Sharon Worcester

Social phobia is an impairing psychiatric disorder that transcends typical human shyness, according to findings from the National Comorbidity Survey-Adolescent Supplement, which examined the rate of shyness and its overlap with social phobia in a nationally representative sample of adolescents. Yet, no significant differences were seen between adolescents characterized as shy and those who met the diagnostic criteria for social phobia in the use of prescribed medications.

© Kai Chiang/iStockphoto

The findings of the study, which involved face-to-face interviews with 10,123 adolescents aged 13-18 years, suggest there is little overlap between shyness and social phobia. The absence of differences in the use of prescribed medications between the two groups raises questions about the "medicalization hypothesis" of social phobia, which is a prevalent belief that the entity of social phobia is little more than medicalization of normal shyness, Marcy Burstein, Ph.D., and her colleagues from the National Institute of Mental Health in Bethesda, Md., argue in the November issue of Pediatrics (2011;128:917-25).

In fact, only 12.4% of 4,749 youth who described themselves as shy, and 10.6% whose parents considered them shy, also met the DSM-IV lifetime diagnostic criteria for social phobia. Furthermore, 5.2% and 5.5% of those who were not considered shy by their own or their parents’ reports, respectively, met the diagnostic criteria for social phobia, the investigators said.

Compared with adolescents with shyness, those with social phobia had significantly greater impairment in school and/or work (mean impairment score of 4.32 vs. 2.68 on a 10-point scale), family relationships (mean scores of 2.23 vs. 1.22), and social life (mean scores of 4.41 vs. 2.80). They also were more likely to be affected by anxiety disorders (odds ratio, 2.79), major depressive disorder (OR, 2.06), oppositional defiant disorder (OR, 1.99), and drug use disorders (OR, 3.27).

Despite these findings, the use of prescribed medications was low in both groups. For example, 0.9% and 2.3% of those who were shy and those with social phobia, respectively, used paroxetine, they noted.

"Statistical comparisons also indicated that adolescents with social phobia were no more likely to be using any prescribed medication, any antidepressant, paroxetine, or any other SSRI (selective serotonin reuptake inhibitor) relative to both other adolescent groups (shy and non-shy adolescents). In the same manner, adolescents with shyness were no more likely to be using prescribed medications, compared with adolescents with no shyness," Dr. Burstein and her associates said.

Differences between shyness and social phobia were seen in this study as well. For example, based on both parent and adolescent reports, shyness was significantly more common in girls than boys, occurring in 65.3% of girls and 59.7% of boys (based on parent reports), and in 50.1% of girls and 43.4% of boys (based on adolescent reports). However, no gender differences were seen for social phobia.

Also, shyness was more common in the youngest age group, compared with the oldest, occurring in 66.2% and 54.8% of the groups, respectively (based on parent reports), or consistent across age groups (based on adolescent reports), while the prevalence of social phobia increased with age, occurring in 6.3% of 13- to 14-year-olds, 9.6% of 15- to 16-year-olds, and 10.4% of 17- to 18-year-olds.

Although limited by numerous factors, such as the inability to examine the degree to which social phobia approximates a form of extreme shyness, the findings in this study were fairly consistent across multiple informants and were similar to those seen in other studies, according to the investigators.

The findings provide "convergent evidence that social phobia is not simply shyness," they said, noting that adolescents who met criteria for social phobia displayed "significantly greater role impairment and were more likely to experience a broad array of psychiatric disorders ... relative to adolescents who were characterized as shy."

These differences in impairment and psychiatric disorders, as well as the unique sociodemographic patterns seen in shyness vs. social phobia in this study, support the conceptualization of shyness and social phobia as distinct constructs, they said.

Furthermore, the estimates of prescribed medication use in this study counter claims that the concept of social phobia is merely the medicalization of shyness, they argued, stating that "contrary to the notion of medicalization, which would predict higher rates of prescribed medication use (in particular, paroxetine use) among adolescents with social phobia or shyness, we found no differences in the rates of prescription medication use across adolescent subgroups."

Of note, nearly 80% of adolescents with social phobia failed to seek or to obtain professional treatment for their anxiety, the investigators said.

"Persistent claims that dispute the severity of this condition among youth likely will do little to alter their course," they concluded.

This study was funded by the NIMH. The authors had no relevant financial disclosures.

Social phobia is an impairing psychiatric disorder that transcends typical human shyness, according to findings from the National Comorbidity Survey-Adolescent Supplement, which examined the rate of shyness and its overlap with social phobia in a nationally representative sample of adolescents. Yet, no significant differences were seen between adolescents characterized as shy and those who met the diagnostic criteria for social phobia in the use of prescribed medications.

© Kai Chiang/iStockphoto

The findings of the study, which involved face-to-face interviews with 10,123 adolescents aged 13-18 years, suggest there is little overlap between shyness and social phobia. The absence of differences in the use of prescribed medications between the two groups raises questions about the "medicalization hypothesis" of social phobia, which is a prevalent belief that the entity of social phobia is little more than medicalization of normal shyness, Marcy Burstein, Ph.D., and her colleagues from the National Institute of Mental Health in Bethesda, Md., argue in the November issue of Pediatrics (2011;128:917-25).

In fact, only 12.4% of 4,749 youth who described themselves as shy, and 10.6% whose parents considered them shy, also met the DSM-IV lifetime diagnostic criteria for social phobia. Furthermore, 5.2% and 5.5% of those who were not considered shy by their own or their parents’ reports, respectively, met the diagnostic criteria for social phobia, the investigators said.

Compared with adolescents with shyness, those with social phobia had significantly greater impairment in school and/or work (mean impairment score of 4.32 vs. 2.68 on a 10-point scale), family relationships (mean scores of 2.23 vs. 1.22), and social life (mean scores of 4.41 vs. 2.80). They also were more likely to be affected by anxiety disorders (odds ratio, 2.79), major depressive disorder (OR, 2.06), oppositional defiant disorder (OR, 1.99), and drug use disorders (OR, 3.27).

Despite these findings, the use of prescribed medications was low in both groups. For example, 0.9% and 2.3% of those who were shy and those with social phobia, respectively, used paroxetine, they noted.

"Statistical comparisons also indicated that adolescents with social phobia were no more likely to be using any prescribed medication, any antidepressant, paroxetine, or any other SSRI (selective serotonin reuptake inhibitor) relative to both other adolescent groups (shy and non-shy adolescents). In the same manner, adolescents with shyness were no more likely to be using prescribed medications, compared with adolescents with no shyness," Dr. Burstein and her associates said.

Differences between shyness and social phobia were seen in this study as well. For example, based on both parent and adolescent reports, shyness was significantly more common in girls than boys, occurring in 65.3% of girls and 59.7% of boys (based on parent reports), and in 50.1% of girls and 43.4% of boys (based on adolescent reports). However, no gender differences were seen for social phobia.

Also, shyness was more common in the youngest age group, compared with the oldest, occurring in 66.2% and 54.8% of the groups, respectively (based on parent reports), or consistent across age groups (based on adolescent reports), while the prevalence of social phobia increased with age, occurring in 6.3% of 13- to 14-year-olds, 9.6% of 15- to 16-year-olds, and 10.4% of 17- to 18-year-olds.

Although limited by numerous factors, such as the inability to examine the degree to which social phobia approximates a form of extreme shyness, the findings in this study were fairly consistent across multiple informants and were similar to those seen in other studies, according to the investigators.

The findings provide "convergent evidence that social phobia is not simply shyness," they said, noting that adolescents who met criteria for social phobia displayed "significantly greater role impairment and were more likely to experience a broad array of psychiatric disorders ... relative to adolescents who were characterized as shy."

These differences in impairment and psychiatric disorders, as well as the unique sociodemographic patterns seen in shyness vs. social phobia in this study, support the conceptualization of shyness and social phobia as distinct constructs, they said.

Furthermore, the estimates of prescribed medication use in this study counter claims that the concept of social phobia is merely the medicalization of shyness, they argued, stating that "contrary to the notion of medicalization, which would predict higher rates of prescribed medication use (in particular, paroxetine use) among adolescents with social phobia or shyness, we found no differences in the rates of prescription medication use across adolescent subgroups."

Of note, nearly 80% of adolescents with social phobia failed to seek or to obtain professional treatment for their anxiety, the investigators said.

"Persistent claims that dispute the severity of this condition among youth likely will do little to alter their course," they concluded.

This study was funded by the NIMH. The authors had no relevant financial disclosures.

Social phobia is an impairing psychiatric disorder that transcends typical human shyness, according to findings from the National Comorbidity Survey-Adolescent Supplement, which examined the rate of shyness and its overlap with social phobia in a nationally representative sample of adolescents. Yet, no significant differences were seen between adolescents characterized as shy and those who met the diagnostic criteria for social phobia in the use of prescribed medications.

© Kai Chiang/iStockphoto

The findings of the study, which involved face-to-face interviews with 10,123 adolescents aged 13-18 years, suggest there is little overlap between shyness and social phobia. The absence of differences in the use of prescribed medications between the two groups raises questions about the "medicalization hypothesis" of social phobia, which is a prevalent belief that the entity of social phobia is little more than medicalization of normal shyness, Marcy Burstein, Ph.D., and her colleagues from the National Institute of Mental Health in Bethesda, Md., argue in the November issue of Pediatrics (2011;128:917-25).

In fact, only 12.4% of 4,749 youth who described themselves as shy, and 10.6% whose parents considered them shy, also met the DSM-IV lifetime diagnostic criteria for social phobia. Furthermore, 5.2% and 5.5% of those who were not considered shy by their own or their parents’ reports, respectively, met the diagnostic criteria for social phobia, the investigators said.

Compared with adolescents with shyness, those with social phobia had significantly greater impairment in school and/or work (mean impairment score of 4.32 vs. 2.68 on a 10-point scale), family relationships (mean scores of 2.23 vs. 1.22), and social life (mean scores of 4.41 vs. 2.80). They also were more likely to be affected by anxiety disorders (odds ratio, 2.79), major depressive disorder (OR, 2.06), oppositional defiant disorder (OR, 1.99), and drug use disorders (OR, 3.27).

Despite these findings, the use of prescribed medications was low in both groups. For example, 0.9% and 2.3% of those who were shy and those with social phobia, respectively, used paroxetine, they noted.

"Statistical comparisons also indicated that adolescents with social phobia were no more likely to be using any prescribed medication, any antidepressant, paroxetine, or any other SSRI (selective serotonin reuptake inhibitor) relative to both other adolescent groups (shy and non-shy adolescents). In the same manner, adolescents with shyness were no more likely to be using prescribed medications, compared with adolescents with no shyness," Dr. Burstein and her associates said.

Differences between shyness and social phobia were seen in this study as well. For example, based on both parent and adolescent reports, shyness was significantly more common in girls than boys, occurring in 65.3% of girls and 59.7% of boys (based on parent reports), and in 50.1% of girls and 43.4% of boys (based on adolescent reports). However, no gender differences were seen for social phobia.

Also, shyness was more common in the youngest age group, compared with the oldest, occurring in 66.2% and 54.8% of the groups, respectively (based on parent reports), or consistent across age groups (based on adolescent reports), while the prevalence of social phobia increased with age, occurring in 6.3% of 13- to 14-year-olds, 9.6% of 15- to 16-year-olds, and 10.4% of 17- to 18-year-olds.

Although limited by numerous factors, such as the inability to examine the degree to which social phobia approximates a form of extreme shyness, the findings in this study were fairly consistent across multiple informants and were similar to those seen in other studies, according to the investigators.

The findings provide "convergent evidence that social phobia is not simply shyness," they said, noting that adolescents who met criteria for social phobia displayed "significantly greater role impairment and were more likely to experience a broad array of psychiatric disorders ... relative to adolescents who were characterized as shy."

These differences in impairment and psychiatric disorders, as well as the unique sociodemographic patterns seen in shyness vs. social phobia in this study, support the conceptualization of shyness and social phobia as distinct constructs, they said.

Furthermore, the estimates of prescribed medication use in this study counter claims that the concept of social phobia is merely the medicalization of shyness, they argued, stating that "contrary to the notion of medicalization, which would predict higher rates of prescribed medication use (in particular, paroxetine use) among adolescents with social phobia or shyness, we found no differences in the rates of prescription medication use across adolescent subgroups."

Of note, nearly 80% of adolescents with social phobia failed to seek or to obtain professional treatment for their anxiety, the investigators said.

"Persistent claims that dispute the severity of this condition among youth likely will do little to alter their course," they concluded.

This study was funded by the NIMH. The authors had no relevant financial disclosures.

The American Academy of Pediatrics has expanded its clinical practice guideline for diagnosing, evaluating, and treating attention-deficit/hyperactivity disorder in children to include preschoolers and adolescents.

The updated guideline was prompted by new evidence that has become available regarding the diagnosis and treatment of ADHD since clinical recommendations for diagnosis and evaluation of the disorder in children aged 6-12 years were published in 2000, and recommendations for treatment in that age group were published in 2001. The guideline, published in the November issue of Pediatrics, now includes recommendations for preschool- and adolescent-age children aged 4-18 years, as well as recommendations for managing symptomatic children and adolescents who don’t meet all the criteria for an ADHD diagnosis (Pediatrics 2011 [doi:10.1542/peds.2011-2654]).

"Since the original guidelines were written in 2000 and 2001, there have been additional studies that further clarified the diagnosis and treatment of children and youths with ADHD," said Dr. Mark Wolraich, chair of the AAP’s subcommittee on ADHD, which developed the updated guideline.

The updated guideline includes six key action statements for primary care clinicians, with most based on level B evidence quality and accompanied by a "strong recommendation."

For example, action statement 1 (based on level B evidence) states that an evaluation for ADHD should be initiated for any child aged 4-18 years who presents with academic or behavioral problems and symptoms of inattention, hyperactivity, or impulsivity. The authors "strongly recommend" this action, stating that ADHD goes undiagnosed in a considerable number of children, and systematic identification of children with these problems will likely decrease the rate of undiagnosed and untreated ADHD.

Furthermore, the subcommittee members stated, "There is now increased evidence that appropriate diagnosis can be provided for preschool-aged children (4-5 years of age) and for adolescents."

Action statement 5 addresses treatment in the various age groups. For example, statement 5a addresses preschool children aged 4-5 years, and notes that evidence-based parent- and/or teacher-administered behavior therapy should be used first line in this age group (a strong recommendation based on level A evidence), and that methylphenidate can be prescribed if behavior interventions are ineffective (a recommendation based on level B evidence). Statement 5b addresses elementary school-age children aged 6-11 years, and notes that Food and Drug Administration-approved medications for ADHD (strong recommendation based on level A evidence), and/or evidence-based parent- and/or teacher-administered behavior therapy – and preferably both (strong recommendation based on level B evidence) should be used in this age group.

"The evidence is particularly strong for stimulant medication and sufficient but less strong for atomoxetine, extended-release guanfacine, and extended release clonidine (in that order)," the subcommittee members wrote.

Statement 5c addresses adolescents aged 12-18 years, and notes that the primary care clinician should prescribe FDA-approved medication for ADHD with the assent of the adolescent (a strong recommendation based on level A evidence), and also that they may prescribe behavioral therapy (a recommendation based on level C evidence). Use of both is preferred.

The remaining action statements address the following:

• ADHD diagnosis should be based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria – after ruling out other causes – and based on information obtained primarily from parents or guardians, teachers, and other school and mental health clinicians involved in the child’s care. This action statement (action statement 2, quality of evidence B, strong recommendation) also provides guidance for use of the Diagnostic and Statistical Manual for Primary Care (DSM-PC) for children with behaviors relating to activity level, impulsivity, and inattention who don’t fully meet DSM-IV criteria for ADHD. The DSM-PC provides guidance on the treatment of these children, and also considers environmental influences on behavior, as well as differential diagnoses with a developmental perspective.

• Assessment for co-existing emotional or behavioral, developmental, and physical conditions is important (action statement 3, quality of evidence B, strong recommendation). The comorbid emotional or behavioral conditions might be anxiety, depressive, oppositional defiant, and conduct disorders, and the comorbid developmental conditions might include learning and language disorders or other neurodevelopmental disorders. The coexisting physical conditions might include tics or sleep apnea.

• ADHD should be recognized as a chronic condition and management of children and youth with this condition should be based on the principles of the chronic care model and the medical home (action statement 4, quality of evidence B/strong recommendation).

• Doses of medication should be titrated to achieve maximum benefit with minimal adverse effects (action statement 6, quality of evidence B/strong recommendation).

Each action statement includes caveats for special circumstances based on age group, certain symptoms, and/or comorbidities to provide further guidance for the clinician.

The updated guideline was developed in collaboration with several organizations whose representatives formed the working subcommittee. The group met over a 2-year period to review changes in practice that have occurred over time and issues that have been identified since the previous guideline were published. A multilevel systematic approach was used to identify the literature that built the evidence base for the diagnosis and treatment recommendations, which underwent extensive peer review by committees, sections, councils, and task forces within the AAP, as well as numerous outside groups and individuals. The guidelines will be reviewed and/or revised in 5 years, unless evidence emerges that warrants an earlier revision, they noted.

"As occurred with the initial guidelines, we hope the revised guidelines will provide the process that primary care clinicians treating children and youth can use to provide the best evidence-based practices for their patients who have or are suspected of having ADHD," Dr. Wolraich said.

Development of the new ADHD guideline was funded by the AAP with support from the Partnership for Policy Implementation initiative. Multiple subcommittee members reported financial disclosures, which are included in the Pediatrics article where the guideline is published. Dr. Wolraich, for example, reported that he has served periodically as a consultant to Shire, Eli Lilly, Shinogi, and Next Wave Pharmaceuticals. The article states that all conflicts were "resolved through a process approved by the AAP Board of Directors."

The American Academy of Pediatrics has expanded its clinical practice guideline for diagnosing, evaluating, and treating attention-deficit/hyperactivity disorder in children to include preschoolers and adolescents.

The updated guideline was prompted by new evidence that has become available regarding the diagnosis and treatment of ADHD since clinical recommendations for diagnosis and evaluation of the disorder in children aged 6-12 years were published in 2000, and recommendations for treatment in that age group were published in 2001. The guideline, published in the November issue of Pediatrics, now includes recommendations for preschool- and adolescent-age children aged 4-18 years, as well as recommendations for managing symptomatic children and adolescents who don’t meet all the criteria for an ADHD diagnosis (Pediatrics 2011 [doi:10.1542/peds.2011-2654]).

"Since the original guidelines were written in 2000 and 2001, there have been additional studies that further clarified the diagnosis and treatment of children and youths with ADHD," said Dr. Mark Wolraich, chair of the AAP’s subcommittee on ADHD, which developed the updated guideline.

The updated guideline includes six key action statements for primary care clinicians, with most based on level B evidence quality and accompanied by a "strong recommendation."

For example, action statement 1 (based on level B evidence) states that an evaluation for ADHD should be initiated for any child aged 4-18 years who presents with academic or behavioral problems and symptoms of inattention, hyperactivity, or impulsivity. The authors "strongly recommend" this action, stating that ADHD goes undiagnosed in a considerable number of children, and systematic identification of children with these problems will likely decrease the rate of undiagnosed and untreated ADHD.

Furthermore, the subcommittee members stated, "There is now increased evidence that appropriate diagnosis can be provided for preschool-aged children (4-5 years of age) and for adolescents."

Action statement 5 addresses treatment in the various age groups. For example, statement 5a addresses preschool children aged 4-5 years, and notes that evidence-based parent- and/or teacher-administered behavior therapy should be used first line in this age group (a strong recommendation based on level A evidence), and that methylphenidate can be prescribed if behavior interventions are ineffective (a recommendation based on level B evidence). Statement 5b addresses elementary school-age children aged 6-11 years, and notes that Food and Drug Administration-approved medications for ADHD (strong recommendation based on level A evidence), and/or evidence-based parent- and/or teacher-administered behavior therapy – and preferably both (strong recommendation based on level B evidence) should be used in this age group.

"The evidence is particularly strong for stimulant medication and sufficient but less strong for atomoxetine, extended-release guanfacine, and extended release clonidine (in that order)," the subcommittee members wrote.

Statement 5c addresses adolescents aged 12-18 years, and notes that the primary care clinician should prescribe FDA-approved medication for ADHD with the assent of the adolescent (a strong recommendation based on level A evidence), and also that they may prescribe behavioral therapy (a recommendation based on level C evidence). Use of both is preferred.

The remaining action statements address the following:

• ADHD diagnosis should be based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria – after ruling out other causes – and based on information obtained primarily from parents or guardians, teachers, and other school and mental health clinicians involved in the child’s care. This action statement (action statement 2, quality of evidence B, strong recommendation) also provides guidance for use of the Diagnostic and Statistical Manual for Primary Care (DSM-PC) for children with behaviors relating to activity level, impulsivity, and inattention who don’t fully meet DSM-IV criteria for ADHD. The DSM-PC provides guidance on the treatment of these children, and also considers environmental influences on behavior, as well as differential diagnoses with a developmental perspective.

• Assessment for co-existing emotional or behavioral, developmental, and physical conditions is important (action statement 3, quality of evidence B, strong recommendation). The comorbid emotional or behavioral conditions might be anxiety, depressive, oppositional defiant, and conduct disorders, and the comorbid developmental conditions might include learning and language disorders or other neurodevelopmental disorders. The coexisting physical conditions might include tics or sleep apnea.

• ADHD should be recognized as a chronic condition and management of children and youth with this condition should be based on the principles of the chronic care model and the medical home (action statement 4, quality of evidence B/strong recommendation).

• Doses of medication should be titrated to achieve maximum benefit with minimal adverse effects (action statement 6, quality of evidence B/strong recommendation).

Each action statement includes caveats for special circumstances based on age group, certain symptoms, and/or comorbidities to provide further guidance for the clinician.

The updated guideline was developed in collaboration with several organizations whose representatives formed the working subcommittee. The group met over a 2-year period to review changes in practice that have occurred over time and issues that have been identified since the previous guideline were published. A multilevel systematic approach was used to identify the literature that built the evidence base for the diagnosis and treatment recommendations, which underwent extensive peer review by committees, sections, councils, and task forces within the AAP, as well as numerous outside groups and individuals. The guidelines will be reviewed and/or revised in 5 years, unless evidence emerges that warrants an earlier revision, they noted.

"As occurred with the initial guidelines, we hope the revised guidelines will provide the process that primary care clinicians treating children and youth can use to provide the best evidence-based practices for their patients who have or are suspected of having ADHD," Dr. Wolraich said.

Development of the new ADHD guideline was funded by the AAP with support from the Partnership for Policy Implementation initiative. Multiple subcommittee members reported financial disclosures, which are included in the Pediatrics article where the guideline is published. Dr. Wolraich, for example, reported that he has served periodically as a consultant to Shire, Eli Lilly, Shinogi, and Next Wave Pharmaceuticals. The article states that all conflicts were "resolved through a process approved by the AAP Board of Directors."

The American Academy of Pediatrics has expanded its clinical practice guideline for diagnosing, evaluating, and treating attention-deficit/hyperactivity disorder in children to include preschoolers and adolescents.

The updated guideline was prompted by new evidence that has become available regarding the diagnosis and treatment of ADHD since clinical recommendations for diagnosis and evaluation of the disorder in children aged 6-12 years were published in 2000, and recommendations for treatment in that age group were published in 2001. The guideline, published in the November issue of Pediatrics, now includes recommendations for preschool- and adolescent-age children aged 4-18 years, as well as recommendations for managing symptomatic children and adolescents who don’t meet all the criteria for an ADHD diagnosis (Pediatrics 2011 [doi:10.1542/peds.2011-2654]).

"Since the original guidelines were written in 2000 and 2001, there have been additional studies that further clarified the diagnosis and treatment of children and youths with ADHD," said Dr. Mark Wolraich, chair of the AAP’s subcommittee on ADHD, which developed the updated guideline.

The updated guideline includes six key action statements for primary care clinicians, with most based on level B evidence quality and accompanied by a "strong recommendation."

For example, action statement 1 (based on level B evidence) states that an evaluation for ADHD should be initiated for any child aged 4-18 years who presents with academic or behavioral problems and symptoms of inattention, hyperactivity, or impulsivity. The authors "strongly recommend" this action, stating that ADHD goes undiagnosed in a considerable number of children, and systematic identification of children with these problems will likely decrease the rate of undiagnosed and untreated ADHD.

Furthermore, the subcommittee members stated, "There is now increased evidence that appropriate diagnosis can be provided for preschool-aged children (4-5 years of age) and for adolescents."

Action statement 5 addresses treatment in the various age groups. For example, statement 5a addresses preschool children aged 4-5 years, and notes that evidence-based parent- and/or teacher-administered behavior therapy should be used first line in this age group (a strong recommendation based on level A evidence), and that methylphenidate can be prescribed if behavior interventions are ineffective (a recommendation based on level B evidence). Statement 5b addresses elementary school-age children aged 6-11 years, and notes that Food and Drug Administration-approved medications for ADHD (strong recommendation based on level A evidence), and/or evidence-based parent- and/or teacher-administered behavior therapy – and preferably both (strong recommendation based on level B evidence) should be used in this age group.

"The evidence is particularly strong for stimulant medication and sufficient but less strong for atomoxetine, extended-release guanfacine, and extended release clonidine (in that order)," the subcommittee members wrote.

Statement 5c addresses adolescents aged 12-18 years, and notes that the primary care clinician should prescribe FDA-approved medication for ADHD with the assent of the adolescent (a strong recommendation based on level A evidence), and also that they may prescribe behavioral therapy (a recommendation based on level C evidence). Use of both is preferred.

The remaining action statements address the following:

• ADHD diagnosis should be based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria – after ruling out other causes – and based on information obtained primarily from parents or guardians, teachers, and other school and mental health clinicians involved in the child’s care. This action statement (action statement 2, quality of evidence B, strong recommendation) also provides guidance for use of the Diagnostic and Statistical Manual for Primary Care (DSM-PC) for children with behaviors relating to activity level, impulsivity, and inattention who don’t fully meet DSM-IV criteria for ADHD. The DSM-PC provides guidance on the treatment of these children, and also considers environmental influences on behavior, as well as differential diagnoses with a developmental perspective.

• Assessment for co-existing emotional or behavioral, developmental, and physical conditions is important (action statement 3, quality of evidence B, strong recommendation). The comorbid emotional or behavioral conditions might be anxiety, depressive, oppositional defiant, and conduct disorders, and the comorbid developmental conditions might include learning and language disorders or other neurodevelopmental disorders. The coexisting physical conditions might include tics or sleep apnea.

• ADHD should be recognized as a chronic condition and management of children and youth with this condition should be based on the principles of the chronic care model and the medical home (action statement 4, quality of evidence B/strong recommendation).

• Doses of medication should be titrated to achieve maximum benefit with minimal adverse effects (action statement 6, quality of evidence B/strong recommendation).

Each action statement includes caveats for special circumstances based on age group, certain symptoms, and/or comorbidities to provide further guidance for the clinician.

The updated guideline was developed in collaboration with several organizations whose representatives formed the working subcommittee. The group met over a 2-year period to review changes in practice that have occurred over time and issues that have been identified since the previous guideline were published. A multilevel systematic approach was used to identify the literature that built the evidence base for the diagnosis and treatment recommendations, which underwent extensive peer review by committees, sections, councils, and task forces within the AAP, as well as numerous outside groups and individuals. The guidelines will be reviewed and/or revised in 5 years, unless evidence emerges that warrants an earlier revision, they noted.

"As occurred with the initial guidelines, we hope the revised guidelines will provide the process that primary care clinicians treating children and youth can use to provide the best evidence-based practices for their patients who have or are suspected of having ADHD," Dr. Wolraich said.

Development of the new ADHD guideline was funded by the AAP with support from the Partnership for Policy Implementation initiative. Multiple subcommittee members reported financial disclosures, which are included in the Pediatrics article where the guideline is published. Dr. Wolraich, for example, reported that he has served periodically as a consultant to Shire, Eli Lilly, Shinogi, and Next Wave Pharmaceuticals. The article states that all conflicts were "resolved through a process approved by the AAP Board of Directors."

Several commonly used vitamin and mineral supplements were significantly associated with increased total mortality risk in 38,772 older women from the Iowa Women’s Health Study who were followed for a mean of 19 years.

Supplemental iron was most strongly associated with increased mortality (hazard ratio of 1.10 in a fully adjusted model), Jaakko Mursu, Ph.D., of the University of Eastern Finland, Kuopio, and colleagues reported in the Oct. 10 issue of Archives of Internal Medicine.

The use of multivitamins, vitamin B₆, folic acid, magnesium, zinc, and copper also was associated with a higher risk of mortality (hazard ratios, 1.06, 1.10, 1.15, 1.08, 1.08, and 1.45, respectively) after adjustment for age, education level, place of residence, diabetes mellitus, high blood pressure, body mass index, waist to hip ratio, hormone therapy, physical activity, smoking status, alcohol intake, energy intake, saturated fatty acids intake, whole grain products intake, and fruit and vegetable intake.

Conversely – and in contrast to findings from some prior studies – calcium supplementation was associated with decreased mortality risk in adjusted models (hazard ratio of 0.91 for the fully adjusted model), the investigators found (Arch. Intern. Med. 2011;171:1625-33).

Participants in the Iowa Women’s Health Study were enrolled in 1986 and those included in the current study had a mean age of 61.6 years. Participants completed a 16-page self-administered questionnaire that included information on food frequency and supplement use. Additional self-reports were provided in 1997 and 2004. As of Dec. 31, 2008, 40% of those included in the current analysis had died.

Self-reported supplement use increased over time, with 62.7%, 75.1%, and 85.1% reporting the use of at least one supplement daily in the 1986, 1997, and 2004 questionnaires, respectively.

The most commonly used supplements were calcium, multivitamins, vitamin C, and vitamin E; the most commonly used combinations were calcium and multivitamins; calcium, multivitamins, and vitamin C; and calcium and vitamin C.

"Although we cannot rule out benefits of supplements, such as improved quality of life, our study raises a concern regarding their long-term safety."

On analyses performed for shorter follow-up intervals of 10, 6, and 4 years, the findings for iron and calcium were replicated; about 15% of the deaths in original participants occurred in each of the following periods: 1986 through 1996, 1997 through 2003, and 2004 through 2008.

"In multivariable adjusted analyses across the shorter follow-up intervals, beginning with the baseline and each follow-up questionnaire, the most consistent findings ... were for supplemental iron (hazard ratios,1.20, 1.43, and 1.56...) and calcium (0.89, 0.90, 0.88)," the investigators said.

Furthermore, increased consistency of use of iron was associated with increased mortality risk; the hazard ratio for mortality (versus nonuse) for those who reported using iron at only one survey was 1.35, compared with 1.62 and 1.60 for use at two and at all three surveys, respectively, they said.

The findings, though observational, are concerning given the popularity of dietary supplements, the investigators said, noting that about half of all adults were using supplements in 2000, and that 66% of women participating in the Iowa Women’s Health Study used at least one supplement daily at baseline, with an increase to 85% in 2004. More than a quarter of participants used four or more.

"Supplemental nutrient intake clearly is beneficial in deficiency conditions. However, in well-nourished populations, supplements often are intended to yield benefit by preventing chronic disease," the investigators noted, adding that studies have produced inconsistent results in regard to the benefits and harms of supplementation.

Several randomized controlled trials and meta-analyses – particularly those evaluating the use of calcium and vitamins B, C, D, and E – have shown no benefit in terms of total mortality rate and in some cases have shown possible harm, they said.

This study provides further evidence that most dietary supplements are unrelated to total mortality rate, and that some are associated with increased total mortality rate.

The strengths of this study are the large sample size and longitudinal design, as well as the fact that the women were questioned three times about diet and supplement use during the course of the follow-up.

"The use of repeated measures enabled evaluation of the consistency of the findings and decreased the risk that the exposure was misclassified," the investigators wrote.

The limitations of the study include the potential for residual confounding despite extensive adjustment, and the possibility that some supplements may have been taken for "reasonable cause in response to symptoms or clinical disease."

Furthermore, 99.2 % of women in the Iowa Women’s Health Study were white, thus generalization to other populations, ethnic groups, and men is problematic.

"Although we cannot rule out benefits of supplements, such as improved quality of life, our study raises a concern regarding their long-term safety ... it is not advisable to make a causal statement of excess risk based on these observational data; however, it is noteworthy that dietary supplements, unlike drugs, do not require rigorous (randomized controlled trial) testing, and observational studies are often the best available method for assessing the safety of long-term use," they wrote.

Therefore, based on existing evidence, they argue that there is little justification for the general and widespread use of dietary supplements.

"We recommend that they be used with strong medically based cause, such as symptomatic nutrient deficiency disease," they concluded.

"Until recently, the available data regarding the adverse effects of dietary supplements has been limited and grossly underreported."

This "large, well-designed, and well-conducted" trial adds to the existing evidence that certain supplements can be harmful, and the findings concur with those of other recent observational studies, Dr. Goran Bjelakovic and Dr. Christian Gluud said in an editorial accompanying the report (Arch. Intern. Med. 2011;171:1633-4).

"The belief that antioxidant supplements are beneficial seems likely to have resulted from a collective error. Perhaps oxidative stress is one of the keys to extension of our life span," they suggested.

Indeed, the shift in the use of dietary supplementation for prevention of deficiency to use for promoting wellness and prevention of diseases – with many consumers believing that supplements are safe for use without the supervision of their physician – is problematic.

"Until recently, the available data regarding the adverse effects of dietary supplements has been limited and grossly underreported. We think the paradigm ‘the more the better’ is wrong," they said.

Rather, there are likely risks with both insufficient and too-large intake, added Dr. Bjelakovic and Dr. Gluud, both of whom are with the Copenhagen trial unit, center for clinical intervention research, Cochrane Hepato-Biliary Group, Rigshospitalet, Copenhagen, University Hospital.

"Therefore, we believe that politicians and regulatory authorities should wake up to their responsibility to allow only safe products on the market," they said, also noting that in a well-nourished population, the use of vitamin and mineral supplements as a preventive measure should not be recommended.

A possible exception based on these and other findings is with vitamin D₃ supplementation, particularly when there is insufficient vitamin D supply from the sun and diet; this may apply to older women, and perhaps older men. The matter of calcium supplementation may require further study, they said.

This study was partially supported by a grant from the National Cancer Institute and by grants from the Academy of Finland, the Finnish Cultural Foundation, and the Fulbright program. One of the study authors (David R. Jacobs Jr., Ph.D.) reported being an unpaid member of the scientific advisory board of the California Walnut Commission. None of the other authors had relevant financial disclosures to report. Neither Dr. Bjelakovic nor Dr. Gluud had relevant financial disclosures to report.

Several commonly used vitamin and mineral supplements were significantly associated with increased total mortality risk in 38,772 older women from the Iowa Women’s Health Study who were followed for a mean of 19 years.

Supplemental iron was most strongly associated with increased mortality (hazard ratio of 1.10 in a fully adjusted model), Jaakko Mursu, Ph.D., of the University of Eastern Finland, Kuopio, and colleagues reported in the Oct. 10 issue of Archives of Internal Medicine.

The use of multivitamins, vitamin B₆, folic acid, magnesium, zinc, and copper also was associated with a higher risk of mortality (hazard ratios, 1.06, 1.10, 1.15, 1.08, 1.08, and 1.45, respectively) after adjustment for age, education level, place of residence, diabetes mellitus, high blood pressure, body mass index, waist to hip ratio, hormone therapy, physical activity, smoking status, alcohol intake, energy intake, saturated fatty acids intake, whole grain products intake, and fruit and vegetable intake.

Conversely – and in contrast to findings from some prior studies – calcium supplementation was associated with decreased mortality risk in adjusted models (hazard ratio of 0.91 for the fully adjusted model), the investigators found (Arch. Intern. Med. 2011;171:1625-33).

Participants in the Iowa Women’s Health Study were enrolled in 1986 and those included in the current study had a mean age of 61.6 years. Participants completed a 16-page self-administered questionnaire that included information on food frequency and supplement use. Additional self-reports were provided in 1997 and 2004. As of Dec. 31, 2008, 40% of those included in the current analysis had died.

Self-reported supplement use increased over time, with 62.7%, 75.1%, and 85.1% reporting the use of at least one supplement daily in the 1986, 1997, and 2004 questionnaires, respectively.

The most commonly used supplements were calcium, multivitamins, vitamin C, and vitamin E; the most commonly used combinations were calcium and multivitamins; calcium, multivitamins, and vitamin C; and calcium and vitamin C.

"Although we cannot rule out benefits of supplements, such as improved quality of life, our study raises a concern regarding their long-term safety."

On analyses performed for shorter follow-up intervals of 10, 6, and 4 years, the findings for iron and calcium were replicated; about 15% of the deaths in original participants occurred in each of the following periods: 1986 through 1996, 1997 through 2003, and 2004 through 2008.

"In multivariable adjusted analyses across the shorter follow-up intervals, beginning with the baseline and each follow-up questionnaire, the most consistent findings ... were for supplemental iron (hazard ratios,1.20, 1.43, and 1.56...) and calcium (0.89, 0.90, 0.88)," the investigators said.

Furthermore, increased consistency of use of iron was associated with increased mortality risk; the hazard ratio for mortality (versus nonuse) for those who reported using iron at only one survey was 1.35, compared with 1.62 and 1.60 for use at two and at all three surveys, respectively, they said.

The findings, though observational, are concerning given the popularity of dietary supplements, the investigators said, noting that about half of all adults were using supplements in 2000, and that 66% of women participating in the Iowa Women’s Health Study used at least one supplement daily at baseline, with an increase to 85% in 2004. More than a quarter of participants used four or more.

"Supplemental nutrient intake clearly is beneficial in deficiency conditions. However, in well-nourished populations, supplements often are intended to yield benefit by preventing chronic disease," the investigators noted, adding that studies have produced inconsistent results in regard to the benefits and harms of supplementation.

Several randomized controlled trials and meta-analyses – particularly those evaluating the use of calcium and vitamins B, C, D, and E – have shown no benefit in terms of total mortality rate and in some cases have shown possible harm, they said.

This study provides further evidence that most dietary supplements are unrelated to total mortality rate, and that some are associated with increased total mortality rate.

The strengths of this study are the large sample size and longitudinal design, as well as the fact that the women were questioned three times about diet and supplement use during the course of the follow-up.

"The use of repeated measures enabled evaluation of the consistency of the findings and decreased the risk that the exposure was misclassified," the investigators wrote.

The limitations of the study include the potential for residual confounding despite extensive adjustment, and the possibility that some supplements may have been taken for "reasonable cause in response to symptoms or clinical disease."

Furthermore, 99.2 % of women in the Iowa Women’s Health Study were white, thus generalization to other populations, ethnic groups, and men is problematic.

"Although we cannot rule out benefits of supplements, such as improved quality of life, our study raises a concern regarding their long-term safety ... it is not advisable to make a causal statement of excess risk based on these observational data; however, it is noteworthy that dietary supplements, unlike drugs, do not require rigorous (randomized controlled trial) testing, and observational studies are often the best available method for assessing the safety of long-term use," they wrote.

Therefore, based on existing evidence, they argue that there is little justification for the general and widespread use of dietary supplements.

"We recommend that they be used with strong medically based cause, such as symptomatic nutrient deficiency disease," they concluded.

"Until recently, the available data regarding the adverse effects of dietary supplements has been limited and grossly underreported."

This "large, well-designed, and well-conducted" trial adds to the existing evidence that certain supplements can be harmful, and the findings concur with those of other recent observational studies, Dr. Goran Bjelakovic and Dr. Christian Gluud said in an editorial accompanying the report (Arch. Intern. Med. 2011;171:1633-4).

"The belief that antioxidant supplements are beneficial seems likely to have resulted from a collective error. Perhaps oxidative stress is one of the keys to extension of our life span," they suggested.

Indeed, the shift in the use of dietary supplementation for prevention of deficiency to use for promoting wellness and prevention of diseases – with many consumers believing that supplements are safe for use without the supervision of their physician – is problematic.

"Until recently, the available data regarding the adverse effects of dietary supplements has been limited and grossly underreported. We think the paradigm ‘the more the better’ is wrong," they said.

Rather, there are likely risks with both insufficient and too-large intake, added Dr. Bjelakovic and Dr. Gluud, both of whom are with the Copenhagen trial unit, center for clinical intervention research, Cochrane Hepato-Biliary Group, Rigshospitalet, Copenhagen, University Hospital.

"Therefore, we believe that politicians and regulatory authorities should wake up to their responsibility to allow only safe products on the market," they said, also noting that in a well-nourished population, the use of vitamin and mineral supplements as a preventive measure should not be recommended.

A possible exception based on these and other findings is with vitamin D₃ supplementation, particularly when there is insufficient vitamin D supply from the sun and diet; this may apply to older women, and perhaps older men. The matter of calcium supplementation may require further study, they said.

This study was partially supported by a grant from the National Cancer Institute and by grants from the Academy of Finland, the Finnish Cultural Foundation, and the Fulbright program. One of the study authors (David R. Jacobs Jr., Ph.D.) reported being an unpaid member of the scientific advisory board of the California Walnut Commission. None of the other authors had relevant financial disclosures to report. Neither Dr. Bjelakovic nor Dr. Gluud had relevant financial disclosures to report.

Several commonly used vitamin and mineral supplements were significantly associated with increased total mortality risk in 38,772 older women from the Iowa Women’s Health Study who were followed for a mean of 19 years.

Supplemental iron was most strongly associated with increased mortality (hazard ratio of 1.10 in a fully adjusted model), Jaakko Mursu, Ph.D., of the University of Eastern Finland, Kuopio, and colleagues reported in the Oct. 10 issue of Archives of Internal Medicine.

The use of multivitamins, vitamin B₆, folic acid, magnesium, zinc, and copper also was associated with a higher risk of mortality (hazard ratios, 1.06, 1.10, 1.15, 1.08, 1.08, and 1.45, respectively) after adjustment for age, education level, place of residence, diabetes mellitus, high blood pressure, body mass index, waist to hip ratio, hormone therapy, physical activity, smoking status, alcohol intake, energy intake, saturated fatty acids intake, whole grain products intake, and fruit and vegetable intake.

Conversely – and in contrast to findings from some prior studies – calcium supplementation was associated with decreased mortality risk in adjusted models (hazard ratio of 0.91 for the fully adjusted model), the investigators found (Arch. Intern. Med. 2011;171:1625-33).

Participants in the Iowa Women’s Health Study were enrolled in 1986 and those included in the current study had a mean age of 61.6 years. Participants completed a 16-page self-administered questionnaire that included information on food frequency and supplement use. Additional self-reports were provided in 1997 and 2004. As of Dec. 31, 2008, 40% of those included in the current analysis had died.

Self-reported supplement use increased over time, with 62.7%, 75.1%, and 85.1% reporting the use of at least one supplement daily in the 1986, 1997, and 2004 questionnaires, respectively.

The most commonly used supplements were calcium, multivitamins, vitamin C, and vitamin E; the most commonly used combinations were calcium and multivitamins; calcium, multivitamins, and vitamin C; and calcium and vitamin C.

"Although we cannot rule out benefits of supplements, such as improved quality of life, our study raises a concern regarding their long-term safety."

On analyses performed for shorter follow-up intervals of 10, 6, and 4 years, the findings for iron and calcium were replicated; about 15% of the deaths in original participants occurred in each of the following periods: 1986 through 1996, 1997 through 2003, and 2004 through 2008.

"In multivariable adjusted analyses across the shorter follow-up intervals, beginning with the baseline and each follow-up questionnaire, the most consistent findings ... were for supplemental iron (hazard ratios,1.20, 1.43, and 1.56...) and calcium (0.89, 0.90, 0.88)," the investigators said.

Furthermore, increased consistency of use of iron was associated with increased mortality risk; the hazard ratio for mortality (versus nonuse) for those who reported using iron at only one survey was 1.35, compared with 1.62 and 1.60 for use at two and at all three surveys, respectively, they said.

The findings, though observational, are concerning given the popularity of dietary supplements, the investigators said, noting that about half of all adults were using supplements in 2000, and that 66% of women participating in the Iowa Women’s Health Study used at least one supplement daily at baseline, with an increase to 85% in 2004. More than a quarter of participants used four or more.

"Supplemental nutrient intake clearly is beneficial in deficiency conditions. However, in well-nourished populations, supplements often are intended to yield benefit by preventing chronic disease," the investigators noted, adding that studies have produced inconsistent results in regard to the benefits and harms of supplementation.

Several randomized controlled trials and meta-analyses – particularly those evaluating the use of calcium and vitamins B, C, D, and E – have shown no benefit in terms of total mortality rate and in some cases have shown possible harm, they said.

This study provides further evidence that most dietary supplements are unrelated to total mortality rate, and that some are associated with increased total mortality rate.

The strengths of this study are the large sample size and longitudinal design, as well as the fact that the women were questioned three times about diet and supplement use during the course of the follow-up.

"The use of repeated measures enabled evaluation of the consistency of the findings and decreased the risk that the exposure was misclassified," the investigators wrote.

The limitations of the study include the potential for residual confounding despite extensive adjustment, and the possibility that some supplements may have been taken for "reasonable cause in response to symptoms or clinical disease."

Furthermore, 99.2 % of women in the Iowa Women’s Health Study were white, thus generalization to other populations, ethnic groups, and men is problematic.

"Although we cannot rule out benefits of supplements, such as improved quality of life, our study raises a concern regarding their long-term safety ... it is not advisable to make a causal statement of excess risk based on these observational data; however, it is noteworthy that dietary supplements, unlike drugs, do not require rigorous (randomized controlled trial) testing, and observational studies are often the best available method for assessing the safety of long-term use," they wrote.

Therefore, based on existing evidence, they argue that there is little justification for the general and widespread use of dietary supplements.

"We recommend that they be used with strong medically based cause, such as symptomatic nutrient deficiency disease," they concluded.

"Until recently, the available data regarding the adverse effects of dietary supplements has been limited and grossly underreported."

This "large, well-designed, and well-conducted" trial adds to the existing evidence that certain supplements can be harmful, and the findings concur with those of other recent observational studies, Dr. Goran Bjelakovic and Dr. Christian Gluud said in an editorial accompanying the report (Arch. Intern. Med. 2011;171:1633-4).

"The belief that antioxidant supplements are beneficial seems likely to have resulted from a collective error. Perhaps oxidative stress is one of the keys to extension of our life span," they suggested.

Indeed, the shift in the use of dietary supplementation for prevention of deficiency to use for promoting wellness and prevention of diseases – with many consumers believing that supplements are safe for use without the supervision of their physician – is problematic.

"Until recently, the available data regarding the adverse effects of dietary supplements has been limited and grossly underreported. We think the paradigm ‘the more the better’ is wrong," they said.

Rather, there are likely risks with both insufficient and too-large intake, added Dr. Bjelakovic and Dr. Gluud, both of whom are with the Copenhagen trial unit, center for clinical intervention research, Cochrane Hepato-Biliary Group, Rigshospitalet, Copenhagen, University Hospital.

"Therefore, we believe that politicians and regulatory authorities should wake up to their responsibility to allow only safe products on the market," they said, also noting that in a well-nourished population, the use of vitamin and mineral supplements as a preventive measure should not be recommended.

A possible exception based on these and other findings is with vitamin D₃ supplementation, particularly when there is insufficient vitamin D supply from the sun and diet; this may apply to older women, and perhaps older men. The matter of calcium supplementation may require further study, they said.

This study was partially supported by a grant from the National Cancer Institute and by grants from the Academy of Finland, the Finnish Cultural Foundation, and the Fulbright program. One of the study authors (David R. Jacobs Jr., Ph.D.) reported being an unpaid member of the scientific advisory board of the California Walnut Commission. None of the other authors had relevant financial disclosures to report. Neither Dr. Bjelakovic nor Dr. Gluud had relevant financial disclosures to report.

Many "detected" and "at-risk" children are falling through the cracks when it comes to referring and interlinking children with suspected developmental-behavioral problems to early intervention and other community services.

At least one group of researchers believes that revisions to the 2006 American Academy of Pediatrics developmental surveillance and screening algorithm are needed to optimize the early detection, prevention, and ongoing monitoring of developmental-behavioral problems. In the September issue of Clinical Pediatrics, Dr. Kevin Marks and his colleagues argue that a more detailed action plan is needed (Clin. Pediatr. 2011;50:853-68).

Specifically, they argue that promotion of behavioral and developmental wellness should be formally included as an action step, that referrals for certain high-risk children should be automatic, and that greater emphasis should be placed on care coordination following a referral for early intervention services.

"As physicians, we play a key role in the early detection of developmental and behavioral problems in children prior to kindergarten entrance. We have the privilege and ability to create opportunities for parents to access services for their children, but there is much work to be done to ensure that these referrals occur in keeping with the six quality aims of the Institute of Medicine, which call for referrals to be made in a safe, equitable, effective, timely, parent-centered, and efficient manner," Dr. Marks, a general pediatrician and pediatric hospitalist in Eugene, Ore., said in an interview.

The comprehensive review of the current literature conducted by Dr. Marks and his colleagues showed that children with a concerning screening test are not consistently referred and interlinked to early intervention services. Furthermore, due to a variety of reasons, only about half of those referred ultimately are deemed eligible for early intervention despite performing well below average and exhibiting numerous predictive academic and psychosocial risk factors.

"Pediatricians are frequently missing young children with suspected developmental delays, social-emotional problems, and autism."

Currently there are three separate algorithms for general pediatricians to follow from three separate AAP statements, which were published in 2006, 2007, and 2010. Together they recommend universal postpartum maternal depression screening in the first year; general developmental screening at 9, 18, and 24 months; autism-specific screening at 18 and 24 months; social-emotional screening whenever a general developmental or autism-specific screen is abnormal; kindergarten readiness screening at 4 years; and mental health/psychosocial function screening at 5 years and every well-visit thereafter.

"Our findings reinforce many of the previous recommendations within various AAP statements in regard to periodic screening with well-standardized, reliable and accurate tools that measure general development and social-emotional/behavioral development, as well as autism-specific and family psychosocial screening tools," Dr. Marks said.

Areas where the findings support revisions, however, include:

• The promotion of developmental and behavioral wellness. An example is literacy counseling through the Reach Out and Read program, which has been shown to improve outcomes. Consistently incorporating positive parenting and strength-based counseling into developmental-behavioral surveillance and screening makes the process more safe, effective, and parent-centered, he said.

Many pediatricians who follow the AAP/Bright Futures guidelines are already doing this, but the point, according to Dr. Marks, is that developmental-behavioral promotion needs to be viewed as key component of surveillance.

• The automatic referral of children with a medical or psychosocial condition or risk factor associated with a high probability of future developmental delay. Screening certain high-risk groups can be deemphasized because the likelihood of these children needing early intervention is sufficiently high so automatic referral is justifiable, Dr. Marks said. Examples of medical risk factors include very low birth weight infants (born weighing less than 1,500 g), those exposed in-utero to harmful substances such as alcohol, methamphetamine or heroin, and those with a genetic syndrome associated with a future developmental delay. A psychosocial risk factor would include those children who have been abused or neglected.

• The automatic referral of children in whom the pediatrician confidently suspects a developmental delay and/or disorder, even when standardized screening results are "typical" or "questionable." The literature shows that pediatrician impression has good specificity but poor sensitivity, meaning that when a pediatrician confidently detects a delay, they are almost always correct; however, they miss the large majority of delays using their less structured surveillance alone, Dr. Marks said.

• The automatic referral of children in whom a psychometrically sound screening tool is found to be positive or concerning. Such tools include the Ages & Stages Questionnaire (ASQ) or the Parents’ Evaluation of Developmental Status (PEDS) for general developmental screening; the ASQ:Social-Emotional for social emotional screening; and the Modified Checklist for Autism in Toddlers (M-CHAT) in combination with its Follow-up Interview for autism-specific screening. Of special note, when an autism-specific screen like the M-CHAT is positive, Dr. Marks said, a referral for an expensive, comprehensive autism-specific evaluation is not necessarily recommended (in the absence of a positive M-CHAT Follow-up Interview).

"When the M-CHAT is positive, an early intervention agency referral is indicated but clinicians need to be careful about how to best explain this result to parents. Clinicians need to combine their less structured surveillance with the results of the M-CHAT to determine the need for an expensive, comprehensive autism-specific evaluation and early intervention plan," he said.

• The use of system-wide programs to help support health care providers with previsit screening and referral care coordination. The nearly 50% of screening test positive referred children who are subsequently deemed ineligible for early intervention services can still benefit from participation in evidence-based community programs that are not supported by the Individuals with Disabilities Education Act (IDEA), such as the Triple P: Positive Parenting Program or Head Start. Whenever a screening test is positive and/or an early intervention referral is generated, the practitioner and a system-wide care coordination program should provide at-risk children with a "back-up plan."

• Early return office visits. Greater emphasis should be placed on early return office visits (in addition to an early intervention referral) whenever a psychometrically sound screening test – particularly an autism-specific screening test – is abnormal at an AAP-recommended well-child visit. Return visits ideally should be scheduled within a month, and parents should be asked if connection with the referral source has been made, Dr. Marks said.

Also, more in-depth assessments with secondary developmental-behavioral and/or medical screening tests should be conducted at this visit, and feedback data from referral sources should be reviewed if possible, with prompt action taken on their recommendations, he added.

For their study, Dr. Marks and his colleagues reviewed 250 articles on a dozen relevant topics and concluded that the current AAP algorithm is indeed in need of revisions that incorporate these six provisions. So they developed a proposed revision of the developmental and behavioral algorithm.

"It’s clear when you look closely at the literature over the past 5 years that pediatricians are frequently missing young children with suspected developmental delays, social-emotional problems, and autism. Busy pediatricians, who typically use informal milestone checklists at 20-minute well-child checks, have a tendency to minimize parents’ concerns and dismiss the need for a community referral – perhaps out of their innate need to reassure," said Dr. Marks.

"Meanwhile," Dr. Marks said, "when pediatricians do decide to refer, there are frequently unnecessary delays in early intervention services due to inefficient communication between medical homes and early intervention agencies or negative parental perceptions about the referral. Especially for overwhelmed, high-risk families, a ‘sugar-coated’ or ‘straight talking’ clinician-parent conversation really needs to occur prior to the referral."

Combined with what may be a "wishful thinking approach" on the part of parents who suspect there is a problem, this is causing unnecessary delays in referrals of early intervention for children with suspected delays, he said.

Mapping out the steps for screening and surveillance in greater detail and adding the proposed action steps has the potential for improving outcomes, he said.

In their article, he and his colleagues also noted that their proposed changes to AAP policy would likely "increase the need for a collaborative or integrated medical home model of care."

Dr. Marks had no disclosures to report in regard to his research. Coauthor Frances Page Glascoe, Ph.D. is the author of, and receives royalties for, the Parent’s Evaluation of Developmental Status (PEDS) and PEDS: Developmental Milestones.

Many "detected" and "at-risk" children are falling through the cracks when it comes to referring and interlinking children with suspected developmental-behavioral problems to early intervention and other community services.

At least one group of researchers believes that revisions to the 2006 American Academy of Pediatrics developmental surveillance and screening algorithm are needed to optimize the early detection, prevention, and ongoing monitoring of developmental-behavioral problems. In the September issue of Clinical Pediatrics, Dr. Kevin Marks and his colleagues argue that a more detailed action plan is needed (Clin. Pediatr. 2011;50:853-68).

Specifically, they argue that promotion of behavioral and developmental wellness should be formally included as an action step, that referrals for certain high-risk children should be automatic, and that greater emphasis should be placed on care coordination following a referral for early intervention services.

"As physicians, we play a key role in the early detection of developmental and behavioral problems in children prior to kindergarten entrance. We have the privilege and ability to create opportunities for parents to access services for their children, but there is much work to be done to ensure that these referrals occur in keeping with the six quality aims of the Institute of Medicine, which call for referrals to be made in a safe, equitable, effective, timely, parent-centered, and efficient manner," Dr. Marks, a general pediatrician and pediatric hospitalist in Eugene, Ore., said in an interview.

The comprehensive review of the current literature conducted by Dr. Marks and his colleagues showed that children with a concerning screening test are not consistently referred and interlinked to early intervention services. Furthermore, due to a variety of reasons, only about half of those referred ultimately are deemed eligible for early intervention despite performing well below average and exhibiting numerous predictive academic and psychosocial risk factors.

"Pediatricians are frequently missing young children with suspected developmental delays, social-emotional problems, and autism."

Currently there are three separate algorithms for general pediatricians to follow from three separate AAP statements, which were published in 2006, 2007, and 2010. Together they recommend universal postpartum maternal depression screening in the first year; general developmental screening at 9, 18, and 24 months; autism-specific screening at 18 and 24 months; social-emotional screening whenever a general developmental or autism-specific screen is abnormal; kindergarten readiness screening at 4 years; and mental health/psychosocial function screening at 5 years and every well-visit thereafter.

"Our findings reinforce many of the previous recommendations within various AAP statements in regard to periodic screening with well-standardized, reliable and accurate tools that measure general development and social-emotional/behavioral development, as well as autism-specific and family psychosocial screening tools," Dr. Marks said.

Areas where the findings support revisions, however, include:

• The promotion of developmental and behavioral wellness. An example is literacy counseling through the Reach Out and Read program, which has been shown to improve outcomes. Consistently incorporating positive parenting and strength-based counseling into developmental-behavioral surveillance and screening makes the process more safe, effective, and parent-centered, he said.

Many pediatricians who follow the AAP/Bright Futures guidelines are already doing this, but the point, according to Dr. Marks, is that developmental-behavioral promotion needs to be viewed as key component of surveillance.

• The automatic referral of children with a medical or psychosocial condition or risk factor associated with a high probability of future developmental delay. Screening certain high-risk groups can be deemphasized because the likelihood of these children needing early intervention is sufficiently high so automatic referral is justifiable, Dr. Marks said. Examples of medical risk factors include very low birth weight infants (born weighing less than 1,500 g), those exposed in-utero to harmful substances such as alcohol, methamphetamine or heroin, and those with a genetic syndrome associated with a future developmental delay. A psychosocial risk factor would include those children who have been abused or neglected.

• The automatic referral of children in whom the pediatrician confidently suspects a developmental delay and/or disorder, even when standardized screening results are "typical" or "questionable." The literature shows that pediatrician impression has good specificity but poor sensitivity, meaning that when a pediatrician confidently detects a delay, they are almost always correct; however, they miss the large majority of delays using their less structured surveillance alone, Dr. Marks said.

• The automatic referral of children in whom a psychometrically sound screening tool is found to be positive or concerning. Such tools include the Ages & Stages Questionnaire (ASQ) or the Parents’ Evaluation of Developmental Status (PEDS) for general developmental screening; the ASQ:Social-Emotional for social emotional screening; and the Modified Checklist for Autism in Toddlers (M-CHAT) in combination with its Follow-up Interview for autism-specific screening. Of special note, when an autism-specific screen like the M-CHAT is positive, Dr. Marks said, a referral for an expensive, comprehensive autism-specific evaluation is not necessarily recommended (in the absence of a positive M-CHAT Follow-up Interview).

"When the M-CHAT is positive, an early intervention agency referral is indicated but clinicians need to be careful about how to best explain this result to parents. Clinicians need to combine their less structured surveillance with the results of the M-CHAT to determine the need for an expensive, comprehensive autism-specific evaluation and early intervention plan," he said.

• The use of system-wide programs to help support health care providers with previsit screening and referral care coordination. The nearly 50% of screening test positive referred children who are subsequently deemed ineligible for early intervention services can still benefit from participation in evidence-based community programs that are not supported by the Individuals with Disabilities Education Act (IDEA), such as the Triple P: Positive Parenting Program or Head Start. Whenever a screening test is positive and/or an early intervention referral is generated, the practitioner and a system-wide care coordination program should provide at-risk children with a "back-up plan."

• Early return office visits. Greater emphasis should be placed on early return office visits (in addition to an early intervention referral) whenever a psychometrically sound screening test – particularly an autism-specific screening test – is abnormal at an AAP-recommended well-child visit. Return visits ideally should be scheduled within a month, and parents should be asked if connection with the referral source has been made, Dr. Marks said.

Also, more in-depth assessments with secondary developmental-behavioral and/or medical screening tests should be conducted at this visit, and feedback data from referral sources should be reviewed if possible, with prompt action taken on their recommendations, he added.

For their study, Dr. Marks and his colleagues reviewed 250 articles on a dozen relevant topics and concluded that the current AAP algorithm is indeed in need of revisions that incorporate these six provisions. So they developed a proposed revision of the developmental and behavioral algorithm.

"It’s clear when you look closely at the literature over the past 5 years that pediatricians are frequently missing young children with suspected developmental delays, social-emotional problems, and autism. Busy pediatricians, who typically use informal milestone checklists at 20-minute well-child checks, have a tendency to minimize parents’ concerns and dismiss the need for a community referral – perhaps out of their innate need to reassure," said Dr. Marks.

"Meanwhile," Dr. Marks said, "when pediatricians do decide to refer, there are frequently unnecessary delays in early intervention services due to inefficient communication between medical homes and early intervention agencies or negative parental perceptions about the referral. Especially for overwhelmed, high-risk families, a ‘sugar-coated’ or ‘straight talking’ clinician-parent conversation really needs to occur prior to the referral."

Combined with what may be a "wishful thinking approach" on the part of parents who suspect there is a problem, this is causing unnecessary delays in referrals of early intervention for children with suspected delays, he said.

Mapping out the steps for screening and surveillance in greater detail and adding the proposed action steps has the potential for improving outcomes, he said.

In their article, he and his colleagues also noted that their proposed changes to AAP policy would likely "increase the need for a collaborative or integrated medical home model of care."

Dr. Marks had no disclosures to report in regard to his research. Coauthor Frances Page Glascoe, Ph.D. is the author of, and receives royalties for, the Parent’s Evaluation of Developmental Status (PEDS) and PEDS: Developmental Milestones.

Many "detected" and "at-risk" children are falling through the cracks when it comes to referring and interlinking children with suspected developmental-behavioral problems to early intervention and other community services.

At least one group of researchers believes that revisions to the 2006 American Academy of Pediatrics developmental surveillance and screening algorithm are needed to optimize the early detection, prevention, and ongoing monitoring of developmental-behavioral problems. In the September issue of Clinical Pediatrics, Dr. Kevin Marks and his colleagues argue that a more detailed action plan is needed (Clin. Pediatr. 2011;50:853-68).

Specifically, they argue that promotion of behavioral and developmental wellness should be formally included as an action step, that referrals for certain high-risk children should be automatic, and that greater emphasis should be placed on care coordination following a referral for early intervention services.

"As physicians, we play a key role in the early detection of developmental and behavioral problems in children prior to kindergarten entrance. We have the privilege and ability to create opportunities for parents to access services for their children, but there is much work to be done to ensure that these referrals occur in keeping with the six quality aims of the Institute of Medicine, which call for referrals to be made in a safe, equitable, effective, timely, parent-centered, and efficient manner," Dr. Marks, a general pediatrician and pediatric hospitalist in Eugene, Ore., said in an interview.

The comprehensive review of the current literature conducted by Dr. Marks and his colleagues showed that children with a concerning screening test are not consistently referred and interlinked to early intervention services. Furthermore, due to a variety of reasons, only about half of those referred ultimately are deemed eligible for early intervention despite performing well below average and exhibiting numerous predictive academic and psychosocial risk factors.

"Pediatricians are frequently missing young children with suspected developmental delays, social-emotional problems, and autism."

Currently there are three separate algorithms for general pediatricians to follow from three separate AAP statements, which were published in 2006, 2007, and 2010. Together they recommend universal postpartum maternal depression screening in the first year; general developmental screening at 9, 18, and 24 months; autism-specific screening at 18 and 24 months; social-emotional screening whenever a general developmental or autism-specific screen is abnormal; kindergarten readiness screening at 4 years; and mental health/psychosocial function screening at 5 years and every well-visit thereafter.

"Our findings reinforce many of the previous recommendations within various AAP statements in regard to periodic screening with well-standardized, reliable and accurate tools that measure general development and social-emotional/behavioral development, as well as autism-specific and family psychosocial screening tools," Dr. Marks said.

Areas where the findings support revisions, however, include:

• The promotion of developmental and behavioral wellness. An example is literacy counseling through the Reach Out and Read program, which has been shown to improve outcomes. Consistently incorporating positive parenting and strength-based counseling into developmental-behavioral surveillance and screening makes the process more safe, effective, and parent-centered, he said.

Many pediatricians who follow the AAP/Bright Futures guidelines are already doing this, but the point, according to Dr. Marks, is that developmental-behavioral promotion needs to be viewed as key component of surveillance.

• The automatic referral of children with a medical or psychosocial condition or risk factor associated with a high probability of future developmental delay. Screening certain high-risk groups can be deemphasized because the likelihood of these children needing early intervention is sufficiently high so automatic referral is justifiable, Dr. Marks said. Examples of medical risk factors include very low birth weight infants (born weighing less than 1,500 g), those exposed in-utero to harmful substances such as alcohol, methamphetamine or heroin, and those with a genetic syndrome associated with a future developmental delay. A psychosocial risk factor would include those children who have been abused or neglected.

• The automatic referral of children in whom the pediatrician confidently suspects a developmental delay and/or disorder, even when standardized screening results are "typical" or "questionable." The literature shows that pediatrician impression has good specificity but poor sensitivity, meaning that when a pediatrician confidently detects a delay, they are almost always correct; however, they miss the large majority of delays using their less structured surveillance alone, Dr. Marks said.

• The automatic referral of children in whom a psychometrically sound screening tool is found to be positive or concerning. Such tools include the Ages & Stages Questionnaire (ASQ) or the Parents’ Evaluation of Developmental Status (PEDS) for general developmental screening; the ASQ:Social-Emotional for social emotional screening; and the Modified Checklist for Autism in Toddlers (M-CHAT) in combination with its Follow-up Interview for autism-specific screening. Of special note, when an autism-specific screen like the M-CHAT is positive, Dr. Marks said, a referral for an expensive, comprehensive autism-specific evaluation is not necessarily recommended (in the absence of a positive M-CHAT Follow-up Interview).

"When the M-CHAT is positive, an early intervention agency referral is indicated but clinicians need to be careful about how to best explain this result to parents. Clinicians need to combine their less structured surveillance with the results of the M-CHAT to determine the need for an expensive, comprehensive autism-specific evaluation and early intervention plan," he said.

• The use of system-wide programs to help support health care providers with previsit screening and referral care coordination. The nearly 50% of screening test positive referred children who are subsequently deemed ineligible for early intervention services can still benefit from participation in evidence-based community programs that are not supported by the Individuals with Disabilities Education Act (IDEA), such as the Triple P: Positive Parenting Program or Head Start. Whenever a screening test is positive and/or an early intervention referral is generated, the practitioner and a system-wide care coordination program should provide at-risk children with a "back-up plan."

• Early return office visits. Greater emphasis should be placed on early return office visits (in addition to an early intervention referral) whenever a psychometrically sound screening test – particularly an autism-specific screening test – is abnormal at an AAP-recommended well-child visit. Return visits ideally should be scheduled within a month, and parents should be asked if connection with the referral source has been made, Dr. Marks said.

Also, more in-depth assessments with secondary developmental-behavioral and/or medical screening tests should be conducted at this visit, and feedback data from referral sources should be reviewed if possible, with prompt action taken on their recommendations, he added.

For their study, Dr. Marks and his colleagues reviewed 250 articles on a dozen relevant topics and concluded that the current AAP algorithm is indeed in need of revisions that incorporate these six provisions. So they developed a proposed revision of the developmental and behavioral algorithm.

"It’s clear when you look closely at the literature over the past 5 years that pediatricians are frequently missing young children with suspected developmental delays, social-emotional problems, and autism. Busy pediatricians, who typically use informal milestone checklists at 20-minute well-child checks, have a tendency to minimize parents’ concerns and dismiss the need for a community referral – perhaps out of their innate need to reassure," said Dr. Marks.

"Meanwhile," Dr. Marks said, "when pediatricians do decide to refer, there are frequently unnecessary delays in early intervention services due to inefficient communication between medical homes and early intervention agencies or negative parental perceptions about the referral. Especially for overwhelmed, high-risk families, a ‘sugar-coated’ or ‘straight talking’ clinician-parent conversation really needs to occur prior to the referral."

Combined with what may be a "wishful thinking approach" on the part of parents who suspect there is a problem, this is causing unnecessary delays in referrals of early intervention for children with suspected delays, he said.

Mapping out the steps for screening and surveillance in greater detail and adding the proposed action steps has the potential for improving outcomes, he said.

In their article, he and his colleagues also noted that their proposed changes to AAP policy would likely "increase the need for a collaborative or integrated medical home model of care."

Dr. Marks had no disclosures to report in regard to his research. Coauthor Frances Page Glascoe, Ph.D. is the author of, and receives royalties for, the Parent’s Evaluation of Developmental Status (PEDS) and PEDS: Developmental Milestones.

A shorter, more intense course of radiotherapy was as effective as conventional intensity-modulated radiation therapy for the treatment of intermediate- to high-risk prostate cancer in a randomized, controlled, phase III dose-escalation trial involving 303 patients.

At 5 years of follow-up, outcomes were similar whether men received hypofractionated intensity-modulated radiation therapy (hIMRT) or conventional IMRT (cIMRT), Dr. Alan Pollack reported during a press conference sponsored by the American Society for Radiation Oncology (ASTRO).

The hypofractionated approach – which compresses the standard prostate cancer treatment schedule by delivering a higher dose of radiation for fewer days – shortened treatment duration to 5.1 weeks without increasing long-term toxicity, he said. Radiotherapy lasted 7.5 weeks with conventional IMRT.

The findings will be presented on Oct. 3 at the ASTRO annual meeting in Miami Beach.

The approach is based on extensive data indicating that hypofractionation confers radiobiological advantages, according to Dr. Pollack, professor and chair of radiation oncology at the University of Miami.

The 151 patients who were randomized to receive hIMRT (70.2 Gy in 27.2 Gy fractions) had a 5-year cumulative incidence rate of biochemical failure of 13.9%, compared with 14.4% in the 152 patients randomized to receive cIMRT (76 Gy in 2.0 Gy fractions).

Clinical failure rates (defined as local/regional failure or distant metastases) were 1.3% in the hIMRT group and 1.0% in the cIMRT groups, Dr. Pollack said. The rates of "any failure" were 15.3% and 15.4% in the groups, respectively.

Dr. Pollack and his colleagues had hypothesized correctly that hIMRT would have a failure rate in the 15% range, but they also hypothesized that it would be superior to cIMRT. Conventional IMRT performed better than expected, he said.

As for side effects, grade 2 or higher genitourinary toxicities occurred in 13.8% and 8.9% of patients in the hIMRT and cIMRT groups, respectively (P = 0.2), and gastrointestinal toxicities occurred in 5.9% and 4.1% of the patients in the groups, respectively (P = 0.5).

More bladder control problems in the men who had received hIMRT accounted for the difference in genitourinary effects, as the frequency of unsatisfactory erections in the groups were similar. However, the rates of persistent urinary symptoms were less than 10% in both groups, which is still less than the 15% typically reported in the literature, Dr. Pollack noted.

"We did find that in general, the side effects were low," said Dr. Pollack, who described HIMRT as "a more sophisticated way of administering radiation."

CIMRT and HIMRT patients, all of whom were treated in 2002-2006, were similar in regard to T categories, Gleason scores, pretreatment initial prostate-specific antigen levels, and use of – and length of – androgen deprivation therapy. Biochemical failure was assessed using the Phoenix definition (PSA nadir + 2 ng/mL), and clinical failure was defined as either locoregional failure or distant metastases, he noted.

"Hypofractionation for prostate cancer does show promise," Dr. Pollack said, noting that work is ongoing to identify the limits and best approaches for applying hypofractionation while limiting side effects – particularly urinary side effects, which tend to cause the greatest amount of problems following most types of treatment for prostate cancer.

The approach has not been broadly adopted, because long-term follow-up and greater understanding of the risks are needed, but Dr. Michael L. Steinberg, professor and chair of radiation oncology at the University of California, Los Angeles, and ASTRO’s president-elect, agreed that hypofractionation represents an emerging trend in the treatment of prostate and other cancers.

It will also likely represent a cost benefit, Dr. Pollack added. The current study did not include a cost-benefit analysis, but the shorter treatment duration should translate into significant savings both in up-front costs and in terms of time away from work, he said.

Dr. Pollack had no relevant disclosures. Dr. Steinberg serves in a leadership position on the American College of Radiology Economics Committee.

A shorter, more intense course of radiotherapy was as effective as conventional intensity-modulated radiation therapy for the treatment of intermediate- to high-risk prostate cancer in a randomized, controlled, phase III dose-escalation trial involving 303 patients.

At 5 years of follow-up, outcomes were similar whether men received hypofractionated intensity-modulated radiation therapy (hIMRT) or conventional IMRT (cIMRT), Dr. Alan Pollack reported during a press conference sponsored by the American Society for Radiation Oncology (ASTRO).

The hypofractionated approach – which compresses the standard prostate cancer treatment schedule by delivering a higher dose of radiation for fewer days – shortened treatment duration to 5.1 weeks without increasing long-term toxicity, he said. Radiotherapy lasted 7.5 weeks with conventional IMRT.

The findings will be presented on Oct. 3 at the ASTRO annual meeting in Miami Beach.

The approach is based on extensive data indicating that hypofractionation confers radiobiological advantages, according to Dr. Pollack, professor and chair of radiation oncology at the University of Miami.

The 151 patients who were randomized to receive hIMRT (70.2 Gy in 27.2 Gy fractions) had a 5-year cumulative incidence rate of biochemical failure of 13.9%, compared with 14.4% in the 152 patients randomized to receive cIMRT (76 Gy in 2.0 Gy fractions).

Clinical failure rates (defined as local/regional failure or distant metastases) were 1.3% in the hIMRT group and 1.0% in the cIMRT groups, Dr. Pollack said. The rates of "any failure" were 15.3% and 15.4% in the groups, respectively.

Dr. Pollack and his colleagues had hypothesized correctly that hIMRT would have a failure rate in the 15% range, but they also hypothesized that it would be superior to cIMRT. Conventional IMRT performed better than expected, he said.

As for side effects, grade 2 or higher genitourinary toxicities occurred in 13.8% and 8.9% of patients in the hIMRT and cIMRT groups, respectively (P = 0.2), and gastrointestinal toxicities occurred in 5.9% and 4.1% of the patients in the groups, respectively (P = 0.5).

More bladder control problems in the men who had received hIMRT accounted for the difference in genitourinary effects, as the frequency of unsatisfactory erections in the groups were similar. However, the rates of persistent urinary symptoms were less than 10% in both groups, which is still less than the 15% typically reported in the literature, Dr. Pollack noted.

"We did find that in general, the side effects were low," said Dr. Pollack, who described HIMRT as "a more sophisticated way of administering radiation."

CIMRT and HIMRT patients, all of whom were treated in 2002-2006, were similar in regard to T categories, Gleason scores, pretreatment initial prostate-specific antigen levels, and use of – and length of – androgen deprivation therapy. Biochemical failure was assessed using the Phoenix definition (PSA nadir + 2 ng/mL), and clinical failure was defined as either locoregional failure or distant metastases, he noted.

"Hypofractionation for prostate cancer does show promise," Dr. Pollack said, noting that work is ongoing to identify the limits and best approaches for applying hypofractionation while limiting side effects – particularly urinary side effects, which tend to cause the greatest amount of problems following most types of treatment for prostate cancer.

The approach has not been broadly adopted, because long-term follow-up and greater understanding of the risks are needed, but Dr. Michael L. Steinberg, professor and chair of radiation oncology at the University of California, Los Angeles, and ASTRO’s president-elect, agreed that hypofractionation represents an emerging trend in the treatment of prostate and other cancers.

It will also likely represent a cost benefit, Dr. Pollack added. The current study did not include a cost-benefit analysis, but the shorter treatment duration should translate into significant savings both in up-front costs and in terms of time away from work, he said.

Dr. Pollack had no relevant disclosures. Dr. Steinberg serves in a leadership position on the American College of Radiology Economics Committee.

A shorter, more intense course of radiotherapy was as effective as conventional intensity-modulated radiation therapy for the treatment of intermediate- to high-risk prostate cancer in a randomized, controlled, phase III dose-escalation trial involving 303 patients.

At 5 years of follow-up, outcomes were similar whether men received hypofractionated intensity-modulated radiation therapy (hIMRT) or conventional IMRT (cIMRT), Dr. Alan Pollack reported during a press conference sponsored by the American Society for Radiation Oncology (ASTRO).

The hypofractionated approach – which compresses the standard prostate cancer treatment schedule by delivering a higher dose of radiation for fewer days – shortened treatment duration to 5.1 weeks without increasing long-term toxicity, he said. Radiotherapy lasted 7.5 weeks with conventional IMRT.

The findings will be presented on Oct. 3 at the ASTRO annual meeting in Miami Beach.

The approach is based on extensive data indicating that hypofractionation confers radiobiological advantages, according to Dr. Pollack, professor and chair of radiation oncology at the University of Miami.

The 151 patients who were randomized to receive hIMRT (70.2 Gy in 27.2 Gy fractions) had a 5-year cumulative incidence rate of biochemical failure of 13.9%, compared with 14.4% in the 152 patients randomized to receive cIMRT (76 Gy in 2.0 Gy fractions).

Clinical failure rates (defined as local/regional failure or distant metastases) were 1.3% in the hIMRT group and 1.0% in the cIMRT groups, Dr. Pollack said. The rates of "any failure" were 15.3% and 15.4% in the groups, respectively.

Dr. Pollack and his colleagues had hypothesized correctly that hIMRT would have a failure rate in the 15% range, but they also hypothesized that it would be superior to cIMRT. Conventional IMRT performed better than expected, he said.

As for side effects, grade 2 or higher genitourinary toxicities occurred in 13.8% and 8.9% of patients in the hIMRT and cIMRT groups, respectively (P = 0.2), and gastrointestinal toxicities occurred in 5.9% and 4.1% of the patients in the groups, respectively (P = 0.5).

More bladder control problems in the men who had received hIMRT accounted for the difference in genitourinary effects, as the frequency of unsatisfactory erections in the groups were similar. However, the rates of persistent urinary symptoms were less than 10% in both groups, which is still less than the 15% typically reported in the literature, Dr. Pollack noted.

"We did find that in general, the side effects were low," said Dr. Pollack, who described HIMRT as "a more sophisticated way of administering radiation."

CIMRT and HIMRT patients, all of whom were treated in 2002-2006, were similar in regard to T categories, Gleason scores, pretreatment initial prostate-specific antigen levels, and use of – and length of – androgen deprivation therapy. Biochemical failure was assessed using the Phoenix definition (PSA nadir + 2 ng/mL), and clinical failure was defined as either locoregional failure or distant metastases, he noted.

"Hypofractionation for prostate cancer does show promise," Dr. Pollack said, noting that work is ongoing to identify the limits and best approaches for applying hypofractionation while limiting side effects – particularly urinary side effects, which tend to cause the greatest amount of problems following most types of treatment for prostate cancer.

The approach has not been broadly adopted, because long-term follow-up and greater understanding of the risks are needed, but Dr. Michael L. Steinberg, professor and chair of radiation oncology at the University of California, Los Angeles, and ASTRO’s president-elect, agreed that hypofractionation represents an emerging trend in the treatment of prostate and other cancers.

It will also likely represent a cost benefit, Dr. Pollack added. The current study did not include a cost-benefit analysis, but the shorter treatment duration should translate into significant savings both in up-front costs and in terms of time away from work, he said.

Dr. Pollack had no relevant disclosures. Dr. Steinberg serves in a leadership position on the American College of Radiology Economics Committee.

Men with localized prostate cancer had fewer acute and late side effects in the bowel and rectum when they were treated with a newer, more targeted form of radiotherapy in a phase III dose-escalation trial conducted by the Radiation Therapy Oncology Group.

The newer procedure, intensity-modulated radiation therapy (IMRT), was associated with 26% fewer late rectal and bowel toxicities, compared with three-dimensional conformal radiation therapy (3D-CRT) in an analysis of men with localized prostate cancer who were part of the study’s high-dose treatment arm.

Although the difference in late toxicity was not statistically significant, acute grade 2 or higher rectal, bowel, and bladder toxicities were significantly fewer, and radiation doses to the bladder and rectum were significantly reduced as well.

Patients in the RTOG 0126 trial were initially treated with 3D-CRT, but the trial protocol was amended after 1 year to allow IMRT, which is a newer, specialized form of 3D-CRT that allows more precise delivery of radiation to the tumor.

The current study represents a preliminary analysis of acute and late toxicities in 491 patients treated with 3D-CRT and 257 patients treated with IMRT. The findings will be presented on Oct. 3 at the annual meeting of the American Society for Radiation Oncology (ASTRO).

Acute grade 2 toxicities occurred in 16.9% in the 3D-CRT arm and 13.9% of patients in the IMRT groups. Acute grade 3 toxicities occurred in 2.5% and 2.4% of patients in the groups, respectively, Dr. Jeff Michalski reported during a press conference held in advance of the ASTRO meeting.

No acute grade 4 toxicities occurred in the 3D-CRT group, but 0.4% of patients in the IMRT group experienced grade 4 toxicities, according to Dr. Michalski, professor and vice chair of radiation oncology at Washington University Medical Center in St. Louis.

Univariate and multivariate analyses demonstrated a significant decrease in acute collective genitourinary and gastrointestinal toxicity for IMRT, but there were no significant differences for acute grade 2 or higher genitourinary toxicities alone, he noted.

As for late toxicities – which are particularly important to control because they can be irreversible – 23.6% and 19.9% of patients in the 3D-CRT and IMRT groups, respectively, experienced grade 2 toxicities; 8.9% and 4.7%, respectively, experienced grade 3 toxicities; 0.4% of patients in both groups experienced grade 4 toxicities, Dr. Michalski said. Although 0.2% of the 3D-CRT group had a late grade 5 toxicity, none was reported in men receiving IMRT.

The difference between 3D-CRT and IMRT in late toxicities did not reach statistical significance, but there was a trend toward a "clinically meaningful" 26% reduction in grade 2 or higher late toxicities with IMRT, he said.

Notably, there was a significant 15% increase in grade 2 or higher rectal toxicity in white men vs. men of other races, regardless of treatment type. The causes of this finding are unclear, but may be associated with differences in treatment tolerance or cultural differences in the reporting of side effects, he suggested.

"IMRT is a safe and very well-tolerated therapy associated with many fewer acute and late complications than 3D-CRT," Dr. Michalski said, adding, "I believe this study supports the use of IMRT in the management of localized prostate cancer."

Although prior findings have supported the notion of a technical advantage with IMRT in terms of delivering a higher dose of radiation to the tumor without increasing toxicity to the bladder and rectum, a good data set allowing direct comparisons of 3D-CRT and IMRT was lacking, he said.

"This is the first contemporary group of patients that demonstrates a benefit," he said.

This study was supported the ASTRO Radiation Oncology Institute and by several grants from the National Cancer Institute. Dr. Michalski reported receiving funding from Augmenix, Elekta, and Viewray.

Men with localized prostate cancer had fewer acute and late side effects in the bowel and rectum when they were treated with a newer, more targeted form of radiotherapy in a phase III dose-escalation trial conducted by the Radiation Therapy Oncology Group.

The newer procedure, intensity-modulated radiation therapy (IMRT), was associated with 26% fewer late rectal and bowel toxicities, compared with three-dimensional conformal radiation therapy (3D-CRT) in an analysis of men with localized prostate cancer who were part of the study’s high-dose treatment arm.

Although the difference in late toxicity was not statistically significant, acute grade 2 or higher rectal, bowel, and bladder toxicities were significantly fewer, and radiation doses to the bladder and rectum were significantly reduced as well.

Patients in the RTOG 0126 trial were initially treated with 3D-CRT, but the trial protocol was amended after 1 year to allow IMRT, which is a newer, specialized form of 3D-CRT that allows more precise delivery of radiation to the tumor.

The current study represents a preliminary analysis of acute and late toxicities in 491 patients treated with 3D-CRT and 257 patients treated with IMRT. The findings will be presented on Oct. 3 at the annual meeting of the American Society for Radiation Oncology (ASTRO).

Acute grade 2 toxicities occurred in 16.9% in the 3D-CRT arm and 13.9% of patients in the IMRT groups. Acute grade 3 toxicities occurred in 2.5% and 2.4% of patients in the groups, respectively, Dr. Jeff Michalski reported during a press conference held in advance of the ASTRO meeting.

No acute grade 4 toxicities occurred in the 3D-CRT group, but 0.4% of patients in the IMRT group experienced grade 4 toxicities, according to Dr. Michalski, professor and vice chair of radiation oncology at Washington University Medical Center in St. Louis.

Univariate and multivariate analyses demonstrated a significant decrease in acute collective genitourinary and gastrointestinal toxicity for IMRT, but there were no significant differences for acute grade 2 or higher genitourinary toxicities alone, he noted.

As for late toxicities – which are particularly important to control because they can be irreversible – 23.6% and 19.9% of patients in the 3D-CRT and IMRT groups, respectively, experienced grade 2 toxicities; 8.9% and 4.7%, respectively, experienced grade 3 toxicities; 0.4% of patients in both groups experienced grade 4 toxicities, Dr. Michalski said. Although 0.2% of the 3D-CRT group had a late grade 5 toxicity, none was reported in men receiving IMRT.

The difference between 3D-CRT and IMRT in late toxicities did not reach statistical significance, but there was a trend toward a "clinically meaningful" 26% reduction in grade 2 or higher late toxicities with IMRT, he said.

Notably, there was a significant 15% increase in grade 2 or higher rectal toxicity in white men vs. men of other races, regardless of treatment type. The causes of this finding are unclear, but may be associated with differences in treatment tolerance or cultural differences in the reporting of side effects, he suggested.

"IMRT is a safe and very well-tolerated therapy associated with many fewer acute and late complications than 3D-CRT," Dr. Michalski said, adding, "I believe this study supports the use of IMRT in the management of localized prostate cancer."

Although prior findings have supported the notion of a technical advantage with IMRT in terms of delivering a higher dose of radiation to the tumor without increasing toxicity to the bladder and rectum, a good data set allowing direct comparisons of 3D-CRT and IMRT was lacking, he said.

"This is the first contemporary group of patients that demonstrates a benefit," he said.

This study was supported the ASTRO Radiation Oncology Institute and by several grants from the National Cancer Institute. Dr. Michalski reported receiving funding from Augmenix, Elekta, and Viewray.

Men with localized prostate cancer had fewer acute and late side effects in the bowel and rectum when they were treated with a newer, more targeted form of radiotherapy in a phase III dose-escalation trial conducted by the Radiation Therapy Oncology Group.

The newer procedure, intensity-modulated radiation therapy (IMRT), was associated with 26% fewer late rectal and bowel toxicities, compared with three-dimensional conformal radiation therapy (3D-CRT) in an analysis of men with localized prostate cancer who were part of the study’s high-dose treatment arm.

Although the difference in late toxicity was not statistically significant, acute grade 2 or higher rectal, bowel, and bladder toxicities were significantly fewer, and radiation doses to the bladder and rectum were significantly reduced as well.

Patients in the RTOG 0126 trial were initially treated with 3D-CRT, but the trial protocol was amended after 1 year to allow IMRT, which is a newer, specialized form of 3D-CRT that allows more precise delivery of radiation to the tumor.

The current study represents a preliminary analysis of acute and late toxicities in 491 patients treated with 3D-CRT and 257 patients treated with IMRT. The findings will be presented on Oct. 3 at the annual meeting of the American Society for Radiation Oncology (ASTRO).

Acute grade 2 toxicities occurred in 16.9% in the 3D-CRT arm and 13.9% of patients in the IMRT groups. Acute grade 3 toxicities occurred in 2.5% and 2.4% of patients in the groups, respectively, Dr. Jeff Michalski reported during a press conference held in advance of the ASTRO meeting.

No acute grade 4 toxicities occurred in the 3D-CRT group, but 0.4% of patients in the IMRT group experienced grade 4 toxicities, according to Dr. Michalski, professor and vice chair of radiation oncology at Washington University Medical Center in St. Louis.

Univariate and multivariate analyses demonstrated a significant decrease in acute collective genitourinary and gastrointestinal toxicity for IMRT, but there were no significant differences for acute grade 2 or higher genitourinary toxicities alone, he noted.

As for late toxicities – which are particularly important to control because they can be irreversible – 23.6% and 19.9% of patients in the 3D-CRT and IMRT groups, respectively, experienced grade 2 toxicities; 8.9% and 4.7%, respectively, experienced grade 3 toxicities; 0.4% of patients in both groups experienced grade 4 toxicities, Dr. Michalski said. Although 0.2% of the 3D-CRT group had a late grade 5 toxicity, none was reported in men receiving IMRT.

The difference between 3D-CRT and IMRT in late toxicities did not reach statistical significance, but there was a trend toward a "clinically meaningful" 26% reduction in grade 2 or higher late toxicities with IMRT, he said.

Notably, there was a significant 15% increase in grade 2 or higher rectal toxicity in white men vs. men of other races, regardless of treatment type. The causes of this finding are unclear, but may be associated with differences in treatment tolerance or cultural differences in the reporting of side effects, he suggested.

"IMRT is a safe and very well-tolerated therapy associated with many fewer acute and late complications than 3D-CRT," Dr. Michalski said, adding, "I believe this study supports the use of IMRT in the management of localized prostate cancer."

Although prior findings have supported the notion of a technical advantage with IMRT in terms of delivering a higher dose of radiation to the tumor without increasing toxicity to the bladder and rectum, a good data set allowing direct comparisons of 3D-CRT and IMRT was lacking, he said.

"This is the first contemporary group of patients that demonstrates a benefit," he said.

This study was supported the ASTRO Radiation Oncology Institute and by several grants from the National Cancer Institute. Dr. Michalski reported receiving funding from Augmenix, Elekta, and Viewray.

The onset of narcolepsy during a 10-year period in China was highly correlated with seasonal and annual patterns of upper airway infections, and was generally independent of H1N1 influenza vaccination, contrary to reports of narcolepsy following H1N1 vaccination in northern Europe and other areas.

Self-reported data on the month and year of narcolepsy onset in 629 patients who were diagnosed between September 1998 and February 2011 indicate that onset is most frequent in April and least frequent in November in this population, with a nearly sevenfold increase from trough to peak, Dr. Fang Han of Peking University People’s Hospital, Beijing, and colleagues reported.

A greater-than-threefold increase in narcolepsy onset occurred about 6 months following the 2009 H1N1 winter influenza pandemic, but interviews with 142 patients who recalled whether they were vaccinated against H1N1 revealed that vaccination was not likely related to the increase, because only 8 (5.6%) of the patients reported having been vaccinated, the investigators said (Ann. Neurol. 2011;70:410-7).

Furthermore, about 25% of 150 patients recalled having been sick with an infection within a few months of narcolepsy onset, and 85% of those reported symptoms of upper airway infection, including 2 who reported "flu" and 2 who reported "strep throat."

Animal studies suggest that about 80% of hypocretin/orexin–producing neurons must be lost before symptoms of narcolepsy are exhibited, which could explain the 6-month delay between winter airway infection and narcolepsy onset occurrence, they noted.

The findings show that narcolepsy onset in China is strongly seasonal, and suggest that it is not related to H1N1 vaccination. The occurrence of narcolepsy onset was more than threefold greater than expected following the 2009-2010 H1N1 pandemic, but 96% of new narcolepsy patients in 2010 did not report being vaccinated. This is in contrast with reports of narcolepsy in Finland, the United States, France, and Canada following H1N1 vaccination with adjuvanted vaccine (particularly Pandemrix), which had caused alarm in those countries.

Indeed, the findings suggest that winter airway infections – such as those caused by influenza A (including H1N1) and/or Streptococcus pyogenes – are triggers for narcolepsy, the investigators wrote, adding that "winter infections would initiate or reactivate an immune response that leads to hypocretin cell loss and narcolepsy in genetically susceptible individuals."

About two-thirds of subjects in prior studies of narcolepsy onset had high titers of ASO (antistreptolysin O) antibody, which is a marker of S. pyogenes infection, primarily strep throat, they explained, noting that those findings are complemented by epidemiologic findings showing a 5.4-fold higher risk of narcolepsy in those reporting physician-diagnosed strep throat before age 21 years.

"As S. pyogenes is known to be associated with the onset of other autoimmune disease, notably rheumatic heart fever and [Sydenham’s] chorea, it was a prime candidate as a potential autoimmune trigger for narcolepsy," they said.

It is difficult to determine, however, whether streptococcus is involved, or is an associated infection, particularly because numerous studies have shown that upper airway infections often involve multiple viral and bacterial coinfections or superinfections, including S. pyogenes.

Available data suggest that two factors may be needed for narcolepsy development, including "a specific immune-mimicry component, mediated through the presentation by DQB1*06:02/DQA1*01:02 of a particular autoantigen to a specific [T-cell receptor] idiotype," and "nonspecific factors such as adjuvants, influenza, or strep infections, streptococcus superantigens and other factors," the investigators wrote, noting that studies are currently ongoing to evaluate this.

Although limited by the single-center and retrospective nature of the data, this study nonetheless supports the concept that H1N1 – either alone or with other winter infections – is associated with narcolepsy onset in a temporal manner, which suggests causality, they said.

The new finding of an association with infection – and not vaccination – is important because it suggests that limiting vaccination out of fear of narcolepsy could actually increase overall risk, they added.

Furthermore, the findings regarding winter upper airway infection as a trigger for narcolepsy also may have implications for other diseases of the central nervous system; a range of autoimmune pathologies of the brain may follow winter infections, they said.

In an accompanying commentary, Dr. Stephen L. Hauser and Dr. S. Claiborne Johnston of the University of California, San Francisco, noted that there is little evidence to support the claims by the authors of this study that the H1N1 pandemic flu virus accounts for the surge of narcolepsy seen in 2009-2010, other than the fact that the infection had been prevalent the previous winter (Ann. Neurol. 2011 Aug. 22 [doi:10.1002/ana.22590]). However, they thought that the data, which they said need to be replicated and confirmed, "add to evidence of a possible association between infection and narcolepsy, and could point to pandemic H1N1 – in addition to streptococcal infection – as a potential environmental culprit."

They also noted that if specific peptides of pandemic H1N1 are shown to interact with narcolepsy-associated genes, an understanding of the triggers of narcolepsy may begin to emerge, potentially leading to new approaches for prevention and treatment.

As for the emerging concerns about adjuvanted vaccine and narcolepsy risk, Dr. Hauser and Dr. Johnston noted that the findings of this study raise the possibility that narcolepsy following infection and vaccination might represent a common immune response to a similar antigenic challenge – a phenomenon seen with ADEM (acute disseminated encephalomyelitis) that can occur following both native infection with measles virus, or after administration of measles vaccine. In the case of ADEM, the risk is far greater with infection than with vaccination.

"Clearly we need to insure that all flu vaccines ... are as safe as possible; however, we need also to keep in mind that the risk of any adverse outcome related to vaccination must be balanced against the known risk of community-acquired infection," they wrote.

This study was supported by research grants from the National Science Foundation of China, the Sino-German Center for Research Promotion, the Beijing Municipal Science and Technology commission, and by the Veterans Administration Research Service. Dr. Emmanuel Mignot, one of the authors, reported serving as a consultant and/or providing expert testimony for Jazz Pharmaceuticals, Merck, Mead, and the Federal Trade Commission. Dr. Mignot also has been in discussion with GlaxoSmithKline, the maker of Pandemrix, regarding the funding of contractual research.

The onset of narcolepsy during a 10-year period in China was highly correlated with seasonal and annual patterns of upper airway infections, and was generally independent of H1N1 influenza vaccination, contrary to reports of narcolepsy following H1N1 vaccination in northern Europe and other areas.

Self-reported data on the month and year of narcolepsy onset in 629 patients who were diagnosed between September 1998 and February 2011 indicate that onset is most frequent in April and least frequent in November in this population, with a nearly sevenfold increase from trough to peak, Dr. Fang Han of Peking University People’s Hospital, Beijing, and colleagues reported.

A greater-than-threefold increase in narcolepsy onset occurred about 6 months following the 2009 H1N1 winter influenza pandemic, but interviews with 142 patients who recalled whether they were vaccinated against H1N1 revealed that vaccination was not likely related to the increase, because only 8 (5.6%) of the patients reported having been vaccinated, the investigators said (Ann. Neurol. 2011;70:410-7).

Furthermore, about 25% of 150 patients recalled having been sick with an infection within a few months of narcolepsy onset, and 85% of those reported symptoms of upper airway infection, including 2 who reported "flu" and 2 who reported "strep throat."

Animal studies suggest that about 80% of hypocretin/orexin–producing neurons must be lost before symptoms of narcolepsy are exhibited, which could explain the 6-month delay between winter airway infection and narcolepsy onset occurrence, they noted.

The findings show that narcolepsy onset in China is strongly seasonal, and suggest that it is not related to H1N1 vaccination. The occurrence of narcolepsy onset was more than threefold greater than expected following the 2009-2010 H1N1 pandemic, but 96% of new narcolepsy patients in 2010 did not report being vaccinated. This is in contrast with reports of narcolepsy in Finland, the United States, France, and Canada following H1N1 vaccination with adjuvanted vaccine (particularly Pandemrix), which had caused alarm in those countries.

Indeed, the findings suggest that winter airway infections – such as those caused by influenza A (including H1N1) and/or Streptococcus pyogenes – are triggers for narcolepsy, the investigators wrote, adding that "winter infections would initiate or reactivate an immune response that leads to hypocretin cell loss and narcolepsy in genetically susceptible individuals."

About two-thirds of subjects in prior studies of narcolepsy onset had high titers of ASO (antistreptolysin O) antibody, which is a marker of S. pyogenes infection, primarily strep throat, they explained, noting that those findings are complemented by epidemiologic findings showing a 5.4-fold higher risk of narcolepsy in those reporting physician-diagnosed strep throat before age 21 years.

"As S. pyogenes is known to be associated with the onset of other autoimmune disease, notably rheumatic heart fever and [Sydenham’s] chorea, it was a prime candidate as a potential autoimmune trigger for narcolepsy," they said.

It is difficult to determine, however, whether streptococcus is involved, or is an associated infection, particularly because numerous studies have shown that upper airway infections often involve multiple viral and bacterial coinfections or superinfections, including S. pyogenes.

Available data suggest that two factors may be needed for narcolepsy development, including "a specific immune-mimicry component, mediated through the presentation by DQB1*06:02/DQA1*01:02 of a particular autoantigen to a specific [T-cell receptor] idiotype," and "nonspecific factors such as adjuvants, influenza, or strep infections, streptococcus superantigens and other factors," the investigators wrote, noting that studies are currently ongoing to evaluate this.

Although limited by the single-center and retrospective nature of the data, this study nonetheless supports the concept that H1N1 – either alone or with other winter infections – is associated with narcolepsy onset in a temporal manner, which suggests causality, they said.

The new finding of an association with infection – and not vaccination – is important because it suggests that limiting vaccination out of fear of narcolepsy could actually increase overall risk, they added.

Furthermore, the findings regarding winter upper airway infection as a trigger for narcolepsy also may have implications for other diseases of the central nervous system; a range of autoimmune pathologies of the brain may follow winter infections, they said.

In an accompanying commentary, Dr. Stephen L. Hauser and Dr. S. Claiborne Johnston of the University of California, San Francisco, noted that there is little evidence to support the claims by the authors of this study that the H1N1 pandemic flu virus accounts for the surge of narcolepsy seen in 2009-2010, other than the fact that the infection had been prevalent the previous winter (Ann. Neurol. 2011 Aug. 22 [doi:10.1002/ana.22590]). However, they thought that the data, which they said need to be replicated and confirmed, "add to evidence of a possible association between infection and narcolepsy, and could point to pandemic H1N1 – in addition to streptococcal infection – as a potential environmental culprit."

They also noted that if specific peptides of pandemic H1N1 are shown to interact with narcolepsy-associated genes, an understanding of the triggers of narcolepsy may begin to emerge, potentially leading to new approaches for prevention and treatment.

As for the emerging concerns about adjuvanted vaccine and narcolepsy risk, Dr. Hauser and Dr. Johnston noted that the findings of this study raise the possibility that narcolepsy following infection and vaccination might represent a common immune response to a similar antigenic challenge – a phenomenon seen with ADEM (acute disseminated encephalomyelitis) that can occur following both native infection with measles virus, or after administration of measles vaccine. In the case of ADEM, the risk is far greater with infection than with vaccination.

"Clearly we need to insure that all flu vaccines ... are as safe as possible; however, we need also to keep in mind that the risk of any adverse outcome related to vaccination must be balanced against the known risk of community-acquired infection," they wrote.

This study was supported by research grants from the National Science Foundation of China, the Sino-German Center for Research Promotion, the Beijing Municipal Science and Technology commission, and by the Veterans Administration Research Service. Dr. Emmanuel Mignot, one of the authors, reported serving as a consultant and/or providing expert testimony for Jazz Pharmaceuticals, Merck, Mead, and the Federal Trade Commission. Dr. Mignot also has been in discussion with GlaxoSmithKline, the maker of Pandemrix, regarding the funding of contractual research.

The onset of narcolepsy during a 10-year period in China was highly correlated with seasonal and annual patterns of upper airway infections, and was generally independent of H1N1 influenza vaccination, contrary to reports of narcolepsy following H1N1 vaccination in northern Europe and other areas.

Self-reported data on the month and year of narcolepsy onset in 629 patients who were diagnosed between September 1998 and February 2011 indicate that onset is most frequent in April and least frequent in November in this population, with a nearly sevenfold increase from trough to peak, Dr. Fang Han of Peking University People’s Hospital, Beijing, and colleagues reported.

A greater-than-threefold increase in narcolepsy onset occurred about 6 months following the 2009 H1N1 winter influenza pandemic, but interviews with 142 patients who recalled whether they were vaccinated against H1N1 revealed that vaccination was not likely related to the increase, because only 8 (5.6%) of the patients reported having been vaccinated, the investigators said (Ann. Neurol. 2011;70:410-7).

Furthermore, about 25% of 150 patients recalled having been sick with an infection within a few months of narcolepsy onset, and 85% of those reported symptoms of upper airway infection, including 2 who reported "flu" and 2 who reported "strep throat."

Animal studies suggest that about 80% of hypocretin/orexin–producing neurons must be lost before symptoms of narcolepsy are exhibited, which could explain the 6-month delay between winter airway infection and narcolepsy onset occurrence, they noted.

The findings show that narcolepsy onset in China is strongly seasonal, and suggest that it is not related to H1N1 vaccination. The occurrence of narcolepsy onset was more than threefold greater than expected following the 2009-2010 H1N1 pandemic, but 96% of new narcolepsy patients in 2010 did not report being vaccinated. This is in contrast with reports of narcolepsy in Finland, the United States, France, and Canada following H1N1 vaccination with adjuvanted vaccine (particularly Pandemrix), which had caused alarm in those countries.

Indeed, the findings suggest that winter airway infections – such as those caused by influenza A (including H1N1) and/or Streptococcus pyogenes – are triggers for narcolepsy, the investigators wrote, adding that "winter infections would initiate or reactivate an immune response that leads to hypocretin cell loss and narcolepsy in genetically susceptible individuals."

About two-thirds of subjects in prior studies of narcolepsy onset had high titers of ASO (antistreptolysin O) antibody, which is a marker of S. pyogenes infection, primarily strep throat, they explained, noting that those findings are complemented by epidemiologic findings showing a 5.4-fold higher risk of narcolepsy in those reporting physician-diagnosed strep throat before age 21 years.

"As S. pyogenes is known to be associated with the onset of other autoimmune disease, notably rheumatic heart fever and [Sydenham’s] chorea, it was a prime candidate as a potential autoimmune trigger for narcolepsy," they said.

It is difficult to determine, however, whether streptococcus is involved, or is an associated infection, particularly because numerous studies have shown that upper airway infections often involve multiple viral and bacterial coinfections or superinfections, including S. pyogenes.

Available data suggest that two factors may be needed for narcolepsy development, including "a specific immune-mimicry component, mediated through the presentation by DQB1*06:02/DQA1*01:02 of a particular autoantigen to a specific [T-cell receptor] idiotype," and "nonspecific factors such as adjuvants, influenza, or strep infections, streptococcus superantigens and other factors," the investigators wrote, noting that studies are currently ongoing to evaluate this.

Although limited by the single-center and retrospective nature of the data, this study nonetheless supports the concept that H1N1 – either alone or with other winter infections – is associated with narcolepsy onset in a temporal manner, which suggests causality, they said.

The new finding of an association with infection – and not vaccination – is important because it suggests that limiting vaccination out of fear of narcolepsy could actually increase overall risk, they added.

Furthermore, the findings regarding winter upper airway infection as a trigger for narcolepsy also may have implications for other diseases of the central nervous system; a range of autoimmune pathologies of the brain may follow winter infections, they said.

In an accompanying commentary, Dr. Stephen L. Hauser and Dr. S. Claiborne Johnston of the University of California, San Francisco, noted that there is little evidence to support the claims by the authors of this study that the H1N1 pandemic flu virus accounts for the surge of narcolepsy seen in 2009-2010, other than the fact that the infection had been prevalent the previous winter (Ann. Neurol. 2011 Aug. 22 [doi:10.1002/ana.22590]). However, they thought that the data, which they said need to be replicated and confirmed, "add to evidence of a possible association between infection and narcolepsy, and could point to pandemic H1N1 – in addition to streptococcal infection – as a potential environmental culprit."

They also noted that if specific peptides of pandemic H1N1 are shown to interact with narcolepsy-associated genes, an understanding of the triggers of narcolepsy may begin to emerge, potentially leading to new approaches for prevention and treatment.

As for the emerging concerns about adjuvanted vaccine and narcolepsy risk, Dr. Hauser and Dr. Johnston noted that the findings of this study raise the possibility that narcolepsy following infection and vaccination might represent a common immune response to a similar antigenic challenge – a phenomenon seen with ADEM (acute disseminated encephalomyelitis) that can occur following both native infection with measles virus, or after administration of measles vaccine. In the case of ADEM, the risk is far greater with infection than with vaccination.

"Clearly we need to insure that all flu vaccines ... are as safe as possible; however, we need also to keep in mind that the risk of any adverse outcome related to vaccination must be balanced against the known risk of community-acquired infection," they wrote.

This study was supported by research grants from the National Science Foundation of China, the Sino-German Center for Research Promotion, the Beijing Municipal Science and Technology commission, and by the Veterans Administration Research Service. Dr. Emmanuel Mignot, one of the authors, reported serving as a consultant and/or providing expert testimony for Jazz Pharmaceuticals, Merck, Mead, and the Federal Trade Commission. Dr. Mignot also has been in discussion with GlaxoSmithKline, the maker of Pandemrix, regarding the funding of contractual research.

The experimental tyrosine kinase inhibitor BIBF 1120 was associated with a clinically meaningful reduction in the rate of decline in forced vital capacity, compared with placebo, in patients with idiopathic pulmonary fibrosis in a yearlong, phase II dose-ranging trial involving 432 patients.

Active treatment was also associated with a reduction in the incidence of acute exacerbations of the disease and with an increase in quality of life scores, compared with placebo, Dr. Luca Richeldi of the University of Modena (Italy) and Reggio Emilia, Policlinico Hospital, Modena, and his colleagues reported in the Sept. 22 issue of the New England Journal of Medicine.

Specifically, 85 patients randomized to receive an oral dose of BIBF 1120 at 150 mg twice daily had a mean decline in forced vital capacity (FVC) of 0.06 L/year, compared with 0.19 L/year in 83 patients randomized to receive placebo, a 68.4% reduction. This difference is not statistically significant but does approach the threshold for significance. Also, the absolute change in FVC from baseline over time in the treatment group, compared with the placebo group, was statistically significant, the investigators wrote (N. Engl. J. Med. 2011;365:1079-87).

Acute exacerbations occurred at a rate of 2.4 vs. 15.7 per 100 patient-years in the 150-mg twice-daily treatment group and the placebo group, respectively, a significant difference. There was a trend toward a dose response with increasing doses of BIBF 1120. In addition, scores on the St. George’s Respiratory Questionnaire (SGRQ) in the treated patients decreased by 0.66 points on a 0-100 scale, but increased by 5.46 points in the placebo group. This difference was also significant.

"There were improvements in two domains of the SGRQ – symptoms and activity – in the group receiving 150 mg of BIBF 1120 twice a day as compared with the placebo group (–3.14 points vs. 6.45 points and 0.32 points vs. 7.48 points, respectively), and there was a dose-dependent trend toward an improvement in the impact domain, which is a broad measure of the impact of respiratory disease on the patient," they said.

There was also a trend toward fewer deaths from respiratory causes in the 150-mg twice-daily treatment group and the 100-mg twice-daily group, with two such deaths in each of those groups, compared with nine and three deaths in the 50-mg once-daily and the 50-mg twice-daily groups, respectively, and eight in the placebo group.

Study participants were adults aged 40 years or older with high-resolution CT–confirmed idiopathic pulmonary fibrosis diagnosed within the previous 5 years. They were recruited from 92 sites in 25 countries, and were randomized in double-blind fashion to receive either placebo, 50 mg once daily, 50 mg twice daily, 100 mg twice daily, or 150 mg twice daily for 52 weeks.

As for adverse events, the overall incidence was similar in each of the groups, as was the incidence of serious and severe adverse events and adverse events requiring hospitalization. The proportion of patients with serious adverse events was lower in the 150-mg twice-daily treatment group than in the placebo group (27.1% vs. 30.6%), and the lowest proportion was in the 100-mg twice-daily group (14%). Most of the adverse events that led to discontinuation of treatment were gastrointestinal in nature, and included diarrhea, nausea, and vomiting. These occurred most often the 150-mg twice-daily group.

However, the number of fatal adverse events decreased with increasing doses of BIBF 1120, with 12, 10, 4, and 5 patients in the placebo, 50-mg once-daily, 50-mg twice-daily, and 100-mg twice-daily groups experiencing a fatal adverse event, and only 1 in the 150-mg twice-daily group experiencing a fatal adverse event.

While this trial failed to show a significant difference in the predefined multiplicity-corrected end point of the annual rate of decline in FVC, the findings nonetheless suggest that BIBF 1120 is a promising treatment for idiopathic pulmonary fibrosis, particularly given the seriousness of this condition and the paucity of therapeutic options, according to the investigators.

Further, the results of the secondary end point analyses support the 150-mg twice-daily dose – and for some end points, the 100-mg twice-daily dose, they noted.

A particularly important finding was the significantly lower incidence of acute exacerbations in the 150-mg twice-daily group, compared with the placebo group.

"This result is clinically important, since acute exacerbations are associated with rapid disease progression, a severe and abrupt decline in forced vital capacity, and high mortality," the investigators wrote.

This finding may have contributed to the higher quality of life scores seen in the higher-dosage groups than in the other groups, which had higher incidences of exacerbations, they added, concluding that the findings warrant additional investigation in phase III clinical studies.

The study by Dr. Richeldi and his colleagues was supported by Boehringer Ingelheim, which employs some of the study authors. More detailed disclosures are available with the full text of the article at NEJM.org.

The experimental tyrosine kinase inhibitor BIBF 1120 was associated with a clinically meaningful reduction in the rate of decline in forced vital capacity, compared with placebo, in patients with idiopathic pulmonary fibrosis in a yearlong, phase II dose-ranging trial involving 432 patients.

Active treatment was also associated with a reduction in the incidence of acute exacerbations of the disease and with an increase in quality of life scores, compared with placebo, Dr. Luca Richeldi of the University of Modena (Italy) and Reggio Emilia, Policlinico Hospital, Modena, and his colleagues reported in the Sept. 22 issue of the New England Journal of Medicine.

Specifically, 85 patients randomized to receive an oral dose of BIBF 1120 at 150 mg twice daily had a mean decline in forced vital capacity (FVC) of 0.06 L/year, compared with 0.19 L/year in 83 patients randomized to receive placebo, a 68.4% reduction. This difference is not statistically significant but does approach the threshold for significance. Also, the absolute change in FVC from baseline over time in the treatment group, compared with the placebo group, was statistically significant, the investigators wrote (N. Engl. J. Med. 2011;365:1079-87).

Acute exacerbations occurred at a rate of 2.4 vs. 15.7 per 100 patient-years in the 150-mg twice-daily treatment group and the placebo group, respectively, a significant difference. There was a trend toward a dose response with increasing doses of BIBF 1120. In addition, scores on the St. George’s Respiratory Questionnaire (SGRQ) in the treated patients decreased by 0.66 points on a 0-100 scale, but increased by 5.46 points in the placebo group. This difference was also significant.

"There were improvements in two domains of the SGRQ – symptoms and activity – in the group receiving 150 mg of BIBF 1120 twice a day as compared with the placebo group (–3.14 points vs. 6.45 points and 0.32 points vs. 7.48 points, respectively), and there was a dose-dependent trend toward an improvement in the impact domain, which is a broad measure of the impact of respiratory disease on the patient," they said.

There was also a trend toward fewer deaths from respiratory causes in the 150-mg twice-daily treatment group and the 100-mg twice-daily group, with two such deaths in each of those groups, compared with nine and three deaths in the 50-mg once-daily and the 50-mg twice-daily groups, respectively, and eight in the placebo group.

Study participants were adults aged 40 years or older with high-resolution CT–confirmed idiopathic pulmonary fibrosis diagnosed within the previous 5 years. They were recruited from 92 sites in 25 countries, and were randomized in double-blind fashion to receive either placebo, 50 mg once daily, 50 mg twice daily, 100 mg twice daily, or 150 mg twice daily for 52 weeks.

As for adverse events, the overall incidence was similar in each of the groups, as was the incidence of serious and severe adverse events and adverse events requiring hospitalization. The proportion of patients with serious adverse events was lower in the 150-mg twice-daily treatment group than in the placebo group (27.1% vs. 30.6%), and the lowest proportion was in the 100-mg twice-daily group (14%). Most of the adverse events that led to discontinuation of treatment were gastrointestinal in nature, and included diarrhea, nausea, and vomiting. These occurred most often the 150-mg twice-daily group.

However, the number of fatal adverse events decreased with increasing doses of BIBF 1120, with 12, 10, 4, and 5 patients in the placebo, 50-mg once-daily, 50-mg twice-daily, and 100-mg twice-daily groups experiencing a fatal adverse event, and only 1 in the 150-mg twice-daily group experiencing a fatal adverse event.

While this trial failed to show a significant difference in the predefined multiplicity-corrected end point of the annual rate of decline in FVC, the findings nonetheless suggest that BIBF 1120 is a promising treatment for idiopathic pulmonary fibrosis, particularly given the seriousness of this condition and the paucity of therapeutic options, according to the investigators.

Further, the results of the secondary end point analyses support the 150-mg twice-daily dose – and for some end points, the 100-mg twice-daily dose, they noted.

A particularly important finding was the significantly lower incidence of acute exacerbations in the 150-mg twice-daily group, compared with the placebo group.

"This result is clinically important, since acute exacerbations are associated with rapid disease progression, a severe and abrupt decline in forced vital capacity, and high mortality," the investigators wrote.

This finding may have contributed to the higher quality of life scores seen in the higher-dosage groups than in the other groups, which had higher incidences of exacerbations, they added, concluding that the findings warrant additional investigation in phase III clinical studies.

The study by Dr. Richeldi and his colleagues was supported by Boehringer Ingelheim, which employs some of the study authors. More detailed disclosures are available with the full text of the article at NEJM.org.

The experimental tyrosine kinase inhibitor BIBF 1120 was associated with a clinically meaningful reduction in the rate of decline in forced vital capacity, compared with placebo, in patients with idiopathic pulmonary fibrosis in a yearlong, phase II dose-ranging trial involving 432 patients.

Active treatment was also associated with a reduction in the incidence of acute exacerbations of the disease and with an increase in quality of life scores, compared with placebo, Dr. Luca Richeldi of the University of Modena (Italy) and Reggio Emilia, Policlinico Hospital, Modena, and his colleagues reported in the Sept. 22 issue of the New England Journal of Medicine.

Specifically, 85 patients randomized to receive an oral dose of BIBF 1120 at 150 mg twice daily had a mean decline in forced vital capacity (FVC) of 0.06 L/year, compared with 0.19 L/year in 83 patients randomized to receive placebo, a 68.4% reduction. This difference is not statistically significant but does approach the threshold for significance. Also, the absolute change in FVC from baseline over time in the treatment group, compared with the placebo group, was statistically significant, the investigators wrote (N. Engl. J. Med. 2011;365:1079-87).

Acute exacerbations occurred at a rate of 2.4 vs. 15.7 per 100 patient-years in the 150-mg twice-daily treatment group and the placebo group, respectively, a significant difference. There was a trend toward a dose response with increasing doses of BIBF 1120. In addition, scores on the St. George’s Respiratory Questionnaire (SGRQ) in the treated patients decreased by 0.66 points on a 0-100 scale, but increased by 5.46 points in the placebo group. This difference was also significant.

"There were improvements in two domains of the SGRQ – symptoms and activity – in the group receiving 150 mg of BIBF 1120 twice a day as compared with the placebo group (–3.14 points vs. 6.45 points and 0.32 points vs. 7.48 points, respectively), and there was a dose-dependent trend toward an improvement in the impact domain, which is a broad measure of the impact of respiratory disease on the patient," they said.

There was also a trend toward fewer deaths from respiratory causes in the 150-mg twice-daily treatment group and the 100-mg twice-daily group, with two such deaths in each of those groups, compared with nine and three deaths in the 50-mg once-daily and the 50-mg twice-daily groups, respectively, and eight in the placebo group.

Study participants were adults aged 40 years or older with high-resolution CT–confirmed idiopathic pulmonary fibrosis diagnosed within the previous 5 years. They were recruited from 92 sites in 25 countries, and were randomized in double-blind fashion to receive either placebo, 50 mg once daily, 50 mg twice daily, 100 mg twice daily, or 150 mg twice daily for 52 weeks.

As for adverse events, the overall incidence was similar in each of the groups, as was the incidence of serious and severe adverse events and adverse events requiring hospitalization. The proportion of patients with serious adverse events was lower in the 150-mg twice-daily treatment group than in the placebo group (27.1% vs. 30.6%), and the lowest proportion was in the 100-mg twice-daily group (14%). Most of the adverse events that led to discontinuation of treatment were gastrointestinal in nature, and included diarrhea, nausea, and vomiting. These occurred most often the 150-mg twice-daily group.

However, the number of fatal adverse events decreased with increasing doses of BIBF 1120, with 12, 10, 4, and 5 patients in the placebo, 50-mg once-daily, 50-mg twice-daily, and 100-mg twice-daily groups experiencing a fatal adverse event, and only 1 in the 150-mg twice-daily group experiencing a fatal adverse event.

While this trial failed to show a significant difference in the predefined multiplicity-corrected end point of the annual rate of decline in FVC, the findings nonetheless suggest that BIBF 1120 is a promising treatment for idiopathic pulmonary fibrosis, particularly given the seriousness of this condition and the paucity of therapeutic options, according to the investigators.

Further, the results of the secondary end point analyses support the 150-mg twice-daily dose – and for some end points, the 100-mg twice-daily dose, they noted.

A particularly important finding was the significantly lower incidence of acute exacerbations in the 150-mg twice-daily group, compared with the placebo group.

"This result is clinically important, since acute exacerbations are associated with rapid disease progression, a severe and abrupt decline in forced vital capacity, and high mortality," the investigators wrote.

This finding may have contributed to the higher quality of life scores seen in the higher-dosage groups than in the other groups, which had higher incidences of exacerbations, they added, concluding that the findings warrant additional investigation in phase III clinical studies.

The study by Dr. Richeldi and his colleagues was supported by Boehringer Ingelheim, which employs some of the study authors. More detailed disclosures are available with the full text of the article at NEJM.org.

Diarrhea-associated health care utilization and costs have decreased considerably since the introduction of routine rotavirus vaccination in infants in 2006, a study has shown.

An assessment of pentavalent rotavirus vaccine (RV5) coverage from July 2007 through June 2009 in children under age 5 years showed that 73% of children under age 1 year, 64% of children aged 1 year, and 8% of children aged 2-4 years received at least one RV5 dose by Dec. 31, 2008. Rates of diarrhea-related hospitalizations declined by 33% from the 2001-2006 time period to 2007-2008 (from 52 to 35 per 10,000 person-years) and by 25% from 2001-2006 to 2008-2009 (from 52 to 39 cases per 10,000 person-years), Dr. Jennifer E. Cortes and her colleagues at the Centers for Disease Control and Prevention reported in the Sept. 22 issue of the New England Journal of Medicine.

Furthermore, the rates of hospitalization that were specifically coded for rotavirus infection declined by nearly 75% from 2001-2006 to 2007-2008 (from 14 to 4 per 10,000 person-years), and by nearly 60% from 2001-2006 to 2008-2009 (from 14 to 6 per 10,000 person-years), the investigators found (N. Engl. J. Med. 2011;365:1108-17).

Emergency department and outpatient visits for diarrhea also declined in 2007-2008 (by 9% and 3%), but the rates of visits in 2008-2009 were similar to prevaccine rates.

Overall, all regions had significant reductions in the rate of hospitalization for diarrhea for children under age 5 years, and in 2007-2008, all regions except the West had declines in emergency department and outpatient visits – although to a lesser extent than for hospitalizations, they noted.

The direct benefits of vaccination include an 89% reduction in rotavirus-coded hospitalizations in vaccinated vs. unvaccinated children in the two postvaccine rotavirus seasons studied, and 44% and 58% reductions in hospitalizations for diarrhea due to any cause in vaccinated vs. unvaccinated children in 2007-2008 and 2008-2009, the investigators said.

Emergency department visits also declined by 37% and 48% in vaccinated vs. unvaccinated children in 2007-2008 and 2008-2009, as did outpatient visits, which declined by 9% and 12% in vaccinated vs. unvaccinated children in 2007-2008 and 2008-2009.

Indirect benefits of vaccination included substantial reductions in the rates of health care utilization for diarrhea due to any cause, and for rotavirus-coded diarrhea among age-eligible, unvaccinated children during the January to June period (peak rotavirus season) of 2008, they noted.

The effects of vaccination on health care utilization translate to an estimated savings of $278 million in hospitalization costs over the 2-year period, Dr. Cortes and her associates said.

"This study provides more evidence that vaccinating against rotavirus substantially reduces suffering and health care costs for this common childhood illness," Dr. Mark Pallansch, director of CDC’s division of viral diseases, said in a written statement. "As more children get vaccinated against rotavirus, we expect to see even greater reductions in disease among all age groups."

For the study, the investigators used MarketScan Commercial Claims and Encounters databases that captured data on more than 2 million children under age 5 years to correlate RV5 coverage with changes in the rates of diarrhea-related hospitalizations, emergency department and outpatient visits, and related health care costs following RV5 introduction. Vaccine coverage was ascertained from a cohort of nearly 300,000 children under age 5 years from 37 states.

"Our findings confirm other reports of a decline in rotavirus activity in the United States after the introduction of rotavirus vaccine," the investigators noted, adding that their findings are generally consistent with the efficacy of the vaccine in prelicensure trials.

Indirect benefits were seen in 2007-2008, when declines in rotavirus disease "greatly exceeded expected declines, given the level of RV5 coverage," but were smaller in 2008-2009.

Although limited by several factors, such as a lack of data on uninsured and Medicaid populations, examination of data from only two postvaccine rotavirus seasons, and possible inconsistencies in rotavirus testing and coding across health care settings, the study nonetheless indicates that diarrhea-associated health care utilization and medical expenditures have declined since implementation of routine rotavirus vaccination in infants in the United States.

"Continued surveillance is needed to further characterize direct and indirect vaccine effects, including those of the recently approved rotavirus vaccine RV1, on diarrhea-associated health care utilization among U.S. children," Dr. Cortes and her associates concluded.

Dr. Cortes and her associates said they had no relevant financial disclosures.

Diarrhea-associated health care utilization and costs have decreased considerably since the introduction of routine rotavirus vaccination in infants in 2006, a study has shown.

An assessment of pentavalent rotavirus vaccine (RV5) coverage from July 2007 through June 2009 in children under age 5 years showed that 73% of children under age 1 year, 64% of children aged 1 year, and 8% of children aged 2-4 years received at least one RV5 dose by Dec. 31, 2008. Rates of diarrhea-related hospitalizations declined by 33% from the 2001-2006 time period to 2007-2008 (from 52 to 35 per 10,000 person-years) and by 25% from 2001-2006 to 2008-2009 (from 52 to 39 cases per 10,000 person-years), Dr. Jennifer E. Cortes and her colleagues at the Centers for Disease Control and Prevention reported in the Sept. 22 issue of the New England Journal of Medicine.

Furthermore, the rates of hospitalization that were specifically coded for rotavirus infection declined by nearly 75% from 2001-2006 to 2007-2008 (from 14 to 4 per 10,000 person-years), and by nearly 60% from 2001-2006 to 2008-2009 (from 14 to 6 per 10,000 person-years), the investigators found (N. Engl. J. Med. 2011;365:1108-17).

Emergency department and outpatient visits for diarrhea also declined in 2007-2008 (by 9% and 3%), but the rates of visits in 2008-2009 were similar to prevaccine rates.

Overall, all regions had significant reductions in the rate of hospitalization for diarrhea for children under age 5 years, and in 2007-2008, all regions except the West had declines in emergency department and outpatient visits – although to a lesser extent than for hospitalizations, they noted.

The direct benefits of vaccination include an 89% reduction in rotavirus-coded hospitalizations in vaccinated vs. unvaccinated children in the two postvaccine rotavirus seasons studied, and 44% and 58% reductions in hospitalizations for diarrhea due to any cause in vaccinated vs. unvaccinated children in 2007-2008 and 2008-2009, the investigators said.

Emergency department visits also declined by 37% and 48% in vaccinated vs. unvaccinated children in 2007-2008 and 2008-2009, as did outpatient visits, which declined by 9% and 12% in vaccinated vs. unvaccinated children in 2007-2008 and 2008-2009.

Indirect benefits of vaccination included substantial reductions in the rates of health care utilization for diarrhea due to any cause, and for rotavirus-coded diarrhea among age-eligible, unvaccinated children during the January to June period (peak rotavirus season) of 2008, they noted.

The effects of vaccination on health care utilization translate to an estimated savings of $278 million in hospitalization costs over the 2-year period, Dr. Cortes and her associates said.

"This study provides more evidence that vaccinating against rotavirus substantially reduces suffering and health care costs for this common childhood illness," Dr. Mark Pallansch, director of CDC’s division of viral diseases, said in a written statement. "As more children get vaccinated against rotavirus, we expect to see even greater reductions in disease among all age groups."

For the study, the investigators used MarketScan Commercial Claims and Encounters databases that captured data on more than 2 million children under age 5 years to correlate RV5 coverage with changes in the rates of diarrhea-related hospitalizations, emergency department and outpatient visits, and related health care costs following RV5 introduction. Vaccine coverage was ascertained from a cohort of nearly 300,000 children under age 5 years from 37 states.

"Our findings confirm other reports of a decline in rotavirus activity in the United States after the introduction of rotavirus vaccine," the investigators noted, adding that their findings are generally consistent with the efficacy of the vaccine in prelicensure trials.

Indirect benefits were seen in 2007-2008, when declines in rotavirus disease "greatly exceeded expected declines, given the level of RV5 coverage," but were smaller in 2008-2009.

Although limited by several factors, such as a lack of data on uninsured and Medicaid populations, examination of data from only two postvaccine rotavirus seasons, and possible inconsistencies in rotavirus testing and coding across health care settings, the study nonetheless indicates that diarrhea-associated health care utilization and medical expenditures have declined since implementation of routine rotavirus vaccination in infants in the United States.

"Continued surveillance is needed to further characterize direct and indirect vaccine effects, including those of the recently approved rotavirus vaccine RV1, on diarrhea-associated health care utilization among U.S. children," Dr. Cortes and her associates concluded.

Dr. Cortes and her associates said they had no relevant financial disclosures.

Diarrhea-associated health care utilization and costs have decreased considerably since the introduction of routine rotavirus vaccination in infants in 2006, a study has shown.

An assessment of pentavalent rotavirus vaccine (RV5) coverage from July 2007 through June 2009 in children under age 5 years showed that 73% of children under age 1 year, 64% of children aged 1 year, and 8% of children aged 2-4 years received at least one RV5 dose by Dec. 31, 2008. Rates of diarrhea-related hospitalizations declined by 33% from the 2001-2006 time period to 2007-2008 (from 52 to 35 per 10,000 person-years) and by 25% from 2001-2006 to 2008-2009 (from 52 to 39 cases per 10,000 person-years), Dr. Jennifer E. Cortes and her colleagues at the Centers for Disease Control and Prevention reported in the Sept. 22 issue of the New England Journal of Medicine.

Furthermore, the rates of hospitalization that were specifically coded for rotavirus infection declined by nearly 75% from 2001-2006 to 2007-2008 (from 14 to 4 per 10,000 person-years), and by nearly 60% from 2001-2006 to 2008-2009 (from 14 to 6 per 10,000 person-years), the investigators found (N. Engl. J. Med. 2011;365:1108-17).

Emergency department and outpatient visits for diarrhea also declined in 2007-2008 (by 9% and 3%), but the rates of visits in 2008-2009 were similar to prevaccine rates.

Overall, all regions had significant reductions in the rate of hospitalization for diarrhea for children under age 5 years, and in 2007-2008, all regions except the West had declines in emergency department and outpatient visits – although to a lesser extent than for hospitalizations, they noted.

The direct benefits of vaccination include an 89% reduction in rotavirus-coded hospitalizations in vaccinated vs. unvaccinated children in the two postvaccine rotavirus seasons studied, and 44% and 58% reductions in hospitalizations for diarrhea due to any cause in vaccinated vs. unvaccinated children in 2007-2008 and 2008-2009, the investigators said.

Emergency department visits also declined by 37% and 48% in vaccinated vs. unvaccinated children in 2007-2008 and 2008-2009, as did outpatient visits, which declined by 9% and 12% in vaccinated vs. unvaccinated children in 2007-2008 and 2008-2009.

Indirect benefits of vaccination included substantial reductions in the rates of health care utilization for diarrhea due to any cause, and for rotavirus-coded diarrhea among age-eligible, unvaccinated children during the January to June period (peak rotavirus season) of 2008, they noted.

The effects of vaccination on health care utilization translate to an estimated savings of $278 million in hospitalization costs over the 2-year period, Dr. Cortes and her associates said.

"This study provides more evidence that vaccinating against rotavirus substantially reduces suffering and health care costs for this common childhood illness," Dr. Mark Pallansch, director of CDC’s division of viral diseases, said in a written statement. "As more children get vaccinated against rotavirus, we expect to see even greater reductions in disease among all age groups."

For the study, the investigators used MarketScan Commercial Claims and Encounters databases that captured data on more than 2 million children under age 5 years to correlate RV5 coverage with changes in the rates of diarrhea-related hospitalizations, emergency department and outpatient visits, and related health care costs following RV5 introduction. Vaccine coverage was ascertained from a cohort of nearly 300,000 children under age 5 years from 37 states.

"Our findings confirm other reports of a decline in rotavirus activity in the United States after the introduction of rotavirus vaccine," the investigators noted, adding that their findings are generally consistent with the efficacy of the vaccine in prelicensure trials.

Indirect benefits were seen in 2007-2008, when declines in rotavirus disease "greatly exceeded expected declines, given the level of RV5 coverage," but were smaller in 2008-2009.

Although limited by several factors, such as a lack of data on uninsured and Medicaid populations, examination of data from only two postvaccine rotavirus seasons, and possible inconsistencies in rotavirus testing and coding across health care settings, the study nonetheless indicates that diarrhea-associated health care utilization and medical expenditures have declined since implementation of routine rotavirus vaccination in infants in the United States.

"Continued surveillance is needed to further characterize direct and indirect vaccine effects, including those of the recently approved rotavirus vaccine RV1, on diarrhea-associated health care utilization among U.S. children," Dr. Cortes and her associates concluded.

Dr. Cortes and her associates said they had no relevant financial disclosures.

Children who are treated with selective serotonin reuptake inhibitors have fivefold greater odds of experiencing periodic limb movements of sleep than do those who are not treated with SSRIs, according to findings from a retrospective review of polysomnography data.

Nearly a third (31.7%) of 41 children receiving SSRIs at the time of the study experienced periodic limb movements of sleep, compared with only 7.8% of 982 children not receiving SSRIs (odds ratio, 5.45), Dr. Martina Vendrame of Boston University and her colleagues reported.

Furthermore, the median periodic limb movement index in those receiving SSRIs was significantly higher than the index in those not receiving SSRIs (11.2 vs. 6.5), the investigators said (Pediatr. Neurol. 2011;45:175-7).

Although periodic limb movements of sleep have been reported in adults taking serotonergic antidepressants – with one study showing that 44% of adults receiving fluoxetine experienced the symptoms, and others showing that restless legs syndrome (RLS) is exacerbated in up to 10% of adult patients on SSRIs – the current study is one of few that provide information about periodic limb movements of sleep in children and adolescents.

Study subjects were all children who underwent overnight diagnostic polysomnography between January 2009 and April 2010 at a single center. The studies were conducted for various sleep disturbances such as snoring, pauses in breathing, daytime sleepiness, and gasping or snorting in sleep; none was conducted for reports of RLS or periodic limb movements of sleep.

The patients who received SSRIs included 31 girls and 10 boys who had a median age of 15.4 years. The SSRIs were prescribed for depression and included citalopram or escitalopram in 15 patients, fluoxetine in 14 patients, and sertraline in 12 patients.

"The mechanism by which SSRIs may cause periodic limb movements of sleep is not clear, but serotonin-mediated dopaminergic inhibition may represent the underlying mechanism," the investigators noted.

Although no significant differences in mean periodic limb movements of sleep indices were seen between different SSRIs in this study, it is possible that different doses and timing of administration could result in better control of limb movements, they said, adding that when periodic limb movements of sleep are found, a careful history should be taken to assess whether they are causing sleep disturbance, and also to determine if the child is experiencing RLS.

"If necessary, the use of antidepressants not associated with periodic limb movements of sleep should be considered," they wrote.

Although limited by the use of single-night polysomnography, a small study population, and possibly by referral bias to a tertiary center, the findings suggest that periodic limb movements of sleep may be an important side effect of SSRIs that is frequently overlooked in children.

"Recognition may result in better control of periodic limb movements of sleep and improved quality of life in these patients," they concluded, noting that future investigations should include a multicenter, prospective study using multinight polysomnography, investigation of various SSRIs separately, and evaluation of the role of underlying diseases for which subjects are treated with antidepressants in the development of periodic limb movements of sleep.

No financial disclosure information was available in the report.

Children who are treated with selective serotonin reuptake inhibitors have fivefold greater odds of experiencing periodic limb movements of sleep than do those who are not treated with SSRIs, according to findings from a retrospective review of polysomnography data.

Nearly a third (31.7%) of 41 children receiving SSRIs at the time of the study experienced periodic limb movements of sleep, compared with only 7.8% of 982 children not receiving SSRIs (odds ratio, 5.45), Dr. Martina Vendrame of Boston University and her colleagues reported.

Furthermore, the median periodic limb movement index in those receiving SSRIs was significantly higher than the index in those not receiving SSRIs (11.2 vs. 6.5), the investigators said (Pediatr. Neurol. 2011;45:175-7).

Although periodic limb movements of sleep have been reported in adults taking serotonergic antidepressants – with one study showing that 44% of adults receiving fluoxetine experienced the symptoms, and others showing that restless legs syndrome (RLS) is exacerbated in up to 10% of adult patients on SSRIs – the current study is one of few that provide information about periodic limb movements of sleep in children and adolescents.

Study subjects were all children who underwent overnight diagnostic polysomnography between January 2009 and April 2010 at a single center. The studies were conducted for various sleep disturbances such as snoring, pauses in breathing, daytime sleepiness, and gasping or snorting in sleep; none was conducted for reports of RLS or periodic limb movements of sleep.

The patients who received SSRIs included 31 girls and 10 boys who had a median age of 15.4 years. The SSRIs were prescribed for depression and included citalopram or escitalopram in 15 patients, fluoxetine in 14 patients, and sertraline in 12 patients.

"The mechanism by which SSRIs may cause periodic limb movements of sleep is not clear, but serotonin-mediated dopaminergic inhibition may represent the underlying mechanism," the investigators noted.

Although no significant differences in mean periodic limb movements of sleep indices were seen between different SSRIs in this study, it is possible that different doses and timing of administration could result in better control of limb movements, they said, adding that when periodic limb movements of sleep are found, a careful history should be taken to assess whether they are causing sleep disturbance, and also to determine if the child is experiencing RLS.

"If necessary, the use of antidepressants not associated with periodic limb movements of sleep should be considered," they wrote.

Although limited by the use of single-night polysomnography, a small study population, and possibly by referral bias to a tertiary center, the findings suggest that periodic limb movements of sleep may be an important side effect of SSRIs that is frequently overlooked in children.

"Recognition may result in better control of periodic limb movements of sleep and improved quality of life in these patients," they concluded, noting that future investigations should include a multicenter, prospective study using multinight polysomnography, investigation of various SSRIs separately, and evaluation of the role of underlying diseases for which subjects are treated with antidepressants in the development of periodic limb movements of sleep.

No financial disclosure information was available in the report.

Children who are treated with selective serotonin reuptake inhibitors have fivefold greater odds of experiencing periodic limb movements of sleep than do those who are not treated with SSRIs, according to findings from a retrospective review of polysomnography data.

Nearly a third (31.7%) of 41 children receiving SSRIs at the time of the study experienced periodic limb movements of sleep, compared with only 7.8% of 982 children not receiving SSRIs (odds ratio, 5.45), Dr. Martina Vendrame of Boston University and her colleagues reported.

Furthermore, the median periodic limb movement index in those receiving SSRIs was significantly higher than the index in those not receiving SSRIs (11.2 vs. 6.5), the investigators said (Pediatr. Neurol. 2011;45:175-7).

Although periodic limb movements of sleep have been reported in adults taking serotonergic antidepressants – with one study showing that 44% of adults receiving fluoxetine experienced the symptoms, and others showing that restless legs syndrome (RLS) is exacerbated in up to 10% of adult patients on SSRIs – the current study is one of few that provide information about periodic limb movements of sleep in children and adolescents.

Study subjects were all children who underwent overnight diagnostic polysomnography between January 2009 and April 2010 at a single center. The studies were conducted for various sleep disturbances such as snoring, pauses in breathing, daytime sleepiness, and gasping or snorting in sleep; none was conducted for reports of RLS or periodic limb movements of sleep.

The patients who received SSRIs included 31 girls and 10 boys who had a median age of 15.4 years. The SSRIs were prescribed for depression and included citalopram or escitalopram in 15 patients, fluoxetine in 14 patients, and sertraline in 12 patients.

"The mechanism by which SSRIs may cause periodic limb movements of sleep is not clear, but serotonin-mediated dopaminergic inhibition may represent the underlying mechanism," the investigators noted.

Although no significant differences in mean periodic limb movements of sleep indices were seen between different SSRIs in this study, it is possible that different doses and timing of administration could result in better control of limb movements, they said, adding that when periodic limb movements of sleep are found, a careful history should be taken to assess whether they are causing sleep disturbance, and also to determine if the child is experiencing RLS.

"If necessary, the use of antidepressants not associated with periodic limb movements of sleep should be considered," they wrote.

Although limited by the use of single-night polysomnography, a small study population, and possibly by referral bias to a tertiary center, the findings suggest that periodic limb movements of sleep may be an important side effect of SSRIs that is frequently overlooked in children.

"Recognition may result in better control of periodic limb movements of sleep and improved quality of life in these patients," they concluded, noting that future investigations should include a multicenter, prospective study using multinight polysomnography, investigation of various SSRIs separately, and evaluation of the role of underlying diseases for which subjects are treated with antidepressants in the development of periodic limb movements of sleep.

No financial disclosure information was available in the report.