe sepsis and high INR. Tifacogin administration was associated with an increase in risk of bleeding, irrespective of baseline INR.      

Antepartum dental radiography and infant low birth weight

Context  Both high- and low-dose radiation exposures in women have been associated with low-birth-weight offspring. It is unclear if radiation affects the hypothalamus-pituitary-thyroid axis and thereby indirectly birth weight, or if the radiation directly affects the reproductive organs. Objective  To investigate whether antepartum dental radiography is associated with low-birth-weight offspring. Design  A population-based case-control study. Participants and Setting  Enrollees of a dental insurance plan with live singleton births in Washington State between January 1993 and December 2000. Cases were 1117 women with low-birth-weight infants (<2500 g), of whom 336 were term low-birth-weight infants (1501-2499 g and gestation =" BORDER="0">37 weeks). Four control pregnancies resulting in normal-birth-weight infants (=" BORDER="0">2500 g) were randomly selected for each case (n = 4468). Main Outcome Measures  Odds of low birth weight and term low birth weight by dental radiographic dose during gestation. Results  An exposure higher than 0.4 milligray (mGy) during gestation occurred in 21 (1.9%) mothers of low-birth-weight infants and, when compared with women who had no known dental radiography, was associated with an adjusted odds ratio (OR) for a low-birth-weight infant of 2.27 (95% confidence interval [CI], 1.11-4.66, P = .03). Exposure higher than 0.4 mGy occurred in 10 (3%) term low-birth-weight pregnancies and was associated with an adjusted OR for a term low-birth-weight infant of 3.61 (95% CI, 1.46-8.92, P = .005). Conclusion  Dental radiography during pregnancy is associated with low birth weight, specifically with term low birth weight.      

Plasma folate levels and risk of spontaneous abortion

Context  Both folate deficiency and folic acid supplements have been reported to increase the risk of spontaneous abortion. The results are inconclusive, however, and measurements of folate have not been available in all studies. Objective  To study the association between plasma folate levels and the risk of spontaneous abortion. Design, Setting, and Population  Population-based, matched, case-control study of case women with spontaneous abortion and control women from January 1996 through December 1998 in Uppsala County, Sweden. Plasma folate measurements were available for 468 cases and 921 controls at 6 to 12 gestational weeks. Main Outcome Measure  Risk of spontaneous abortion vs maternal plasma folate level. Results  Compared with women with plasma folate levels between 2.20 and 3.95 ng/mL (5.0 and 8.9 nmol/L), women with low (2.19 ng/mL [4.9 nmol/L]) folate levels were at increased risk of spontaneous abortion (adjusted odds ratio [OR], 1.47; 95% confidence interval [CI], 1.01-2.14), whereas women with higher folate levels (3.96-6.16 ng/mL [9.0-13.9 nmol/L] and 6.17 ng/mL [14.0 nmol/L]) showed no increased risk of spontaneous abortion (OR, 0.84; 95% CI, 0.59-1.20; and OR, 0.74; 95% CI, 0.47-1.16, respectively). Low folate levels were associated with a significantly increased risk when the fetal karyotype was abnormal (OR, 1.95; 95% CI, 1.09-3.48) but not when the fetal karyotype was normal (OR, 1.11; 95% CI, 0.55-2.24) or unknown (OR, 1.45; 95% CI, 0.90-2.33). Conclusion  Low plasma folate levels were associated with an increased risk of early spontaneous abortion.      

Mycobacterium tuberculosis infection in health care workers in rural India: comparison of a whole-blood interferon gamma assay with tuberculin skin testing

Context  Mycobacterium tuberculosis infection in health care workers has not been adequately studied in developing countries using newer diagnostic tests. Objectives  To estimate latent tuberculosis infection prevalence in health care workers using the tuberculin skin test (TST) and a whole-blood interferon (IFN-) assay; to determine agreement between the tests; and to compare their correlation with risk factors. Design, Setting, and Participants  A cross-sectional comparison study of 726 health care workers aged 18 to 61 years (median age, 22 years) with no history of active tuberculosis conducted from January to May 2004, at a rural medical school in India. A total of 493 (68%) of the health care workers had direct contact with patients with tuberculosis and 514 (71%) had BCG vaccine scars. Interventions  Tuberculin skin testing was performed using 1-TU dose of purified protein derivative RT23, and the IFN- assay was performed by measuring IFN- response to early secreted antigenic target 6, culture filtrate protein 10, and a portion of tuberculosis antigen TB7.7. Main Outcome Measures  Agreement between TST and the IFN- assay, and comparison of the tests with respect to their association with risk factors. Results  A large proportion of the health care workers were latently infected; 360 (50%) were positive by either TST or IFN- assay, and 226 (31%) were positive by both tests. The prevalence estimates of TST and IFN- assay positivity were comparable (41%; 95% confidence interval [CI], 38%-45% and 40%; 95% CI, 37%-43%, respectively). Agreement between the tests was high (81.4%;  = 0.61; 95% CI, 0.56-0.67). Increasing age and years in the health profession were significant risk factors for both IFN- assay and TST positivity. BCG vaccination had little impact on TST and IFN- assay results. Conclusions  Our study showed high latent tuberculosis infection prevalence in Indian health care workers, high agreement between TST and IFN- assay, and similar association between positive test results and risk factors. Although TST and IFN- assay appear comparable in this population, they have different performance and operational characteristics; therefore, the decision to select one test over the other will depend on the population, purpose of testing, and resource availability.      

Neuropsychological outcomes of army personnel following deployment to the Iraq war

Context  The effects of war-zone deployment on neuropsychological health remain poorly understood. Neuropsychological performance deficits serve as sensitive measures of neural dysfunction and are often associated with psychosocial and occupational problems. Previous studies have not conducted objective neuropsychological assessments both before and after a major war-zone deployment. Objective  To examine objective neuropsychological outcomes of Iraq War deployment in a large military cohort. Design, Setting, and Participants  The Neurocognition Deployment Health Study, a prospective, cohort-controlled study conducted at military installations. This report centers on 961 male and female active-duty Army soldiers drawn from the larger cohort. Deploying Army soldiers (n = 654) were examined prior to deployment to Iraq (April-December 2003) and shortly after return (within a mean of 73 days [median, 75 days]; January-May 2005) from Iraq deployment. A comparison group of soldiers (n = 307) similar in military characteristics but not deploying overseas during the study was assessed in sessions timed to be as close as possible to the assessment of deployers. Military unit sampling procedures facilitated representation of combat, combat support, and combat service support functions among both deployers and nondeployers. Main Outcome Measures  Individually administered, performance-based neuropsychological tasks. Estimates (; the unstandardized parameter estimate) for the absolute differences in adjusted mean outcome scores between deployed and nondeployed groups were determined using generalized estimating equations. Results  Multiple linear regression analyses adjusted for battalion membership revealed that Iraq deployment, compared with nondeployment, was associated with neuropsychological compromise on tasks of sustained attention ( = 0.11; P<.001), verbal learning ( = –1.51; P = .003), and visual-spatial memory ( = –3.82; P<.001). Iraq deployment was also associated with increased negative state affect on measures of confusion ( = 1.40; P<.001) and tension ( = 1.24; P<.001). In contrast, deployment was associated with improved simple reaction time ( = 4.30; P = .003). Deployment effects remained statistically significant after taking into account deployment-related head injury and stress and depression symptoms. Conclusions  Deployment to Iraq is associated with increased risk of neuropsychological compromise. Findings point to the need to investigate further the impact of deployment on neural functioning. Public health implications include consideration of neuropsychological compromise in health prevention and postdeployment clinical and occupational management.      

The APOE-{epsilon}4 Allele and the Risk of Alzheimer Disease Among African Americans, Whites, and Hispanics

Context.— Although the association between Alzheimer disease (AD) and the apolipoprotein E 4 (APOE-4) allele has been confirmed worldwide, it appears to be inconsistent among African Americans, Hispanics, and Nigerians. Objective.— To investigate the association between the APOE-4 allele and AD in elderly African Americans, Hispanics, and whites. Design.— Prospective, population-based, longitudinal study over a 5-year period (1991-1996). Setting.— The Washington Heights–Inwood community of New York City. Participants.— A total of 1079 Medicare recipients without AD or a related disorder at baseline. Main Outcome Measures.— Risk of clinically diagnosed AD in the 3 ethnic groups and among individuals with and without an APOE-4 allele. Results.— Compared with individuals with the APOE-3/3 genotype, the relative risk (RR) of AD associated with 1 or more copies of the APOE-4 allele was significantly increased among whites (RR, 2.5; 95% confidence interval [CI], 1.1-6.4), but not among African Americans (RR, 1.0; 95% CI, 0.6-1.6) or Hispanics (RR, 1.1; 95% CI, 0.7-1.6). In the absence of the APOE-4 allele, the cumulative risks of AD to age 90 years, adjusted for education and sex, were 4 times higher for African Americans (RR, 4.4; 95% CI, 2.3-8.6) and 2 times higher for Hispanics (RR, 2.3; 95% CI, 1.2-4.3) than for whites. In the presence of an APOE-4 allele, the cumulative risk of AD to age 90 years was similar for individuals in all 3 ethnic groups. Conclusion.— The presence of an APOE-4 allele is a determinant of AD risk in whites, but African Americans and Hispanics have an increased frequency of AD regardless of their APOE genotype. These results suggest that other genes or risk factors may contribute to the increased risk of AD in African Americans and Hispanics.      

Are {beta}-Blockers Efficacious as First-line Therapy for Hypertension in the Elderly?: A Systematic Review

Objective.— To assess antihypertensive efficacy of -blockers and their effects on cardiovascular morbidity and mortality and all-cause morbidity compared with diuretics in elderly patients with hypertension. Data Source.— A MEDLINE search of English-language articles published between January 1966 and January 1998 using the terms hypertension (drug therapy) and elderly or aged or geriatric, and cerebrovascular or cardiovascular diseases, and morbidity or mortality. References from identified articles were also reviewed. Data Selection.— Randomized trials lasting at least 1 year, which used as first-line agents diuretics and/or -blockers, and reported morbidity and mortality outcomes in elderly patients with hypertension. Data Synthesis and Results.— Ten trials involving a total of 16164 elderly patients (60 years) were included. Two thirds of the patients assigned to diuretics were well controlled on monotherapy, whereas less than a third of the patients assigned to -blockers were well controlled on monotherapy. Diuretic therapy was superior to -blockade with regard to all end points and was effective in preventing cerebrovascular events (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.51-0.72), fatal stroke (OR, 0.67; 95% CI, 0.49-0.90), coronary heart disease (OR, 0.74; 95% CI, 0.64-0.85), cardiovascular mortality (OR, 0.75; 95% CI, 0.64-0.87), and all-cause mortality (OR, 0.86; 95% CI, 0.77-0.96). In contrast, -blocker therapy only reduced the odds for cerebrovascular events (OR, 0.75; 95% CI, 0.57-0.98) but was ineffective in preventing coronary heart disease, cardiovascular mortality, and all-cause mortality (ORs, 1.01, 0.98, and 1.05, respectively). Conclusions.— In contrast to diuretics, which remain the standard first-line therapy, -blockers, until proven otherwise, should no longer be considered appropriate first-line therapy of uncomplicated hypertension in the elderly hypertensive patient.      

MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis

Context  In observational studies, individuals with elevated levels of plasma homocysteine tend to have moderately increased risk of coronary heart disease (CHD). The MTHFR 677CT polymorphism is a genetic alteration in an enzyme involved in folate metabolism that causes elevated homocysteine concentrations, but its relevance to risk of CHD is uncertain. Objective  To assess the relation of MTHFR 677CT polymorphism and risk of CHD by conducting a meta-analysis of individual participant data from all case-control observational studies with data on this polymorphism and risk of CHD. Data Sources  Studies were identified by searches of the electronic literature (MEDLINE and Current Contents) for relevant reports published before June 2001 (using the search terms MTHFR and coronary heart disease), hand searches of reference lists of original studies and review articles (including meta-analyses) on this topic, and contact with investigators in the field. Study Selection  Studies were included if they had data on the MTHFR 677CT genotype and a case-control design (retrospective or nested case-control) and involved CHD as an end point. Data were obtained from 40 (34 published and 6 unpublished) observational studies involving a total of 11 162 cases and 12 758 controls. Data Extraction  Data were collected on MTHFR 677CT genotype, case-control status, and plasma levels of homocysteine, folate, and other cardiovascular risk factors. Data were checked for consistency with the published article or with information provided by the investigators and converted into a standard format for incorporation into a central database. Combined odds ratios (ORs) for the association between the MTHFR 677CT polymorphism and CHD were assessed by logistic regression. Data Synthesis  Individuals with the MTHFR 677 TT genotype had a 16% (OR, 1.16; 95% confidence interval [CI], 1.05-1.28) higher odds of CHD compared with individuals with the CC genotype. There was significant heterogeneity between the results obtained in European populations (OR, 1.14; 95% CI, 1.01-1.28) compared with North American populations (OR, 0.87; 95% CI, 0.73-1.05), which might largely be explained by interaction between the MTHFR 677CT polymorphism and folate status. Conclusions  Individuals with the MTHFR 677 TT genotype had a significantly higher risk of CHD, particularly in the setting of low folate status. These results support the hypothesis that impaired folate metabolism, resulting in high homocysteine levels, is causally related to increased risk of CHD.      

Time to Clinical Stability in Patients Hospitalized With Community-Acquired Pneumonia: Implications for Practice Guidelines

Context.— Many groups have developed guidelines to shorten hospital length of stay in pneumonia in order to decrease costs, but the length of time until a patient hospitalized with pneumonia becomes clinically stable has not been established. Objective.— To describe the time to resolution of abnormalities in vital signs, ability to eat, and mental status in patients with community-acquired pneumonia and assess clinical outcomes after achieving stability. Design.— Prospective, multicenter, observational cohort study. Setting.— Three university and 1 community teaching hospital in Boston, Mass, Pittsburgh, Pa, and Halifax, Nova Scotia. Patients.— Six hundred eighty-six adults hospitalized with community-acquired pneumonia. Main Outcome Measures.— Time to resolution of vital signs, ability to eat, mental status, hospital length of stay, and admission to an intensive care, coronary care, or telemetry unit. Results.— The median time to stability was 2 days for heart rate (100 beats/min) and systolic blood pressure (90 mm Hg), and 3 days for respiratory rate (24 breaths/min), oxygen saturation (90%), and temperature (37.2°C [99°F]). The median time to overall clinical stability was 3 days for the most lenient definition of stability and 7 days for the most conservative definition. Patients with more severe cases of pneumonia at presentation took longer to reach stability. Once stability was achieved, clinical deterioration requiring intensive care, coronary care, or telemetry monitoring occurred in 1% of cases or fewer. Between 65% to 86% of patients stayed in the hospital more than 1 day after reaching stability, and fewer than 29% to 46% were converted to oral antibiotics within 1 day of stability, depending on the definition of stability. Conclusions.— Our estimates of time to stability in pneumonia and explicit criteria for defining stability can provide an evidence-based estimate of optimal length of stay, and outline a clinically sensible approach to improving the efficiency of inpatient management.