Jeff Evans

Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase confer the single strongest risk for developing Parkinson's disease of any gene that has been discovered, according to a multicenter analysis of patients from around the world.

A single mutant copy of the gene, GBA, was found in 15% of Ashkenazi Jewish patients with Parkinson's disease and in 3% of Parkinson's patients of other ethnicities, compared with 3% of control patients with Ashkenazi ethnicity and less than 1% with non-Ashkenazi background.

“The high frequency of mutations among ethnically diverse, heterogeneous cohorts of patients with Parkinson's disease makes the mutations in this gene the most common genetic risk factor for Parkinson's disease that has been identified to date,” Dr. Ellen Sidransky of the National Human Genome Research Institute and her associates wrote in the the New England Journal of Medicine.

Although previous smaller studies have indicated a potential association between heterozygous carriers of a single defective copy of GBA and the risk of Parkinson's disease, this is the first time that it has been conclusively shown that even a single copy of the mutated gene can contribute to disease.

Holders of two defective GBA alleles develop Gaucher's disease, which is characterized by an accumulation of glucocerebroside, an essential component of cell membranes. This can lead to a broad spectrum of disease manifestations, including hepatosplenomegaly, anemia, thrombocytopenia, bone disease, and neurologic impairment.

Dr. Mark Hallett, chief of the medical neurology branch of the National Institute of Neurological Disorders and Stroke, said in an interview that the discovery of the contribution of GBA mutations to Parkinson's disease risk is “far from the whole answer, but it's a piece of the puzzle that I think is becoming clearer now. It seems very clear that there's going to be a number of risk genes that all add up together that will lead to Parkinson's disease.”

Dr. Hallett, who was not involved in the study, likened the GBA finding to the discovery of the apolipoprotein E gene's contribution to the increased risk for developing Alzheimer's disease, in combination with other susceptibility alleles and various environmental factors.

In the study, Dr. Sidransky and her colleagues pooled data from 16 centers that had genotyped 5,691 patients with Parkinson's disease and 4,898 control patients for mutations in GBA. The centers were located in North America (4), South America (1), Asia (3), Israel (2), and Europe (6). The analysis included 980 Ashkenazi Jewish patients with Parkinson's disease and 387 Ashkenazi Jewish control patients (N. Engl. J. Med. 2009;361:1651–61).

At least 6 out of 100 people of Ashkenazi descent carry a defective GBA allele, compared with fewer than 1 out of 100 people in the general population.

Among all patients, carriers of any GBA mutation had more than five times greater odds of developing Parkinson's disease than did noncarriers. Two mutations in particular–N370S and L444P–accounted for most of the GBA mutations and were most prevalent in Ashkenazi patients.

Individuals with the N370S or L444P mutation were nearly four times or nearly seven times more likely, respectively, to develop Parkinson's disease than were noncarriers.

The investigators found that incomplete sequencing of GBA, such as only screening for the N370S or L444P mutations, could miss many mutant alleles in non-Ashkenazi ethnic groups. For example, complete sequencing of GBA in non-Ashkenazi Jewish patients indicated that up to 45% of mutant alleles could be missed if only N370S and L444P were targeted.

Patients with GBA mutations developed Parkinson's disease at a significantly earlier mean age than did noncarriers (54.9 years vs. 58.8 years). A significantly higher proportion of patients with a GBA mutation also reported having a first- or second-degree relative with Parkinson's disease, compared with noncarriers (24% vs. 18%).

Some disease features showed up significantly more often among those with GBA mutations than in those without mutations, such as asymmetric onset, bradykinesia, resting tremor, rigidity, and cognitive changes.

The study was funded impart by large number of international grants. Dr. Sidransky had no disclosures to report, but many other investigators reported potential conflicts of interest.

Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase confer the single strongest risk for developing Parkinson's disease of any gene that has been discovered, according to a multicenter analysis of patients from around the world.

A single mutant copy of the gene, GBA, was found in 15% of Ashkenazi Jewish patients with Parkinson's disease and in 3% of Parkinson's patients of other ethnicities, compared with 3% of control patients with Ashkenazi ethnicity and less than 1% with non-Ashkenazi background.

“The high frequency of mutations among ethnically diverse, heterogeneous cohorts of patients with Parkinson's disease makes the mutations in this gene the most common genetic risk factor for Parkinson's disease that has been identified to date,” Dr. Ellen Sidransky of the National Human Genome Research Institute and her associates wrote in the the New England Journal of Medicine.

Although previous smaller studies have indicated a potential association between heterozygous carriers of a single defective copy of GBA and the risk of Parkinson's disease, this is the first time that it has been conclusively shown that even a single copy of the mutated gene can contribute to disease.

Holders of two defective GBA alleles develop Gaucher's disease, which is characterized by an accumulation of glucocerebroside, an essential component of cell membranes. This can lead to a broad spectrum of disease manifestations, including hepatosplenomegaly, anemia, thrombocytopenia, bone disease, and neurologic impairment.

Dr. Mark Hallett, chief of the medical neurology branch of the National Institute of Neurological Disorders and Stroke, said in an interview that the discovery of the contribution of GBA mutations to Parkinson's disease risk is “far from the whole answer, but it's a piece of the puzzle that I think is becoming clearer now. It seems very clear that there's going to be a number of risk genes that all add up together that will lead to Parkinson's disease.”

Dr. Hallett, who was not involved in the study, likened the GBA finding to the discovery of the apolipoprotein E gene's contribution to the increased risk for developing Alzheimer's disease, in combination with other susceptibility alleles and various environmental factors.

In the study, Dr. Sidransky and her colleagues pooled data from 16 centers that had genotyped 5,691 patients with Parkinson's disease and 4,898 control patients for mutations in GBA. The centers were located in North America (4), South America (1), Asia (3), Israel (2), and Europe (6). The analysis included 980 Ashkenazi Jewish patients with Parkinson's disease and 387 Ashkenazi Jewish control patients (N. Engl. J. Med. 2009;361:1651–61).

At least 6 out of 100 people of Ashkenazi descent carry a defective GBA allele, compared with fewer than 1 out of 100 people in the general population.

Among all patients, carriers of any GBA mutation had more than five times greater odds of developing Parkinson's disease than did noncarriers. Two mutations in particular–N370S and L444P–accounted for most of the GBA mutations and were most prevalent in Ashkenazi patients.

Individuals with the N370S or L444P mutation were nearly four times or nearly seven times more likely, respectively, to develop Parkinson's disease than were noncarriers.

The investigators found that incomplete sequencing of GBA, such as only screening for the N370S or L444P mutations, could miss many mutant alleles in non-Ashkenazi ethnic groups. For example, complete sequencing of GBA in non-Ashkenazi Jewish patients indicated that up to 45% of mutant alleles could be missed if only N370S and L444P were targeted.

Patients with GBA mutations developed Parkinson's disease at a significantly earlier mean age than did noncarriers (54.9 years vs. 58.8 years). A significantly higher proportion of patients with a GBA mutation also reported having a first- or second-degree relative with Parkinson's disease, compared with noncarriers (24% vs. 18%).

Some disease features showed up significantly more often among those with GBA mutations than in those without mutations, such as asymmetric onset, bradykinesia, resting tremor, rigidity, and cognitive changes.

The study was funded impart by large number of international grants. Dr. Sidransky had no disclosures to report, but many other investigators reported potential conflicts of interest.

Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase confer the single strongest risk for developing Parkinson's disease of any gene that has been discovered, according to a multicenter analysis of patients from around the world.

A single mutant copy of the gene, GBA, was found in 15% of Ashkenazi Jewish patients with Parkinson's disease and in 3% of Parkinson's patients of other ethnicities, compared with 3% of control patients with Ashkenazi ethnicity and less than 1% with non-Ashkenazi background.

“The high frequency of mutations among ethnically diverse, heterogeneous cohorts of patients with Parkinson's disease makes the mutations in this gene the most common genetic risk factor for Parkinson's disease that has been identified to date,” Dr. Ellen Sidransky of the National Human Genome Research Institute and her associates wrote in the the New England Journal of Medicine.

Although previous smaller studies have indicated a potential association between heterozygous carriers of a single defective copy of GBA and the risk of Parkinson's disease, this is the first time that it has been conclusively shown that even a single copy of the mutated gene can contribute to disease.

Holders of two defective GBA alleles develop Gaucher's disease, which is characterized by an accumulation of glucocerebroside, an essential component of cell membranes. This can lead to a broad spectrum of disease manifestations, including hepatosplenomegaly, anemia, thrombocytopenia, bone disease, and neurologic impairment.

Dr. Mark Hallett, chief of the medical neurology branch of the National Institute of Neurological Disorders and Stroke, said in an interview that the discovery of the contribution of GBA mutations to Parkinson's disease risk is “far from the whole answer, but it's a piece of the puzzle that I think is becoming clearer now. It seems very clear that there's going to be a number of risk genes that all add up together that will lead to Parkinson's disease.”

Dr. Hallett, who was not involved in the study, likened the GBA finding to the discovery of the apolipoprotein E gene's contribution to the increased risk for developing Alzheimer's disease, in combination with other susceptibility alleles and various environmental factors.

In the study, Dr. Sidransky and her colleagues pooled data from 16 centers that had genotyped 5,691 patients with Parkinson's disease and 4,898 control patients for mutations in GBA. The centers were located in North America (4), South America (1), Asia (3), Israel (2), and Europe (6). The analysis included 980 Ashkenazi Jewish patients with Parkinson's disease and 387 Ashkenazi Jewish control patients (N. Engl. J. Med. 2009;361:1651–61).

At least 6 out of 100 people of Ashkenazi descent carry a defective GBA allele, compared with fewer than 1 out of 100 people in the general population.

Among all patients, carriers of any GBA mutation had more than five times greater odds of developing Parkinson's disease than did noncarriers. Two mutations in particular–N370S and L444P–accounted for most of the GBA mutations and were most prevalent in Ashkenazi patients.

Individuals with the N370S or L444P mutation were nearly four times or nearly seven times more likely, respectively, to develop Parkinson's disease than were noncarriers.

The investigators found that incomplete sequencing of GBA, such as only screening for the N370S or L444P mutations, could miss many mutant alleles in non-Ashkenazi ethnic groups. For example, complete sequencing of GBA in non-Ashkenazi Jewish patients indicated that up to 45% of mutant alleles could be missed if only N370S and L444P were targeted.

Patients with GBA mutations developed Parkinson's disease at a significantly earlier mean age than did noncarriers (54.9 years vs. 58.8 years). A significantly higher proportion of patients with a GBA mutation also reported having a first- or second-degree relative with Parkinson's disease, compared with noncarriers (24% vs. 18%).

Some disease features showed up significantly more often among those with GBA mutations than in those without mutations, such as asymmetric onset, bradykinesia, resting tremor, rigidity, and cognitive changes.

The study was funded impart by large number of international grants. Dr. Sidransky had no disclosures to report, but many other investigators reported potential conflicts of interest.

BALTIMORE – An algorithm that analyzes recordings from a scalp, rather than an intracranial, EEG has been demonstrated to predict seizures with odds significantly greater than chance.

Dr. J. Chris Sackellares, chief scientific officer of Optima Neuroscience Inc., Gainesville, Fla., presented these findings at the annual meeting of the American Neurological Association.

At regular intervals, the algorithm sequentially calculates a pattern match regularity statistic–a measure of how ordered an electrical signal is–in four different channel groups located on patients' scalps.

Comparisons of the electrical activity in the four channels are used to predict seizures by detecting when the electrical activity of certain channels begins to converge on specific pattern match regularity statistics over time, indicating that a seizure is imminent.

Dr. Sackellares and his colleagues tested their algorithm in 51 patients with temporal lobe epilepsy. They captured 159 seizures and analyzed 93 segments of scalp EEG recordings. Each segment recording lasted a mean of 26 hours, with a total length of 48 hours per patient.

The researchers' automated prediction algorithm detected seizures with 95% sensitivity, generating one false-positive result every 8.6 hours, compared with a random predictor model that had an overall sensitivity of 83% and a rate of one false-positive result every 2.5 hours in individual patients.

The algorithm could detect seizures with nearly 70% sensitivity and a false-positive rate of about 0.22 per hour. The prediction was not sensitive enough for use in inpatient monitoring units or ambulatory EEC recording.

The study was supported by a grant from the National Institute of Neurological Disorders and Stroke.

BALTIMORE – An algorithm that analyzes recordings from a scalp, rather than an intracranial, EEG has been demonstrated to predict seizures with odds significantly greater than chance.

Dr. J. Chris Sackellares, chief scientific officer of Optima Neuroscience Inc., Gainesville, Fla., presented these findings at the annual meeting of the American Neurological Association.

At regular intervals, the algorithm sequentially calculates a pattern match regularity statistic–a measure of how ordered an electrical signal is–in four different channel groups located on patients' scalps.

Comparisons of the electrical activity in the four channels are used to predict seizures by detecting when the electrical activity of certain channels begins to converge on specific pattern match regularity statistics over time, indicating that a seizure is imminent.

Dr. Sackellares and his colleagues tested their algorithm in 51 patients with temporal lobe epilepsy. They captured 159 seizures and analyzed 93 segments of scalp EEG recordings. Each segment recording lasted a mean of 26 hours, with a total length of 48 hours per patient.

The researchers' automated prediction algorithm detected seizures with 95% sensitivity, generating one false-positive result every 8.6 hours, compared with a random predictor model that had an overall sensitivity of 83% and a rate of one false-positive result every 2.5 hours in individual patients.

The algorithm could detect seizures with nearly 70% sensitivity and a false-positive rate of about 0.22 per hour. The prediction was not sensitive enough for use in inpatient monitoring units or ambulatory EEC recording.

The study was supported by a grant from the National Institute of Neurological Disorders and Stroke.

BALTIMORE – An algorithm that analyzes recordings from a scalp, rather than an intracranial, EEG has been demonstrated to predict seizures with odds significantly greater than chance.

Dr. J. Chris Sackellares, chief scientific officer of Optima Neuroscience Inc., Gainesville, Fla., presented these findings at the annual meeting of the American Neurological Association.

At regular intervals, the algorithm sequentially calculates a pattern match regularity statistic–a measure of how ordered an electrical signal is–in four different channel groups located on patients' scalps.

Comparisons of the electrical activity in the four channels are used to predict seizures by detecting when the electrical activity of certain channels begins to converge on specific pattern match regularity statistics over time, indicating that a seizure is imminent.

Dr. Sackellares and his colleagues tested their algorithm in 51 patients with temporal lobe epilepsy. They captured 159 seizures and analyzed 93 segments of scalp EEG recordings. Each segment recording lasted a mean of 26 hours, with a total length of 48 hours per patient.

The researchers' automated prediction algorithm detected seizures with 95% sensitivity, generating one false-positive result every 8.6 hours, compared with a random predictor model that had an overall sensitivity of 83% and a rate of one false-positive result every 2.5 hours in individual patients.

The algorithm could detect seizures with nearly 70% sensitivity and a false-positive rate of about 0.22 per hour. The prediction was not sensitive enough for use in inpatient monitoring units or ambulatory EEC recording.

The study was supported by a grant from the National Institute of Neurological Disorders and Stroke.

Major Finding: Men with spinal and bulbar muscular atrophy who were treated with dutasteride for 2 years had significantly better physical quality of life, but significantly worse mental quality of life, than did placebo-treated patients. No differences in muscle strength were found.

Data Source: A phase II, randomized, double-blind, placebo-controlled trial of 50 men

Disclosures: The trial was funded by the National Institute of Neurological Diseases and Stroke. None of the investigators had relevant disclosures.

BALTIMORE — Long-term dutasteride therapy in men with spinal and bulbar muscular atrophy does not appear to improve muscle strength or fatigue and might actually lower mental quality of life, according to the results of a phase II, randomized, double-blind, placebo-controlled trial.

Patients derived some benefit from treatment with the 5-alpha reductase inhibitor, which converts testosterone into more potent dihydrotestosterone, as a result of a significant reduction in their number of falls and improvement in their physical quality of life.

Spinal and bulbar muscular atrophy (SBMA) is characterized by a toxic buildup of mutant androgen receptors with an excessively long string of glutamine residues in motor neurons. This buildup weakens bulbar and extremity muscles, causing difficulty with gait and dysphagia, and also might lead to gynecomastia, infertility, and other manifestations of androgen insensitivity. Dutasteride has been thought to be a potential therapy for SBMA because experiments in mice that were bred to express the mutant androgen receptor showed that reducing androgen levels could mitigate the toxicity of the mutant phenotype.

To evaluate the efficacy and safety of dutasteride (Avodart), Dr. Kenneth H. Fischbeck, chief of the Neurogenetics Branch of the National Institute of Neurological Diseases and Stroke and his colleagues randomized 50 men with SBMA to either 0.5 mg/day of dutasteride or placebo. That dose of dutasteride is the same as that approved for treating symptomatic benign prostatic hyperplasia.

The men in each group were an average age of about 53 years, and had an average CAG repeat length of 4 codons (compared with wild-type human repeat length of 36 codons or less), a mean duration of weakness of about 12 years, and an average body mass index of about 28 kg/m

After 2 years, patients treated with dutasteride had virtually no appreciable increase in weight-scaled quantitative muscle assessment scores from baseline—the primary efficacy measure—whereas the scores in patients taking placebo declined by 5% from baseline. This difference was not significant, according to the investigators, who reported their results in a poster session at the annual meeting of the American Neurological Association.

On the Short Form–36 quality of life questionnaire (version 2), the physical component summary improved by about 14% from baseline for dutasteride-treated patients, which was significantly different from the 10% drop recorded in placebo-treated patients.

Significantly fewer falls occurred among patients who were treated with dutasteride than among those who received placebo (9 patients reporting 40 falls vs. 16 subjects reporting 63 falls).

However, patients who took dutasteride fared more poorly than those who took placebo on the mental component summary of the questionnaire, in which patients on placebo had a 10% improvement and patients on dutasteride worsened by about 7%.

Modified barium swallow scores, a measurement for dysphagia severity, worsened by a similar amount in subsets of patients from both arms.

Major Finding: Men with spinal and bulbar muscular atrophy who were treated with dutasteride for 2 years had significantly better physical quality of life, but significantly worse mental quality of life, than did placebo-treated patients. No differences in muscle strength were found.

Data Source: A phase II, randomized, double-blind, placebo-controlled trial of 50 men

Disclosures: The trial was funded by the National Institute of Neurological Diseases and Stroke. None of the investigators had relevant disclosures.

BALTIMORE — Long-term dutasteride therapy in men with spinal and bulbar muscular atrophy does not appear to improve muscle strength or fatigue and might actually lower mental quality of life, according to the results of a phase II, randomized, double-blind, placebo-controlled trial.

Patients derived some benefit from treatment with the 5-alpha reductase inhibitor, which converts testosterone into more potent dihydrotestosterone, as a result of a significant reduction in their number of falls and improvement in their physical quality of life.

Spinal and bulbar muscular atrophy (SBMA) is characterized by a toxic buildup of mutant androgen receptors with an excessively long string of glutamine residues in motor neurons. This buildup weakens bulbar and extremity muscles, causing difficulty with gait and dysphagia, and also might lead to gynecomastia, infertility, and other manifestations of androgen insensitivity. Dutasteride has been thought to be a potential therapy for SBMA because experiments in mice that were bred to express the mutant androgen receptor showed that reducing androgen levels could mitigate the toxicity of the mutant phenotype.

To evaluate the efficacy and safety of dutasteride (Avodart), Dr. Kenneth H. Fischbeck, chief of the Neurogenetics Branch of the National Institute of Neurological Diseases and Stroke and his colleagues randomized 50 men with SBMA to either 0.5 mg/day of dutasteride or placebo. That dose of dutasteride is the same as that approved for treating symptomatic benign prostatic hyperplasia.

The men in each group were an average age of about 53 years, and had an average CAG repeat length of 4 codons (compared with wild-type human repeat length of 36 codons or less), a mean duration of weakness of about 12 years, and an average body mass index of about 28 kg/m

After 2 years, patients treated with dutasteride had virtually no appreciable increase in weight-scaled quantitative muscle assessment scores from baseline—the primary efficacy measure—whereas the scores in patients taking placebo declined by 5% from baseline. This difference was not significant, according to the investigators, who reported their results in a poster session at the annual meeting of the American Neurological Association.

On the Short Form–36 quality of life questionnaire (version 2), the physical component summary improved by about 14% from baseline for dutasteride-treated patients, which was significantly different from the 10% drop recorded in placebo-treated patients.

Significantly fewer falls occurred among patients who were treated with dutasteride than among those who received placebo (9 patients reporting 40 falls vs. 16 subjects reporting 63 falls).

However, patients who took dutasteride fared more poorly than those who took placebo on the mental component summary of the questionnaire, in which patients on placebo had a 10% improvement and patients on dutasteride worsened by about 7%.

Modified barium swallow scores, a measurement for dysphagia severity, worsened by a similar amount in subsets of patients from both arms.

Major Finding: Men with spinal and bulbar muscular atrophy who were treated with dutasteride for 2 years had significantly better physical quality of life, but significantly worse mental quality of life, than did placebo-treated patients. No differences in muscle strength were found.

Data Source: A phase II, randomized, double-blind, placebo-controlled trial of 50 men

Disclosures: The trial was funded by the National Institute of Neurological Diseases and Stroke. None of the investigators had relevant disclosures.

BALTIMORE — Long-term dutasteride therapy in men with spinal and bulbar muscular atrophy does not appear to improve muscle strength or fatigue and might actually lower mental quality of life, according to the results of a phase II, randomized, double-blind, placebo-controlled trial.

Patients derived some benefit from treatment with the 5-alpha reductase inhibitor, which converts testosterone into more potent dihydrotestosterone, as a result of a significant reduction in their number of falls and improvement in their physical quality of life.

Spinal and bulbar muscular atrophy (SBMA) is characterized by a toxic buildup of mutant androgen receptors with an excessively long string of glutamine residues in motor neurons. This buildup weakens bulbar and extremity muscles, causing difficulty with gait and dysphagia, and also might lead to gynecomastia, infertility, and other manifestations of androgen insensitivity. Dutasteride has been thought to be a potential therapy for SBMA because experiments in mice that were bred to express the mutant androgen receptor showed that reducing androgen levels could mitigate the toxicity of the mutant phenotype.

To evaluate the efficacy and safety of dutasteride (Avodart), Dr. Kenneth H. Fischbeck, chief of the Neurogenetics Branch of the National Institute of Neurological Diseases and Stroke and his colleagues randomized 50 men with SBMA to either 0.5 mg/day of dutasteride or placebo. That dose of dutasteride is the same as that approved for treating symptomatic benign prostatic hyperplasia.

The men in each group were an average age of about 53 years, and had an average CAG repeat length of 4 codons (compared with wild-type human repeat length of 36 codons or less), a mean duration of weakness of about 12 years, and an average body mass index of about 28 kg/m

After 2 years, patients treated with dutasteride had virtually no appreciable increase in weight-scaled quantitative muscle assessment scores from baseline—the primary efficacy measure—whereas the scores in patients taking placebo declined by 5% from baseline. This difference was not significant, according to the investigators, who reported their results in a poster session at the annual meeting of the American Neurological Association.

On the Short Form–36 quality of life questionnaire (version 2), the physical component summary improved by about 14% from baseline for dutasteride-treated patients, which was significantly different from the 10% drop recorded in placebo-treated patients.

Significantly fewer falls occurred among patients who were treated with dutasteride than among those who received placebo (9 patients reporting 40 falls vs. 16 subjects reporting 63 falls).

However, patients who took dutasteride fared more poorly than those who took placebo on the mental component summary of the questionnaire, in which patients on placebo had a 10% improvement and patients on dutasteride worsened by about 7%.

Modified barium swallow scores, a measurement for dysphagia severity, worsened by a similar amount in subsets of patients from both arms.

BALTIMORE — Surveillance programs for progressive multifocal leukoencephalopathy have many hurdles to clear before any become a reality in federal agencies or state health departments, despite concern over new cases that are associated with the use of monoclonal antibody therapies.

Dr. James J. Sejvar of the Centers for Disease Control and Prevention said that in addition to a lack of funding, attempts to conduct surveillance for progressive multifocal leukoencephalopathy (PML) are hampered by a lack of clear diagnostic criteria, a definition for a confirmed case, and case validation methods.

Dr. Sejvar, a neurologist and epidemiologist with the division of viral and rickettsial diseases at the CDC's National Center for Zoonotic, Vector-Borne, and Enteric Disease, described potential benefits and limitations of various approaches to PML surveillance at the annual meeting of the American Neurological Association.

Reports thus far have estimated that PML occurs in 1 of every 1,000 patients exposed to natalizumab (Tysabri), 1 of every 500 exposed to efalizumab (which has been taken off the U.S. market), and at an unknown, but probably lower, rate in patients exposed to rituximab (Rituxan).

National surveillance for PML could be conducted by making it a nationally notifiable infectious disease, establishing a national registry, or by gathering information from physicians, states, or laboratories.

A mechanism for surveillance still would need to have the capacity to determine a case definition of PML, which samples of patient data should be analyzed, the level of diagnostic certainty necessary for prompt reporting/confirming of cases, who should analyze patients' samples and data, and how it would be funded, Dr. Sejvar said.

NNIDs Designation

The CDC could add PML to the list of nationally notifiable infectious diseases (NNIDs), which are normally restricted to diseases with significant risk to public health. Although a rough infrastructure is already in place to add PML, and the condition would gain greater attention from physicians if it were added to the list, Dr. Sejvar said that “making it reportable doesn't mean it will be reported.”

Diagnosing PML is difficult in part because of inaccurate reporting of cases, which points to the need for methods for validating cases. PML is probably also underascertained in clinics, he said, noting that no simple laboratory test for it is available.

Dr. Sejvar said state governments are unlikely to view PML as a public health imperative that is worthy of the investments that would have to be made to conduct surveillance.

National Registry for PML

Another option would be for PML to be tracked in a national registry by the Agency for Toxic Substances and Diseases Registry (ATSDR). The congressionally mandated national amyotrophic lateral sclerosis registry that was recently developed with the ATSDR could serve as a template, Dr. Sejvar said.

“This would provide for an infrastructure to start to get a handle on PML and also allow for the collection of detailed clinical information.”

The registry would rely on self-reports by patients and entries from physicians, and would need funding and endorsement from various stakeholders, he said. Congress would have to be actively lobbied for a national PML registry.

Active, Physician-Based Surveillance

Surveillance for PML under the CDC's Emerging Infections Program, a network formed by the CDC and 10 state health departments covering 44 million people, would provide a relatively accurate estimation of incidence and prevalence. The EIP contains sites with many tertiary neurologic care institutes where patients with PML would be best diagnosed, Dr. Sejvar noted.

The proactive outreach approach of the EIP would provide direct contact with the neurologic community, but it is limited by the resources of its partners. Adding PML surveillance would require endorsement by principal investigators at all EIP sites, who are unlikely to view PML as important enough to add.

State-Based Surveillance

State-based surveillance by the CDC or ATSDR, performed in cooperation with the Council of State and Territorial Epidemiologists (CSTE), “may be one of the best options,” Dr. Sejvar said.

The CSTE is already involved in surveillance for Creutzfeldt-Jakob disease, another rare neurologic disorder that is difficult to diagnose. If PML surveillance was performed with CSTE, state surveillance officers would identify and report cases to the CDC. The CSTE would need to receive a proposal to add PML to its surveillance list and then endorse it.

There is also potential for collaborating with the National Prion Disease Pathology Surveillance Center to confirm cases pathologically, Dr. Sejvar said.

Laboratory-Based Surveillance

A system of laboratory-based surveillance is already used for other infectious diseases, particularly ones that can be readily identified in the lab and then reported to state health departments and the CDC. If a lab-based system was assembled, investigators could collect data rapidly from the relatively few labs that perform JC virus polymerase chain reaction assays, requiring minimal resources, Dr. Sejvar said.

However, lab-based surveillance would produce many false-negative results. Clinical data, which would be hard to obtain, would be necessary to interpret the lab data.

BALTIMORE — Surveillance programs for progressive multifocal leukoencephalopathy have many hurdles to clear before any become a reality in federal agencies or state health departments, despite concern over new cases that are associated with the use of monoclonal antibody therapies.

Dr. James J. Sejvar of the Centers for Disease Control and Prevention said that in addition to a lack of funding, attempts to conduct surveillance for progressive multifocal leukoencephalopathy (PML) are hampered by a lack of clear diagnostic criteria, a definition for a confirmed case, and case validation methods.

Dr. Sejvar, a neurologist and epidemiologist with the division of viral and rickettsial diseases at the CDC's National Center for Zoonotic, Vector-Borne, and Enteric Disease, described potential benefits and limitations of various approaches to PML surveillance at the annual meeting of the American Neurological Association.

Reports thus far have estimated that PML occurs in 1 of every 1,000 patients exposed to natalizumab (Tysabri), 1 of every 500 exposed to efalizumab (which has been taken off the U.S. market), and at an unknown, but probably lower, rate in patients exposed to rituximab (Rituxan).

National surveillance for PML could be conducted by making it a nationally notifiable infectious disease, establishing a national registry, or by gathering information from physicians, states, or laboratories.

A mechanism for surveillance still would need to have the capacity to determine a case definition of PML, which samples of patient data should be analyzed, the level of diagnostic certainty necessary for prompt reporting/confirming of cases, who should analyze patients' samples and data, and how it would be funded, Dr. Sejvar said.

NNIDs Designation

The CDC could add PML to the list of nationally notifiable infectious diseases (NNIDs), which are normally restricted to diseases with significant risk to public health. Although a rough infrastructure is already in place to add PML, and the condition would gain greater attention from physicians if it were added to the list, Dr. Sejvar said that “making it reportable doesn't mean it will be reported.”

Diagnosing PML is difficult in part because of inaccurate reporting of cases, which points to the need for methods for validating cases. PML is probably also underascertained in clinics, he said, noting that no simple laboratory test for it is available.

Dr. Sejvar said state governments are unlikely to view PML as a public health imperative that is worthy of the investments that would have to be made to conduct surveillance.

National Registry for PML

Another option would be for PML to be tracked in a national registry by the Agency for Toxic Substances and Diseases Registry (ATSDR). The congressionally mandated national amyotrophic lateral sclerosis registry that was recently developed with the ATSDR could serve as a template, Dr. Sejvar said.

“This would provide for an infrastructure to start to get a handle on PML and also allow for the collection of detailed clinical information.”

The registry would rely on self-reports by patients and entries from physicians, and would need funding and endorsement from various stakeholders, he said. Congress would have to be actively lobbied for a national PML registry.

Active, Physician-Based Surveillance

Surveillance for PML under the CDC's Emerging Infections Program, a network formed by the CDC and 10 state health departments covering 44 million people, would provide a relatively accurate estimation of incidence and prevalence. The EIP contains sites with many tertiary neurologic care institutes where patients with PML would be best diagnosed, Dr. Sejvar noted.

The proactive outreach approach of the EIP would provide direct contact with the neurologic community, but it is limited by the resources of its partners. Adding PML surveillance would require endorsement by principal investigators at all EIP sites, who are unlikely to view PML as important enough to add.

State-Based Surveillance

State-based surveillance by the CDC or ATSDR, performed in cooperation with the Council of State and Territorial Epidemiologists (CSTE), “may be one of the best options,” Dr. Sejvar said.

The CSTE is already involved in surveillance for Creutzfeldt-Jakob disease, another rare neurologic disorder that is difficult to diagnose. If PML surveillance was performed with CSTE, state surveillance officers would identify and report cases to the CDC. The CSTE would need to receive a proposal to add PML to its surveillance list and then endorse it.

There is also potential for collaborating with the National Prion Disease Pathology Surveillance Center to confirm cases pathologically, Dr. Sejvar said.

Laboratory-Based Surveillance

A system of laboratory-based surveillance is already used for other infectious diseases, particularly ones that can be readily identified in the lab and then reported to state health departments and the CDC. If a lab-based system was assembled, investigators could collect data rapidly from the relatively few labs that perform JC virus polymerase chain reaction assays, requiring minimal resources, Dr. Sejvar said.

However, lab-based surveillance would produce many false-negative results. Clinical data, which would be hard to obtain, would be necessary to interpret the lab data.

BALTIMORE — Surveillance programs for progressive multifocal leukoencephalopathy have many hurdles to clear before any become a reality in federal agencies or state health departments, despite concern over new cases that are associated with the use of monoclonal antibody therapies.

Dr. James J. Sejvar of the Centers for Disease Control and Prevention said that in addition to a lack of funding, attempts to conduct surveillance for progressive multifocal leukoencephalopathy (PML) are hampered by a lack of clear diagnostic criteria, a definition for a confirmed case, and case validation methods.

Dr. Sejvar, a neurologist and epidemiologist with the division of viral and rickettsial diseases at the CDC's National Center for Zoonotic, Vector-Borne, and Enteric Disease, described potential benefits and limitations of various approaches to PML surveillance at the annual meeting of the American Neurological Association.

Reports thus far have estimated that PML occurs in 1 of every 1,000 patients exposed to natalizumab (Tysabri), 1 of every 500 exposed to efalizumab (which has been taken off the U.S. market), and at an unknown, but probably lower, rate in patients exposed to rituximab (Rituxan).

National surveillance for PML could be conducted by making it a nationally notifiable infectious disease, establishing a national registry, or by gathering information from physicians, states, or laboratories.

A mechanism for surveillance still would need to have the capacity to determine a case definition of PML, which samples of patient data should be analyzed, the level of diagnostic certainty necessary for prompt reporting/confirming of cases, who should analyze patients' samples and data, and how it would be funded, Dr. Sejvar said.

NNIDs Designation

The CDC could add PML to the list of nationally notifiable infectious diseases (NNIDs), which are normally restricted to diseases with significant risk to public health. Although a rough infrastructure is already in place to add PML, and the condition would gain greater attention from physicians if it were added to the list, Dr. Sejvar said that “making it reportable doesn't mean it will be reported.”

Diagnosing PML is difficult in part because of inaccurate reporting of cases, which points to the need for methods for validating cases. PML is probably also underascertained in clinics, he said, noting that no simple laboratory test for it is available.

Dr. Sejvar said state governments are unlikely to view PML as a public health imperative that is worthy of the investments that would have to be made to conduct surveillance.

National Registry for PML

Another option would be for PML to be tracked in a national registry by the Agency for Toxic Substances and Diseases Registry (ATSDR). The congressionally mandated national amyotrophic lateral sclerosis registry that was recently developed with the ATSDR could serve as a template, Dr. Sejvar said.

“This would provide for an infrastructure to start to get a handle on PML and also allow for the collection of detailed clinical information.”

The registry would rely on self-reports by patients and entries from physicians, and would need funding and endorsement from various stakeholders, he said. Congress would have to be actively lobbied for a national PML registry.

Active, Physician-Based Surveillance

Surveillance for PML under the CDC's Emerging Infections Program, a network formed by the CDC and 10 state health departments covering 44 million people, would provide a relatively accurate estimation of incidence and prevalence. The EIP contains sites with many tertiary neurologic care institutes where patients with PML would be best diagnosed, Dr. Sejvar noted.

The proactive outreach approach of the EIP would provide direct contact with the neurologic community, but it is limited by the resources of its partners. Adding PML surveillance would require endorsement by principal investigators at all EIP sites, who are unlikely to view PML as important enough to add.

State-Based Surveillance

State-based surveillance by the CDC or ATSDR, performed in cooperation with the Council of State and Territorial Epidemiologists (CSTE), “may be one of the best options,” Dr. Sejvar said.

The CSTE is already involved in surveillance for Creutzfeldt-Jakob disease, another rare neurologic disorder that is difficult to diagnose. If PML surveillance was performed with CSTE, state surveillance officers would identify and report cases to the CDC. The CSTE would need to receive a proposal to add PML to its surveillance list and then endorse it.

There is also potential for collaborating with the National Prion Disease Pathology Surveillance Center to confirm cases pathologically, Dr. Sejvar said.

Laboratory-Based Surveillance

A system of laboratory-based surveillance is already used for other infectious diseases, particularly ones that can be readily identified in the lab and then reported to state health departments and the CDC. If a lab-based system was assembled, investigators could collect data rapidly from the relatively few labs that perform JC virus polymerase chain reaction assays, requiring minimal resources, Dr. Sejvar said.

However, lab-based surveillance would produce many false-negative results. Clinical data, which would be hard to obtain, would be necessary to interpret the lab data.

BETHESDA, MD. — Few board certification examinations require physicians to understand concepts related to genetic testing and counseling or how to take or interpret family history, according to an analysis of the content outlines of such exams for 43 medical specialties.

“The lack of genetics and genomics knowledge by our current physicians is based in part on the competing priorities among the certifying specialty boards. … Few physicians are expected to know the practical applications of genetics to become certified; thus, the curriculum does not make genetics content a priority,” Carrie A. Zabel said at the annual meeting of the National Coalition for Health Professional Education in Genetics.

In an analysis of the exam outlines for 24 specialties certified by the American Board of Medical Specialties and 19 subspecialties certified by the American Board of Internal Medicine (ABIM), Ms. Zabel and her colleague at the Mayo Clinic in Rochester, Minn., Dr. Paul V. Targonski, found that 11 did not mention genetics or genomics in their certification exam outline or no outline was available.

Fifteen exam outlines referred only to syndromes that were specific to the practice of a particular specialty and for which an underlying genetic etiology was known. These outlines did not otherwise specify basic genetics knowledge within their content, said Ms. Zabel, a certified genetics counselor at the Mayo Clinic.

A total of seven content outlines made reference to having an understanding of basic genetics. Another 10 content outlines provided a detailed listing of specific genetics content and concepts.

The 10 exam outlines that listed specific content mentioned family history in only two cases—the exams for the American Board of Medical Genetics and the American Board of Obstetrics and Gynecology. This “may be due to a lack of evidence of the utility of family history,” said Ms. Zabel, who had no relevant financial disclosures to make.

Even though 8 of the 10 detailed content outlines included genetic testing, only 4 also mentioned genetic counseling, “which is more than just services provided by a genetic counselor. It's the informed consent process and the discussion of the implications of results,” Ms. Zabel said. “I think this is potentially doing a disservice to those patients.”

The study was supported by the George M. Eisenberg Foundation for Charities.

BETHESDA, MD. — Few board certification examinations require physicians to understand concepts related to genetic testing and counseling or how to take or interpret family history, according to an analysis of the content outlines of such exams for 43 medical specialties.

“The lack of genetics and genomics knowledge by our current physicians is based in part on the competing priorities among the certifying specialty boards. … Few physicians are expected to know the practical applications of genetics to become certified; thus, the curriculum does not make genetics content a priority,” Carrie A. Zabel said at the annual meeting of the National Coalition for Health Professional Education in Genetics.

In an analysis of the exam outlines for 24 specialties certified by the American Board of Medical Specialties and 19 subspecialties certified by the American Board of Internal Medicine (ABIM), Ms. Zabel and her colleague at the Mayo Clinic in Rochester, Minn., Dr. Paul V. Targonski, found that 11 did not mention genetics or genomics in their certification exam outline or no outline was available.

Fifteen exam outlines referred only to syndromes that were specific to the practice of a particular specialty and for which an underlying genetic etiology was known. These outlines did not otherwise specify basic genetics knowledge within their content, said Ms. Zabel, a certified genetics counselor at the Mayo Clinic.

A total of seven content outlines made reference to having an understanding of basic genetics. Another 10 content outlines provided a detailed listing of specific genetics content and concepts.

The 10 exam outlines that listed specific content mentioned family history in only two cases—the exams for the American Board of Medical Genetics and the American Board of Obstetrics and Gynecology. This “may be due to a lack of evidence of the utility of family history,” said Ms. Zabel, who had no relevant financial disclosures to make.

Even though 8 of the 10 detailed content outlines included genetic testing, only 4 also mentioned genetic counseling, “which is more than just services provided by a genetic counselor. It's the informed consent process and the discussion of the implications of results,” Ms. Zabel said. “I think this is potentially doing a disservice to those patients.”

The study was supported by the George M. Eisenberg Foundation for Charities.

BETHESDA, MD. — Few board certification examinations require physicians to understand concepts related to genetic testing and counseling or how to take or interpret family history, according to an analysis of the content outlines of such exams for 43 medical specialties.

“The lack of genetics and genomics knowledge by our current physicians is based in part on the competing priorities among the certifying specialty boards. … Few physicians are expected to know the practical applications of genetics to become certified; thus, the curriculum does not make genetics content a priority,” Carrie A. Zabel said at the annual meeting of the National Coalition for Health Professional Education in Genetics.

In an analysis of the exam outlines for 24 specialties certified by the American Board of Medical Specialties and 19 subspecialties certified by the American Board of Internal Medicine (ABIM), Ms. Zabel and her colleague at the Mayo Clinic in Rochester, Minn., Dr. Paul V. Targonski, found that 11 did not mention genetics or genomics in their certification exam outline or no outline was available.

Fifteen exam outlines referred only to syndromes that were specific to the practice of a particular specialty and for which an underlying genetic etiology was known. These outlines did not otherwise specify basic genetics knowledge within their content, said Ms. Zabel, a certified genetics counselor at the Mayo Clinic.

A total of seven content outlines made reference to having an understanding of basic genetics. Another 10 content outlines provided a detailed listing of specific genetics content and concepts.

The 10 exam outlines that listed specific content mentioned family history in only two cases—the exams for the American Board of Medical Genetics and the American Board of Obstetrics and Gynecology. This “may be due to a lack of evidence of the utility of family history,” said Ms. Zabel, who had no relevant financial disclosures to make.

Even though 8 of the 10 detailed content outlines included genetic testing, only 4 also mentioned genetic counseling, “which is more than just services provided by a genetic counselor. It's the informed consent process and the discussion of the implications of results,” Ms. Zabel said. “I think this is potentially doing a disservice to those patients.”

The study was supported by the George M. Eisenberg Foundation for Charities.

The Centers for Disease Control and Prevention updated its recommendations on early and late antiviral treatment during the 2009–2010 influenza season, and provided more guidance on the use of the investigational antiviral drug peramivir.

When to Start Antivirals

▸ Patients with mild, uncomplicated illness who are not considered to be at increased risk of developing severe or complicated illness are not likely to benefit from antiviral treatment if started more than 48 hours after illness onset. Similarly, patients who are already recovering from influenza do not need antiviral medications. For patients who present within 48 hours of onset, clinical judgment should be used to decide if patients with mild or uncomplicated illness and no risk factors need antiviral drugs.

▸ Antiviral regimens lasting 5 days are recommended for patients with confirmed or suspected 2009 H1N1 influenza who have severe, complicated, or progressive illness, or who are hospitalized. The 5-day treatment duration might be extended in some patients. Limited data from observational studies of hospitalized patients suggest that the initiation of antiviral treatment more than 48 hours after onset reduces mortality or duration of hospitalization in patients with prolonged or severe illness.

▸ Promptly begin empiric antiviral therapy for patients with confirmed or suspected influenza who have an increased risk for complications, the CDC advised. These include children younger than 2 years of age, children and adolescents younger than 19 years of age who are receiving long-term aspirin therapy, adults aged 65 years and older, pregnant women, and individuals with certain medical conditions (asthma; neurological and neurodevelopmental disorders; chronic lung disease; heart disease; blood, endocrine, kidney, liver, or metabolic disorders; and a weakened immune system due to disease or medication).

▸ Available data suggest pregnant women should receive prompt antiviral therapy, although no clinical studies have assessed the safety and efficacy of oseltamivir (Tamiflu) or zanamivir (Relenza) for pregnant women. The systemic activity of oseltamivir makes it the preferred treatment for pregnant women. The agency also advises prompt antiviral treatment of women up to 2 weeks postpartum with suspected or confirmed 2009 H1N1 influenza (regardless of the pregnancy outcome), because anecdotal reports have suggested that they also may be at risk for severe complications and death.

Antivirals for Vaccinated Patients

A history of vaccination does not rule out influenza, the CDC advised, because vaccination for 2009 H1N1 or seasonal influenza is effective only after 2 weeks. In addition, each vaccine is not expected to provide protection against influenza viruses other than the targeted virus. The agency recommends treating vaccinated patients as if they had not been vaccinated. People who are vaccinated with live attenuated influenza vaccines and who are given antivirals within 48 hours before or up to 2 weeks after vaccination might not develop immunity and should be revaccinated.

Oseltamivir Dosing for Infants

The CDC also updated its recommendations for dosing oseltamivir to pediatric patients. For treatment purposes, infants younger than 1 year of age should receive 3 mg/kg of the drug twice per day. For chemoprophylaxis, those aged 3 months to less than 1 year should receive 3 mg/kg oseltamivir once per day. Due to limited data, it is not recommended that the drug be given prophylactically to infants younger than 3 months unless the situation is judged to be critical. The weight-based dosing recommendations are not intended for premature infants.

Although oseltamivir dosing by weight is preferred for full-term infants younger than 1 year, it can be given according to age for treatment: 12 mg at 0–3 months, 20 mg at 3–5 months, and 25 mg at 6–11 months. Those doses should be halved for prophylaxis.

Peramivir Availability and Dosing

The Food and Drug Administration (FDA) approved the use of intravenously administered peramivir under an Emergency Use Authorization for hospitalized patients who have not responded to either oral oseltamivir or inhaled zanamivir antiviral drugs. Peramivir also is indicated when patients are expected not to have a dependable or feasible route of delivery other than intravenous, or when a clinician judges intravenous therapy to be appropriate because of other circumstances.

Pediatric patients may receive the drug if either of the first two criteria applies.

As of October, the FDA has received safety and efficacy data on the use of peramivir for 1,891 patients with acute uncomplicated seasonal influenza A. The drug has not been evaluated in hospitalized patients. It is available from the CDC upon request by a licensed physician.

The FDA now recommends that adult patients with end-stage renal disease and a creatinine clearance of less than 10 mL/minute per 1.73 m

The updated dosing regimen for pediatric patients who have that rate of creatinine clearance but are on intermittent hemodialysis varies according to age. From birth through 30 days, infants should receive 1 mg/kg peramivir on day 1, followed by 1 mg/kg 2 hours after each hemodialysis session on hemodialysis days only. Following the same instructions, the dose increases to 1.3 mg/kg for infants 31–90 days old, 1.6 mg/kg for infants aged 91–180 days, 1.9 mg/kg for children 181 days to 5 years of age, and then back to 1.6 mg/kg for children aged 6–17 years.

Peramivir dosing for children who have a creatinine clearance of less than 10 mL/minute per 1.73 m

The recommendations are available at

www.flu.gov/individualfamily/prevention/medicine/antiviralsrecommend.html

The Centers for Disease Control and Prevention updated its recommendations on early and late antiviral treatment during the 2009–2010 influenza season, and provided more guidance on the use of the investigational antiviral drug peramivir.

When to Start Antivirals

▸ Patients with mild, uncomplicated illness who are not considered to be at increased risk of developing severe or complicated illness are not likely to benefit from antiviral treatment if started more than 48 hours after illness onset. Similarly, patients who are already recovering from influenza do not need antiviral medications. For patients who present within 48 hours of onset, clinical judgment should be used to decide if patients with mild or uncomplicated illness and no risk factors need antiviral drugs.

▸ Antiviral regimens lasting 5 days are recommended for patients with confirmed or suspected 2009 H1N1 influenza who have severe, complicated, or progressive illness, or who are hospitalized. The 5-day treatment duration might be extended in some patients. Limited data from observational studies of hospitalized patients suggest that the initiation of antiviral treatment more than 48 hours after onset reduces mortality or duration of hospitalization in patients with prolonged or severe illness.

▸ Promptly begin empiric antiviral therapy for patients with confirmed or suspected influenza who have an increased risk for complications, the CDC advised. These include children younger than 2 years of age, children and adolescents younger than 19 years of age who are receiving long-term aspirin therapy, adults aged 65 years and older, pregnant women, and individuals with certain medical conditions (asthma; neurological and neurodevelopmental disorders; chronic lung disease; heart disease; blood, endocrine, kidney, liver, or metabolic disorders; and a weakened immune system due to disease or medication).

▸ Available data suggest pregnant women should receive prompt antiviral therapy, although no clinical studies have assessed the safety and efficacy of oseltamivir (Tamiflu) or zanamivir (Relenza) for pregnant women. The systemic activity of oseltamivir makes it the preferred treatment for pregnant women. The agency also advises prompt antiviral treatment of women up to 2 weeks postpartum with suspected or confirmed 2009 H1N1 influenza (regardless of the pregnancy outcome), because anecdotal reports have suggested that they also may be at risk for severe complications and death.

Antivirals for Vaccinated Patients

A history of vaccination does not rule out influenza, the CDC advised, because vaccination for 2009 H1N1 or seasonal influenza is effective only after 2 weeks. In addition, each vaccine is not expected to provide protection against influenza viruses other than the targeted virus. The agency recommends treating vaccinated patients as if they had not been vaccinated. People who are vaccinated with live attenuated influenza vaccines and who are given antivirals within 48 hours before or up to 2 weeks after vaccination might not develop immunity and should be revaccinated.

Oseltamivir Dosing for Infants

The CDC also updated its recommendations for dosing oseltamivir to pediatric patients. For treatment purposes, infants younger than 1 year of age should receive 3 mg/kg of the drug twice per day. For chemoprophylaxis, those aged 3 months to less than 1 year should receive 3 mg/kg oseltamivir once per day. Due to limited data, it is not recommended that the drug be given prophylactically to infants younger than 3 months unless the situation is judged to be critical. The weight-based dosing recommendations are not intended for premature infants.

Although oseltamivir dosing by weight is preferred for full-term infants younger than 1 year, it can be given according to age for treatment: 12 mg at 0–3 months, 20 mg at 3–5 months, and 25 mg at 6–11 months. Those doses should be halved for prophylaxis.

Peramivir Availability and Dosing

The Food and Drug Administration (FDA) approved the use of intravenously administered peramivir under an Emergency Use Authorization for hospitalized patients who have not responded to either oral oseltamivir or inhaled zanamivir antiviral drugs. Peramivir also is indicated when patients are expected not to have a dependable or feasible route of delivery other than intravenous, or when a clinician judges intravenous therapy to be appropriate because of other circumstances.

Pediatric patients may receive the drug if either of the first two criteria applies.

As of October, the FDA has received safety and efficacy data on the use of peramivir for 1,891 patients with acute uncomplicated seasonal influenza A. The drug has not been evaluated in hospitalized patients. It is available from the CDC upon request by a licensed physician.

The FDA now recommends that adult patients with end-stage renal disease and a creatinine clearance of less than 10 mL/minute per 1.73 m

The updated dosing regimen for pediatric patients who have that rate of creatinine clearance but are on intermittent hemodialysis varies according to age. From birth through 30 days, infants should receive 1 mg/kg peramivir on day 1, followed by 1 mg/kg 2 hours after each hemodialysis session on hemodialysis days only. Following the same instructions, the dose increases to 1.3 mg/kg for infants 31–90 days old, 1.6 mg/kg for infants aged 91–180 days, 1.9 mg/kg for children 181 days to 5 years of age, and then back to 1.6 mg/kg for children aged 6–17 years.

Peramivir dosing for children who have a creatinine clearance of less than 10 mL/minute per 1.73 m

The recommendations are available at

www.flu.gov/individualfamily/prevention/medicine/antiviralsrecommend.html

The Centers for Disease Control and Prevention updated its recommendations on early and late antiviral treatment during the 2009–2010 influenza season, and provided more guidance on the use of the investigational antiviral drug peramivir.

When to Start Antivirals

▸ Patients with mild, uncomplicated illness who are not considered to be at increased risk of developing severe or complicated illness are not likely to benefit from antiviral treatment if started more than 48 hours after illness onset. Similarly, patients who are already recovering from influenza do not need antiviral medications. For patients who present within 48 hours of onset, clinical judgment should be used to decide if patients with mild or uncomplicated illness and no risk factors need antiviral drugs.

▸ Antiviral regimens lasting 5 days are recommended for patients with confirmed or suspected 2009 H1N1 influenza who have severe, complicated, or progressive illness, or who are hospitalized. The 5-day treatment duration might be extended in some patients. Limited data from observational studies of hospitalized patients suggest that the initiation of antiviral treatment more than 48 hours after onset reduces mortality or duration of hospitalization in patients with prolonged or severe illness.

▸ Promptly begin empiric antiviral therapy for patients with confirmed or suspected influenza who have an increased risk for complications, the CDC advised. These include children younger than 2 years of age, children and adolescents younger than 19 years of age who are receiving long-term aspirin therapy, adults aged 65 years and older, pregnant women, and individuals with certain medical conditions (asthma; neurological and neurodevelopmental disorders; chronic lung disease; heart disease; blood, endocrine, kidney, liver, or metabolic disorders; and a weakened immune system due to disease or medication).

▸ Available data suggest pregnant women should receive prompt antiviral therapy, although no clinical studies have assessed the safety and efficacy of oseltamivir (Tamiflu) or zanamivir (Relenza) for pregnant women. The systemic activity of oseltamivir makes it the preferred treatment for pregnant women. The agency also advises prompt antiviral treatment of women up to 2 weeks postpartum with suspected or confirmed 2009 H1N1 influenza (regardless of the pregnancy outcome), because anecdotal reports have suggested that they also may be at risk for severe complications and death.

Antivirals for Vaccinated Patients

A history of vaccination does not rule out influenza, the CDC advised, because vaccination for 2009 H1N1 or seasonal influenza is effective only after 2 weeks. In addition, each vaccine is not expected to provide protection against influenza viruses other than the targeted virus. The agency recommends treating vaccinated patients as if they had not been vaccinated. People who are vaccinated with live attenuated influenza vaccines and who are given antivirals within 48 hours before or up to 2 weeks after vaccination might not develop immunity and should be revaccinated.

Oseltamivir Dosing for Infants

The CDC also updated its recommendations for dosing oseltamivir to pediatric patients. For treatment purposes, infants younger than 1 year of age should receive 3 mg/kg of the drug twice per day. For chemoprophylaxis, those aged 3 months to less than 1 year should receive 3 mg/kg oseltamivir once per day. Due to limited data, it is not recommended that the drug be given prophylactically to infants younger than 3 months unless the situation is judged to be critical. The weight-based dosing recommendations are not intended for premature infants.

Although oseltamivir dosing by weight is preferred for full-term infants younger than 1 year, it can be given according to age for treatment: 12 mg at 0–3 months, 20 mg at 3–5 months, and 25 mg at 6–11 months. Those doses should be halved for prophylaxis.

Peramivir Availability and Dosing

The Food and Drug Administration (FDA) approved the use of intravenously administered peramivir under an Emergency Use Authorization for hospitalized patients who have not responded to either oral oseltamivir or inhaled zanamivir antiviral drugs. Peramivir also is indicated when patients are expected not to have a dependable or feasible route of delivery other than intravenous, or when a clinician judges intravenous therapy to be appropriate because of other circumstances.

Pediatric patients may receive the drug if either of the first two criteria applies.

As of October, the FDA has received safety and efficacy data on the use of peramivir for 1,891 patients with acute uncomplicated seasonal influenza A. The drug has not been evaluated in hospitalized patients. It is available from the CDC upon request by a licensed physician.

The FDA now recommends that adult patients with end-stage renal disease and a creatinine clearance of less than 10 mL/minute per 1.73 m

The updated dosing regimen for pediatric patients who have that rate of creatinine clearance but are on intermittent hemodialysis varies according to age. From birth through 30 days, infants should receive 1 mg/kg peramivir on day 1, followed by 1 mg/kg 2 hours after each hemodialysis session on hemodialysis days only. Following the same instructions, the dose increases to 1.3 mg/kg for infants 31–90 days old, 1.6 mg/kg for infants aged 91–180 days, 1.9 mg/kg for children 181 days to 5 years of age, and then back to 1.6 mg/kg for children aged 6–17 years.

Peramivir dosing for children who have a creatinine clearance of less than 10 mL/minute per 1.73 m

The recommendations are available at

www.flu.gov/individualfamily/prevention/medicine/antiviralsrecommend.html

BALTIMORE — A low hemoglobin level following cardiac surgery is associated with significantly increased odds of experiencing a stroke after cardiopulmonary bypass, results of a case-control study suggest.

Although previous studies have associated anemia with adverse cerebrovascular outcomes, including stroke, it is unclear whether low hemoglobin levels contribute to postoperative surgical complications, Dr. Rebecca F. Gottesman and her colleagues at Johns Hopkins University, Baltimore, said in a poster presented at the annual meeting of the American Neurological Association.

The researchers identified the postoperative outcomes of 357 patients who underwent various cardiac surgery procedures with cardiopulmonary bypass at Johns Hopkins Hospital and compared them with the outcomes of 714 control patients matched by age range, gender, and type and year of surgery.

The patients had a mean age of 65 years, and 59% in each group were male. Compared with controls, stroke patients were significantly more likely to have hypertension (77% vs. 68%) and peripheral vascular disease (20% vs. 10%). The stroke and control groups had similar rates of diabetes (30% vs. 25%, respectively), history of MI (37% vs. 32%), and high cholesterol (51% vs. 45%), Dr. Gottesman and her associates reported.

In a conditional logistic regression analysis, the researchers found that, for each 1 g/dL decline in hemoglobin, the odds of having a stroke significantly increased by 37%. Patients with a postoperative hemoglobin level below the group median of 8.8 g/dL had a 78% greater chance of having a stroke than did those above the median. (Normal hemoglobin levels are greater than 13 g/dL in men and greater than 12 g/dL in women.)

Postoperative hemoglobin levels were below the median in significantly more patients who had a new stroke (57%) than in those who did not have a stroke (41%).

“The association between stroke and post–cardiopulmonary bypass hemoglobin could be the result of hemodilution or cerebral hypoperfusion,” the investigators suggested.

The study was supported by grants from the National Institutes of Health and the Dana Foundation.

BALTIMORE — A low hemoglobin level following cardiac surgery is associated with significantly increased odds of experiencing a stroke after cardiopulmonary bypass, results of a case-control study suggest.

Although previous studies have associated anemia with adverse cerebrovascular outcomes, including stroke, it is unclear whether low hemoglobin levels contribute to postoperative surgical complications, Dr. Rebecca F. Gottesman and her colleagues at Johns Hopkins University, Baltimore, said in a poster presented at the annual meeting of the American Neurological Association.

The researchers identified the postoperative outcomes of 357 patients who underwent various cardiac surgery procedures with cardiopulmonary bypass at Johns Hopkins Hospital and compared them with the outcomes of 714 control patients matched by age range, gender, and type and year of surgery.

The patients had a mean age of 65 years, and 59% in each group were male. Compared with controls, stroke patients were significantly more likely to have hypertension (77% vs. 68%) and peripheral vascular disease (20% vs. 10%). The stroke and control groups had similar rates of diabetes (30% vs. 25%, respectively), history of MI (37% vs. 32%), and high cholesterol (51% vs. 45%), Dr. Gottesman and her associates reported.

In a conditional logistic regression analysis, the researchers found that, for each 1 g/dL decline in hemoglobin, the odds of having a stroke significantly increased by 37%. Patients with a postoperative hemoglobin level below the group median of 8.8 g/dL had a 78% greater chance of having a stroke than did those above the median. (Normal hemoglobin levels are greater than 13 g/dL in men and greater than 12 g/dL in women.)

Postoperative hemoglobin levels were below the median in significantly more patients who had a new stroke (57%) than in those who did not have a stroke (41%).

“The association between stroke and post–cardiopulmonary bypass hemoglobin could be the result of hemodilution or cerebral hypoperfusion,” the investigators suggested.

The study was supported by grants from the National Institutes of Health and the Dana Foundation.

BALTIMORE — A low hemoglobin level following cardiac surgery is associated with significantly increased odds of experiencing a stroke after cardiopulmonary bypass, results of a case-control study suggest.

Although previous studies have associated anemia with adverse cerebrovascular outcomes, including stroke, it is unclear whether low hemoglobin levels contribute to postoperative surgical complications, Dr. Rebecca F. Gottesman and her colleagues at Johns Hopkins University, Baltimore, said in a poster presented at the annual meeting of the American Neurological Association.

The researchers identified the postoperative outcomes of 357 patients who underwent various cardiac surgery procedures with cardiopulmonary bypass at Johns Hopkins Hospital and compared them with the outcomes of 714 control patients matched by age range, gender, and type and year of surgery.

The patients had a mean age of 65 years, and 59% in each group were male. Compared with controls, stroke patients were significantly more likely to have hypertension (77% vs. 68%) and peripheral vascular disease (20% vs. 10%). The stroke and control groups had similar rates of diabetes (30% vs. 25%, respectively), history of MI (37% vs. 32%), and high cholesterol (51% vs. 45%), Dr. Gottesman and her associates reported.

In a conditional logistic regression analysis, the researchers found that, for each 1 g/dL decline in hemoglobin, the odds of having a stroke significantly increased by 37%. Patients with a postoperative hemoglobin level below the group median of 8.8 g/dL had a 78% greater chance of having a stroke than did those above the median. (Normal hemoglobin levels are greater than 13 g/dL in men and greater than 12 g/dL in women.)

Postoperative hemoglobin levels were below the median in significantly more patients who had a new stroke (57%) than in those who did not have a stroke (41%).

“The association between stroke and post–cardiopulmonary bypass hemoglobin could be the result of hemodilution or cerebral hypoperfusion,” the investigators suggested.

The study was supported by grants from the National Institutes of Health and the Dana Foundation.

A testing method that uses positive blood cultures and an automated DNA-based polymerase chain reaction and microarray system accurately identified bacteria in sepsis much faster than a standard culture-based process.

The test identified bacterial species in patients with suspected sepsis with 95% sensitivity and 99% specificity, with a mean turnaround time of 23 hours—compared with 41.5–48 hours for the standard culture-based method, according to a report.

Although the sepsis assay is a “major advance” that encompasses the best of nucleic acid and standard culture-based methods, it is unknown whether determining the species of a pathogen 18 hours earlier than usual will “translate into demonstrable clinical benefit commensurate to the cost of undertaking the additional test,” commented Dr. Shin Lin of Stanford (Calif.) University and Dr. Samuel Yang of Johns Hopkins University, Baltimore, who were not involved in the study (Lancet 2009 Dec. 10 [doi:10.1016/S0140-6736(09)61791-8]).

In the study, Dr. Päivi Tissari of the Helsinki University Hospital Laboratory and colleagues tested the Prove-it sepsis assay, manufactured by Helsinki-based Mobidiag, against standard blood culture and pathogen identification. The analysis included 3,318 blood samples from patients with suspected sepsis at two large academic medical centers (Lancet 2009 Dec. 10 [doi:10.1016/S0140-6736(09)61569-5]).

The assay identifies more than 50 species of gram-positive and gram-negative bacteria that cause most cases of sepsis. A total of 2,107 blood culture samples tested positive, including 1,807 that were covered by the sepsis assay. The researchers compared DNA sequences of topoisomerase and 16S rRNA genes and original microbiologic laboratory data for samples when the results differed between the assay and standard blood culture method.

For organisms that could be detected with the sepsis assay, the results of the assay were between 93% and 100% concordant with the results of blood culturing for all species except one. The assay identified 133 of the 163 coagulase-negative staphylococci that were identified through blood culture.

False-positive results were identified in 52 of the 3,318 samples put through the assay. Those 52 false positives included 34 that were due to contamination or software failure, 11 with more bacterial species detected than with conventional blood culture, 3 with Staphylococcus epidermidis reported, 3 attributed to cross-hybridization between species, and 1 sample in which the assay also detected Bacteroides fragilis.

False-negative results occurred in 34 samples due to inadequate sensitivity for certain species, and in 60 samples because the sepsis assay did not detect all the bacteria it should have. The assay also had difficulty in resolving species in polymicrobial samples.

The median difference in turnaround time between the Prove-it assay and the reference method for 39 samples was 18 hours 19 minutes.

The assay provided 100% sensitivity and specificity for methicillin-resistant Staphylococcus aureus, although it is the only type of antibiotic resistance testing that can be performed with the assay.

“The Prove-it sepsis assay cannot replace standard methods but could have a role alongside them,” Dr. Lin and Dr. Yang wrote.

Five of the investigators are employees of Mobidiag, which provided the equipment and reagents for the assay. None of the other researchers had conflicts of interest. Dr. Lin and Dr. Yang had no conflicts of interest to report. The study was performed without outside funding.

My Take

Sepsis Assay Requires More Study

As Dr. Lin and Dr. Yang note, until someone shows that being able to diagnose bacterial sepsis 18 hours faster makes a difference in patient care, it's not clear that this assay would be a clinically important advance.

One could speculate about other possible benefits, such as reductions in empiric antibiotic use, antibiotic exposure and resistance, or costs for medication and lab testing. But someone needs to demonstrate such benefits. Otherwise, who cares?

FRANK MICHOTA, M.D., is the Director of Academic Affairs in the Department of Hospital Medicine at the Cleveland Clinic. He reports no relevant conflicts of interest.

A testing method that uses positive blood cultures and an automated DNA-based polymerase chain reaction and microarray system accurately identified bacteria in sepsis much faster than a standard culture-based process.

The test identified bacterial species in patients with suspected sepsis with 95% sensitivity and 99% specificity, with a mean turnaround time of 23 hours—compared with 41.5–48 hours for the standard culture-based method, according to a report.

Although the sepsis assay is a “major advance” that encompasses the best of nucleic acid and standard culture-based methods, it is unknown whether determining the species of a pathogen 18 hours earlier than usual will “translate into demonstrable clinical benefit commensurate to the cost of undertaking the additional test,” commented Dr. Shin Lin of Stanford (Calif.) University and Dr. Samuel Yang of Johns Hopkins University, Baltimore, who were not involved in the study (Lancet 2009 Dec. 10 [doi:10.1016/S0140-6736(09)61791-8]).

In the study, Dr. Päivi Tissari of the Helsinki University Hospital Laboratory and colleagues tested the Prove-it sepsis assay, manufactured by Helsinki-based Mobidiag, against standard blood culture and pathogen identification. The analysis included 3,318 blood samples from patients with suspected sepsis at two large academic medical centers (Lancet 2009 Dec. 10 [doi:10.1016/S0140-6736(09)61569-5]).

The assay identifies more than 50 species of gram-positive and gram-negative bacteria that cause most cases of sepsis. A total of 2,107 blood culture samples tested positive, including 1,807 that were covered by the sepsis assay. The researchers compared DNA sequences of topoisomerase and 16S rRNA genes and original microbiologic laboratory data for samples when the results differed between the assay and standard blood culture method.

For organisms that could be detected with the sepsis assay, the results of the assay were between 93% and 100% concordant with the results of blood culturing for all species except one. The assay identified 133 of the 163 coagulase-negative staphylococci that were identified through blood culture.

False-positive results were identified in 52 of the 3,318 samples put through the assay. Those 52 false positives included 34 that were due to contamination or software failure, 11 with more bacterial species detected than with conventional blood culture, 3 with Staphylococcus epidermidis reported, 3 attributed to cross-hybridization between species, and 1 sample in which the assay also detected Bacteroides fragilis.

False-negative results occurred in 34 samples due to inadequate sensitivity for certain species, and in 60 samples because the sepsis assay did not detect all the bacteria it should have. The assay also had difficulty in resolving species in polymicrobial samples.

The median difference in turnaround time between the Prove-it assay and the reference method for 39 samples was 18 hours 19 minutes.

The assay provided 100% sensitivity and specificity for methicillin-resistant Staphylococcus aureus, although it is the only type of antibiotic resistance testing that can be performed with the assay.

“The Prove-it sepsis assay cannot replace standard methods but could have a role alongside them,” Dr. Lin and Dr. Yang wrote.

Five of the investigators are employees of Mobidiag, which provided the equipment and reagents for the assay. None of the other researchers had conflicts of interest. Dr. Lin and Dr. Yang had no conflicts of interest to report. The study was performed without outside funding.

My Take

Sepsis Assay Requires More Study

As Dr. Lin and Dr. Yang note, until someone shows that being able to diagnose bacterial sepsis 18 hours faster makes a difference in patient care, it's not clear that this assay would be a clinically important advance.

One could speculate about other possible benefits, such as reductions in empiric antibiotic use, antibiotic exposure and resistance, or costs for medication and lab testing. But someone needs to demonstrate such benefits. Otherwise, who cares?

FRANK MICHOTA, M.D., is the Director of Academic Affairs in the Department of Hospital Medicine at the Cleveland Clinic. He reports no relevant conflicts of interest.

A testing method that uses positive blood cultures and an automated DNA-based polymerase chain reaction and microarray system accurately identified bacteria in sepsis much faster than a standard culture-based process.

The test identified bacterial species in patients with suspected sepsis with 95% sensitivity and 99% specificity, with a mean turnaround time of 23 hours—compared with 41.5–48 hours for the standard culture-based method, according to a report.

Although the sepsis assay is a “major advance” that encompasses the best of nucleic acid and standard culture-based methods, it is unknown whether determining the species of a pathogen 18 hours earlier than usual will “translate into demonstrable clinical benefit commensurate to the cost of undertaking the additional test,” commented Dr. Shin Lin of Stanford (Calif.) University and Dr. Samuel Yang of Johns Hopkins University, Baltimore, who were not involved in the study (Lancet 2009 Dec. 10 [doi:10.1016/S0140-6736(09)61791-8]).

In the study, Dr. Päivi Tissari of the Helsinki University Hospital Laboratory and colleagues tested the Prove-it sepsis assay, manufactured by Helsinki-based Mobidiag, against standard blood culture and pathogen identification. The analysis included 3,318 blood samples from patients with suspected sepsis at two large academic medical centers (Lancet 2009 Dec. 10 [doi:10.1016/S0140-6736(09)61569-5]).

The assay identifies more than 50 species of gram-positive and gram-negative bacteria that cause most cases of sepsis. A total of 2,107 blood culture samples tested positive, including 1,807 that were covered by the sepsis assay. The researchers compared DNA sequences of topoisomerase and 16S rRNA genes and original microbiologic laboratory data for samples when the results differed between the assay and standard blood culture method.

For organisms that could be detected with the sepsis assay, the results of the assay were between 93% and 100% concordant with the results of blood culturing for all species except one. The assay identified 133 of the 163 coagulase-negative staphylococci that were identified through blood culture.

False-positive results were identified in 52 of the 3,318 samples put through the assay. Those 52 false positives included 34 that were due to contamination or software failure, 11 with more bacterial species detected than with conventional blood culture, 3 with Staphylococcus epidermidis reported, 3 attributed to cross-hybridization between species, and 1 sample in which the assay also detected Bacteroides fragilis.

False-negative results occurred in 34 samples due to inadequate sensitivity for certain species, and in 60 samples because the sepsis assay did not detect all the bacteria it should have. The assay also had difficulty in resolving species in polymicrobial samples.

The median difference in turnaround time between the Prove-it assay and the reference method for 39 samples was 18 hours 19 minutes.

The assay provided 100% sensitivity and specificity for methicillin-resistant Staphylococcus aureus, although it is the only type of antibiotic resistance testing that can be performed with the assay.

“The Prove-it sepsis assay cannot replace standard methods but could have a role alongside them,” Dr. Lin and Dr. Yang wrote.

Five of the investigators are employees of Mobidiag, which provided the equipment and reagents for the assay. None of the other researchers had conflicts of interest. Dr. Lin and Dr. Yang had no conflicts of interest to report. The study was performed without outside funding.

My Take

Sepsis Assay Requires More Study

As Dr. Lin and Dr. Yang note, until someone shows that being able to diagnose bacterial sepsis 18 hours faster makes a difference in patient care, it's not clear that this assay would be a clinically important advance.

One could speculate about other possible benefits, such as reductions in empiric antibiotic use, antibiotic exposure and resistance, or costs for medication and lab testing. But someone needs to demonstrate such benefits. Otherwise, who cares?

FRANK MICHOTA, M.D., is the Director of Academic Affairs in the Department of Hospital Medicine at the Cleveland Clinic. He reports no relevant conflicts of interest.

The Centers for Disease Control and Prevention updated its recommendations on early and late antiviral treatment during the 2009–2010 influenza season, and provided more guidance on the use of the investigational antiviral drug peramivir.

When to Start Antivirals

▸ Patients with mild, uncomplicated illness who are not considered to be at increased risk of developing severe or complicated illness are not likely to benefit from antiviral treatment if started more than 48 hours after illness onset. Similarly, patients who are already recovering from influenza do not need antiviral medications. For patients who present within 48 hours of onset, clinical judgment should be used to decide if patients with mild or uncomplicated illness and no risk factors need antiviral drugs.

▸ Antiviral regimens lasting 5 days are recommended for patients with confirmed or suspected 2009 H1N1 influenza who have severe, complicated, or progressive illness, or who are hospitalized. The 5-day treatment duration might be extended in some patients. Limited data from observational studies of hospitalized patients suggest that the initiation of antiviral treatment more than 48 hours after onset reduces mortality or duration of hospitalization in patients with prolonged or severe illness.

▸ Promptly begin empiric antiviral therapy for patients with confirmed or suspected influenza who have an increased risk for complications, the CDC advised. These include children and adolescents younger than 19 years of age who are receiving long-term aspirin therapy, adults aged 65 years and older, pregnant women, and individuals with certain medical conditions (asthma; neurological and neurodevelopmental disorders; chronic lung disease; heart disease; blood, endocrine, kidney, liver, or metabolic disorders; and a weakened immune system due to disease or medication).

▸ Available data suggest pregnant women should receive prompt antiviral therapy, although no clinical studies have assessed the safety and efficacy of oseltamivir (Tamiflu) or zanamivir (Relenza) for pregnant women. The systemic activity of oseltamivir makes it the preferred treatment for pregnant women. The agency also advises prompt antiviral treatment of women up to 2 weeks post partum with suspected or confirmed 2009 H1N1 influenza (regardless of the pregnancy outcome), because anecdotal reports have suggested that they also may be at risk for severe complications and death.

Giving Antivirals to Vaccinated Patients

A history of vaccination does not rule out influenza, the CDC advised, because vaccination for 2009 H1N1 or seasonal influenza is effective only after 2 weeks. In addition, each vaccine is not expected to provide protection against influenza viruses other than the targeted virus. The agency recommends treating vaccinated patients as if they had not been vaccinated. People who are vaccinated with live attenuated influenza vaccines and who are given antivirals within 48 hours before or up to 2 weeks after vaccination might not develop immunity and should be revaccinated.

Peramivir Availability and Dosing

The Food and Drug Administration (FDA) approved the use of intravenously administered peramivir under an Emergency Use Authorization for hospitalized patients who have not responded to either oral oseltamivir or inhaled zanamivir. Peramivir also is indicated when patients are expected not to have a dependable or feasible route of delivery other than intravenous, or when a clinician judges intravenous therapy to be appropriate because of other circumstances. Pediatric patients may receive the drug if either of the first two criteria applies.

As of October, the FDA has received safety and efficacy data on the use of peramivir for 1,891 patients with acute uncomplicated seasonal influenza A. The drug has not been evaluated in hospitalized patients. It is available from the CDC upon request by a licensed physician.

The FDA now recommends that adult patients with end-stage renal disease and a creatinine clearance of less than 10 mL/minute per 1.73 m

The updated dosing regimen for pediatric patients who have that rate of creatinine clearance but are on intermittent hemodialysis varies according to age. Such children aged 6–17 years should receive 1.6 mg/kg peramivir on day 1, followed by 1.6 mg/kg 2 hours after each hemodialysis session on hemodialysis days only.

Peramivir dosing for children who have a creatinine clearance of less than 10 mL/minute per 1.73 m

The recommendations are available at

www.flu.gov/individualfamily/prevention/medicine/antiviralsrecommend.html

The Centers for Disease Control and Prevention updated its recommendations on early and late antiviral treatment during the 2009–2010 influenza season, and provided more guidance on the use of the investigational antiviral drug peramivir.

When to Start Antivirals

▸ Patients with mild, uncomplicated illness who are not considered to be at increased risk of developing severe or complicated illness are not likely to benefit from antiviral treatment if started more than 48 hours after illness onset. Similarly, patients who are already recovering from influenza do not need antiviral medications. For patients who present within 48 hours of onset, clinical judgment should be used to decide if patients with mild or uncomplicated illness and no risk factors need antiviral drugs.

▸ Antiviral regimens lasting 5 days are recommended for patients with confirmed or suspected 2009 H1N1 influenza who have severe, complicated, or progressive illness, or who are hospitalized. The 5-day treatment duration might be extended in some patients. Limited data from observational studies of hospitalized patients suggest that the initiation of antiviral treatment more than 48 hours after onset reduces mortality or duration of hospitalization in patients with prolonged or severe illness.

▸ Promptly begin empiric antiviral therapy for patients with confirmed or suspected influenza who have an increased risk for complications, the CDC advised. These include children and adolescents younger than 19 years of age who are receiving long-term aspirin therapy, adults aged 65 years and older, pregnant women, and individuals with certain medical conditions (asthma; neurological and neurodevelopmental disorders; chronic lung disease; heart disease; blood, endocrine, kidney, liver, or metabolic disorders; and a weakened immune system due to disease or medication).

▸ Available data suggest pregnant women should receive prompt antiviral therapy, although no clinical studies have assessed the safety and efficacy of oseltamivir (Tamiflu) or zanamivir (Relenza) for pregnant women. The systemic activity of oseltamivir makes it the preferred treatment for pregnant women. The agency also advises prompt antiviral treatment of women up to 2 weeks post partum with suspected or confirmed 2009 H1N1 influenza (regardless of the pregnancy outcome), because anecdotal reports have suggested that they also may be at risk for severe complications and death.

Giving Antivirals to Vaccinated Patients

A history of vaccination does not rule out influenza, the CDC advised, because vaccination for 2009 H1N1 or seasonal influenza is effective only after 2 weeks. In addition, each vaccine is not expected to provide protection against influenza viruses other than the targeted virus. The agency recommends treating vaccinated patients as if they had not been vaccinated. People who are vaccinated with live attenuated influenza vaccines and who are given antivirals within 48 hours before or up to 2 weeks after vaccination might not develop immunity and should be revaccinated.

Peramivir Availability and Dosing

The Food and Drug Administration (FDA) approved the use of intravenously administered peramivir under an Emergency Use Authorization for hospitalized patients who have not responded to either oral oseltamivir or inhaled zanamivir. Peramivir also is indicated when patients are expected not to have a dependable or feasible route of delivery other than intravenous, or when a clinician judges intravenous therapy to be appropriate because of other circumstances. Pediatric patients may receive the drug if either of the first two criteria applies.

As of October, the FDA has received safety and efficacy data on the use of peramivir for 1,891 patients with acute uncomplicated seasonal influenza A. The drug has not been evaluated in hospitalized patients. It is available from the CDC upon request by a licensed physician.

The FDA now recommends that adult patients with end-stage renal disease and a creatinine clearance of less than 10 mL/minute per 1.73 m

The updated dosing regimen for pediatric patients who have that rate of creatinine clearance but are on intermittent hemodialysis varies according to age. Such children aged 6–17 years should receive 1.6 mg/kg peramivir on day 1, followed by 1.6 mg/kg 2 hours after each hemodialysis session on hemodialysis days only.

Peramivir dosing for children who have a creatinine clearance of less than 10 mL/minute per 1.73 m

The recommendations are available at

www.flu.gov/individualfamily/prevention/medicine/antiviralsrecommend.html

The Centers for Disease Control and Prevention updated its recommendations on early and late antiviral treatment during the 2009–2010 influenza season, and provided more guidance on the use of the investigational antiviral drug peramivir.

When to Start Antivirals

▸ Patients with mild, uncomplicated illness who are not considered to be at increased risk of developing severe or complicated illness are not likely to benefit from antiviral treatment if started more than 48 hours after illness onset. Similarly, patients who are already recovering from influenza do not need antiviral medications. For patients who present within 48 hours of onset, clinical judgment should be used to decide if patients with mild or uncomplicated illness and no risk factors need antiviral drugs.

▸ Antiviral regimens lasting 5 days are recommended for patients with confirmed or suspected 2009 H1N1 influenza who have severe, complicated, or progressive illness, or who are hospitalized. The 5-day treatment duration might be extended in some patients. Limited data from observational studies of hospitalized patients suggest that the initiation of antiviral treatment more than 48 hours after onset reduces mortality or duration of hospitalization in patients with prolonged or severe illness.

▸ Promptly begin empiric antiviral therapy for patients with confirmed or suspected influenza who have an increased risk for complications, the CDC advised. These include children and adolescents younger than 19 years of age who are receiving long-term aspirin therapy, adults aged 65 years and older, pregnant women, and individuals with certain medical conditions (asthma; neurological and neurodevelopmental disorders; chronic lung disease; heart disease; blood, endocrine, kidney, liver, or metabolic disorders; and a weakened immune system due to disease or medication).

▸ Available data suggest pregnant women should receive prompt antiviral therapy, although no clinical studies have assessed the safety and efficacy of oseltamivir (Tamiflu) or zanamivir (Relenza) for pregnant women. The systemic activity of oseltamivir makes it the preferred treatment for pregnant women. The agency also advises prompt antiviral treatment of women up to 2 weeks post partum with suspected or confirmed 2009 H1N1 influenza (regardless of the pregnancy outcome), because anecdotal reports have suggested that they also may be at risk for severe complications and death.

Giving Antivirals to Vaccinated Patients

A history of vaccination does not rule out influenza, the CDC advised, because vaccination for 2009 H1N1 or seasonal influenza is effective only after 2 weeks. In addition, each vaccine is not expected to provide protection against influenza viruses other than the targeted virus. The agency recommends treating vaccinated patients as if they had not been vaccinated. People who are vaccinated with live attenuated influenza vaccines and who are given antivirals within 48 hours before or up to 2 weeks after vaccination might not develop immunity and should be revaccinated.

Peramivir Availability and Dosing

The Food and Drug Administration (FDA) approved the use of intravenously administered peramivir under an Emergency Use Authorization for hospitalized patients who have not responded to either oral oseltamivir or inhaled zanamivir. Peramivir also is indicated when patients are expected not to have a dependable or feasible route of delivery other than intravenous, or when a clinician judges intravenous therapy to be appropriate because of other circumstances. Pediatric patients may receive the drug if either of the first two criteria applies.

As of October, the FDA has received safety and efficacy data on the use of peramivir for 1,891 patients with acute uncomplicated seasonal influenza A. The drug has not been evaluated in hospitalized patients. It is available from the CDC upon request by a licensed physician.

The FDA now recommends that adult patients with end-stage renal disease and a creatinine clearance of less than 10 mL/minute per 1.73 m

The updated dosing regimen for pediatric patients who have that rate of creatinine clearance but are on intermittent hemodialysis varies according to age. Such children aged 6–17 years should receive 1.6 mg/kg peramivir on day 1, followed by 1.6 mg/kg 2 hours after each hemodialysis session on hemodialysis days only.

Peramivir dosing for children who have a creatinine clearance of less than 10 mL/minute per 1.73 m

The recommendations are available at

www.flu.gov/individualfamily/prevention/medicine/antiviralsrecommend.html

BETHESDA, MD. — Few board certification examinations require physicians to understand concepts related to genetic testing and counseling or how to take or interpret family history, according to an analysis of the content outlines of such exams for 43 medical specialties.

“The lack of genetics and genomics knowledge by our current physicians is based in part on the competing priorities among the certifying specialty boards…. Few physicians are expected to know the practical applications of genetics to become certified; thus, the curriculum does not make genetics content a priority,” Carrie A. Zabel said at the annual meeting of the National Coalition for Health Professional Education in Genetics.

In an analysis of the exam outlines for 24 specialties certified by the American Board of Medical Specialties and 19 subspecialties certified by the American Board of Internal Medicine (ABIM), 11 did not mention genetics or genomics in their certification exam content outline, or had no outline, according to a review done by Ms. Zabel and her colleague at the Mayo Clinic in Rochester, Minn., Dr. Paul V. Targonski.

Fifteen exam outlines referred only to syndromes that were specific to the practice of a particular specialty and for which an underlying genetic etiology was known. These outlines did not otherwise specify basic genetics knowledge within their content, said Ms. Zabel, a certified genetics counselor at the Mayo Clinic.

A total of seven content outlines made reference to having an understanding of basic genetics. Another 10 content outlines provided a detailed listing of specific genetics content and concepts, but only two of them—the exams for the American Board of Medical Genetics and the American Board of Obstetrics and Gynecology—mentioned family history. This “may be due to a lack of evidence of the utility of family history,” said Ms. Zabel, who had no relevant financial disclosures to make.

Even though 8 of the 10 detailed content outlines included genetic testing, only 4 also mentioned genetic counseling, “which is more than just services provided by a genetic counselor. It's the informed consent process and the discussion of the implications of results,” Ms. Zabel said. “I think this is potentially doing a disservice to those patients.”

The study was supported by the George M. Eisenberg Foundation for Charities.

BETHESDA, MD. — Few board certification examinations require physicians to understand concepts related to genetic testing and counseling or how to take or interpret family history, according to an analysis of the content outlines of such exams for 43 medical specialties.

“The lack of genetics and genomics knowledge by our current physicians is based in part on the competing priorities among the certifying specialty boards…. Few physicians are expected to know the practical applications of genetics to become certified; thus, the curriculum does not make genetics content a priority,” Carrie A. Zabel said at the annual meeting of the National Coalition for Health Professional Education in Genetics.

In an analysis of the exam outlines for 24 specialties certified by the American Board of Medical Specialties and 19 subspecialties certified by the American Board of Internal Medicine (ABIM), 11 did not mention genetics or genomics in their certification exam content outline, or had no outline, according to a review done by Ms. Zabel and her colleague at the Mayo Clinic in Rochester, Minn., Dr. Paul V. Targonski.

Fifteen exam outlines referred only to syndromes that were specific to the practice of a particular specialty and for which an underlying genetic etiology was known. These outlines did not otherwise specify basic genetics knowledge within their content, said Ms. Zabel, a certified genetics counselor at the Mayo Clinic.

A total of seven content outlines made reference to having an understanding of basic genetics. Another 10 content outlines provided a detailed listing of specific genetics content and concepts, but only two of them—the exams for the American Board of Medical Genetics and the American Board of Obstetrics and Gynecology—mentioned family history. This “may be due to a lack of evidence of the utility of family history,” said Ms. Zabel, who had no relevant financial disclosures to make.

Even though 8 of the 10 detailed content outlines included genetic testing, only 4 also mentioned genetic counseling, “which is more than just services provided by a genetic counselor. It's the informed consent process and the discussion of the implications of results,” Ms. Zabel said. “I think this is potentially doing a disservice to those patients.”

The study was supported by the George M. Eisenberg Foundation for Charities.

BETHESDA, MD. — Few board certification examinations require physicians to understand concepts related to genetic testing and counseling or how to take or interpret family history, according to an analysis of the content outlines of such exams for 43 medical specialties.

“The lack of genetics and genomics knowledge by our current physicians is based in part on the competing priorities among the certifying specialty boards…. Few physicians are expected to know the practical applications of genetics to become certified; thus, the curriculum does not make genetics content a priority,” Carrie A. Zabel said at the annual meeting of the National Coalition for Health Professional Education in Genetics.

In an analysis of the exam outlines for 24 specialties certified by the American Board of Medical Specialties and 19 subspecialties certified by the American Board of Internal Medicine (ABIM), 11 did not mention genetics or genomics in their certification exam content outline, or had no outline, according to a review done by Ms. Zabel and her colleague at the Mayo Clinic in Rochester, Minn., Dr. Paul V. Targonski.

Fifteen exam outlines referred only to syndromes that were specific to the practice of a particular specialty and for which an underlying genetic etiology was known. These outlines did not otherwise specify basic genetics knowledge within their content, said Ms. Zabel, a certified genetics counselor at the Mayo Clinic.

A total of seven content outlines made reference to having an understanding of basic genetics. Another 10 content outlines provided a detailed listing of specific genetics content and concepts, but only two of them—the exams for the American Board of Medical Genetics and the American Board of Obstetrics and Gynecology—mentioned family history. This “may be due to a lack of evidence of the utility of family history,” said Ms. Zabel, who had no relevant financial disclosures to make.

Even though 8 of the 10 detailed content outlines included genetic testing, only 4 also mentioned genetic counseling, “which is more than just services provided by a genetic counselor. It's the informed consent process and the discussion of the implications of results,” Ms. Zabel said. “I think this is potentially doing a disservice to those patients.”

The study was supported by the George M. Eisenberg Foundation for Charities.