Physical exertion, exercise, and sudden cardiac death in women

Context  Exercise is associated with a lower risk of cardiovascular events but may transiently increase the risk of ventricular arrhythmias. Its short-term and long-term associations with risk of sudden cardiac death among women are unclear. Objectives  To compare the risk of sudden cardiac death in women during moderate to vigorous exertion with the risk of sudden cardiac death during lighter or no exertion; and to assess the long-term association between moderate to vigorous exercise and sudden cardiac death. Design, Setting, and Participants  Prospective, nested case-crossover study of 288 cases of sudden cardiac death within the Nurses' Health Study (1980-2004); and a prospective cohort analysis of 69 693 participants without prior cardiovascular disease followed up from 1986-2004. Main Outcome Measure  Risk of sudden cardiac death associated with moderate to vigorous exertion. Results  The absolute risk of sudden cardiac death associated with moderate to vigorous exertion was exceedingly low at 1 per 36.5 million hours of exertion. In case-crossover analyses, the risk of sudden cardiac death was transiently elevated during moderate to vigorous exertion (relative risk [RR], 2.38; 95% confidence interval [CI], 1.23-4.60; P = .01) compared with the risk during lesser or no exertion. Habitual moderate to vigorous exertion modified this transient risk (P = .005 for interaction) and the risk was no longer significantly elevated among those who exercised 2 or more hours per week. In the cohort analyses, an increasing amount of moderate to vigorous exercise was associated with a lower long-term risk of sudden cardiac death in age-adjusted and multivariable models that excluded biological intermediates (P = .006 for trend). This relationship was attenuated when biological intermediates were included (P = .06 for trend); however, the reduction in risk remained significant among women who exercised 4 or more hours per week (adjusted RR, 0.41; 95% CI, 0.20-0.83; P = .01) compared with women who did not exercise. Conclusions  These prospective data suggest that sudden cardiac death during exertion is an extremely rare event in women. Regular exercise may significantly minimize this small transient risk and may lower the overall long-term risk of sudden cardiac death.      

Proportion of Cystic Fibrosis Gene Mutations Not Detected by Routine Testing in Men With Obstructive Azoospermia

Context  Infertile men with obstructive azoospermia may have mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, many of which are rare in classic cystic fibrosis and not evaluated in most routine mutation screening. Objective  To assess how often CFTR mutations or sequence alterations undetected by routine screening are detected with more extensive screening in obstructive azoospermia. Design  Routine screening for the 31 most common CFTR mutations associated with the CF phenotype in white populations, testing for the 5-thymidine variant of the polythymidine tract of intron 8 (IVS8-5T) by allele-specific oligonucleotide hybridization, and screening of all exons through multiplex heteroduplex shift analysis followed by direct DNA sequencing. Setting  Male infertility clinic of a Canadian university-affiliated hospital. Subjects  Of 198 men with obstructive (n=149) or nonobstructive (n=49; control group) azoospermia, 64 had congenital bilateral absence of the vas deferens (CBAVD), 10 had congenital unilateral absence of the vas deferens (CUAVD), and 75 had epididymal obstruction (56/75 were idiopathic). Main Outcome Measure  Frequency of mutations found by routine and nonroutine tests in men with obstructive vs nonobstructive azoospermia. Results  Frequency of mutations and the IVS8-5T variant in the nonobstructive azoospermia group (controls) (2% and 5.1% allele frequency, respectively) did not differ significantly from that in the general population (2% and 5.2%, respectively). In the CBAVD group, 72 mutations were found by DNA sequencing and IVS8-5T testing (47 and 25, respectively; P<.001 and P=.002 vs controls) vs 39 by the routine panel (P<.001 vs controls). In the idiopathic epididymal obstruction group, 24 mutations were found by DNA sequencing and IVS8-5T testing (12 each; P=.01 and P=.14 vs controls) vs 5 by the routine panel (P=.33 vs controls). In the CUAVD group, 2 mutations were found by routine testing (P=.07 vs controls) vs 4 (2 each, respectively; P=.07 and P=.40 vs controls) by DNA sequencing and IVS8-5T testing. The routine panel did not identify 33 (46%) of 72, 2 (50%) of 4, and 19 (79%) of 24 detectable CFTR mutations and IVS8-5T in the CBAVD, CUAVD, and idiopathic epididymal obstruction groups, respectively. Conclusions  Routine testing for CFTR mutations may miss mild or rare gene alterations. The barrier to conception for men with obstructive infertility has been overcome by assisted reproductive technologies, thus raising the concern of iatrogenically transmitting pathogenic CFTR mutations to the progeny.      

Effect of a Garlic Oil Preparation on Serum Lipoproteins and Cholesterol Metabolism: A Randomized Controlled Trial

Context.— Garlic-containing drugs have been used in the treatment of hypercholesterolemia even though their efficacy is not generally established. Little is known about the mechanisms of action of the possible effects on cholesterol in humans. Objective.— To estimate the hypocholesterolemic effect of garlic oil and to investigate the possible mechanism of action. Design.— Double-blind, randomized, placebo-controlled trial. Setting.— Outpatient lipid clinic. Patients.— We investigated 25 patients (mean age, 58 years) with moderate hypercholesterolemia. Intervention.— Steam-distilled garlic oil preparation (5 mg twice a day) vs placebo each for 12 weeks with wash-out periods of 4 weeks. Main Outcome Measures.— Serum lipoprotein concentrations, cholesterol absorption, and cholesterol synthesis. Results.— Baseline lipoprotein profiles were (mean [SD]): total cholesterol, 7.53 (0.75) mmol/L (291 [29] mg/dL); low-density lipoprotein cholesterol (LDL-C), 5.35 (0.78) mmol/L (207 [30] mg/dL); high-density lipoprotein cholesterol (HDL-C), 1.50 (0.41) mmol/L (58 [16] mg/dL); and triglycerides, 1.45 (0.73) mmol/L (127 [64] mg/dL). Lipoprotein levels were virtually unchanged at the end of both treatment periods (mean difference [95% confidence interval]): total cholesterol, 0.085 (-0.201 to 0.372) mmol/L (3.3 [-7.8 to 14.4] mg/dL), P=.54; LDL-C, 0.001 (-0.242 to 0.245) mmol/L (0.04 [-9.4 to 9.5] mg/dL), P=.99; HDL-C, 0.050 (-0.028 to 0.128) mmol/L (1.9 [-1.1 to 4.9] mg/dL), P=.20; triclycerides, 0.047 (-0.229 to 0.135) mmol/L (4.2 [-20.3 to 12.0]) mg/dL, P=.60. Cholesterol absorption (37.5% [10.5%] vs 38.3% [10.7%], P=.58), cholesterol synthesis (12.7 [6.5] vs 13.4 [6.6] mg/kg of body weight per day, P=.64), mevalonic acid excretion (192 [66] vs 187 [66] µg/d, P=.78), and changes in the ratio of lathosterol to cholesterol in serum (4.4% [24.3%] vs 10.6% [21.1%], P=.62) were not different in garlic and placebo treatment. Conclusions.— The commercial garlic oil preparation investigated had no influence on serum lipoproteins, cholesterol absorption, or cholesterol synthesis. Garlic therapy for treatment of hypercholesterolemia cannot be recommended on the basis of this study.      

Extracranial thrombotically active carotid plaque as a risk factor for ischemic stroke

Context  Recent studies suggest that factors other than the degree of carotid stenosis are involved in ischemic stroke pathogenesis, especially modifications of plaque composition and related complications. Objective  To examine the role of carotid plaque rupture and thrombosis in ischemic stroke pathogenesis in patients undergoing carotid endarterectomy, excluding those with possible cardiac embolization or with severe stenosis of the circle of Willis. Design, Setting, and Patients  A total of 269 carotid plaques selected from an Interinstitutional Carotid Tissue Bank were studied by histology after surgical endarterectomy between January 1995 and December 2002. A total of 96 plaques were from patients with ipsilateral major stroke, 91 plaques from patients with transient ischemic attack (TIA), and 82 plaques from patients without symptoms. Main Outcome Measures  Differences in the frequency of thrombosis, cap rupture, cap erosion, inflammatory infiltrate, and major cardiovascular risk factors between study groups. Results  A thrombotically active carotid plaque associated with high inflammatory infiltrate was observed in 71 (74.0%) of 96 patients with ipsilateral major stroke (and in all 32 plaques from patients operated within 2 months of symptom onset) compared with 32 (35.2%) of 91 patients with TIA (P < .001) or 12 (14.6%) of 82 patients who were without symptoms (P < .001). In addition, a fresh thrombus was observed in 53.8% of patients with stroke operated 13 to 24 months after the cerebrovascular event. An acute thrombus was associated with cap rupture in 64 (90.1%) of 71 thrombosed plaques from patients with stroke and with cap erosion in the remaining 7 cases (9.9%). Ruptured plaques of patients affected by stroke were characterized by the presence of a more severe inflammatory infiltrate, constituted by monocytes, macrophages, and T lymphocyte cells compared with that observed in the TIA and asymptomatic groups (P = .001). There was no significant difference between groups in major cardiovascular risk factors. Conclusion  These results demonstrate a major role of carotid thrombosis and inflammation in ischemic stroke in patients affected by carotid atherosclerotic disease.      

Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial

Context  Men with overactive bladder and other lower urinary tract symptoms may not respond to monotherapy with antimuscarinic agents or -receptor antagonists. Objective  To evaluate the efficacy and safety of tolterodine extended release (ER), tamsulosin, or both in men who met research criteria for both overactive bladder and benign prostatic hyperplasia. Design, Setting, and Participants  Randomized, double-blind, placebo-controlled trial conducted at 95 urology clinics in the United States involving men 40 years or older who had a total International Prostate Symptom Score of 12 or higher and, an International Prostate Symptom Score quality-of-life (QOL) item score of 3 or higher, a self-rated bladder condition of at least moderate bother, and a bladder diary documenting micturition frequency (8 micturitions per 24 hours) and urgency (3 episodes per 24 hours), with or without urgency urinary incontinence. Patients were recruited between November 2004 and February 2006, and the study was completed May 2006. Interventions  Patients were randomly assigned to receive placebo (n = 222), 4 mg of tolterodine ER (n = 217), 0.4 mg of tamsulosin (n = 215), or both tolterodine ER plus tamsulosin (n = 225) for 12 weeks. Main Outcome Measures  Patient perception of treatment benefit, bladder diary variables, International Prostate Symptom Scores, and safety and tolerability were assessed. Results  A total of 172 men (80%) receiving tolterodine ER plus tamsulosin reported treatment benefit by week 12 compared with 132 patients (62%) receiving placebo (P<.001), 146 (71%) receiving tamsulosin (P=.06 vs placebo), or 135 (65%) receiving tolterodine ER (P=.48 vs placebo). Patients receiving tolterodine ER plus tamsulosin compared with placebo experienced significant reductions in urgency urinary incontinence (–0.88 vs –0.31, P=.005), urgency episodes without incontinence (–3.33 vs –2.54, P=.03), micturitions per 24 hours (–2.54 vs –1.41, P<.001), and micturitions per night (–0.59 vs –0.39, P.02). Patients receiving tolterodine ER plus tamsulosin demonstrated significant improvements on the total International Prostate Symptom Score (–8.02 vs placebo, –6.19, P=.003) and QOL item (–1.61 vs –1.17, P=.003). All interventions were well tolerated. The incidence of acute urinary retention requiring catheterization was low (tolterodine ER plus tamsulosin, 0.4%; tolterodine ER, 0.5%; tamsulosin, 0%; and placebo, 0%). Conclusions  These results suggest that treatment with tolterodine ER plus tamsulosin for 12 weeks provides benefit for men with moderate to severe lower urinary tract symptoms including overactive bladder. Clinical Trials Registration  clinicaltrials.gov Identifier: NCT00147654      

Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial

Context  High-density lipoprotein (HDL) cholesterol is an inverse predictor of coronary atherosclerotic disease. Preliminary data have suggested that HDL infusions can induce atherosclerosis regression. Objective  To investigate the effects of reconstituted HDL on plaque burden as assessed by intravascular ultrasound (IVUS). Design and Setting  A randomized placebo-controlled trial was conducted at 17 centers in Canada. Intravascular ultrasound was performed to assess coronary atheroma at baseline and 2 to 3 weeks after the last study infusion. Patients  Between July 2005 and October 2006, 183 patients had a baseline IVUS examination and of those, 145 had evaluable serial IVUS examinations after 6 weeks. Intervention  Sixty patients were randomly assigned to receive 4 weekly infusions of placebo (saline), 111 to receive 40 mg/kg of reconstituted HDL (CSL-111); and 12 to receive 80 mg/kg of CSL-111. Main Outcome Measures  The primary efficacy parameter was the percentage change in atheroma volume. Nominal changes in plaque volume and plaque characterization index on IVUS and coronary score on quantitative coronary angiography were also prespecified end points. Results  The higher-dosage CSL-111 treatment group was discontinued early because of liver function test abnormalities. The percentage change in atheroma volume was –3.4% with CSL-111 and –1.6% for placebo (P = .48 between groups, P<.001 vs baseline for CSL-111). The nominal change in plaque volume was –5.3 mm³ with CSL-111 and –2.3 mm³ with placebo (P = .39 between groups, P<.001 vs baseline for CSL-111). The mean changes in plaque characterization index on IVUS (–0.0097 for CSL-111 and 0.0128 with placebo) and mean changes in coronary score (–0.039 mm for CSL-111 and –0.071 mm with placebo) on quantitative coronary angiography were significantly different between groups (P = .01 and P =.03, respectively). Administration of CSL-111 40 mg/kg was associated with mild, self-limiting transaminase elevation but was clinically well tolerated. Conclusions  Short-term infusions of reconstituted HDL resulted in no significant reductions in percentage change in atheroma volume or nominal change in plaque volume compared with placebo but did result in statistically significant improvement in the plaque characterization index and coronary score on quantitative coronary angiography. Elevation of HDL remains a valid target in vascular disease and further studies of HDL infusions, including trials with clinical end points, appear warranted. Trial Registration  clinicaltrials.gov Identifier: NCT00225719 Published online: March 26, 2007 (doi:10.1001/jama.297.15.jpc70004).      

Primary Prevention of Acute Coronary Events With Lovastatin in Men and Women With Average Cholesterol Levels: Results of AFCAPS/TexCAPS

Context.— Although cholesterol-reducing treatment has been shown to reduce fatal and nonfatal coronary disease in patients with coronary heart disease (CHD), it is unknown whether benefit from the reduction of low-density lipoprotein cholesterol (LDL-C) in patients without CHD extends to individuals with average serum cholesterol levels, women, and older persons. Objective.— To compare lovastatin with placebo for prevention of the first acute major coronary event in men and women without clinically evident atherosclerotic cardiovascular disease with average total cholesterol (TC) and LDL-C levels and below-average high-density lipoprotein cholesterol (HDL-C) levels. Design.— A randomized, double-blind, placebo-controlled trial. Setting.— Outpatient clinics in Texas. Participants.— A total of 5608 men and 997 women with average TC and LDL-C and below-average HDL-C (as characterized by lipid percentiles for an age- and sex-matched cohort without cardiovascular disease from the National Health and Nutrition Examination Survey [NHANES] III). Mean (SD) TC level was 5.71 (0.54) mmol/L (221 [21] mg/dL) (51st percentile), mean (SD) LDL-C level was 3.89 (0.43) mmol/L (150 [17] mg/dL) (60th percentile), mean (SD) HDL-C level was 0.94 (0.14) mmol/L (36 [5] mg/dL) for men and 1.03 (0.14) mmol/L (40 [5] mg/dL) for women (25th and 16th percentiles, respectively), and median (SD) triglyceride levels were 1.78 (0.86) mmol/L (158 [76] mg/dL) (63rd percentile). Intervention.— Lovastatin (20-40 mg daily) or placebo in addition to a low–saturated fat, low-cholesterol diet. Main Outcome Measures.— First acute major coronary event defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. Results.— After an average follow-up of 5.2 years, lovastatin reduced the incidence of first acute major coronary events (183 vs 116 first events; relative risk [RR], 0.63; 95% confidence interval [CI], 0.50-0.79; P<.001), myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% CI, 0.43-0.83; P=.002), unstable angina (87 vs 60 first unstable angina events; RR, 0.68; 95% CI, 0.49-0.95; P=.02), coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95% CI, 0.52-0.85; P=.001), coronary events (215 vs 163 coronary events; RR, 0.75; 95% CI, 0.61-0.92; P=.006), and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95% CI, 0.62-0.91; P=.003). Lovastatin (20-40 mg daily) reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6% to 1.02 mmol/L (39 mg/dL). There were no clinically relevant differences in safety parameters between treatment groups. Conclusions.— Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL-C levels. These findings support the inclusion of HDL-C in risk-factor assessment, confirm the benefit of LDL-C reduction to a target goal, and suggest the need for reassessment of the National Cholesterol Education Program guidelines regarding pharmacological intervention.      

Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial

Context  Despite the high prevalence, chronicity, and associated comorbidity of posttraumatic stress disorder (PTSD) in the community, few placebo-controlled studies have evaluated the efficacy of pharmacotherapy for this disorder. Objective  To determine if treatment with sertraline hydrochloride effectively diminishes symptoms of PTSD of moderate to marked severity. Design  Twelve-week, double-blind, placebo-controlled trial preceded by a 2-week, single-blind placebo lead-in period, conducted between May 1996 and June 1997. Setting  Outpatient psychiatric clinics in 8 academic medical centers and 6 clinical research centers. Patients  A total of 187 outpatients with a Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition diagnosis of PTSD and a Clinician Administered PTSD Scale Part 2 (CAPS-2) minimum total severity score of at least 50 at baseline (mean age, 40 years; mean duration of illness, 12 years; 73% were women; and 61.5% experienced physical or sexual assault). Intervention  Patients were randomized to acute treatment with sertraline hydrochloride in flexible daily dosages of 50 to 200 mg/d, following 1 week at 25 mg/d (n=94); or placebo (n=93). Main Outcome Measures  Baseline-to-end-point changes in CAPS-2 total severity score, Impact of Event Scale total score (IES), and Clinical Global Impression–Severity (CGI-S), and CGI-Improvement (CGI-I) ratings, compared by treatment vs placebo groups. Results  Sertraline treatment yielded significantly greater improvement than placebo on 3 of the 4 primary outcome measures (mean change from baseline to end point for CAPS-2 total score, -33.0 vs -23.2 [P=.02], and for CGI-S, -1.2 vs -0.8 [P=.01]; mean CGI-I score at end point, 2.5 vs 3.0 [P=.02]), with the fourth measure, the IES total score, showing a trend toward significance (mean change from baseline to end point, -16.2 vs -12.1; P=.07). Using a conservative last-observation-carried-forward analysis, treatment with sertraline resulted in a responder rate of 53% at study end point compared with 32% for placebo (P=.008, with responder defined as >30% reduction from baseline in CAPS-2 total severity score and a CGI-I score of 1 [very much improved], or 2 [much improved]). Significant (P<.05) efficacy was evident for sertraline from week 2 on the CAPS-2 total severity score. Sertraline had significant efficacy vs placebo on the CAPS-2 PTSD symptom clusters of avoidance/numbing (P=.02) and increased arousal (P=.03) but not on reexperiencing/intrusion (P=.14). Sertraline was well tolerated, with insomnia the only adverse effect reported significantly more often than placebo (16.0% vs 4.3%; P=.01). Conclusions  Our data suggest that sertraline is a safe, well-tolerated, and effective treatment for PTSD.      

Trends in serum lipids and lipoproteins of adults, 1960-2002

Context  Serum total and low-density lipoprotein (LDL) cholesterol contribute significantly to atherosclerosis and its clinical sequelae. Previous analyses of data from the National Health and Nutrition Examination Surveys (NHANES) showed that mean levels of total cholesterol of US adults had declined from 1960-1962 to 1988-1994, and mean levels of LDL cholesterol (available beginning in 1976) had declined between 1976-1980 and 1988-1994. Objective  To examine trends in serum lipid levels among US adults between 1960 and 2002, with a particular focus on changes since the 1988-1994 NHANES survey. Design, Setting, and Participants  Blood lipid measurements taken from 6098 to 15 719 adults who were examined in 5 distinct cross-sectional surveys of the US population during 1960-1962, 1971-1974, 1976-1980, 1988-1994, and 1999-2002. Main Outcome Measures  Mean serum total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and geometric mean serum triglyceride levels, and the percentage of adults with a serum total cholesterol level of at least 240 mg/dL (6.22 mmol/L). Results  Between 1988-1994 and 1999-2002, total serum cholesterol level of adults aged 20 years or older decreased from 206 mg/dL (5.34 mmol/L) to 203 mg/dL (5.26 mmol/L) (P=.009) and LDL cholesterol levels decreased from 129 mg/dL (3.34 mmol/L) to 123 mg/dL (3.19 mmol/L) (P<.001). Greater and significant decreases were observed in men 60 years or older and in women 50 years or older. The percentage of adults with a total cholesterol level of at least 240 mg/dL (6.22 mmol/L) decreased from 20% during 1988-1994 to 17% during 1999-2002 (P<.001). There was no change in mean HDL cholesterol levels and a nonsignificant increase in geometric mean serum triglyceride levels (P = .06). Conclusions  The decrease in total cholesterol level observed during 1960-1994 and LDL cholesterol level observed during 1976-1994 has continued during 1999-2002 in men 60 to 74 years and women 50 to 74 years. The target value of no more than 17% of US adults with a total cholesterol level of at least 240 mg/dL (6.22 mmol/L), an objective of Healthy People 2010, has been attained. The increase in the proportion of adults using lipid-lowering medication, particularly in older age groups, likely contributed to the decreases in total and LDL cholesterol levels observed. The increased prevalence of obesity in the US population may have contributed to the increase in mean serum triglyceride levels.      

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.      

Impairment of Endothelial Functions by Acute Hyperhomocysteinemia and Reversal by Antioxidant Vitamins

Context  Increased levels of homocysteine are associated with risk of cardiovascular disease. Homocysteine may cause this risk by impairing endothelial cell function. Objective  To evaluate the effect of acute hyperhomocysteinemia with and without antioxidant vitamin pretreatment on cardiovascular risk factors and endothelial functions. Design and Setting  Observer-blinded, randomized crossover study conducted at a university hospital in Italy. Subjects  Twenty healthy hospital staff volunteers (10 men, 10 women) aged 25 to 45 years. Interventions  Subjects were given each of 3 loads in random order at 1-week intervals: oral methionine, 100 mg/kg in fruit juice; the same methionine load immediately following ingestion of antioxidant vitamin E, 800 IU, and ascorbic acid, 1000 mg; and methionine-free fruit juice (placebo). Ten of the 20 subjects also ingested a placebo load with vitamins. Main Outcome Measures  Lipid, coagulation, glucose, and circulating adhesion molecule parameters, blood pressure, and endothelial functions as assessed by hemodynamic and rheologic responses to L-arginine, evaluated at baseline and 4 hours following ingestion of the loads. Results  The oral methionine load increased mean (SD) plasma homocysteine level from 10.5 (3.8) µmol/L at baseline to 27.1 (6.7) µmol/L at 4 hours (P<.001). A similar increase was observed with the same load plus vitamins (10.0 [4.0] to 22.7 [7.8] µmol/L; P<.001) but no significant increase was observed with placebo (10.1 [3.7] to 10.4 [3.2] µmol/L; P=.75). Coagulation and circulating adhesion molecule levels significantly increased after methionine ingestion alone (P<.05) but not after placebo or methionine ingestion with vitamins. While the mean (SD) blood pressure (-7.0% [2.7%]; P<.001), platelet aggregation response to adenosine diphosphate (-11.4% [4.5%]; P=.009) and blood viscosity (-3.0% [1.2%]; P=.04) declined in these parameters 10 minutes after an L-arginine load (3 g) following placebo, the increase after methionine alone (-2.3% [1.5%], 4.0% [3.0%], and 1.5% [1.0%], respectively; P<.05), did not occur following methionine load with vitamin pretreatment (-6.3% [2.5%], -7.9% [3.5%], and -1.5% [1.0%], respectively; P=.24). Conclusion  Our data suggest that mild to moderate elevations of plasma homocysteine levels in healthy subjects activate coagulation, modify the adhesive properties of endothelium, and impair the vascular responses to L-arginine. Pretreatment with antioxidant vitamin E and ascorbic acid blocks the effects of hyperhomocysteinemia, suggesting an oxidative mechanism.      

Publication Bias and Research on Passive Smoking: Comparison of Published and Unpublished Studies

Context.— The results of reviews may be biased by delays in publication and failure to publish nonsignificant results. Objective.— To determine the extent of unpublished results on the health effects of passive smoking and whether passive smoking studies with statistically nonsignificant results would have longer time to publication than those with statistically significant results. Design.— Semistructured telephone interviews of principal investigators of published or unpublished studies funded between 1981 and 1995, identified by information obtained from 76 (85%) of 89 organizations contacted that potentially funded research on passive smoking. Participants.— Seventy-eight investigators were eligible and could be located; 65 (83%) responded. They had conducted 61 studies of the health effects of passive smoke in humans or animals between 1981 and 1995 that met the criteria for the analysis of time to publication. Main Outcome Measure.— Time to publication for published studies and statistical significance of results of published and unpublished studies. Results.— Fourteen of the 61 studies were unpublished. Median time to publication was 5 years (95% confidence interval [CI], 4-7 years) for statistically nonsignificant studies and 3 years (95% CI, 3-5 years) for statistically significant studies (P=.004). Statistically significant results (P=.004), experimental study design (P=.01), study size less than or equal to 500 (P=.01), and animals as subjects (P=.03) were predictive of time to publication. When the studies with human participants were analyzed separately, only statistically significant data were predictive of publication (P=.007). Multivariate analysis of all studies indicated that statistical significance (P=.001) and study design (P=.01) were the only independent predictors of time to publication, while for the human studies only statistical significance was predictive of publication (P=.007). Conclusion.— There is a publication delay for passive smoking studies with nonsignificant results compared with those with significant results.      

Effects of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: results of the OmniHeart randomized trial

Context  Reduced intake of saturated fat is widely recommended for prevention of cardiovascular disease. The type of macronutrient that should replace saturated fat remains uncertain. Objective  To compare the effects of 3 healthful diets, each with reduced saturated fat intake, on blood pressure and serum lipids. Design, Setting, and Participants  Randomized, 3-period, crossover feeding study (April 2003 to June 2005) conducted in Baltimore, Md, and Boston, Mass. Participants were 164 adults with prehypertension or stage 1 hypertension. Each feeding period lasted 6 weeks and body weight was kept constant. Interventions  A diet rich in carbohydrates; a diet rich in protein, about half from plant sources; and a diet rich in unsaturated fat, predominantly monounsaturated fat. Main Outcome Measures  Systolic blood pressure and low-density lipoprotein cholesterol. Results  Blood pressure, low-density lipoprotein cholesterol, and estimated coronary heart disease risk were lower on each diet compared with baseline. Compared with the carbohydrate diet, the protein diet further decreased mean systolic blood pressure by 1.4 mm Hg (P = .002) and by 3.5 mm Hg (P = .006) among those with hypertension and decreased low-density lipoprotein cholesterol by 3.3 mg/dL (0.09 mmol/L; P = .01), high-density lipoprotein cholesterol by 1.3 mg/dL (0.03 mmol/L; P = .02), and triglycerides by 15.7 mg/dL (0.18 mmol/L; P<.001). Compared with the carbohydrate diet, the unsaturated fat diet decreased systolic blood pressure by 1.3 mm Hg (P = .005) and by 2.9 mm Hg among those with hypertension (P = .02), had no significant effect on low-density lipoprotein cholesterol, increased high-density lipoprotein cholesterol by 1.1 mg/dL (0.03 mmol/L; P = .03), and lowered triglycerides by 9.6 mg/dL (0.11 mmol/L; P = .02). Compared with the carbohydrate diet, estimated 10-year coronary heart disease risk was lower and similar on the protein and unsaturated fat diets. Conclusion  In the setting of a healthful diet, partial substitution of carbohydrate with either protein or monounsaturated fat can further lower blood pressure, improve lipid levels, and reduce estimated cardiovascular risk. Clinical Trials Registration  ClinicalTrials.gov Identifier: NCT00051350.      

Are Guidelines Following Guidelines?: The Methodological Quality of Clinical Practice Guidelines in the Peer-Reviewed Medical Literature

Context  Practice guidelines play an important role in medicine. Methodological principles have been formulated to guide their development. Objective  To determine whether practice guidelines in peer-reviewed medical literature adhered to established methodological standards for practice guidelines. Design  Structured review of guidelines published from 1985 through June 1997 identified by a MEDLINE search. Main Outcome Measures  Mean number of standards met based on a 25-item instrument and frequency of adherence. Results  We evaluated 279 guidelines, published from 1985 through June 1997, produced by 69 different developers. Mean overall adherence to standards by each guideline was 43.1% (10.77/25). Mean (SD) adherence to methodological standards on guideline development and format was 51.1% (25.3%); on identification and summary of evidence, 33.6% (29.9%); and on the formulation of recommendations, 46% (45%). Mean adherence to standards by each guideline improved from 36.9% (9.2/25) in 1985 to 50.4% (12.6/25) in 1997 (P<.001). However, there was little improvement over time in adherence to standards on identification and summary of evidence from 34.6% prior to 1990 to 36.1% after 1995 (P=.11). There was no difference in the mean number of standards satisfied by guidelines produced by subspecialty medical societies, general medical societies, or government agencies (P=.55). Guideline length was positively correlated with adherence to methodological standards (P=.001). Conclusion  Guidelines published in the peer-reviewed medical literature during the past decade do not adhere well to established methodological standards. While all areas of guideline development need improvement, greatest improvement is needed in the identification, evaluation, and synthesis of the scientific evidence.      

Effectiveness of influenza vaccine in health care professionals: a randomized trial

Context  Data are limited and conflicting regarding the effectiveness of influenza vaccine in health care professionals. Objective  To determine the effectiveness of trivalent influenza vaccine in reducing infection, illness, and absence from work in young, healthy health care professionals. Design  Randomized, prospective, double-blind, controlled trial over 3 consecutive years, from 1992-1993 to 1994-1995. Setting  Two large teaching hospitals in Baltimore, Md. Participants  Two hundred sixty-four hospital-based health care professionals without chronic medical problems were recruited; 49 participated for 2 seasons; 24 participated for 3 seasons. The mean age was 28.4 years, 75% were resident physicians, and 57% were women. Intervention  Participants were randomly assigned to receive either an influenza vaccine or a control (meningococcal vaccine, pneumococcal vaccine, or placebo). Serum samples for antibody assays were collected at the time of vaccination, 1 month after vaccination, and at the end of the influenza season. Active weekly surveillance for illness was conducted during each influenza epidemic period. Main Outcome Measures  Serologically defined influenza infection (4-fold increase in hemagglutination-inhibiting antibodies), days of febrile respiratory illness, and days absent from work. Results  We conducted 359 person-winters of serologic surveillance (99.4% follow-up) and 4746 person-weeks of illness surveillance (100% follow-up). Twenty-four (13.4%) of 179 control subjects and 3 (1.7%) of 180 influenza vaccine recipients had serologic evidence of influenza type A or B infection during the study period. Vaccine efficacy against serologically defined infection was 88% for influenza A (95% confidence interval [CI], 47%-97%; P=.001) and 89% for influenza B (95% CI, 14%-99%; P=.03). Among influenza vaccinees, cumulative days of reported febrile respiratory illness were 28.7 per 100 subjects compared with 40.6 per 100 subjects in controls (P=.57) and days of absence were 9.9 per 100 subjects vs 21.1 per 100 subjects in controls (P=.41). Conclusions  Influenza vaccine is effective in preventing infection by influenza A and B in health care professionals and may reduce reported days of work absence and febrile respiratory illness. These data support a policy of annual influenza vaccination of health care professionals.      

Obesity, weight gain, and the risk of kidney stones

Context  Larger body size may result in increased urinary excretion of calcium, oxalate, and uric acid, thereby increasing the risk for calcium-containing kidney stones. It is unclear if obesity increases the risk of stone formation, and it is not known if weight gain influences risk. Objective  To determine if weight, weight gain, body mass index (BMI), and waist circumference are associated with kidney stone formation. Design, Setting, and Participants  A prospective study of 3 large cohorts: the Health Professionals Follow-up Study (N = 45 988 men; age range at baseline, 40-75 years), the Nurses’ Health Study I (N = 93 758 older women; age range at baseline, 34-59 years), and the Nurses’ Health Study II (N = 101 877 younger women; age range at baseline, 27-44 years). Main Outcome Measures  Incidence of symptomatic kidney stones. Results  We documented 4827 incident kidney stones over a combined 46 years of follow-up. After adjusting for age, dietary factors, fluid intake, and thiazide use, the relative risk (RR) for stone formation in men weighing more than 220 lb (100.0 kg) vs men less than 150 lb (68.2 kg) was 1.44 (95% confidence interval [CI], 1.11-1.86; P = .002 for trend). In older and younger women, RRs for these weight categories were 1.89 (95% CI, 1.52-2.36; P<.001 for trend) and 1.92 (95% CI, 1.59-2.31; P<.001 for trend), respectively. The RR in men who gained more than 35 lb (15.9 kg) since age 21 years vs men whose weight did not change was 1.39 (95% CI, 1.14-1.70; P = .001 for trend). Corresponding RRs for the same categories of weight gain since age 18 years in older and younger women were 1.70 (95% CI, 1.40-2.05; P<.001 for trend) and 1.82 (95% CI, 1.50-2.21; P<.001 for trend). Body mass index was associated with the risk of kidney stone formation: the RR for men with a BMI of 30 or greater vs those with a BMI of 21 to 22.9 was 1.33 (95% CI, 1.08-1.63; P<.001 for trend). Corresponding RRs for the same categories of BMI in older and younger women were 1.90 (95% CI, 1.61-2.25; P<.001 for trend) and 2.09 (95% CI, 1.77-2.48; P<.001 for trend). Waist circumference was also positively associated with risk in men (P = .002 for trend) and in older and younger women (P<.001 for trend for both). Conclusions  Obesity and weight gain increase the risk of kidney stone formation. The magnitude of the increased risk may be greater in women than in men.      

Enduring effects of nurse home visitation on maternal life course: a 3-year follow-up of a randomized trial

Context  A home visitation program using nurses to improve maternal and child outcomes had favorable results in a randomized trial with a primarily white, semirural population. Many of the short-term findings have been replicated with urban blacks, but whether the program will continue to demonstrate effectiveness after its conclusion is uncertain. Objective  To determine the effectiveness of a prenatal and infancy home visitation program on the maternal life course of women in an urban environment 3 years after the program ended. Design and Setting  Three-year follow-up of a randomized controlled trial of women seen consecutively between June 1990 and August 1991 at an obstetrical clinic in Memphis, Tenn, who were enrolled in a visitation program for 2 years after the birth of their first child. Participants  A cohort of 743 women who were primarily black, were pregnant for less than 29 weeks, had no previous live births, and had at least 2 sociodemographic risk factors (unmarried, <12 years of education, or unemployed). Intervention  An average of 7 (range, 0-18) home visits during pregnancy and 26 (range, 0-71) from birth to the child's second birthday. Main Outcome Measures  Rate of subsequent pregnancy, mean interval between first and second birth, and mean number of months of welfare use. Results  Compared with the control group, women who received home visits by nurses had fewer subsequent pregnancies (1.15 vs 1.34; P=.03), fewer closely spaced subsequent pregnancies (0.22 vs 0.32; P=.03), longer intervals between the birth of the first and second child (30.25 vs 26.60 months; P=.004), and fewer months of using Aid to Families with Dependent Children (32.55 vs 36.19; P=.01) and food stamps (41.57 vs 45.04; P=.005). Compared with the effect of the program while the program was in operation, the effect after it ended was essentially equal for Aid to Families with Dependent Children, greater for food stamps, greater for rates of closely spaced subsequent pregnancies, and smaller for rates of subsequent pregnancy overall. Conclusions  We found enduring effects of a home visitation program on the lives of black women living in an urban setting. While these results were smaller in magnitude than those achieved in a previous trial with white women living in a semirural setting, the direction of the effects was consistent across the 2 studies.      

Trends in sudden cardiovascular death in young competitive athletes after implementation of a preparticipation screening program

Context  A nationwide systematic preparticipation athletic screening was introduced in Italy in 1982. The impact of such a program on prevention of sudden cardiovascular death in the athlete remains to be determined. Objective  To analyze trends in incidence rates and cardiovascular causes of sudden death in young competitive athletes in relation to preparticipation screening. Design, Setting, and Participants  A population-based study of trends in sudden cardiovascular death in athletic and nonathletic populations aged 12 to 35 years in the Veneto region of Italy between 1979 and 2004. A parallel study examined trends in cardiovascular causes of disqualification from competitive sports in 42 386 athletes undergoing preparticipation screening at the Center for Sports Medicine in Padua (22 312 in the early screening period [1982-1992] and 20 074 in the late screening period [1993-2004]). Main Outcome Measures  Incidence trends of total cardiovascular and cause-specific sudden death in screened athletes and unscreened nonathletes of the same age range over a 26-year period. Results  During the study period, 55 sudden cardiovascular deaths occurred in screened athletes (1.9 deaths/100 000 person-years) and 265 sudden deaths in unscreened nonathletes (0.79 deaths/100 000 person-years). The annual incidence of sudden cardiovascular death in athletes decreased by 89% (from 3.6/100 000 person-years in 1979-1980 to 0.4/100 000 person-years in 2003-2004; P for trend < .001), whereas the incidence of sudden death among the unscreened nonathletic population did not change significantly. The mortality decline started after mandatory screening was implemented and persisted to the late screening period. Compared with the prescreening period (1979-1981), the relative risk of sudden cardiovascular death in athletes was 0.56 in the early screening period (95% CI, 0.29-1.15; P = .04) and 0.21 in the late screening period (95% CI, 0.09-0.48; P = .001). Most of the reduced mortality was due to fewer cases of sudden death from cardiomyopathies (from 1.50/100 000 person-years in the prescreening period to 0.15/100 000 person-years in the late screening period; P for trend = .002). During the study period, 879 athletes (2.0%) were disqualified from competition due to cardiovascular causes at the Center for Sports Medicine: 455 (2.0%) in the early screening period and 424 (2.1%) in the late screening period. The proportion of athletes who were disqualified for cardiomyopathies increased from 20 (4.4%) of 455 in the early screening period to 40 (9.4%) of 424 in the late screening period (P = .005). Conclusions  The incidence of sudden cardiovascular death in young competitive athletes has substantially declined in the Veneto region of Italy since the introduction of a nationwide systematic screening. Mortality reduction was predominantly due to a lower incidence of sudden death from cardiomyopathies that paralleled the increasing identification of athletes with cardiomyopathies at preparticipation screening.      

Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women

Context  Elevated nonfasting triglycerides indicate the presence of remnant lipoproteins, which may promote atherosclerosis. Objective  To test the hypothesis that very high levels of nonfasting triglycerides predict myocardial infarction (MI), ischemic heart disease (IHD), and death. Design, Setting, and Participants  A prospective cohort study of 7587 women and 6394 men from the general population of Copenhagen, Denmark, aged 20 to 93 years, followed up from baseline (1976-1978) until 2004. Main Outcome Measures  Hazard ratios (HRs) for incident MI, IHD, and total death according to baseline nonfasting triglyceride level categories of 1 to 1.99 mmol/L (88.5-176.1 mg/dL), 2 to 2.99 mmol/L (177.0-264.6 mg/dL), 3 to 3.99 mmol/L (265.5-353.0 mg/dL), 4 to 4.99 mmol/L (354.0-441.6 mg/dL), and 5 mmol/L or more (442.5 mg/dL) vs triglyceride levels of less than 1 mmol/L (<88.5 mg/dL). Results  With increasing levels of nonfasting triglycerides, levels of remnant lipoprotein cholesterol increased. During a mean follow-up of 26 years, 1793 participants (691 women and 1102 men) developed MI, 3479 (1567 women and 1912 men) developed IHD, and 7818 (3731 women and 4087 men) died. For MI, among women, the age-adjusted HRs and multifactorially adjusted HRs (aHRs) for each respective category per 1-mmol/L increase in nonfasting triglyceride levels were 2.2 (aHR, 1.7), 4.4 (aHR, 2.5), 3.9 (aHR, 2.1), 5.1 (aHR, 2.4), and 16.8 (aHR, 5.4); for both, P for trend < .001. For MI, among men, the values were 1.6 (aHR, 1.4), 2.3 (aHR, 1.6), 3.6 (aHR, 2.3), 3.3 (aHR, 1.9), and 4.6 (aHR, 2.4); for both, P for trend < .001. For IHD, among women, the values were 1.7 (aHR, 1.4), 2.8 (aHR, 1.8), 3.0 (aHR, 1.8), 2.1 (aHR, 1.2), and 5.9 (aHR, 2.6); for both, P for trend < .001. For IHD, among men, the values were 1.3 (aHR, 1.1), 1.7 (aHR, 1.3), 2.1 (aHR, 1.3), 2.0 (aHR, 1.2), and 2.9 (aHR, 1.5); P for trend < .001 for age-adjusted and P for trend = .03 for multifactorially adjusted. For total death, among women, the values were 1.3 (aHR, 1.3), 1.7 (aHR, 1.6), 2.2 (aHR, 2.2), 2.2 (aHR, 1.9), and 4.3 (aHR, 3.3); for both, P for trend < .001. For total death, among men, the values were 1.3 (aHR, 1.2), 1.4 (aHR, 1.4), 1.7 (aHR, 1.5), 1.8 (aHR, 1.6), and 2.0 (aHR, 1.8); for both, P for trend < .001. Conclusion  In this general population cohort, elevated nonfasting triglyceride levels were associated with increased risk of MI, IHD, and death in men and women.      

Improved Prognosis of Thoracic Aortic Aneurysms: A Population-Based Study

Context.— Managing thoracic aortic aneurysms identified incidentally by increased use of computed tomography, echocardiography, and magnetic resonance imaging is problematic, especially in the elderly. Objective.— To ascertain whether the previously reported poor prognosis for individuals with thoracic aortic aneurysms has changed with better medical therapies and improved surgical techniques that can now be applied to aneurysm management. Design.— Population-based cohort study. Setting and Patients.— All 133 patients with the diagnosis of degenerative thoracic aortic aneurysms among Olmsted County, Minnesota, residents between 1980 and 1994 compared with a previously reported cohort of similar patients between 1951 and 1980. Main Outcome Measures.— The primary clinical end points were incidence, cumulative rupture risk, rupture risk as a function of aneurysm size, and survival. Results.— In contrast to abdominal aortic aneurysms, for which men are affected predominately, 51% of thoracic aortic aneurysms were identified in women who were considerably older at recognition than men (mean age, 75.9 vs 62.8 years, respectively; P=.01). The overall incidence rate of 10.4 per 100,000 person-years (95% confidence interval [CI], 8.6-12.2) between 1980 and 1994 was more than 3-fold higher than the rate from 1951 to 1980. The cumulative risk of rupture was 20% after 5 years. Seventy-nine percent of ruptures occurred in women (P=.01). The 5-year risk of rupture as a function of aneurysm size at recognition was 0% for aneurysms less than 4 cm in diameter, 16% (95% CI, 4%-28%) for those 4 to 5.9 cm, and 31% (95% CI, 5%-56%) for aneurysms 6 cm or more. Overall 5-year survival improved to 56% (95% CI, 48%-66%) between 1980 and 1994 compared with only 19% between 1951 and 1980 (P<.01). Conclusions.— In this population, elderly women represent an increasing portion of all patients with clinically recognized thoracic aortic aneurysms and constitute the majority of patients whose aneurysm eventually ruptures. Overall survival for thoracic aortic aneurysms has improved significantly in the past 15 years.