TORONTO, April 29 — Adding an antiviral drug to standard hepatitis C therapy shortened the treatment time and increased response rates, two studies found.

In the phase II studies, with slightly different designs, the investigational protease inhibitor telaprevir increased response rates by about 50%, the researchers reported in the April 30, 2009 issue of the New England Journal of Medicine.

The finding appears to be the first “material advance” in hepatitis C therapy since the introduction of pegylated interferon in 2001, according to Jay Hoofnagle, M.D., of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md.

Commenting on the studies in an accompanying editorial, Dr. Hoofnagle said the drug — which inhibits a specific serine protease of the hepatitis C virus — marks the “beginning (of) a new era of treatment — an era of antiviral agents developed specifically to target this virus.”

In the first of the two studies — both sponsored by the drug’s developer — John McHutchison, M.D., of Duke University, and colleagues randomized 250 patients with genotype 1 hepatitis C to one of four regimens.

The control group got standard therapy — 48 weeks of ribavirin (Copegus, Rebetol) and peginterferon alfa-2a (Pegasys) — and was compared with three other groups:

79 patients who got telaprevir for 12 weeks and 24 weeks of the standard drugs
79 patients who got 12 weeks of telaprevir and 48 weeks of standard therapy
A small exploratory group of 17 patients who got telaprevir (1,250 milligrams on day one and 750 milligrams every eight hours thereafter) for 12 weeks, as well as peginterferon alfa-2a and ribavirin for the same 12 weeks

The primary outcome was sustained virologic response, defined as an undetectable level of hepatitis C RNA 24 weeks after the end of therapy.

The researchers reported that the sustained virologic response rate was 41% in the control group, compared with 61% in the patients who got 12 weeks of telaprevir and 24 weeks of the standard drugs, a difference that was significant at P=0.02.

The response rate was 67% in the patients who got 12 weeks of telaprevir and 48 weeks of the standard drugs, which was significant at P=0.002, compared with standard therapy.

In the exploratory group, which was not compared with the control group, the rate was 35%.

Standard treatment “cures less than half of patients and has significant side effects that make it very difficult for some patients to continue their treatment,” Dr. McHutchison said in a statement.

“Our study found that by combining the standard therapy with the direct antiviral drug telaprevir, we could reduce the duration of treatment by 50%, to 24 weeks, and, at the same time, improve the cure rate by 50%.”

One problem with telaprevir therapy was the incidence of adverse drug reactions — primarily occurrence of rash — which was higher than in the control group. This led to a higher rate of drug discontinuation than in the control group.

Results were similar in the second study, although the drug combinations analyzed were slightly different, according to Jean-Michel Pawlotsky, M.D., Ph.D., of the Henri Mondor Hospital in Paris, and colleagues.

The researchers compared outcomes in a control group of 82 patients who got standard therapy with outcomes among:

81 patients who got telaprevir for 12 weeks and 24 weeks of the standard drugs
82 patients who were treated with all three drugs for 12 weeks only
78 patients who got telaprevir and peginterferon alfa-2a — without ribavirin — for 12 weeks

The rate of sustained virologic response for the control group was 46%, compared with 69% in the patients who got telaprevir and 24 weeks of peginterferon alfa-2a ribavirin. The difference was significant at P=0.004.

On the other hand, the rate in the other two telaprevir groups combined was not significantly different from that in the control group, the researchers found.

They concluded that ribavirin was a critical part of the treatment regimen.

The studies were supported by Vertex Pharmaceuticals.

Dr. McHutchison reported financial links with Vertex Pharmaceuticals, Schering-Plough, and Roche.

Dr. Pawlotsky reported financial links with Abbott, Astra-Zeneca, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Roche, Schering-Plough, Tibotec Pharmaceuticals, Valeant Pharmaceuticals, and Vertex Pharmaceuticals.

Dr. Hoofnagle reported no conflicts.

Primary source: New England Journal of Medicine

Source reference:

McHutchison JG, et al “Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection” N Engl J Med 2009; 360: 1827-38.

Additional source: New England Journal of Medicine

Source reference:

H?©zode C, et al “Telaprevir and peginterferon with or without ribavirin for chronic HCV infection” N Engl J Med 2009; 360: 1839-50.

Additional source: New England Journal of Medicine

Source reference:

Hoofnagle, JH “A step forward in therapy for hepatitis C” N Engl J Med 2009; 360: 1899-1901.

People with phobic anxieties, like fear of crowded places, fear of heights or fear of going outside, are at higher risk for heart disease than those with fewer or no anxieties.

Several studies have suggested that anxiety and anger are associated with an elevated risk of sudden cardiac death. This is when death occurs within one hour of the onset of symptoms; it’s usually associated with a lethal heart rhythm disturbance.

The following questions, suggested by the American Heart Association, may help you determine if you need to see a mental health professional:

Do you have an unreasonable fear of being in enclosed spaces like shops, elevators, etc.?
Do you find yourself worrying about getting some incurable illness?
Are you exceptionally afraid of heights?
Do you feel panicky in crowds?
Do you worry unduly when relatives are late in coming home?
Do you feel more relaxed indoors?
Do you dislike going out alone?
Do you feel uneasy traveling on buses or trains even if they are not crowded?

WASHINGTON, Jan. 28 — House Democrats have introduced a bill to establish a government-controlled prescription drug plan to compete with private plans that provide Medicare prescription drug coverage.

A key element in the bill would permit the HHS secretary to directly negotiate drug prices with pharmaceutical companies. The proposed Medicare-run drug plan is modeled after a similar plan in the VA.

The VA has reaped massive savings by negotiating drug prices for veterans, said Jan Schakowsky (D-Ill.), a co-sponsor of the bill.

She said the VA has negotiated drug prices that were 20% to 30% lower than the price of drugs available through the 50 or so private plans that provide Medicare Part D coverage.

The government-run plan or plans would compete with current Medicare Part D providers by offering Medicare beneficiaries a potentially cheaper option, said Rep. Marion Berry (D-Ark) another co-sponsor of the bill.

And by offering this alternative, the government could realize substantial savings, said Berry, who estimated that the savings could add up to as much as $20 billion a year for the next 10 years if half of the current Medicare Part D beneficiaries switched to a government-run prescription plan.

Although there is no Senate companion measure yet, Sen. Dick Durbin (D-Ill.), who supports the House bill, said the Obama administration favors allowing Medicare to negotiate drug prices.

Durbin said he would consider offering the bill as an amendment to a larger healthcare reform bill that is expected later this year.

Democrats tried and failed to add an identical provision into the original Part D legislation, and tried again in the last congress, but both attempts gained little traction given the opposition of the Bush administration.

Schakowsky said a government-run plan would also be a simpler option than the private plans now available.

Medicare Part D offers too many plans, all of which make frequent changes to formularies so the result is confusion for Medicare beneficiaries.

But Robert Zirkelbach, a spokesman for America’s Health Insurance Plans, said most Medicare Part D users were satisfied with the coverage and were not confused by the numerous plans.

Rather than a government plan, “seniors want a choice of programs,” said Zirkelbach.

UTRECHT, The Netherlands, March 29 – In patients with rheumatoid arthritis, corticosteroids encapsulated in targeted liposomes might one day home in on inflammation sites and provide lasting relief and prevention of joint deterioration, researchers here reported.

Liposomes with coupled RGD (arginine-glycine-aspartate) peptides on their surfaces can be targeted to angiogenic vascular endothelial cells at the inflammation sites of rats with experimental arthritis, according to Gert Storm, Ph.D., and colleagues at Utrecht University and other centers.

The liposomes with steroid payloads were shown to be effective for quick relief of arthritis in the rat models, the investigators reported in the April issue of Arthritis & Rheumatism.

“This is the first time that specific targeting of liposomes has been shown to be effective in arthritis and represents an important step forward as well as raising some intriguing questions,” wrote Toby Garrood, M.D., Ph.D., and Costantino Pitzalis, M.D., Ph.D., of King’s College London in an accompanying editorial.

“Although free corticosteroid was not used as a control in these experiments, previous work has shown dramatic differences in efficacy of nontargeted liposomal steroid over the free drug, along with dramatic reductions in cartilage damage,” they added.

In their experiments, the Dutch researchers used RGD peptide liposomes to deliver a dose of dexamethasone phosphate to vascular endothelial cells at the site of inflammation in rats with experimental arthritis.

They chose RGD peptides because they are chemically stable and have a high degree of affinity for alpha-v-beta-3 integrins expressed on the surface of angiogenic vascular endothelial cells, which are key mediators of inflammation.

They conducted in-vitro studies and in vivo studies using rats with adjuvant-induced arthritis, and rats and mice with lipopolysaccharide induced inflammation.

Following disease onset (about 12 days after injections) the subjects were randomly assigned to receive a single intravenous injection of dexamethasone phosphate 1 mg encapsulated in targeted RGD peptide-exposing polyethylene glycol (PEG) liposomes, or the same dosage of the corticosteroid encapsulated in non-targeted PEG liposomes. Controls were injected with empty liposomes.

The investigators used a mouse dorsal skin-flap window model to allow visualization of fluorescent-labeled liposome interactions with endothelium.

They found that the targeted RGD-PEG liposomes were taken up by proliferating human vascular endothelial cells in vitro.

They then turned their attention to the living models, and found evidence of increased targeting of radiolabeled RGD-PEG-liposomes to areas of lipopolysaacharide-induced inflammation in rats. Using intravital microscopy, they next peered through the skin flaps of the mice to confirm that there were specific associations of the targeted liposomes with the blood vessel wall at the site of inflammation.

Just one hour after injection of both targeted and untargeted liposomes, the researchers saw that there was strong binding of the RGD-PEG liposomes to endothelium at the site of inflammation, and threefold greater binding of the targeted liposomes to vascular endothelial cells compared with the untargeted liposomes.

When the investigators looked at disease activity in the rats with adjuvant induced arthritis, they found that the animals treated with the targeted liposomes containing the corticosteroids had significantly lower overall arthritis severity scores, more evidence of anti-inflammatory effects, and delayed disease progression.

“Treatment with RGD-dexamethasone phosphate-PEG-liposomes strongly inhibited disease development during the first three days after treatment and also strongly reduced the peak levels of arthritis severity during the entire course of the disease,” Dr. Storm and colleagues wrote.

They plan in future studies to focus more precisely on the therapeutic mechanisms involved, and may also look at the utility of RGD-targeted liposomes for delivery of other anti-inflammatory agents, they wrote.

Primary source: Arthritis & Rheumatism

Source reference:

Koning GA et al. “Targeting of Angiogenic Endothelial Cells at Sites of Inflammation by Dexamethasone Phosphate-Containing RGD Peptide Liposomes Inhibits Experimental Arthritis.” Arthritis & Rheumatism, 2006, 54;4:1198-1208.

Additional source: Arthritis & Rheumatism

Source reference:
Garrood T and Pitzalis C. “Targeting the Inflamed Synovium: The Quest for Specificity” Arthritis & Rheumatism, 2006, 54;4:1055-60.

Care at the end of life for heart failure patients has grown progressively more expensive — but with a shift toward greater use of hospice care, two studies from the U.S. and Canada have found.
The retrospective U.S. study, encompassing almost 230,000 Medicare heart failure patients, found the use of hospice during the last six months of life jumped from 19% in 2000 to 38% in 2007 (P<0.001), reported Lesley H. Curtis, PhD, of Duke University, and colleagues.
The Canadian study, led by Padma Kaul, PhD, of the University of Alberta in Edmonton, examined data from more than 33,000 heart failure patients and found that the proportion of those patients who died in the hospital declined from 60% in 2000 to 54% in 2006 (P<0.01).

The two studies, done in collaboration by the lead authors, appeared together online in the Archives of Internal Medicine.

Although mean healthcare costs accrued in a patient’s final six months rose in both studies — by an unadjusted 26% from $28,766 to $36,216 in the U.S. (P<0.001) and from $25,069 to $27,983 in Canadian dollars — the increase wasn’t as bad as might have been expected, Curtis and Kaul explained.

Kaul’s group called the rate of increase more modest than that of other high-cost populations, such as those with renal failure receiving hemodialysis.

“Although it is commonly assumed that inappropriate use of expensive technologies like biventricular pacemakers and implantable cardioverter defibrillators are driving end-of-life costs, their use in this population is low,” the researchers wrote in Archives.

The shift toward hospice and palliative care may actually be saving money, they speculated.

“Increasing the availability of alternative venues of care, such as long-term care and home care, may be effective in further reducing hospitalizations and containing costs,” Kaul and colleagues wrote.

Guidelines in both Canada and the U.S. that support palliative care for heart failure patients may have helped boost its use — but other factors may also be likely at work too, according to an accompanying editorial.

Rosemary Gibson, MSc, who led end-of-life care efforts at the Robert Wood Johnson Foundation for more than a decade, wrote that palliative care works — despite differences in the two nations’ healthcare systems.

“High-quality palliative care — provided in hospitals, nursing homes, at home, or in hospice — can help patients understand their illness and make informed decisions about their care, together with their families,” she wrote in the editorial. “It must be integrated into the care of patients in all settings.”

The study by Kaul’s group examined all 33,144 patients ages 65 and older who died of heart failure between 2000 and 2006 in the Canadian province of Alberta.

They found a trend of increasing comorbidity burden over the study period, which was associated with higher costs to the healthcare system in the last six months of life in multivariate analysis.

The study didn’t look at hospice care specifically, but did document an increase in use of outpatient services at the end of life — from 52% in 2000 to 69.8% in 2006 (P<0.001).

Most patients did end up at the hospital at least once over their last six months, although this percentage dropped from 84.0% in 2000 to 76.2% in 2006 (P<0.001).

Discharge to home care increased from 15% to 18% (P<0.001). Discharge to a continuing care facility at the end of life was remained fairly stable at 16%.

The location of death also shifted away from acute care hospitals somewhat — 60.4% in 2000 versus 54.0% in 2006.

“The hospitalization during which death occurred was a major driver of resource use,” Kaul and colleagues noted in Archives, but added that it may have also influenced quality of life.

They cautioned that their study did not account for costs associated with continuing care and home care or indirect costs to families who provided home care.

The study of American patients found much the same associations.

Curtis’ group retrospectively analyzed administrative data on a sample of 229,543 Medicare beneficiaries with heart failure who died between 2000 and 2007.

Comorbidity rose over the study period with an increase from 61% to 73% in the number with four or more comorbid conditions (P<0.001).

As in Canada, most patients were hospitalized at least once during their last six months of life — although the proportion remained consistent at around 80%.

This finding suggested “that the potential for hospice to prevent costly hospitalizations has yet to be fully realized,” according to the paper.

Hospice care became increasingly likely to be used directly after hospital discharge (34% in 2007). Patient death while receiving hospice care rose from 17% in 2000 to more than one-third in 2007.

In-hospital deaths declined slightly from 40.2% to 35.2% (P<0.001) over the same period.

Deaths among heart failure patients who received home health services were low and didn’t change over time — although almost one-third of patients utilized home health services.

A stay at a skilled nursing facility also became somewhat more common, rising to 38.8% in 2007 compared with 33.4% in 2000 (P<0.001).

Overall costs for care rose just 11% from 2000 to 2007 after adjustment for age, sex, race, comorbid conditions, duration of heart failure, and geographic region.

Curtis’ group cautioned that their results cannot provide any insight into outcomes or out-of-pocket costs to patients and did not include any data on functional status to determine appropriateness of care. Their estimates also did not include costs to Medicaid or private insurance.

They noted that patients who remained in skilled nursing facilities after exhausting Medicare post–acute care benefits paid privately or used Medicaid; deaths in such facilities were not captured.

Kaul’s group acknowledged that they did not take account of the costs of inpatient, outpatient, emergency department,
physician services, and outpatient drugs within a single-payer system that provides universal access — as well as costs associated with continuing and home care.

Therefore, they said, estimates of total costs during the last six months of life are likely to be underestimates of the true costs to the healthcare system.

The Canadian results may not be generalizable to Medicare managed care patients due to differences in the countries’ healthcare systems.

Kaul’s study was funded by a Canadian Institutes of Health Research (CIHR) operating grant.

Kaul is supported by CIHR New Investigator Awards and by Population Health Investigator Awards from Alberta Innovates – Health Solutions.

Curtis has been a consultant for Pfizer and has received research grants or contracts from Allergan, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Medtronic, Merck, Novartis, OSI Eyetech, Pfizer, and sanofi-aventis.

Gibson reported having no conflicts of interest to disclose.

SAN FRANCISCO, March 6 — For most arthritis patients, X-ray is sufficient to determine the need for arthroplasty, researchers said here.

More than 60% of patients having total knee replacement for osteoarthritis had had an MRI ordered within two years of the surgery, according to a small observational study presented at the American Academy of Orthopaedic Surgeons meeting.

Fewer than half had had radiographs taken before the MRI was done, reported Wayne Goldstein, M.D., of the University of Illinois at Chicago, and colleagues.

“There is no or minimal benefit to MRI in patients with osteoarthritis of the knee that is obviously apparent on weight-bearing and skyline patella-view X-rays,” Dr. Goldstein said.

He and colleagues reviewed charts and interviewed a random sample of 50 patients who underwent primary total knee arthroplasty for osteoarthritis by a single surgeon.

Among them, 64% (32) had had an MRI of their knee done within two years of surgery and before consultation with the orthopedic surgeon. Most of those MRIs had been ordered by primary care physicians.

“The patient is often referred by the primary care physician with the finding of ‘torn meniscus,’” Dr. Goldstein said. “Many patients expect an arthroscopy and seem upset that the orthopedic surgeon does not use the MRIs to make the diagnosis and direct treatment.”

Dr. Goldstein said he routinely uses knee radiographs including weight-bearing and Rosenberg notch views to determine whether there is bone-on-bone articulation that would require treatment.

MRI can be necessary in rare cases, he said, such as sudden onset of knee pain, especially on weight-bearing, accompanied by localized tenderness on physical examination in an older woman for whom radiographic findings are normal.

“In this case, MRI can be useful to diagnose spontaneous osteonecrosis of the knee or a stress fracture,” he said.

Although lack of musculoskeletal education could be one reason for overuse of MRI, financial incentive is likely to play a part as well, the researchers noted.

The charge for an MRI at a group practice in Illinois in 2007 was $1,116; the charge for a four-view arthritis X-ray series of the knee at the same center was $136.

Medicare allowable reimbursement in 2007 was $470.91 for MRI compared with $42.46 for X-ray.

“Commercial insurance reimbursement can be significantly higher,” Dr. Goldstein said.

Overuse of MRI contributes to growing costs for medical imaging, which now accounts for 10% to 15% of Medicare payments to physicians compared with less than 5% a decade ago, he noted.

“This study suggests the need for strict guidelines or credentialing of those who order musculoskeletal MRIs,” Dr. Goldstein concluded.

The researchers reported no support from industry for their study.

Dr. Goldstein reported receiving research or institutional support from DePuy, being a consultant for and receiving miscellaneous funding from DePuy and Smith & Nephew, and receiving royalties from both those companies and from Innomed.

Primary source: American Academy of Orthopaedic Surgeons meeting

Source reference:
Gordon AC, et al “Over-utilization of MRI in the osteoarthritis patient” AAOS meeting 2008; P145.

ATLANTA — For patients with unprotected left main coronary artery disease, stenting and bypass grafting resulted in similar mortality, Q-wave myocardial infarction, and stroke in the long term, South Korean researchers found.

However, the rate of target vessel revascularization was significantly higher through five years in patients who underwent angioplasty (16% versus 4%, P<0.001), the MAIN-COMPARE study registry showed.

The results were reported by Seung-Jung Park, MD, PhD, of the Asan Medical Center in Seoul, at the American College of Cardiology meeting here.

The five-year results are consistent with the three-year results reported at the ACC meeting in 2008 and subsequently published in the New England Journal of Medicine. (See ACC: Stents Match CABG Survival At Three Years in Left Main Disease)

Numerous studies have compared the effects of stenting and coronary artery bypass grafting (CABG), but long-term outcomes among patients with unprotected left main disease had not been extensively studied, according to Park.

CABG is the recommended treatment for these patients, with stenting generally reserved for poor surgical candidates.

To compare outcomes between stenting and CABG, Park and colleagues turned to the MAIN-COMPARE registry, which included information on patients undergoing percutaneous coronary intervention or surgery at 12 centers in South Korea from 2000 to 2006.

There were 1,102 patients who received stents (318 bare-metal and 784 drug-eluting) and 1,138 patients who received CABG.

All had unprotected left main disease (defined as stenosis of more than 50%). Some 52% had complex distal bifurcation lesions.

The researchers used propensity-score matching to account for patient differences at baseline.

Follow-up ranged from three to nine years (median 5.2).

In the overall cohort, the risk of all-cause death (HR 1.02, 95% CI 0.74 to 1.39) and of a composite of all-cause death, Q-wave MI, or stroke (HR 1.10, 95% CI 0.74 to 1.38) were not significantly different between stenting and CABG.

There was a nonsignificant trend toward increased mortality in the drug-eluting stent group compared with CABG through five years.

One of the discussants at Park’s presentation, Donald Cutlip, MD, of Beth Israel Deaconess Medical Center in Boston, said, “I think that has to raise a little bit of caution and concern to those of us who do interventions.”

The rate of target vessel revascularization was significantly elevated in the stenting group overall compared with CABG (HR 4.55, 95% CI 2.88 to 7.20).

This increased risk was consistent for both bare-metal stents (HR 7.97) and drug-eluting stents (HR 6.69) (P<0.001 for both).

Park noted some limitations of the study: It was observational, and treatment assignment was not based on randomized assignment, but on choice of the physician and/or patient. Hidden bias may remain due to unmeasured confounders. The study might have been underpowered to detect significant differences in mortality, especially in the comparison of drug-eluting stents with CABG.

The MAIN-COMPARE registry is supported by research grants from the Korean Society of Interventional Cardiology and the CardioVascular Research Foundation.

Park reported no conflicts of interest.

Cutlip reported no conflicts of interest.

WASHINGTON — An FDA advisory committee is holding a two-day meeting this week to discuss how the agency can better track the safety and efficacy of silicone gel-filled breast implants years after a woman has received them.

FDA’s General and Plastic Surgery Devices Panel on Tuesday and Wednesday will discuss whether current studies that track women who’ve had silicone implants are adequate, how future follow-up studies should be designed, and how to encourage more women to get magnetic resonance imaging (MRI) of their breasts every few years to make sure the implants haven’t ruptured.

Silicone implants became controversial in the 1990s when thousands of women claimed their implants had caused neurological and rheumatological illnesses.

The implants were first marketed in the U.S. in 1962. Thirty years later, in 1992, the FDA requested that manufacturers of silicone implants stop providing them and that surgeons stop implanting them until the agency could determine whether they were safe. Later that year, an advisory committee voted that no manufacturers of silicone breast implants on the market at the time had proved they were safe, and they should be removed from the market.

The FDA decided that women undergoing reconstructive surgery or having their old silicone implants replaced could continue to receive the silicone implants. (Breast cancer patients seem to be happier with breast reconstruction after mastectomy when they choose silicone rather than saline implants, a study found).

The first saline-filled implant was approved in 2000.

In 2006, the FDA approved two types of silicone implants for reconstruction or augmentation, after it determined the makers of the implants — Mentor and Allergan — had shown the devices are safe and effective. That was the first time the silicone implant had been available since the 1992 moratorium.

Between five and 10 million women worldwide have breast implants, according to the FDA.

About 297,000 breast augmentation procedures and 90,000 reconstructions with implants were performed in the U.S. in 2010, according to Jeffrey Shuren, MD, director of the FDA’s Center for Devices and Radiological Health. About half of those involved silicone implants.

As part of the approval process for the two types of silicone implants, the FDA ordered a number of follow-up studies, and those are the main subject of this week’s meeting. Taken together, the studies — some of which won’t end until as late as 2016 — are intended to follow 40,000 women who had received the silicone implants to test that the devices are safe and effective 10 years after having them implanted.

Data currently available from those studies will be examined to make sure that the implants don’t cause connective tissue disease, neurological diseases, or reproductive problems, and that they don’t rupture. All implants that rupture or otherwise malfunction will be analyzed to determine the cause.

The studies also will look at whether the implants have been “effective,” i.e., are women satisfied with the appearance of their breasts?

In February, the FDA announced that an early review of 10-year data on breast implants uncovered 34 cases of anaplastic large-cell lymphoma (ALCL) among women with breast implants, primarily the silicone-filled type. The FDA cautioned that the link requires confirmation, and that it still believes FDA-approved breast implants are safe and effective.

But in June, the FDA found that a preliminary review of the follow-up data on silicone implants found no evidence that the products increase the risk of breast cancer, reproductive abnormalities, or other problems.

However, agency reviewers did find that local complications such as capsule contracture, reoperation, and implant removal are common, and that the implants often needed revision within 10 years.

“Breast implants are not lifetime devices,” Shuren told reporters. “The longer a woman has silicone gel-filled breast implants, the more likely she is to experience complications.”

Other local complications include implant rupture, wrinkling, asymmetry, scarring, and pain.

Participation in follow-up studies has been lower than expected. It appears that women who receive breast augmentation are less likely to participate in follow-up studies than women who receive implants as part of reconstruction surgery after mastectomy, likely because women who have had cancer continue to receive medical care, FDA reviewers wrote in briefing documents released posted ahead of this week’s meeting.

The reviewers said the lagging enrollment in follow-up studies may impact the agency’s ability to truly determine whether silicone implants are safe, particularly if the numbers are too low to rule out the implants’ connection to rare disorders.

The FDA recommends that women with implants get a breast MRI three years after receiving the implants and every two years thereafter to screen for ruptures — even if the woman is having no problems with her implants — but rates of the screening MRIs have been low.

On Tuesday and Wednesday, the FDA’s General and Plastic Surgery Devices Panel will discuss how to improve MRI rates, whether current follow-up studies are adequate, and how to best measure safety and effectiveness of breast implants in future studies.

To avoid type 2 diabetes, seniors may need to watch their weight just as closely as younger individuals do, a prospective cohort study showed.
Among individuals 65 and older, several measures of adiposity and weight gain were associated with a greater risk of developing type 2 diabetes during follow-up, according to Mary Biggs, PhD, of the University of Washington School of Public Health and Community Medicine in Seattle, and colleagues.
The hazard ratios ranged from 1.9 to 6.0 when broken down by sex, they reported in the June 23/30 issue of the Journal of the American Medical Association.
Self-reported body mass index at age 50 and weight gain from age 50 to study baseline were both also associated with risk of incident diabetes.

“We found it surprising that the relationship between adiposity or body fat and diabetes was so strong among older adults,” Biggs said in a video interview with JAMA reporters. “I think the results affirm the importance of weight control during middle age and suggest that weight control remains important into older ages in terms of reducing diabetes risks.”

Although overweight and obesity are well-recognized risk factors for type 2 diabetes among young and middle-age individuals, the relationship has not been well studied in older adults, according to the researchers.

So they turned to the Cardiovascular Health Study, which prospectively followed 4,193 men and women who were at least 65 and free of diabetes at baseline from 1989 to 2007. The participants came from four counties in North Carolina, Maryland, California, and Pennsylvania.

At baseline, mean age of participants was 72 and their mean BMI was 26 kg/m2 for both men and women; 45% had prediabetes (fasting glucose of 100 to 125 mg/dL).

Through a median follow-up of 12.4 years, there were 339 incident cases of type 2 diabetes, defined as use of diabetes medication or a fasting glucose of at least 126 mg/dL.

With increasing quintiles of various measures of adiposity, there was a corresponding greater risk of developing diabetes, with no significant differences by sex or race.

All multivariate models were adjusted for age, sex, race, smoking, alcohol consumption, physical activity, and dietary factors.

For men and women combined, the adjusted hazard ratios for diabetes for those in the highest quintile of baseline measures versus those in the lowest were: 4.3 (95% CI 2.9 to 6.5) for BMI 4.2 (95% CI 2.8 to 6.4) for weight 4.2 (95% CI 2.8 to 6.2) for waist circumference 4.0 (95% CI 2.6 to 6.0) for fat mass 3.8 (95% CI 2.6 to 5.5) for waist-height ratio 2.4 (95% CI 1.6 to 3.5) for waist-hip ratio

Similarly, self-reported BMI at age 50 was associated with diabetes risk in both men (HR 2.6, 95% CI 1.5 to 4.3) and women (HR 3.2, 95% CI 1.9 to 5.5).

The magnitude of the increased risk associated with various measures appeared to fade with age, with about half the risk in individuals 75 and older compared with those 65 to 74. However, the interaction with age was significant only for BMI at age 50 and at baseline and for fat mass.

There are several possible reasons risk might be increased to a lesser extent in older individuals, according to the researchers.

“Among older adults, standard anthropometric measures may not adequately quantify body fat due to age-related changes in body composition, including decreases in skeletal muscle mass and height,” they wrote.

In addition, among older individuals, regional fat distribution may be more important in the etiology of diabetes than absolute fat mass, the pathophysiology of diabetes may differ, and selective survival may be involved.

Changes in body weight were also associated with diabetes risk.

Compared with individuals who had a weight fluctuation of no more than about 4 pounds, those who gained 20 or more pounds from age 50 to baseline or 13 pounds or more from baseline to the third follow-up visit had a two- to threefold increased risk developing diabetes.

“Results of this study affirm the importance of maintaining optimal weight during middle age for prevention of diabetes and, while requiring confirmation, suggest that weight control remains important in reducing diabetes risk among adults 65 years of age and older,” the researchers wrote.

They acknowledged some limitations of the study, including the possible misclassification of individuals with untreated diabetes and potential residual confounding due to unknown factors.

The study was supported by contracts from the National Heart, Lung, and Blood Institute, the National Institute on Aging, and the University of Pittsburgh Claude D. Pepper Older Americans Independence Center. Additional funding came from the National Institute of Neurological Disorders and Stroke.

The authors reported that they had no financial disclosures.

An undiagnosed genetic disease appears to have been the critical factor in the 2009 death of a University of Chicago researcher from plague, investigators have concluded.
The 60-year-old man, Malcolm Casadaban, PhD, had been working with an attenuated strain of Yersinia pestis, the plague bacterium, as part of his research. The strain was subsequently cultured from his blood after death.
Although a forensic team from state and local health departments and the CDC were unable to determine how exactly Casadaban came into contact with the organism, autopsy results also indicated he had hereditary hemochromatosis, according to a report in the Feb. 25 issue of the CDC’s Morbidity and Mortality Weekly Report.

The incident should heighten researchers’ rigorous adherence to biosafety practices whenever they work with live bacteria, and clinicians should routinely ask about patients’ occupations and possibly related exposures when they seek treatment, MMWR’s editors urged.

Casadaban, who was also diabetic, died in September 2009 after flu-like symptoms worsened over the course of a week into respiratory distress and cardiac arrest.

He had reportedly been working with the bacterium as part of a federal bioterrorism research project.

He was not named in the MMWR report but his identity was given in news reports at the time of his death. It attracted international attention not only because it involved plague but because the attenuated strain involved — known as KIM D27 — was not supposed to be dangerous.

Key to solving the mystery of how Casadaban died was that the specific attenuation in KIM D27 is removal of an element known as pgm. It allows Y. pestis to absorb iron from its host. Deprived of iron, the bacterium is rendered nonvirulent — or at least, that’s what the infectious-disease community thought.

In the MMWR report, Kathy Ritger, MD, MPH, of the Chicago Department of Health, and colleagues said that the iron overload characteristic of hemochromatosis may have allowed the KIM D27 strain to overcome the pgm deletion and acquire enough iron to become dangerous.

Postmortem tests revealed that Casadaban had a total serum iron level of 541 μg/dL, more than triple the upper limit of normal (160 μg/dL). Iron saturation was 83.5% and total iron binding capacity was 648 μg/dL, both also well above the reference ranges.

DNA testing showed that the man had two copies of the C282Y mutation in the HFE gene, known to be a cause of hemochromatosis.

“Investigators found no evidence that the researcher knew he had hemochromatosis or that he exhibited any symptoms of this condition,” Ritger and colleagues wrote.

As for how Casadaban became infected, the investigators were less sure. “The patient’s family members and co-workers were asked about knowledge of any possible exposure events, such as a needle puncture or splash of liquid to the face, and none were reported,” they indicated.

But, Ritger and colleagues added, “interviews with laboratory co-workers revealed that the patient inconsistently complied with the laboratory policy to wear gloves while handling Y. pestis KIM D27 bacterial cultures.”

Regulations mandate special containment procedures or facilities for research with wild-type Y. pestis, but not for the KIM D27 strain.

An accompanying unsigned editorial noted that Casadaban’s death was the first laboratory-acquired fatal plague infection in the U.S. since 1959. That case involved an unattenuated virulent strain.

The MMWR editors indicated that the researcher’s diabetes may also have contributed to the severity of the infection.

They wrote that the incident holds lessons both for the research community and for clinicians.

“Researchers working with attenuated Y. pestis and other potentially infectious material should always use at least biosafety level 2 practices, and laboratory managers should ensure that staff adheres to recommended biosafety practices,” the editorial said.

“Institutional safety committees should implement and maintain effective surveillance programs to identify and monitor acute illness among laboratory workers, and healthcare providers should routinely inquire about occupational exposures when evaluating patients.”

Study authors and the editorialists were all government employees. There was no external funding for the work.