Mary Ann Moon

Compared with watchful waiting, early adenotonsillectomy did not significantly improve attention or executive function as measured by neuropsychological testing in school-aged children with obstructive sleep apnea syndrome, according to a new report.

The findings were published online May 21 in the New England Journal of Medicine and simultaneously reported at the annual meeting of the American Thoracic Society.

However, early surgery did markedly improve polysomnographic abnormalities, as well as parent- and teacher-reported measures of behavior, executive function, and sleep symptoms, compared with watchful waiting, said Dr. Carole L. Marcus, director of the sleep center at Children’s Hospital of Philadelphia, and her associates.

"We observed no significant difference between the two groups in the change from baseline to follow-up in our primary outcome, the attention and executive-function score of the NEPSY [Developmental NeuroPsychological Assessment]; thus our trial is a negative one. However, other tests showed evidence of changes in behavior," noted Dr. Marcus and her associates in the Childhood Adenotonsillectomy Trial (CHAT).

Previous studies examining cognitive and behavioral outcomes after adenotonsillectomy for obstructive sleep apnea syndrome "have been limited by small samples, lack of randomization or appropriate controls, heterogenous study groups, and sole reliance on parent questionnaires rather than including neuropsychological testing," the investigators said.

In contrast, CHAT involved 453 children aged 5-9 years treated at seven academic sleep centers, who underwent standardized polysomnographic assessments and extensive testing via the Developmental Neuropsychological Assessment (NEPSY); Behavior Rating Inventory of Executive Function (BRIEF); Differential Ability Scales (DAS), which measures general intellectual functioning; Conners’ Rating Scale Revised (CRS-R); Pediatric Sleep Questionnaire sleep-related breathing disorder scale (PSQ-SRBD); Epworth Sleepiness Scale modified for children; Pediatric Quality of Life Inventory (PedsQL); and the Obstructive Sleep Apnea–18 assessment tool that measures disease-specific quality of life.

The children were randomly assigned to undergo adenotonsillectomy within 1 month (226 patients) or to be followed with watchful waiting (227 control subjects), and were formally assessed 7 months later. Demographic and clinical characteristics were well-balanced between the two study groups at baseline, and cognitive and behavioral scores were close to population means. A similar number of children in each group used nasal glucocorticoids or montelukast for allergic rhinitis or asthma.

Approximately half of the children in each group were overweight or obese.

The primary efficacy outcome was change in attention and executive-function score on the NEPSY. These scores improved more in children who underwent adenotonsillectomy than in the controls, but the difference did not reach statistical significance.

However, outcomes were significantly better with surgery than with watchful waiting on measures of obstructive apnea-hypopnea, oxygen desaturation index, hypercapnia, sleep arousal index, and percentage of sleep time in light sleep. This last measure is an indication of improved sleep continuity.

In particular, many more children who underwent early adenotonsillectomy (79%) achieved normalization of the obstructive sleep apnea syndrome, compared with control subjects (46%) (N. Engl. J. Med. 2013 May 21 [doi:10.1056/NEJMoa1215881]).

Adenotonsillectomy also improved outcomes to a significantly greater degree than did watchful waiting on the Conners’ Rating Scale assessing restlessness, impulsiveness, and emotional lability, as well as on all other measures of behavior and quality of life. The effect sizes were in the moderate-to-large range, indicating that the changes were clinically significant.

These benefits were noted in all subgroup analyses, most importantly in both obese and nonobese children. Obese children and children with more severe apnea symptoms showed larger absolute improvements after surgery than did other study subjects.

However, normalization of symptoms was less likely to occur in black children than in those of other races, regardless of treatment assignment. Obstructive sleep apnea has previously been reported to be more severe in black children, as it was in this study population. Black subjects in this study also showed less improvement in parent- and teacher-reported measures after adenotonsillectomy, relative to children of other races.

"The reasons for this racial disparity are unclear. Possible explanations include differences in parents’ expectations, coping mechanisms, or perceptions of their child’s behavior and the presence of risk factors for behavioral problems unrelated to the obstructive sleep apnea syndrome," Dr. Marcus and her associates said.

Regarding adverse effects, the number of serious events was similar between the two study groups. Eight events were related to perioperative complications, but three of these occurred in children assigned to the watchful waiting group who later crossed over to the surgery group.

Overall, the rate of perioperative complications was low, and the only treatment failures in this study occurred in the watchful waiting group. "Thus, this trial supports the overall safety of both early adenotonsillectomy and watchful waiting, but suggests the need for clinical monitoring of children who are being treated conservatively," the researchers said.

They added that it is possible the 7-month follow-up was not long enough to demonstrate "the full response to surgery." It may be that the neurobehavioral sequelae of sleepiness resolve quickly but those related to hypoxemia may stem from neuronal damage and thus take longer to resolve.

This study was limited in that it excluded patients with prolonged oxyhemoglobin desaturation and those taking attention deficit/hyperactivity disorder medications. Therefore "the study results cannot be extrapolated to these vulnerable groups," Dr. Marcus and her colleagues said.

CHAT was supported by the National Institutes of Health. Dr. Marcus reported receiving research equipment from Philips Respironics and Ventus Medical; her associates reported numerous ties to industry sources.

Compared with watchful waiting, early adenotonsillectomy did not significantly improve attention or executive function as measured by neuropsychological testing in school-aged children with obstructive sleep apnea syndrome, according to a new report.

The findings were published online May 21 in the New England Journal of Medicine and simultaneously reported at the annual meeting of the American Thoracic Society.

However, early surgery did markedly improve polysomnographic abnormalities, as well as parent- and teacher-reported measures of behavior, executive function, and sleep symptoms, compared with watchful waiting, said Dr. Carole L. Marcus, director of the sleep center at Children’s Hospital of Philadelphia, and her associates.

"We observed no significant difference between the two groups in the change from baseline to follow-up in our primary outcome, the attention and executive-function score of the NEPSY [Developmental NeuroPsychological Assessment]; thus our trial is a negative one. However, other tests showed evidence of changes in behavior," noted Dr. Marcus and her associates in the Childhood Adenotonsillectomy Trial (CHAT).

Previous studies examining cognitive and behavioral outcomes after adenotonsillectomy for obstructive sleep apnea syndrome "have been limited by small samples, lack of randomization or appropriate controls, heterogenous study groups, and sole reliance on parent questionnaires rather than including neuropsychological testing," the investigators said.

In contrast, CHAT involved 453 children aged 5-9 years treated at seven academic sleep centers, who underwent standardized polysomnographic assessments and extensive testing via the Developmental Neuropsychological Assessment (NEPSY); Behavior Rating Inventory of Executive Function (BRIEF); Differential Ability Scales (DAS), which measures general intellectual functioning; Conners’ Rating Scale Revised (CRS-R); Pediatric Sleep Questionnaire sleep-related breathing disorder scale (PSQ-SRBD); Epworth Sleepiness Scale modified for children; Pediatric Quality of Life Inventory (PedsQL); and the Obstructive Sleep Apnea–18 assessment tool that measures disease-specific quality of life.

The children were randomly assigned to undergo adenotonsillectomy within 1 month (226 patients) or to be followed with watchful waiting (227 control subjects), and were formally assessed 7 months later. Demographic and clinical characteristics were well-balanced between the two study groups at baseline, and cognitive and behavioral scores were close to population means. A similar number of children in each group used nasal glucocorticoids or montelukast for allergic rhinitis or asthma.

Approximately half of the children in each group were overweight or obese.

The primary efficacy outcome was change in attention and executive-function score on the NEPSY. These scores improved more in children who underwent adenotonsillectomy than in the controls, but the difference did not reach statistical significance.

However, outcomes were significantly better with surgery than with watchful waiting on measures of obstructive apnea-hypopnea, oxygen desaturation index, hypercapnia, sleep arousal index, and percentage of sleep time in light sleep. This last measure is an indication of improved sleep continuity.

In particular, many more children who underwent early adenotonsillectomy (79%) achieved normalization of the obstructive sleep apnea syndrome, compared with control subjects (46%) (N. Engl. J. Med. 2013 May 21 [doi:10.1056/NEJMoa1215881]).

Adenotonsillectomy also improved outcomes to a significantly greater degree than did watchful waiting on the Conners’ Rating Scale assessing restlessness, impulsiveness, and emotional lability, as well as on all other measures of behavior and quality of life. The effect sizes were in the moderate-to-large range, indicating that the changes were clinically significant.

These benefits were noted in all subgroup analyses, most importantly in both obese and nonobese children. Obese children and children with more severe apnea symptoms showed larger absolute improvements after surgery than did other study subjects.

However, normalization of symptoms was less likely to occur in black children than in those of other races, regardless of treatment assignment. Obstructive sleep apnea has previously been reported to be more severe in black children, as it was in this study population. Black subjects in this study also showed less improvement in parent- and teacher-reported measures after adenotonsillectomy, relative to children of other races.

"The reasons for this racial disparity are unclear. Possible explanations include differences in parents’ expectations, coping mechanisms, or perceptions of their child’s behavior and the presence of risk factors for behavioral problems unrelated to the obstructive sleep apnea syndrome," Dr. Marcus and her associates said.

Regarding adverse effects, the number of serious events was similar between the two study groups. Eight events were related to perioperative complications, but three of these occurred in children assigned to the watchful waiting group who later crossed over to the surgery group.

Overall, the rate of perioperative complications was low, and the only treatment failures in this study occurred in the watchful waiting group. "Thus, this trial supports the overall safety of both early adenotonsillectomy and watchful waiting, but suggests the need for clinical monitoring of children who are being treated conservatively," the researchers said.

They added that it is possible the 7-month follow-up was not long enough to demonstrate "the full response to surgery." It may be that the neurobehavioral sequelae of sleepiness resolve quickly but those related to hypoxemia may stem from neuronal damage and thus take longer to resolve.

This study was limited in that it excluded patients with prolonged oxyhemoglobin desaturation and those taking attention deficit/hyperactivity disorder medications. Therefore "the study results cannot be extrapolated to these vulnerable groups," Dr. Marcus and her colleagues said.

CHAT was supported by the National Institutes of Health. Dr. Marcus reported receiving research equipment from Philips Respironics and Ventus Medical; her associates reported numerous ties to industry sources.

Compared with watchful waiting, early adenotonsillectomy did not significantly improve attention or executive function as measured by neuropsychological testing in school-aged children with obstructive sleep apnea syndrome, according to a new report.

The findings were published online May 21 in the New England Journal of Medicine and simultaneously reported at the annual meeting of the American Thoracic Society.

However, early surgery did markedly improve polysomnographic abnormalities, as well as parent- and teacher-reported measures of behavior, executive function, and sleep symptoms, compared with watchful waiting, said Dr. Carole L. Marcus, director of the sleep center at Children’s Hospital of Philadelphia, and her associates.

"We observed no significant difference between the two groups in the change from baseline to follow-up in our primary outcome, the attention and executive-function score of the NEPSY [Developmental NeuroPsychological Assessment]; thus our trial is a negative one. However, other tests showed evidence of changes in behavior," noted Dr. Marcus and her associates in the Childhood Adenotonsillectomy Trial (CHAT).

Previous studies examining cognitive and behavioral outcomes after adenotonsillectomy for obstructive sleep apnea syndrome "have been limited by small samples, lack of randomization or appropriate controls, heterogenous study groups, and sole reliance on parent questionnaires rather than including neuropsychological testing," the investigators said.

In contrast, CHAT involved 453 children aged 5-9 years treated at seven academic sleep centers, who underwent standardized polysomnographic assessments and extensive testing via the Developmental Neuropsychological Assessment (NEPSY); Behavior Rating Inventory of Executive Function (BRIEF); Differential Ability Scales (DAS), which measures general intellectual functioning; Conners’ Rating Scale Revised (CRS-R); Pediatric Sleep Questionnaire sleep-related breathing disorder scale (PSQ-SRBD); Epworth Sleepiness Scale modified for children; Pediatric Quality of Life Inventory (PedsQL); and the Obstructive Sleep Apnea–18 assessment tool that measures disease-specific quality of life.

The children were randomly assigned to undergo adenotonsillectomy within 1 month (226 patients) or to be followed with watchful waiting (227 control subjects), and were formally assessed 7 months later. Demographic and clinical characteristics were well-balanced between the two study groups at baseline, and cognitive and behavioral scores were close to population means. A similar number of children in each group used nasal glucocorticoids or montelukast for allergic rhinitis or asthma.

Approximately half of the children in each group were overweight or obese.

The primary efficacy outcome was change in attention and executive-function score on the NEPSY. These scores improved more in children who underwent adenotonsillectomy than in the controls, but the difference did not reach statistical significance.

However, outcomes were significantly better with surgery than with watchful waiting on measures of obstructive apnea-hypopnea, oxygen desaturation index, hypercapnia, sleep arousal index, and percentage of sleep time in light sleep. This last measure is an indication of improved sleep continuity.

In particular, many more children who underwent early adenotonsillectomy (79%) achieved normalization of the obstructive sleep apnea syndrome, compared with control subjects (46%) (N. Engl. J. Med. 2013 May 21 [doi:10.1056/NEJMoa1215881]).

Adenotonsillectomy also improved outcomes to a significantly greater degree than did watchful waiting on the Conners’ Rating Scale assessing restlessness, impulsiveness, and emotional lability, as well as on all other measures of behavior and quality of life. The effect sizes were in the moderate-to-large range, indicating that the changes were clinically significant.

These benefits were noted in all subgroup analyses, most importantly in both obese and nonobese children. Obese children and children with more severe apnea symptoms showed larger absolute improvements after surgery than did other study subjects.

However, normalization of symptoms was less likely to occur in black children than in those of other races, regardless of treatment assignment. Obstructive sleep apnea has previously been reported to be more severe in black children, as it was in this study population. Black subjects in this study also showed less improvement in parent- and teacher-reported measures after adenotonsillectomy, relative to children of other races.

"The reasons for this racial disparity are unclear. Possible explanations include differences in parents’ expectations, coping mechanisms, or perceptions of their child’s behavior and the presence of risk factors for behavioral problems unrelated to the obstructive sleep apnea syndrome," Dr. Marcus and her associates said.

Regarding adverse effects, the number of serious events was similar between the two study groups. Eight events were related to perioperative complications, but three of these occurred in children assigned to the watchful waiting group who later crossed over to the surgery group.

Overall, the rate of perioperative complications was low, and the only treatment failures in this study occurred in the watchful waiting group. "Thus, this trial supports the overall safety of both early adenotonsillectomy and watchful waiting, but suggests the need for clinical monitoring of children who are being treated conservatively," the researchers said.

They added that it is possible the 7-month follow-up was not long enough to demonstrate "the full response to surgery." It may be that the neurobehavioral sequelae of sleepiness resolve quickly but those related to hypoxemia may stem from neuronal damage and thus take longer to resolve.

This study was limited in that it excluded patients with prolonged oxyhemoglobin desaturation and those taking attention deficit/hyperactivity disorder medications. Therefore "the study results cannot be extrapolated to these vulnerable groups," Dr. Marcus and her colleagues said.

CHAT was supported by the National Institutes of Health. Dr. Marcus reported receiving research equipment from Philips Respironics and Ventus Medical; her associates reported numerous ties to industry sources.

In patients with acute COPD exacerbations, 5-day systemic glucocorticoid therapy was as effective as a conventional 14-day course of the drugs at preventing further exacerbations, according to a report published online May 21 in JAMA.

In a multicenter, randomized clinical trial, the 6-month rate of recurrent COPD exacerbation was 35.9% among patients who received the short course of systemic glucocorticoids, which was noninferior to the 36.8% rate among those who received the usual 2-week course, said Dr. Jörg D. Leuppi of the University Hospital of Basel (Switzerland) and his associates (JAMA 2013 May 21 [doi:10.1001/jama.2013.5023]).

The short-term approach’s main advantage is its significant reduction of patients’ exposure to glucocorticoids, which in turn will likely decrease short-term adverse effects such as hyperglycemia, weight gain, increased blood pressure, and insomnia, the investigators said. The short course also should prevent or delay longer-term steroid toxicities such as diabetes, osteoporosis, bone fractures, adrenal suppression, and ocular complications.

The investigators performed the noninferiority trial, known as the REDUCE (Reduction in the Use of Corticosteroids in Exacerbated COPD) study, because no adequately powered, randomized clinical trial has compared directly the outcomes of these two treatment durations. Despite that, "it has become quite common clinical practice to administer glucocorticoids in COPD exacerbations for shorter periods," the study authors noted.

The REDUCE trial’s results were published online and simultaneously reported at the annual meeting of the American Thoracic Society.

The study included 311 consecutive patients who presented with COPD exacerbations to emergency departments at five Swiss teaching hospitals during a 5-year period. All patients were older than 40 years, were current or past smokers, and had a smoking history of 20 or more pack-years.

All the study subjects received 40 mg of IV methylprednisolone on day 1, followed by 40 mg of oral prednisone on days 2-5. On days 6-14, 155 patients were randomly assigned to continue receiving oral prednisone (conventional therapy) and 156 to receive a matching placebo (short-course therapy). Patients, caregivers, and researchers were blinded to group assignment.

All the patients also received a broad-spectrum antibiotic for 7 days to prevent pneumonia; nebulized short-acting bronchodilators as needed while hospitalized; inhaled glucocorticoids combined with an inhaled beta-agonist twice daily; and inhaled tiotropium once daily. They all also received physiotherapy, supplemental oxygen, and ventilatory support according to accepted guidelines.

Patients who received short-course glucocorticoid therapy had a median cumulative prednisone dose of 200 mg and a mean cumulative dose of 379 mg. In contrast, those who received a longer duration of treatment had a median cumulative prednisone dose of 560 mg and a mean cumulative dose of 793 mg.

After 180 days of follow-up, 56 (35.9%) of patients in the short-course therapy group and 57 (36.8%) in the conventional therapy group reached the primary endpoint of a recurrent COPD exacerbation. The time to recurrence did not differ between the two groups.

In addition, the hazard ratios for experiencing a recurrence were nearly identical between the two study groups in both an intention-to-treat analysis and a per-protocol analysis, "meeting our noninferiority criterion," Dr. Leuppi and his colleagues said.

The findings remained robust in sensitivity analyses that adjusted for variables such as patient age and sex. They also persisted in subgroup analyses that compared patients who had different severities of underlying COPD and different past histories of glucocorticoid use.

Overall survival was not significantly different between patients who received 5 days and those who received 14 days of systemic glucocorticoids. The short-course therapy group also showed no increase in the need for mechanical ventilation during hospitalization.

Measures of forced expiratory volume in 1 second improved significantly in both groups by day 6 and remained stable thereafter, with "almost no differences" between groups. Patients in both groups reported significantly ameliorated dyspnea, as well as similarly improved bronchitis-related quality of life and overall performance.

Regarding short-term adverse effects of exposure to glucocorticoids, rates of new or worsening hypertension and new or worsening hyperglycemia were comparable between the two study groups. "We surmise that the length of hospital stay was insufficient to detect significant differences in blood pressure and blood glucose levels between groups, because these glucocorticoid adverse effects do not develop immediately after initiation of treatment," the researchers said.

There also were no differences in longer-term toxicities such as rates of infection, gastrointestinal bleeding, insomnia, fractures, psychiatric symptoms, or heart failure.

A surprising finding was that patients who received short-term glucocorticoids had a significantly shorter hospital stay (median, 8 days) than did those who received conventional glucocorticoids (median, 9 days). "Because we did not observe significant differences in glucocorticoid-related, short-term adverse effects, we cannot readily explain this observation, which might be a chance finding," Dr. Leuppi and his associates said.

This study was supported by the University Hospital Basel, the Hospital Center of Biel-Bienne, Freiwilligen Akademische Gesellschaft, Fonds für Lehre und Forschung, AstraZeneca, Viollier Laboratory, and Gottfried und Julia Bangerter-Rhyner-Stiftung für Medizinische Forschung. Dr. Leuppi reported ties to these groups and Boehringer-Ingelheim, Chibret, Merck Sharp & Dohme, Novartis, Nycomed, and Pharmaxis, and his associates reported ties to numerous industry sources.

In patients with acute COPD exacerbations, 5-day systemic glucocorticoid therapy was as effective as a conventional 14-day course of the drugs at preventing further exacerbations, according to a report published online May 21 in JAMA.

In a multicenter, randomized clinical trial, the 6-month rate of recurrent COPD exacerbation was 35.9% among patients who received the short course of systemic glucocorticoids, which was noninferior to the 36.8% rate among those who received the usual 2-week course, said Dr. Jörg D. Leuppi of the University Hospital of Basel (Switzerland) and his associates (JAMA 2013 May 21 [doi:10.1001/jama.2013.5023]).

The short-term approach’s main advantage is its significant reduction of patients’ exposure to glucocorticoids, which in turn will likely decrease short-term adverse effects such as hyperglycemia, weight gain, increased blood pressure, and insomnia, the investigators said. The short course also should prevent or delay longer-term steroid toxicities such as diabetes, osteoporosis, bone fractures, adrenal suppression, and ocular complications.

The investigators performed the noninferiority trial, known as the REDUCE (Reduction in the Use of Corticosteroids in Exacerbated COPD) study, because no adequately powered, randomized clinical trial has compared directly the outcomes of these two treatment durations. Despite that, "it has become quite common clinical practice to administer glucocorticoids in COPD exacerbations for shorter periods," the study authors noted.

The REDUCE trial’s results were published online and simultaneously reported at the annual meeting of the American Thoracic Society.

The study included 311 consecutive patients who presented with COPD exacerbations to emergency departments at five Swiss teaching hospitals during a 5-year period. All patients were older than 40 years, were current or past smokers, and had a smoking history of 20 or more pack-years.

All the study subjects received 40 mg of IV methylprednisolone on day 1, followed by 40 mg of oral prednisone on days 2-5. On days 6-14, 155 patients were randomly assigned to continue receiving oral prednisone (conventional therapy) and 156 to receive a matching placebo (short-course therapy). Patients, caregivers, and researchers were blinded to group assignment.

All the patients also received a broad-spectrum antibiotic for 7 days to prevent pneumonia; nebulized short-acting bronchodilators as needed while hospitalized; inhaled glucocorticoids combined with an inhaled beta-agonist twice daily; and inhaled tiotropium once daily. They all also received physiotherapy, supplemental oxygen, and ventilatory support according to accepted guidelines.

Patients who received short-course glucocorticoid therapy had a median cumulative prednisone dose of 200 mg and a mean cumulative dose of 379 mg. In contrast, those who received a longer duration of treatment had a median cumulative prednisone dose of 560 mg and a mean cumulative dose of 793 mg.

After 180 days of follow-up, 56 (35.9%) of patients in the short-course therapy group and 57 (36.8%) in the conventional therapy group reached the primary endpoint of a recurrent COPD exacerbation. The time to recurrence did not differ between the two groups.

In addition, the hazard ratios for experiencing a recurrence were nearly identical between the two study groups in both an intention-to-treat analysis and a per-protocol analysis, "meeting our noninferiority criterion," Dr. Leuppi and his colleagues said.

The findings remained robust in sensitivity analyses that adjusted for variables such as patient age and sex. They also persisted in subgroup analyses that compared patients who had different severities of underlying COPD and different past histories of glucocorticoid use.

Overall survival was not significantly different between patients who received 5 days and those who received 14 days of systemic glucocorticoids. The short-course therapy group also showed no increase in the need for mechanical ventilation during hospitalization.

Measures of forced expiratory volume in 1 second improved significantly in both groups by day 6 and remained stable thereafter, with "almost no differences" between groups. Patients in both groups reported significantly ameliorated dyspnea, as well as similarly improved bronchitis-related quality of life and overall performance.

Regarding short-term adverse effects of exposure to glucocorticoids, rates of new or worsening hypertension and new or worsening hyperglycemia were comparable between the two study groups. "We surmise that the length of hospital stay was insufficient to detect significant differences in blood pressure and blood glucose levels between groups, because these glucocorticoid adverse effects do not develop immediately after initiation of treatment," the researchers said.

There also were no differences in longer-term toxicities such as rates of infection, gastrointestinal bleeding, insomnia, fractures, psychiatric symptoms, or heart failure.

A surprising finding was that patients who received short-term glucocorticoids had a significantly shorter hospital stay (median, 8 days) than did those who received conventional glucocorticoids (median, 9 days). "Because we did not observe significant differences in glucocorticoid-related, short-term adverse effects, we cannot readily explain this observation, which might be a chance finding," Dr. Leuppi and his associates said.

This study was supported by the University Hospital Basel, the Hospital Center of Biel-Bienne, Freiwilligen Akademische Gesellschaft, Fonds für Lehre und Forschung, AstraZeneca, Viollier Laboratory, and Gottfried und Julia Bangerter-Rhyner-Stiftung für Medizinische Forschung. Dr. Leuppi reported ties to these groups and Boehringer-Ingelheim, Chibret, Merck Sharp & Dohme, Novartis, Nycomed, and Pharmaxis, and his associates reported ties to numerous industry sources.

In patients with acute COPD exacerbations, 5-day systemic glucocorticoid therapy was as effective as a conventional 14-day course of the drugs at preventing further exacerbations, according to a report published online May 21 in JAMA.

In a multicenter, randomized clinical trial, the 6-month rate of recurrent COPD exacerbation was 35.9% among patients who received the short course of systemic glucocorticoids, which was noninferior to the 36.8% rate among those who received the usual 2-week course, said Dr. Jörg D. Leuppi of the University Hospital of Basel (Switzerland) and his associates (JAMA 2013 May 21 [doi:10.1001/jama.2013.5023]).

The short-term approach’s main advantage is its significant reduction of patients’ exposure to glucocorticoids, which in turn will likely decrease short-term adverse effects such as hyperglycemia, weight gain, increased blood pressure, and insomnia, the investigators said. The short course also should prevent or delay longer-term steroid toxicities such as diabetes, osteoporosis, bone fractures, adrenal suppression, and ocular complications.

The investigators performed the noninferiority trial, known as the REDUCE (Reduction in the Use of Corticosteroids in Exacerbated COPD) study, because no adequately powered, randomized clinical trial has compared directly the outcomes of these two treatment durations. Despite that, "it has become quite common clinical practice to administer glucocorticoids in COPD exacerbations for shorter periods," the study authors noted.

The REDUCE trial’s results were published online and simultaneously reported at the annual meeting of the American Thoracic Society.

The study included 311 consecutive patients who presented with COPD exacerbations to emergency departments at five Swiss teaching hospitals during a 5-year period. All patients were older than 40 years, were current or past smokers, and had a smoking history of 20 or more pack-years.

All the study subjects received 40 mg of IV methylprednisolone on day 1, followed by 40 mg of oral prednisone on days 2-5. On days 6-14, 155 patients were randomly assigned to continue receiving oral prednisone (conventional therapy) and 156 to receive a matching placebo (short-course therapy). Patients, caregivers, and researchers were blinded to group assignment.

All the patients also received a broad-spectrum antibiotic for 7 days to prevent pneumonia; nebulized short-acting bronchodilators as needed while hospitalized; inhaled glucocorticoids combined with an inhaled beta-agonist twice daily; and inhaled tiotropium once daily. They all also received physiotherapy, supplemental oxygen, and ventilatory support according to accepted guidelines.

Patients who received short-course glucocorticoid therapy had a median cumulative prednisone dose of 200 mg and a mean cumulative dose of 379 mg. In contrast, those who received a longer duration of treatment had a median cumulative prednisone dose of 560 mg and a mean cumulative dose of 793 mg.

After 180 days of follow-up, 56 (35.9%) of patients in the short-course therapy group and 57 (36.8%) in the conventional therapy group reached the primary endpoint of a recurrent COPD exacerbation. The time to recurrence did not differ between the two groups.

In addition, the hazard ratios for experiencing a recurrence were nearly identical between the two study groups in both an intention-to-treat analysis and a per-protocol analysis, "meeting our noninferiority criterion," Dr. Leuppi and his colleagues said.

The findings remained robust in sensitivity analyses that adjusted for variables such as patient age and sex. They also persisted in subgroup analyses that compared patients who had different severities of underlying COPD and different past histories of glucocorticoid use.

Overall survival was not significantly different between patients who received 5 days and those who received 14 days of systemic glucocorticoids. The short-course therapy group also showed no increase in the need for mechanical ventilation during hospitalization.

Measures of forced expiratory volume in 1 second improved significantly in both groups by day 6 and remained stable thereafter, with "almost no differences" between groups. Patients in both groups reported significantly ameliorated dyspnea, as well as similarly improved bronchitis-related quality of life and overall performance.

Regarding short-term adverse effects of exposure to glucocorticoids, rates of new or worsening hypertension and new or worsening hyperglycemia were comparable between the two study groups. "We surmise that the length of hospital stay was insufficient to detect significant differences in blood pressure and blood glucose levels between groups, because these glucocorticoid adverse effects do not develop immediately after initiation of treatment," the researchers said.

There also were no differences in longer-term toxicities such as rates of infection, gastrointestinal bleeding, insomnia, fractures, psychiatric symptoms, or heart failure.

A surprising finding was that patients who received short-term glucocorticoids had a significantly shorter hospital stay (median, 8 days) than did those who received conventional glucocorticoids (median, 9 days). "Because we did not observe significant differences in glucocorticoid-related, short-term adverse effects, we cannot readily explain this observation, which might be a chance finding," Dr. Leuppi and his associates said.

This study was supported by the University Hospital Basel, the Hospital Center of Biel-Bienne, Freiwilligen Akademische Gesellschaft, Fonds für Lehre und Forschung, AstraZeneca, Viollier Laboratory, and Gottfried und Julia Bangerter-Rhyner-Stiftung für Medizinische Forschung. Dr. Leuppi reported ties to these groups and Boehringer-Ingelheim, Chibret, Merck Sharp & Dohme, Novartis, Nycomed, and Pharmaxis, and his associates reported ties to numerous industry sources.

A common polymorphism in the promoter of a mucin gene, MUC5B rs35705950, is significantly associated with improved survival in patients who have idiopathic pulmonary fibrosis, according to a report published online May 21 in JAMA.

The 2-year cumulative rate of death was lower among IPF patients who carried one or more copies of this variant than in those who did not in a cohort of 438 patients, and this finding was replicated in a validation cohort of another 148 patients, said Anna L. Peljto, Dr.P.H., of the department of epidemiology, University of Colorado School of Public Health, Denver, and her associates.

Their report was published simultaneously with its presentation at the annual meeting of the American Thoracic Society.

Paradoxically, this same polymorphism was previously reported to be strongly associated with the development of both sporadic IPF and familial interstitial pneumonia, and is considered a risk allele for these disorders.

It is not yet known how the MUC5B rs35705950 polymorphism confers a survival advantage in IPF, but "enhanced mucosal host defense, reduction in infectious complications, a beneficial drug response, and a potential dual role in wound repair should all be considered," the investigators said.

"Regardless of the mechanism, the results suggest that patients with IPF with the MUC5B promoter polymorphism may represent a pathogenically distinct disease entity that incorporates both a significantly higher predisposition to disease and a significantly longer survival," they noted.

Dr. Peljto and her colleagues examined whether carrying this variant affected survival by analyzing data on 438 patients who participated in a 3-year study of interferon treatment for IPF. A total of 37% of study participants were found to carry the MUC5B polymorphism.

The unadjusted 2-year cumulative incidence of death was lower in patients who carried one or more copies of the variant than in those who did not.

The researchers then assessed the polymorphism in a second population: 148 patients treated at the interstitial lung disease clinic at the University of Chicago beginning in the late 2000s and followed for a median of 1.6 years. The frequency of the MUC5B polymorphism was 39%, similar to that in the first cohort.

The unadjusted cumulative incidence of death also was significantly lower in patients who carried the genetic variant in this cohort.

The data from both groups were pooled and adjusted for patient age, sex, smoking history, forced vital capacity at baseline, and diffusing capacity of carbon monoxide at baseline.

"The MUC5B genotype remained a statistically significant predictor of survival," Dr. Peljto and her associates said.

The data were adjusted further to account for study subjects’ plasma concentrations of matrix metalloproteinase-7 (MMP-7); high levels of this substance are associated with poor outcomes in IPF. The association between the MUC5B polymorphism and improved survival remained constant in this analysis.

"This study is, to our knowledge, the first to demonstrate that a genetic variant is associated with survival in IPF," the researchers said (JAMA 2013 May 21 [doi:10.1001/jama.2013.5827]).

However, it would be premature to consider routine clinical genotyping of IPF patients at this time, "given that the addition of MUC5B resulted in relatively small gains in predictive accuracy in patients with established disease."

It may be helpful to combine the predictive value of MUC5B with other genetic and molecular factors to obtain a prognosis in patients who have subclinical or early-stage disease, before lung function has declined notably. "This is especially important because there are currently no IPF pharmalogical therapies approved for use in the United States, and opportunities for early genetic counseling or lung transplantation may be a patient’s only recourse," the investigators said.

This study was supported by the National Heart, Lung, and Blood Institute and the Dorothy P. and Richard P. Simmons Endowed Chair for Pulmonary Research at the University of Pittsburgh. Dr. Peljto reported no relevant financial conflicts; her associates reported numerous ties to industry sources.

A common polymorphism in the promoter of a mucin gene, MUC5B rs35705950, is significantly associated with improved survival in patients who have idiopathic pulmonary fibrosis, according to a report published online May 21 in JAMA.

The 2-year cumulative rate of death was lower among IPF patients who carried one or more copies of this variant than in those who did not in a cohort of 438 patients, and this finding was replicated in a validation cohort of another 148 patients, said Anna L. Peljto, Dr.P.H., of the department of epidemiology, University of Colorado School of Public Health, Denver, and her associates.

Their report was published simultaneously with its presentation at the annual meeting of the American Thoracic Society.

Paradoxically, this same polymorphism was previously reported to be strongly associated with the development of both sporadic IPF and familial interstitial pneumonia, and is considered a risk allele for these disorders.

It is not yet known how the MUC5B rs35705950 polymorphism confers a survival advantage in IPF, but "enhanced mucosal host defense, reduction in infectious complications, a beneficial drug response, and a potential dual role in wound repair should all be considered," the investigators said.

"Regardless of the mechanism, the results suggest that patients with IPF with the MUC5B promoter polymorphism may represent a pathogenically distinct disease entity that incorporates both a significantly higher predisposition to disease and a significantly longer survival," they noted.

Dr. Peljto and her colleagues examined whether carrying this variant affected survival by analyzing data on 438 patients who participated in a 3-year study of interferon treatment for IPF. A total of 37% of study participants were found to carry the MUC5B polymorphism.

The unadjusted 2-year cumulative incidence of death was lower in patients who carried one or more copies of the variant than in those who did not.

The researchers then assessed the polymorphism in a second population: 148 patients treated at the interstitial lung disease clinic at the University of Chicago beginning in the late 2000s and followed for a median of 1.6 years. The frequency of the MUC5B polymorphism was 39%, similar to that in the first cohort.

The unadjusted cumulative incidence of death also was significantly lower in patients who carried the genetic variant in this cohort.

The data from both groups were pooled and adjusted for patient age, sex, smoking history, forced vital capacity at baseline, and diffusing capacity of carbon monoxide at baseline.

"The MUC5B genotype remained a statistically significant predictor of survival," Dr. Peljto and her associates said.

The data were adjusted further to account for study subjects’ plasma concentrations of matrix metalloproteinase-7 (MMP-7); high levels of this substance are associated with poor outcomes in IPF. The association between the MUC5B polymorphism and improved survival remained constant in this analysis.

"This study is, to our knowledge, the first to demonstrate that a genetic variant is associated with survival in IPF," the researchers said (JAMA 2013 May 21 [doi:10.1001/jama.2013.5827]).

However, it would be premature to consider routine clinical genotyping of IPF patients at this time, "given that the addition of MUC5B resulted in relatively small gains in predictive accuracy in patients with established disease."

It may be helpful to combine the predictive value of MUC5B with other genetic and molecular factors to obtain a prognosis in patients who have subclinical or early-stage disease, before lung function has declined notably. "This is especially important because there are currently no IPF pharmalogical therapies approved for use in the United States, and opportunities for early genetic counseling or lung transplantation may be a patient’s only recourse," the investigators said.

This study was supported by the National Heart, Lung, and Blood Institute and the Dorothy P. and Richard P. Simmons Endowed Chair for Pulmonary Research at the University of Pittsburgh. Dr. Peljto reported no relevant financial conflicts; her associates reported numerous ties to industry sources.

A common polymorphism in the promoter of a mucin gene, MUC5B rs35705950, is significantly associated with improved survival in patients who have idiopathic pulmonary fibrosis, according to a report published online May 21 in JAMA.

The 2-year cumulative rate of death was lower among IPF patients who carried one or more copies of this variant than in those who did not in a cohort of 438 patients, and this finding was replicated in a validation cohort of another 148 patients, said Anna L. Peljto, Dr.P.H., of the department of epidemiology, University of Colorado School of Public Health, Denver, and her associates.

Their report was published simultaneously with its presentation at the annual meeting of the American Thoracic Society.

Paradoxically, this same polymorphism was previously reported to be strongly associated with the development of both sporadic IPF and familial interstitial pneumonia, and is considered a risk allele for these disorders.

It is not yet known how the MUC5B rs35705950 polymorphism confers a survival advantage in IPF, but "enhanced mucosal host defense, reduction in infectious complications, a beneficial drug response, and a potential dual role in wound repair should all be considered," the investigators said.

"Regardless of the mechanism, the results suggest that patients with IPF with the MUC5B promoter polymorphism may represent a pathogenically distinct disease entity that incorporates both a significantly higher predisposition to disease and a significantly longer survival," they noted.

Dr. Peljto and her colleagues examined whether carrying this variant affected survival by analyzing data on 438 patients who participated in a 3-year study of interferon treatment for IPF. A total of 37% of study participants were found to carry the MUC5B polymorphism.

The unadjusted 2-year cumulative incidence of death was lower in patients who carried one or more copies of the variant than in those who did not.

The researchers then assessed the polymorphism in a second population: 148 patients treated at the interstitial lung disease clinic at the University of Chicago beginning in the late 2000s and followed for a median of 1.6 years. The frequency of the MUC5B polymorphism was 39%, similar to that in the first cohort.

The unadjusted cumulative incidence of death also was significantly lower in patients who carried the genetic variant in this cohort.

The data from both groups were pooled and adjusted for patient age, sex, smoking history, forced vital capacity at baseline, and diffusing capacity of carbon monoxide at baseline.

"The MUC5B genotype remained a statistically significant predictor of survival," Dr. Peljto and her associates said.

The data were adjusted further to account for study subjects’ plasma concentrations of matrix metalloproteinase-7 (MMP-7); high levels of this substance are associated with poor outcomes in IPF. The association between the MUC5B polymorphism and improved survival remained constant in this analysis.

"This study is, to our knowledge, the first to demonstrate that a genetic variant is associated with survival in IPF," the researchers said (JAMA 2013 May 21 [doi:10.1001/jama.2013.5827]).

However, it would be premature to consider routine clinical genotyping of IPF patients at this time, "given that the addition of MUC5B resulted in relatively small gains in predictive accuracy in patients with established disease."

It may be helpful to combine the predictive value of MUC5B with other genetic and molecular factors to obtain a prognosis in patients who have subclinical or early-stage disease, before lung function has declined notably. "This is especially important because there are currently no IPF pharmalogical therapies approved for use in the United States, and opportunities for early genetic counseling or lung transplantation may be a patient’s only recourse," the investigators said.

This study was supported by the National Heart, Lung, and Blood Institute and the Dorothy P. and Richard P. Simmons Endowed Chair for Pulmonary Research at the University of Pittsburgh. Dr. Peljto reported no relevant financial conflicts; her associates reported numerous ties to industry sources.

Dupilumab reduced exacerbations of moderate to severe asthma by 87% in adults with poorly controlled disease, and induced rapid and sustained improvements in numerous other measures of asthma severity in an industry-sponsored phase II study published online May 21 in the New England Journal of Medicine.

Dupilumab, a monoclonal antibody that inhibits interleukin-4 and interleukin-13 signaling, "showed substantial efficacy with regard to both objective and patient-reported end points" when it was used concomitantly with inhaled glucocorticoids and long-acting beta-agonists (LABAs), as well as when those background therapies were withdrawn, reported Dr. Sally Wenzel of the University of Pittsburgh and her associates.

"The magnitude and breadth of efficacy that we observed exceed those in other studies of Th2 [type 2 helper T-cell] cytokine inhibition," the researchers noted in the online report, which was presented simultaneously at the annual meeting of the American Thoracic Society.

Dupilumab currently is being assessed for the treatment of several diseases mediated by Th2 pathways. The goal of this phase II trial was to evaluate its safety and efficacy in adults with persistent moderate to severe asthma and elevated eosinophil levels whose symptoms were not well controlled with medium- to high-dose inhaled glucocorticoids plus LABAs (usually fluticasone and salmeterol).

The 104 participants were treated at 28 sites across the United States for 12 weeks, and then followed for another 8 weeks. During the intervention phase of the study, approximately half were randomized to receive once-weekly subcutaneous injections of dupilumab (300 mg) and half to receive matching placebo injections, in addition to the background asthma medications.

At week 4, the study subjects discontinued LABAs, and at weeks 6-9 they tapered off inhaled glucocorticoids. "This approach enabled us to observe the effects of dupilumab when added to background therapy, after LABA discontinuation, during the tapering of inhaled glucocorticoids, and as monotherapy," the researchers said.

The primary endpoint of the study was an asthma exacerbation during the 12-week intervention period. Exacerbations occurred in 3 patients receiving dupilumab (6%), compared with 23 receiving placebo (44%), a highly significant difference.

In addition, the time to an asthma exacerbation was significantly longer with dupilumab than placebo. And forced expiratory volume in 1 second (FEV₁) "improved by more than 200 mL when dupilumab, as compared with placebo, was added to inhaled glucocorticoids and LABAs, an increase sustained during their tapering and discontinuation," the researchers noted (N. Engl. J. Med. 2013 May 21 [doi: 10.1056/NEJMoa1304048]).

Several other secondary endpoints also favored dupilumab over placebo, including morning peak expiratory flow values, scores on the Asthma Control Questionnaire (ACQ5), morning and evening asthma symptom scores, and the number of albuterol or levalbuterol inhalations needed per day. These measures improved at the beginning of the intervention in both study groups, then quickly returned to baseline levels in the placebo group while remaining constant in the dupilumab group.

The percentage of patients reporting adverse events was similar between the dupilumab and placebo groups (81% vs. 77%). These events tended to be nonspecific and mild, and included nasopharyngitis, nausea, and headache. One patient developed a progressive papular rash, urticaria, and edema after his ninth injection of dupilumab, which responded to nonurgent treatment of the symptoms and did not recur once the drug was withdrawn.

No serious adverse events were attributed to the study drug, and no patient showed clinically significant changes in vital signs, findings on physical examination, laboratory tests, or ECGs.

"Further studies are needed to confirm these observations and better define the target population, dosing regimen, and long-term efficacy and safety," Dr. Wenzel noted.

However, the study findings support the theory that the Th2 cytokines interleukin-4 and interleukin-13 play a pathogenic role in persistent, moderate-to-severe asthma, she added.

This study was funded by Sanofi and Regeneron Pharmaceuticals. Dr. Wenzel reported ties to Sanofi, Regeneron, Amgen, Merck, and other companies. Her associates reported ties to numerous industry sources.

Dupilumab reduced exacerbations of moderate to severe asthma by 87% in adults with poorly controlled disease, and induced rapid and sustained improvements in numerous other measures of asthma severity in an industry-sponsored phase II study published online May 21 in the New England Journal of Medicine.

Dupilumab, a monoclonal antibody that inhibits interleukin-4 and interleukin-13 signaling, "showed substantial efficacy with regard to both objective and patient-reported end points" when it was used concomitantly with inhaled glucocorticoids and long-acting beta-agonists (LABAs), as well as when those background therapies were withdrawn, reported Dr. Sally Wenzel of the University of Pittsburgh and her associates.

"The magnitude and breadth of efficacy that we observed exceed those in other studies of Th2 [type 2 helper T-cell] cytokine inhibition," the researchers noted in the online report, which was presented simultaneously at the annual meeting of the American Thoracic Society.

Dupilumab currently is being assessed for the treatment of several diseases mediated by Th2 pathways. The goal of this phase II trial was to evaluate its safety and efficacy in adults with persistent moderate to severe asthma and elevated eosinophil levels whose symptoms were not well controlled with medium- to high-dose inhaled glucocorticoids plus LABAs (usually fluticasone and salmeterol).

The 104 participants were treated at 28 sites across the United States for 12 weeks, and then followed for another 8 weeks. During the intervention phase of the study, approximately half were randomized to receive once-weekly subcutaneous injections of dupilumab (300 mg) and half to receive matching placebo injections, in addition to the background asthma medications.

At week 4, the study subjects discontinued LABAs, and at weeks 6-9 they tapered off inhaled glucocorticoids. "This approach enabled us to observe the effects of dupilumab when added to background therapy, after LABA discontinuation, during the tapering of inhaled glucocorticoids, and as monotherapy," the researchers said.

The primary endpoint of the study was an asthma exacerbation during the 12-week intervention period. Exacerbations occurred in 3 patients receiving dupilumab (6%), compared with 23 receiving placebo (44%), a highly significant difference.

In addition, the time to an asthma exacerbation was significantly longer with dupilumab than placebo. And forced expiratory volume in 1 second (FEV₁) "improved by more than 200 mL when dupilumab, as compared with placebo, was added to inhaled glucocorticoids and LABAs, an increase sustained during their tapering and discontinuation," the researchers noted (N. Engl. J. Med. 2013 May 21 [doi: 10.1056/NEJMoa1304048]).

Several other secondary endpoints also favored dupilumab over placebo, including morning peak expiratory flow values, scores on the Asthma Control Questionnaire (ACQ5), morning and evening asthma symptom scores, and the number of albuterol or levalbuterol inhalations needed per day. These measures improved at the beginning of the intervention in both study groups, then quickly returned to baseline levels in the placebo group while remaining constant in the dupilumab group.

The percentage of patients reporting adverse events was similar between the dupilumab and placebo groups (81% vs. 77%). These events tended to be nonspecific and mild, and included nasopharyngitis, nausea, and headache. One patient developed a progressive papular rash, urticaria, and edema after his ninth injection of dupilumab, which responded to nonurgent treatment of the symptoms and did not recur once the drug was withdrawn.

No serious adverse events were attributed to the study drug, and no patient showed clinically significant changes in vital signs, findings on physical examination, laboratory tests, or ECGs.

"Further studies are needed to confirm these observations and better define the target population, dosing regimen, and long-term efficacy and safety," Dr. Wenzel noted.

However, the study findings support the theory that the Th2 cytokines interleukin-4 and interleukin-13 play a pathogenic role in persistent, moderate-to-severe asthma, she added.

This study was funded by Sanofi and Regeneron Pharmaceuticals. Dr. Wenzel reported ties to Sanofi, Regeneron, Amgen, Merck, and other companies. Her associates reported ties to numerous industry sources.

Dupilumab reduced exacerbations of moderate to severe asthma by 87% in adults with poorly controlled disease, and induced rapid and sustained improvements in numerous other measures of asthma severity in an industry-sponsored phase II study published online May 21 in the New England Journal of Medicine.

Dupilumab, a monoclonal antibody that inhibits interleukin-4 and interleukin-13 signaling, "showed substantial efficacy with regard to both objective and patient-reported end points" when it was used concomitantly with inhaled glucocorticoids and long-acting beta-agonists (LABAs), as well as when those background therapies were withdrawn, reported Dr. Sally Wenzel of the University of Pittsburgh and her associates.

"The magnitude and breadth of efficacy that we observed exceed those in other studies of Th2 [type 2 helper T-cell] cytokine inhibition," the researchers noted in the online report, which was presented simultaneously at the annual meeting of the American Thoracic Society.

Dupilumab currently is being assessed for the treatment of several diseases mediated by Th2 pathways. The goal of this phase II trial was to evaluate its safety and efficacy in adults with persistent moderate to severe asthma and elevated eosinophil levels whose symptoms were not well controlled with medium- to high-dose inhaled glucocorticoids plus LABAs (usually fluticasone and salmeterol).

The 104 participants were treated at 28 sites across the United States for 12 weeks, and then followed for another 8 weeks. During the intervention phase of the study, approximately half were randomized to receive once-weekly subcutaneous injections of dupilumab (300 mg) and half to receive matching placebo injections, in addition to the background asthma medications.

At week 4, the study subjects discontinued LABAs, and at weeks 6-9 they tapered off inhaled glucocorticoids. "This approach enabled us to observe the effects of dupilumab when added to background therapy, after LABA discontinuation, during the tapering of inhaled glucocorticoids, and as monotherapy," the researchers said.

The primary endpoint of the study was an asthma exacerbation during the 12-week intervention period. Exacerbations occurred in 3 patients receiving dupilumab (6%), compared with 23 receiving placebo (44%), a highly significant difference.

In addition, the time to an asthma exacerbation was significantly longer with dupilumab than placebo. And forced expiratory volume in 1 second (FEV₁) "improved by more than 200 mL when dupilumab, as compared with placebo, was added to inhaled glucocorticoids and LABAs, an increase sustained during their tapering and discontinuation," the researchers noted (N. Engl. J. Med. 2013 May 21 [doi: 10.1056/NEJMoa1304048]).

Several other secondary endpoints also favored dupilumab over placebo, including morning peak expiratory flow values, scores on the Asthma Control Questionnaire (ACQ5), morning and evening asthma symptom scores, and the number of albuterol or levalbuterol inhalations needed per day. These measures improved at the beginning of the intervention in both study groups, then quickly returned to baseline levels in the placebo group while remaining constant in the dupilumab group.

The percentage of patients reporting adverse events was similar between the dupilumab and placebo groups (81% vs. 77%). These events tended to be nonspecific and mild, and included nasopharyngitis, nausea, and headache. One patient developed a progressive papular rash, urticaria, and edema after his ninth injection of dupilumab, which responded to nonurgent treatment of the symptoms and did not recur once the drug was withdrawn.

No serious adverse events were attributed to the study drug, and no patient showed clinically significant changes in vital signs, findings on physical examination, laboratory tests, or ECGs.

"Further studies are needed to confirm these observations and better define the target population, dosing regimen, and long-term efficacy and safety," Dr. Wenzel noted.

However, the study findings support the theory that the Th2 cytokines interleukin-4 and interleukin-13 play a pathogenic role in persistent, moderate-to-severe asthma, she added.

This study was funded by Sanofi and Regeneron Pharmaceuticals. Dr. Wenzel reported ties to Sanofi, Regeneron, Amgen, Merck, and other companies. Her associates reported ties to numerous industry sources.

Among patients receiving an implantable cardioverter-defibrillator for primary prevention who don’t have indications for pacing, the use of a dual-chamber rather than a single-chamber ICD doesn’t appear to confer any advantage, according to a report in the May 15 issue of JAMA.

In a nationwide retrospective cohort study involving over 32,000 such patients, there was no significant difference between patients who received single-chamber devices and those who received dual-chamber devices in 1-year mortality, rate of hospitalization for any cause, or rate of hospitalization for heart failure, said Dr. Pamela N. Peterson of the Denver Health Medical Center, and her associates.

However, there was an important disadvantage with the dual-chamber ICDs: They carried a higher rate of complications such as infection and lead displacement. They also were more costly than were single-chamber devices because placement is more complex, and time-consuming and later mechanical dysfunction is more common.

"Therefore, among patients without clear pacing indications, the decision to implant a dual-chamber ICD for primary prevention should be considered carefully," Dr. Peterson and her colleagues said.

They performed this cohort study because of the "lack of clarity" regarding the long-term safety and outcomes of dual-chamber ICDs compared with single-chamber ICDs. "Despite the absence of compelling evidence to support these more costly devices ... current practice is highly variable," they noted.

The investigators used data from the National Cardiovascular Data Registry’s ICD component to identify 32,034 patients who received ICDs at 1,270 hospitals across the country during 2006-2009. A total of 19,788 (62%) received a dual-chamber device and 12,246 (38%) a single-chamber device.

All of these study subjects received the ICDs for primary prevention only, and none had any indications for pacing.

The initial data analysis examined rates of any serious complications, including pneumothorax requiring a chest tube (within 30 days of the placement), hematoma requiring a blood transfusion or evacuation (within 30 days), cardiac tamponade (within 30 days), lead revision (within 90 days), device-related infection (within 90 days), and recurrent ICD implantation (within 90 days).

The unadjusted rate of any such complications were significantly higher with dual-chamber ICDs. The largest difference between single- and dual-chamber devices occurred with the most common complication in this study: mechanical dysfunction of the ICD requiring repeat operation for system revision.

At 1 year, the unadjusted rates of hospitalization for heart failure (14.7% vs 15.5%), of hospitalization for all causes (43.8% vs. 44.9%), and of mortality (9.9% vs. 10.1%) were similar between patients who received a single-chamber device and those who received a dual-chamber device.

The investigators then performed a propensity-matched analysis involving 11,619 patients who received a single-chamber and the same number who received a dual-chamber ICD. In this analysis, the rate of serious complications also was significantly lower with single-chamber devices (3.5%) than with dual-chamber devices (4.7%), with the largest absolute difference again occurring in mechanical complications requiring system revision.

Again, rates of all-cause hospitalization, heart failure hospitalization, and mortality were comparable between the two study groups at 1 year, the investigators said (JAMA 2013;309:2025-34).

The results remained consistent in further analyses of clinically important subgroups of patients, regardless of age, sex, or the presence or absence of renal dysfunction at the time of operation.

These findings indicate that dual-chamber ICDs "do not appear to offer any clinical benefit" over single-chamber ICDs, at least with regard to death or hospital readmission, Dr. Peterson and her associates said.

Their study was limited in that it could not address other important outcomes, such as patients’ quality of life or the development of atrial fibrillation, because no data were available regarding these factors.

This study was supported by the Agency for Healthcare Research and Quality and the American College of Cardiology Foundation’s National Cardiovascular Data Registry. Dr. Peterson reported no financial conflicts of interest; one of her associates reported receiving grant money from Boston Scientific.

Among patients receiving an implantable cardioverter-defibrillator for primary prevention who don’t have indications for pacing, the use of a dual-chamber rather than a single-chamber ICD doesn’t appear to confer any advantage, according to a report in the May 15 issue of JAMA.

In a nationwide retrospective cohort study involving over 32,000 such patients, there was no significant difference between patients who received single-chamber devices and those who received dual-chamber devices in 1-year mortality, rate of hospitalization for any cause, or rate of hospitalization for heart failure, said Dr. Pamela N. Peterson of the Denver Health Medical Center, and her associates.

However, there was an important disadvantage with the dual-chamber ICDs: They carried a higher rate of complications such as infection and lead displacement. They also were more costly than were single-chamber devices because placement is more complex, and time-consuming and later mechanical dysfunction is more common.

"Therefore, among patients without clear pacing indications, the decision to implant a dual-chamber ICD for primary prevention should be considered carefully," Dr. Peterson and her colleagues said.

They performed this cohort study because of the "lack of clarity" regarding the long-term safety and outcomes of dual-chamber ICDs compared with single-chamber ICDs. "Despite the absence of compelling evidence to support these more costly devices ... current practice is highly variable," they noted.

The investigators used data from the National Cardiovascular Data Registry’s ICD component to identify 32,034 patients who received ICDs at 1,270 hospitals across the country during 2006-2009. A total of 19,788 (62%) received a dual-chamber device and 12,246 (38%) a single-chamber device.

All of these study subjects received the ICDs for primary prevention only, and none had any indications for pacing.

The initial data analysis examined rates of any serious complications, including pneumothorax requiring a chest tube (within 30 days of the placement), hematoma requiring a blood transfusion or evacuation (within 30 days), cardiac tamponade (within 30 days), lead revision (within 90 days), device-related infection (within 90 days), and recurrent ICD implantation (within 90 days).

The unadjusted rate of any such complications were significantly higher with dual-chamber ICDs. The largest difference between single- and dual-chamber devices occurred with the most common complication in this study: mechanical dysfunction of the ICD requiring repeat operation for system revision.

At 1 year, the unadjusted rates of hospitalization for heart failure (14.7% vs 15.5%), of hospitalization for all causes (43.8% vs. 44.9%), and of mortality (9.9% vs. 10.1%) were similar between patients who received a single-chamber device and those who received a dual-chamber device.

The investigators then performed a propensity-matched analysis involving 11,619 patients who received a single-chamber and the same number who received a dual-chamber ICD. In this analysis, the rate of serious complications also was significantly lower with single-chamber devices (3.5%) than with dual-chamber devices (4.7%), with the largest absolute difference again occurring in mechanical complications requiring system revision.

Again, rates of all-cause hospitalization, heart failure hospitalization, and mortality were comparable between the two study groups at 1 year, the investigators said (JAMA 2013;309:2025-34).

The results remained consistent in further analyses of clinically important subgroups of patients, regardless of age, sex, or the presence or absence of renal dysfunction at the time of operation.

These findings indicate that dual-chamber ICDs "do not appear to offer any clinical benefit" over single-chamber ICDs, at least with regard to death or hospital readmission, Dr. Peterson and her associates said.

Their study was limited in that it could not address other important outcomes, such as patients’ quality of life or the development of atrial fibrillation, because no data were available regarding these factors.

This study was supported by the Agency for Healthcare Research and Quality and the American College of Cardiology Foundation’s National Cardiovascular Data Registry. Dr. Peterson reported no financial conflicts of interest; one of her associates reported receiving grant money from Boston Scientific.

Among patients receiving an implantable cardioverter-defibrillator for primary prevention who don’t have indications for pacing, the use of a dual-chamber rather than a single-chamber ICD doesn’t appear to confer any advantage, according to a report in the May 15 issue of JAMA.

In a nationwide retrospective cohort study involving over 32,000 such patients, there was no significant difference between patients who received single-chamber devices and those who received dual-chamber devices in 1-year mortality, rate of hospitalization for any cause, or rate of hospitalization for heart failure, said Dr. Pamela N. Peterson of the Denver Health Medical Center, and her associates.

However, there was an important disadvantage with the dual-chamber ICDs: They carried a higher rate of complications such as infection and lead displacement. They also were more costly than were single-chamber devices because placement is more complex, and time-consuming and later mechanical dysfunction is more common.

"Therefore, among patients without clear pacing indications, the decision to implant a dual-chamber ICD for primary prevention should be considered carefully," Dr. Peterson and her colleagues said.

They performed this cohort study because of the "lack of clarity" regarding the long-term safety and outcomes of dual-chamber ICDs compared with single-chamber ICDs. "Despite the absence of compelling evidence to support these more costly devices ... current practice is highly variable," they noted.

The investigators used data from the National Cardiovascular Data Registry’s ICD component to identify 32,034 patients who received ICDs at 1,270 hospitals across the country during 2006-2009. A total of 19,788 (62%) received a dual-chamber device and 12,246 (38%) a single-chamber device.

All of these study subjects received the ICDs for primary prevention only, and none had any indications for pacing.

The initial data analysis examined rates of any serious complications, including pneumothorax requiring a chest tube (within 30 days of the placement), hematoma requiring a blood transfusion or evacuation (within 30 days), cardiac tamponade (within 30 days), lead revision (within 90 days), device-related infection (within 90 days), and recurrent ICD implantation (within 90 days).

The unadjusted rate of any such complications were significantly higher with dual-chamber ICDs. The largest difference between single- and dual-chamber devices occurred with the most common complication in this study: mechanical dysfunction of the ICD requiring repeat operation for system revision.

At 1 year, the unadjusted rates of hospitalization for heart failure (14.7% vs 15.5%), of hospitalization for all causes (43.8% vs. 44.9%), and of mortality (9.9% vs. 10.1%) were similar between patients who received a single-chamber device and those who received a dual-chamber device.

The investigators then performed a propensity-matched analysis involving 11,619 patients who received a single-chamber and the same number who received a dual-chamber ICD. In this analysis, the rate of serious complications also was significantly lower with single-chamber devices (3.5%) than with dual-chamber devices (4.7%), with the largest absolute difference again occurring in mechanical complications requiring system revision.

Again, rates of all-cause hospitalization, heart failure hospitalization, and mortality were comparable between the two study groups at 1 year, the investigators said (JAMA 2013;309:2025-34).

The results remained consistent in further analyses of clinically important subgroups of patients, regardless of age, sex, or the presence or absence of renal dysfunction at the time of operation.

These findings indicate that dual-chamber ICDs "do not appear to offer any clinical benefit" over single-chamber ICDs, at least with regard to death or hospital readmission, Dr. Peterson and her associates said.

Their study was limited in that it could not address other important outcomes, such as patients’ quality of life or the development of atrial fibrillation, because no data were available regarding these factors.

This study was supported by the Agency for Healthcare Research and Quality and the American College of Cardiology Foundation’s National Cardiovascular Data Registry. Dr. Peterson reported no financial conflicts of interest; one of her associates reported receiving grant money from Boston Scientific.

Abdominal sacrocolpopexy, with or without concomitant urethropexy, "is less effective than desired" for long-term treatment of pelvic organ prolapse, according to a report in the May 15 issue of JAMA.

In extended follow-up of 215 women who had undergone the surgery in 2001-2006 to correct pelvic organ prolapse (POP), nearly one-third of the procedures had failed at the 7-year mark. And for women whose surgery involved the placement of synthetic mesh, the estimated probability of mesh erosion was 10.5%, said Dr. Ingrid Nygaard of the University of Utah, Salt Lake City, and her associates.

Nevertheless, only 5% of the women in this study sought retreatment for POP – a result that the investigators interpreted to mean that the procedures had addressed their symptoms adequately.

"Based on our results, women considering abdominal sacrocolpopexy should be counseled that this procedure effectively provides relief from POP symptoms; however, the anatomic support deteriorates over time," they said.

"Surgical counseling about the ongoing risk of mesh-related events even for abdominal sacrocolpopexy is critical. Women should be aware that symptoms such as vaginal bleeding, discharge, and pain may be due to mesh erosion and should seek help accordingly," the researchers noted (JAMA 2013;309:2016-24).

Even though some 225,000 women in the United States undergo POP surgeries every year, "little is known about long-term durability, complications, and pelvic floor symptoms" associated with the procedure. To examine the issue, Dr. Nygaard and her colleagues performed an extended follow-up of women who had participated in the CARE (Colpopexy and Urinary Reduction Efforts) trial, which concluded in 2006.

CARE was a multicenter trial funded by the National Institutes of Health in which 322 women who did not have stress urinary incontinence and were undergoing abdominal sacrocolpopexy were randomly assigned to concomitant Burch urethropexy (to prevent the common postoperative adverse effect of stress urinary incontinence) or to serve as controls. At 2 years, the incidence of stress urinary incontinence was 32.0% in women who had the prophylactic urethropexy, significantly lower than the 45.2% incidence in the control group.

Dr. Nygaard and her associates were able to follow up on 215 of these CARE participants up to 7 years later. "We were surprised by the magnitude of treatment failure rates," they said.

"By year 7, the estimated probabilities of treatment failure for the urethropexy group and the no urethropexy group, respectively, were 0.27 and 0.22 for anatomic pelvic organ prolapse, 0.29 and 0.24 for symptomatic pelvic organ prolapse, and 0.48 and 0.34 for composite pelvic organ prolapse," the investigators said.

The estimated probability that in a few years the women would develop stress urinary incontinence was 0.62 for those who had undergone urethropexy specifically to prevent that adverse effect and 0.77 for those who had not undergone urethropexy.

In addition, by year 7, 4 women had suture erosion and 23 had mesh erosion. Mesh erosion occurred with every type of mesh that had been placed.

"By year 7, at least 36 of 215 women (16.7%) ... had additional surgery related to pelvic floor disorders: 11 for recurrent POP, 14 for stress urinary incontinence, and 11 for mesh complications," the investigators said.

Their findings have three important implications.

"First, as a criterion standard for surgical treatment of POP, abdominal sacrocolpopexy is less effective than desired.

"For this study, we chose a clinically relevant definition of anatomic failure that some would argue is still not stringent enough, yet by 5 years, nearly one-third of women met our composite failure definition," they noted.

Nevertheless, the procedure generally appears to relieve POP symptoms, even though anatomic support wanes. Only 5% of the study population sought retreatment for POP, which "may imply that women found the treatment adequate," Dr. Nygaard and her colleagues said.

Second, "surgical prevention of stress urinary incontinence at the time of abdominal POP surgery involves no clinically significant trade-offs to date." Adding an anti–urinary-incontinence procedure to sacrocolpopexy decreases but does not eliminate the risk that such incontinence will develop.

And third, mesh-related complications continue to develop over time. "Long-term follow-up is mandatory to understand the long-term patient burden associated with surgical materials and devices," they said.

One limitation of this study was that participants at some sites could not be followed at all, and participants at other sites could only be followed by telephone interview rather than physical examination, because research funding for that purpose was not renewed over time.

The researchers added that clinical practice has shifted since the original CARE trial was conducted; midurethral slings are now more commonplace, and sacrocolpopexy now is often performed via laparoscopic or even robotic approaches. "It is unclear to what degree [our] results can be extrapolated to the newer procedures because we only evaluated open abdominal sacrocolpopexy and Burch urethropexy."

The extended CARE study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Office of Research on Women’s Health at the National Institutes of Health. Dr. Nygaard reported no financial conflicts of interest; some of her associates reported ties to Johnson & Johnson, Key Tech, Pelvalon, Astellas, Pfizer, Warner Chilcott, GlaxoSmithKline, Uromedica, IDEO, Xanodyne, and Intuitive Surgical.

Abdominal sacrocolpopexy, with or without concomitant urethropexy, "is less effective than desired" for long-term treatment of pelvic organ prolapse, according to a report in the May 15 issue of JAMA.

In extended follow-up of 215 women who had undergone the surgery in 2001-2006 to correct pelvic organ prolapse (POP), nearly one-third of the procedures had failed at the 7-year mark. And for women whose surgery involved the placement of synthetic mesh, the estimated probability of mesh erosion was 10.5%, said Dr. Ingrid Nygaard of the University of Utah, Salt Lake City, and her associates.

Nevertheless, only 5% of the women in this study sought retreatment for POP – a result that the investigators interpreted to mean that the procedures had addressed their symptoms adequately.

"Based on our results, women considering abdominal sacrocolpopexy should be counseled that this procedure effectively provides relief from POP symptoms; however, the anatomic support deteriorates over time," they said.

"Surgical counseling about the ongoing risk of mesh-related events even for abdominal sacrocolpopexy is critical. Women should be aware that symptoms such as vaginal bleeding, discharge, and pain may be due to mesh erosion and should seek help accordingly," the researchers noted (JAMA 2013;309:2016-24).

Even though some 225,000 women in the United States undergo POP surgeries every year, "little is known about long-term durability, complications, and pelvic floor symptoms" associated with the procedure. To examine the issue, Dr. Nygaard and her colleagues performed an extended follow-up of women who had participated in the CARE (Colpopexy and Urinary Reduction Efforts) trial, which concluded in 2006.

CARE was a multicenter trial funded by the National Institutes of Health in which 322 women who did not have stress urinary incontinence and were undergoing abdominal sacrocolpopexy were randomly assigned to concomitant Burch urethropexy (to prevent the common postoperative adverse effect of stress urinary incontinence) or to serve as controls. At 2 years, the incidence of stress urinary incontinence was 32.0% in women who had the prophylactic urethropexy, significantly lower than the 45.2% incidence in the control group.

Dr. Nygaard and her associates were able to follow up on 215 of these CARE participants up to 7 years later. "We were surprised by the magnitude of treatment failure rates," they said.

"By year 7, the estimated probabilities of treatment failure for the urethropexy group and the no urethropexy group, respectively, were 0.27 and 0.22 for anatomic pelvic organ prolapse, 0.29 and 0.24 for symptomatic pelvic organ prolapse, and 0.48 and 0.34 for composite pelvic organ prolapse," the investigators said.

The estimated probability that in a few years the women would develop stress urinary incontinence was 0.62 for those who had undergone urethropexy specifically to prevent that adverse effect and 0.77 for those who had not undergone urethropexy.

In addition, by year 7, 4 women had suture erosion and 23 had mesh erosion. Mesh erosion occurred with every type of mesh that had been placed.

"By year 7, at least 36 of 215 women (16.7%) ... had additional surgery related to pelvic floor disorders: 11 for recurrent POP, 14 for stress urinary incontinence, and 11 for mesh complications," the investigators said.

Their findings have three important implications.

"First, as a criterion standard for surgical treatment of POP, abdominal sacrocolpopexy is less effective than desired.

"For this study, we chose a clinically relevant definition of anatomic failure that some would argue is still not stringent enough, yet by 5 years, nearly one-third of women met our composite failure definition," they noted.

Nevertheless, the procedure generally appears to relieve POP symptoms, even though anatomic support wanes. Only 5% of the study population sought retreatment for POP, which "may imply that women found the treatment adequate," Dr. Nygaard and her colleagues said.

Second, "surgical prevention of stress urinary incontinence at the time of abdominal POP surgery involves no clinically significant trade-offs to date." Adding an anti–urinary-incontinence procedure to sacrocolpopexy decreases but does not eliminate the risk that such incontinence will develop.

And third, mesh-related complications continue to develop over time. "Long-term follow-up is mandatory to understand the long-term patient burden associated with surgical materials and devices," they said.

One limitation of this study was that participants at some sites could not be followed at all, and participants at other sites could only be followed by telephone interview rather than physical examination, because research funding for that purpose was not renewed over time.

The researchers added that clinical practice has shifted since the original CARE trial was conducted; midurethral slings are now more commonplace, and sacrocolpopexy now is often performed via laparoscopic or even robotic approaches. "It is unclear to what degree [our] results can be extrapolated to the newer procedures because we only evaluated open abdominal sacrocolpopexy and Burch urethropexy."

The extended CARE study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Office of Research on Women’s Health at the National Institutes of Health. Dr. Nygaard reported no financial conflicts of interest; some of her associates reported ties to Johnson & Johnson, Key Tech, Pelvalon, Astellas, Pfizer, Warner Chilcott, GlaxoSmithKline, Uromedica, IDEO, Xanodyne, and Intuitive Surgical.

Abdominal sacrocolpopexy, with or without concomitant urethropexy, "is less effective than desired" for long-term treatment of pelvic organ prolapse, according to a report in the May 15 issue of JAMA.

In extended follow-up of 215 women who had undergone the surgery in 2001-2006 to correct pelvic organ prolapse (POP), nearly one-third of the procedures had failed at the 7-year mark. And for women whose surgery involved the placement of synthetic mesh, the estimated probability of mesh erosion was 10.5%, said Dr. Ingrid Nygaard of the University of Utah, Salt Lake City, and her associates.

Nevertheless, only 5% of the women in this study sought retreatment for POP – a result that the investigators interpreted to mean that the procedures had addressed their symptoms adequately.

"Based on our results, women considering abdominal sacrocolpopexy should be counseled that this procedure effectively provides relief from POP symptoms; however, the anatomic support deteriorates over time," they said.

"Surgical counseling about the ongoing risk of mesh-related events even for abdominal sacrocolpopexy is critical. Women should be aware that symptoms such as vaginal bleeding, discharge, and pain may be due to mesh erosion and should seek help accordingly," the researchers noted (JAMA 2013;309:2016-24).

Even though some 225,000 women in the United States undergo POP surgeries every year, "little is known about long-term durability, complications, and pelvic floor symptoms" associated with the procedure. To examine the issue, Dr. Nygaard and her colleagues performed an extended follow-up of women who had participated in the CARE (Colpopexy and Urinary Reduction Efforts) trial, which concluded in 2006.

CARE was a multicenter trial funded by the National Institutes of Health in which 322 women who did not have stress urinary incontinence and were undergoing abdominal sacrocolpopexy were randomly assigned to concomitant Burch urethropexy (to prevent the common postoperative adverse effect of stress urinary incontinence) or to serve as controls. At 2 years, the incidence of stress urinary incontinence was 32.0% in women who had the prophylactic urethropexy, significantly lower than the 45.2% incidence in the control group.

Dr. Nygaard and her associates were able to follow up on 215 of these CARE participants up to 7 years later. "We were surprised by the magnitude of treatment failure rates," they said.

"By year 7, the estimated probabilities of treatment failure for the urethropexy group and the no urethropexy group, respectively, were 0.27 and 0.22 for anatomic pelvic organ prolapse, 0.29 and 0.24 for symptomatic pelvic organ prolapse, and 0.48 and 0.34 for composite pelvic organ prolapse," the investigators said.

The estimated probability that in a few years the women would develop stress urinary incontinence was 0.62 for those who had undergone urethropexy specifically to prevent that adverse effect and 0.77 for those who had not undergone urethropexy.

In addition, by year 7, 4 women had suture erosion and 23 had mesh erosion. Mesh erosion occurred with every type of mesh that had been placed.

"By year 7, at least 36 of 215 women (16.7%) ... had additional surgery related to pelvic floor disorders: 11 for recurrent POP, 14 for stress urinary incontinence, and 11 for mesh complications," the investigators said.

Their findings have three important implications.

"First, as a criterion standard for surgical treatment of POP, abdominal sacrocolpopexy is less effective than desired.

"For this study, we chose a clinically relevant definition of anatomic failure that some would argue is still not stringent enough, yet by 5 years, nearly one-third of women met our composite failure definition," they noted.

Nevertheless, the procedure generally appears to relieve POP symptoms, even though anatomic support wanes. Only 5% of the study population sought retreatment for POP, which "may imply that women found the treatment adequate," Dr. Nygaard and her colleagues said.

Second, "surgical prevention of stress urinary incontinence at the time of abdominal POP surgery involves no clinically significant trade-offs to date." Adding an anti–urinary-incontinence procedure to sacrocolpopexy decreases but does not eliminate the risk that such incontinence will develop.

And third, mesh-related complications continue to develop over time. "Long-term follow-up is mandatory to understand the long-term patient burden associated with surgical materials and devices," they said.

One limitation of this study was that participants at some sites could not be followed at all, and participants at other sites could only be followed by telephone interview rather than physical examination, because research funding for that purpose was not renewed over time.

The researchers added that clinical practice has shifted since the original CARE trial was conducted; midurethral slings are now more commonplace, and sacrocolpopexy now is often performed via laparoscopic or even robotic approaches. "It is unclear to what degree [our] results can be extrapolated to the newer procedures because we only evaluated open abdominal sacrocolpopexy and Burch urethropexy."

The extended CARE study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Office of Research on Women’s Health at the National Institutes of Health. Dr. Nygaard reported no financial conflicts of interest; some of her associates reported ties to Johnson & Johnson, Key Tech, Pelvalon, Astellas, Pfizer, Warner Chilcott, GlaxoSmithKline, Uromedica, IDEO, Xanodyne, and Intuitive Surgical.

Primary care clinicians should screen all patients aged 18 years and older for "alcohol misuse" and provide brief behavioral counseling to patients identified as having a drinking problem, according to an updated recommendation statement from the U. S. Preventive Services Task Force.

The recommendations also put greater emphasis on screening for less risky but still hazardous patterns of alcohol use.

The most recent literature shows that the USPSTF’s suggested approach reduces these patients’ weekly alcohol consumption, promotes short- and long-term adherence to recommended drinking limits, and decreases binge drinking, according to the statement, which was published online May 14 in the Annals of Internal Medicine (Ann Intern Med. 14 May 2013 [doi:10.7326/0003-4819-159-3-201308060-00652].)

©thinkstockphotos.com

"Alcohol misuse" covers a spectrum of behaviors, ranging from "risky use" at the less severe end of the scale (for example, drinking more than the recommended daily, weekly, or per-occasion amounts), to "alcohol dependence" at the more severe end (for example, experiencing physical cravings and withdrawal symptoms).

The USPSTF last issued alcohol screening recommendations in 2004. The latest updates were spurred by evidence that has accumulated since 2004 showing that several brief screening tools and brief behavioral counseling interventions are effective in the primary care setting.

The new recommendations clarify the concept of alcohol misuse to include less-severe but still hazardous drinking behaviors. In fact, most of the current research concerning alcohol focuses entirely on this end of the spectrum, said Dr. Virginia A. Moyer, chair of the USPSTF and vice president for maintenance of certification and quality at the American Board of Pediatrics, and her associates.

The task force highlighted the evidence backing screening in adults, but it cautioned against extending the approach to younger populations.

The new research data show "with high certainty" that screening adults in the primary care setting for alcohol misuse and providing brief behavioral counseling interventions for those found to be engaging in risky or hazardous drinking will yield a moderate benefit – both for individual patients and for the general public.

However, the current evidence is insufficient to support this approach among adolescents. The data are lacking, of poor quality, or are conflicting, the group noted. Thus, the balance of benefits and harms cannot be determined for screening and offering behavioral counseling to adolescents in the primary care setting.

Numerous screening instruments have been developed that detect alcohol misuse among patients aged 18 years and older with good sensitivity and specificity. The three tools of choice for primary care physicians are the Alcohol Use Disorders Identification Test (AUDIT), the abbreviated AUDIT-Consumption (AUDIT-C), and a single-question screening.

The AUDIT is the most widely studied of these tools. It includes 10 questions and requires an estimated 2-5 minutes to administer. AUDIT-C includes three questions and requires 1-2 minutes to administer. Both have good sensitivity and specificity for detecting the full spectrum of alcohol misuse.

Both instruments are available from the Substance Abuse and Mental Health Services Administration at www.integration.samhsa.gov/clinical-practice/screening-tools.

The single-question screen has "adequate" sensitivity and specificity, and requires less than 1 minute to administer. For example, the National Institute on Alcohol Abuse and Alcoholism recommends simply asking patients, "How many times in the past year have you had at least five [for men] or four [for women and people older than 65 years] drinks in 1 day?"

Notably, the Cut-Down, Annoyed, Guilty, and Eye-Opener (CAGE) questionnaire has often been used by primary physicians "as a low-burden screening tool for alcohol disorders." However, that instrument "has comparatively poor sensitivity for identifying risky or hazardous drinking, particularly among older adults (only 14%-39%) and pregnant women (38%-49%)," Dr. Moyer and her associates said.

The optimal interval for rescreening patients cannot be determined yet, because the evidence is lacking, they added.

There are several behavioral counseling interventions that can be used by the primary care physician for any adult patients who test positive on these screens. Interventions often include cognitive behavioral techniques such as keeping drinking diaries and formulating action plans. They can be administered face-to-face or via written self-help materials, computer- or Web-based programs, or telephone counseling.

The most effective approaches use brief, multiple contacts – a series of interactions with the patient that last from 6 to 15 minutes each. Very brief (less than 5 minutes) single or multiple contacts appear to be less effective, as do extended (longer than 15 minutes) single or multiple contacts.

There is good evidence that brief counseling interventions can induce patients to reduce their weekly alcohol consumption and adhere to recommended drinking limits, both in the short term and long term. They also decrease the proportion of patients who engage in episodes of heavy (binge) drinking, which in turn reduces the likelihood of traumatic injury or death, particularly involving motor vehicles.

The task force cautions, however, that these brief counseling interventions usually are not effective for the more severe forms of alcohol misuse.

Those include abuse, which is characterized by drinking that leads to recurrent failure in major home, work, or school responsibilities; drinking in physically hazardous situations, such as when operating heavy machinery; or having alcohol-related legal or social problems. Severe forms of alcohol misuse also include dependence, characterized by physical cravings and withdrawal symptoms; frequent drinking in larger amounts than intended over longer periods; and the need for markedly increased amounts of alcohol to achieve intoxication.

For this update, the USPSTF did not evaluate interventions – such as pharmacotherapy and outpatient treatment programs – for these higher levels of severity. "But the benefits of specialty treatment are well established and recommended" for such patients, Dr. Moyer and her colleagues said.

Reprints of the updated recommendations are available here.

No potential conflicts of interest were reported. The USPSTF is funded by the Agency for Healthcare Research and Quality under a congressional mandate. The voluntary group of clinicians and public health experts is independent of the federal government, and it compiles recommendations about preventive care for a range of health conditions.

Primary care clinicians should screen all patients aged 18 years and older for "alcohol misuse" and provide brief behavioral counseling to patients identified as having a drinking problem, according to an updated recommendation statement from the U. S. Preventive Services Task Force.

The recommendations also put greater emphasis on screening for less risky but still hazardous patterns of alcohol use.

The most recent literature shows that the USPSTF’s suggested approach reduces these patients’ weekly alcohol consumption, promotes short- and long-term adherence to recommended drinking limits, and decreases binge drinking, according to the statement, which was published online May 14 in the Annals of Internal Medicine (Ann Intern Med. 14 May 2013 [doi:10.7326/0003-4819-159-3-201308060-00652].)

©thinkstockphotos.com

"Alcohol misuse" covers a spectrum of behaviors, ranging from "risky use" at the less severe end of the scale (for example, drinking more than the recommended daily, weekly, or per-occasion amounts), to "alcohol dependence" at the more severe end (for example, experiencing physical cravings and withdrawal symptoms).

The USPSTF last issued alcohol screening recommendations in 2004. The latest updates were spurred by evidence that has accumulated since 2004 showing that several brief screening tools and brief behavioral counseling interventions are effective in the primary care setting.

The new recommendations clarify the concept of alcohol misuse to include less-severe but still hazardous drinking behaviors. In fact, most of the current research concerning alcohol focuses entirely on this end of the spectrum, said Dr. Virginia A. Moyer, chair of the USPSTF and vice president for maintenance of certification and quality at the American Board of Pediatrics, and her associates.

The task force highlighted the evidence backing screening in adults, but it cautioned against extending the approach to younger populations.

The new research data show "with high certainty" that screening adults in the primary care setting for alcohol misuse and providing brief behavioral counseling interventions for those found to be engaging in risky or hazardous drinking will yield a moderate benefit – both for individual patients and for the general public.

However, the current evidence is insufficient to support this approach among adolescents. The data are lacking, of poor quality, or are conflicting, the group noted. Thus, the balance of benefits and harms cannot be determined for screening and offering behavioral counseling to adolescents in the primary care setting.

Numerous screening instruments have been developed that detect alcohol misuse among patients aged 18 years and older with good sensitivity and specificity. The three tools of choice for primary care physicians are the Alcohol Use Disorders Identification Test (AUDIT), the abbreviated AUDIT-Consumption (AUDIT-C), and a single-question screening.

The AUDIT is the most widely studied of these tools. It includes 10 questions and requires an estimated 2-5 minutes to administer. AUDIT-C includes three questions and requires 1-2 minutes to administer. Both have good sensitivity and specificity for detecting the full spectrum of alcohol misuse.

Both instruments are available from the Substance Abuse and Mental Health Services Administration at www.integration.samhsa.gov/clinical-practice/screening-tools.

The single-question screen has "adequate" sensitivity and specificity, and requires less than 1 minute to administer. For example, the National Institute on Alcohol Abuse and Alcoholism recommends simply asking patients, "How many times in the past year have you had at least five [for men] or four [for women and people older than 65 years] drinks in 1 day?"

Notably, the Cut-Down, Annoyed, Guilty, and Eye-Opener (CAGE) questionnaire has often been used by primary physicians "as a low-burden screening tool for alcohol disorders." However, that instrument "has comparatively poor sensitivity for identifying risky or hazardous drinking, particularly among older adults (only 14%-39%) and pregnant women (38%-49%)," Dr. Moyer and her associates said.

The optimal interval for rescreening patients cannot be determined yet, because the evidence is lacking, they added.

There are several behavioral counseling interventions that can be used by the primary care physician for any adult patients who test positive on these screens. Interventions often include cognitive behavioral techniques such as keeping drinking diaries and formulating action plans. They can be administered face-to-face or via written self-help materials, computer- or Web-based programs, or telephone counseling.

The most effective approaches use brief, multiple contacts – a series of interactions with the patient that last from 6 to 15 minutes each. Very brief (less than 5 minutes) single or multiple contacts appear to be less effective, as do extended (longer than 15 minutes) single or multiple contacts.

There is good evidence that brief counseling interventions can induce patients to reduce their weekly alcohol consumption and adhere to recommended drinking limits, both in the short term and long term. They also decrease the proportion of patients who engage in episodes of heavy (binge) drinking, which in turn reduces the likelihood of traumatic injury or death, particularly involving motor vehicles.

The task force cautions, however, that these brief counseling interventions usually are not effective for the more severe forms of alcohol misuse.

Those include abuse, which is characterized by drinking that leads to recurrent failure in major home, work, or school responsibilities; drinking in physically hazardous situations, such as when operating heavy machinery; or having alcohol-related legal or social problems. Severe forms of alcohol misuse also include dependence, characterized by physical cravings and withdrawal symptoms; frequent drinking in larger amounts than intended over longer periods; and the need for markedly increased amounts of alcohol to achieve intoxication.

For this update, the USPSTF did not evaluate interventions – such as pharmacotherapy and outpatient treatment programs – for these higher levels of severity. "But the benefits of specialty treatment are well established and recommended" for such patients, Dr. Moyer and her colleagues said.

Reprints of the updated recommendations are available here.

No potential conflicts of interest were reported. The USPSTF is funded by the Agency for Healthcare Research and Quality under a congressional mandate. The voluntary group of clinicians and public health experts is independent of the federal government, and it compiles recommendations about preventive care for a range of health conditions.

Primary care clinicians should screen all patients aged 18 years and older for "alcohol misuse" and provide brief behavioral counseling to patients identified as having a drinking problem, according to an updated recommendation statement from the U. S. Preventive Services Task Force.

The recommendations also put greater emphasis on screening for less risky but still hazardous patterns of alcohol use.

The most recent literature shows that the USPSTF’s suggested approach reduces these patients’ weekly alcohol consumption, promotes short- and long-term adherence to recommended drinking limits, and decreases binge drinking, according to the statement, which was published online May 14 in the Annals of Internal Medicine (Ann Intern Med. 14 May 2013 [doi:10.7326/0003-4819-159-3-201308060-00652].)

©thinkstockphotos.com

"Alcohol misuse" covers a spectrum of behaviors, ranging from "risky use" at the less severe end of the scale (for example, drinking more than the recommended daily, weekly, or per-occasion amounts), to "alcohol dependence" at the more severe end (for example, experiencing physical cravings and withdrawal symptoms).

The USPSTF last issued alcohol screening recommendations in 2004. The latest updates were spurred by evidence that has accumulated since 2004 showing that several brief screening tools and brief behavioral counseling interventions are effective in the primary care setting.

The new recommendations clarify the concept of alcohol misuse to include less-severe but still hazardous drinking behaviors. In fact, most of the current research concerning alcohol focuses entirely on this end of the spectrum, said Dr. Virginia A. Moyer, chair of the USPSTF and vice president for maintenance of certification and quality at the American Board of Pediatrics, and her associates.

The task force highlighted the evidence backing screening in adults, but it cautioned against extending the approach to younger populations.

The new research data show "with high certainty" that screening adults in the primary care setting for alcohol misuse and providing brief behavioral counseling interventions for those found to be engaging in risky or hazardous drinking will yield a moderate benefit – both for individual patients and for the general public.

However, the current evidence is insufficient to support this approach among adolescents. The data are lacking, of poor quality, or are conflicting, the group noted. Thus, the balance of benefits and harms cannot be determined for screening and offering behavioral counseling to adolescents in the primary care setting.

Numerous screening instruments have been developed that detect alcohol misuse among patients aged 18 years and older with good sensitivity and specificity. The three tools of choice for primary care physicians are the Alcohol Use Disorders Identification Test (AUDIT), the abbreviated AUDIT-Consumption (AUDIT-C), and a single-question screening.

The AUDIT is the most widely studied of these tools. It includes 10 questions and requires an estimated 2-5 minutes to administer. AUDIT-C includes three questions and requires 1-2 minutes to administer. Both have good sensitivity and specificity for detecting the full spectrum of alcohol misuse.

Both instruments are available from the Substance Abuse and Mental Health Services Administration at www.integration.samhsa.gov/clinical-practice/screening-tools.

The single-question screen has "adequate" sensitivity and specificity, and requires less than 1 minute to administer. For example, the National Institute on Alcohol Abuse and Alcoholism recommends simply asking patients, "How many times in the past year have you had at least five [for men] or four [for women and people older than 65 years] drinks in 1 day?"

Notably, the Cut-Down, Annoyed, Guilty, and Eye-Opener (CAGE) questionnaire has often been used by primary physicians "as a low-burden screening tool for alcohol disorders." However, that instrument "has comparatively poor sensitivity for identifying risky or hazardous drinking, particularly among older adults (only 14%-39%) and pregnant women (38%-49%)," Dr. Moyer and her associates said.

The optimal interval for rescreening patients cannot be determined yet, because the evidence is lacking, they added.

There are several behavioral counseling interventions that can be used by the primary care physician for any adult patients who test positive on these screens. Interventions often include cognitive behavioral techniques such as keeping drinking diaries and formulating action plans. They can be administered face-to-face or via written self-help materials, computer- or Web-based programs, or telephone counseling.

The most effective approaches use brief, multiple contacts – a series of interactions with the patient that last from 6 to 15 minutes each. Very brief (less than 5 minutes) single or multiple contacts appear to be less effective, as do extended (longer than 15 minutes) single or multiple contacts.

There is good evidence that brief counseling interventions can induce patients to reduce their weekly alcohol consumption and adhere to recommended drinking limits, both in the short term and long term. They also decrease the proportion of patients who engage in episodes of heavy (binge) drinking, which in turn reduces the likelihood of traumatic injury or death, particularly involving motor vehicles.

The task force cautions, however, that these brief counseling interventions usually are not effective for the more severe forms of alcohol misuse.

Those include abuse, which is characterized by drinking that leads to recurrent failure in major home, work, or school responsibilities; drinking in physically hazardous situations, such as when operating heavy machinery; or having alcohol-related legal or social problems. Severe forms of alcohol misuse also include dependence, characterized by physical cravings and withdrawal symptoms; frequent drinking in larger amounts than intended over longer periods; and the need for markedly increased amounts of alcohol to achieve intoxication.

For this update, the USPSTF did not evaluate interventions – such as pharmacotherapy and outpatient treatment programs – for these higher levels of severity. "But the benefits of specialty treatment are well established and recommended" for such patients, Dr. Moyer and her colleagues said.

Reprints of the updated recommendations are available here.

No potential conflicts of interest were reported. The USPSTF is funded by the Agency for Healthcare Research and Quality under a congressional mandate. The voluntary group of clinicians and public health experts is independent of the federal government, and it compiles recommendations about preventive care for a range of health conditions.

Preclinical beta-amyloid deposition in the brains of cognitively normal volunteers was associated with poor sleep quality but not sleep quantity in a study published in the May issue of JAMA Neurology (formerly Archives of Neurology).

"Our findings support the hypothesis that sleep-wake abnormalities are associated with the presence of amyloid deposition in the preclinical stage of AD [Alzheimer’s disease]," wrote Dr. Yo-El Ju of the Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, and her associates.

In addition, "our findings may expand the temporal window during which sleep abnormalities are identifiable and potentially modifiable in AD," they noted.

©Silvia Jansen/iStockphoto

Dr. Ju and her colleagues observed that sleep-wake problems are common in AD, and that early in its course, the disease affects brain regions and pathways important for sleep and wake mechanisms. "Even in mild cognitive impairment, or very mild dementia, there are abnormalities in sleep architecture and electroencephalography measures.

The investigators assessed the sleep of 142 research volunteers aged 45-75 years (mean age, 66 years) using 2 weeks of actigraphy and sleep diary records. They recorded total sleep time, sleep efficiency (sleep time divided by time in bed), and wake time after sleep onset. Some had a parental history of symptomatic AD and were participating in longitudinal studies of healthy aging and dementia. All the study subjects scored 0 on the Clinical Dementia Rating.

Overall, 32 participants (22.5%) had a cerebrospinal fluid level of amyloid beta 42 of less than 500 pg/mL, indicating a strong likelihood of amyloid deposition in the brain.

Study subjects with a strong likelihood of amyloid deposition had significantly worse sleep efficiency (80.4% vs. 83.7%) than did those without amyloid deposition. This association remained significant when the data were adjusted to correct for age, sex, and apolipoprotein E epsilon-4 allele carrier status.

This difference in sleep efficiency also was significant in a subgroup analysis involving only the 100 study subjects who reported that their sleep had not changed during the preceding 5 years.

Wake time after sleep onset also was significantly higher (worse) among subjects with a strong likelihood of amyloid deposition than it was among those without it (63.1 min vs. 54 min).

In contrast, there were no differences between these two study groups in sleep quantity.

The participants with amyloid deposition showed a trend for spending more nonsleeping time in bed, but the trend didn’t reach statistical significance. Similarly, they reported taking more naps per week, but the difference between the groups’ average number of naps didn’t reach statistical significance.

However, "when we looked at the proportion of frequent nappers, defined as those taking naps on 3 or more days per week, this was significantly higher in the group with amyloid deposition, compared with the group without amyloid deposition (31.2% vs. 14.7%)," Dr. Ju and her associates wrote (JAMA Neurol. 2013;70:587-93).

This study could not determine causality. Amyloid deposition could cause sleep-wake disruption through several mechanisms, such as direct interference with neuronal function in areas of the brain that are critical for sleep. But poor sleep could just as well contribute to amyloid deposition, such as by increasing neuronal activity to a pathological degree, which is thought to facilitate deposition. It is likely that both of these processes play a role in a kind of positive feedback loop, the investigators said.

The findings of this study lay important groundwork for future research. "Longitudinal follow-up with ongoing measurement of amyloid and sleep should enable us to begin to tease apart the details of the abnormalities in sleep that begin to occur with the onset of AD pathology, as well as the directionality of the relationship between sleep and amyloid deposition," they noted.

If sleep disruption is found to raise the risk of future AD, "then this provides an even stronger motivation to identify and treat individuals with sleep disorders, such as obstructive sleep apnea," Dr. Ju and her colleagues added.

This study was supported by grants from the U.S. National Institutes of Health, the Ellison Medical Foundation Senior Scholar Award, and the National Center for Research Resources. Dr. Ju reported no financial conflicts of interest, but some of her associates reported ties to UCB, Jazz Pharmaceuticals, and other companies.

Preclinical beta-amyloid deposition in the brains of cognitively normal volunteers was associated with poor sleep quality but not sleep quantity in a study published in the May issue of JAMA Neurology (formerly Archives of Neurology).

"Our findings support the hypothesis that sleep-wake abnormalities are associated with the presence of amyloid deposition in the preclinical stage of AD [Alzheimer’s disease]," wrote Dr. Yo-El Ju of the Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, and her associates.

In addition, "our findings may expand the temporal window during which sleep abnormalities are identifiable and potentially modifiable in AD," they noted.

©Silvia Jansen/iStockphoto

Dr. Ju and her colleagues observed that sleep-wake problems are common in AD, and that early in its course, the disease affects brain regions and pathways important for sleep and wake mechanisms. "Even in mild cognitive impairment, or very mild dementia, there are abnormalities in sleep architecture and electroencephalography measures.

The investigators assessed the sleep of 142 research volunteers aged 45-75 years (mean age, 66 years) using 2 weeks of actigraphy and sleep diary records. They recorded total sleep time, sleep efficiency (sleep time divided by time in bed), and wake time after sleep onset. Some had a parental history of symptomatic AD and were participating in longitudinal studies of healthy aging and dementia. All the study subjects scored 0 on the Clinical Dementia Rating.

Overall, 32 participants (22.5%) had a cerebrospinal fluid level of amyloid beta 42 of less than 500 pg/mL, indicating a strong likelihood of amyloid deposition in the brain.

Study subjects with a strong likelihood of amyloid deposition had significantly worse sleep efficiency (80.4% vs. 83.7%) than did those without amyloid deposition. This association remained significant when the data were adjusted to correct for age, sex, and apolipoprotein E epsilon-4 allele carrier status.

This difference in sleep efficiency also was significant in a subgroup analysis involving only the 100 study subjects who reported that their sleep had not changed during the preceding 5 years.

Wake time after sleep onset also was significantly higher (worse) among subjects with a strong likelihood of amyloid deposition than it was among those without it (63.1 min vs. 54 min).

In contrast, there were no differences between these two study groups in sleep quantity.

The participants with amyloid deposition showed a trend for spending more nonsleeping time in bed, but the trend didn’t reach statistical significance. Similarly, they reported taking more naps per week, but the difference between the groups’ average number of naps didn’t reach statistical significance.

However, "when we looked at the proportion of frequent nappers, defined as those taking naps on 3 or more days per week, this was significantly higher in the group with amyloid deposition, compared with the group without amyloid deposition (31.2% vs. 14.7%)," Dr. Ju and her associates wrote (JAMA Neurol. 2013;70:587-93).

This study could not determine causality. Amyloid deposition could cause sleep-wake disruption through several mechanisms, such as direct interference with neuronal function in areas of the brain that are critical for sleep. But poor sleep could just as well contribute to amyloid deposition, such as by increasing neuronal activity to a pathological degree, which is thought to facilitate deposition. It is likely that both of these processes play a role in a kind of positive feedback loop, the investigators said.

The findings of this study lay important groundwork for future research. "Longitudinal follow-up with ongoing measurement of amyloid and sleep should enable us to begin to tease apart the details of the abnormalities in sleep that begin to occur with the onset of AD pathology, as well as the directionality of the relationship between sleep and amyloid deposition," they noted.

If sleep disruption is found to raise the risk of future AD, "then this provides an even stronger motivation to identify and treat individuals with sleep disorders, such as obstructive sleep apnea," Dr. Ju and her colleagues added.

This study was supported by grants from the U.S. National Institutes of Health, the Ellison Medical Foundation Senior Scholar Award, and the National Center for Research Resources. Dr. Ju reported no financial conflicts of interest, but some of her associates reported ties to UCB, Jazz Pharmaceuticals, and other companies.

Preclinical beta-amyloid deposition in the brains of cognitively normal volunteers was associated with poor sleep quality but not sleep quantity in a study published in the May issue of JAMA Neurology (formerly Archives of Neurology).

"Our findings support the hypothesis that sleep-wake abnormalities are associated with the presence of amyloid deposition in the preclinical stage of AD [Alzheimer’s disease]," wrote Dr. Yo-El Ju of the Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, and her associates.

In addition, "our findings may expand the temporal window during which sleep abnormalities are identifiable and potentially modifiable in AD," they noted.

©Silvia Jansen/iStockphoto

Dr. Ju and her colleagues observed that sleep-wake problems are common in AD, and that early in its course, the disease affects brain regions and pathways important for sleep and wake mechanisms. "Even in mild cognitive impairment, or very mild dementia, there are abnormalities in sleep architecture and electroencephalography measures.

The investigators assessed the sleep of 142 research volunteers aged 45-75 years (mean age, 66 years) using 2 weeks of actigraphy and sleep diary records. They recorded total sleep time, sleep efficiency (sleep time divided by time in bed), and wake time after sleep onset. Some had a parental history of symptomatic AD and were participating in longitudinal studies of healthy aging and dementia. All the study subjects scored 0 on the Clinical Dementia Rating.

Overall, 32 participants (22.5%) had a cerebrospinal fluid level of amyloid beta 42 of less than 500 pg/mL, indicating a strong likelihood of amyloid deposition in the brain.

Study subjects with a strong likelihood of amyloid deposition had significantly worse sleep efficiency (80.4% vs. 83.7%) than did those without amyloid deposition. This association remained significant when the data were adjusted to correct for age, sex, and apolipoprotein E epsilon-4 allele carrier status.

This difference in sleep efficiency also was significant in a subgroup analysis involving only the 100 study subjects who reported that their sleep had not changed during the preceding 5 years.

Wake time after sleep onset also was significantly higher (worse) among subjects with a strong likelihood of amyloid deposition than it was among those without it (63.1 min vs. 54 min).

In contrast, there were no differences between these two study groups in sleep quantity.

The participants with amyloid deposition showed a trend for spending more nonsleeping time in bed, but the trend didn’t reach statistical significance. Similarly, they reported taking more naps per week, but the difference between the groups’ average number of naps didn’t reach statistical significance.

However, "when we looked at the proportion of frequent nappers, defined as those taking naps on 3 or more days per week, this was significantly higher in the group with amyloid deposition, compared with the group without amyloid deposition (31.2% vs. 14.7%)," Dr. Ju and her associates wrote (JAMA Neurol. 2013;70:587-93).

This study could not determine causality. Amyloid deposition could cause sleep-wake disruption through several mechanisms, such as direct interference with neuronal function in areas of the brain that are critical for sleep. But poor sleep could just as well contribute to amyloid deposition, such as by increasing neuronal activity to a pathological degree, which is thought to facilitate deposition. It is likely that both of these processes play a role in a kind of positive feedback loop, the investigators said.

The findings of this study lay important groundwork for future research. "Longitudinal follow-up with ongoing measurement of amyloid and sleep should enable us to begin to tease apart the details of the abnormalities in sleep that begin to occur with the onset of AD pathology, as well as the directionality of the relationship between sleep and amyloid deposition," they noted.

If sleep disruption is found to raise the risk of future AD, "then this provides an even stronger motivation to identify and treat individuals with sleep disorders, such as obstructive sleep apnea," Dr. Ju and her colleagues added.

This study was supported by grants from the U.S. National Institutes of Health, the Ellison Medical Foundation Senior Scholar Award, and the National Center for Research Resources. Dr. Ju reported no financial conflicts of interest, but some of her associates reported ties to UCB, Jazz Pharmaceuticals, and other companies.

Researchers have identified oncogenic mutations in the CSF3R gene that appear to be "the defining molecular abnormality" of both chronic neutrophilic leukemia and atypical chronic myeloid leukemia, according to a report published online May 8 in the New England Journal of Medicine.

Testing patients for these mutations will aid in the diagnosis of these two rare diseases, and also may prove useful in assessing other disorders of unknown etiology that are characterized by neutrophilia. Genetic testing should also "help refine the molecular classification of myeloproliferative neoplasms," said Julia E. Maxson, Ph.D., of the division of hematology and medical oncology, Oregon Health and Science University, Portland, and her associates.

Discovering the mutations allowed the investigators to test tissue samples for susceptibility to different anticancer drugs. Then, administering the likeliest candidate drug – the JAK-family tyrosine kinase inhibitor ruxolitinib – to one CML patient produced a marked decrease in the total number of white cells and the absolute neutrophil count, and complete normalization of the platelet count.

This excellent clinical response "constitutes a proof of concept. Although anecdotal, this observation provides an impetus for further investigation of tyrosine kinase inhibitors for the treatment of patients with neutrophilic leukemia who have CSF3R (colony-stimulating factor 3) mutations," Dr. Maxson and her colleagues said.

The researchers began with the hypothesis that patients with CNL or atypical CML may carry oncogenes that could be sensitive to small-molecule kinase inhibitors. They screened cell samples from 27 patients with the two diseases and from more than 300 patients with other hematologic cancers including acute myeloid leukemia, T-cell acute lymphoblastic leukemia, and B-cell acute lymphoblastic leukemia. Regions from 1,862 candidate genes known to be involved with cancer signaling, such as those related to kinases, phosphatases, and nonkinase growth factor or cytokine receptors, were sequenced.

Sixteen of the 27 CNL or atypical CML patients (59%) were found to carry certain novel CSF3R mutations, which were present in less than 1% of the other study subjects. The finding suggests that these CSF3R mutations were specific for the two diseases. No other genetic markers specific to these myeloid neoplasms have been previously identified, the investigators said (N. Engl. J. Med. 2013 May 8 [doi:10.1056/NEJMoa1214514]).

They then assessed whether specimens harboring the CSF3R mutations were sensitive to either chemical kinase inhibitors or small interfering RNA directed against kinases. One set of mutations – frameshift or nonsense mutations that truncated the cytoplasmic tails of CSF3R – were sensitive to the multikinase inhibitor dasatinib. Another set of mutations – membrane proximal mutations – were susceptible only to inhibitors such as ruxolitinib that target JAK family kinases.

In vitro colony-forming assays confirmed that the two types of mutation had different transformation capacities and that they were susceptible to different drugs.

A patient who had CNL and carried the CSF3R membrane proximal mutations, had cells that were hypersensitive in vitro to ruxolitinib. The patient was given oral ruxolitinib at a dose of 10 mg twice per day, which induced a marked decrease in white cells and in the absolute neutrophil count. Raising the dose to 15 mg twice daily further decreased both white cells and the absolute neutrophil count, normalizing the platelet count.

These CSF3R mutations "define a new molecular subset of hematologic cancers," and point the way toward new therapeutic approaches, Dr. Maxson and her colleagues said.

This study had no industry support and was funded by the Leukemia and Lymphoma Society, the National Cancer Institute, the National Center for Advancing Translational Sciences, the National Heart, Lung, and Blood Institute, and several others. Dr. Maxson reported no ties to industry sources; her associates reported numerous ties to industry sources.

Researchers have identified oncogenic mutations in the CSF3R gene that appear to be "the defining molecular abnormality" of both chronic neutrophilic leukemia and atypical chronic myeloid leukemia, according to a report published online May 8 in the New England Journal of Medicine.

Testing patients for these mutations will aid in the diagnosis of these two rare diseases, and also may prove useful in assessing other disorders of unknown etiology that are characterized by neutrophilia. Genetic testing should also "help refine the molecular classification of myeloproliferative neoplasms," said Julia E. Maxson, Ph.D., of the division of hematology and medical oncology, Oregon Health and Science University, Portland, and her associates.

Discovering the mutations allowed the investigators to test tissue samples for susceptibility to different anticancer drugs. Then, administering the likeliest candidate drug – the JAK-family tyrosine kinase inhibitor ruxolitinib – to one CML patient produced a marked decrease in the total number of white cells and the absolute neutrophil count, and complete normalization of the platelet count.

This excellent clinical response "constitutes a proof of concept. Although anecdotal, this observation provides an impetus for further investigation of tyrosine kinase inhibitors for the treatment of patients with neutrophilic leukemia who have CSF3R (colony-stimulating factor 3) mutations," Dr. Maxson and her colleagues said.

The researchers began with the hypothesis that patients with CNL or atypical CML may carry oncogenes that could be sensitive to small-molecule kinase inhibitors. They screened cell samples from 27 patients with the two diseases and from more than 300 patients with other hematologic cancers including acute myeloid leukemia, T-cell acute lymphoblastic leukemia, and B-cell acute lymphoblastic leukemia. Regions from 1,862 candidate genes known to be involved with cancer signaling, such as those related to kinases, phosphatases, and nonkinase growth factor or cytokine receptors, were sequenced.

Sixteen of the 27 CNL or atypical CML patients (59%) were found to carry certain novel CSF3R mutations, which were present in less than 1% of the other study subjects. The finding suggests that these CSF3R mutations were specific for the two diseases. No other genetic markers specific to these myeloid neoplasms have been previously identified, the investigators said (N. Engl. J. Med. 2013 May 8 [doi:10.1056/NEJMoa1214514]).

They then assessed whether specimens harboring the CSF3R mutations were sensitive to either chemical kinase inhibitors or small interfering RNA directed against kinases. One set of mutations – frameshift or nonsense mutations that truncated the cytoplasmic tails of CSF3R – were sensitive to the multikinase inhibitor dasatinib. Another set of mutations – membrane proximal mutations – were susceptible only to inhibitors such as ruxolitinib that target JAK family kinases.

In vitro colony-forming assays confirmed that the two types of mutation had different transformation capacities and that they were susceptible to different drugs.

A patient who had CNL and carried the CSF3R membrane proximal mutations, had cells that were hypersensitive in vitro to ruxolitinib. The patient was given oral ruxolitinib at a dose of 10 mg twice per day, which induced a marked decrease in white cells and in the absolute neutrophil count. Raising the dose to 15 mg twice daily further decreased both white cells and the absolute neutrophil count, normalizing the platelet count.

These CSF3R mutations "define a new molecular subset of hematologic cancers," and point the way toward new therapeutic approaches, Dr. Maxson and her colleagues said.

This study had no industry support and was funded by the Leukemia and Lymphoma Society, the National Cancer Institute, the National Center for Advancing Translational Sciences, the National Heart, Lung, and Blood Institute, and several others. Dr. Maxson reported no ties to industry sources; her associates reported numerous ties to industry sources.

Researchers have identified oncogenic mutations in the CSF3R gene that appear to be "the defining molecular abnormality" of both chronic neutrophilic leukemia and atypical chronic myeloid leukemia, according to a report published online May 8 in the New England Journal of Medicine.

Testing patients for these mutations will aid in the diagnosis of these two rare diseases, and also may prove useful in assessing other disorders of unknown etiology that are characterized by neutrophilia. Genetic testing should also "help refine the molecular classification of myeloproliferative neoplasms," said Julia E. Maxson, Ph.D., of the division of hematology and medical oncology, Oregon Health and Science University, Portland, and her associates.

Discovering the mutations allowed the investigators to test tissue samples for susceptibility to different anticancer drugs. Then, administering the likeliest candidate drug – the JAK-family tyrosine kinase inhibitor ruxolitinib – to one CML patient produced a marked decrease in the total number of white cells and the absolute neutrophil count, and complete normalization of the platelet count.

This excellent clinical response "constitutes a proof of concept. Although anecdotal, this observation provides an impetus for further investigation of tyrosine kinase inhibitors for the treatment of patients with neutrophilic leukemia who have CSF3R (colony-stimulating factor 3) mutations," Dr. Maxson and her colleagues said.

The researchers began with the hypothesis that patients with CNL or atypical CML may carry oncogenes that could be sensitive to small-molecule kinase inhibitors. They screened cell samples from 27 patients with the two diseases and from more than 300 patients with other hematologic cancers including acute myeloid leukemia, T-cell acute lymphoblastic leukemia, and B-cell acute lymphoblastic leukemia. Regions from 1,862 candidate genes known to be involved with cancer signaling, such as those related to kinases, phosphatases, and nonkinase growth factor or cytokine receptors, were sequenced.

Sixteen of the 27 CNL or atypical CML patients (59%) were found to carry certain novel CSF3R mutations, which were present in less than 1% of the other study subjects. The finding suggests that these CSF3R mutations were specific for the two diseases. No other genetic markers specific to these myeloid neoplasms have been previously identified, the investigators said (N. Engl. J. Med. 2013 May 8 [doi:10.1056/NEJMoa1214514]).

They then assessed whether specimens harboring the CSF3R mutations were sensitive to either chemical kinase inhibitors or small interfering RNA directed against kinases. One set of mutations – frameshift or nonsense mutations that truncated the cytoplasmic tails of CSF3R – were sensitive to the multikinase inhibitor dasatinib. Another set of mutations – membrane proximal mutations – were susceptible only to inhibitors such as ruxolitinib that target JAK family kinases.

In vitro colony-forming assays confirmed that the two types of mutation had different transformation capacities and that they were susceptible to different drugs.

A patient who had CNL and carried the CSF3R membrane proximal mutations, had cells that were hypersensitive in vitro to ruxolitinib. The patient was given oral ruxolitinib at a dose of 10 mg twice per day, which induced a marked decrease in white cells and in the absolute neutrophil count. Raising the dose to 15 mg twice daily further decreased both white cells and the absolute neutrophil count, normalizing the platelet count.

These CSF3R mutations "define a new molecular subset of hematologic cancers," and point the way toward new therapeutic approaches, Dr. Maxson and her colleagues said.

This study had no industry support and was funded by the Leukemia and Lymphoma Society, the National Cancer Institute, the National Center for Advancing Translational Sciences, the National Heart, Lung, and Blood Institute, and several others. Dr. Maxson reported no ties to industry sources; her associates reported numerous ties to industry sources.

In otherwise healthy preterm infants, palivizumab injections during the winter months to prevent respiratory syncytial virus also reduced the number of wheezing days by 61% for a full year, according to a report published online May 9 in the New England Journal of Medicine.

"Our study underlines the important role that RSV [respiratory syncytial virus] plays in the pathogenesis of recurrent wheeze. We hypothesize that RSV primarily causes direct pulmonary epithelial damage and local immunologic alterations in the lungs, leading to long-term airway hyperresponsiveness and wheezing," said Dr. Maarten O. Blanken of the division of pediatric immunology and infectious diseases, University Medical Center Utrecht (the Netherlands), and his associates for the Dutch RSV Neonatal Network.

© Dr. Craig Lyerla / CDC

Whether or not RSV plays a causal role in recurrent wheezing has been controversial. Dr. Blanken and his colleagues performed a double-blind randomized trial to further examine the issue.

They enrolled 429 preterm (gestational age, 33-35 weeks) but otherwise healthy infants at 1 university and 15 regional hospitals in the Netherlands during a 2-year period. All the babies were 6 months of age or younger at the start of the RSV season.

The babies were randomly assigned to receive either palivizumab (Synagis, MedImmune) (214 subjects) or placebo (215 subjects) injections during the winter months. Parents recorded airway symptoms, doctor visits, and the use of airway medications until the children reached 1 year of age.

Parents also were instructed to take nasopharyngeal swabs whenever the children developed respiratory symptoms that lasted more than 1 day, to be tested for the presence of RSV RNA.

As expected, the incidence of RSV-related hospitalizations was significantly lower among infants who received palivizumab immunoprophylaxis (0.9%) than among those who received placebo (5.1%). The rate of RSV infection requiring medical attendance but not hospitalization also was significantly lower in the immunoprophylaxis group.

The primary outcome measure of this study was the number of parent-reported days in which the baby wheezed during the first year of life. This was significantly lower in the active-treatment group (1.8% of days) than in the placebo group (4.5% of days), which is a relative reduction of 61%, the investigators said (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1211917]).

In addition, the proportion of babies who developed recurrent wheezing was approximately half as high among those who received palivizumab (11.2%) as among those who received placebo (20.9%). The proportion who were given bronchodilator therapy was similarly lower in the palivizumab group (13%) than in the placebo group (23%).

Notably, the efficacy of immunoprophylaxis was not significantly different between children who had a family history of atopy (54% reduction in wheezing days) and those who did not (72% reduction in wheezing days). Palivizumab’s efficacy was similarly consistent whether the children’s parents had asthma (68% reduction) or did not have asthma (35% reduction).

Children in the RSV-prevention group were less likely than those in the placebo group to have adverse effects requiring hospitalization. There were 32 hospitalizations in 27 children (12.6%) in the palivizumab group, compared with 52 hospitalizations in 47 children (21.9%) in the placebo group, the researchers said.

"In this proof-of-concept study, treatment with a monoclonal antibody for RSV prevention in late preterm infants greatly reduced the number of parent-reported wheezing days during the first year of life, even after the end of therapy and outside the RSV season," Dr. Blanken and his associates said.

"Our results are in line with other studies that acknowledge the relationship between RSV bronchiolitis and recurrent wheeze," they said.

It is unknown whether these results can be generalized to term infants, they added.

This study was supported by an unrestricted grant from Abbott Laboratories and a grant from the Netherlands Organization for Health Research and Development to Dr. Blanken. Dr. Blanken reported conflicts of interest, and his associates reported ties to MedImmune and GlaxoSmithKline.

In otherwise healthy preterm infants, palivizumab injections during the winter months to prevent respiratory syncytial virus also reduced the number of wheezing days by 61% for a full year, according to a report published online May 9 in the New England Journal of Medicine.

"Our study underlines the important role that RSV [respiratory syncytial virus] plays in the pathogenesis of recurrent wheeze. We hypothesize that RSV primarily causes direct pulmonary epithelial damage and local immunologic alterations in the lungs, leading to long-term airway hyperresponsiveness and wheezing," said Dr. Maarten O. Blanken of the division of pediatric immunology and infectious diseases, University Medical Center Utrecht (the Netherlands), and his associates for the Dutch RSV Neonatal Network.

© Dr. Craig Lyerla / CDC

Whether or not RSV plays a causal role in recurrent wheezing has been controversial. Dr. Blanken and his colleagues performed a double-blind randomized trial to further examine the issue.

They enrolled 429 preterm (gestational age, 33-35 weeks) but otherwise healthy infants at 1 university and 15 regional hospitals in the Netherlands during a 2-year period. All the babies were 6 months of age or younger at the start of the RSV season.

The babies were randomly assigned to receive either palivizumab (Synagis, MedImmune) (214 subjects) or placebo (215 subjects) injections during the winter months. Parents recorded airway symptoms, doctor visits, and the use of airway medications until the children reached 1 year of age.

Parents also were instructed to take nasopharyngeal swabs whenever the children developed respiratory symptoms that lasted more than 1 day, to be tested for the presence of RSV RNA.

As expected, the incidence of RSV-related hospitalizations was significantly lower among infants who received palivizumab immunoprophylaxis (0.9%) than among those who received placebo (5.1%). The rate of RSV infection requiring medical attendance but not hospitalization also was significantly lower in the immunoprophylaxis group.

The primary outcome measure of this study was the number of parent-reported days in which the baby wheezed during the first year of life. This was significantly lower in the active-treatment group (1.8% of days) than in the placebo group (4.5% of days), which is a relative reduction of 61%, the investigators said (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1211917]).

In addition, the proportion of babies who developed recurrent wheezing was approximately half as high among those who received palivizumab (11.2%) as among those who received placebo (20.9%). The proportion who were given bronchodilator therapy was similarly lower in the palivizumab group (13%) than in the placebo group (23%).

Notably, the efficacy of immunoprophylaxis was not significantly different between children who had a family history of atopy (54% reduction in wheezing days) and those who did not (72% reduction in wheezing days). Palivizumab’s efficacy was similarly consistent whether the children’s parents had asthma (68% reduction) or did not have asthma (35% reduction).

Children in the RSV-prevention group were less likely than those in the placebo group to have adverse effects requiring hospitalization. There were 32 hospitalizations in 27 children (12.6%) in the palivizumab group, compared with 52 hospitalizations in 47 children (21.9%) in the placebo group, the researchers said.

"In this proof-of-concept study, treatment with a monoclonal antibody for RSV prevention in late preterm infants greatly reduced the number of parent-reported wheezing days during the first year of life, even after the end of therapy and outside the RSV season," Dr. Blanken and his associates said.

"Our results are in line with other studies that acknowledge the relationship between RSV bronchiolitis and recurrent wheeze," they said.

It is unknown whether these results can be generalized to term infants, they added.

This study was supported by an unrestricted grant from Abbott Laboratories and a grant from the Netherlands Organization for Health Research and Development to Dr. Blanken. Dr. Blanken reported conflicts of interest, and his associates reported ties to MedImmune and GlaxoSmithKline.

In otherwise healthy preterm infants, palivizumab injections during the winter months to prevent respiratory syncytial virus also reduced the number of wheezing days by 61% for a full year, according to a report published online May 9 in the New England Journal of Medicine.

"Our study underlines the important role that RSV [respiratory syncytial virus] plays in the pathogenesis of recurrent wheeze. We hypothesize that RSV primarily causes direct pulmonary epithelial damage and local immunologic alterations in the lungs, leading to long-term airway hyperresponsiveness and wheezing," said Dr. Maarten O. Blanken of the division of pediatric immunology and infectious diseases, University Medical Center Utrecht (the Netherlands), and his associates for the Dutch RSV Neonatal Network.

© Dr. Craig Lyerla / CDC

Whether or not RSV plays a causal role in recurrent wheezing has been controversial. Dr. Blanken and his colleagues performed a double-blind randomized trial to further examine the issue.

They enrolled 429 preterm (gestational age, 33-35 weeks) but otherwise healthy infants at 1 university and 15 regional hospitals in the Netherlands during a 2-year period. All the babies were 6 months of age or younger at the start of the RSV season.

The babies were randomly assigned to receive either palivizumab (Synagis, MedImmune) (214 subjects) or placebo (215 subjects) injections during the winter months. Parents recorded airway symptoms, doctor visits, and the use of airway medications until the children reached 1 year of age.

Parents also were instructed to take nasopharyngeal swabs whenever the children developed respiratory symptoms that lasted more than 1 day, to be tested for the presence of RSV RNA.

As expected, the incidence of RSV-related hospitalizations was significantly lower among infants who received palivizumab immunoprophylaxis (0.9%) than among those who received placebo (5.1%). The rate of RSV infection requiring medical attendance but not hospitalization also was significantly lower in the immunoprophylaxis group.

The primary outcome measure of this study was the number of parent-reported days in which the baby wheezed during the first year of life. This was significantly lower in the active-treatment group (1.8% of days) than in the placebo group (4.5% of days), which is a relative reduction of 61%, the investigators said (N. Engl. J. Med. 2013 [doi:10.1056/NEJMoa1211917]).

In addition, the proportion of babies who developed recurrent wheezing was approximately half as high among those who received palivizumab (11.2%) as among those who received placebo (20.9%). The proportion who were given bronchodilator therapy was similarly lower in the palivizumab group (13%) than in the placebo group (23%).

Notably, the efficacy of immunoprophylaxis was not significantly different between children who had a family history of atopy (54% reduction in wheezing days) and those who did not (72% reduction in wheezing days). Palivizumab’s efficacy was similarly consistent whether the children’s parents had asthma (68% reduction) or did not have asthma (35% reduction).

Children in the RSV-prevention group were less likely than those in the placebo group to have adverse effects requiring hospitalization. There were 32 hospitalizations in 27 children (12.6%) in the palivizumab group, compared with 52 hospitalizations in 47 children (21.9%) in the placebo group, the researchers said.

"In this proof-of-concept study, treatment with a monoclonal antibody for RSV prevention in late preterm infants greatly reduced the number of parent-reported wheezing days during the first year of life, even after the end of therapy and outside the RSV season," Dr. Blanken and his associates said.

"Our results are in line with other studies that acknowledge the relationship between RSV bronchiolitis and recurrent wheeze," they said.

It is unknown whether these results can be generalized to term infants, they added.

This study was supported by an unrestricted grant from Abbott Laboratories and a grant from the Netherlands Organization for Health Research and Development to Dr. Blanken. Dr. Blanken reported conflicts of interest, and his associates reported ties to MedImmune and GlaxoSmithKline.