Latest Research

January 19, 2007

A summary of the "must-read" articles from the journals in that pile on your desk.

Pexelizumab of No Benefit in Angioplasty Trial

Mortality unaffected by antibody treatment in patients with ST-elevation myocardial infarction

Patients with acute ST-elevation myocardial infarction who are treated with pexelizumab before undergoing percutaneous coronary intervention do not have a lower mortality than placebo-treated patients, according to a report in the Jan. 3 issue of the Journal of the American Medical Association. Pexelizumab is a monoclonal antibody that binds a complement component.

Paul W. Armstrong, M.D., of the University of Alberta in Edmonton, Canada, and colleagues randomly assigned 5,745 patients with acute ST-elevation myocardial infarction to either placebo or pexelizumab prior to reperfusion with percutaneous transluminal coronary intervention.

The investigators found that 30-day mortality rate was similar in both groups, as well as the composite risk of death, shock or heart failure at 30 and 90 days.

"In this large clinical trial of ST-elevation myocardial infarction patients treated with primary percutaneous coronary intervention and usage of evidence-based therapies, mortality was low and unaffected by administration of pexelizumab," the authors conclude.

The study was funded by Procter & Gamble Pharmaceuticals and Alexion Pharmaceuticals.

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Not All Performance Measures Cut Heart Failure Mortality

ACE inhibitors and angiotensin receptor blockers do reduce the risk of mortality, rehospitalization

The prescription of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker reduces the risk of post-discharge mortality or rehospitalization in heart failure patients, but other factors used as performance measures have little impact on patients' chances of survival, researchers report in the Jan. 3 issue of the Journal of the American Medical Association. Prescribing a beta-blocker, which is not currently a performance measure, also reduces the risk of mortality and rehospitalization.

Gregg C. Fonarow, M.D., of the University of California Los Angeles Medical Center, and colleagues examined the association between current heart failure performance measures and clinical outcomes using 60- to 90-day post-discharge data from 5,791 patients hospitalized for heart failure. The five performance measures were as defined by the American College of Cardiology/American Heart Association.

The investigators found that the mortality rate was 8.6 percent and the combined mortality/rehospitalization rate was 36.2 percent. Most of the performance measures were not associated with mortality, although patients who were prescribed an ACE inhibitor or an angiotensin receptor blocker at discharge had a lower risk of post-discharge mortality (hazard ratio 0.61) or mortality/rehospitalization (HR, 0.51)

Despite the fact that beta-blockade at discharge is not currently a performance measure, the report indicates that it reduced the risk of mortality (HR, 0.48) and mortality/rehospitalization (HR, 0.73).

"Current heart failure performance measures, aside from prescription of an ACE inhibitor or angiotensin receptor blocker at discharge, have little relationship to patient mortality and combined mortality/rehospitalization in the first 60 to 90 days after discharge," the authors conclude.

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Score Predicts Risk of Bacterial Meningitis in Children

Only 0.1 percent who don't meet Bacterial Meningitis Score criteria have bacterial meningitis

A clinical prediction score can be used to accurately determine the risk of bacterial meningitis in children with cerebrospinal fluid (CSF) pleocytosis, according to a study in the Jan. 3 issue of the Journal of the American Medical Association.

Lise E. Nigrovic, M.D., M.P.H., of Children's Hospital Boston, and colleagues assessed the usefulness of the Bacterial Meningitis Score in 3,295 children with CSF pleocytosis. The score is based on CSF Gram staining, CSF and peripheral blood neutrophil count, CSF protein, as well as the history of seizure.

The investigators found that 3.7 percent of patients had bacterial meningitis and the remainder had aseptic meningitis. The Bacterial Meningitis Score classified 1,714 patients as being at low risk, and only two of these patients, both of whom were under 2 months old, had bacterial meningitis.

"This large multicenter study validates the Bacterial Meningitis Score prediction rule in the era of conjugate pneumococcal vaccine as an accurate decision support tool," Nigrovic and colleagues conclude. "The risk of bacterial meningitis is very low (0.1 percent) in patients with none of these criteria."

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Clinical Data Can Boost Hospital Quality Measures

Present-on-admission codes, numerical laboratory values improve models

Adding clinical data to administrative claims, such as present-on-admission codes and laboratory values, can improve hospitals' inpatient mortality rates in risk-adjustment models, according to study findings published in the Jan. 3 issue of the Journal of the American Medical Association.

Michael Pine, M.D., of the University of Chicago in Illinois, and colleagues examined whether adding such data would affect risk-adjusted hospital mortality rates, based on the c-statistic of risk-adjustment equations for inpatient mortality. Information was obtained from an administrative database collected at 188 Pennsylvania hospitals between 2000 and 2003. The patients had any of five conditions, such as acute myocardial infarction or gastrointestinal hemorrhage, and three procedures.

The investigators found that the mean c-statistic of the model was 0.79, which was substantially improved by adding present-on-admission codes (mean c-statistic 0.84) and numerical laboratory data (mean c-statistic 0.86). Adding clinical data that was more difficult and expensive to collect only slightly improved the mean c-statistic to 0.88, the report indicates.

"This study supports the value of adding present-on-admission codes and numerical laboratory values to administrative databases," Pine and colleagues conclude.

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U.S. Stroke Incidence Has Declined Over Past 50 Years

Strokes in men dropped from 7.6 per 1000 person-years to 5.3 per 1000 person-years

Over the past 50 years there has been a decline in the incidence of stroke in the United States, but lifetime risk has not declined, possibly due to longer life expectancies, researchers report in the Dec. 27 issue of the Journal of the American Medical Association.

Philip A. Wolf, M.D., of Boston University School of Medicine, and colleagues analyzed data on 9,152 men and women who had not had a stroke at baseline and who were followed up at three periods during the course of 50 years. This amounted to 174,917 person-years of follow-up. Data on stroke risk factors and surveillance for incidence of stroke were conducted every two years.

During the course of follow-up, there were 1,030 strokes, of which 629 (61 percent) were atherothrombotic brain infarctions. Men accounted for 450 (44 percent) of the cases. In men, the age-adjusted stroke incidence was 7.6 per 1000 person-years in 1950-1977, 6.2 in 1978-1989, and 5.3 in 1990-2004. The incidence for women over the same three periods was 6.2 per 1000 person-years, 5.8 and 5.1, respectively. There was a decline in lifetime risk at age 65, from 19.5 percent to 14.5 percent for men and from 18.0 percent to 16.1 percent for women, but it was not statistically significant.

"The results of this study suggest that improved control of risk factors has lowered stroke incidence but emphasize the need for continued primary prevention efforts," the authors conclude.

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Women Can Take a Break from Alendronate After Five Years

Osteoporosis drug can be discontinued in many cases with no greater risk of fracture

Many of the women taking the osteoporosis drug alendronate can discontinue treatment after five years without increasing the risk of fracture, according to the results of a study published in the Dec. 27 issue of the Journal of the American Medical Association.

Dennis M. Black, Ph.D., of the University of California San Francisco, and colleagues conducted a randomized, double-blind study of 1,099 postmenopausal women who had been taking alendronate for five years at baseline. The women were randomized into three groups: 329 took 5 mg per day of alendronate, 333 took 10 mg/d, and 437 took a placebo for the following five years.

The women in the placebo group experienced a decline in total hip bone mineral density (BMD) of 2.4 percent compared with those in the alendronate groups, and a decline of 3.7 percent in spine BMD. However, the mean levels did not decline below those before treatment began a decade earlier. Serum markers of bone turnover increased in the placebo group but were also below pretreatment levels.

The cumulative risk of non-vertebrate fractures was almost the same in both the treatment and the placebo groups, although the placebo group had a higher risk of vertebral fractures. "For many women, discontinuation of alendronate for up to five years does not appear to significantly increase fracture risk. However, women at very high risk of clinical vertebral fractures may benefit by continuing beyond five years," the authors conclude.

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Proton Pump Inhibitors Increase Hip Fracture Risk

Patients on long-term acid suppression therapy, particularly at high doses, should have adequate calcium intake

Long-term use of proton pump inhibitors may increase the risk of hip fracture, particularly when used at high doses, according to a report published in the Dec. 27 issue of the Journal of the American Medical Association.

Yu-Xiao Yang, M.D., of the University of Pennsylvania in Philadelphia, and colleagues conducted a study of 13,556 hip fracture cases and 135,386 controls, using the U.K. General Practice Research Database (1987-2003). All the study participants were aged 50 years and older and included both users and non-users of proton pump inhibitors.

Among patients taking high doses of proton pump inhibitors, there was a significantly increased risk of hip fracture with long-term use (adjusted odds ratio, 2.65). The risk of hip fracture increased with the duration of proton pump inhibitor therapy, from a 1.22 adjusted odds ratio at one year to 1.41 at two years and 1.54 at three years.

"At this point, physicians should be aware of this potential association when considering proton pump inhibitor therapy and should use the lowest effective dose for patients with appropriate indications. For elderly patients who require long-term and particularly high-dose proton pump inhibitor therapy, it may be prudent to re-emphasize increased calcium intake, preferably from a dairy source, and co-ingestion of a meal when taking insoluble calcium supplements," the authors write.

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Genetic Alterations Associated with Head and Neck Cancer

Researchers find high degree of abnormalities in patients who developed smoking-related cancers

Several stroma-specific genetic alterations may be associated with the development of smoking-related head and neck squamous cell carcinoma, researchers report in the Jan. 10 issue of the Journal of the American Medical Association.

Charis Eng, M.D., Ph.D., of the Genomic Medicine Institute at the Cleveland Clinic Foundation in Ohio, and colleagues isolated the tumor epithelium and surrounding stroma from 122 patients with oral cavity and oropharyngeal or hypopharyngeal squamous cell cancers and subjected the tissues to whole genome analysis.

The researchers found a high degree of genomic alterations in the tumor-associated stroma isolated from smokers. They found an association between tumor aggressiveness and a specific set of five stroma-specific loci, three of which were associated with tumor size and regional nodal metastases. They also associated two specific genomic alterations with node metastases and clinical stage.

"We hope that our genomic observations, which point to genomic regions that may harbor many genes, will guide future in-depth functional and mechanistic studies," the authors state. "Nevertheless, our current observations can be used to identify new biomarkers for prediction of clinical outcome and potentially novel compartments for targeted therapy and prevention."

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Medication Adherence Benefits Heart Attack Survivors

Mortality significantly lower in patients who take statins and beta-blockers as prescribed

Myocardial infarction survivors with high adherence to statin and beta-blocker regimens are less likely to die than those with intermediate or low adherence, according to a population study published in the Jan. 10 issue of the Journal of the American Medical Association.

Between 1999 and 2003, Jeppe N. Rasmussen, M.D., of the National Institute of Public Health in Copenhagen, Denmark, and colleagues studied outcomes in 31,455 elderly myocardial infarction survivors who filled prescriptions for statins, beta-blockers or calcium channel blockers.

The researchers found that mortality was significantly lower for patients with high statin adherence (16 percent) than for patients with intermediate or low adherence (20 percent and 24 percent, respectively). They also observed similar but less significant associations between beta-blocker adherence and mortality and no relationship between calcium channel blocker adherence and mortality.

"The differential class effects of drug adherence on long-term survival following myocardial infarction suggest that adherence-related mortality benefits associated with evidence-based pharmacotherapies are mediated by drug effects more so than by generic healthy adherer behavioral attributes," the authors conclude. "The beneficial biological effects associated with higher drug adherence on survival underscores the need to optimize adherent patient behavior patterns to maximize the survival gains of evidence-based therapies in real-world populations, which may be enhanced through the implementation of pharmacy or other preventive care programs."

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Biomarker May Help Predict Risk of Cardiovascular Events

Testing for plasma biomarker may help guide risk stratification

In patients with heart disease, a blood test to measure levels of the amino terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP) may help identify those at highest risk of cardiovascular events and death, according to a report published in the Jan. 10 issue of the Journal of the American Medical Association.

Kirsten Bibbins-Domingo, Ph.D., M.D., of the University of California San Francisco, and colleagues studied 987 patients for an average of 3.7 years, during which 256 (26.2 percent) either had a cardiovascular event or died.

The researchers found that patients whose NT-proBNP levels were in the highest quartile had an eightfold increased risk of cardiovascular events or death compared to those whose levels were in the lowest quartile (19.6 percent versus 2.6 percent). They also found that each incremental increase in log NT-proBNP level (1.3 pg/mL) was associated with a 2.3-fold increased rate of adverse cardiovascular outcomes. The addition of NT-proBNP to clinical assessment and echocardiographic examination improved the area under the receiver operating characteristic curves compared to clinical assessment and echocardiographic examination alone (0.80 versus 0.76 respectively).

"Further research is warranted to determine whether plasma natriuretic peptide levels correlate with the degree and extent of vascular disease," states the author of an accompanying editorial.

Roche Diagnostics Corporation provided funding for the NT-proBNP assays used in the study.

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Rare T. evansi Infection Linked to Apolipoprotein Gene

Case study suggests that infection is due to mutations in the apolipoprotein L-I gene

Most humans are immune to the parasite Trypanosoma evansi, which most often causes disease in animals, but patients who have mutations in the apolipoprotein L-I (APOL1) gene may be susceptible, according to a case report in the Dec. 28 issue of the New England Journal of Medicine.

Etienne Pays, Ph.D., of the Universite Libre de Bruxelles in Gosselies, Belgium, and colleagues diagnosed a T. evansi infection in an Indian cattle farmer who presented with a five-month history of fluctuating trypanosome parasitemia associated with febrile episodes. They treated the patient with suramin, which led to a complete cure.

The researchers found that the patient's serum had no trypanolytic activity because of a lack of APOL1, which they attributed to frameshift mutations in both APOL1 alleles. They were able to restore trypanolytic activity with recombinant APOL1.

"This case of human infection with T. evansi could be due either to acquired resistance to normal human serum by the parasite or to deficient trypanolytic activity of the host," the authors write. "T. evansi-infected human serum did not affect the two T. evansi strains (from Morocco and from Vietnam) that we tested."

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Five-Gene Signature May Predict Survival in Lung Cancer

Patients with signature have threefold higher risk of death, study finds

Researchers have identified a five-gene signature that is closely associated with relapse-free survival and overall survival in patients with non-small-cell lung cancer, according to a report in the Jan. 4 issue of the New England Journal of Medicine.

Pan-Chyr Yang, M.D., Ph.D., of the National Taiwan University Hospital in Taipei, and colleagues analyzed 185 frozen specimens of non-small-cell lung cancer using microarray or real-time reverse-transcriptase polymerase chain reaction analysis, or both, to develop a gene expression model for prediction of non-small-cell lung cancer outcome.

The investigators identified sixteen genes that correlated with survival among patients and selected five genes for further analysis. These genes included DUSP6, MMD, STAT1, ERBB3 and LCK. The five-gene signature was an independent predictor of relapse-free and overall survival and was validated in an independent cohort.

The hazard ratio for death from having the five-gene signature ranged from 2.83 in the original study to 3.36 in the validation study. "This signature could be useful in stratifying patients according to risk in trials of adjuvant treatment of the disease," the authors conclude.

One of the study authors is an employee of Advpharma.

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Pet Rodents May Cause Human Salmonella Infection

Study identifies drug-resistant S. enterica in pet rodents

Pet rodents may be an unrecognized source of human salmonella infection in the United States, according to a report in the Jan. 4 issue of the New England Journal of Medicine.

Stephen J. Swanson, M.D., of Hennepin County Medical Center in Minneapolis, Minn., and colleagues reviewed salmonella pulsed-field gel electrophoresis patterns submitted to the National Molecular Subtyping Network for Foodborne Disease Surveillance. They looked for subtypes related to infections caused by pet rodents.

The investigators identified 28 patients infected with the S. enterica serotype Typhimurium between December 2003 and September 2004. Thirteen of 22 patients interviewed from 10 different states reported exposure to pet hamsters, mice or rats. Thirteen pet stores that were supplied by various distributors were identified, but no single source of infected rodents could be found.

Multidrug-resistant S. enterica serotype Typhimurium isolates were obtained from one patient's pet mouse and from seven hamsters from pet stores, and closely related serotypes were identified in transport containers. The authors write that those who work with the animals, and consumers -- especially children -- should be aware of the hazards and wash their hands after handling the animals and their cages.

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Rapid Angioplasty Best for ST-Segment Elevation MI

Authors review clinical features of ST-segment myocardial infarction, treatment guidelines and recommendations

Patients with acute myocardial infarction (MI) with ST-segment elevation who have additional high-risk features should receive immediate percutaneous coronary intervention at an experienced facility, according to the authors of a clinical vignette in the Jan. 4 issue of the New England Journal of Medicine.

Ellen C. Keeley, M.D., of the University of Virginia School of Medicine in Charlottesville, and L. David Hillis, M.D., of the University of Texas Southwestern Medical Center at Dallas, reviewed the pathophysiology and clinical evidence associated with acute MI with ST-segment elevation, as well as the current treatment guidelines.

Recent evidence suggests that percutaneous coronary intervention has significantly reduced mortality due to ST-segment elevation MI. Percutaneous coronary intervention is preferred within 90 minutes of initial medical contact, especially in subjects who also have additional high-risk features including tachycardia, rales, and anterior location of the infarct. The authors recommend that patients be transferred to a facility with a high-volume catheterization laboratory and an experienced operator.

"On the basis of the data available on facilitated percutaneous coronary intervention, we do not recommend administration of a fibrinolytic agent or glycoprotein IIb/IIIa inhibitor before the transfer," the authors add.

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Studies Link Valve Problems to Ergot-Dopamine Agonists

Increased rate of cardiac valve regurgitation seen in patients treated with pergolide or cabergoline

The risk of cardiac-valve regurgitation is higher in patients with Parkinson disease taking ergot-derived dopamine agonists compared with those taking non-ergot-derived agonists, according to the results of two studies published in the Jan. 4 issue of the New England Journal of Medicine.

Rene Schade, M.D., of the Charite-Universitatsmedizin Berlin in Germany, and colleagues used the United Kingdom General Practice Research Database to measure rates of cardiac-valve regurgitation in patients taking antiparkinsonian drugs between 1988 and 2005. Of 31 patients with newly diagnosed cardiac-valve regurgitation, six each were exposed to pergolide or cabergoline within the past year. Use of either drug was associated with an increased incidence-rate ratio for cardiac-valve regurgitation (7.1 for pergolide, 4.9 for cabergoline).

In the second study, Renzo Zanettini, M.D., and colleagues at the Istituti Clinici di Perfezionamento in Milan, Italy, performed echocardiograms on 155 patients taking dopamine agonists. Moderate-to-severe regurgitation was found in valves in 23.4 percent of pergolide-taking patients, 28.6 percent of cabergoline-taking patients, 5.6 percent of control subjects, and none of the patients taking non-ergot-derived dopamine agonists.

"These two studies reinforce the notion of a causal association between 5-HT2B agonism and valvular heart disease. Such an association has now been seen with drugs for diverse indications, including anorectic agents (fenfluramine), antimigraine drugs (dihydroergotamine, methysergide and ergotamine), and antiparkinsonian agents (pergolide and cabergoline)," according to the author of a Perspective accompanying the studies.

Some of the authors report receiving compensation from Schering, GlaxoSmithKline, Boehringer Ingelheim, Pfizer, AstraZeneca, Organon or Novartis.

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Dietary Nitrate Lowers Blood Pressure

Arterial and diastolic blood pressure lower by a mean of 3 mm Hg after supplement ingestion

Dietary nitrate, taken in amounts equivalent to 150-250 grams of spinach, beetroot or lettuce, lowers diastolic blood pressure a mean of 3.7 mm Hg and arterial blood pressure a mean of 3.2 mm Hg in healthy subjects, according to a report in the Dec. 28 issue of the New England Journal of Medicine.

Eddie Weitzberg, M.D., Ph.D., of the Karolinska Institute in Stockholm, Sweden, and colleagues assessed three-day supplementation with sodium nitrate (0.1 mmol/kg/body weight/day) or placebo on blood pressure in 17 active, healthy volunteers.

After nitrate supplementation, there were no significant changes in systolic blood pressure and heart rate compared to placebo. However, the diastolic blood pressure in treated individuals averaged 3.7 mm Hg lower than in controls and the mean arterial pressure was 3.2 mm Hg lower in the treated group compared to those given placebo. After nitrate ingestion, plasma nitrate and nitrite levels were higher than after placebo supplementation.

"Short-term dietary supplementation with inorganic nitrate reduces diastolicblood pressure in healthy young volunteers," the authors conclude.

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Gene Implicated in Recessive Osteogenesis Imperfecta

Study links mutations in CRTAP gene to recessive form of osteogenesis imperfecta

Mutations in the cartilage-associated protein (CRTAP) gene may cause the recessive form of osteogenesis imperfecta, according to a report in the Dec. 28 issue of the New England Journal of Medicine.

Building on findings from murine studies, Aileen M. Barnes, M.S., of the National Institutes of Health in Bethesda, Md., and colleagues screened dermal fibroblasts from 10 children with lethal or severe osteogenesis imperfecta who did not have primary collagen mutations. Researchers had suspected that there was a recessive form of the disease to account for the 10 to 15 percent of people with osteogenesis imperfecta who don't have a mutation in their collagen genes.

The investigators found that CRTAP genes were non-functional in three of the 10 children. Each parent carried one mutant CRTAP gene and one normal CRTAP gene in the two of three sets of parents who were available for genetic screening.

"This discovery provides a basis for counseling families that have lost a child to this previously unexplained form of osteogenesis imperfecta [and] it also offers insight into a crucial step needed in the formation of bone and other tissues," said Duane Alexander, M.D., the director of the National Institute of Child Health and Human Development in Bethesda, Md., in a written statement.

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Female Predominance of Long-QT Syndrome Examined

Study sheds light on female predominance, transmission distortion in long-QT syndrome

Transmission distortion among people with long-QT syndrome is due to positive selection of the mutated allele, researchers report in the Dec. 28 issue of the New England Journal of Medicine.

Medea Imboden, Ph.D., of the University of Zurich in Switzerland, and colleagues studied the distribution of alleles for the long-QT syndrome in 484 nuclear families with type 1 disease and 269 nuclear families with type 2 disease, all of whom had fully genotyped families.

The investigators found that positive selection of the mutated alleles that cause the long-QT syndrome leads to transmission distortion, with increased proportions of mutation carriers among the offspring of affected families. Moreover, the probability of inheriting a mutation for the long-QT syndrome was higher than expected according to mendelian inheritance. The study also showed that daughters are favored during maternal transmission.

"The skewed segregation of the mutation from mothers to their daughters might contribute substantially to the observed female predominance in the long-QT syndrome," the study authors conclude.

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Handwashing Slashes Risk of Catheter Infections in Hospitals

Five simple measures dramatically reduce risk of catheter-related bloodstream infections

Handwashing, the use of full-barrier precautions during insertion and other tried-and-true safety measures can dramatically cut the risk of catheter-based bloodstream infections in intensive care units, according to the results of a new study of 103 Michigan ICUs published in the Dec. 28 issue of the New England Journal of Medicine.

Peter Pronovost, M.D., Ph.D., of Johns Hopkins University in Baltimore, and colleagues reviewed the rate of catheter-related bloodstream infections among ICUs before, during and up to 18 months after implementing five safety measures. The safety measures included handwashing, using full-barrier precautions during the insertion of central venous catheters, cleaning skin with chlorhexidine, avoiding the femoral site whenever possible and removing unnecessary catheters.

These relatively simple interventions reduced rates of catheter-based infections by 66 percent and improvements were maintained for the 18-month study period. Specifically, the median rate of catheter-related bloodstream infections per 1,000 days decreased from 2.7 at baseline to 0 post-implementation of the safety measures. The mean rate decreased from 7.7 at baseline to 1.4 at 16- to 18-month follow-up.

"The story is compelling and the costs and efforts so relatively minor that the five components of the intervention should be widely adopted," write Richard P. Wenzel, M.D., and Michael B. Edmond, M.D., of the Virginia Commonwealth University in Richmond, in an accompanying editorial.

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Drugs Increase Breast Cancer Progression-Free Survival

Overall survival unchanged

Lapatinib plus capecitabine significantly increase the time to progression, but not overall survival, compared with capecitabine alone, in women with advanced breast cancer who have failed other treatments, according to a study in the Dec. 28 issue of the New England Journal of Medicine.

Charles E. Geyer, M.D., from the Allegheny General Hospital in Pittsburgh, and colleagues randomly assigned 324 women with HER2-positive advanced or metastatic breast cancer who had failed chemotherapy plus trastuzumab to capecitabine alone or combined with lapatinib.

The researchers found that the combined therapy significantly increased the median time to progression (8.4 versus 4.4 months, hazard ratio 0.49). There was no increase in toxic effects, including cardiotoxicity, with combined therapy. Women receiving combination therapy tended to have a higher tumor response rate and fewer central nervous system metastases. However, survival was similar in the two groups, with 22 percent mortality, the report indicates.

"The results provide support for the use of lapatinib and capecitabine in women with progression of HER2-positive breast cancer after treatment with trastuzumab," Geyer and colleagues conclude. "The findings also warrant evaluation of the role of lapatinib, which has a mechanism of action distinct from that of trastuzumab, earlier in the treatment of HER2-positive breast cancer."

The study was supported by GlaxoSmithKline.

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Drug Lowers LDL Cholesterol in High-Risk Patients

Also raises liver aminotransferase and leads to accumulation of hepatic fat

A drug that inhibits the microsomal triglyceride transfer protein lowers low-density lipoprotein (LDL) cholesterol and apolipoprotein B levels by about 50 percent in patients with familial hypercholesterolemia, but with elevation of liver aminotransferase levels and accumulation of hepatic fat, according to a study in the Jan. 11 issue of the New England Journal of Medicine.

Daniel J. Rader, M.D., from the University of Pennsylvania Medical Center in Philadelphia, and colleagues assessed the safety and efficacy of BMS-201038 in six patients with homozygous familial hypercholesterolemia. After discontinuation of lipid-lowering therapies for four weeks, patients received escalating doses of the drug (0.03, 0.1, 0.3 and 1.0 mg/kg of body weight per day), each for four weeks, followed by a four-week washout period.

The researchers found that all patients could tolerate the 1.0-mg dose, which significantly decreased the levels of LDL by 50.9 percent and apolipoprotein B by 55.6 percent. However, there was an increase in liver aminotransferase levels and hepatic fat accumulation of less than 10 percent to more than 40 percent at the highest dose.

"Inhibition of the microsomal triglyceride transfer protein by BMS-201038 resulted in the reduction of LDL cholesterol levels in patients with homozygous familial hypercholesterolemia, owing to reduced production of apolipoprotein B," Rader and colleagues conclude.

Bristol-Myers Squibb provided the drug for the study and one of the authors is an employee of the company. Rader has an equity interest in Aegerion Pharmaceuticals, which has the license to develop BMS-201038.

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Prison Inmates Have High Risk of Death After Release

Risk highest during the first two weeks

Prisoners have a more than threefold increased risk of death soon after being released from prison, with an almost 13-fold higher risk during the first two weeks, according to the results of a study published in the Jan. 11 issue of the New England Journal of Medicine.

Ingrid A. Binswanger, M.D., from the University of Colorado at Denver, and colleagues examined the mortality rates of 30,237 prisoners soon after their release from Washington State prisons from 1999-2003 and compared this with adjusted mortality rates of other state residents.

During a mean follow-up of 1.9 years, the researchers found that 443 inmates died, with an overall mortality rate of 777 per 100,000 person-years. The overall prisoner mortality rate was 3.5 times higher than state residents but was 12.7 times higher during the first two weeks after release, during which there was a markedly higher risk of death from drug overdose. Cardiovascular disease, drug overdose, homicide and suicide were the leading causes of death, the report indicates.

"Former prison inmates were at high risk for death after release from prison, particularly during the first two weeks," Binswanger and colleagues conclude.

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More HIV Treatment Failure After Perinatal Nevirapine

However, no significant difference observed if women initiate treatment at least six months after birth

HIV-infected women and their infants who are treated with a single dose of nevirapine to block HIV transmission at birth are at significantly higher risk of failing subsequent nevirapine-based treatment unless the woman begins treatment six months or more after birth, according to a report in the Jan. 11 issue of the New England Journal of Medicine.

Shahin Lockman, M.D., from Brigham and Women's Hospital in Boston, and colleagues studied 218 HIV-infected women from Botswana who had been given either placebo or a single dose of nevirapine before giving birth to prevent HIV transmission. The researchers examined the virologic failure rate after subsequent nevirapine-based treatment in both mothers and infants.

After six months of antiretroviral treatment, the investigators found that the overall virologic failure rate was significantly higher in women who had received nevirapine (18.4 percent versus 5 percent). Women who received antiretroviral treatment within six months of giving birth had a substantially higher failure rate (41.7 percent versus 0 percent), while there was no significant difference in the failure rate in women who started treatment at least six months after giving birth (7.8 percent for placebo versus 12 percent for nevirapine).

Similar results were observed in infants, with a significantly higher virologic failure rate six months after treatment in infants who had received nevirapine, the report indicates.

"Women who received a single dose of nevirapine to prevent perinatal transmission of HIV-1 had higher rates of virologic failure with subsequent nevirapine-based antiretroviral therapy than did women without previous exposure to nevirapine," the authors conclude. "However, this applied only when nevirapine-based antiretroviral therapy was initiated within six months after receipt of a single, peripartum dose of nevirapine."

The study was partially supported by Boehringer Ingelheim and GlaxoSmithKline.

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Drugs Prolong Survival in Advanced Renal Cancer

Sunitinib and sorafenib have similar mechanism of action

Two drugs with a similar mechanism of action, sunitinib and sorafenib, are effective at prolonging progression-free survival in patients with advanced renal-cell carcinoma, according to two studies in the Jan. 11 issue of the New England Journal of Medicine.

In the first study, Robert J. Motzer, M.D., from the Memorial Sloan-Kettering Cancer Center in New York City, and colleagues randomized 750 patients with untreated, metastatic renal-cell carcinoma to repeated six-week cycles of sunitinib or three injections per week of interferon-alfa. They found that sunitinib was associated with a significantly longer median progression-free survival (11 months versus five months) as well as a higher objective response rate (31 percent versus 6 percent). The study was supported by Pfizer.

In the second study, Bernard Escudier, M.D., from the Institut Gustave Roussy in Villejuif, France, and colleagues randomized 903 patients with advanced renal-cell carcinoma who had failed standard treatment to treatment with oral sorafenib twice a day or placebo. They found that the median progression-free survival was significantly higher in patients receiving sorafenib (5.5 months versus 2.8 months, hazard ratio 0.44). The sorafenib group also had a lower risk of death (HR, 0.72). However, sorafenib was associated with increased toxic side effects, the report indicates. The study was supported by Bayer Pharmaceuticals and Onyx Pharmaceuticals.

Noting that both drugs are small-molecule kinase inhibitors, James Brugarolas, M.D., Ph.D., from the University of Texas Southwestern Medical Center at Dallas, writes in an accompanying editorial that "clinical trials of sunitinib, sorafenib and temsirolimus in patients with advanced renal-cell carcinoma show how promising treatments can emerge from an understanding of the molecular genetics and biology of tumors."

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Herceptin for One Year May Boost Breast Cancer Survival

In women with HER2-receptor positive disease, the drug may reduce recurrence

Women with HER2-receptor positive breast cancer treated for one year with Herceptin (trastuzumab) after chemotherapy have improved two-year survival rates, according to a report published in the Jan. 6 issue of The Lancet.

Ian Smith, M.D., of the Royal Marsden Hospital in London, U.K., and colleagues analyzed data from a trial comprising 5,102 women with HER2-positive node-positive or high-risk node-negative breast cancer who were randomized to receive trastuzumab for one or two years or to be observed. Their study compared the outcomes for the 1,703 women who took trastuzumab for one year and the 1,698 women in the control group.

There were fewer deaths in the trastuzumab group: 59 versus 90 for the control group. The unadjusted hazard ratio (HR) for the risk of death with trastuzumab versus observation alone was 0.66. There were 218 and 321 disease-free survival events in the trastuzumab and observation groups, respectively (HR, 0.64).

"The survival benefit that has emerged over such a short period emphasizes the potential of this approach and underlines the importance of developing further specific targeted therapies in breast and other cancers," the authors conclude. However, an accompanying editorial points out that it remains to be seen whether long-term harm, including increased risk of heart failure, will outweigh the short-term benefits.

Several authors of the study have received honoraria or fees from Roche.

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Improvements in Neonatal Care Reduce Cerebral Palsy

Incidence among children with very low birth weight has dropped since 1980

The incidence of cerebral palsy among children with a birth weight of less than 1,500 grams has fallen thanks to improvements in neonatal care, according to study findings published in the Jan. 6 issue of The Lancet.

Mary Jane Platt, M.B., of the University of Liverpool in Liverpool, U.K., and colleagues analyzed data from 16 surveillance centers across Europe, comprising data on 1,575 very low birth weight infants who were born with cerebral palsy between 1980 and 1996. Of these, 414 (26 percent) weighed less than 1,000 g at birth, and 317 (20 percent) were from multiple pregnancies. The condition affected more boys than girls in the 1,000-1,499 g birth weight category.

In 1980, the prevalence of cerebral palsy among very low birth weight infants was 60.6 per 1,000 live births, falling to 39.5 per 1,000 in 1996. "Infants of birth weight less than 1,500 g, and in particular those of less than 1,000 g, now have a better chance of survival than previously, and more importantly, a better chance of survival without severe neurological impairment, which demonstrates that improvement in neonatal care has not resulted in increased survival at the cost of substantial morbidity," the authors conclude.

However, an accompanying editorial warns that there is little room for complacency as the disease is associated with severe physical disability and mental retardation.

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Gender Affects Heritability of Stroke

Women with female relatives who experienced ischemic stroke have a higher stroke risk

Women with female relatives who experienced an ischemic stroke are at higher risk of having a stroke than men with affected relatives, independent of traditional risk factors, according to the results of a study published online Dec. 22 in the Lancet Neurology.

Peter M. Rothwell, F.R.C.P., and Emmanuel Touze, M.D., from the Radcliffe Infirmary in Oxford, U.K., examined the role of gender in the heritability of ischemic stroke using data on 806 probands from a population-based study.

The researchers found that women were more likely to have an affected first-degree relative (odds ratio, 1.4), which was almost entirely due to having more affected female relatives. Women were more likely to have a history of stroke in mothers rather than fathers (OR, 1.8) and in sisters rather than brothers (OR, 3.1). Among affected females, there was a correlation between age at first stroke and having more affected female relatives. Traditional risk factors and stroke subtype did not affect the results, the investigators found.

"Heritability of ischemic stroke is greater in women than in men, with an excess of affected mothers and affected sisters in female probands independent of traditional vascular risk factors, which could be explained by sex-specific genetic, epigenetic, or non-genetic mechanisms," Rothwell and Touze conclude.

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Advanced Management Saved Terror Victims' Lives

Robust trauma system helped reduce critical mortality after the 2005 London bombings

After the July 7, 2005 terrorist bombings in London, a fast and effective medical response helped reduce deaths among critically injured patients, according to a study published in the Dec. 23/30 issue of The Lancet.

Karim Brohi, M.D., of the Royal London Hospital in the U.K., and colleagues conducted a retrospective analysis of the London-wide prehospital response and the in-hospital response of one academic trauma center.

The researchers found that there were 775 casualties and 56 deaths (53 at the scene). Of 55 patients who were triaged to priority dispatch, 20 were critically injured. The investigators found that the Royal London's Helicopter Emergency Medical Service (London-HEMS) achieved 33 percent over-triage rates at Aldgate and King's Cross, which was significantly lower than the 89 percent rate seen after the Madrid train bombing in March 2004. They also found that the 15 percent death rate among critically injured patients was lower than that seen during most previous terrorist attacks.

"Critical mortality was reduced by rapid advanced major incident management and seems unrelated to over-triage," the authors conclude. "Hospital surge capacity can be maintained by repeated effective triage and implementing a hospital-wide damage control philosophy, keeping investigations to a minimum, and transferring patients rapidly to definitive care."

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New Flu Pandemic Could Kill 62 Million People

Researchers' analysis of 1918-1920 pandemic suggests that the toll would be highest in the developing world

An influenza pandemic similar to the one that occurred in 1918-1920 would kill 62 million people in just one year and strike poorer nations the hardest, according to a report published in the Dec. 23/30 issue of The Lancet.

Christopher Murray, M.D., Ph.D., of Harvard University in Cambridge, Mass., and colleagues used death registration data to calculate excess mortality during the 1918-1920 influenza pandemic and developed ordinary least squares regression models to estimate excess mortality during a hypothetical 2004 pandemic.

The researchers found that population mortality in the 1918 outbreak varied over 30-fold across 27 nations and was highest in poorer countries. They estimated that a similar pandemic in 2004 would have killed 62 million people (10th-90th percentile range 51-81 million), 96 percent of them in the developing world.

"So what can be done to mitigate the depressingly familiar wealth-related distribution of disease burden predicted by Murray and colleagues?" asks the author of an accompanying comment. "Access to vaccines, antivirals and antibiotics for the most vulnerable populations is clearly part of the solution."

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New Filtration Device Removes Prions from Blood

Animal study suggests it could be used to prevent transmission of variant Creutzfeldt-Jakob disease

A new filtration device can effectively remove disease-causing prions from scrapie-infected animal blood and could be used to remove prions from variant Creutzfeldt-Jakob disease (vCJD)-infected human blood, according to a study published in the Dec. 23/30 issue of The Lancet.

Robert Rohwer, Ph.D., of the Veterans Affairs Medical Center at the University of Maryland in Baltimore, and colleagues identified an affinity resin -- L13 -- that selectively binds the prion protein.

The researchers injected white blood cell-depleted, scrapie-infected blood into 99 hamsters, 15 of which became infected. After filtering infected blood through a device containing L13, they injected another 96 hamsters, none of which became infected. They also found that L13 could selectively bind to prion protein from vCJD.

"This builds on previous work by this group and others showing that prion reduction via filtration could reduce the risk of transmitting vCJD by blood transfusion," states the author of an accompanying comment. "The U.K. and Irish Blood Services have produced quality, efficacy, and operational specifications for such filters and are considering an assessment program that will include independent investigation of efficacy and clinical safety studies."

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Folic Acid Supplements May Curb Hearing Loss

Study of older Dutch residents shows folate supplements may slow low-frequency hearing loss

A study of older Dutch residents during a time when food was not fortified with folate suggests that folic acid supplementation may slow age-related hearing loss, according to a report in the Jan. 2 issue of the Annals of Internal Medicine.

Jane Durga, Ph.D., of Wageningen University in the Netherlands, and colleagues conducted a double-blind, randomized, placebo-controlled trial of folic acid supplements in 728 older Dutch men and women from 2000 to 2004. Folic acid fortification of food was prohibited in the Netherlands during this time so the baseline folate levels were about half of those found in the U.S. population.

The investigators found that supplementation with 800 micrograms of daily oral folic acid for three years slowed decline in hearing of low frequencies by 0.7 dB but had no affect on hearing at higher frequencies.

If the improvements are confirmed in other studies, folic acid supplementation could be an inexpensive way to curb hearing loss in populations with folic acid deficiency, notes Robert Dobie, M.D., University of California-Davis, in an accompanying editorial. The results might also provide "just enough justification for dietary folate supplementation to convince nations that do not now require it," he writes.

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Moderate Drinking OK for Hypertensive Men

Study suggest one to two drinks per day does not increase risk for cardiovascular events

New research suggests that men with high blood pressure can have one or two drinks a day without increasing their risk for myocardial infarction or stroke, according to a report in the Jan. 2 issue of the Annals of Internal Medicine.

Joline Beulens, M.Sc., of Wageningen University in the Netherlands, and colleagues conducted a prospective cohort study of 11,711 men with hypertension to determine if self-reported alcohol consumption affected their risk of cardiovascular disease. From 1986 to 2002, the participants submitted questionnaire responses regarding food frequency and cardiovascular events.

The investigators found that moderate drinkers, consuming 12.5 grams of alcohol or about one drink per day, had an adjusted hazard ratio for myocardial infarction of 0.68 and a significant trend was observed for increased alcohol consumption. There was no effect on prevalence of stroke.

The authors conclude that men who drink "moderately and safely may not need to change their drinking habits." In an accompanying editorial, Anne Thiebaut, Ph.D., of the National Cancer Institute in Bethesda, Md., and colleagues discuss the importance of correcting for error in measurements when presenting studies with nutritional recommendations.

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Heavy Staff Workload on Admission Bad for Patients

The heavier the workload at admission, the worse the patient outcome

Patients who are admitted to the hospital on days when health care teams have high workloads tend to use more resources and have an increased risk of mortality compared to those admitted on less busy days, according to study findings published in the Jan. 8 issue of the Archives of Internal Medicine. However, patients treated by teams that have heavy workloads during other days of the patient's hospital stay are at no higher risk, and use fewer resources.

Michael Ong, M.D., Ph.D., of the University of California Los Angeles, and colleagues analyzed data on 5,742 adult inpatients at an academic general medical service to assess the impact of workload on length of stay, costs of care and inpatient mortality.

For each additional patient admitted by the team, (which consisted of an attending physician, resident and one or two interns) on the patient's admission day, there were increases in length of stay (difference, 3.09 percent), total costs of care (difference, 2.31 percent) and inpatient mortality risk (odds ratio, 1.09). The trend on length of stay and total costs was reversed when the patient's entire length of stay was analyzed. Over the patient's entire stay, increased patient load reduced total costs and length of stay.

"Programs seeking to minimize total costs and lengths of stay may want to find ways to reduce team admission loads, while maximizing availability of other resources on non-admitting days," the authors write. "Balancing the clinical and economic outcomes with available resources and the educational impact of changes in the organization of house staff teams will be important tasks for training programs and teaching hospitals in coming years," they conclude.

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Family and Friends Main Source of End-of-Life Care

Most found it rewarding despite large time commitment and little support

Most end-of-life care is provided by family and friends rather than by formal caregivers, researchers report in the Jan. 8 issue of the Archives of Internal Medicine.

Jennifer L. Wolff, Ph.D., and colleagues at the Johns Hopkins Bloomberg School of Health in Baltimore, analyzed data from the 1999 National Long-Term Care Survey and its Informal Caregivers Survey, covering 1,149 primary caregivers who were followed-up for a maximum of 12 months.

Among the 11.2 percent of care recipients who died within a year of the surveys, 72.3 percent were under the care of a primary informal caregiver who provided an average of 43 hours of care a week. Over 84 percent of carers provided help on a daily basis, and less than 5 percent of caregivers called on respite care or support groups.

Women accounted for three-quarters of the carers and just under half were spouses, while 39 percent were children and 19.5 percent were of another type of relationship. End-of-life caregivers reported significant emotional (28.9 percent), physical (18.4 percent) and financial (14 percent) strains, and more than two-thirds endorsed personal rewards related to their helping role.

"These data underscore the relevance of families to end-of-life care, and the potential benefit of better integrating families in patient care," the authors conclude.

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Research on Specialists Versus Generalists Full of Flaws

Poor research quality means it is impossible to make valid comparisons of patient outcomes

Research that aims to assess the relative merits of specialist care versus generalist care for discrete conditions is full of flaws and not a useful health care policy tool, according to a report published in the Jan. 8 issue of the Archives of Internal Medicine.

Gerald W. Smetana, M.D., of Beth Israel Deaconess Medical Center in Boston, and colleagues conducted an analysis of 49 studies of clinical outcomes when discrete conditions are treated under specialist or generalist care. Specialty care was found to achieve better outcomes in 24 studies, while 13 concluded that there was no difference, seven varied by individual outcome, one depended on physician experience and four concluded in favor of generalist care.

However, the methodology of the studies was found lacking: the factor of integration into health systems was only taken into consideration in eight studies, while only two assessed the effect of care management programs, four looked at the experience of the physicians and three considered the role of information technology support.

"Studies that favored specialty care were less likely to consider four key, potentially confounding physician or practice characteristics compared with studies that found no difference or favored generalist care," the authors write. "Further research is needed to inform health care policy as it pertains to the optimal role of generalists and specialists in the physician marketplace."

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Mistletoe Extract Injections Mimic Metastatic Cancer

Patient-administered homeopathic remedy caused abdominal mass

A lymphoma patient who self-administered mistletoe extract injections developed an inflammatory non-malignant abdominal mass that mimicked metastatic malignancy, according to a case report in the Dec. 23 issue of BMJ.

Alison Finall, of Cardiff and Vale NHS Trust in Cardiff, Wales, and colleagues microscopically analyzed the 4x2x2 cm subcutaneous tissue mass, which was removed from the 61-year old woman. She had injected subcutaneous aqueous whole plant mistletoe extract (Abnoba viscum fraxini) as complementary therapy to treat her lymphoma, which was diagnosed in April 2001, and was stable after five chemotherapy cycles. She had injected 20 mg three times weekly for 12 months before presentation.

Microscopic evaluation showed a large proportion of eosinophils and normal lymphocytes. Immunohistochemistry confirmed normal T cell and B cell distribution. Further tests confirmed a reactive lymphoid infiltrate with no sign of follicular lymphoma. Lymphocytes and eosinophils, present within small blood vessel walls, indicated vasculitis.

"In summary, we found no evidence of malignancy after the tissue was examined microscopically on multiple levels," the authors conclude. "Mistletoe has been tested extensively as a treatment for cancer, but the most reliable randomized controlled trials fail to show benefit, and some reports show considerable potential for harm," according to an accompanying editorial.

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Drug-Eluting Stents May Impair Growth of Collateral Vessels

Study suggests that collateral vessel formation may be lower than with bare-metal stents

As the U.S. Food and Drug Administration evaluates the safety of drug-eluting stents, a new study suggests that such stents may impair collateral vessel formation in the months after implantation compared with bare-metal stents, according to a report in the Jan. 2 issue of the Journal of the American College of Cardiology.

Pascal Meier, M.D., of University Hospital in Bern, Switzerland, and colleagues compared coronary collateral function among 120 patients six months after bare-metal stent or drug-eluting stent implantation.

There were no differences in the groups in regards to in-stent stenosis severity and/or duration of follow-up. However, the collateral flow index was reduced in the drug-eluting stent group compared to bare-metal stent group (0.154 versus 0.224). Patients with drug-eluting stents were more likely to have insufficient vessel formation to prevent ST-segment elevation during balloon occlusion (50 of 60 patients) than those in the bare-stent group (33 of 60).

The researchers hypothesize that drug-eluting stents have an inhibitory effect on the production of cytokines, chemotactic proteins and growth factors, and as a result, may impair coronary collateral growth. "Although it is still of largely theoretical concern, should abrupt late occlusion occur after drug-eluting stent, the normal collateral protection would be impaired to some degree, with more ischemia potentially permitting a larger ischemic insult and higher mortality risk than would otherwise occur," writes Morton J. Kern, M.D., of the University of California-Irvine, in an accompanying editorial.

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One-Third of ICD Patients May Not Benefit; Test Can Tell

All-cause mortality risk reduction benefit seen in patients with non-negative test for microvolt T-wave alternans

About one-third of patients who receive an implantable cardioverter-debrillator (ICD) treatment don't get the reduction in mortality seen in other patients, and a pre-implantation test for microvolt T-wave alternans can determine which patients will benefit, according to a study in the Jan. 2 issue of the Journal of the American College of Cardiology.

Theodore Chow, M.D., of the Lindner Clinical Trial Center at the Christ Hospital in Cincinnati, Ohio, and colleagues evaluated a prospective cohort of 768 ischemic cardiomyopathy patients, 392 of whom received ICDs. The patients had no prior history of ventricular arrythmia and had ejection fractions of 35 percent or lower.

Overall, 67 percent of patients had non-negative (indeterminate) results for microvolt T-wave alternans. In those patients, ICD implantation was associated with a 55 percent reduction in all-cause mortality. Patients who were negative for microvolt T-wave alternans did not show a significant benefit, however. The number needed for ICD treatment to save one life was 9 in the non-negative patients and 76 in the negative patients.

"In patients with ischemic cardiomyopathy and no prior history of ventricular arrhythmia, mortality reduction with ICD implantation differs by microvolt T-wave alternans status, with implications for risk stratification and health policy," the authors conclude.

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Heart Problems Can Persist in Hyperthyroidism Patients

Even with antithyroid treatment, palpitations, dypsnea, cough and other symptoms can linger

Patients with overt hyperthyroidism often have cardiovascular anomalies when they initially see a physician, and these symptoms can persist even with antithyroid treatment, researchers report in the Jan. 2 issue of the Journal of the American College of Cardiology.

Faizel Osman, M.D., of the University of Birmingham in England, and colleagues compared cardiac symptoms in 312 women and 81 men with overt hyperthyroidism and 393 matched euthyroid controls. Results were compared at recruitment, post treatment in patients with biochemical subclinical hyperthyroidism, and after antithyroid therapy when patients had become euthyroid.

The researchers found that hyperthyroid patients exhibited more cardiovascular anomalies and had more cardiac symptoms at first presentation than controls, especially supraventricular cardiac dysrhythmia. Treated subclinical hyperthyroidism patients had atrial fibrillation, palpitation, dyspnea, and a drop in systolic pressure more often than controls, even after being chemically rendered euthyroid.

Lower blood pressure at presentation and hypothyroidism caused by antithyroid treatment forecast the successful restoration of sinus rhythm in patients with atrial fibrillation connected to hyperthyroidism, the researchers report.

"Cardiovascular abnormalities are common in patients with overt hyperthyroidism at presentation, but some persist despite effective antithyroid therapy," the authors write.

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Iron Deficiency Anemia Common in Heart Failure Patients

Deficiency responsible in about three-quarters of cases

The cause of anemia in about three-quarters of patients with congestive heart failure is iron deficiency, according to study findings published in the Dec. 19 issue of the Journal of the American College of Cardiology.

John N. Nanas, M.D., Ph.D., from the University of Athens School of Medicine in Greece, and colleagues investigated the causes of anemia in 37 patients who were hospitalized for decompensated advanced congestive heart failure and had clinically significant anemia (hemoglobin less than 12 g/dL for men and less than 11.5 g/dL for women).

The researchers found that 73 percent of patients had iron deficiency anemia, 5.4 percent had dilutional anemia, 2.7 percent had drug-induced anemia and the remaining 18.9 percent had no specific cause and were considered to have "anemia of chronic disease."

"In this group of patients, iron deficiency was the most common cause of anemia," the authors conclude. "The iron status of patients with end-stage chronic congestive heart failure should be thoroughly evaluated and corrected before considering other therapeutic interventions."

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Insulin Resistance Linked to Platelet Activation

Can be improved by weight loss, drugs to improve insulin sensitivity in obese women

Insulin resistance in obese women is associated with high platelet activation, which can be improved by weight loss or drug treatment to improve insulin sensitivity, researchers report in the Dec. 19 issue of the Journal of the American College of Cardiology.

Giovanni Davi, M.D., from the University of Chieti in Italy, and colleagues investigated whether insulin resistance contributes to increased platelet activation independent of underlying inflammation in 40 obese women and 20 non-obese healthy women.

The researchers found that the waist-to-hip ratio and insulin sensitivity index predicted the 11-dehydro-thromboxane B2 excretion rate (a marker of platelet activation) independently of CD40 ligand, lipid patterns, adiponectin and C-reactive protein.

After a 12-week weight-loss program, the five subjects who succeeded in losing weight had a 92 percent improvement in the insulin sensitivity index, and decreases of 27 percent, 37 percent and 53 percent in CD40 ligand, C-reactive protein and urinary 11-dehydro-thromboxane B2, respectively. Treatment with pioglitazone to improve insulin sensitivity also led to a 43 percent decrease in urinary 11-dehydro-thromboxane B2 while maintaining body weight.

"Insulin resistance is a major determinant of platelet activation in female obesity," Davi and colleagues conclude.

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Congenital Heart Disease on the Rise in the United States

Among adults, severe disease rose by 85 percent from 1985 to 2000

Congenital heart disease has increased in the general U.S. population from 1985 to 2000, according to a report in the Jan. 16 issue of Circulation: Journal of the American Heart Association. This is the first study to present empirical data on the changing epidemiology of congenital heart disease.

In the study, Ariane J. Marelli, M.D., of McGill University Health Center in Montreal, Quebec, Canada, and colleagues used administrative databases from universal health care systems that recorded diagnoses and claims of congenital heart disease to determine the prevalence, age distribution and proportion of adults and children with severe forms of the disease in the U.S. population from 1985 to 2000.

The investigators found that severe congenital heart disease rose by 85 percent in adults and 22 percent in children during this time. The median age of patients with congenital heart disease rose from 11 years in 1985 to 17 years in 2000.

"These data underscore the published estimates and recommendations stating that more specialized care facilities for adults with congenital heart disease are necessary to meet the needs of this growing patient population," the authors write.

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Early Signs of Cardiac Decline Found in Some Young Adults

Cardiac structural changes apparent in young population prone to obesity, diabetes

Preclinical cardiac structural changes are apparent in young subjects who are overweight or diabetic and have signs of hypertension, according to study findings published in the Jan. 16 issue of Circulation: Journal of the American Heart Association.

Richard B. Devereux, M.D., of New York Presbyterian Hospital in New York City, and colleagues analyzed clinical characteristics, hemodynamics and cardiac structure and function in 1,940 American Indian subjects, aged 14 to 39 years, who have a high prevalence of obesity, diabetes and hypertension.

Hypertension and prehypertension occurred in 15 and 35 percent of the population, respectively, and were more common in men, older subjects and those who also had diabetes. Both prehypertensive and hypertensive subjects had increased left ventricular wall thickness, left ventricular mass, relative wall thickness, and higher prevalences of left ventricular hypertrophy than normotensive subjects.

"Our results show that even small elevations in blood pressure, as seen with prehypertension, can have detrimental effects on hemodynamics and cardiovascular structure and function in an adolescent and young adult American Indian population with many of the same risk factors plaguing the United States and industrialized countries around the world," the authors write.

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Cardiovascular Disease Kills One-Third of Americans

New statistics show that prevalence varies by region

Cardiovascular disease accounted for more than one-third of U.S. deaths in 2004, with prevalence varying by region, according to the American Heart Association's Heart Disease and Stroke Statistics - 2007 Update, published online Dec. 28 in Circulation: Journal of the American Heart Association.

The data show that the burden from cardiovascular disease (CVD), which includes heart disease, stroke, hypertension, heart failure and congenital defects, varies nationwide. Mississippi had the highest rate of deaths from CVD (405.9 per 100,000) while Minnesota has the lowest (221.2 per 100,000).

Between 1994 and 2004, the rate of deaths from stroke fell by 20.1 percent and the actual number of stroke deaths fell by 2.1 percent. This also varied by region, with a higher prevalence of strokes in 10 southeastern states. In 2005, 25.5 percent of respondents reported having hypertension.

The report notes that obesity reduces life expectancy, with overweight and obese 40-year-old non-smokers losing three to seven years. Obesity is also increasing among children, ranging from 14 to 17.5 percent, and the prevalence of metabolic syndrome is rising, affecting 23.7 percent of adults and 4.2 percent of adolescents. Meanwhile, diabetes is on the rise, the report indicates, with 1.5 million new cases diagnosed in adults in 2005. And while children are exposed to less secondhand smoke, smoking continues to reduce life expectancy in adults.

"There's still room for improvement," chair of the AHA Statistics Committee Wayne Rosamond, Ph.D., noted in a statement. "Changes in lifestyle behaviors such as healthy diet and exercise could reduce the burden of CVD."

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Beta-Blockers May Suppress Central Sleep Apnea

Small study suggests the drugs may improve apnea in patients with chronic heart failure

Beta-blocker therapy may have a dose-dependent effect in the suppression of central sleep apnea in patients with chronic heart failure, according to the results of a study published in the January issue of Chest.

Akira Tamura, M.D., of Oita University in Oita, Japan, and colleagues performed polysomnography on 45 patients with chronic heart failure.

The researchers found that the 27 patients who took beta-blockers had a significantly lower apnea-hypopnea index and central apnea index than the 18 patients who did not take beta-blockers, and saw the greatest benefits in patients who took the highest doses. After conducting serial sleep studies on five patients who initiated beta-blocker therapy, they found that the central apnea index significantly decreased after six months of treatment.

"Considering the results of the present study and beneficial effects of beta-blocker therapy on mortality in chronic heart failure, widespread use of beta-blockers may modify the prevalence and prognostic significance of central sleep apnea in patients with chronic heart failure," the authors write. "The impact of beta-blockers on central sleep apnea remains to be clarified in patients with chronic heart failure."

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Sleep Apnea Linked to Family History of Premature Death

Association persists whether or not patients have coronary artery disease risk factors

Patients with obstructive sleep apnea are more than twice as likely as patients without obstructive sleep apnea to have a family history of premature coronary artery disease mortality, according to study findings published in the January issue of Chest.

Between May 2000 and June 2004, Virend K. Somers, M.D., Ph.D., of the Mayo Clinic College of Medicine in Rochester, Minn., and colleagues studied 588 patients who underwent polysomnography, which confirmed obstructive sleep apnea in 316 patients and excluded it in 202 patients.

The researchers calculated an unadjusted odds ratio of 2.11 for obstructive sleep apnea and a family history of premature coronary artery disease mortality. After adjusting for each patient's sex, body mass index and history of coronary artery disease, they still found a significant and independent association between obstructive sleep apnea and a family history of premature coronary artery disease mortality (OR, 2.13).

"These findings suggest that individuals with obstructive sleep apnea, regardless of whether they are healthy or have coronary artery disease risk factors, have an increased risk of coronary artery disease that is partly due to presently unknown familial factors acting independently of traditional coronary artery disease risk factors," the authors conclude.

Dr. Somers is a consultant for Respironics and has received honorarium from ResMed.

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Hospital Transfers Affect Standardized Mortality Ratio

Transferring even a few critically ill patients out of a hospital can artificially improve these benchmarks

Transferring even a few critically ill patients out of a hospital can significantly improve an intensive care unit's standardized mortality ratio, or SMR, and lead to an incorrect assumption of ICU quality, according to a simulation study published in the January issue of Chest.

Jeremy M. Kahn, M.D., of the University of Pennsylvania School of Medicine in Philadelphia, and colleagues used 2002-2003 data to calculate the mean SMR for 85 ICUs. During the simulation, they randomly transferred a set number of patients and recalculated the mean SMR.

The researchers found that the mean baseline SMR was 1.06. During the simulation, they found that increasing the number of transfers by 2 percent and 6 percent over baseline decreased the mean SMR by 0.10 and 0.14, respectively. They also found that a 2 percent increase in transfers resulted in a SMR decrease of greater than 0.10 at 27 ICUs and a decrease of greater than 0.20 at two ICUs. According to their calculations, transferring just one additional patient per month was sufficient to create a bias of greater than 0.10 in 27 ICUs.

"Uncritical use of the SMR to benchmark ICU performance is likely to misinform rather than provide meaningful information about ICU quality," the authors conclude. "ICU directors and administrators can monitor the number of transfer patients as a potential explanation for a decreasing SMR."

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Florida Red-Tide Aggravates Asthma Symptoms

Symptoms worse in subjects regularly taking asthma medications

Toxins from Florida red-tide microalgae aggravate respiratory symptoms in people with asthma, particularly those regularly taking asthma medications, according to a report in the January issue of Chest.

Lora E. Fleming, M.D., Ph.D., from the University of Miami School of Medicine in Florida, and colleagues examined whether red-tide (marine microalgae Karenia brevis) aggravates asthma. They assessed respiratory parameters in 97 individuals at least 12 years old with asthma one hour before and after aerosol exposure or no exposure to red tides.

The researchers found that red-tide exposure significantly increased the likelihood of subjects reporting respiratory symptoms. There were small but significant decreases in forced expiratory volume in one second and forced expiratory flow after exposure, particularly in subjects who regularly used asthma medications.

"This study demonstrated objectively measurable adverse changes in lung function from exposure to aerosolized Florida red-tide toxins in asthmatic subjects, particularly among those requiring regular therapy with asthma medications," Fleming and colleagues conclude.

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Prepared jointly by the editors of Medical Economics and HealthDay's Physicians' Briefing (www.physicianbriefing.com)

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