NSAID Use Associated With Future Stroke in Healthy Population

September 8, 2010 (Stockholm, Sweden) — Short-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an increased risk of stroke in a Danish population study including only healthy individuals.
Presenting the study at last week's European Society of Cardiology (ESC) 2010 Congress, Dr Gunnar Gislason (Gentofte University Hospital, Hellerup, Denmark) said the results could have "massive public-health implications."
"First we found an increased risk of MI with NSAIDs. Now we are finding the same thing for stroke. This is very serious, as these drugs are very widely used, with many available over the counter," Gislason told heartwire . "We need to get the message out to healthcare authorities that these drugs need to be regulated more carefully."
Cochair of the session at which the study was presented, Dr Robert Califf (Duke Clinical Research Institute, Durham, NC), agreed that the results raised a major public-health issue, especially in the US, where many NSAIDs were available without a prescription.
For the current study, Gislason and colleagues examined the risk of stroke and NSAID use in healthy individuals living in Denmark. He explained to heartwire that information on each individual in the Danish population is kept in various national registries. His team started with the whole population of Denmark aged over 10 years. To select just the healthy individuals, they excluded anyone admitted to the hospital within the past five years or those prescribed chronic medications for more than two years. This left a population of around half a million, who were included in the study. By linking to prescribing registries, the researchers found that 45% of these healthy individuals had received at least one prescription for an NSAID between 1997 and 2005. They then used stroke data from further hospitalization and death registries and estimated the risk of fatal and nonfatal stroke associated with the use of NSAIDs by Cox proportional-hazard models and case-crossover analyses.
Results showed that NSAID use was associated with an increased risk of stroke. This increased risk ranged from about 30% with ibuprofen and naproxen to 86% with diclofenac.
Risk of Stroke With Various Nsaids

NSAID	HR (95% CI) for risk of stroke
Ibuprofen	1.28 (1.14–1.44)
Diclofenac	1.86 (1.58–2.19)
Rofecoxib	1.61 (1.14–2.29)
Celecoxib	1.69 (1.11–2.26)
Naproxen	1.35 (1.01–1.79)

Gislason noted that there was also a dose-relationship found, with the increased risk of stroke reaching 90% (HR 1.90) with doses of ibuprofen over 200 mg and 100% (HR 2.0) with diclofenac doses over 100 mg. He pointed out that the results were particularly striking, given that this study was conducted in healthy individuals.
He conceded that his results could have some confounding but noted that the data were controlled for age, gender, and socioeconomic status and the patient population did not include those with chronic diseases. "We also have to think about the degree of confounding needed to nullify risk. It would have to increase risk four- to fivefold, which is very unlikely," he commented.
He said he did not find the results that surprising in view of the accumulating evidence of increased MI risk with these drugs, adding that the mechanism was probably the same. There have been several hypotheses about the mechanism linking NSAIDs with cardiovascular events, including increased thrombotic effect on platelets, the endothelium, and/or atherosclerotic plaques; increasing blood pressure; and effect on the kidneys and salt retention.
Gislason told heartwire that there is reluctance among the medical profession to limit the prescribing of these drugs. "The problem is that we don't have randomized trials, and it is very hard to change the habits of doctors. They have been using these drugs for decades without thinking about cardiovascular side effects."
He also stressed that the public needs to be protected by not allowing NSAIDs to be bought without a prescription. He has had some success in this regard in Denmark at least, where diclofenac became available over the counter recently, but after some of the MI data came out, Gislason's group campaigned the health authorities, and it has now become a prescription-only drug again. But he noted that many more NSAIDs are available over the counter in the US.
He believes the harmful effects of these agents are relevant to huge numbers of people. "If half the population takes these drugs, even on an occasional basis, then this could be responsible for a 50% to 100% increase in stroke risk. It is an enormous effect."
These results have been partly published in Circulation: Cardiovascular Quality and Outcomes earlier this year [1]. Gislason told heart wire that the novelty of the results presented at the ESC meeting was that "we had further analyzed our data regarding specific stroke and looked at the risk of ischemic stroke, and we confirmed that the risk of ischemic stroke was substantially elevated." He added: "We are in the process of analyzing these data related to time to risk and the effect of duration of treatment on stroke risk."

Metformin Might Prevent Colorectal, Lung Cancers

September 3, 2010 — The chance observation that diabetes patients taking metformin have a 40% reduced risk for cancer triggered intense research interest in this old off-patent drug.
Data from a small clinical trial and from an animal study reported in the September issue of Cancer Prevention Research suggest that metformin might suppress the development of precancerous colorectal lesions in humans and prevent tobacco-induced lung cancers in mice. The drug appears to alter cellular energy metabolism in a way that is particularly bad for cancers and precancerous cells. It is also attractive because it is relatively nontoxic.
During a press briefing organized by the American Association for Cancer Research to discuss the metformin data, Michael Pollak, MD, from McGill University in Montreal, Quebec, said that the new studies are important because they indicate the usefulness of metformin as a preventive agent. Dr. Pollak wrote a review of metformin and other biguanides in oncology that appears in the same issue of Cancer Prevention Research.
"Unlike chemotherapy or radiotherapy, which are intended to kill cancer cells in a directly toxic manner, metformin appears to target the cancer in a more subtle way, which involves cancer energetics. It also may act in some patients, especially diabetic cancer patients, by reducing levels of hormones that can stimulate cell growth, including insulin itself," Dr. Pollak said.
In the first human trial of metformin as a cancer preventive, Kunihiro Hosono, MD, and colleagues from the Yokohama City University School of Medicine in Japan report that nondiabetic patients randomized to 1 month of low-dose of metformin (250 mg/day) had a significant decrease in the mean number of rectal aberrant crypt foci (ACF), an endoscopic surrogate marker of colorectal cancer.
The researchers randomized 12 nondiabetic patients with ACF to treatment with metformin and 14 to no treatment. After 1 month, the metformin patients not only had fewer ACFs, they also had significant decreases in the proliferating cell nuclear antigen index.
Dr. Hosono and colleagues write that "this first reported trial of metformin for inhibiting colorectal carcinogenesis in humans provides preliminary evidence that metformin suppresses colonic epithelial proliferation and rectal ACF formation in humans, suggesting its promise for the chemoprevention of colorectal cancer."
Low-dose metformin did not cause any adverse effects, such as lactic acidosis, hypoglycemia, or diarrhea in this study.
In related work, a research team led by Phillip A. Dennis, MD, and Regan M. Memmott, MD, from the National Cancer Institute (NCI) Medical Oncology Branch in Bethesda, Maryland, studied metformin for prevention in a mouse model of smoking-related lung cancer. They exposed mice to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and then treated the mice with metformin in drinking water.
The researchers expected that a specific target (the rapamycin or mTOR pathway, an early event in tobacco-induced lung cancer) would be inhibited by metformin.
"After about 10% of the mouse lifespan — about 12 weeks — with the highest dose in the drinking water, we found a 33% reduction in tumor multiplicity and a 34% reduction in tumor size in the mice. In mice that did not get metformin, 100% got tobacco carcinogen-induced lung tumors," Dr. Dennis said at the press briefing. Overall, metformin reduced lung tumor burden by up to 53% at steady-state plasma concentrations that can be achieved in humans.
Despite this, mTOR was only modestly inhibited, so the researchers moved to intraperitoeal administration to achieve higher dose levels. This showed that metformin activated 5′-AMP-activated protein kinase in liver tissue (but not lung tissue), where it inhibited phosphorylation of the insulin-like growth factor (IGF)-1/insulin receptor. Mice injected with metformin daily for 12 weeks had a 72% reduction in tumor burden.
"We think that metformin was able to inhibit lung tumorigenesis caused by a tobacco carcinogen — when given in drinking water to achieve levels that could be attained in humans and when given by injection — and that the mechanism involves hormone release from the liver. We are planning to move forward to study metformin as a chemopreventive agent in clinical trials," Dr. Dennis said.
Lewis Cantley, MD, from Beth Israel Deaconess Medical Center in Boston, Massachusetts, suggested at the press briefing that metformin might prevent tumors by reducing levels of insulin and IGF-1. He noted that 2 approaches to treating type 2 diabetes (insulin, which increases insulin levels, and metformin, which decreases them) appear to have opposite effects on cancer risk.
Dr. Pollak said that "metformin's effects in animals are similar to those of a brief period of fasting. On a normal diet, metformin fools the liver into thinking it is fasting."
It fell to Dr. Cantley to mention the elephant in the room: metformin is off patent and unlikely to attract pharmaceutical industry support for clinical trials to established the drug as a general cancer preventive. "This will have to have millions of dollars in either private or NCI support," he said.
Dr. Pollak reports consulting for Merck, Novo-Nordisk, Lilly, Pfizer, and Sanofi-Aventis. Dr. Hosono and Dr. Dennis have disclosed no relevant financial relationships. Dr. Cantley is founder of and a consultant for Agios.
Cancer Prev Res (Phila Pa). 2010;3:1049-1052, 1060-1065, 1066-1076, 1077-1083.

Artificially Sweetened Soft Drinks Linked to Preterm Delivery

August 31, 2010 — Daily consumption of artificially sweetened soft drinks may increase the risk for preterm delivery, according to the results of a Danish prospective cohort study reported in the September issue of the American Journal of Clinical Nutrition.
"Sugar-sweetened soft drinks have been linked to a number of adverse health outcomes such as high weight gain," write Thorhallur I. Halldorsson, from Statens Serum Institut in Copenhagen, Denmark, and colleagues. "Therefore, artificially sweetened soft drinks are often promoted as an alternative. However, the safety of artificial sweeteners has been disputed, and consequences of high intakes of artificial sweeteners for pregnant women have been minimally addressed."
The goal of the study was to evaluate the association between consumption of sugar-sweetened and artificially sweetened soft drinks and preterm delivery.
Participants were 59,334 women enrolled in the Danish National Birth Cohort from 1996 to 2002. With use of a food frequency questionnaire, soft drink consumption was evaluated in midpregnancy, and telephone interviews determined covariate information. The main study endpoint was preterm delivery, defined as less than 37 weeks of gestation.
Consumption of artificially sweetened carbonated and noncarbonated soft drinks was associated with an increased risk for preterm delivery (P for trend ≤ .001 for both variables). Compared with women who did not drink artificially sweetened carbonated soft drinks, the adjusted odds ratio (OR) for women who drank at least 1 serving daily was 1.38 (95% confidence interval [CI], 1.15 - 1.65), and the adjusted OR for women who drank at least 4 servings daily was 1.78 (95% CI, 1.19 - 2.66). These associations were noted in normal-weight as well as in overweight women. Increased risk was stronger for early preterm and moderately preterm delivery vs late-preterm delivery.
For sugar-sweetened carbonated or noncarbonated soft drinks, no apparent association with the risk for preterm delivery was observed.
"Daily intake of artificially sweetened soft drinks may increase the risk of preterm delivery," the study authors write. "Further studies are needed to reject or confirm these findings."
Limitations of this study include possible reverse causality, inability to implicate specific artificial sweetener(s), observational design, and unidentified or residual confounders.
"The relative consistency of our findings for carbonated and noncarbonated soft drinks and the absence of an association for sugar-sweetened soft drinks suggest that the content of artificial sweeteners might be the causal factor," the study authors conclude. "However, the replication of our findings in another experimental setting is warranted."
The European Union (EU) Integrated Research Project EARNEST supported this study. The EU project EARNEST receives financial support from the Commission of the European Communities. The Danish National Birth Cohort has been financed by the March of Dimes Birth Defects Foundation, the Danish Heart Association, the Danish Medical Research Council, and the Sygekassernes Helsefond Danish National Research Foundation, Danish Pharmaceutical Association, Ministry of Health, National Board of Health, Statens Serum Institut. The study authors have disclosed no relevant financial relationships.
Am J Clin Nutr. 2010;92:626-633

U.S. Births Decline; Economy to Blame?

August 30, 2010 — The number of babies born in the United States declined an estimated 2.6% in 2009 compared to the previous year, the CDC says. And it may be the result of the downturn in the economy.
The new report, by the CDC’s National Center for Health Statistics, says provisional data indicate that an estimated 4,136,000 babies were born in 2009, compared to 4,247,000 in 2008.
The report also found that:

• Births also dropped in 2008, compared to the previous year, with an estimated 4,251,095 babies born.
• In the preliminary analysis for 2008, births dropped for women under 40, but increased for women 40 and over. The decline in births in 2009 may well be associated with the severe downturn in the U.S. economy, which started late in 2007. But it’s too early to know for sure until more statistics are available.

Preliminary Data
The statistics are contained in National Vital Statistics Reports, a publication of the CDC and its National Center for Health Statistics.
It presents early data from all 50 states and Washington, D.C., plus Puerto Rico, but stresses the statistics are preliminary.
The study also reports that:

• The busiest month for births in 2009 was July, when 369,000 babies were born. In 2008, July also witnessed the greatest number of births, 376,000.
• California had the most live births in both years, 530,659 in 2009, down from 551,592 in 2008.
• The fewest number of births in 2009 occurred in Vermont, where 6,118 live births were recorded. Vermont also had the fewest births in 2008 -- 6,275. California reported the most marriages for the second straight year, 213,922, down considerably from 247,022 in 2008. Washington, D.C., reported the fewest number of marriages in 2009 at 1,892, a significant drop from 2,367 in 2008.

SOURCES:
Tejada-Vera, B. National Vital Statistics Reports, Aug. 27, 2010; vol 58.

Exercise Can Treat Cardiovascular Disease as Well as Prevent It

August 30, 2010 (Stockholm, Sweden) — A series of presentations here at the European Society of 2010 Cardiology Congress emphasized how even moderate regular exercise can reverse the damage of existing heart disease while also preventing it.
In one such study, from a session entitled "Exercise: From leisure activity to a therapeutic option,"Dr Brage Amundsen (Norwegian University of Science and Technology [NUST], Trondheim) explained how his group is learning how to improve heart-failure patients' peak oxygen consumption (VO₂). Low peak VO₂ is a driver of poor prognosis in postinfarction heart-failure patients, he explained. The NUST group has conducted similar studies on the benefits of interval training for patients with metabolic syndrome.
Amundsen's group is preparing the randomized SMARTEX-HF study comparing aerobic interval training with moderate continuous training in about 200 patients. The interval-training regimen is built on four four-minute intervals walking on the treadmill at 90% to 95% of peak heart rate, with three-minute "active pauses"--walking at 50% to 70% of peak heart rate--between each interval. Including warm-up and cool-down periods, the total workout lasts 38 minutes. Patients in the moderate continued-training group will walk continuously at 70% to 75% of peak heart rate for 47 minutes.
Preliminary studies show that patients using the interval regimen improve their peak VO₂by a much larger margin than the moderate continuous-training group and that patients in the interval-training group exhibited reverse left ventricular remodeling, reduction in pro-B-type natriuretic-peptide (proBNP)--a marker of hypertrophy and severity of heart failure--and improvement in left ventricular ejection fraction. In vitro cell studies showed that interval training was associated with a reduction of endothelial-cell volume, and functional measures of single myocytes indicate improvements to muscle contractility and oxygen consumption in the interval group.
"A lot of people think this [high-intensity exercise] must be very hard, so we have to be a bit more realistic and inform the patients that it's not that hard and that anybody can do it," he said.
A Role for Strength Training
In a separate presentation, Dr François Carré (Hôpital Pontchaillou, Rennes, France) described research on a variety of exercise modalities showing that cardiovascular patients benefit from strengthening large muscles in addition to aerobic exercise, so "well-done" resistance training should be encouraged on top of aerobic exercise. His group's research has shown that the benefits of exercise generally far outweigh the risks for cardiovascular-disease patients, but exertion does increase the risk for cardiovascular adverse events, "so the physician must evaluate the individual risk, propose an individual program, and give a good education to the patients."
As well, Dr Rainer Rauramaa (Kuopio Research Institute of Exercise Medicine, Finland) presented research that suggests regular moderate-intensity exercise ought to be considered a "cornerstone" in the treatment of hypertension even if the impact is modest.
Early studies suggested that exercise did not improve resting blood pressure, but a more detailed look at the data showed that genetic factors play a major role in determining the response of a patient's blood pressure to exercise. Rauramaa's group also found that exercise's influence on blood pressure lasts only a few days, so the earlier studies may have simply missed the benefit of exercise by measuring the patients' blood pressure several days after their last exercise. His group found an improvement in carotid intima-media thickness in patients who exercised, but the improvement did not appear until three years into their study.
"There was a clear antiatherosclerotic effect of exercise." He pointed out that the antihypertensive benefits of exercise can be achieved even without weight reduction.

Dr Rainer Hambrecht

Finally, Dr Rainer Hambrecht (HerzzentrumBremen, Germany) presented unpublished results from the PET Multicenter study. As reported by heartwire , that study, showing that 12 months of exercise training was just as good as PCI for myocardial perfusion and symptom relief in patients with stable angina, had to be stopped early due to slow enrollment, but the data from the patients who were enrolled plus the results from a small pilot study show that both strategies improve myocardial perfusion, angina threshold, and exercise capacity. However, only exercise improves endothelial function and slows the progression of disease, because PCI is only a local palliative therapy, while exercise training has an impact on the underlying disease in the entire coronary tree, Hambrecht said.
"I would be happy if I could convince everybody with coronary artery disease to participate in a moderate exercise program," he said. He recommends patients stick to the professional guidelines by exercising three or four times a week, 30 minutes per session, at moderate exertion. He cited previous studies showing that patients who attempt to exceed that effort are at increased risk for potentially lethal arrhythmias.

Black Rice Is Cheap Way to Get Antioxidants

August 27, 2010 — Inexpensive black rice contains health-promoting anthocyanin antioxidants, similar to those found in blackberries and blueberries, new research from Louisiana State University indicates.
"Just a spoonful of black rice bran contains more health promoting anthocyanin antioxidants than are found in a spoonful or blueberries, but with less sugar and more fiber and vitamin E antioxidants," Zhimin Xu, PhD, of Louisiana State University Agricultural Center, says in a news release. "If berries are used to boost health, why not black rice and black rice bran?"
Xu and colleagues analyzed samples of black rice bran from rice grown in the Southern U.S.
He says black rice bran would be a unique and inexpensive way to increase people's intake of antioxidants, which promote health.
Black rice is rich in anthocyanin antioxidants, substances that show promise for fighting cancer, heart disease, and other health problems, Xu says.
He adds that food manufacturers could use black rice bran or bran extracts to boost the health value of breakfast cereals, beverages, cakes, cookies, and other foods.
Black Rice vs. Brown Rice
The most widely produced rice worldwide is brown. Millers of rice remove the chaff, or outer husks, from each grain to make it brown.
White rice is made when rice is milled more than is done for brown rice; the bran is also removed, Xu says.
The bran of brown rice contains high levels of one of the vitamin E compounds known as "gamma-tocotrienol" as well as "gamma-oryzanol" antioxidants.
Many studies have shown that these antioxidants can reduce blood levels of LDL "bad" cholesterol and may fight heart disease.
So black rice bran may be even healthier than brown rice, Xu says.
He and his colleagues also showed that pigments in black rice bran extracts can produce a variety of colors, from pink to black, and may be a healthier alternative to artificial food colorants that manufacturers now add to some foods and beverages.
He writes that several studies have linked some artificial colorants to cancer, behavioral problems in children, and other adverse health effects.
Currently, black rice is used mainly in Asia for food decoration, noodles, sushi, and pudding, and Xu says that he would like to see it eaten by more Americans.
Black rice bran could be used to boost the health value of foods, such as snacks, cakes, and breakfast cereals, Xu and his colleagues suggest.
This study was presented at a medical conference in Boston. The findings should be considered preliminary because they have not yet undergone the "peer review" process, in which outside experts scrutinize the data prior to publication in a medical journal.
SOURCES:
News release, American Chemical Society.
2010 National Meeting of the American Chemical Society, Boston, Aug. 22-26, 2010.

Pay Growing Faster for Nurse Practitioners Than Physicians

August 25, 2010 — In a sign of their value in a shorthanded clinical workforce, nurse practitioners (NPs) in group practices saw their compensation increase 4.9% last year, outpacing physicians as a whole, according to the Medical Group Management Association (MGMA).
Compensation for primary care physicians rose 2.9% in 2009, the MGMA reports in its latest Physician Compensation and Production Survey: 2010 Report Based on 2009 Data. Specialists took a 4.1% pay cut, although some individual specialties such as dermatology (12.3%) and ophthalmology (7.7%) posted sizable gains.
At $85,706, the median compensation for NPs in 2009 was far less than what primary care and specialist physicians earned — $191,401 and $325,916, respectively — in group practices. Still, NPs are slowly gaining ground. Since 2005, their compensation has risen 21.9% compared with 13.9% for primary care physicians and 2.9% for their specialty counterparts, according to the MGMA.
"We're in demand," said NP Jan Towers, PhD, director of health policy for the American Academy of Nurse Practitioners, about the compensation trend. "NPs don't have any problems getting work."
The job market is so good that it has been able to absorb a tidal wave of new NPs. The ranks of the profession have grown from 82,000 NPs in 2000 to 140,000 today, according to Dr. Towers.
At the same time, Dr. Towers told Medscape Medical News, a 4.9% pay raise in 2009 is not spectacular. "We should be getting more of an increase," she said.
Physician assistants (PAs) are not far behind NPs in their earnings trajectory. Compensation has risen 17.8% for PAs in primary care and 19.8% for those in surgical specialties since 2005. PA pay hikes in 2009 were less impressive, however, at 1.8% and 0.3%, respectively.
NPs Generate More Revenue Relative to Compensation Than Physicians
The current shortage of primary care physicians is creating higher demand for NPs, which in turn increases their compensation, said Justin Chamblee, a consultant with the Coker Group, a practice management consulting firm in Atlanta, Georgia.
By all accounts, this demand promises to grow stronger under healthcare reform, which will extend insurance coverage to 32 million additional individuals through 2019. Healthcare reformers view both NPs and PAs as an economical way to help tend to these newly insured individuals. Licensed to diagnose illness and prescribe medications, NPs, along with PAs, can perform about 80% of the services provided by primary care physicians, with comparable quality, according to a number of published studies.
Dave Duncan, a senior search consultant with the healthcare recruitment firm Cejka Search in St. Louis, Missouri, said medical practices hire NPs to relieve overworked physicians, share call duty, and staff rural clinics. "But it's getting tougher to find these folks," Duncan told Medscape Medical News. One reason is the growing number of retail clinics operated by drug stores, big-box retailers, and health systems, which also hire NPs to treat patients.
NPs can boost the bottom line of a medical practice in several ways, experts say. By assigning simpler medical cases to NPs, physicians can concentrate on the more complex ones, which insurers reimburse at higher rates.
At the same time, a primary care medical practice that traditionally would hire extra physicians to help carry a burgeoning patient workload can get more bang for its buck hiring NPs instead, based on the ratio of compensation to collections — that is, revenue — for the 2 professions. General internists, for example, received a median $197,080 in compensation last year while generating $366,622 in collections, according to the MGMA. In contrast, the ratio of compensation to collections is better for an NP in primary care, at $84,488 to $228,668. Put another way, 2 such NPs would generate more revenue than a single internist, but their combined compensation would be less than the internist's. The same math also works in favor of PAs.

Physicians' Religious Beliefs Influence End-of-Life Decisions

August 26, 2010 — Physicians who describe themselves as nonreligious are almost twice as likely to make decisions that may end a patient's life compared with physicians who described themselves as religious, according to new research.
Clive Seale, PhD, from Barts and the London School of Medicine and Dentistry, in the United Kingdom, reported the findings online August 26 in the Journal of Medical Ethics.
"The relationship of UK doctors' religiosity and ethnicity to actual end-of-life decisions is poorly understood," noted Dr. Seale in his report. "The present study reports findings on these from a nationally representative survey of doctors, using methods that allow for comparison with censuses and surveys of the general UK population."
A total of 8857 UK medical practitioners were mailed an anonymous questionnaire to assess their end-of-life decisions for patients. Of those, 3733 (42.1%) responded, and 2923 reported on the care of a patient who had died. Specialties included were weighted for those in which end-of-life decisions are more common, such as neurology, elderly care, palliative care, intensive care, and general practice.
Physicians who described themselves as "extremely" or "very non-religious" were almost twice as likely to report having taken the kinds of decisions expected or partly intended to end life as were those with a religious belief.
Ethnicity was not related to rates of reporting ethically controversial decisions, although it was related to support for assisted dying/euthanasia legislation. Specialty was strongly related to whether a physician reported having taken decisions expected or partly intended to end life. Physicians in hospital specialties were almost 10 times as likely to report this as palliative care specialists.
The most religious physicians were also significantly less likely to have discussed end-of-life care decisions with their patients than other physicians.
Specialists in the care of the elderly were more likely to be Hindu or Muslim, whereas palliative care physicians were more likely than other physicians to be Christian and white and to state that they were "religious." Overall, white physicians, who were the largest ethnic group, were the least likely to report strong religious beliefs.
These attitudes were reflected in support for assisted dying/euthanasia legislation, with palliative care specialists and those with a strong faith more strongly opposed to euthanasia. Asian and white physicians were less opposed to such legislation than physicians from other ethnic groups.
"Whether religious or non-religious, it would seem advisable that doctors become more aware of how broader sets of values, such as those associated with religiosity or a non-religious outlook, may enter into their decision-making in end-of-life care," Dr. Seale concludes.
The study was supported by the National Council for Palliative Care. The author has disclosed no relevant financial relationships.
J Med Ethics. Published online August 26. 2010.

Headache in Teens Related to Lack of Exercise, Weight Gain, Smoking

August 19, 2010 — Teenagers who get little exercise, are overweight, or who smoke are more likely to have frequent headaches or migraines, report researchers.
"There was a significant trend for stronger associations between the number of negative lifestyle factors that were present and the different headache diagnoses and headache frequency," point out the investigators led by John-Anker Zwart, MD, from Oslo University in Norway. "We believe that the associations observed and the additive effect of these negative lifestyle factors on the prevalence of recurrent headache strongly indicates that these lifestyle factors are possible targets for headache preventive measures."
The new study appears in the August 18 issue of Neurology. As part of the cross-sectional study, researchers interviewed more than 5500 students about headache complaints. The adolescents also completed a questionnaire and underwent a clinical examination with height and weight measurements.
Investigators classified adolescents who were very physically fit and who were not current smokers as having a good lifestyle. Negative lifestyle factors were surprisingly common with low physical activity in 31%, smoking in 19%, and overweight in 16% of these teens.
In adjusted multivariate analyses, recurrent headache was associated with overweight (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.2 – 1.6; P < .0001), low physical activity (OR, 1.2; 95% CI, 1.1 – 1.4; P = .002), and smoking (OR, 1.5; 95% CI, 1.3 – 1.7; P < .0001). The presence of more than 1 negative lifestyle factor heightened the risk of headache.
Table 1. Prevalence Odds Ratios for Headache Diagnoses

Lifestyle	Total (n = 5588)	Recurrent (n = 1601)	Migraine (n = 392)	Tension Type (n = 950)	Nonclassifiable (n = 259)
Good	2856	1.0	1.0	1.0	1.0
Intermediate	1920	1.3	1.5	1.2	1.3
Poor	717	1.8	2.1	1.6	1.8
Very poor	95	3.4	3.7	2.8	5.0
P value	–	<.0001	<.0001	<.0001	<.0001

Table 2. Headache Frequency in Relation to Lifestyle

Lifestyle	Total (n = 5529)	Less Than Monthly (n = 306)	Monthly (n = 790)	Weekly or Daily (n = 446)
Good	2827	1.0	1.0	1.0
Intermediate	1897	1.0	1.3	1.3
Poor	712	1.4	1.9	2.0
Very poor	93	1.2	3.7	5.0
P value	–	.103	<.0001	<.0001

This study shows overweight, low physical activity, and smoking are independently and in combination associated with recurrent headache among adolescents, report the study authors.
In an accompanying editorial, Dr. Andrew Hershey and Dr. Richard Lipton say that "this study is a vital step toward a better understanding of lifestyle effects and the potential for behavioral interventions for adolescents with headache disorders."
Dr. Hershey is at the University of Cincinnati in Ohio and Dr. Lipton is at the Albert Einstein College of Medicine in the Bronx, New York. They point out the effects of each negative lifestyle factor were similar in magnitude for each headache type. "This lack of specificity for headache type raises the possibility that these factors may be associated not just with headache but with all-cause pain."
These results mirror those of another study published in June in the journal Headache. Investigators led by Rudiger von Kries, MD, from Ludwig-Maximilians-University in Munich, Germany, found that being physically active and abstaining from alcohol, caffeine, and tobacco could help prevent headaches in adolescents.
The study included 1260 students, and after controlling for socioeconomic variables, the prevalence of any headache was increased in teens who reported regularly drinking cocktails (OR, 2.0; 95% CI, 1.3 – 3.0), who drank at least 1 cup of coffee per day (OR, 2.0; 95% CI, 1.2 – 3.5), and who were physically less active (OR, 2.0; 95% CI, 1.3 – 3.1). Smoking daily had an OR of 1.8.
These findings, say editorialists, suggest that a better understanding of modifiable risk factors and trigger factors may lead to novel intervention strategies.
Study coauthor Dr. Stovner has received financial support from BTG, Minster Pharmaceuticals, Pfizer, GlaxoSmithKline, Merck, AstraZeneca, Allergan, Nycomed, Desitin Pharmaceuticals, GmbH, and EMD Serono. Dr. Stovner has also served as an expert legal witness for Oslo Tingrett. Dr. Holmen receives research support from the Norwegian Research Council.
Neurology. 2010;75:712-717.

H1N1 Influenza Pandemic Is Over, WHO Declares

August 10, 2010 — The controversial H1N1 influenza pandemic is officially over, the World Health Organization (WHO) declared today.
"We are now moving into the postpandemic period," said WHO Director-General Margaret Chan, MD. "The new H1N1 virus has largely run its course."
The 2009 H1N1 influenza virus has not disappeared, Dr. Chan noted, and it still poses a risk for serious illness, especially for young children, pregnant women, and persons with respiratory or chronic illnesses. However, the agency expects the virus to circulate and behave as one of several seasonal varieties in years to come, and not to dominate the pack.
"Many countries are reporting a mix of influenza viruses, again as is typically seen during seasonal epidemics," said Dr. Chan.
On June 11, 2009, WHO declared that transmission of the novel influenza virus had morphed into a full-blown pandemic, which is level 6 on a scale that the agency uses to classify influenza outbreaks. The postpandemic phase, which is at the end of the scale, indicates that influenza activity is at seasonal levels.
Earlier today, an emergency committee that advises Dr. Chan on the pandemic convened by teleconference and concluded that "the world was no longer experiencing an influenza pandemic, but that some countries continue to experience significant H1N1 (2009) epidemics," according to WHO.
During the spring and summer, virus transmission has dramatically tapered off in the Northern Hemisphere. WHO said on Tuesday that it had delayed making a decision on whether the pandemic was over until the emergency committee could assess the virus' behavior in the southern hemisphere during its winter influenza season. The committee concluded that for both hemispheres, 2009 H1N1 virus activity "no longer represented an extraordinary event requiring immediate emergency actions on an international scale."
Pandemic Less Deadly Than Feared Because of Hard Work, Good Luck
WHO has been accused in some quarters of declaring a "fake" pandemic, given that the H1N1 virus has killed fewer people than seasonal flu viruses on an annual basis in countries such as the United States. The agency has denied intentionally exaggerating the pandemic's severity for ulterior motives, such as boosting sales for vaccine manufacturers. Nevertheless, Dr. Chan said today that the pandemic "has turned out to be much more fortunate than what we feared a little over a year ago."
Dr. Chan attributed the fortunate outcome in the pandemic saga to a combination of hard work and "pure good luck."
"The virus did not mutate during the pandemic to a more lethal form," she said. "Widespread resistance to oseltamivir [Tamiflu; Roche Inc] did not develop. The vaccine proved to be a good match with circulating viruses and showed an excellent safety profile."
On another positive note, Dr. Chan said that infection rates of 20% to 40% in some areas have created a level of protective immunity, augmented by good vaccination coverage in many countries.
However, public health authorities should continue to remain vigilant about the 2009 H1N1 virus instead of letting down their guard, she said. For one thing, a small proportion of pandemic influenza patients — including young, healthy ones — experienced a severe form of primary viral pneumonia that was very hard to treat. Dr. Chan said nobody knows whether this pattern will continue during the postpandemic phase.
In addition, WHO expects the virus to change as a result of antigenic drift, lowering the protection offered by the community-wide immunity that has developed so far. At the same time, significant influenza outbreaks could occur in areas that got off lightly during the pandemic.
The WHO prescription for the postpandemic era mirrors its advice during the pandemic itself:

• Clinicians should vaccinate individuals against the 2009 H1N1 virus with either a monovalent vaccine or a trivalent seasonal vaccine that contains a strain of the pandemic virus (the United States will use the latter this fall).
• Good personal hygiene is still in order — clinicians should advise their patients to continue to cover their mouths when they sneeze or cough and to diligently wash their hands.
• As during the pandemic, patients who have a severe or deteriorating case of influenza should be treated with oseltamivir immediately, and clinicians should prescribe either oseltamivir or zanamivir (Relenza; GlaxoSmithKline) as soon as possible for patients who are higher risk for severe or complicated influenza.

ACIP Updates Guidelines for Prevention and Control of Influenza With Vaccines

August 3, 2010 — The US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) has issued new 2010 recommendations for prevention and control of influenza with vaccines, according to guidelines reported early release in the July 29 issue of Morbidity and Mortality Weekly Report. This report updates the 2009 ACIP recommendations concerning the use of influenza vaccine for influenza prevention and control.
The report also describes a US Food and Drug Administration labeling change for Afluria (CSL Biotherapies) influenza virus vaccine to reflect the risk for fever and febrile seizure.
"Influenza A subtypes that are generated by a major genetic reassortment (i.e., antigenic shift) or that are substantially different from viruses that have caused infections over the previous several decades have the potential to cause a pandemic," write Anthony E. Fiore, MD, from the Influenza Division, National Center for Immunization and Respiratory Diseases, CDC, Atlanta, Georgia, and colleagues.
"In April 2009, a novel influenza A (H1N1) virus, 2009 influenza A (H1N1), that is similar to but genetically and antigenically distinct from influenza A (H1N1) viruses previously identified in swine, was determined to be the cause of respiratory illnesses that spread across North America and were identified in many areas of the world by May 2009. Influenza morbidity caused by 2009 pandemic influenza A (H1N1) remained above seasonal baselines throughout spring and summer 2009 and was the cause of the first pandemic since 1968."
Highlights of 2010 Guidelines
The 2010 guidelines emphasize the following:

• All persons at least 6 months old should receive annual vaccination for the 2010-2011 influenza season;
• During the 2010-2011 season, 2 doses of a 2010-2011 seasonal influenza vaccine should be given at a minimal interval of 4 weeks to children aged 6 months to 8 years with unknown vaccination status who have never received seasonal influenza vaccine before (or who received seasonal vaccine for the first time in 2009-2010 but received only 1 dose in their first year of vaccination), as well as to children who did not receive at least 1 dose of an influenza A (H1N1) 2009 monovalent vaccine regardless of previous influenza vaccine history;
• Vaccines should contain the 2010-2011 trivalent vaccine virus strains A/California/7/2009 (H1N1)-like (the same strain as was used for 2009 H1N1 monovalent vaccines), A/Perth/16/2009 (H3N2)-like, and B/Brisbane/60/2008-like antigens;
• The report describes Fluzone High-Dose (sanofi pasteur), a newly approved vaccine for persons at least 65 years old; and
• The report also provides information about other newly approved, standard-dose influenza vaccines and expanded age indications for previously approved vaccines.

The updated guidelines recommend starting vaccination efforts as soon as the 2010-2011 seasonal influenza vaccine is available and continuing throughout the influenza season, and they also provide a summary of safety data for US-licensed influenza vaccines. During the 2010-2011 influenza season, vaccination and healthcare providers should check CDC's influenza Web site for any updates or supplements that might be needed to these recommendations, as well as for recommendations for influenza diagnosis and antiviral use published before the start of the 2010-2011 influenza season.
Recommendations for 2010
A summary of recommendations for influenza vaccination for 2010 is as follows:

• Annual vaccination is recommended for all persons aged 6 months or older.
• As providers and programs make the transition to routine vaccination of all persons aged 6 months or older, a focus of vaccination efforts should continue to be protection of persons at higher risk for influenza-related complications.
• When vaccine supply is limited, vaccination efforts should prioritize persons who:   
  • Are aged 6 to 59 months or at least 50 years;
  • Have chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, neurologic, hematologic, or metabolic disorders (including diabetes mellitus);
  • Have disorders of immunosuppression, including those caused by medications or by HIV);
  • Are or will be pregnant during the influenza season;
  • Might be at risk for Reye's syndrome after influenza virus infection because they are aged 6 months to 18 years and are receiving long-term aspirin therapy;
  • Are residents of nursing homes and other long-term care facilities; American Indians/Alaska Natives; morbidly obese (body mass index ≥ 40 kg/m²); and/or healthcare personnel;
  • Are household contacts and caregivers of persons with medical conditions putting them at greater risk for severe complications from influenza, or of children younger than 5 years and adults 50 years or older. The guidelines particularly emphasize vaccinating contacts of children younger than 6 months.

"Emphasis on providing routine vaccination annually to certain groups at higher risk for influenza infection or complications is advised, including all children aged 6 months–18 years, all persons aged ≥50 years, and other persons at risk for medical complications from influenza," the authors of the report write. "Despite a recommendation for vaccination for approximately 85% of the U.S. population over the past two seasons, <50% of the U.S. population received a seasonal influenza vaccination in 2008–09 or 2009–10. Estimated vaccine coverage for the 2009 H1N1 monovalent vaccine coverage was <40%."
MMWR Morb Mortal Wkly Rep. July 29, 2010;59(Early Release);1-62.

High School Incompletion Rates Highest in Teens With ADHD

July 29, 2010 — Teenagers with attention-deficit/hyperactivity disorder (ADHD) are more likely to drop out of high school or delay high school graduation than their counterparts with more "serious" mental health conditions, new national data suggest.
Investigators at the UC Davis MIND Institute in Sacramento, California, found that compared with teens with no psychiatric disorders, those with the combined type of ADHD were more than twice as likely to drop out or finish high school on time. In addition, ADHD trumped high school incompletion rates for other mental health disorders, including mania, mood disorders, and panic disorders.
Conduct disorder and smoking were also significantly associated with an increased risk of failing to complete high school on time, but ADHD still led the pack.
"Most people think that the student who is acting out, who is lying and stealing, is most likely to drop out of school. But we found that students with the combined type of ADHD — the most common type — have a higher likelihood of dropping out than student with disciplinary problems," study investigator Julie Schweitzer, PhD, said in a statement.
"This study shows that ADHD is a serious disorder that affects a child's ability to be successful in school and subsequently in a way that can limit success in life," she added.
The study was published online July 16 in the Journal of Psychiatric Research.
According to the investigators, one-third of youth in the United State do not complete high school on time. "Sorting out which disorders are most likely to affect educational progress is important because different disorders might affect educational outcomes through distinct causal pathways and might require different approaches to (and timing of) interventions," the study authors write.
For the study the investigators examined the joint, predictive effects of childhood- and adolescent-onset psychiatric and substance use disorders on failure to graduate high school on time using data from the 2001 and 2002 National Epidemiological Survey of Alcohol and Related Conditions.
The final study cohort included 29,662 respondents 18 years and older who were interviewed about the age of onset of psychiatric diagnoses, substance use, and high school graduation.
Of the total sample, 5310 (16.9%) did not complete high school on time. Of those with no history of any psychiatric disorder before the age of 18 years, 15.2% did not graduate on time. In comparison, rates for those with ADHD combined type were 33.2%.
At 28.6% the highest dropout rates were found in those whose conditions were diagnosed in childhood or adolescence with either the combined or inattentive type of ADHD. Those with mania, a mood disorder, and panic disorder dropped out at 26.6% and 24.9% respectively.
After adjusting for co-occurring disorders, significant associations with failure to graduate on time remained only for conduct disorder and the 3 ADHD subtypes (inattentive, hyperactive-impulsive, and combined).
However, more predictive of dropping out than all other mental health disorders except ADHD and conduct disorder was tobacco use. The study showed that 29.1% of those who used tobacco failed to complete high school on time.
In comparison, 20.5% of those who used alcohol and 24.6% of those who used drugs dropped out.
"This study suggests that focusing on a relatively narrow and hopefully more manageable range of mental-health conditions may have a consequential impact of improving school performance in secondary education," study investigator Joshua Breslau, PhD, said in a statement.
The study authors have disclosed no relevant financial relationships.
J Psychiatr Res. Published online July 16, 2010.

H1N1 Can Be Transmitted From Humans to Pets

July 20, 2010 (Atlanta, Georgia) — Cases of H1N1 in cats and ferrets appear to have been transmitted from symptomatic human household members, according to a new analysis from the Oregon Department of Human Services.
Emilio E. DeBess, DVM, from the Oregon Department of Human Services, in Portland, presented the findings here at a poster session at the International Conference on Emerging Infectious Diseases 2010.
"We are reporting the first cluster of laboratory-confirmed cases of H1N1 in the US," the authors note, "in 4 ferrets and 2 cats."
According to Dr. DeBess, the cases represent the first description of the pathology and viral antigen distribution of lethal respiratory disease in domestic cats after natural pandemic (H1N1) 2009 influenza virus infection, which was probably transmitted from humans.
"Pets can be affected by H1N1 by the same means as humans; therefore, patients with H1N1 should also wash their hands and cover their cough to protect their pets," he told Medscape Medical News.
A total of 4 ferrets were infected, presenting with sneezing, coughing, lethargy and nasal discharge. Three of the ferrets had elevated temperatures. In addition, 2 cats affected with H1N1 presented with severe respiratory distress, dyspnea, and cyanosis but did not have an increased temperature. The 2 cats, one a 10-year-old neutered domestic shorthair and the other an 8-year-old spayed domestic shorthair, died shortly after developing severe respiratory disease.
The samples were found to be positive for H1N1 by both the matrix and N1 real-time reverse transcriptase polymer chain reaction assays for the 2009 H1N1 pandemic influenza virus and were subsequently confirmed by the US Department of Agriculture/Animal and Plant Health Inspection Service/Veterinary Services/National Veterinary Services Laboratories.
Marked consolidation of the lung lobes and air bronchograms throughout the chest were observed on x-ray of the cats, and pleural effusion was identified in one. Both cats also exhibited pneumonia and fibrin exudation in bronchioles and alveoli.
According to Dr. DeBess, transmission of H1N1 to pets is the same as it is for humans, but it is unknown at this point whether H1N1 could spread back from pets to humans, although "it could only make sense," he said.
Brett Sponseller, DVM, PhD, assistant professor of vet microbiology and preventive medicine at Iowa State University, in Ames, and colleagues recently reported a similar single case of suspected human-to-cat transmission earlier this year. He commented that the frequency of cross-species transmission to companion animals is unknown at this point. "However, I suspect that it is uncommon, yet underdiagnosed," he told Medscape Medical News. "As in humans, most cases in animals appear to be self-limiting and may go undiagnosed," he added.
According to Dr. Sponseller, with the advent of H1N1, "medical professionals need to be aware of the (reverse) zoonotic potential of this virus and recommend safety precautions to minimize spread to and from companion animals." Recommendations are outlined on the American Veterinary Medical Association Web site.
The authors and commentators have disclosed no relevant financial relationships.
International Conference on Emerging Infectious Diseases (ICEID) 2010: Poster Session. Presented July 13, 2010.

Antibodies Induced by HIV Vaccines May Give False-Positive HIV Test Results

July 20, 2010 — Trials of vaccines designed to prevent HIV infection might induce antibodies that will cause false-positive results on routine antibody tests for HIV infection. Although the goal of much vaccine development is to induce the production of protective antibodies, they might also cause a state of vaccine-induced seropositivity/reactivity (VISP), which can confound the interpretation of HIV tests in the absence of HIV infection.

Dr. Lindsey Baden

In the July 21 issue of JAMA, which focuses on HIV/AIDS, Lindsey Baden, MD, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, said that more than 30,000 people have participated in clinical trials of a variety of potential prophylactic vaccines against HIV. These vaccines have used a variety of delivery methods and antigenic compounds and were aimed at inducing different forms of immunity. Dr. Baden discussed the findings at AIDS 2010: XVIII International AIDS Conference in Vienna, Austria.
"The goal of HIV vaccines is to elicit an immune response against HIV. The goal of HIV testing is to see if there is the presence of an immune response to HIV," Dr. Baden explained. "VISP occurs when the antibody or the immune response elicited cross-reacts with the diagnostic test; there can be confusion if one is not aware of this possibility."
VISP might have important ramifications, Dr. Baden said. "Participants may be at risk for misdiagnosis, and if that occurs, then many social harms occur . . . related to insurance, military service, blood [and] tissue donation, immigration, and a variety of other issues that may arise."
Dr. Baden and coworkers studied VISP occurring with various vaccines that were studied by the HIV Vaccine Trials Network. VISP was determined using 3 common US Food and Drug Administration–approved enzyme immunoassay (EIA) test kits. They evaluated VISP in healthy HIV-seronegative adults who participated in any of 25 phase 1 or 2 phase 2a vaccine trials conducted between 2000 and 2010 in the United States and internationally.
VISP was defined as a positive reaction on 1 or more of the EIA tests and a Western blot result that was negative, indeterminate, or atypical-positive — meaning a blot profile consistent with the vaccine product — in conjunction with a negative test for HIV-1 by nucleic acid testing.
Of the 2176 trial participants receiving a test vaccine, 908 (41.7%; 95% confidence interval [CI], 39.6% - 43.8%) had VISP. The occurrence of VISP varied greatly according to the kind of vaccine being tested (e.g., 86.7% for an adenovirus 5 product but only 6.3% for a DNA-alone product). Similarly, results varied substantially according to the test kit used (range, 8.8% to 40.9% VISP).
Dr. Baden concluded that VISP is a common but highly variable outcome in people who participate in vaccine trials. "The occurrence of this is dependent on several factors, including the vaccine or delivery system, the insert used in the vaccine, and the diagnostic test," he said.
These results indicate the need to develop novel rapid-detection methods that do not detect candidate vaccine antigens; several candidate diagnostics are now being investigated that use antigens that are unlikely to be used in vaccines, he noted.
But Dr. Baden said the easiest way to minimize the concern about false-positive test results is for healthcare providers to be aware of the issue as more people participate in vaccine studies. "All they need to do is ask their patients, and if their patients say they are in a vaccine study, then that should be an important consideration in how diagnostic testing is performed," he advised. In addition, testing might best be done by the vaccine trial site, which would be familiar with results related to the specific vaccine.
Because trial participants with VISP might subsequently become infected with HIV, appropriate testing is imperative, Dr. Baden emphasized, including testing for HIV RNA. Trial sites should also test for VISP at the end of the trial and tell participants their VISP status so that they can inform their healthcare providers.
Jason Haukoos, MD, MSc, assistant professor of surgery at the University of Colorado and an emergency physician in the Department of Emergency Medicine at the Denver Health Medical Center, told Medscape Medical News that relatively few patients have been in HIV vaccine trials, so concerns about VISP are small and Dr. Baden's work should go a long way toward solving the problem of false-positive results caused by VISP.
"And there are also a lot of diagnostics coming out now . . . [that will] not only look for antibodies but also antigens," he said. "If you have a combination antibody–antigen assay, then the VISP issue, I think, goes away on some level." He added that, unfortunately, we are still a long way from having an approved vaccine that will be used widely, so the problem of VISP for the near term is minimal.
Melanie Thompson, MD, from the AIDS Research Consortium of Atlanta, Georgia, and chair of the International AIDS Society–USA Antiretroviral Therapy Guidelines Panel, who was not involved in the study, agreed that false-positive HIV test results from VISP are not yet a problem given the small number of trial participants.
"As vaccine studies are expanding, it is going to become a more general issue," she told Medscape Medical News. Patients in vaccine trials will need to be aware of the issue "because they are going to educate the doctors in the community about VISP," she said. "Any HIV testers in the community need to be aware that persons who have been in vaccine trials may have a false-positive HIV test on the antibody testing."
Even in countries with limited healthcare resources, where many of the vaccine trials occur, she said the problem of VISP should be small if the test sites encourage their trial subjects to come back to them for HIV testing, where the proper test methodologies exist, if they have a positive test result elsewhere.
The work was funded by the National Institute of Allergy and Infectious Diseases and by a University of Washington Center for AIDS Research grant. Dr. Baden has disclosed no relevant financial relationships. Dr. Haukoos reports receiving unrestricted research support from Abbott Laboratories and being supported in part by the Centers for Disease Control and Prevention and the Agency for Healthcare Research and Quality. Dr. Thompson reports receiving research grants awarded to the AIDS Research Consortium of Atlanta from Abbott Laboratories, Avexa, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Sciences, GeoVax, Katketsuken, Koronis Pharmaceuticals, Merck Research Laboratories, Myriad, Ora-Sure, Panacos Pharmaceuticals (now Myriad), Pfizer, Progenics Pharmaceuticals, Roche Laboratories, Roche Molecular Systems, Serono, Theratechnologies Tibotec Therapeutics, Tobira Therapeutics, Trimeris, and VaxGen; serving on the scientific advisory boards or as a clinical trial design consultant for Chimerix, GeoVax, GlaxoSmithKline, Panacos Pharmaceuticals, Progenics Pharmaceuticals, and Tibotec Therapeutics; receiving honoraria for scientific lectures from GlaxoSmithKline and Serono; and serving on data and safety monitoring boards for Tibotec Therapeutics.
JAMA. 2010;304:275-283. Abstract
AIDS 2010: XVIII International AIDS Conference. Presented July 18, 2010.

Significant Weight Loss in Obese and Overweight Patients Treated With Lorcaserin

July 15, 2010 (Winter Park, Florida) — Treatment with the investigational obesity drug lorcaserin (Arena Pharmaceuticals, San Diego, CA) results in significantly greater weight loss than placebo in obese or overweight patients, a new study shows [1]. After one year of treatment, patients treated with the novel weight-loss drug lost 4 kg more than those treated with placebo, with significantly more lorcaserin-treated patients losing more than 5% of their body weight compared with the placebo-treated patients.
"I see the obesity epidemic in the US as a medical issue of pretty amazing proportions when you have one-third of the US population that's obese," lead investigator Dr Steven Smith (Florida Hospital, Winter Park) told heartwire . "If you look at the risk for developing diabetes, cardiovascular disease, and all the way down to orthopedic problems, I think there is a huge unmet need out there for multiple medical conditions . . .  a huge unmet need that lorcaserin has the potential to fill."
Importantly, an assessment of adverse events at one and two years did not show any difference in the rates of cardiac valvulopathy, a problem that was observed with less selective obesity agents, report investigators. "In phase 3 studies, particularly in obesity studies, the sample size goes up, which gives us a better picture not just of the efficacy, which I don't think requires many thousands of patients, but lets us really nail some of the safety issues regarding lorcaserin," added Smith.
Lorcaserin is a selective serotonin 2C receptor agonist, and previous studies have shown that drugs targeting serotonin are beneficial in weight loss. The nonselective serotonin agonist fenfluramine, which, along with phentermine, made up the antiobesity medication fen-phen, for example, was approved by the Food and Drug Administration (FDA) in the early 1970s as an adjunct for the treatment of obesity. It was pulled from the market after reports it caused valve disease and pulmonary hypertension.
The results of the study, known as the Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) trial, are published in the July 15, 2010 issue of the New England Journal of Medicine.
Safety of the 5-HT_2C Receptor
In BLOOM, 3182 obese or overweight patients--defined as a body-mass index (BMI) between 30 to 45 kg/m² (or BMI 27 to 45 with at least one preexisting condition, including hypertension, diabetes, cardiovascular disease, impaired glucose tolerance, or sleep apnea)--were randomized to lorcaserin 10 mg twice daily or placebo for 52 weeks. All patients were instructed to exercise moderately for 30 minutes daily and to reduce caloric intake 600 kcal below their estimated daily energy requirements.
At one year, 47.5% of the lorcaserin-treated patients lost 5% or more of their body weight compared with 20.3% of the placebo-treated patients. In addition, 22.7% of the lorcaserin-treated individuals lost 10% of their body weight, while just 7.7% lost the same amount of weight in the placebo arm. On average, individuals treated with lorcaserin lost 5.8 kg compared with 2.2 kg lost in the placebo-treated patients.
After one year of treatment, patients who received lorcaserin were randomly assigned 2:1 to continue treatment for an additional year or to receive placebo. The lorcaserin patients switched to placebo regained the weight lost in the first year and ended year two with roughly the same body weight as those who received placebo for the full two-year study.
"I have thought that for not only lorcaserin, but for other pharmacotherapy approaches, that obesity is a chronic condition, like high blood pressure and hypercholesterolemia," said Smith. "We know that, [just like with other drugs], if you stop taking them, just like you saw here, people regain their body weight. I personally believe that long-term treatment with antiobesity therapies matches the disease and makes a lot of sense, just like treating hypertension."
Asked about the 5.8-kg reduction in weight, Smith told heartwire that for individuals with obesity, every pound lost counts. Medically accepted weight loss, he noted, is approximately 5% of body weight and is generally needed to improve cardiovascular risk factors. Overall, there were small but statistically significant improvements in blood pressure, triglycerides, insulin sensitivity, fibrinogen, and C-reactive protein (CRP), among other measures, compared with placebo. "All the arrows are pointing in the right direction," he said.
In BLOOM, the percentage of patients who remained in the trial at one year was 55.4% in the lorcaserin arm and 45.1% in the placebo arm. The high dropout rate, said Smith, is on par with other antiobesity studies and is likely the result of individuals being able to observe the drug effects by stepping on a scale or tightening their belt buckles, and deciding they no longer needed or wanted to take the drug. He noted that the most frequently reported side effects with lorcaserin were headache, dizziness, and nausea, which occurred early and usually went away. That more people stayed on the drug than on placebo speaks to the tolerability of lorcaserin, said Smith.
Regarding the more serious concern of cardiac valvulopathy, the BLOOM investigators report that at one year FDA-defined valvulopathy developed in 2.3% of patients in the placebo arm and 2.7% of patients in the lorcaserin group, a nonsignificant difference. At two years, the rates were similar.
The Heart Valves
Recent evidence suggests that different serotonin receptors are responsible for different effects, with the 5-HT_2B receptor believed responsible for the adverse cardiac valvular effects, while the 5-HT_2C receptor targeted by lorcaserin is responsible for weight loss. A smaller 12-week study with lorcaserin showed the drug reduced weight without any adverse effects on the cardiac valves or pulmonary arterial pressure. The Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM) trial, previously reported by heartwire , showed lorcaserin did not increase the risk of cardiac valvulopathy or worsen valve problems, including in some patients with preexisting mild to greater aortic or mitral regurgitation.
Speaking with heartwire , Dr Frank Greenway (Pennington Biomedical Research Center, Baton Rouge, LA), an obesity expert who does research in obesity drug development but was not affiliated with the BLOOM trial, agreed that most of the concerns with antiobesity drugs stemmed from the lack of specificity with earlier agents.
"Everybody was very excited about fen-phen because it caused a 15% to 20% reduction in weight loss, so after it was taken off the market, the pharmaceutical industry tried to developed a drug specific to the 5-HT_2C receptor, which is in the brain and regulates appetite," he said. "Judging from the affinity constants and so forth, it would appear there shouldn't be a problem with heart-valve pathology with lorcaserin because it's a specific 5-HT_2C receptor agonist."
The lack of valve problems in a study extended to two years suggests this is no longer a problem, and "the issue has been put to rest," said Greenway.
In an editorial accompany the study [2], Dr Arne Astrup (University of Copenhagen, Denmark) writes that the "history of pharmacologic treatment of obesity is characterized by repetition," with drugs approved and then later yanked because of serious adverse effects detected during postmarketing surveillance.
In addition to fenfluramine, Astrup cites rimonabant, which was scrapped by Sanofi-Aventis after concerns were raised about the drug's psychiatric side effects, and sibutramine (Meridia, Abbott Laboratories), which has been removed from the European market and is contraindicated in individuals with a history of cardiovascular disease. Still, despite these setbacks, Astrup notes that "it makes good sense to develop more selective agents" that work on the 5-HT_2C receptors.
However, putting lorcaserin on the market to treat obesity should be based not on the greater efficacy of the drug, which is slightly less than other compounds, but on improved safety and an improved adverse-event profile, as well as meaningful benefits on risk factors for type 2 diabetes mellitus and cardiovascular disease. "Given the history, we will need to be doubly sure about the safety of lorcaserin, used either alone or in combination with other weight-loss drugs," writes Astrup.
Arena Pharmaceuticals sponsored the BLOOM study. Smith reports consulting fees/honorarium from Arena Pharmaceuticals and has received financial support for travel expenses related to the BLOOM study. Smith spoke with heartwire on a conference call set up by Russo Partners, a public-relations firm. Present on the call were David Schull (Russo Partners, New York), Lena Evans (Russo Partners), and Cindy McGee (Arena Pharmaceuticals). Astrup reports receiving grant support from NeuroSearch and Novo Nordisk and currently sits on an external advisory board for Merck and NeuroSearch.

New AAN Guideline Advocates MRI Over CT for Stroke Diagnosis

July 15, 2010 — After reviewing the relevant literature, a panel of neurologists, neuroradiologists, and radiologists has concluded that diffusion-weighted imaging (DWI) MRI is superior to noncontrast computed tomography (CT) scans, which are the current imaging standard, for diagnosing acute ischemic stroke within 12 hours of symptom onset.
However, although the research shows that DWI is better than CT, the decision about which imaging test to use in clinical practice will depend on issues such as availability and cost, the panel concludes in the new guideline from the American Academy of Neurology.
"The doctors taking care of acute stroke patients, as well as the patients themselves, need to be aware that MRI-DWI is a superior diagnostic tool in acute stroke less than 12 hours," lead author Peter Schellinger, MD, PhD, from Johannes Wesling Clinical Center and the University of Erlangen, Germany, told Medscape Medical News.
"Whether this translates into a change in practice remains to be seen," Dr. Schellinger added. "Logistical, financial, and personnel requirements need to be weighed against better diagnosis which — and this was not within the scope of our assessment — may influence management and ultimately the outcome of the stroke."
The panel's recommendations appear in the July 13 issue of Neurology.
For their review, the panel members addressed 2 questions:

1. Are DWI and PWI (perfusion-weighted imaging) sensitive and specific in the diagnosis of acute ischemic stroke compared with concurrent imaging with other techniques, established by follow-up imaging, clinical follow-up, and final discharge diagnosis?
2. Does the volume of the DWI or PWI abnormality predict initial clinical severity, final infarct size, and late clinical outcome?

The panel performed a literature search of Medline, Embase, and Biosis up to January 2008. For the first question, the search was restricted to studies with a time window of 12 hours after symptom onset. For the second, the search was restricted to studies related to acute ischemic stroke less than 24 hours after symptom onset.
The panel classified evidence using a 4-tier classification scheme for diagnostic (question 1) and prognostic (question 2) articles. Recommendations were based on these levels of evidence.
For question 1, the panel identified 62 articles that fulfilled the inclusion criteria. For DWI, there was 1 class I and 3 class II studies. All PWI studies were class IV.
The class I study assessed the accuracy of MRI (DWI and gradient echo scans) vs CT in 356 consecutive patients presenting to a hospital emergency department over 18 months with a possible diagnosis of acute stroke. In the subset of 221 patients scanned within 12 hours of symptom onset, the majority of blinded readers correctly diagnosed acute ischemic stroke by MRI more often than by CT (94 vs 22; P < .0001).
Single Study Justifies Level A Recommendation
"The odds ratio and its 95% confidence interval (CI) of the difference in the proportions was 25 (8-79), indicating an effect size sufficiently large for this single study to justify a Level A recommendation," the authors write. "A similar direction and magnitude of difference were also seen in the subset of 90 patients scanned within 3 hours of onset."
They added that the sensitivity, specificity, and accuracy of DWI in this study were 77%, 96%, and 86% respectively, compared with 16%, 97% and 55% for CT.
One of the class II studies prospectively evaluated 50 patients with ischemic stroke and 4 with transient ischemic attacks. Patients were randomly assigned to receive MRI or CT within 6 hours of stroke onset. The sensitivity of infarct detection by experts blinded to the patients' symptoms but aware that it was an ischemic stroke population was significantly better with DWI (91%) than CT (61%), as was the accuracy (DWI, 91%; CT, 61%).
The sensitivity of DWI for the diagnosis of ischemic stroke in patients with possible stroke is not perfect; the panel found that its "true sensitivity" is probably 80% to 90%.
The panel concluded from this and the other evidence that DWI is superior to CT for the diagnosis of acute ischemic stroke within 12 hours of symptom onset.
For question 2, the panel identified 8 studies fulfilling the inclusion criteria — 4 class IV studies that assessed only the correlation of baseline DWI and PWI lesion volume with chronic lesion volume, 1 class II study that assessed only the correlation of baseline DWI and PWI lesion volume with clinical outcome, and 2 class II studies and 1 class III study that assessed both clinical and morphologic outcomes. None of the studies compared CT with MRI in predicting these outcomes.
From this research, the panel concluded that baseline DWI volume probably predicts baseline clinical stroke severity and final lesion volume in anterior-circulation stroke syndromes and is possibly accurate in predicting clinical outcome. In addition, the evidence showed that baseline DWI volume possibly does not predict the baseline National Institute of Health Stroke Scale score in posterior circulation stroke syndromes.
In addition to its recommendation that DWI should be considered superior to CT for the diagnosis of ischemic stroke in patients presenting within 12 hours of symptom onset, the panel recommended that baseline DWI volume should be considered useful in predicting baseline clinical stroke severity and final lesion volume in anterior-circulation stroke syndromes, but not in predicting baseline National Institute of Health Stroke Scale score in posterior-circulation stroke syndromes.
The panel found there was insufficient evidence to support or refute the value of PWI in diagnosing acute ischemic stroke but said baseline PWI volume may be considered useful in predicting baseline clinical stroke severity. Prospective, well-designed studies are needed to investigate the diagnostic utility of PWI in acute stroke, according to the panel.
When CT Is the Best Diagnostic Tool
Still, there are circumstances under which CT should remain the primary diagnostic tool, said Dr. Schellinger. "Most typically, this would be in comatose patients, patients with contraindications for MRI such as implanted cardiac pacemakers, and in patients who are candidates for intravenous thrombolytic therapy with rt-PA [tissue plasminogen activator]. Here, a CT-based exclusion of intracranial hemorrhage is enough to make a treatment decision."
A plain CT scan is usually performed faster than a multisequence MRI scan, noted Dr. Schellinger. "Loss of time from arrival at the hospital to initiation of thrombolytic therapy is associated with a loss of efficacy and reduction of chance for a good outcome, and potentially also with a higher bleeding risk, and therefore should be avoided by all means."
In situations in which CT was performed first — for example, in a candidate for thrombolysis — and diagnostic uncertainty remains, MRI may be performed in addition to CT after initiation of thrombolytic therapy to optimize diagnostic assessment, added Dr. Schellinger.
A disadvantage of MRI imaging in acute stroke is its relatively high cost. According to Dr. Schellinger, superior technologists often cost more, although this study did not address cost implications of using MRI to diagnose stroke. "Our objective was an assessment; how and whether this is taken as a means to change [emergency department] practice and stroke care practice remains to be seen."
Lack of Availability
Another perceived disadvantage of MRI is its lack of ready availability. MRIs should be as accessible as CT scans in typical hospital settings, said Dr. Schellinger, adding that the technology has been available at all hours in every center he himself has worked in. "Many of the major stroke services in the United States have implemented MRI as an emergency imaging tool. It is a question of dedication and also a question of whether stroke patients should be treated in stroke centers or not."
Until now, noncontrast CT has been the diagnostic standard for acute stroke. "There was nothing else available, and it was clear pretty early that the most important differential diagnosis of acute ischemic stroke — for example, intracranial hemorrhage — can be detected by CT with a close to 100% sensitivity," explained Dr. Schellinger. "By deduction, it is assumed that a clear stroke syndrome that is not caused by hemorrhage likely is caused by ischemic stroke, even if the CT does not show it."
Best Identification of Early Strokes
Approached for a comment, Gary Abrams, MD, professor of neurology at the University of California–San Francisco, said the new guideline is "very timely and important," as therapeutic interventions for acute ischemic stroke continue to advance.
The article validates what most clinicians already know — that DWI is the most effective and sensitive way to diagnose an acute stroke and is superior to CT — said Dr. Abrams. "As we move forward in the future, this may the way that we need to go in terms of best identification of early strokes and identifying the group that's most amenable to treatment."
As well, the guideline begins to address the issue of PWI, added Dr. Abrams. "This is much less widespread in terms of availability and clinical impact, but it's important, and as the authors suggest, the combination of DWI and PWI may turn out to be the most effective way to understand what's going on in terms of diagnosis and prognosis in acute stroke."
Dr. Schellinger has served or serves on scientific advisory boards for Boehringer Ingelheim, ImaRx Therapeutics, Photothera, Cerevast, and CoAxia Inc; has served or serves on speakers' bureaus for and received funding for travel and speaker honoraria from Boehringer Ingelheim, Sanofi, ImaRx Therapeutics, Photothera, Cerevast, CoAxia Inc, Solvay Pharmaceuticals Inc, and GlaxoSmithKline; serves on editorial boards of Stroke and European Neurology; receives royalties from the publication of NeuroIntensiv (Springer, 2008) and received royalties from the publication of Stroke MRI (Steinkopff, 2004); has served as a consultant for CoAxia Inc, Photothera, Cerevast, ImaRx, and Boehringer Ingelheim; and has provided expert testimony, affidavits, and acted as a witness or consultant in legal proceedings. For disclosure information on the other authors, please see the original article.
Neurology. 2010;75:177-185. 

Fish Oil May Lower Risk for Breast Cancer in Postmenopausal Women

July 12, 2010 — Fish oil supplement intake is associated with a lower risk for breast cancer in postmenopausal women, according to the results of the VITamins And Lifestyle (VITAL) Cohort study reported in the July issue of Cancer Epidemiology, Biomarkers & Prevention.
"Use of nonvitamin, nonmineral 'specialty' supplements has increased substantially over recent decades," write Theodore M. Brasky, from Hutchinson Cancer Research Center, University of Washington in Seattle, and colleagues. "Several supplements may have anti-inflammatory or anticancer properties. Additionally, supplements taken for symptoms of menopause have been associated with reduced risk of breast cancer in two case-control studies [but] there have been no prospective studies of the association between the long-term use of these supplements and breast cancer risk."
At baseline in 2000 to 2002, a total of 35,016 postmenopausal women, aged 50 to 76 years and living in western Washington State, completed a 24-page questionnaire concerning their use of specialty supplements. Use was characterized by recency (current vs past), frequency (days/week), and duration (number of years). The Surveillance, Epidemiology, and End Results (SEER) registry showed that from 2000 to 2007, there were 880 incident invasive breast cancers. Cox proportional hazards models allowed estimation of multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).
For ductal, but not lobular, cancers, current use of fish oil was associated with a reduced risk for breast cancer (HR, 0.68; 95% CI, 0.50 - 0.92), and 10-year average use suggested a trend toward a lower risk (P = .09). Use of the other specialty supplements, including those sometimes taken for menopausal symptoms (black cohosh, dong quai, soy, or St. John's wort) was not associated with breast cancer risk.
"Fish oil may be inversely associated with breast cancer risk," the study authors write. "Fish oil is a potential candidate for chemoprevention studies. Until that time, it is not recommended for individual use for breast cancer prevention."
Limitations of this study include lack of data on supplement dose, reliance on self-report, lack of updated exposure information after baseline, power limited by the relatively low prevalence of use of some specialty supplements, and the possibility of chance findings because 15 specialty supplements were examined.
"[T]his is the first prospective study to report on the association of specialty supplements with breast cancer risk," the study authors conclude. "Our finding of a reduced risk of breast cancer with use of fish oil warrants further study of this agent, focused particularly on timing of exposure and dose, as well as on mechanisms of action that might explain differences by tumor stage or histologic type."
The National Institutes of Health, National Cancer Institute supported this study. The study authors have disclosed no relevant financial relationships.
Cancer Epidemiol Biomarkers Prev. 2010;19:1696-1708. Abstract

Childhood Adversities May Be Risk Factors for Suicidal Behavior Throughout Life

July 2, 2010 — Children who experience serious adversities are at a greater risk for the onset and persistence of suicidal behavior throughout life, according to a new multicountry survey study.
Although exposure to many different adversities "are powerful predictors" for suicidal behavior in later life, sexual or physical abuse during childhood are the strongest risk factors of all, write lead study author Ronny Bruffaerts, PhD, associate professor of psychiatry in the Department of Neurosciences at Katholieke Universiteit Leuven in Belgium, and colleagues.
"Even after rigorously controlling for a broad set of variables, there was at least a threefold increase in lifetime suicide attempt and lifetime suicide ideation among individuals with a history of sexual or physical abuse," they note.
"The point is that childhood trauma has a systematic strong predictive value towards both worse mental and somatic health, as well as increased suicidal behavior," Dr. Bruffaerts told Medscape Medical News.
"Identifying those families at risk of problems, and offering help, may be a way of decreasing suicide around the world," he added in a statement.
The study is published in the July issue of the British Journal of Psychiatry.
Worldwide Suicide Rate Increasing
"Suicides are still one of the major causes of death worldwide," said Dr. Bruffaerts. He added that a report from the World Health Organization showed that the worldwide suicide rate has been increasing steadily since the 1950s.
"Most research on predictors of suicidal behavior focuses on mental disorders as main risk factors, but in the past years there have been some important findings that linked adversities with suicidality," he noted. Also, "the field of childhood adversities is especially an important field to study because its long-term effects have not been studied extensively."
For this study, the investigators evaluated data from nationally representative samples from the World Mental Health surveys. A total of 55,299 people from 21 countries in Africa, the Americas, Asia and the Pacific, Europe, and the Middle East were included.
All participants were interviewed in person about their childhood and whether they had experienced any of the following before they turned 18 years of age: physical abuse, sexual abuse, neglect, parental death, parent divorce, other parental loss, family violence, physical illness, and financial adversity.
Core diagnostic assessments of mental disorders were also made at that time, and the Composite International Diagnostic Interview 3.0 was used to assess lifetime suicidal behavior.
By using these surveys, "we were able to check whether this association [between adversities and suicidal behaviors] held for different countries, different cultures, and different contexts," said Dr. Bruffaerts.
Strong Associations Found
Results showed that 12.2% of the study participants had experienced the death of a parent, 8% had been the victim of physical abuse, and 6.9% had experienced family violence.
A total of 2.7% reported at least 1 suicide attempt, and 9.4% said they had thought about killing themselves.
Among those who had tried to kill themselves, 29.3% had been the victim of physical abuse, 24.8% had experienced family violence, and 14.5% had been sexually abused.
In both bivariate and multivariate models, the childhood adversities were associated with an increased risk for suicide attempt and ideation (odd ratio [OR] range, 1.2 – 5.7) and "the risk increased with the number of adversities experienced, but at a decreasing rate," report the study authors.
In the bivariate models, physical and sexual abuse had the highest odds for suicide attempts (OR, 3.7 and 5.7, respectively) and for suicide ideation (OR, 2.7 and 3.4, respectively). In multivariate additive models, "odds ratios decreased but none lost their statistical significance," the study authors write.
In addition, "associations remained similar after additional adjustment for respondents' lifetime mental disorder status," they add.
Finally, significantly strong associations were found between childhood adversities and suicide attempts in childhood (median OR, 3.8). These associations decreased during the teen years (median OR, 2.5) and in young adulthood (median OR, 2.0) before increasing again in later adulthood (median OR, 2.3).
"Specifically, a history of childhood sexual abuse was associated with a 10.9-fold increase in the odds of a [suicide] attempt between the ages of 4 and 12 years, a 6.1-fold increase in the odds of an attempt between the ages of 13 and 19 years, and a 2.9-fold increase among those between the ages of 20 and 29 years," write the study authors.
Associations Valid Worldwide
The study's overall finding of a strong association between childhood adversities and suicidal behaviors "was not really surprising because prior studies have also shown this," said Dr. Bruffaerts.
However, he noted that "important new findings" included the lifelong effects of childhood adversities, that their highest impact was in childhood and teen years, and that "bodily intrusive adversities" had a stronger impact than other events. But again, "this was not really surprising because it fits with impressions clinicians have."
"That we were able to show that the associations are valid for general populations worldwide was a major step ahead," added Dr. Bruffaerts. "I was [also] surprised...how prevalent childhood adversities actually are in the general population."
When asked about his plans for future research, Dr. Bruffaerts said that a valuable next step pertains to the question, "How can we change the suicidal process?"
"We know that the suicidal process is a treatable condition, but we don’t know exactly how many suicidal persons actually receive treatment," he explained. "In general, I think it is quintessential to generate prevalence estimates of mental disorders worldwide, their correlates and predictors, [and] the ways and why people with psychological problems seek help or not.
"In my opinion, this is an important way to gather data to build national and country-specific policies on," concluded Dr. Bruffaerts.
This study was funded by the US National Institute of Mental Health, the John D. and Catherine T. MacArthur Foundation, the Pfizer Foundation, the US Public Health Service, the Fogarty International Center, the Pan American Health Organization, the Eli Lilly & Company Foundation, Ortho-McNeil Pharmaceutical, GlaxoSmithKline, and Bristol-Myers Squibb. A list of all funders for the various countries' individual health surveys can be found in the original article. Dr. Bruffaerts and all but one of the study authors have disclosed no relevant financial relationships. Investigational team member Ronald C. Kessler reported several declarations of interest, which are listed in full in the original article.
Br J Psychiatry. 2010;197:20-27.