Investigators from the Research Department of the Spine Center of Southern [...]]]> New research suggests that some 40% of chronic lower back pain (CLBP) could be caused by bacteria, and that a significant percentage of people with lower back pain following a herniated disc and swelling in the spine could find relief by taking an antibiotic.

Investigators from the Research Department of the Spine Center of Southern Denmark, University of Southern Denmark, Odense, led by Hanne B. Albert, PhD, conclude that antibiotics may be considered as a treatment option for patients with chronic low back pain, but with caution.

The authors suggest that long-term antibiotics should not be prescribed “without due consideration.” Low back pain is so common in the community that there could be hazards if used indiscriminately, they write.

“However, as many patients, as in this trial, are on sick leave at risk of losing their jobs and have a high analgesic intake, we suggest that antibiotics, when applied along the lines of this MAST [Modic antibiotic spine therapy] protocol may be appropriate in this subgroup, i.e., CLBP with Modic type 1 changes. We do not support the proposition that all patients with lumbar pain should have a trial course of antibiotics.”

Their findings, published in 2 papers, 1 a randomized trial of antibiotics for low back pain, are published in the April issue of the European Spine Journal.

Positive Cultures

An estimated 80% of Americans have low back pain at some point in their life, the authors write, and back pain is the most common reason for workplace absence.

The first of 2 studies shows that patients with an anaerobic infected disc are more likely to develop Modic change (MC) (bone edema) in the adjacent vertebrae after disc herniation, suggesting a role of bacteria in developing Modic changes.

The study included 61 adults (mean age, 46.4 years; 27% female) who had MRI-confirmed lumbar disc herniation and were undergoing surgery. All patients were immunocompetent. No patient had received a previous epidural steroid injection or had previous back surgery.

Using stringent antiseptic sterile protocols, researchers collected 5 tissue samples from each patient. In total, microbiological cultures were positive in 46% of the patients. Anaerobic cultures were positive in 43% of patients, and of these, 7% had dual microbial infections, containing 1 aerobic and 1 anaerobic culture. No tissue specimens had more than 2 types of bacteria.

The anaerobic microorganism Propionibacterium acnes was found in 40% of the total cohort and in 86% of those with positive microbiology. These bacteria typically live in human skin and hair follicles and gums.

The results showed that in the discs with a nucleus with anaerobic bacteria, 80% developed new MC in the vertebrae adjacent to the previous disc herniation. In contrast, none of the patients with aerobic bacteria and only 44% of those with negative cultures developed new MC.

The association between an anaerobic culture and new MCs was highly statistically significant (P = .0038), with an odds ratio of 5.60 (95% confidence interval, 1.51 – 21.95).

The authors said that the detected bacteria are unlikely the result of intraoperative skin contamination. They pointed out that the procedures were conducted under the strictest of sterile conditions. As well, if skin contamination was the cause of the infection, a pattern of multiple skin bacteria cultures would be observed, which was not the case.

Why would some patients develop MC when no microorganisms are present in their herniated nuclear tissue? The authors speculate this could be due to a biochemical effect reflecting edema secondary to microfractures and subsequent inflammation, or the result of an inflammatory process from proinflammatory chemicals penetrating through the microfractures from the nucleus pulposus.

Antibiotic Randomized Trial

The second study, a double-blind, randomized trial, showed that an antibiotic protocol was significantly more effective than placebo in reducing pain and disability. This study included 162 adults who had chronic lower back pain that had developed after a previous disc herniation and had lasted more than 6 months.

These patients also had bone edema, as shown by Modic type 1 changes in the vertebrae adjacent to the previous herniation. Such changes in the vertebrae are present in 6% of the general population and 35% to 40% of those with low back pain.

The patients were randomly assigned to amoxicillin-clavulanate (500 mg/125 mg; Bioclavid) or identical placebo 3 times daily for 100 days and were blindly evaluated at baseline, end of treatment, and 1 year.

The analysis included 144 patients who completed the 1-year follow-up. The antibiotic group improved on all primary outcome measures, including disease-specific score on Roland Morris Disability Questionnaire (RMDQ), and lumbar pain. The improvement continued from the 100-day follow-up until the 1-year follow up.

The improvements in the antibiotic group were highly statistically significant on all outcomes measured, including secondary outcomes of leg pain, number of hours with pain in the last 4 weeks, global perceived health, and days with sick leave, among others.

For example, at baseline, 100 days, and 1 year, the disease-specific disability-RMDQ scores for the antibiotic group were 15.0, 11.5, and 7.0, and for placebo they were 15.0, 14.0, and 14.0 (P = .0001 for the difference between placebo and antibiotic group at 1 year follow up). For back pain, the figures for the antibiotic group were 6.7, 5.0, and 3.7 and for placebo they were 6.3, 6.3, and 6.3. (P = .0001 for difference).

For low back pain, which was experienced by all patients at the beginning of the study, 67.5% of the antibiotic group reported this pain after 1 year compared with 94.0% of the placebo group (P = .0001 for difference). The percentage of those with constant pain was reduced from 73.5% to 19.5% in the antibiotic group and from 73.1% to 67.2% in the placebo group (P = .0001 for difference).

There was a trend toward a dose-response relationship, with double-dose antibiotics being more effective; however, this was not statistically significant because the study was not powered for this comparison.

Adverse events were more common in the antibiotic group (65% of participants) than in the placebo group (23%).

Surgical Setting

In an editorial accompanying the publication, Max Aebi, MD, from the MEM Research Center for Orthopaedic Surgery, Institute for Evaluative Research in Orthopedic Surgery, University of Berne, Switzerland, and editor-in-chief of the European Spine Journal, points out that previous studies have shown that MC I occurs 6 times more frequently in the low back pain population than the general population. The relationship may be mechanical, he writes, “but under certain circumstances, low virulent infections may play a key role.”

These new papers not only demonstrate that patients infected with herniated nucleus material by anaerobic bacteria in lumbar disc herniation develop new MC I in adjacent vertebrae but also that patients with low back pain and MC I after lumbar disc herniation improved significantly with an antibiotic protocol, Dr. Aebi writes.

“This strongly suggests one cause of low back pain in combination of MC I to be of low-grade infectious nature in case of previous disc herniation,” he said.

However, he cautions that it is ethically impossible to take biopsy samples from all of these patients; this could be done only those who have surgery subsequent to disc herniation. The authors ask “the obvious key question” of whether the bacteria found in the nuclear material results from infection or could be due to intraoperative contamination, he writes, and then provide a “plausible” answer as to why such contamination is “highly improbable.”

Information from Industry

“Nevertheless,” Dr. Aebi writes, “further research is necessary to show what exactly happens in patients with disc herniation who develop MC I and low back pain and who have not been operated on. How could we show that in this fraction of patients there could be the same number of anaerobic infections of the nucleus material? By markers of the anaerobic bacteria or of specific infectious tissue, which could be made visible in imaging? By fine needle biopsy?”

Knowing these answers would make the current study results “even more explosive” in terms of better understanding low back pain and corresponding MRI changes, said Dr. Aebi. “We are keen to wait for further innovative research in this field.”

The authors have disclosed no relevant financial relationships.

Eur Spine J. 2013;22:690-696, 697-707, 689. Abstract Abstract Editorial

The study showed that people who drank green tea or coffee regularly had about a 20% lower risk for stroke than their peers who seldom drank these beverages.

“This is the first large-scale study to examine the combined [...]]]> Green tea and coffee consumption may help protect against stroke, according to a large Japanese population-based study.

The study showed that people who drank green tea or coffee regularly had about a 20% lower risk for stroke than their peers who seldom drank these beverages.

“This is the first large-scale study to examine the combined effects of both green tea and coffee on stroke risks,” Yoshihiro Kokubo, MD, PhD, head of the Department of Preventive Cardiology, National Cerebral and Cardiovascular Center in Osaka, said in a statement.

Their findings were published online March 14 in Stroke.

Inverse Link

The study involved 82,369 Japanese adults aged 45 to 65 years without cardiovascular disease or cancer at baseline who were followed for a mean of 13 years. “Green tea and coffee consumption was assessed by self-administered food-frequency questionnaire at baseline,” Dr. Kokubo toldMedscape Medical News.

During more than 1 million person-years of follow-up, the researchers documented 3425 strokes (1964 cerebral infarctions, 1001 intracerebral hemorrhages, and 460 subarachnoid hemorrhages) and 910 coronary heart disease (CHD) events (489 definite myocardial infarctions and 28 sudden cardiac deaths).

In multivariate analysis, higher coffee and green tea consumption were inversely associated with risk for cardiovascular disease (CVD) and stroke.

For example, people who drank at least 1 cup of coffee daily had a 20% lower risk for any stroke (adjusted hazard ratio [aHR], 0.80; 95% confidence interval [CI], 0.72 – 0.90) compared with those who seldom drank coffee.

People who drank 2 to 3 cups of green tea daily had a 14% lower risk for any stroke (aHR, 0.86; 95% CI, 0.78 – 0.95), and those who consumed at least 4 cups had a 20% lower risk (aHR, 0.80; 95% CI, 0.73 – 0.89), compared with those who seldom drank green tea.

The risk reduction for intracerebral hemorrhage was 17% (aHR, 0.83; 95% CI, 0.68 – 1.02) with consumption of at least 1 cup of coffee daily and 23% (aHR, 0.77; 95% CI, 0.63 – 0.92) for 2 cups of green tea daily compared with rare consumption of either beverage.

There was no significant association between coffee and tea consumption and CHD, largely mirroring findings from other studies.

Experts Weigh In

Victoria J. Burley, PhD, senior lecturer in nutritional epidemiology, School of Food Science and Nutrition, University of Leeds, United Kingdom, who wasn’t involved in the study, called it “very interesting.”

She noted that “both high-fiber foods and these particular beverages may have anti-inflammatory properties. Whole grains, fruit and vegetables, and these beverages are all rich in polyphenols, which appear to have multiple potential actions on markers of CVD risk: blood pressure, glucose homeostasis, lipid metabolism, and so on.”

“This appears to be a well-conducted study,” Dr. Burley said, “with good power (plenty of cases), with long follow-up and a respectable method of assessing green tea and coffee intake (for these dietary aspects I think an FFQ [food-frequency questionnaire] is likely the best approach).”

She cautioned, however, that the intakes of green tea in this Japanese cohort “far exceed” usual consumption in western populations and that, conversely, intakes of coffee may generally be somewhat lower in Japan.

“The highest coffee intake category was 2-3 cups per day, which is not particularly high. Other studies (eg, conducted in Sweden) have reported elevated CVD risk in people with much higher intakes ( > 7 cups per day), so in setting their highest category this low these study authors may not have been able to pick up evidence of increased CVD risk with greater intakes,” Dr. Burley said.

“Overall, it’s encouraging data that suggest people who incorporate coffee and green tea in their diet may experience lower CVD risk in later life,” she added.

Commenting on the coffee findings, Susanna C. Larsson, PhD, from the Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, found it “interesting that such a small amount as 1 cup of coffee per day reduces the risk of stroke by 20% (quite a large reduction in risk).”

“Otherwise, this Japanese study confirms results from studies conducted in the US and Europe showing an inverse association between coffee consumption and stroke risk. This study adds further support that moderate coffee consumption may lower the risk of stroke,” said Dr. Larsson, who was not involved in the study.

The study was supported by Grants-in-Aid for Cancer Research and the Third-Term Comprehensive Ten-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan. The authors, Dr. Burley, and Dr. Larsson have disclosed no relevant financial relationships.

Stroke. Published online March 14, 2013

Access to patients is the number one problem in clinical research.
Eighty percent of patients come from 20% of sites, but sponsors keep going back to 100% of sites.
Monitoring [...]]]> There are a number of common adages that float around the clinical trial industry, which are usually based in some form of truth:

Access to patients is the number one problem in clinical research.
Eighty percent of patients come from 20% of sites, but sponsors keep going back to 100% of sites.
Monitoring hours are one of the highest costs in a clinical trial.

Laurie Jassenoff, Vice President, Palm Beach Research Center
These phrases, while sounding cliché, do highlight some of the most frequent and cost-heavy challenges in clinical research and relate in one way or another to effective clinical trial management. But the questions remain: How do organizations proactively manage the many different moving pieces and parts of a trial? How can sponsors and CROs alike harvest and institutionalize information on how to run trials effectively? How can operational managers see useful information across dozens of trials to keep programs on track and identify potential problems before they happen?
These are the types of problems a clinical trial management system (CTMS) can address. However, it is not always a smooth and seamless process.

When web-based EDC and automated randomization systems emerged over a dozen years ago it seemed that some of these new systems might eliminate the need for standalone CTMSs. That has not proven to be the case. The need for CTMS is still important for sponsors, CROs, and sites.

Many technology systems are touted to include “business intelligence” or digital dashboards and compatibility with other systems. It’s also become common to include compatibility and integration with other data management systems as a core capability of eClinical systems, but it’s more difficult to implement in ways that are meaningful and beneficial to end users.

This was the case with Palm Beach Research Center, an investigation site that conducts Phase I-IV clinical programs. Laurie Jassenoff, MBA, Vice President of Palm Beach explains, “Today, to get any kind of information on a clinical research program we have to query a particular database. If we want to look at studies, that’s one database. If we want to look at studies with patients, that’s a different database. It takes a lot of extra time and effort. When I log into my bank account I can view all my accounts at once. It would be great if as a researcher I could sign on to one integrated database with the same kind of front page to access all the information I need.”

And while many systems can integrate with other systems, providing compliance and industry standards capabilities, there are cost and time considerations to integration that must be accounted for. Because integration can be difficult, many organizations can end up using different data sources during trial conduct and go through the process of merging data at the end. Jassenoff says, “for example, it would be a huge time saver if we can enter our source data and it merges with the eCRF.”

Palm Beach Research Center is rolling out a CTMS in 2013. “Our goal is for the CTMS to become a huge patient database that will be able to show cross references of studies and patients, and patients in studies, in addition to having budget information integrated to show what we are invoicing and what is outstanding.” Jassenoff said, “Ideally I’d like to be able to review this integrated data on my iPad anywhere, any time.”

CTMS integrations make a great deal of business sense. The combined data streams provide real-time trial information that may come from ePRO, IVRS, and EDC systems that roll directly into CTMSs and roll up into a real time view of a trial.

How will CTMS look 10 years from now? That’s what vendors and organizations alike are contemplating.

The likelihood seems strong that cloud-based computing will make it easier to provide meaningful dashboards from data across trials. The resulting information should flow more easily across systems into data warehouses and reporting servers that provide that actionable knowledge to a variety of stakeholders about the way trials are run.

—Sheila Rocchio, Vice President of PHT Corporation

Dr. Steven Feldman, a dermatologist with Wake Forest University, said his office recently tracked the compliance rate of seven patients using adalimumab (Humira) and [...]]]> Pills, lotions, syringes and infusions. Caring for psoriasis and psoriatic arthritis can seem like a chore at best, which makes it all that much harder to stick to a treatment plan.

Dr. Steven Feldman, a dermatologist with Wake Forest University, said his office recently tracked the compliance rate of seven patients using adalimumab (Humira) and found that only one of the seven used the drug exactly as directed.

Stopping a drug, administering it incorrectly or reducing the dosage without a physician’s advice can results in flare-ups or cause the medicine to stop working, Feldman said. And increasing the dosage without a doctor’s guidance can result in very serious consequences — even death.

Still, there are many reasons why people with psoriasis and psoriatic arthritis have trouble following a treatment plan. Here are some of most common reasons — and how to overcome them:

They fear side effects.
Patients hear the word “steroid” — a common ingredient in topical creams and ointments — and picture balding men and beefy women, Feldman said. But the steroid used in most creams is cortisone, which is the same hormone the human body naturally creates. It’s common for people to be wary of systemic drugs, such as methotrexate or a biologic. Feldman said he urges patients to weigh the real risk of a side effect, such as the extremely small risk of developing lymphoma from a biologic, with the potential for relief from psoriasis or psoriatic arthritis. If the risk of side effects is too much, patients should work with their doctor on an alternative treatment plan.

Treatment is messy/inconvenient/uncomfortable.
For people with mild to moderate psoriasis, treatment often consists of an ointment or cream. However, topical ointments can be messy or inconvenient to apply to certain parts of the body, such as the scalp. Patients and doctors need to agree on a treatment that the patient is willing to use as directed, Feldman said.

Confused by or forget dosing instructions.
It’s human nature to forget the details, which is why Feldman makes a point of writing down dosage instructions for his patients. “If you don’t give it in writing, it’s almost as if you didn’t tell the person.” If you can’t remember if you should take a drug once a week, or daily for a week, don’t guess. Taking too much of a medicine can result in serious consequences. Taking too little could trigger a flare or make the drug less effective. Call the doctor’s office and get the correct information, Feldman said.

Treatment is too expensive.
It may be tempting to cut back or stop taking a medicine when costs go up or when your insurance status changes, but don’t. Low-income people and those without insurance usually can contact the drug companies for help, Feldman said. Those who don’t qualify for help should work with their doctor to find a less-expensive treatment.

Being substantially obese, based on measure called body [...]]]> In a finding that could undermine many New Year’s resolutions, a new government study shows that people who are overweight are less likely to die in any given period than people of normal weight. Even those who are moderately obese don’t have a higher-than-normal risk of dying.

Being substantially obese, based on measure called body mass index, or BMI, of 35 and higher, does raise the risk of death by 29%, researchers found.

But people with a BMI of 25 to 30—who are considered overweight and make up more than 30% of the U.S. population—have a 6% lower risk of death than people whose BMI is in the normal range of 18.5 to 25, according to the study, being published Wednesday in the Journal of the American Medical Association.

People who had a BMI of 30 to 35—considered the first stage of obesity—had a 5% lower risk of dying, but those figures weren’t considered statistically significant.

Still, health experts said that Americans shouldn’t treat the new study as a license to eat more.

“That would be a mistake—and this study did show an increase in mortality for people who are obese,” said Thomas Frieden, director of the U.S. Centers for Disease Control and Prevention, which conducted the study. “I don’t think anyone would disagree with the basic fact that being more physically active and eating a healthier diet is very important for your health.”

The new report is the latest, and largest, to document what scientists call the “obesity paradox.” Other studies have shown that people with heart disease, diabetes and other chronic health conditions tend to live longer if they carry excess pounds even though excess weight is associated with heightened risk of heart disease, Type 2 diabetes and several cancers which in turn raise the risk of premature death.

CDC researchers analyzed 97 studies involving nearly three million people and 270,000 deaths around the world. “The findings are very consistent across all different ages and continents,” said lead author Katherine Flegal, a senior scientist at the CDC. She stressed that the study looks at all causes of mortality, not overall health risks. “This is not meant to suggest that the conventional wisdom is wrong,” she said.

BMI is calculated by dividing weight in kilograms by height in meters squared. Someone who is 6 feet tall and 180 pounds would have a BMI of 24.4, considered normal; at 200 pounds, his BMI would be 27.1, or slightly overweight, and at 230, his BMI of 30 would be considered obese.

Other experts said the study underscores that BMI is an inexact measure of health—largely because it doesn’t differentiate between fat and muscle mass. Many athletes are technically obese, based on BMI, even though they are extremely fit.

Nor does BMI assess how fat is distributed, which experts say may be more important than total fat overall.

Excess belly fat seems to be particularly toxic, while extra fat in the buttocks and legs may have a protective effect, research suggests.

Doctors at the Mayo Clinic in Rochester, Minn., recently found that among 14,000 people, those with a normal BMI, but a high waist-to-hip ratio, were the most likely to die of cardiovascular disease during the 14-year follow up, even more than those in obese ranges.

“BMI gives the same value to good fat, bad fat and muscle, and it doesn’t make a lot of sense to mix all those things together,” said Francisco Lopez-Jimenez, a preventive cardiologist at Mayo, who wasn’t involved in the CDC study.

Some experts noted that studies of all causes of mortality include deaths from traumatic injuries, and that small amounts of excess fat may provide extra padding.

It isn’t clear why people with heart disease, diabetes, hypertension and kidney disease live longer if they are overweight or obese.

One theory is that extra pounds give such patients some metabolic reserve if they are unable to consume adequate nourishment.

The tendency for people to lose weight and waste away as they become severely ill could artificially inflate the death rate for those in normal BMI ranges, some experts said.

The new report didn’t assess mortality rates for people with below-normal BMI, Dr. Flegal said, because there weren’t enough underweight subjects to provide sufficient data. But other research associates BMIs below 18.5 with a slightly higher risk of death. In such comparisons, researchers measure only deaths that occur specific time period. The studies in the JAMA analysis ran for five to 15 years. Experts stressed that physicians should rely less on BMI and more on specific health measures such as blood pressure, blood sugar, cholesterol, triglycerides, waist circumference and strength and endurance tests.

Patients should focus more on staying fit and eating healthy than hitting a particular number on the scale.

“You’d hate to have the message get out there that it’s good to be overweight,” said Mercedes Carnethon, an epidemiologist at Northwestern University’s Feinberg School of Medicine. “The reality is that people who are overweight very often become obese and that’s clearly not good.”