Christine Kilgore

The long-held perception that medical records should never be altered at a patient's request is quickly becoming erroneous, according to health lawyer and ethicist George Annas.

“We can delete (items from the record), as long as we note that something has been deleted and who did it,” said Mr. Annas, chairman of the department of health law, bioethics, and human rights at Boston University.

In a Webcast sponsored by the National Institutes of Health, he braced physicians for a future in which patients will increasingly ask them to correct, delete, or change items in the medical record that are either errors or items that they are concerned may pose harm to them.

“The real reason patients don't ask to make deletions [now] is because most people don't look at their records,” he said. But with the advent of the Health Insurance Portability and Accountability Act (HIPAA), “now there's a federal right of access to medical records.”

Moreover, President Bush's current emphasis on electronic medical records (EMRs) embraces “the idea that patients should be in control,” and patients are generally much more concerned about the content of electronic records than paper records, said Mr. Annas, who is also professor of sociomedical sciences and community medicine at Boston University.

The Bush administration has not addressed, in the context of its EMR proposals, whether “a patient [should] be able to delete accurate, factual information [from medical records],” he said.

The bottom line, however, is that “we're in the process of radically changing the medical record … into the patient's record,” Mr. Annas said.

There are “lots of mistakes in medical records,” making it likely that many changes made in the future will address actual errors. Debate about other types of alterations will ensue, but under this new climate “you could argue that patients should be able to change anything,” he told the physicians.

HIPAA addresses the issue of corrections to medical records, saying that “patients have a right to request corrections in the record, and if there's no response, they can write their own letter and have it added,” Mr. Annas explained.

The physicians who attended the NIH session reviewed a case in which a patient presented at the National Institute of Neurological Diseases and Stroke to enroll in a sleep study. He had a chief complaint of insomnia but, during a visit with an NIH clinical social worker, he also reported symptoms of severe depression and a history of drug use.

The day after the social worker evaluated the 37-year-old unemployed man, he requested that the information entered in the computerized record be deleted. “He was vague in his request, but he was concerned that someone would illegally obtain access … and use [the information] against him,” said Elaine Chase, of the social work department at the NIH Clinical Center, Bethesda, Md.

Mr. Annas said that if he were the provider faced with this request, he would agree to delete the information most disconcerting to the patient. “And if he wanted it out of a paper record, I'd still say yes,” though, in the interest of research integrity, the patient should then be excluded from the NIH study, he said.

He offered his verdict on the case example after a free-ranging discussion in which some physicians voiced concern that a move from “physician's record” to “patient's record” would hinder communication among providers.

“Part of the purpose [of the medical record] is it helps individuals plan care,” said one physician. “So from this standpoint, you can't just delete things. … Or if there's going to be a patient medical record, maybe there needs to be another record [for providers],” she said.

It's true, Mr. Annas said, that “defense attorneys still say today that your best defense is a complete medical record.”

Still, physicians, overall, “take the record too seriously” and, although questions remain, they are going to have to be more willing to consider patient requests to alter the medical records, Mr. Annas told this newspaper.

Theoretically, at least, the doctor and patient should review the content of the record before the visit ends, he said.

The long-held perception that medical records should never be altered at a patient's request is quickly becoming erroneous, according to health lawyer and ethicist George Annas.

“We can delete (items from the record), as long as we note that something has been deleted and who did it,” said Mr. Annas, chairman of the department of health law, bioethics, and human rights at Boston University.

In a Webcast sponsored by the National Institutes of Health, he braced physicians for a future in which patients will increasingly ask them to correct, delete, or change items in the medical record that are either errors or items that they are concerned may pose harm to them.

“The real reason patients don't ask to make deletions [now] is because most people don't look at their records,” he said. But with the advent of the Health Insurance Portability and Accountability Act (HIPAA), “now there's a federal right of access to medical records.”

Moreover, President Bush's current emphasis on electronic medical records (EMRs) embraces “the idea that patients should be in control,” and patients are generally much more concerned about the content of electronic records than paper records, said Mr. Annas, who is also professor of sociomedical sciences and community medicine at Boston University.

The Bush administration has not addressed, in the context of its EMR proposals, whether “a patient [should] be able to delete accurate, factual information [from medical records],” he said.

The bottom line, however, is that “we're in the process of radically changing the medical record … into the patient's record,” Mr. Annas said.

There are “lots of mistakes in medical records,” making it likely that many changes made in the future will address actual errors. Debate about other types of alterations will ensue, but under this new climate “you could argue that patients should be able to change anything,” he told the physicians.

HIPAA addresses the issue of corrections to medical records, saying that “patients have a right to request corrections in the record, and if there's no response, they can write their own letter and have it added,” Mr. Annas explained.

The physicians who attended the NIH session reviewed a case in which a patient presented at the National Institute of Neurological Diseases and Stroke to enroll in a sleep study. He had a chief complaint of insomnia but, during a visit with an NIH clinical social worker, he also reported symptoms of severe depression and a history of drug use.

The day after the social worker evaluated the 37-year-old unemployed man, he requested that the information entered in the computerized record be deleted. “He was vague in his request, but he was concerned that someone would illegally obtain access … and use [the information] against him,” said Elaine Chase, of the social work department at the NIH Clinical Center, Bethesda, Md.

Mr. Annas said that if he were the provider faced with this request, he would agree to delete the information most disconcerting to the patient. “And if he wanted it out of a paper record, I'd still say yes,” though, in the interest of research integrity, the patient should then be excluded from the NIH study, he said.

He offered his verdict on the case example after a free-ranging discussion in which some physicians voiced concern that a move from “physician's record” to “patient's record” would hinder communication among providers.

“Part of the purpose [of the medical record] is it helps individuals plan care,” said one physician. “So from this standpoint, you can't just delete things. … Or if there's going to be a patient medical record, maybe there needs to be another record [for providers],” she said.

It's true, Mr. Annas said, that “defense attorneys still say today that your best defense is a complete medical record.”

Still, physicians, overall, “take the record too seriously” and, although questions remain, they are going to have to be more willing to consider patient requests to alter the medical records, Mr. Annas told this newspaper.

Theoretically, at least, the doctor and patient should review the content of the record before the visit ends, he said.

The long-held perception that medical records should never be altered at a patient's request is quickly becoming erroneous, according to health lawyer and ethicist George Annas.

“We can delete (items from the record), as long as we note that something has been deleted and who did it,” said Mr. Annas, chairman of the department of health law, bioethics, and human rights at Boston University.

In a Webcast sponsored by the National Institutes of Health, he braced physicians for a future in which patients will increasingly ask them to correct, delete, or change items in the medical record that are either errors or items that they are concerned may pose harm to them.

“The real reason patients don't ask to make deletions [now] is because most people don't look at their records,” he said. But with the advent of the Health Insurance Portability and Accountability Act (HIPAA), “now there's a federal right of access to medical records.”

Moreover, President Bush's current emphasis on electronic medical records (EMRs) embraces “the idea that patients should be in control,” and patients are generally much more concerned about the content of electronic records than paper records, said Mr. Annas, who is also professor of sociomedical sciences and community medicine at Boston University.

The Bush administration has not addressed, in the context of its EMR proposals, whether “a patient [should] be able to delete accurate, factual information [from medical records],” he said.

The bottom line, however, is that “we're in the process of radically changing the medical record … into the patient's record,” Mr. Annas said.

There are “lots of mistakes in medical records,” making it likely that many changes made in the future will address actual errors. Debate about other types of alterations will ensue, but under this new climate “you could argue that patients should be able to change anything,” he told the physicians.

HIPAA addresses the issue of corrections to medical records, saying that “patients have a right to request corrections in the record, and if there's no response, they can write their own letter and have it added,” Mr. Annas explained.

The physicians who attended the NIH session reviewed a case in which a patient presented at the National Institute of Neurological Diseases and Stroke to enroll in a sleep study. He had a chief complaint of insomnia but, during a visit with an NIH clinical social worker, he also reported symptoms of severe depression and a history of drug use.

The day after the social worker evaluated the 37-year-old unemployed man, he requested that the information entered in the computerized record be deleted. “He was vague in his request, but he was concerned that someone would illegally obtain access … and use [the information] against him,” said Elaine Chase, of the social work department at the NIH Clinical Center, Bethesda, Md.

Mr. Annas said that if he were the provider faced with this request, he would agree to delete the information most disconcerting to the patient. “And if he wanted it out of a paper record, I'd still say yes,” though, in the interest of research integrity, the patient should then be excluded from the NIH study, he said.

He offered his verdict on the case example after a free-ranging discussion in which some physicians voiced concern that a move from “physician's record” to “patient's record” would hinder communication among providers.

“Part of the purpose [of the medical record] is it helps individuals plan care,” said one physician. “So from this standpoint, you can't just delete things. … Or if there's going to be a patient medical record, maybe there needs to be another record [for providers],” she said.

It's true, Mr. Annas said, that “defense attorneys still say today that your best defense is a complete medical record.”

Still, physicians, overall, “take the record too seriously” and, although questions remain, they are going to have to be more willing to consider patient requests to alter the medical records, Mr. Annas told this newspaper.

Theoretically, at least, the doctor and patient should review the content of the record before the visit ends, he said.

When James A. Taylor, M.D., and his colleagues found that an educational pamphlet and a video changed parents' attitudes about antibiotic use 2 years ago, they assumed that such a change would lead to fewer demands on pediatricians and fewer antibiotic prescriptions.

They were wrong.

In a randomized controlled trial, their educational intervention did not result in a decrease in antibiotic prescriptions.

Prescriptions were high over a 12-month postintervention period, with antibiotics prescribed during 46% of all visits for upper respiratory infection (URI) symptoms—regardless of whether the parent had received the pamphlet and video or another control intervention.

It could be that “although attitudes about antibiotic use were modified, parents still desired these medications when their child was ill,” said Dr. Taylor of the Child Health Institute at the University of Washington, Seattle, and his colleagues.

It's also possible that “pediatricians may have failed to detect a change in expectations for antibiotics by parents of children in the intervention group,” they wrote (Pediatr. Infect. Dis. J. 2005;24:489–93). Their study was conducted by the Puget Sound Pediatric Research Network, a regional practice-based research group composed of Seattle-area pediatricians.

Parents of 499 healthy children under age 2 years were enrolled at the time of an office visit and randomized to receive either a pamphlet and video promoting the judicious use of antibiotics (the intervention) or brochures about injury prevention (the control group).

The educational pamphlet, “Your Child and Antibiotics,” was developed by the American Academy of Pediatrics, the Centers for Disease Control and Prevention, and the American Society of Microbiology. The video was professionally produced and featured one of the physicians from the child's pediatric practice.

At the end of a 12-month period, each child's medical record was reviewed. Of 4,924 outpatient visits, almost 1,420 (29%) were for URI symptoms as the chief complaint. Pediatricians were not informed about which children/parents were involved in the project.

At least one antibiotic was prescribed during 46% of the visits for URI, 92% of which were for a diagnosis of otitis media or sinusitis. Antibiotics were prescribed at only 10 visits at which the only diagnosis made was URI and at 7 visits at which the diagnosis was bronchitis.

Overall, the “average” study patient had approximately 10 visits—a remarkably high level of utilization, the investigators noted—3 of which were visits for URI symptoms. The average patient also had two diagnoses of otitis media and received two prescriptions for antibiotics during the 12-month period. There were no significant differences in any of the outcomes—number of visits, specific diagnoses, or prescriptions—between children in the intervention and control groups.

Although antibiotics were “clearly indicated” for a proportion of patients with the diagnoses of otitis media or sinusitis, “it is equally certain that for a significant proportion … there was uncertainty regarding the diagnosis and/or need for antibiotic therapy, or the diagnosis was made by the practitioners to justify the use of antibiotics,” Dr. Taylor and his associates said.

In an earlier study of the pamphlet and video, they had found that these educational tools resulted in “changes in parental attitudes that were more supportive of the judicious use of [antibiotics],” the investigators said. “We postulated that if parental expectations could be altered by an educational intervention, pediatricians would perceive less demand for antibiotics and prescribe fewer of these medications.”

Now, they said, “it is clear that more research is needed to identify methods for reducing antibiotic use in children that are effective, inexpensive, and easily implemented.”

When James A. Taylor, M.D., and his colleagues found that an educational pamphlet and a video changed parents' attitudes about antibiotic use 2 years ago, they assumed that such a change would lead to fewer demands on pediatricians and fewer antibiotic prescriptions.

They were wrong.

In a randomized controlled trial, their educational intervention did not result in a decrease in antibiotic prescriptions.

Prescriptions were high over a 12-month postintervention period, with antibiotics prescribed during 46% of all visits for upper respiratory infection (URI) symptoms—regardless of whether the parent had received the pamphlet and video or another control intervention.

It could be that “although attitudes about antibiotic use were modified, parents still desired these medications when their child was ill,” said Dr. Taylor of the Child Health Institute at the University of Washington, Seattle, and his colleagues.

It's also possible that “pediatricians may have failed to detect a change in expectations for antibiotics by parents of children in the intervention group,” they wrote (Pediatr. Infect. Dis. J. 2005;24:489–93). Their study was conducted by the Puget Sound Pediatric Research Network, a regional practice-based research group composed of Seattle-area pediatricians.

Parents of 499 healthy children under age 2 years were enrolled at the time of an office visit and randomized to receive either a pamphlet and video promoting the judicious use of antibiotics (the intervention) or brochures about injury prevention (the control group).

The educational pamphlet, “Your Child and Antibiotics,” was developed by the American Academy of Pediatrics, the Centers for Disease Control and Prevention, and the American Society of Microbiology. The video was professionally produced and featured one of the physicians from the child's pediatric practice.

At the end of a 12-month period, each child's medical record was reviewed. Of 4,924 outpatient visits, almost 1,420 (29%) were for URI symptoms as the chief complaint. Pediatricians were not informed about which children/parents were involved in the project.

At least one antibiotic was prescribed during 46% of the visits for URI, 92% of which were for a diagnosis of otitis media or sinusitis. Antibiotics were prescribed at only 10 visits at which the only diagnosis made was URI and at 7 visits at which the diagnosis was bronchitis.

Overall, the “average” study patient had approximately 10 visits—a remarkably high level of utilization, the investigators noted—3 of which were visits for URI symptoms. The average patient also had two diagnoses of otitis media and received two prescriptions for antibiotics during the 12-month period. There were no significant differences in any of the outcomes—number of visits, specific diagnoses, or prescriptions—between children in the intervention and control groups.

Although antibiotics were “clearly indicated” for a proportion of patients with the diagnoses of otitis media or sinusitis, “it is equally certain that for a significant proportion … there was uncertainty regarding the diagnosis and/or need for antibiotic therapy, or the diagnosis was made by the practitioners to justify the use of antibiotics,” Dr. Taylor and his associates said.

In an earlier study of the pamphlet and video, they had found that these educational tools resulted in “changes in parental attitudes that were more supportive of the judicious use of [antibiotics],” the investigators said. “We postulated that if parental expectations could be altered by an educational intervention, pediatricians would perceive less demand for antibiotics and prescribe fewer of these medications.”

Now, they said, “it is clear that more research is needed to identify methods for reducing antibiotic use in children that are effective, inexpensive, and easily implemented.”

When James A. Taylor, M.D., and his colleagues found that an educational pamphlet and a video changed parents' attitudes about antibiotic use 2 years ago, they assumed that such a change would lead to fewer demands on pediatricians and fewer antibiotic prescriptions.

They were wrong.

In a randomized controlled trial, their educational intervention did not result in a decrease in antibiotic prescriptions.

Prescriptions were high over a 12-month postintervention period, with antibiotics prescribed during 46% of all visits for upper respiratory infection (URI) symptoms—regardless of whether the parent had received the pamphlet and video or another control intervention.

It could be that “although attitudes about antibiotic use were modified, parents still desired these medications when their child was ill,” said Dr. Taylor of the Child Health Institute at the University of Washington, Seattle, and his colleagues.

It's also possible that “pediatricians may have failed to detect a change in expectations for antibiotics by parents of children in the intervention group,” they wrote (Pediatr. Infect. Dis. J. 2005;24:489–93). Their study was conducted by the Puget Sound Pediatric Research Network, a regional practice-based research group composed of Seattle-area pediatricians.

Parents of 499 healthy children under age 2 years were enrolled at the time of an office visit and randomized to receive either a pamphlet and video promoting the judicious use of antibiotics (the intervention) or brochures about injury prevention (the control group).

The educational pamphlet, “Your Child and Antibiotics,” was developed by the American Academy of Pediatrics, the Centers for Disease Control and Prevention, and the American Society of Microbiology. The video was professionally produced and featured one of the physicians from the child's pediatric practice.

At the end of a 12-month period, each child's medical record was reviewed. Of 4,924 outpatient visits, almost 1,420 (29%) were for URI symptoms as the chief complaint. Pediatricians were not informed about which children/parents were involved in the project.

At least one antibiotic was prescribed during 46% of the visits for URI, 92% of which were for a diagnosis of otitis media or sinusitis. Antibiotics were prescribed at only 10 visits at which the only diagnosis made was URI and at 7 visits at which the diagnosis was bronchitis.

Overall, the “average” study patient had approximately 10 visits—a remarkably high level of utilization, the investigators noted—3 of which were visits for URI symptoms. The average patient also had two diagnoses of otitis media and received two prescriptions for antibiotics during the 12-month period. There were no significant differences in any of the outcomes—number of visits, specific diagnoses, or prescriptions—between children in the intervention and control groups.

Although antibiotics were “clearly indicated” for a proportion of patients with the diagnoses of otitis media or sinusitis, “it is equally certain that for a significant proportion … there was uncertainty regarding the diagnosis and/or need for antibiotic therapy, or the diagnosis was made by the practitioners to justify the use of antibiotics,” Dr. Taylor and his associates said.

In an earlier study of the pamphlet and video, they had found that these educational tools resulted in “changes in parental attitudes that were more supportive of the judicious use of [antibiotics],” the investigators said. “We postulated that if parental expectations could be altered by an educational intervention, pediatricians would perceive less demand for antibiotics and prescribe fewer of these medications.”

Now, they said, “it is clear that more research is needed to identify methods for reducing antibiotic use in children that are effective, inexpensive, and easily implemented.”

Children with rotavirus gastroenteritis face a small but real risk of developing enteric gram-negative sepsis, investigators have reported.

Physicians “should be aware of the possibility of this complication, especially when a child is developing a high fever and lethargy several days after the beginning of gastroenteritis,” said Amos Adler, M.D., and his colleagues at the Sapir Medical Center in Kfar Saba, Israel.

“In such cases, prompt initiation of wide-spectrum antibiotics is crucial, even in previously diagnosed rotavirus infection,” they said (Clinical Pediatrics 2005:44;351–4).

The investigators described three previously healthy infants who developed enteric gram-negative rods (EGNR) bacteremia during rotavirus gastroenteritis. The children were hospitalized at the medical center in 2000 and 2001.

The infants had the characteristic clinical course of rotavirus gastroenteritis at the beginning of their illness. Then, 3–5 days after the onset of disease, they presented with an abrupt onset of high fever, lethargy, and poor perfusion.

Laboratory results suggested bacterial sepsis, and in one case, there also was radiographic evidence of severe intestinal injury due to pneumatosis intestinalis.

In all of them, the EGNR isolated from the blood cultures were sensitive to aminoglycosides and to second- or third-generation cephalosporins.

(Stool cultures in each patient tested negative for Shigella, Salmonella, enteropathogenic Escherichia coli, and Campylobacter.)

Differentiating between secondary EGHR infection and the deterioration of rotavirus gastroenteritis to a severe course “may be difficult,” the investigators said.

It also is difficult to pinpoint the mechanism of bacterial breakthrough and spreading in these three cases, especially since rotavirus is not known to cause extensive inflammation and cell destruction, they said.

Still, the investigators said, they hypothesize that the pathogenesis of the bacteremia “was dissemination of normal intestinal flora through the damaged mucosa”— just as viral infection of the respiratory tract can antecede and predispose children to colonization and invasion of bacteria such as Streptococcus pneumoniae.

It is possible that bacteremia took hold through other sites—the urinary tract or the respiratory tract, for instance—but it's less likely since no clinical or laboratory findings support it, Dr. Adler and his colleagues said.

They said they could not find in the English literature a description of EGNR bacteremia as a complication of rotavirus infection.

One of their patients, for example, was a healthy 9-month-old boy, admitted after 1 day of vomiting and diarrhea. On admission, he was afebrile and appeared lethargic and moderately dehydrated.

The child had normal blood count and electrolytes, urea 53 mg/dL, mild metabolic acidosis and normal urine analysis. His general condition improved after treatment with intravenous fluids. His diarrhea continued, but vomiting subsided. Stool bacterial cultures were negative, and rotavirus antigen was detected in his stool.

On the third day of hospitalization, his temperature rose to 39.5° C, and he became more lethargic.

A plain abdominal radiograph showed intraluminal air in the small bowel (pneumatosis intestinalis) without free air or intraportal gas. Abdominal ultrasound appeared normal. Laboratory analysis showed white blood cell counts of 14,400 cells/μL with 9% bands and 59% neutrophils, urea 15 mg/dL, pH 7.37, partial pressure of carbon dioxide 20.7 mm Hg, bicarbonate 11.8 mmol/L, and normal U/A.

The infant was treated with intravenous piperacillin-tazobactam, and oral feeding was discontinued. His fever resolved, and his general condition improved. Klebsiella pneumoniae was recovered from the blood culture and was sensitive to cephalosporins, aminoglycosides, trimethoprim-sulfamethoxazole, and amoxicillin-clavulanate.

After 4 days of fasting, the infant began receiving semi-elemental nutrition. The infant completed 10 days of intravenous antibiotics and resumed a normal diet by the 13th day of hospitalization. He was discharged and appeared to be in excellent health at follow-up 1 month later.

Children with rotavirus gastroenteritis face a small but real risk of developing enteric gram-negative sepsis, investigators have reported.

Physicians “should be aware of the possibility of this complication, especially when a child is developing a high fever and lethargy several days after the beginning of gastroenteritis,” said Amos Adler, M.D., and his colleagues at the Sapir Medical Center in Kfar Saba, Israel.

“In such cases, prompt initiation of wide-spectrum antibiotics is crucial, even in previously diagnosed rotavirus infection,” they said (Clinical Pediatrics 2005:44;351–4).

The investigators described three previously healthy infants who developed enteric gram-negative rods (EGNR) bacteremia during rotavirus gastroenteritis. The children were hospitalized at the medical center in 2000 and 2001.

The infants had the characteristic clinical course of rotavirus gastroenteritis at the beginning of their illness. Then, 3–5 days after the onset of disease, they presented with an abrupt onset of high fever, lethargy, and poor perfusion.

Laboratory results suggested bacterial sepsis, and in one case, there also was radiographic evidence of severe intestinal injury due to pneumatosis intestinalis.

In all of them, the EGNR isolated from the blood cultures were sensitive to aminoglycosides and to second- or third-generation cephalosporins.

(Stool cultures in each patient tested negative for Shigella, Salmonella, enteropathogenic Escherichia coli, and Campylobacter.)

Differentiating between secondary EGHR infection and the deterioration of rotavirus gastroenteritis to a severe course “may be difficult,” the investigators said.

It also is difficult to pinpoint the mechanism of bacterial breakthrough and spreading in these three cases, especially since rotavirus is not known to cause extensive inflammation and cell destruction, they said.

Still, the investigators said, they hypothesize that the pathogenesis of the bacteremia “was dissemination of normal intestinal flora through the damaged mucosa”— just as viral infection of the respiratory tract can antecede and predispose children to colonization and invasion of bacteria such as Streptococcus pneumoniae.

It is possible that bacteremia took hold through other sites—the urinary tract or the respiratory tract, for instance—but it's less likely since no clinical or laboratory findings support it, Dr. Adler and his colleagues said.

They said they could not find in the English literature a description of EGNR bacteremia as a complication of rotavirus infection.

One of their patients, for example, was a healthy 9-month-old boy, admitted after 1 day of vomiting and diarrhea. On admission, he was afebrile and appeared lethargic and moderately dehydrated.

The child had normal blood count and electrolytes, urea 53 mg/dL, mild metabolic acidosis and normal urine analysis. His general condition improved after treatment with intravenous fluids. His diarrhea continued, but vomiting subsided. Stool bacterial cultures were negative, and rotavirus antigen was detected in his stool.

On the third day of hospitalization, his temperature rose to 39.5° C, and he became more lethargic.

A plain abdominal radiograph showed intraluminal air in the small bowel (pneumatosis intestinalis) without free air or intraportal gas. Abdominal ultrasound appeared normal. Laboratory analysis showed white blood cell counts of 14,400 cells/μL with 9% bands and 59% neutrophils, urea 15 mg/dL, pH 7.37, partial pressure of carbon dioxide 20.7 mm Hg, bicarbonate 11.8 mmol/L, and normal U/A.

The infant was treated with intravenous piperacillin-tazobactam, and oral feeding was discontinued. His fever resolved, and his general condition improved. Klebsiella pneumoniae was recovered from the blood culture and was sensitive to cephalosporins, aminoglycosides, trimethoprim-sulfamethoxazole, and amoxicillin-clavulanate.

After 4 days of fasting, the infant began receiving semi-elemental nutrition. The infant completed 10 days of intravenous antibiotics and resumed a normal diet by the 13th day of hospitalization. He was discharged and appeared to be in excellent health at follow-up 1 month later.

Children with rotavirus gastroenteritis face a small but real risk of developing enteric gram-negative sepsis, investigators have reported.

Physicians “should be aware of the possibility of this complication, especially when a child is developing a high fever and lethargy several days after the beginning of gastroenteritis,” said Amos Adler, M.D., and his colleagues at the Sapir Medical Center in Kfar Saba, Israel.

“In such cases, prompt initiation of wide-spectrum antibiotics is crucial, even in previously diagnosed rotavirus infection,” they said (Clinical Pediatrics 2005:44;351–4).

The investigators described three previously healthy infants who developed enteric gram-negative rods (EGNR) bacteremia during rotavirus gastroenteritis. The children were hospitalized at the medical center in 2000 and 2001.

The infants had the characteristic clinical course of rotavirus gastroenteritis at the beginning of their illness. Then, 3–5 days after the onset of disease, they presented with an abrupt onset of high fever, lethargy, and poor perfusion.

Laboratory results suggested bacterial sepsis, and in one case, there also was radiographic evidence of severe intestinal injury due to pneumatosis intestinalis.

In all of them, the EGNR isolated from the blood cultures were sensitive to aminoglycosides and to second- or third-generation cephalosporins.

(Stool cultures in each patient tested negative for Shigella, Salmonella, enteropathogenic Escherichia coli, and Campylobacter.)

Differentiating between secondary EGHR infection and the deterioration of rotavirus gastroenteritis to a severe course “may be difficult,” the investigators said.

It also is difficult to pinpoint the mechanism of bacterial breakthrough and spreading in these three cases, especially since rotavirus is not known to cause extensive inflammation and cell destruction, they said.

Still, the investigators said, they hypothesize that the pathogenesis of the bacteremia “was dissemination of normal intestinal flora through the damaged mucosa”— just as viral infection of the respiratory tract can antecede and predispose children to colonization and invasion of bacteria such as Streptococcus pneumoniae.

It is possible that bacteremia took hold through other sites—the urinary tract or the respiratory tract, for instance—but it's less likely since no clinical or laboratory findings support it, Dr. Adler and his colleagues said.

They said they could not find in the English literature a description of EGNR bacteremia as a complication of rotavirus infection.

One of their patients, for example, was a healthy 9-month-old boy, admitted after 1 day of vomiting and diarrhea. On admission, he was afebrile and appeared lethargic and moderately dehydrated.

The child had normal blood count and electrolytes, urea 53 mg/dL, mild metabolic acidosis and normal urine analysis. His general condition improved after treatment with intravenous fluids. His diarrhea continued, but vomiting subsided. Stool bacterial cultures were negative, and rotavirus antigen was detected in his stool.

On the third day of hospitalization, his temperature rose to 39.5° C, and he became more lethargic.

A plain abdominal radiograph showed intraluminal air in the small bowel (pneumatosis intestinalis) without free air or intraportal gas. Abdominal ultrasound appeared normal. Laboratory analysis showed white blood cell counts of 14,400 cells/μL with 9% bands and 59% neutrophils, urea 15 mg/dL, pH 7.37, partial pressure of carbon dioxide 20.7 mm Hg, bicarbonate 11.8 mmol/L, and normal U/A.

The infant was treated with intravenous piperacillin-tazobactam, and oral feeding was discontinued. His fever resolved, and his general condition improved. Klebsiella pneumoniae was recovered from the blood culture and was sensitive to cephalosporins, aminoglycosides, trimethoprim-sulfamethoxazole, and amoxicillin-clavulanate.

After 4 days of fasting, the infant began receiving semi-elemental nutrition. The infant completed 10 days of intravenous antibiotics and resumed a normal diet by the 13th day of hospitalization. He was discharged and appeared to be in excellent health at follow-up 1 month later.

As Paul L. Rowland III, M.D., now sees it, physicians can talk to parents and their overweight children about diet and physical activity, or they can really counsel—that is, ask, listen, listen some more, and talk.

It's only through real counseling, he said, that doctors can hope to prevent and treat obesity and overweight—and all the morbidities that accompany it. “I've learned how to approach this in a positive way, how not to alienate [the families].”

Dr. Rowland is 1 of 20 pediatricians in the Pittsburgh area who participated in a two-pronged practice-based pilot project in which they changed and intensified their counseling—and implemented behavioral treatment programs in their two practices for overweight 8- to 12-year-old children and their families.

The short-term results have encouraged Dr. Rowland and his colleagues to continue. Thirty-seven children who were counseled during well-child visits and subsequently completed the 5-month-long intervention had a mean weight loss of 4 pounds. Seventeen of these children, who were followed for 6 months or more, had a mean decrease in BMI of 2 absolute units, or approximately 7% of their baseline BMI.

Perhaps more importantly, the children made dietary changes and changes in their activity levels that Dr. Rowland and his colleagues believe will have a long-lasting impact.

“We didn't see great weight loss. But these children are at an age where they're expected to gain weight and height, so any weight loss is fabulous,” said Ellen Wald, M.D., who codirected the project.

The call for physicians to incorporate weight management into their practices is intensifying. Numerous bodies have recommended that childhood obesity be prevented and treated in the primary care setting, and both the American Academy of Pediatrics (AAP) and the American Medical Association soon plan to issue clinical guidelines for weight management in children.

Surveys have repeatedly revealed what holds back primary care physicians: a lack of training and perceived competence, a lack of time, parent unwillingness to become involved, few available treatment options, and a lack of third-party reimbursement.

Dr. Rowland said he “didn't need any prompting” when asked to participate in the project almost 2 years ago. He and the five other full-time pediatricians in his ethnically and economically diverse practice, Pittsburgh Pediatric Associates, had only recently begun measuring BMI in some patients. Still, he said, overweight “was a concern that [had been] weighing on our minds for a long time.”

Dr. Rowland also is a member of a 3-year-old practice-based research network—Pediatric PitNet—comprising physicians in practices that are partially owned by Children's Hospital of Pittsburgh. The network had been awarded a $125,000 grant through the Robert Wood Johnson Foundation's “Prescription for Health” program—an initiative that funds practice-based pilot projects aimed at combating unhealthy behaviors in primary care.

For their part, he and the other physician participants completed a 60-minute self-study packet that included 7-year-old recommendations on obesity management from the federal Maternal and Child Health Bureau, the AAP's 2003 policy statement on pediatric overweight and obesity, and reports by Leonard H. Epstein, Ph.D., on his successes with behavioral family-based treatment.

(In 1994, Dr. Epstein and his colleagues reported 10-year outcomes showing that significant numbers of children who lost weight through family-based behavioral treatment maintained that weight loss, or lost more, through adolescence and into adulthood.)

They then attended a 90-minute session—led by health psychologists from the Western Psychiatric Institute and Clinic—in which they revamped their approach to talking during well-child visits about weight and BMI, nutrition, and physical activity.

“The important thing is not to come off sounding judgmental, but to solicit and tease out their concerns a little bit better,” said Dr. Rowland. “I learned to see where the family's coming from—to ask open-ended questions and restate what they're saying—before I start sharing my opinions.”

He said he was surprised by how many parents are concerned about their child's excess weight, but just need to be prompted to talk about it. When parents don't voluntarily express concern, “I show them the [BMI] curve and see how they respond. I might ask, are you concerned? Many will say 'Yes, I didn't bring it up before, but yes.'”

“We almost always end up talking about activity or snacking. Parents will sometimes say, 'He's eating a lot of healthy foods' but when I restated their thoughts, they'd start talking about portion size, how 'He eats seconds or thirds.'”

Per the study protocol, Dr. Rowland encouraged children with a BMI at the 85th percentile or higher, whenever possible, to participate with their parents in a behavioral treatment program. Each run of the program consisted of eight weekly group sessions and three individual follow-up sessions held right in his practice. (See box below at right.)

On his own initiative, Dr. Rowland went further. He attended many of the sessions, sitting in with the kids and keeping his own food and activity logs.

“I don't have any weight issues, and I am physically fit, but I really wanted to learn what these kids were thinking. And I started thinking, maybe I could also do better. I realized what a huge issue these lifestyle changes are,” Dr. Rowland said. “That's why the whole family has to be on board—one member can't make [the] change if other members aren't trying, too.”

Of 73 families who enrolled in the program, 37 completed it. (Families were “completers” if they attended six of the eight group sessions and one of the three follow-up sessions.)

In addition to the mean drop in weight and BMI, the 37 children decreased their consumption of high-fat, low-nutrient foods by half or more. Twenty-one of these children who used pedometers throughout the intervention period also saw a 50% increase in steps per day. (All children started the intervention using pedometers, but many discontinued using the pedometers after the first few weeks.)

Interviews with parents showed that the physicians used what they'd been taught, said Linda Ewing, Ph.D., a codirector of the project who presented some of the findings at the annual meeting of the Pediatric Academic Societies.

Twenty-seven randomly selected parents were interviewed before and after the program. Prior to the training, 37% reported that their child's doctor had discussed physical activity during their well-child visit; after training, this jumped to 89%.

The percentage of parents who reported that the doctor had discussed their child's eating habits jumped from 37% before training to 82% afterward, she said.

“We've shown that it's feasible—that pediatricians will [adopt new skills] and address issues of weight more confidently, and that parents will come to an evidence-based intervention in the office,” said Dr. Ewing of the University of Pittsburgh. “It's the first step, but by no means the last.”

Clinical Growth Charts 'To Go'

If your practice is already working on weight management or getting ready to work with the upcoming clinical guidelines on weight management, the Centers for Disease Control and Prevention's National Center for Health Statistics can help with the record keeping. Copyright-free, customizable PowerPoint charts for tracking boys' and girls' stature-for-age, weight-for-age, and BMI-for-age are available online (

www.cdc.gov/nchs/about/major/nhanes/growthcharts/Powerpt.htm

From Weigh-Ins to Group Sessions: What Behavioral Treatment Entails

Children who attended the behavioral treatment program at Dr. Rowland's practice started each of the eight weekly sessions with a “weigh-in” and an individual family “coaching” session.

The children then met in a group with a clinical psychologist from outside the practice while the parents met primarily with the pediatric office's nurse-practitioner, M. Kathleen Kelly.

“The kids are very honest, and they're encouraged by small changes,” said Dr. Rowland, who attended many of the children's group sessions. “They would readily answer to 'What was difficult for you?' and 'What can you do for next week?'”

Sessions for both parents and children focused on self-monitoring of diet and activity, stimulus control, goal setting, positive reinforcement, social assertion, and relapse prevention.

The goals were to decrease intake of high-fat, low-nutrient foods; to increase intake of low-fat, high-nutrient foods; to decrease sedentary behaviors; and to increase activity and exercise.

Many of the children already had received a small BMI chart color-coded into red, yellow, and green zones to indicate overweight, at-risk, and healthy ranges of BMI. The colors correspond to the red, yellow, and green categories of food in the “stop-light diet”—a concept that the project directors incorporated into the nutritional counseling element of the project. They had the chart designed as an educational tool.

Of 73 children who enrolled, only 4 had a BMI between the 85th and 94th percentiles; the rest of the children were heavier.

Each run of the program in each of the two participating practices—Pittsburgh Pediatric Associates, Dr. Rowland's practice, and Children's Community Care, a rural practice right outside Pittsburgh—consisted of fairly even numbers of boys and girls, with a mean age of 10 years.

As Paul L. Rowland III, M.D., now sees it, physicians can talk to parents and their overweight children about diet and physical activity, or they can really counsel—that is, ask, listen, listen some more, and talk.

It's only through real counseling, he said, that doctors can hope to prevent and treat obesity and overweight—and all the morbidities that accompany it. “I've learned how to approach this in a positive way, how not to alienate [the families].”

Dr. Rowland is 1 of 20 pediatricians in the Pittsburgh area who participated in a two-pronged practice-based pilot project in which they changed and intensified their counseling—and implemented behavioral treatment programs in their two practices for overweight 8- to 12-year-old children and their families.

The short-term results have encouraged Dr. Rowland and his colleagues to continue. Thirty-seven children who were counseled during well-child visits and subsequently completed the 5-month-long intervention had a mean weight loss of 4 pounds. Seventeen of these children, who were followed for 6 months or more, had a mean decrease in BMI of 2 absolute units, or approximately 7% of their baseline BMI.

Perhaps more importantly, the children made dietary changes and changes in their activity levels that Dr. Rowland and his colleagues believe will have a long-lasting impact.

“We didn't see great weight loss. But these children are at an age where they're expected to gain weight and height, so any weight loss is fabulous,” said Ellen Wald, M.D., who codirected the project.

The call for physicians to incorporate weight management into their practices is intensifying. Numerous bodies have recommended that childhood obesity be prevented and treated in the primary care setting, and both the American Academy of Pediatrics (AAP) and the American Medical Association soon plan to issue clinical guidelines for weight management in children.

Surveys have repeatedly revealed what holds back primary care physicians: a lack of training and perceived competence, a lack of time, parent unwillingness to become involved, few available treatment options, and a lack of third-party reimbursement.

Dr. Rowland said he “didn't need any prompting” when asked to participate in the project almost 2 years ago. He and the five other full-time pediatricians in his ethnically and economically diverse practice, Pittsburgh Pediatric Associates, had only recently begun measuring BMI in some patients. Still, he said, overweight “was a concern that [had been] weighing on our minds for a long time.”

Dr. Rowland also is a member of a 3-year-old practice-based research network—Pediatric PitNet—comprising physicians in practices that are partially owned by Children's Hospital of Pittsburgh. The network had been awarded a $125,000 grant through the Robert Wood Johnson Foundation's “Prescription for Health” program—an initiative that funds practice-based pilot projects aimed at combating unhealthy behaviors in primary care.

For their part, he and the other physician participants completed a 60-minute self-study packet that included 7-year-old recommendations on obesity management from the federal Maternal and Child Health Bureau, the AAP's 2003 policy statement on pediatric overweight and obesity, and reports by Leonard H. Epstein, Ph.D., on his successes with behavioral family-based treatment.

(In 1994, Dr. Epstein and his colleagues reported 10-year outcomes showing that significant numbers of children who lost weight through family-based behavioral treatment maintained that weight loss, or lost more, through adolescence and into adulthood.)

They then attended a 90-minute session—led by health psychologists from the Western Psychiatric Institute and Clinic—in which they revamped their approach to talking during well-child visits about weight and BMI, nutrition, and physical activity.

“The important thing is not to come off sounding judgmental, but to solicit and tease out their concerns a little bit better,” said Dr. Rowland. “I learned to see where the family's coming from—to ask open-ended questions and restate what they're saying—before I start sharing my opinions.”

He said he was surprised by how many parents are concerned about their child's excess weight, but just need to be prompted to talk about it. When parents don't voluntarily express concern, “I show them the [BMI] curve and see how they respond. I might ask, are you concerned? Many will say 'Yes, I didn't bring it up before, but yes.'”

“We almost always end up talking about activity or snacking. Parents will sometimes say, 'He's eating a lot of healthy foods' but when I restated their thoughts, they'd start talking about portion size, how 'He eats seconds or thirds.'”

Per the study protocol, Dr. Rowland encouraged children with a BMI at the 85th percentile or higher, whenever possible, to participate with their parents in a behavioral treatment program. Each run of the program consisted of eight weekly group sessions and three individual follow-up sessions held right in his practice. (See box below at right.)

On his own initiative, Dr. Rowland went further. He attended many of the sessions, sitting in with the kids and keeping his own food and activity logs.

“I don't have any weight issues, and I am physically fit, but I really wanted to learn what these kids were thinking. And I started thinking, maybe I could also do better. I realized what a huge issue these lifestyle changes are,” Dr. Rowland said. “That's why the whole family has to be on board—one member can't make [the] change if other members aren't trying, too.”

Of 73 families who enrolled in the program, 37 completed it. (Families were “completers” if they attended six of the eight group sessions and one of the three follow-up sessions.)

In addition to the mean drop in weight and BMI, the 37 children decreased their consumption of high-fat, low-nutrient foods by half or more. Twenty-one of these children who used pedometers throughout the intervention period also saw a 50% increase in steps per day. (All children started the intervention using pedometers, but many discontinued using the pedometers after the first few weeks.)

Interviews with parents showed that the physicians used what they'd been taught, said Linda Ewing, Ph.D., a codirector of the project who presented some of the findings at the annual meeting of the Pediatric Academic Societies.

Twenty-seven randomly selected parents were interviewed before and after the program. Prior to the training, 37% reported that their child's doctor had discussed physical activity during their well-child visit; after training, this jumped to 89%.

The percentage of parents who reported that the doctor had discussed their child's eating habits jumped from 37% before training to 82% afterward, she said.

“We've shown that it's feasible—that pediatricians will [adopt new skills] and address issues of weight more confidently, and that parents will come to an evidence-based intervention in the office,” said Dr. Ewing of the University of Pittsburgh. “It's the first step, but by no means the last.”

Clinical Growth Charts 'To Go'

If your practice is already working on weight management or getting ready to work with the upcoming clinical guidelines on weight management, the Centers for Disease Control and Prevention's National Center for Health Statistics can help with the record keeping. Copyright-free, customizable PowerPoint charts for tracking boys' and girls' stature-for-age, weight-for-age, and BMI-for-age are available online (

www.cdc.gov/nchs/about/major/nhanes/growthcharts/Powerpt.htm

From Weigh-Ins to Group Sessions: What Behavioral Treatment Entails

Children who attended the behavioral treatment program at Dr. Rowland's practice started each of the eight weekly sessions with a “weigh-in” and an individual family “coaching” session.

The children then met in a group with a clinical psychologist from outside the practice while the parents met primarily with the pediatric office's nurse-practitioner, M. Kathleen Kelly.

“The kids are very honest, and they're encouraged by small changes,” said Dr. Rowland, who attended many of the children's group sessions. “They would readily answer to 'What was difficult for you?' and 'What can you do for next week?'”

Sessions for both parents and children focused on self-monitoring of diet and activity, stimulus control, goal setting, positive reinforcement, social assertion, and relapse prevention.

The goals were to decrease intake of high-fat, low-nutrient foods; to increase intake of low-fat, high-nutrient foods; to decrease sedentary behaviors; and to increase activity and exercise.

Many of the children already had received a small BMI chart color-coded into red, yellow, and green zones to indicate overweight, at-risk, and healthy ranges of BMI. The colors correspond to the red, yellow, and green categories of food in the “stop-light diet”—a concept that the project directors incorporated into the nutritional counseling element of the project. They had the chart designed as an educational tool.

Of 73 children who enrolled, only 4 had a BMI between the 85th and 94th percentiles; the rest of the children were heavier.

Each run of the program in each of the two participating practices—Pittsburgh Pediatric Associates, Dr. Rowland's practice, and Children's Community Care, a rural practice right outside Pittsburgh—consisted of fairly even numbers of boys and girls, with a mean age of 10 years.

As Paul L. Rowland III, M.D., now sees it, physicians can talk to parents and their overweight children about diet and physical activity, or they can really counsel—that is, ask, listen, listen some more, and talk.

It's only through real counseling, he said, that doctors can hope to prevent and treat obesity and overweight—and all the morbidities that accompany it. “I've learned how to approach this in a positive way, how not to alienate [the families].”

Dr. Rowland is 1 of 20 pediatricians in the Pittsburgh area who participated in a two-pronged practice-based pilot project in which they changed and intensified their counseling—and implemented behavioral treatment programs in their two practices for overweight 8- to 12-year-old children and their families.

The short-term results have encouraged Dr. Rowland and his colleagues to continue. Thirty-seven children who were counseled during well-child visits and subsequently completed the 5-month-long intervention had a mean weight loss of 4 pounds. Seventeen of these children, who were followed for 6 months or more, had a mean decrease in BMI of 2 absolute units, or approximately 7% of their baseline BMI.

Perhaps more importantly, the children made dietary changes and changes in their activity levels that Dr. Rowland and his colleagues believe will have a long-lasting impact.

“We didn't see great weight loss. But these children are at an age where they're expected to gain weight and height, so any weight loss is fabulous,” said Ellen Wald, M.D., who codirected the project.

The call for physicians to incorporate weight management into their practices is intensifying. Numerous bodies have recommended that childhood obesity be prevented and treated in the primary care setting, and both the American Academy of Pediatrics (AAP) and the American Medical Association soon plan to issue clinical guidelines for weight management in children.

Surveys have repeatedly revealed what holds back primary care physicians: a lack of training and perceived competence, a lack of time, parent unwillingness to become involved, few available treatment options, and a lack of third-party reimbursement.

Dr. Rowland said he “didn't need any prompting” when asked to participate in the project almost 2 years ago. He and the five other full-time pediatricians in his ethnically and economically diverse practice, Pittsburgh Pediatric Associates, had only recently begun measuring BMI in some patients. Still, he said, overweight “was a concern that [had been] weighing on our minds for a long time.”

Dr. Rowland also is a member of a 3-year-old practice-based research network—Pediatric PitNet—comprising physicians in practices that are partially owned by Children's Hospital of Pittsburgh. The network had been awarded a $125,000 grant through the Robert Wood Johnson Foundation's “Prescription for Health” program—an initiative that funds practice-based pilot projects aimed at combating unhealthy behaviors in primary care.

For their part, he and the other physician participants completed a 60-minute self-study packet that included 7-year-old recommendations on obesity management from the federal Maternal and Child Health Bureau, the AAP's 2003 policy statement on pediatric overweight and obesity, and reports by Leonard H. Epstein, Ph.D., on his successes with behavioral family-based treatment.

(In 1994, Dr. Epstein and his colleagues reported 10-year outcomes showing that significant numbers of children who lost weight through family-based behavioral treatment maintained that weight loss, or lost more, through adolescence and into adulthood.)

They then attended a 90-minute session—led by health psychologists from the Western Psychiatric Institute and Clinic—in which they revamped their approach to talking during well-child visits about weight and BMI, nutrition, and physical activity.

“The important thing is not to come off sounding judgmental, but to solicit and tease out their concerns a little bit better,” said Dr. Rowland. “I learned to see where the family's coming from—to ask open-ended questions and restate what they're saying—before I start sharing my opinions.”

He said he was surprised by how many parents are concerned about their child's excess weight, but just need to be prompted to talk about it. When parents don't voluntarily express concern, “I show them the [BMI] curve and see how they respond. I might ask, are you concerned? Many will say 'Yes, I didn't bring it up before, but yes.'”

“We almost always end up talking about activity or snacking. Parents will sometimes say, 'He's eating a lot of healthy foods' but when I restated their thoughts, they'd start talking about portion size, how 'He eats seconds or thirds.'”

Per the study protocol, Dr. Rowland encouraged children with a BMI at the 85th percentile or higher, whenever possible, to participate with their parents in a behavioral treatment program. Each run of the program consisted of eight weekly group sessions and three individual follow-up sessions held right in his practice. (See box below at right.)

On his own initiative, Dr. Rowland went further. He attended many of the sessions, sitting in with the kids and keeping his own food and activity logs.

“I don't have any weight issues, and I am physically fit, but I really wanted to learn what these kids were thinking. And I started thinking, maybe I could also do better. I realized what a huge issue these lifestyle changes are,” Dr. Rowland said. “That's why the whole family has to be on board—one member can't make [the] change if other members aren't trying, too.”

Of 73 families who enrolled in the program, 37 completed it. (Families were “completers” if they attended six of the eight group sessions and one of the three follow-up sessions.)

In addition to the mean drop in weight and BMI, the 37 children decreased their consumption of high-fat, low-nutrient foods by half or more. Twenty-one of these children who used pedometers throughout the intervention period also saw a 50% increase in steps per day. (All children started the intervention using pedometers, but many discontinued using the pedometers after the first few weeks.)

Interviews with parents showed that the physicians used what they'd been taught, said Linda Ewing, Ph.D., a codirector of the project who presented some of the findings at the annual meeting of the Pediatric Academic Societies.

Twenty-seven randomly selected parents were interviewed before and after the program. Prior to the training, 37% reported that their child's doctor had discussed physical activity during their well-child visit; after training, this jumped to 89%.

The percentage of parents who reported that the doctor had discussed their child's eating habits jumped from 37% before training to 82% afterward, she said.

“We've shown that it's feasible—that pediatricians will [adopt new skills] and address issues of weight more confidently, and that parents will come to an evidence-based intervention in the office,” said Dr. Ewing of the University of Pittsburgh. “It's the first step, but by no means the last.”

Clinical Growth Charts 'To Go'

If your practice is already working on weight management or getting ready to work with the upcoming clinical guidelines on weight management, the Centers for Disease Control and Prevention's National Center for Health Statistics can help with the record keeping. Copyright-free, customizable PowerPoint charts for tracking boys' and girls' stature-for-age, weight-for-age, and BMI-for-age are available online (

www.cdc.gov/nchs/about/major/nhanes/growthcharts/Powerpt.htm

From Weigh-Ins to Group Sessions: What Behavioral Treatment Entails

Children who attended the behavioral treatment program at Dr. Rowland's practice started each of the eight weekly sessions with a “weigh-in” and an individual family “coaching” session.

The children then met in a group with a clinical psychologist from outside the practice while the parents met primarily with the pediatric office's nurse-practitioner, M. Kathleen Kelly.

“The kids are very honest, and they're encouraged by small changes,” said Dr. Rowland, who attended many of the children's group sessions. “They would readily answer to 'What was difficult for you?' and 'What can you do for next week?'”

Sessions for both parents and children focused on self-monitoring of diet and activity, stimulus control, goal setting, positive reinforcement, social assertion, and relapse prevention.

The goals were to decrease intake of high-fat, low-nutrient foods; to increase intake of low-fat, high-nutrient foods; to decrease sedentary behaviors; and to increase activity and exercise.

Many of the children already had received a small BMI chart color-coded into red, yellow, and green zones to indicate overweight, at-risk, and healthy ranges of BMI. The colors correspond to the red, yellow, and green categories of food in the “stop-light diet”—a concept that the project directors incorporated into the nutritional counseling element of the project. They had the chart designed as an educational tool.

Of 73 children who enrolled, only 4 had a BMI between the 85th and 94th percentiles; the rest of the children were heavier.

Each run of the program in each of the two participating practices—Pittsburgh Pediatric Associates, Dr. Rowland's practice, and Children's Community Care, a rural practice right outside Pittsburgh—consisted of fairly even numbers of boys and girls, with a mean age of 10 years.

Watchful waiting for nonsevere acute otitis media can be as acceptable to parents as immediate antibiotic treatment—if parents are properly educated about the options, new study findings and survey results indicate.

Parents' satisfaction with their children's care was no different among parents whose children were randomized to receive either immediate antibiotic treatment or watchful waiting in an outcomes study of the two approaches. The parents all were educated at the study site—a pediatric clinic in Galveston, Texas—about the risks and benefits of treatment.

In a separate study, only a minority of parents who were randomly surveyed by mail about a hypothetical visit for an ear infection—without being given much information—said they would feel comfortable with a watchful waiting approach. Most said they would feel neutral or dissatisfied with such an approach.

The studies show that “when it's properly explained, parents are equally satisfied with watchful waiting and antibiotic treatment [for nonsevere acute otitis media],” said Allan S. Lieberthal, M.D., who led development of the American Academy of Pediatrics' guidelines on the diagnosis and management of acute otitis media.

“Now we need tools for educating parents within the confines of a busy pediatric office,” he said in an interview.

Investigators in the randomized study used a handheld flip chart for a 5- to 10-minute review with parents of the definition and causes of ear infections, characteristics of nonsevere and severe acute otitis media (AOM), antibiotic resistance and costs, rate of symptom response to antibiotics, and possible adverse outcomes associated with immediate treatment versus observation.

Parent satisfaction was no different between a group of 111 children randomized to a watchful waiting group and 112 randomized to receive immediate antibiotics, either at day 12 or day 30 after the children were seen, reported David P. McCormick, M.D., of the University of Texas, Galveston, and his colleagues (Pediatrics 2005:115;1455–65).

In the survey, 5,129 parents in 16 Massachusetts communities were asked to rate their level of satisfaction “if your child's doctor diagnosed an ear infection and recommended waiting 1 or 2 days before starting antibiotics (to see if the symptoms get better on their own).”

Of 2,054 parents who returned the survey, 34% said they would be somewhat or extremely satisfied. Another 26% indicated they would be neutral, and the remaining 40% said they would be somewhat or extremely dissatisfied, reported Jonathan A. Finkelstein, M.D., of Harvard Medical School, Boston, and his associates (Pediatrics 2005:115;1466–73).

Both studies were conducted before the AAP guidelines were published last year.

In addition to offering new insight into issues of parent acceptance, findings from the randomized study affirm what the guidelines say: that some children with nonsevere AOM may be observed with watchful waiting as long as they maintain nonsevere status and are kept comfortable with appropriate symptom management, Dr. Lieberthal said.

Of the children randomized to the watchful waiting group, 66% completed the study without antibiotics.

Immediate antibiotic treatment was associated with 16% fewer treatment failures—a difference that the investigators said was larger than they “expected from [their] review of the literature”—and improved symptom control.

Antibiotic treatment also was associated, however, with increased antibiotic-related adverse events. And although immediate treatment resulted in eradication of Streptococcus pneumoniae carriage in the majority of children, the S. pneumoniae strains cultured from children in the antibiotic group at day 12 were more likely to be multidrug-resistant than were strains from the watchful waiting group, the investigators reported.

“Watchful waiting seems to be an alternative that is acceptable to parents, reduces the number and cost of antibiotic prescriptions, and reduces the percent of multidrug-resistant bacteria colonizing the nasopharynx of children after an episode of AOM,” Dr. McCormick and his associates said.

Regardless of the intervention, children who had received antibiotics within the previous 30 days were more than twice as likely to fail treatment as those who had not recently received antibiotics.

In addition to parent education, key factors for implementation of a watchful waiting strategy include access to follow-up care, management of AOM symptoms, and a method to classify AOM severity, the investigators said.

They assessed AOM severity based on four factors: parental perception of severity, otoscopic examination, body temperature, and tympanogram scores.

However, “in retrospect,” they reported, they “could have obtained the same results”—identifying 87% of the nonsevere cases identified with the four-factor scoring system—by using a two-factor scoring system that omitted body temperature and tympanogram.

“Most children with AOM are afebrile at the time of diagnosis as a result of antipyretic medication,” they said. “Practicing clinicians rarely use the tympanogram to make a diagnosis of AOM.”

Dr. Lieberthal, cochair of the AAP's subcommittee on management of AOM and professor of pediatrics at the University of Southern California, Los Angeles, said the issue of how to accurately and uniformly assess AOM severity is still unresolved. “We still need a validated scoring system.”

Watchful waiting for nonsevere acute otitis media can be as acceptable to parents as immediate antibiotic treatment—if parents are properly educated about the options, new study findings and survey results indicate.

Parents' satisfaction with their children's care was no different among parents whose children were randomized to receive either immediate antibiotic treatment or watchful waiting in an outcomes study of the two approaches. The parents all were educated at the study site—a pediatric clinic in Galveston, Texas—about the risks and benefits of treatment.

In a separate study, only a minority of parents who were randomly surveyed by mail about a hypothetical visit for an ear infection—without being given much information—said they would feel comfortable with a watchful waiting approach. Most said they would feel neutral or dissatisfied with such an approach.

The studies show that “when it's properly explained, parents are equally satisfied with watchful waiting and antibiotic treatment [for nonsevere acute otitis media],” said Allan S. Lieberthal, M.D., who led development of the American Academy of Pediatrics' guidelines on the diagnosis and management of acute otitis media.

“Now we need tools for educating parents within the confines of a busy pediatric office,” he said in an interview.

Investigators in the randomized study used a handheld flip chart for a 5- to 10-minute review with parents of the definition and causes of ear infections, characteristics of nonsevere and severe acute otitis media (AOM), antibiotic resistance and costs, rate of symptom response to antibiotics, and possible adverse outcomes associated with immediate treatment versus observation.

Parent satisfaction was no different between a group of 111 children randomized to a watchful waiting group and 112 randomized to receive immediate antibiotics, either at day 12 or day 30 after the children were seen, reported David P. McCormick, M.D., of the University of Texas, Galveston, and his colleagues (Pediatrics 2005:115;1455–65).

In the survey, 5,129 parents in 16 Massachusetts communities were asked to rate their level of satisfaction “if your child's doctor diagnosed an ear infection and recommended waiting 1 or 2 days before starting antibiotics (to see if the symptoms get better on their own).”

Of 2,054 parents who returned the survey, 34% said they would be somewhat or extremely satisfied. Another 26% indicated they would be neutral, and the remaining 40% said they would be somewhat or extremely dissatisfied, reported Jonathan A. Finkelstein, M.D., of Harvard Medical School, Boston, and his associates (Pediatrics 2005:115;1466–73).

Both studies were conducted before the AAP guidelines were published last year.

In addition to offering new insight into issues of parent acceptance, findings from the randomized study affirm what the guidelines say: that some children with nonsevere AOM may be observed with watchful waiting as long as they maintain nonsevere status and are kept comfortable with appropriate symptom management, Dr. Lieberthal said.

Of the children randomized to the watchful waiting group, 66% completed the study without antibiotics.

Immediate antibiotic treatment was associated with 16% fewer treatment failures—a difference that the investigators said was larger than they “expected from [their] review of the literature”—and improved symptom control.

Antibiotic treatment also was associated, however, with increased antibiotic-related adverse events. And although immediate treatment resulted in eradication of Streptococcus pneumoniae carriage in the majority of children, the S. pneumoniae strains cultured from children in the antibiotic group at day 12 were more likely to be multidrug-resistant than were strains from the watchful waiting group, the investigators reported.

“Watchful waiting seems to be an alternative that is acceptable to parents, reduces the number and cost of antibiotic prescriptions, and reduces the percent of multidrug-resistant bacteria colonizing the nasopharynx of children after an episode of AOM,” Dr. McCormick and his associates said.

Regardless of the intervention, children who had received antibiotics within the previous 30 days were more than twice as likely to fail treatment as those who had not recently received antibiotics.

In addition to parent education, key factors for implementation of a watchful waiting strategy include access to follow-up care, management of AOM symptoms, and a method to classify AOM severity, the investigators said.

They assessed AOM severity based on four factors: parental perception of severity, otoscopic examination, body temperature, and tympanogram scores.

However, “in retrospect,” they reported, they “could have obtained the same results”—identifying 87% of the nonsevere cases identified with the four-factor scoring system—by using a two-factor scoring system that omitted body temperature and tympanogram.

“Most children with AOM are afebrile at the time of diagnosis as a result of antipyretic medication,” they said. “Practicing clinicians rarely use the tympanogram to make a diagnosis of AOM.”

Dr. Lieberthal, cochair of the AAP's subcommittee on management of AOM and professor of pediatrics at the University of Southern California, Los Angeles, said the issue of how to accurately and uniformly assess AOM severity is still unresolved. “We still need a validated scoring system.”

Watchful waiting for nonsevere acute otitis media can be as acceptable to parents as immediate antibiotic treatment—if parents are properly educated about the options, new study findings and survey results indicate.

Parents' satisfaction with their children's care was no different among parents whose children were randomized to receive either immediate antibiotic treatment or watchful waiting in an outcomes study of the two approaches. The parents all were educated at the study site—a pediatric clinic in Galveston, Texas—about the risks and benefits of treatment.

In a separate study, only a minority of parents who were randomly surveyed by mail about a hypothetical visit for an ear infection—without being given much information—said they would feel comfortable with a watchful waiting approach. Most said they would feel neutral or dissatisfied with such an approach.

The studies show that “when it's properly explained, parents are equally satisfied with watchful waiting and antibiotic treatment [for nonsevere acute otitis media],” said Allan S. Lieberthal, M.D., who led development of the American Academy of Pediatrics' guidelines on the diagnosis and management of acute otitis media.

“Now we need tools for educating parents within the confines of a busy pediatric office,” he said in an interview.

Investigators in the randomized study used a handheld flip chart for a 5- to 10-minute review with parents of the definition and causes of ear infections, characteristics of nonsevere and severe acute otitis media (AOM), antibiotic resistance and costs, rate of symptom response to antibiotics, and possible adverse outcomes associated with immediate treatment versus observation.

Parent satisfaction was no different between a group of 111 children randomized to a watchful waiting group and 112 randomized to receive immediate antibiotics, either at day 12 or day 30 after the children were seen, reported David P. McCormick, M.D., of the University of Texas, Galveston, and his colleagues (Pediatrics 2005:115;1455–65).

In the survey, 5,129 parents in 16 Massachusetts communities were asked to rate their level of satisfaction “if your child's doctor diagnosed an ear infection and recommended waiting 1 or 2 days before starting antibiotics (to see if the symptoms get better on their own).”

Of 2,054 parents who returned the survey, 34% said they would be somewhat or extremely satisfied. Another 26% indicated they would be neutral, and the remaining 40% said they would be somewhat or extremely dissatisfied, reported Jonathan A. Finkelstein, M.D., of Harvard Medical School, Boston, and his associates (Pediatrics 2005:115;1466–73).

Both studies were conducted before the AAP guidelines were published last year.

In addition to offering new insight into issues of parent acceptance, findings from the randomized study affirm what the guidelines say: that some children with nonsevere AOM may be observed with watchful waiting as long as they maintain nonsevere status and are kept comfortable with appropriate symptom management, Dr. Lieberthal said.

Of the children randomized to the watchful waiting group, 66% completed the study without antibiotics.

Immediate antibiotic treatment was associated with 16% fewer treatment failures—a difference that the investigators said was larger than they “expected from [their] review of the literature”—and improved symptom control.

Antibiotic treatment also was associated, however, with increased antibiotic-related adverse events. And although immediate treatment resulted in eradication of Streptococcus pneumoniae carriage in the majority of children, the S. pneumoniae strains cultured from children in the antibiotic group at day 12 were more likely to be multidrug-resistant than were strains from the watchful waiting group, the investigators reported.

“Watchful waiting seems to be an alternative that is acceptable to parents, reduces the number and cost of antibiotic prescriptions, and reduces the percent of multidrug-resistant bacteria colonizing the nasopharynx of children after an episode of AOM,” Dr. McCormick and his associates said.

Regardless of the intervention, children who had received antibiotics within the previous 30 days were more than twice as likely to fail treatment as those who had not recently received antibiotics.

In addition to parent education, key factors for implementation of a watchful waiting strategy include access to follow-up care, management of AOM symptoms, and a method to classify AOM severity, the investigators said.

They assessed AOM severity based on four factors: parental perception of severity, otoscopic examination, body temperature, and tympanogram scores.

However, “in retrospect,” they reported, they “could have obtained the same results”—identifying 87% of the nonsevere cases identified with the four-factor scoring system—by using a two-factor scoring system that omitted body temperature and tympanogram.

“Most children with AOM are afebrile at the time of diagnosis as a result of antipyretic medication,” they said. “Practicing clinicians rarely use the tympanogram to make a diagnosis of AOM.”

Dr. Lieberthal, cochair of the AAP's subcommittee on management of AOM and professor of pediatrics at the University of Southern California, Los Angeles, said the issue of how to accurately and uniformly assess AOM severity is still unresolved. “We still need a validated scoring system.”

WASHINGTON — Auden C. McClure, M.D., and her colleagues noticed some time ago that children and young teens in their New Hampshire community and pediatric practice often wore T-shirts, hats, and other merchandise bearing alcohol brand names and logos.

Now, armed with research findings showing that ownership of such merchandise is associated with early-onset drinking, Dr. McClure is calling on the alcohol industry to follow the example of the tobacco industry and stop distributing the merchandise.

“The alcohol industry should institute a voluntary ban … because of the association with early drinking and because students become a walking advertisement for alcohol consumption,” Dr. McClure said at the annual meeting of the Pediatric Academic Societies.

She reported on a survey of fifth- to eighth-grade students in eight rural public schools in New Hampshire. Approximately 2,400 who said they had never used alcohol were asked by telephone 1–2 years later whether they owned an alcohol promotional item and if they had begun using alcohol.

Fourteen percent reported owning at least one alcohol promotional item (mostly clothing), and 15% reported using alcohol.

Those who owned alcohol promotional items had higher rates of alcohol use, compared with those who did not own the merchandise—approximately 25% vs. 13%, said Dr. McClure, a pediatrician at the Dartmouth-Hitchcock Medical Center in Lebanon, N.H.

Ownership of alcohol promotional items was associated with peer drinking, poor school performance, and high-risk behaviors, such as sensation seeking and rebelliousness.

Even after adjusting for these factors, Dr. McClure and her associates found that students who owned alcohol promotional items were more than 1.5 times more likely to try drinking than their peers.

Tobacco companies spent more than $2 billion in the 1990s on cigarette promotional items, but in 1999 they voluntarily gave up distribution and sale of the products after the practice was found to be associated with adolescent smoking.

Tobacco companies agreed to the ban as part of the master settlement agreement with the state attorneys general.

“Multiple studies during that time documented that tobacco promotional items are prevalent among adolescents, that ownership is associated with smoking, that it's independent of other adolescent risk factors, and also that ownership … precedes the decision to smoke,” Dr. McClure said at the meeting, sponsored by the American Pediatric Society, the Society for Pediatric Research, the Ambulatory Pediatric Association, and the American Academy of Pediatrics.

Unlike the smoking research, their study on alcohol promotional items does not prove causality, she said. The survey also did not ascertain where the items came from—whether they were purchased or received free at sporting events, for instance—and it did not ascertain alcohol brands.

The study also excluded students who, at baseline, had already begun drinking, which means “we potentially could have eliminated a higher-risk population,” Dr. McClure said.

Alcohol use was assessed in the telephone survey with the question, “Have you ever had beer, wine, or another drink of alcohol that your parents didn't know about?” The other main question was: “Do you own something that has the name of a beer or alcohol brand on it like a T-shirt, or a backpack, or a hat?”

A national sample of adolescents is being surveyed currently, she said.

Until more research is completed and action is taken, “parents and schools should help … to eliminate the ownership and display of alcohol promotional items in our schools and homes,” she said.

WASHINGTON — Auden C. McClure, M.D., and her colleagues noticed some time ago that children and young teens in their New Hampshire community and pediatric practice often wore T-shirts, hats, and other merchandise bearing alcohol brand names and logos.

Now, armed with research findings showing that ownership of such merchandise is associated with early-onset drinking, Dr. McClure is calling on the alcohol industry to follow the example of the tobacco industry and stop distributing the merchandise.

“The alcohol industry should institute a voluntary ban … because of the association with early drinking and because students become a walking advertisement for alcohol consumption,” Dr. McClure said at the annual meeting of the Pediatric Academic Societies.

She reported on a survey of fifth- to eighth-grade students in eight rural public schools in New Hampshire. Approximately 2,400 who said they had never used alcohol were asked by telephone 1–2 years later whether they owned an alcohol promotional item and if they had begun using alcohol.

Fourteen percent reported owning at least one alcohol promotional item (mostly clothing), and 15% reported using alcohol.

Those who owned alcohol promotional items had higher rates of alcohol use, compared with those who did not own the merchandise—approximately 25% vs. 13%, said Dr. McClure, a pediatrician at the Dartmouth-Hitchcock Medical Center in Lebanon, N.H.

Ownership of alcohol promotional items was associated with peer drinking, poor school performance, and high-risk behaviors, such as sensation seeking and rebelliousness.

Even after adjusting for these factors, Dr. McClure and her associates found that students who owned alcohol promotional items were more than 1.5 times more likely to try drinking than their peers.

Tobacco companies spent more than $2 billion in the 1990s on cigarette promotional items, but in 1999 they voluntarily gave up distribution and sale of the products after the practice was found to be associated with adolescent smoking.

Tobacco companies agreed to the ban as part of the master settlement agreement with the state attorneys general.

“Multiple studies during that time documented that tobacco promotional items are prevalent among adolescents, that ownership is associated with smoking, that it's independent of other adolescent risk factors, and also that ownership … precedes the decision to smoke,” Dr. McClure said at the meeting, sponsored by the American Pediatric Society, the Society for Pediatric Research, the Ambulatory Pediatric Association, and the American Academy of Pediatrics.

Unlike the smoking research, their study on alcohol promotional items does not prove causality, she said. The survey also did not ascertain where the items came from—whether they were purchased or received free at sporting events, for instance—and it did not ascertain alcohol brands.

The study also excluded students who, at baseline, had already begun drinking, which means “we potentially could have eliminated a higher-risk population,” Dr. McClure said.

Alcohol use was assessed in the telephone survey with the question, “Have you ever had beer, wine, or another drink of alcohol that your parents didn't know about?” The other main question was: “Do you own something that has the name of a beer or alcohol brand on it like a T-shirt, or a backpack, or a hat?”

A national sample of adolescents is being surveyed currently, she said.

Until more research is completed and action is taken, “parents and schools should help … to eliminate the ownership and display of alcohol promotional items in our schools and homes,” she said.

WASHINGTON — Auden C. McClure, M.D., and her colleagues noticed some time ago that children and young teens in their New Hampshire community and pediatric practice often wore T-shirts, hats, and other merchandise bearing alcohol brand names and logos.

Now, armed with research findings showing that ownership of such merchandise is associated with early-onset drinking, Dr. McClure is calling on the alcohol industry to follow the example of the tobacco industry and stop distributing the merchandise.

“The alcohol industry should institute a voluntary ban … because of the association with early drinking and because students become a walking advertisement for alcohol consumption,” Dr. McClure said at the annual meeting of the Pediatric Academic Societies.

She reported on a survey of fifth- to eighth-grade students in eight rural public schools in New Hampshire. Approximately 2,400 who said they had never used alcohol were asked by telephone 1–2 years later whether they owned an alcohol promotional item and if they had begun using alcohol.

Fourteen percent reported owning at least one alcohol promotional item (mostly clothing), and 15% reported using alcohol.

Those who owned alcohol promotional items had higher rates of alcohol use, compared with those who did not own the merchandise—approximately 25% vs. 13%, said Dr. McClure, a pediatrician at the Dartmouth-Hitchcock Medical Center in Lebanon, N.H.

Ownership of alcohol promotional items was associated with peer drinking, poor school performance, and high-risk behaviors, such as sensation seeking and rebelliousness.

Even after adjusting for these factors, Dr. McClure and her associates found that students who owned alcohol promotional items were more than 1.5 times more likely to try drinking than their peers.

Tobacco companies spent more than $2 billion in the 1990s on cigarette promotional items, but in 1999 they voluntarily gave up distribution and sale of the products after the practice was found to be associated with adolescent smoking.

Tobacco companies agreed to the ban as part of the master settlement agreement with the state attorneys general.

“Multiple studies during that time documented that tobacco promotional items are prevalent among adolescents, that ownership is associated with smoking, that it's independent of other adolescent risk factors, and also that ownership … precedes the decision to smoke,” Dr. McClure said at the meeting, sponsored by the American Pediatric Society, the Society for Pediatric Research, the Ambulatory Pediatric Association, and the American Academy of Pediatrics.

Unlike the smoking research, their study on alcohol promotional items does not prove causality, she said. The survey also did not ascertain where the items came from—whether they were purchased or received free at sporting events, for instance—and it did not ascertain alcohol brands.

The study also excluded students who, at baseline, had already begun drinking, which means “we potentially could have eliminated a higher-risk population,” Dr. McClure said.

Alcohol use was assessed in the telephone survey with the question, “Have you ever had beer, wine, or another drink of alcohol that your parents didn't know about?” The other main question was: “Do you own something that has the name of a beer or alcohol brand on it like a T-shirt, or a backpack, or a hat?”

A national sample of adolescents is being surveyed currently, she said.

Until more research is completed and action is taken, “parents and schools should help … to eliminate the ownership and display of alcohol promotional items in our schools and homes,” she said.

The Food and Drug Administration's approval of a genotyping test for cystic fibrosis detection should improve screening accuracy and availability and could result in more uniform reporting of test results to physicians, experts say.

The new test—coined the “Tag-It Cystic Fibrosis Kit”—is the first multiplexed genotyping test to be cleared by the FDA as an in vitro device for diagnosing human disease.

Laboratories traditionally have purchased what are known as “analyzed specific reagents” and then have had to establish and validate assays and test kits themselves. The newly approved device, on the other hand, is a “standardized, validated testing kit. … It moves us past the 'home brews,' and makes for a more accurate test,” said Michael Watson, Ph.D., executive director of the American College of Medical Genetics.

Dr. Watson was a lead author of the clinical and laboratory guidelines for cystic fibrosis (CF) carrier screening that were published in 2001, and updated in 2004, by the ACMG and the American College of Obstetricians and Gynecologists (ACOG).

The kit is approved for use in carrier testing, as an aid in newborn screening, and in confirmatory diagnostic testing in newborns and children.

It can be used to detect and identify simultaneously 39 mutations in the gene for CF—known as the cystic fibrosis transmembrane conductance regulator (CFTR) gene—as well as 4 polymorphisms.

These variations include the 23 mutations recommended in the updated ACOG-ACMG guidelines as a “core mutation panel” for carrier screening in the general population. According to the manufacturer, the kit covers additional mutations seen in the African American and Hispanic communities.

“The percent of carriers picked up in [these communities] will go up,” said Graham Henderson, marketing manager for Tm Bioscience Corp. of Toronto.

The original 2001 guidelines recommended a standard screening panel covering 25 mutations, but one mutation subsequently was found to occur less frequently than expected, and another was found not to be a true mutation.

Laboratories today typically use the recommended 23-mutation panel and then supplement this, if possible, with tests for such additional mutations when screening particular racial or ethnic groups.

According to the ACOG-ACMG guidelines, the standard “pan-ethnic” 23-mutation panel has an expected sensitivity of 80% in Caucasians of European descent, 90% in Caucasians of Northern European descent, and 97% in Ashkenazi Jews. Even when the panel is supplemented with additional mutations, there is always some “residual risk,” or “small possibility of an affected offspring,” the guidelines say.

Donna Galehouse, Ph.D., technical director of the molecular diagnostics lab at Akron (Ohio) Children's Hospital, said the new device will enable more labs to perform screening, and will enable them to accurately handle high test volumes.

If use of the device becomes a standard of care, Dr. Watson said, physicians should get more “uniform” test result reports. “Right now, residual risks vary, depending on where testing is done” for instance, he said. “Physicians have to check carefully on what exactly was done and how it translates” into clinical meaning.

According to the ACOG-ACMG guidelines, screening should be offered to couples with a family history of CF, partners of individuals with CF, and Caucasian couples of European or Ashkenazi Jewish descent that are planning a pregnancy or seeking prenatal care.

Information about CF screening should be provided to patients in other ethnic and racial groups, the guidelines say.

A survey done 2 years after the guidelines were first issued showed that the vast majority of 632 ob.gyns.—89% of the respondents—ask obstetric patients about their family history of CF and offer CF carrier screening. Nearly two-thirds offer screening to all prenatal patients.

In the gynecologic setting, practice patterns were much different. Almost one-half of physicians who responded to the survey indicated that they do not ask nonpregnant patients about their family history of CF or provide them with information about screening (Genet. Med. 2004:6;450–5). (The survey was mailed to 1,165 ACOG members—approximately half of whom participate in the College's Collaborative Ambulatory Research Network, and half of whom were randomly selected.)

Reports on CF screening, according to the guidelines, should include the reported ethnicity of the patient and the indication for testing as well as the mutations tested and the method of testing. Negative screening tests should define “as accurately as possible” the residual risk of the person tested. “This will vary by ethnic or racial group and should be so specified in the test report,” the guidelines say.

Since the CFTR gene and the most common genetic mutation causing CF were identified about 15 years ago, more than 1,300 genetic variations have been identified in the gene. Many of these, Dr. Watson said, “are rare or private to an individual or family.” The newly approved device is not indicated for use in fetal diagnostic or preimplantation testing, and it is not indicated for stand-alone diagnostic purposes, according to a statement issued by the FDA.

Physicians should “interpret test results in the context of the patient's clinical condition, ethnicity, and family history,” the statement said.

The Tag-It Cystic Fibrosis Kit is approved for use in carrier testing and can identify 39 mutations in the CF gene. Tm Bioscience Corp.

The Food and Drug Administration's approval of a genotyping test for cystic fibrosis detection should improve screening accuracy and availability and could result in more uniform reporting of test results to physicians, experts say.

The new test—coined the “Tag-It Cystic Fibrosis Kit”—is the first multiplexed genotyping test to be cleared by the FDA as an in vitro device for diagnosing human disease.

Laboratories traditionally have purchased what are known as “analyzed specific reagents” and then have had to establish and validate assays and test kits themselves. The newly approved device, on the other hand, is a “standardized, validated testing kit. … It moves us past the 'home brews,' and makes for a more accurate test,” said Michael Watson, Ph.D., executive director of the American College of Medical Genetics.

Dr. Watson was a lead author of the clinical and laboratory guidelines for cystic fibrosis (CF) carrier screening that were published in 2001, and updated in 2004, by the ACMG and the American College of Obstetricians and Gynecologists (ACOG).

The kit is approved for use in carrier testing, as an aid in newborn screening, and in confirmatory diagnostic testing in newborns and children.

It can be used to detect and identify simultaneously 39 mutations in the gene for CF—known as the cystic fibrosis transmembrane conductance regulator (CFTR) gene—as well as 4 polymorphisms.

These variations include the 23 mutations recommended in the updated ACOG-ACMG guidelines as a “core mutation panel” for carrier screening in the general population. According to the manufacturer, the kit covers additional mutations seen in the African American and Hispanic communities.

“The percent of carriers picked up in [these communities] will go up,” said Graham Henderson, marketing manager for Tm Bioscience Corp. of Toronto.

The original 2001 guidelines recommended a standard screening panel covering 25 mutations, but one mutation subsequently was found to occur less frequently than expected, and another was found not to be a true mutation.

Laboratories today typically use the recommended 23-mutation panel and then supplement this, if possible, with tests for such additional mutations when screening particular racial or ethnic groups.

According to the ACOG-ACMG guidelines, the standard “pan-ethnic” 23-mutation panel has an expected sensitivity of 80% in Caucasians of European descent, 90% in Caucasians of Northern European descent, and 97% in Ashkenazi Jews. Even when the panel is supplemented with additional mutations, there is always some “residual risk,” or “small possibility of an affected offspring,” the guidelines say.

Donna Galehouse, Ph.D., technical director of the molecular diagnostics lab at Akron (Ohio) Children's Hospital, said the new device will enable more labs to perform screening, and will enable them to accurately handle high test volumes.

If use of the device becomes a standard of care, Dr. Watson said, physicians should get more “uniform” test result reports. “Right now, residual risks vary, depending on where testing is done” for instance, he said. “Physicians have to check carefully on what exactly was done and how it translates” into clinical meaning.

According to the ACOG-ACMG guidelines, screening should be offered to couples with a family history of CF, partners of individuals with CF, and Caucasian couples of European or Ashkenazi Jewish descent that are planning a pregnancy or seeking prenatal care.

Information about CF screening should be provided to patients in other ethnic and racial groups, the guidelines say.

A survey done 2 years after the guidelines were first issued showed that the vast majority of 632 ob.gyns.—89% of the respondents—ask obstetric patients about their family history of CF and offer CF carrier screening. Nearly two-thirds offer screening to all prenatal patients.

In the gynecologic setting, practice patterns were much different. Almost one-half of physicians who responded to the survey indicated that they do not ask nonpregnant patients about their family history of CF or provide them with information about screening (Genet. Med. 2004:6;450–5). (The survey was mailed to 1,165 ACOG members—approximately half of whom participate in the College's Collaborative Ambulatory Research Network, and half of whom were randomly selected.)

Reports on CF screening, according to the guidelines, should include the reported ethnicity of the patient and the indication for testing as well as the mutations tested and the method of testing. Negative screening tests should define “as accurately as possible” the residual risk of the person tested. “This will vary by ethnic or racial group and should be so specified in the test report,” the guidelines say.

Since the CFTR gene and the most common genetic mutation causing CF were identified about 15 years ago, more than 1,300 genetic variations have been identified in the gene. Many of these, Dr. Watson said, “are rare or private to an individual or family.” The newly approved device is not indicated for use in fetal diagnostic or preimplantation testing, and it is not indicated for stand-alone diagnostic purposes, according to a statement issued by the FDA.

Physicians should “interpret test results in the context of the patient's clinical condition, ethnicity, and family history,” the statement said.

The Tag-It Cystic Fibrosis Kit is approved for use in carrier testing and can identify 39 mutations in the CF gene. Tm Bioscience Corp.

The Food and Drug Administration's approval of a genotyping test for cystic fibrosis detection should improve screening accuracy and availability and could result in more uniform reporting of test results to physicians, experts say.

The new test—coined the “Tag-It Cystic Fibrosis Kit”—is the first multiplexed genotyping test to be cleared by the FDA as an in vitro device for diagnosing human disease.

Laboratories traditionally have purchased what are known as “analyzed specific reagents” and then have had to establish and validate assays and test kits themselves. The newly approved device, on the other hand, is a “standardized, validated testing kit. … It moves us past the 'home brews,' and makes for a more accurate test,” said Michael Watson, Ph.D., executive director of the American College of Medical Genetics.

Dr. Watson was a lead author of the clinical and laboratory guidelines for cystic fibrosis (CF) carrier screening that were published in 2001, and updated in 2004, by the ACMG and the American College of Obstetricians and Gynecologists (ACOG).

The kit is approved for use in carrier testing, as an aid in newborn screening, and in confirmatory diagnostic testing in newborns and children.

It can be used to detect and identify simultaneously 39 mutations in the gene for CF—known as the cystic fibrosis transmembrane conductance regulator (CFTR) gene—as well as 4 polymorphisms.

These variations include the 23 mutations recommended in the updated ACOG-ACMG guidelines as a “core mutation panel” for carrier screening in the general population. According to the manufacturer, the kit covers additional mutations seen in the African American and Hispanic communities.

“The percent of carriers picked up in [these communities] will go up,” said Graham Henderson, marketing manager for Tm Bioscience Corp. of Toronto.

The original 2001 guidelines recommended a standard screening panel covering 25 mutations, but one mutation subsequently was found to occur less frequently than expected, and another was found not to be a true mutation.

Laboratories today typically use the recommended 23-mutation panel and then supplement this, if possible, with tests for such additional mutations when screening particular racial or ethnic groups.

According to the ACOG-ACMG guidelines, the standard “pan-ethnic” 23-mutation panel has an expected sensitivity of 80% in Caucasians of European descent, 90% in Caucasians of Northern European descent, and 97% in Ashkenazi Jews. Even when the panel is supplemented with additional mutations, there is always some “residual risk,” or “small possibility of an affected offspring,” the guidelines say.

Donna Galehouse, Ph.D., technical director of the molecular diagnostics lab at Akron (Ohio) Children's Hospital, said the new device will enable more labs to perform screening, and will enable them to accurately handle high test volumes.

If use of the device becomes a standard of care, Dr. Watson said, physicians should get more “uniform” test result reports. “Right now, residual risks vary, depending on where testing is done” for instance, he said. “Physicians have to check carefully on what exactly was done and how it translates” into clinical meaning.

According to the ACOG-ACMG guidelines, screening should be offered to couples with a family history of CF, partners of individuals with CF, and Caucasian couples of European or Ashkenazi Jewish descent that are planning a pregnancy or seeking prenatal care.

Information about CF screening should be provided to patients in other ethnic and racial groups, the guidelines say.

A survey done 2 years after the guidelines were first issued showed that the vast majority of 632 ob.gyns.—89% of the respondents—ask obstetric patients about their family history of CF and offer CF carrier screening. Nearly two-thirds offer screening to all prenatal patients.

In the gynecologic setting, practice patterns were much different. Almost one-half of physicians who responded to the survey indicated that they do not ask nonpregnant patients about their family history of CF or provide them with information about screening (Genet. Med. 2004:6;450–5). (The survey was mailed to 1,165 ACOG members—approximately half of whom participate in the College's Collaborative Ambulatory Research Network, and half of whom were randomly selected.)

Reports on CF screening, according to the guidelines, should include the reported ethnicity of the patient and the indication for testing as well as the mutations tested and the method of testing. Negative screening tests should define “as accurately as possible” the residual risk of the person tested. “This will vary by ethnic or racial group and should be so specified in the test report,” the guidelines say.

Since the CFTR gene and the most common genetic mutation causing CF were identified about 15 years ago, more than 1,300 genetic variations have been identified in the gene. Many of these, Dr. Watson said, “are rare or private to an individual or family.” The newly approved device is not indicated for use in fetal diagnostic or preimplantation testing, and it is not indicated for stand-alone diagnostic purposes, according to a statement issued by the FDA.

Physicians should “interpret test results in the context of the patient's clinical condition, ethnicity, and family history,” the statement said.

The Tag-It Cystic Fibrosis Kit is approved for use in carrier testing and can identify 39 mutations in the CF gene. Tm Bioscience Corp.

Soon-to-be published reports describing three patients who developed a progressive, demyelinating brain disorder during treatment with natalizumab have some experts wondering whether the drug—now under voluntary suspension from the market—might safely be given to multiple sclerosis patients if they are carefully monitored.

“Compared with what I knew before, I'm more optimistic,” said John Richert, M.D., who heads research and clinical programs for the National Multiple Sclerosis Society. “We still need to hear more …, but I think there's a reasonable likelihood that the drug will be brought back.”

He and others point mainly to two observations detailed in the reports—that progressive multifocal leukoencephalopathy (PML), caused by activation of the human polyomavirus JC virus, may be preceded by JC virus viremia, and that the disorder is not necessarily life-threatening—in explaining their new but guarded optimism. It might be possible to discontinue the drug in patients in time to prevent PML from developing into a life-threatening illness.

The reports, to be published in the July 28 issue of the New England Journal of Medicine, detail the clinical course of three patients who participated in clinical trials of the monoclonal antibody natalizumab (Tysabri) for MS, Crohn's disease, and rheumatoid arthritis.

Two of the patients had MS and developed PML after having taken natalizumab for over 2 years in combination with interferon β-1a. Their cases were the impetus for the drug makers' suspension earlier this year of all dosing and marketing of the drug (see CLINICAL NEUROLOGY NEWS, April 2005, p. 5).

The third patient had Crohn's disease and took the drug—which received accelerated approval from the FDA in late 2004 for the treatment of immune-mediated disorders, including MS—for a much shorter duration. He was found to have had PML after the MS cases prompted investigators to reevaluate a presumed malignant astrocytoma.

The New England Journal of Medicine, which had published some of the original studies on the efficacy of the drug, lifted its embargo early and posted the reports—as well as two editorials and correspondence from one manufacturer—on the its Web site last month after the Boston Globe reported that the FDA was investigating a possible case of PML in a fourth patient who received natalizumab. (A press report of a fifth case of suspected PML being reported to the FDA was published since then. At press time, the FDA said only that there were “no additional confirmed cases.”)

In the case of the Crohn's disease patient, who had previously received other immunomodulatory agents with no reactivation of JC virus infection, retrospective analysis of serum samples showed that JC virus became detectable after only three injections of natalizumab monotherapy and 2 months before the appearance of symptomatic PML, which led to the patient's death.

Within those 2 months, the serum viral load increased by a factor of 12, Gert Van Assche, M.D., and associates at the University of Leuven (Belgium) Hospitals (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMoa051586. Available from www.nejm.org

Before recovering partially, one patient's condition worsened after the cessation of natalizumab therapy—despite treatment with corticosteroids, cidofovir, and intravenous immune globulin—but eventually improved (not completely, but significantly) 2 months after initiation of systemic therapy with cytarabine, which penetrates the CNS poorly.

It is possible, however, “that the extensive breakdown of his blood-brain barrier improved penetration of cytarabine into the CNS,” wrote Annette Langer-Gould, M.D., of Stanford (Calif.) University, and her colleagues (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMoa051847. Available from www.nejm.org

Such findings, Dr. Richert said, give him hope that it may be possible to fashion preventive strategies against development of PML in patients wanting to take natalizumab or similar drugs in the future. And in an editorial, Joseph R. Berger, M.D., of the University of Kentucky, Lexington, and Igor J. Koralnik, M.D., of Harvard Medical School, Boston, expressed similar optimism.

“The prospective measurement of the JC viral load in plasma and the preemptive reduction of doses or interruption of treatment if JC virus DNA appears in the blood might actually prevent the development of PML in this setting,” they wrote (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMe058122. Available from www.nejm.org

Dr. Langer-Gould and her colleagues also note in their report that “more frequent MRI monitoring of patients who receive natalizumab may be warranted.”

Kenneth L. Tyler, M.D., an author on the second MS case report, cautioned that “it's exceedingly dangerous to prognosticate on the future with such a small subset (of patients.” Still, he told this newspaper, he is left with the questions, “is viremia a useful warning sign? And if you discontinue the medicine, will [development of PML] subside?”

The case of the Crohn's patient, Dr. Tyler noted, is significant because it indicates “that neither concurrent use of Avonex [interferon β-1a] or underlying neurologic disease like MS is necessary” for the development of PML in patients taking Tysabri.

All agree that while the new reports clarify the association between treatment with natalizumab and the occurrence of PML, questions about the magnitude of risk need to be answered before the drug can be brought back to the market.

“There's a big interest in bringing [Tysabri] back, but the viability of the drug will depend on our ability to predict risk of PML and know how great a risk PML is for MS patients,” said Michael Kaufman, M.D., director of the MS Center at Carolinas Health Care in Charlotte, N.C., and an investigator in one of the Tysabri trials.

“Two cases out of hundreds with MS … could be the tip of the iceberg, or it could be the only two who were susceptible to it,” he said.

Despite her patient's partial recovery, Dr. Langer-Gould told this newspaper she fears that if the drug were prescribed for longer periods of time, “it would be highly likely we would see many more cases of PML resulting in death or significant life-long disability as well as other toxicities.”

According to a short “correspondence” written by leaders at the Cambridge, Mass.-based Biogen Idec Inc., a panel established by the company is currently reviewing all suspicious and ambiguous findings to evaluate them for PML (NEJM [Epub ahead of print], June 9, 2005. Article DOI:10.1056/NEJMc055235. Available from www.nejm.com

A spokesman for Biogen Idec and Elan Corp. told CLINICAL NEUROLOGY NEWS that once they have a better understanding of the risks of PML—perhaps later this summer—the companies will share their findings with the FDA and European regulatory agencies, and “together, the compan[ies] and agencies will make a decision about how to proceed with the drug.”

In the NEJM reports, Dr. Langer-Gould, Dr. Berger, and Dr. Koralnik each report having received consulting and/or lecture fees from Biogen Idec.

Soon-to-be published reports describing three patients who developed a progressive, demyelinating brain disorder during treatment with natalizumab have some experts wondering whether the drug—now under voluntary suspension from the market—might safely be given to multiple sclerosis patients if they are carefully monitored.

“Compared with what I knew before, I'm more optimistic,” said John Richert, M.D., who heads research and clinical programs for the National Multiple Sclerosis Society. “We still need to hear more …, but I think there's a reasonable likelihood that the drug will be brought back.”

He and others point mainly to two observations detailed in the reports—that progressive multifocal leukoencephalopathy (PML), caused by activation of the human polyomavirus JC virus, may be preceded by JC virus viremia, and that the disorder is not necessarily life-threatening—in explaining their new but guarded optimism. It might be possible to discontinue the drug in patients in time to prevent PML from developing into a life-threatening illness.

The reports, to be published in the July 28 issue of the New England Journal of Medicine, detail the clinical course of three patients who participated in clinical trials of the monoclonal antibody natalizumab (Tysabri) for MS, Crohn's disease, and rheumatoid arthritis.

Two of the patients had MS and developed PML after having taken natalizumab for over 2 years in combination with interferon β-1a. Their cases were the impetus for the drug makers' suspension earlier this year of all dosing and marketing of the drug (see CLINICAL NEUROLOGY NEWS, April 2005, p. 5).

The third patient had Crohn's disease and took the drug—which received accelerated approval from the FDA in late 2004 for the treatment of immune-mediated disorders, including MS—for a much shorter duration. He was found to have had PML after the MS cases prompted investigators to reevaluate a presumed malignant astrocytoma.

The New England Journal of Medicine, which had published some of the original studies on the efficacy of the drug, lifted its embargo early and posted the reports—as well as two editorials and correspondence from one manufacturer—on the its Web site last month after the Boston Globe reported that the FDA was investigating a possible case of PML in a fourth patient who received natalizumab. (A press report of a fifth case of suspected PML being reported to the FDA was published since then. At press time, the FDA said only that there were “no additional confirmed cases.”)

In the case of the Crohn's disease patient, who had previously received other immunomodulatory agents with no reactivation of JC virus infection, retrospective analysis of serum samples showed that JC virus became detectable after only three injections of natalizumab monotherapy and 2 months before the appearance of symptomatic PML, which led to the patient's death.

Within those 2 months, the serum viral load increased by a factor of 12, Gert Van Assche, M.D., and associates at the University of Leuven (Belgium) Hospitals (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMoa051586. Available from www.nejm.org

Before recovering partially, one patient's condition worsened after the cessation of natalizumab therapy—despite treatment with corticosteroids, cidofovir, and intravenous immune globulin—but eventually improved (not completely, but significantly) 2 months after initiation of systemic therapy with cytarabine, which penetrates the CNS poorly.

It is possible, however, “that the extensive breakdown of his blood-brain barrier improved penetration of cytarabine into the CNS,” wrote Annette Langer-Gould, M.D., of Stanford (Calif.) University, and her colleagues (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMoa051847. Available from www.nejm.org

Such findings, Dr. Richert said, give him hope that it may be possible to fashion preventive strategies against development of PML in patients wanting to take natalizumab or similar drugs in the future. And in an editorial, Joseph R. Berger, M.D., of the University of Kentucky, Lexington, and Igor J. Koralnik, M.D., of Harvard Medical School, Boston, expressed similar optimism.

“The prospective measurement of the JC viral load in plasma and the preemptive reduction of doses or interruption of treatment if JC virus DNA appears in the blood might actually prevent the development of PML in this setting,” they wrote (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMe058122. Available from www.nejm.org

Dr. Langer-Gould and her colleagues also note in their report that “more frequent MRI monitoring of patients who receive natalizumab may be warranted.”

Kenneth L. Tyler, M.D., an author on the second MS case report, cautioned that “it's exceedingly dangerous to prognosticate on the future with such a small subset (of patients.” Still, he told this newspaper, he is left with the questions, “is viremia a useful warning sign? And if you discontinue the medicine, will [development of PML] subside?”

The case of the Crohn's patient, Dr. Tyler noted, is significant because it indicates “that neither concurrent use of Avonex [interferon β-1a] or underlying neurologic disease like MS is necessary” for the development of PML in patients taking Tysabri.

All agree that while the new reports clarify the association between treatment with natalizumab and the occurrence of PML, questions about the magnitude of risk need to be answered before the drug can be brought back to the market.

“There's a big interest in bringing [Tysabri] back, but the viability of the drug will depend on our ability to predict risk of PML and know how great a risk PML is for MS patients,” said Michael Kaufman, M.D., director of the MS Center at Carolinas Health Care in Charlotte, N.C., and an investigator in one of the Tysabri trials.

“Two cases out of hundreds with MS … could be the tip of the iceberg, or it could be the only two who were susceptible to it,” he said.

Despite her patient's partial recovery, Dr. Langer-Gould told this newspaper she fears that if the drug were prescribed for longer periods of time, “it would be highly likely we would see many more cases of PML resulting in death or significant life-long disability as well as other toxicities.”

According to a short “correspondence” written by leaders at the Cambridge, Mass.-based Biogen Idec Inc., a panel established by the company is currently reviewing all suspicious and ambiguous findings to evaluate them for PML (NEJM [Epub ahead of print], June 9, 2005. Article DOI:10.1056/NEJMc055235. Available from www.nejm.com

A spokesman for Biogen Idec and Elan Corp. told CLINICAL NEUROLOGY NEWS that once they have a better understanding of the risks of PML—perhaps later this summer—the companies will share their findings with the FDA and European regulatory agencies, and “together, the compan[ies] and agencies will make a decision about how to proceed with the drug.”

In the NEJM reports, Dr. Langer-Gould, Dr. Berger, and Dr. Koralnik each report having received consulting and/or lecture fees from Biogen Idec.

Soon-to-be published reports describing three patients who developed a progressive, demyelinating brain disorder during treatment with natalizumab have some experts wondering whether the drug—now under voluntary suspension from the market—might safely be given to multiple sclerosis patients if they are carefully monitored.

“Compared with what I knew before, I'm more optimistic,” said John Richert, M.D., who heads research and clinical programs for the National Multiple Sclerosis Society. “We still need to hear more …, but I think there's a reasonable likelihood that the drug will be brought back.”

He and others point mainly to two observations detailed in the reports—that progressive multifocal leukoencephalopathy (PML), caused by activation of the human polyomavirus JC virus, may be preceded by JC virus viremia, and that the disorder is not necessarily life-threatening—in explaining their new but guarded optimism. It might be possible to discontinue the drug in patients in time to prevent PML from developing into a life-threatening illness.

The reports, to be published in the July 28 issue of the New England Journal of Medicine, detail the clinical course of three patients who participated in clinical trials of the monoclonal antibody natalizumab (Tysabri) for MS, Crohn's disease, and rheumatoid arthritis.

Two of the patients had MS and developed PML after having taken natalizumab for over 2 years in combination with interferon β-1a. Their cases were the impetus for the drug makers' suspension earlier this year of all dosing and marketing of the drug (see CLINICAL NEUROLOGY NEWS, April 2005, p. 5).

The third patient had Crohn's disease and took the drug—which received accelerated approval from the FDA in late 2004 for the treatment of immune-mediated disorders, including MS—for a much shorter duration. He was found to have had PML after the MS cases prompted investigators to reevaluate a presumed malignant astrocytoma.

The New England Journal of Medicine, which had published some of the original studies on the efficacy of the drug, lifted its embargo early and posted the reports—as well as two editorials and correspondence from one manufacturer—on the its Web site last month after the Boston Globe reported that the FDA was investigating a possible case of PML in a fourth patient who received natalizumab. (A press report of a fifth case of suspected PML being reported to the FDA was published since then. At press time, the FDA said only that there were “no additional confirmed cases.”)

In the case of the Crohn's disease patient, who had previously received other immunomodulatory agents with no reactivation of JC virus infection, retrospective analysis of serum samples showed that JC virus became detectable after only three injections of natalizumab monotherapy and 2 months before the appearance of symptomatic PML, which led to the patient's death.

Within those 2 months, the serum viral load increased by a factor of 12, Gert Van Assche, M.D., and associates at the University of Leuven (Belgium) Hospitals (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMoa051586. Available from www.nejm.org

Before recovering partially, one patient's condition worsened after the cessation of natalizumab therapy—despite treatment with corticosteroids, cidofovir, and intravenous immune globulin—but eventually improved (not completely, but significantly) 2 months after initiation of systemic therapy with cytarabine, which penetrates the CNS poorly.

It is possible, however, “that the extensive breakdown of his blood-brain barrier improved penetration of cytarabine into the CNS,” wrote Annette Langer-Gould, M.D., of Stanford (Calif.) University, and her colleagues (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMoa051847. Available from www.nejm.org

Such findings, Dr. Richert said, give him hope that it may be possible to fashion preventive strategies against development of PML in patients wanting to take natalizumab or similar drugs in the future. And in an editorial, Joseph R. Berger, M.D., of the University of Kentucky, Lexington, and Igor J. Koralnik, M.D., of Harvard Medical School, Boston, expressed similar optimism.

“The prospective measurement of the JC viral load in plasma and the preemptive reduction of doses or interruption of treatment if JC virus DNA appears in the blood might actually prevent the development of PML in this setting,” they wrote (NEJM [Epub ahead of print], June 9, 2005. Article DOI number:10.1056/NEJMe058122. Available from www.nejm.org

Dr. Langer-Gould and her colleagues also note in their report that “more frequent MRI monitoring of patients who receive natalizumab may be warranted.”

Kenneth L. Tyler, M.D., an author on the second MS case report, cautioned that “it's exceedingly dangerous to prognosticate on the future with such a small subset (of patients.” Still, he told this newspaper, he is left with the questions, “is viremia a useful warning sign? And if you discontinue the medicine, will [development of PML] subside?”

The case of the Crohn's patient, Dr. Tyler noted, is significant because it indicates “that neither concurrent use of Avonex [interferon β-1a] or underlying neurologic disease like MS is necessary” for the development of PML in patients taking Tysabri.

All agree that while the new reports clarify the association between treatment with natalizumab and the occurrence of PML, questions about the magnitude of risk need to be answered before the drug can be brought back to the market.

“There's a big interest in bringing [Tysabri] back, but the viability of the drug will depend on our ability to predict risk of PML and know how great a risk PML is for MS patients,” said Michael Kaufman, M.D., director of the MS Center at Carolinas Health Care in Charlotte, N.C., and an investigator in one of the Tysabri trials.

“Two cases out of hundreds with MS … could be the tip of the iceberg, or it could be the only two who were susceptible to it,” he said.

Despite her patient's partial recovery, Dr. Langer-Gould told this newspaper she fears that if the drug were prescribed for longer periods of time, “it would be highly likely we would see many more cases of PML resulting in death or significant life-long disability as well as other toxicities.”

According to a short “correspondence” written by leaders at the Cambridge, Mass.-based Biogen Idec Inc., a panel established by the company is currently reviewing all suspicious and ambiguous findings to evaluate them for PML (NEJM [Epub ahead of print], June 9, 2005. Article DOI:10.1056/NEJMc055235. Available from www.nejm.com

A spokesman for Biogen Idec and Elan Corp. told CLINICAL NEUROLOGY NEWS that once they have a better understanding of the risks of PML—perhaps later this summer—the companies will share their findings with the FDA and European regulatory agencies, and “together, the compan[ies] and agencies will make a decision about how to proceed with the drug.”

In the NEJM reports, Dr. Langer-Gould, Dr. Berger, and Dr. Koralnik each report having received consulting and/or lecture fees from Biogen Idec.

New recommendations from the European League Against Rheumatism on the management of hip osteoarthritis come from two camps—the best available research evidence, and expert opinion/current practice—and these camps are not always in agreement.

Discordances between expert opinion and the literature demonstrate the need for more clinical trial data specifically on hip osteoarthritis (OA) and make EULAR's 10 treatment recommendations truly an “open recommendation set” that should provide a frame of reference for physicians, said Maxime Dougados, M.D., who led the multidisciplinary task force that wrote the recommendations.

“We provide 10 take-home messages, but without providing any strict guidelines or a treatment algorithm,” said Dr. Dougados, chief of rheumatology at the Hospital Cochin in Paris.

Total hip replacement is not supported by strong research evidence, for instance, but “nevertheless, all the experts consider it of clinical benefit,” he said.

In their report, he and his colleagues note that “more clinical trial data specific to hip OA are required, especially because some interventions appear to show different efficacy according to the joint site” (Ann. Rheum. Dis. 2005;64:669–81).

Despite shortcomings in research, the recommendations are useful and “eminently reasonable,” said Marc C. Hochberg, M.D., who helped develop the American College of Rheumatology's recommendations for managing osteoarthritis of the hip and knee. ACR's recommendations were published in 2000.

The recommendations, each of which includes an analysis of cost effectiveness, indicate that optimal management of hip OA should be individually tailored; that it requires a combination of nonpharmacologic and pharmacologic treatment modalities; and that nonpharmacologic treatment should include education, exercise, devices such as insoles, and weight reduction if necessary.

The experts were asked to assess separately the strength of each intervention based on research evidence and clinical expertise. Of the 21 interventions reviewed in the new recommendations, 15 were positively supported by evidence of various grades. However, only 15% of the hip OA studies were randomized controlled trials.

Here's a look at some of the recommendations:

▸ Acetaminophen is the oral analgesic of first choice for mild to moderate pain, and if successful, is the preferred long-term oral analgesic.

▸ NSAIDs should be added or substituted, at the lowest effective dose, in patients who respond inadequately to paracetamol. In patients with increased gastrointestinal risk, nonselective NSAIDS plus a gastroprotective agent, or a selective cyclooxygenase-2 inhibitor, should be used.

▸ Opioid analgesics, with or without acetaminophen, are useful alternatives in patients in whom NSAIDS (including coxibs) are contraindicated, ineffective, and/or poorly tolerated.

▸ Joint replacement has to be considered in patients with radiographic evidence of hip OA who have refractory pain and disability.

▸ Osteotomy and joint preserving surgical procedures should be considered in young adults with symptomatic hip OA, especially in the presence of dysplasia or varus/valgus deformity.

▸ Diacerhein and avocado soybean unsaponifiable (ASU) were found to “have a symptomatic effect and low toxicity.” However, their “effect sizes are small, suitable patients are not well defined, and structure-modifying effects are not well established,” according to the recommendations. In any case, such guidance has limited applicability in the United States, given the lack of availability of these two compounds, noted Dr. Hochberg, head of rheumatology and clinical immunology at the University of Maryland.

Three interventions—acetaminophen, glucosamine, and exercise—had no direct, hip-specific evidence to support their use, and another three interventions—ASU, diacerhein, and intraarticular steroid injection—had either evidence showing no symptomatic benefit or inconclusive evidence. Still, based on clinical experience, these treatments were deemed effective and have been recommended for knee OA.

“There may be true treatment differences for OA according to the site affected,” wrote the task force members, who had excluded from the literature review most of the studies that combined hip and knee OA.

Acetaminophen—one of the three interventions with no direct efficacy data—received a relatively high mean “strength of recommendation” rating (79%) based on clinical expertise, for instance.

Total hip replacement was similar: It received a low “strength of recommendation” rating based on research evidence (a C on an A-D scale), but a high rating (86%) based on clinical expertise.

Opioids, on the other hand, received a high rating (A on an A-D scale) based on research evidence but a low rating (44%) based on clinical expertise. NSAIDs were rated highly with respect both to research evidence of efficacy (A) and to clinical expertise (80%).

“It's clear now that NSAIDs might have a controversial toxicity,” said Dr. Dougados in an interview. “But these drugs are very powerful and very efficient. I think prescriptions will continue but with more emphasis on decreasing dose and duration.”

We [need to] answer the question of when exactly to recommend and perform THR.

New recommendations from the European League Against Rheumatism on the management of hip osteoarthritis come from two camps—the best available research evidence, and expert opinion/current practice—and these camps are not always in agreement.

Discordances between expert opinion and the literature demonstrate the need for more clinical trial data specifically on hip osteoarthritis (OA) and make EULAR's 10 treatment recommendations truly an “open recommendation set” that should provide a frame of reference for physicians, said Maxime Dougados, M.D., who led the multidisciplinary task force that wrote the recommendations.

“We provide 10 take-home messages, but without providing any strict guidelines or a treatment algorithm,” said Dr. Dougados, chief of rheumatology at the Hospital Cochin in Paris.

Total hip replacement is not supported by strong research evidence, for instance, but “nevertheless, all the experts consider it of clinical benefit,” he said.

In their report, he and his colleagues note that “more clinical trial data specific to hip OA are required, especially because some interventions appear to show different efficacy according to the joint site” (Ann. Rheum. Dis. 2005;64:669–81).

Despite shortcomings in research, the recommendations are useful and “eminently reasonable,” said Marc C. Hochberg, M.D., who helped develop the American College of Rheumatology's recommendations for managing osteoarthritis of the hip and knee. ACR's recommendations were published in 2000.

The recommendations, each of which includes an analysis of cost effectiveness, indicate that optimal management of hip OA should be individually tailored; that it requires a combination of nonpharmacologic and pharmacologic treatment modalities; and that nonpharmacologic treatment should include education, exercise, devices such as insoles, and weight reduction if necessary.

The experts were asked to assess separately the strength of each intervention based on research evidence and clinical expertise. Of the 21 interventions reviewed in the new recommendations, 15 were positively supported by evidence of various grades. However, only 15% of the hip OA studies were randomized controlled trials.

Here's a look at some of the recommendations:

▸ Acetaminophen is the oral analgesic of first choice for mild to moderate pain, and if successful, is the preferred long-term oral analgesic.

▸ NSAIDs should be added or substituted, at the lowest effective dose, in patients who respond inadequately to paracetamol. In patients with increased gastrointestinal risk, nonselective NSAIDS plus a gastroprotective agent, or a selective cyclooxygenase-2 inhibitor, should be used.

▸ Opioid analgesics, with or without acetaminophen, are useful alternatives in patients in whom NSAIDS (including coxibs) are contraindicated, ineffective, and/or poorly tolerated.

▸ Joint replacement has to be considered in patients with radiographic evidence of hip OA who have refractory pain and disability.

▸ Osteotomy and joint preserving surgical procedures should be considered in young adults with symptomatic hip OA, especially in the presence of dysplasia or varus/valgus deformity.

▸ Diacerhein and avocado soybean unsaponifiable (ASU) were found to “have a symptomatic effect and low toxicity.” However, their “effect sizes are small, suitable patients are not well defined, and structure-modifying effects are not well established,” according to the recommendations. In any case, such guidance has limited applicability in the United States, given the lack of availability of these two compounds, noted Dr. Hochberg, head of rheumatology and clinical immunology at the University of Maryland.

Three interventions—acetaminophen, glucosamine, and exercise—had no direct, hip-specific evidence to support their use, and another three interventions—ASU, diacerhein, and intraarticular steroid injection—had either evidence showing no symptomatic benefit or inconclusive evidence. Still, based on clinical experience, these treatments were deemed effective and have been recommended for knee OA.

“There may be true treatment differences for OA according to the site affected,” wrote the task force members, who had excluded from the literature review most of the studies that combined hip and knee OA.

Acetaminophen—one of the three interventions with no direct efficacy data—received a relatively high mean “strength of recommendation” rating (79%) based on clinical expertise, for instance.

Total hip replacement was similar: It received a low “strength of recommendation” rating based on research evidence (a C on an A-D scale), but a high rating (86%) based on clinical expertise.

Opioids, on the other hand, received a high rating (A on an A-D scale) based on research evidence but a low rating (44%) based on clinical expertise. NSAIDs were rated highly with respect both to research evidence of efficacy (A) and to clinical expertise (80%).

“It's clear now that NSAIDs might have a controversial toxicity,” said Dr. Dougados in an interview. “But these drugs are very powerful and very efficient. I think prescriptions will continue but with more emphasis on decreasing dose and duration.”

We [need to] answer the question of when exactly to recommend and perform THR.

New recommendations from the European League Against Rheumatism on the management of hip osteoarthritis come from two camps—the best available research evidence, and expert opinion/current practice—and these camps are not always in agreement.

Discordances between expert opinion and the literature demonstrate the need for more clinical trial data specifically on hip osteoarthritis (OA) and make EULAR's 10 treatment recommendations truly an “open recommendation set” that should provide a frame of reference for physicians, said Maxime Dougados, M.D., who led the multidisciplinary task force that wrote the recommendations.

“We provide 10 take-home messages, but without providing any strict guidelines or a treatment algorithm,” said Dr. Dougados, chief of rheumatology at the Hospital Cochin in Paris.

Total hip replacement is not supported by strong research evidence, for instance, but “nevertheless, all the experts consider it of clinical benefit,” he said.

In their report, he and his colleagues note that “more clinical trial data specific to hip OA are required, especially because some interventions appear to show different efficacy according to the joint site” (Ann. Rheum. Dis. 2005;64:669–81).

Despite shortcomings in research, the recommendations are useful and “eminently reasonable,” said Marc C. Hochberg, M.D., who helped develop the American College of Rheumatology's recommendations for managing osteoarthritis of the hip and knee. ACR's recommendations were published in 2000.

The recommendations, each of which includes an analysis of cost effectiveness, indicate that optimal management of hip OA should be individually tailored; that it requires a combination of nonpharmacologic and pharmacologic treatment modalities; and that nonpharmacologic treatment should include education, exercise, devices such as insoles, and weight reduction if necessary.

The experts were asked to assess separately the strength of each intervention based on research evidence and clinical expertise. Of the 21 interventions reviewed in the new recommendations, 15 were positively supported by evidence of various grades. However, only 15% of the hip OA studies were randomized controlled trials.

Here's a look at some of the recommendations:

▸ Acetaminophen is the oral analgesic of first choice for mild to moderate pain, and if successful, is the preferred long-term oral analgesic.

▸ NSAIDs should be added or substituted, at the lowest effective dose, in patients who respond inadequately to paracetamol. In patients with increased gastrointestinal risk, nonselective NSAIDS plus a gastroprotective agent, or a selective cyclooxygenase-2 inhibitor, should be used.

▸ Opioid analgesics, with or without acetaminophen, are useful alternatives in patients in whom NSAIDS (including coxibs) are contraindicated, ineffective, and/or poorly tolerated.

▸ Joint replacement has to be considered in patients with radiographic evidence of hip OA who have refractory pain and disability.

▸ Osteotomy and joint preserving surgical procedures should be considered in young adults with symptomatic hip OA, especially in the presence of dysplasia or varus/valgus deformity.

▸ Diacerhein and avocado soybean unsaponifiable (ASU) were found to “have a symptomatic effect and low toxicity.” However, their “effect sizes are small, suitable patients are not well defined, and structure-modifying effects are not well established,” according to the recommendations. In any case, such guidance has limited applicability in the United States, given the lack of availability of these two compounds, noted Dr. Hochberg, head of rheumatology and clinical immunology at the University of Maryland.

Three interventions—acetaminophen, glucosamine, and exercise—had no direct, hip-specific evidence to support their use, and another three interventions—ASU, diacerhein, and intraarticular steroid injection—had either evidence showing no symptomatic benefit or inconclusive evidence. Still, based on clinical experience, these treatments were deemed effective and have been recommended for knee OA.

“There may be true treatment differences for OA according to the site affected,” wrote the task force members, who had excluded from the literature review most of the studies that combined hip and knee OA.

Acetaminophen—one of the three interventions with no direct efficacy data—received a relatively high mean “strength of recommendation” rating (79%) based on clinical expertise, for instance.

Total hip replacement was similar: It received a low “strength of recommendation” rating based on research evidence (a C on an A-D scale), but a high rating (86%) based on clinical expertise.

Opioids, on the other hand, received a high rating (A on an A-D scale) based on research evidence but a low rating (44%) based on clinical expertise. NSAIDs were rated highly with respect both to research evidence of efficacy (A) and to clinical expertise (80%).

“It's clear now that NSAIDs might have a controversial toxicity,” said Dr. Dougados in an interview. “But these drugs are very powerful and very efficient. I think prescriptions will continue but with more emphasis on decreasing dose and duration.”

We [need to] answer the question of when exactly to recommend and perform THR.

Rheumatoid arthritis patients' response to treatment with infliximab may be improved by adjusting the dosage according to serum trough levels of infliximab, as well as to pretreatment levels of C-reactive protein, a study has indicated.

An open, prospective observational study of 105 consecutive patients with rheumatoid arthritis “confirms the relationship” between trough serum concentrations of infliximab and the extent of clinical improvement in patients taking the drug, reported G.J. Wolbink, M.D., of the Jan van Breemen Institute in Amsterdam, and associates.

The study also showed that levels of pretreatment C-reactive protein (CRP) correlate negatively with serum trough levels of infliximab and clinical response, they said.

“As infliximab is expensive, it might be efficient to adjust the infliximab dosing schedule after measurement of the serum infliximab concentration,” the investigators said.

In addition, “patients with high pretreatment CRP levels might benefit from higher dosages of infliximab than patients with low CRP levels,” they said (Ann. Rheum. Dis. 2005;64:704–7).

The investigators measured serum trough infliximab levels before intravenous infusions of 3 mg/kg infliximab, a TNF blocking treatment, at 0, 2, 6, and 14 weeks.

They assessed disease activity before each infusion using the 28-joint count Disease Activity Score (DAS28). In addition, they used European League Against Rheumatism response criteria to classify patients at 14 weeks as “responders” or “nonresponders,” and they categorized patients into three groups according to their infliximab levels.

(Nonresponse was defined as a DAS28 decrease after 14 weeks of 0.6 or less, or a decrease between 0.6 and 1.2 with an attained DAS of greater than 5.1).

At 14 weeks, nonresponders had significantly lower median serum trough infliximab concentrations than responders (0.5 vs. 3.6 mg/L). The association remained significant after correction for potential confounders such as baseline CPR, baseline DAS28 score, and rheumatoid factor.

Moreover, patients categorized as having low infliximab levels at 14 weeks less often fulfilled the EULAR response criteria than patients with intermediate and high infliximab levels (50% vs. 90% and 88%). They also had significantly less improvement in the DAS28 score (−0.9 vs. −2.0 and −2.4).

Pretreatment levels of CRP—used as an indirect marker for TNF production—correlated negatively with infliximab levels at each dosage interval.

And during the last treatment interval (6–14 weeks) the change in the DAS28 score of patients with low pretreatment CRP levels differed significantly from that of patients with high pretreatment CRP levels (−0.2 vs. 0.6), the investigators reported.

The majority of patients were women (82%) with a mean disease duration of 12 years and a mean DAS28 score at entry of 6.1. Most had used methotrexate, and this as well as other stable drug treatments were continued during the study.

Rheumatoid arthritis patients' response to treatment with infliximab may be improved by adjusting the dosage according to serum trough levels of infliximab, as well as to pretreatment levels of C-reactive protein, a study has indicated.

An open, prospective observational study of 105 consecutive patients with rheumatoid arthritis “confirms the relationship” between trough serum concentrations of infliximab and the extent of clinical improvement in patients taking the drug, reported G.J. Wolbink, M.D., of the Jan van Breemen Institute in Amsterdam, and associates.

The study also showed that levels of pretreatment C-reactive protein (CRP) correlate negatively with serum trough levels of infliximab and clinical response, they said.

“As infliximab is expensive, it might be efficient to adjust the infliximab dosing schedule after measurement of the serum infliximab concentration,” the investigators said.

In addition, “patients with high pretreatment CRP levels might benefit from higher dosages of infliximab than patients with low CRP levels,” they said (Ann. Rheum. Dis. 2005;64:704–7).

The investigators measured serum trough infliximab levels before intravenous infusions of 3 mg/kg infliximab, a TNF blocking treatment, at 0, 2, 6, and 14 weeks.

They assessed disease activity before each infusion using the 28-joint count Disease Activity Score (DAS28). In addition, they used European League Against Rheumatism response criteria to classify patients at 14 weeks as “responders” or “nonresponders,” and they categorized patients into three groups according to their infliximab levels.

(Nonresponse was defined as a DAS28 decrease after 14 weeks of 0.6 or less, or a decrease between 0.6 and 1.2 with an attained DAS of greater than 5.1).

At 14 weeks, nonresponders had significantly lower median serum trough infliximab concentrations than responders (0.5 vs. 3.6 mg/L). The association remained significant after correction for potential confounders such as baseline CPR, baseline DAS28 score, and rheumatoid factor.

Moreover, patients categorized as having low infliximab levels at 14 weeks less often fulfilled the EULAR response criteria than patients with intermediate and high infliximab levels (50% vs. 90% and 88%). They also had significantly less improvement in the DAS28 score (−0.9 vs. −2.0 and −2.4).

Pretreatment levels of CRP—used as an indirect marker for TNF production—correlated negatively with infliximab levels at each dosage interval.

And during the last treatment interval (6–14 weeks) the change in the DAS28 score of patients with low pretreatment CRP levels differed significantly from that of patients with high pretreatment CRP levels (−0.2 vs. 0.6), the investigators reported.

The majority of patients were women (82%) with a mean disease duration of 12 years and a mean DAS28 score at entry of 6.1. Most had used methotrexate, and this as well as other stable drug treatments were continued during the study.

Rheumatoid arthritis patients' response to treatment with infliximab may be improved by adjusting the dosage according to serum trough levels of infliximab, as well as to pretreatment levels of C-reactive protein, a study has indicated.

An open, prospective observational study of 105 consecutive patients with rheumatoid arthritis “confirms the relationship” between trough serum concentrations of infliximab and the extent of clinical improvement in patients taking the drug, reported G.J. Wolbink, M.D., of the Jan van Breemen Institute in Amsterdam, and associates.

The study also showed that levels of pretreatment C-reactive protein (CRP) correlate negatively with serum trough levels of infliximab and clinical response, they said.

“As infliximab is expensive, it might be efficient to adjust the infliximab dosing schedule after measurement of the serum infliximab concentration,” the investigators said.

In addition, “patients with high pretreatment CRP levels might benefit from higher dosages of infliximab than patients with low CRP levels,” they said (Ann. Rheum. Dis. 2005;64:704–7).

The investigators measured serum trough infliximab levels before intravenous infusions of 3 mg/kg infliximab, a TNF blocking treatment, at 0, 2, 6, and 14 weeks.

They assessed disease activity before each infusion using the 28-joint count Disease Activity Score (DAS28). In addition, they used European League Against Rheumatism response criteria to classify patients at 14 weeks as “responders” or “nonresponders,” and they categorized patients into three groups according to their infliximab levels.

(Nonresponse was defined as a DAS28 decrease after 14 weeks of 0.6 or less, or a decrease between 0.6 and 1.2 with an attained DAS of greater than 5.1).

At 14 weeks, nonresponders had significantly lower median serum trough infliximab concentrations than responders (0.5 vs. 3.6 mg/L). The association remained significant after correction for potential confounders such as baseline CPR, baseline DAS28 score, and rheumatoid factor.

Moreover, patients categorized as having low infliximab levels at 14 weeks less often fulfilled the EULAR response criteria than patients with intermediate and high infliximab levels (50% vs. 90% and 88%). They also had significantly less improvement in the DAS28 score (−0.9 vs. −2.0 and −2.4).

Pretreatment levels of CRP—used as an indirect marker for TNF production—correlated negatively with infliximab levels at each dosage interval.

And during the last treatment interval (6–14 weeks) the change in the DAS28 score of patients with low pretreatment CRP levels differed significantly from that of patients with high pretreatment CRP levels (−0.2 vs. 0.6), the investigators reported.

The majority of patients were women (82%) with a mean disease duration of 12 years and a mean DAS28 score at entry of 6.1. Most had used methotrexate, and this as well as other stable drug treatments were continued during the study.