Mary Ann Moon

Microarray testing is more likely to identify a genetic abnormality than is standard karyotyping in cases of stillbirth, according to a report published online Dec. 6 in the New England Journal of Medicine.

Microarray analysis is more productive in such cases chiefly because it can be used on nonviable tissue, even on macerated tissue, with some success, said Dr. Uma M. Reddy of the National Institute of Child Health and Human Development, Bethesda, Md., and her associates.

Until now, only two small studies, involving only 44 stillbirths in all, have assessed the usefulness of microarray testing to identify a cause in stillbirths.

The investigators performed a population-based study of genetic findings in cases of stillbirth using data from the Stillbirth Collaborative Research Network, a racially and ethnically diverse cohort drawn from five geographic catchment areas in the United States. They assessed 532 stillbirths (from 524 pregnancies) that occurred at 59 hospitals during 2006-2008.

Standard karyotyping was attempted on fetal tissue, placental tissue, cord blood, fetal muscle, and/or fetal liver, and results were obtained in 375 (71%) of these stillbirths. A total of 31 were classified as abnormal, with findings including trisomy 21, trisomy 18, trisomy 13, monosomy X, and other sex-chromosome abnormalities.

When microarray testing was performed on the same samples, results were obtained in 465 (87.4%) of the stillbirths, which is a significantly greater yield than that obtained with karyotyping. "We thus were able to obtain a result in 90 more cases (24% more) than we would have done using karyotype analysis alone," the researchers said.

Microarray testing showed no "benign" or "probably benign" chromosomal abnormalities in these stillbirths. It showed aneuploidy in 32, other pathogenic variants in 12, and variants "of unknown significance" in 25.

"Microarray analysis provided improved detection of genomic abnormalities, as compared with karyotype analysis (8.3% vs. 5.8%), a 41.9% increase. ... When we included variants of unknown significance in this comparison, we observed an even greater detection of abnormalities with the use of microarray analysis, as compared with karyotype analysis (13% vs. 5.8%), a 122.6% increase," Dr. Reddy and her colleagues said.

"Of the 157 stillbirths for which karyotype analysis failed to provide a definitive result, 79.6% yielded a definitive microarray result: 73.9% were normal or probably benign, and 5.7% were abnormal," they noted.

Looked at another way, karyotyping either failed altogether or produced normal results in 41% of the 44 stillbirths in which microarray testing demonstrated aneuploidy or a known pathogenic chromosomal variant (N. Engl. J. Med. 2012 Dec. 6 [doi:10.1056/NEJMoa1201569]).

The investigators also performed a subgroup analysis of the 443 antepartum stillbirths in this series. As with the entire study cohort, microarray analysis detected more abnormalities (8.8%) in this subgroup than did karyotyping (6.5%), representing a 35% increase in diagnostic yield.

In a subgroup analysis of the 472 stillbirths in which postmortem examinations were conducted, microarray analysis also detected more abnormalities (29.9%) than did karyotyping (19.4%), which represents a 54% increase in diagnostic yield.

In addition, the microarray technique, but not karyotyping, identified three stillbirths with abnormalities on chromosome 22q11.2, a region that is known to be disrupted in DiGeorge syndrome (also known as velocardiofacial syndrome). One of these fetuses was found to have multiple cardiopulmonary, facial, skeletal, urogenital, and thymic anomalies on postmortem examination.

This result suggests that genomic imbalances in the 22q11.2 region may be associated with stillbirth as well as with DiGeorge syndrome. Identifying such variations in cases of stillbirth would be important so that parental studies can be performed. The risk of recurrence of DiGeorge syndrome in subsequent pregnancies can vary from less than 0.1% in genotypically normal parents to 50% if one parent has a deletion, Dr. Reddy and her associates said.

In another eight stillbirths, the microarray method, but not karyotyping, also identified variations "of unknown significance" in the region of chromosome 19p13.3. This region is known to harbor frequent variations that are not yet understood. No congenital anomalies were present in these eight cases on postmortem examination, but there were "substantially abnormal" placental findings, including chronic deciduitis, villous infarction, chronic cytomegalovirus villitis, and abruption.

Chromosomal variations in this region previously have been associated with disease but not with stillbirth, so the variation identified on microarray testing in these eight stillbirths may be benign or may confer a risk of stillbirth; further research should supply the answer, the investigators said.

This study was supported by NICHD. Dr. Reddy reported no potential financial conflicts of interest, and her associates reported numerous ties to industry sources.

Microarray testing is more likely to identify a genetic abnormality than is standard karyotyping in cases of stillbirth, according to a report published online Dec. 6 in the New England Journal of Medicine.

Microarray analysis is more productive in such cases chiefly because it can be used on nonviable tissue, even on macerated tissue, with some success, said Dr. Uma M. Reddy of the National Institute of Child Health and Human Development, Bethesda, Md., and her associates.

Until now, only two small studies, involving only 44 stillbirths in all, have assessed the usefulness of microarray testing to identify a cause in stillbirths.

The investigators performed a population-based study of genetic findings in cases of stillbirth using data from the Stillbirth Collaborative Research Network, a racially and ethnically diverse cohort drawn from five geographic catchment areas in the United States. They assessed 532 stillbirths (from 524 pregnancies) that occurred at 59 hospitals during 2006-2008.

Standard karyotyping was attempted on fetal tissue, placental tissue, cord blood, fetal muscle, and/or fetal liver, and results were obtained in 375 (71%) of these stillbirths. A total of 31 were classified as abnormal, with findings including trisomy 21, trisomy 18, trisomy 13, monosomy X, and other sex-chromosome abnormalities.

When microarray testing was performed on the same samples, results were obtained in 465 (87.4%) of the stillbirths, which is a significantly greater yield than that obtained with karyotyping. "We thus were able to obtain a result in 90 more cases (24% more) than we would have done using karyotype analysis alone," the researchers said.

Microarray testing showed no "benign" or "probably benign" chromosomal abnormalities in these stillbirths. It showed aneuploidy in 32, other pathogenic variants in 12, and variants "of unknown significance" in 25.

"Microarray analysis provided improved detection of genomic abnormalities, as compared with karyotype analysis (8.3% vs. 5.8%), a 41.9% increase. ... When we included variants of unknown significance in this comparison, we observed an even greater detection of abnormalities with the use of microarray analysis, as compared with karyotype analysis (13% vs. 5.8%), a 122.6% increase," Dr. Reddy and her colleagues said.

"Of the 157 stillbirths for which karyotype analysis failed to provide a definitive result, 79.6% yielded a definitive microarray result: 73.9% were normal or probably benign, and 5.7% were abnormal," they noted.

Looked at another way, karyotyping either failed altogether or produced normal results in 41% of the 44 stillbirths in which microarray testing demonstrated aneuploidy or a known pathogenic chromosomal variant (N. Engl. J. Med. 2012 Dec. 6 [doi:10.1056/NEJMoa1201569]).

The investigators also performed a subgroup analysis of the 443 antepartum stillbirths in this series. As with the entire study cohort, microarray analysis detected more abnormalities (8.8%) in this subgroup than did karyotyping (6.5%), representing a 35% increase in diagnostic yield.

In a subgroup analysis of the 472 stillbirths in which postmortem examinations were conducted, microarray analysis also detected more abnormalities (29.9%) than did karyotyping (19.4%), which represents a 54% increase in diagnostic yield.

In addition, the microarray technique, but not karyotyping, identified three stillbirths with abnormalities on chromosome 22q11.2, a region that is known to be disrupted in DiGeorge syndrome (also known as velocardiofacial syndrome). One of these fetuses was found to have multiple cardiopulmonary, facial, skeletal, urogenital, and thymic anomalies on postmortem examination.

This result suggests that genomic imbalances in the 22q11.2 region may be associated with stillbirth as well as with DiGeorge syndrome. Identifying such variations in cases of stillbirth would be important so that parental studies can be performed. The risk of recurrence of DiGeorge syndrome in subsequent pregnancies can vary from less than 0.1% in genotypically normal parents to 50% if one parent has a deletion, Dr. Reddy and her associates said.

In another eight stillbirths, the microarray method, but not karyotyping, also identified variations "of unknown significance" in the region of chromosome 19p13.3. This region is known to harbor frequent variations that are not yet understood. No congenital anomalies were present in these eight cases on postmortem examination, but there were "substantially abnormal" placental findings, including chronic deciduitis, villous infarction, chronic cytomegalovirus villitis, and abruption.

Chromosomal variations in this region previously have been associated with disease but not with stillbirth, so the variation identified on microarray testing in these eight stillbirths may be benign or may confer a risk of stillbirth; further research should supply the answer, the investigators said.

This study was supported by NICHD. Dr. Reddy reported no potential financial conflicts of interest, and her associates reported numerous ties to industry sources.

Microarray testing is more likely to identify a genetic abnormality than is standard karyotyping in cases of stillbirth, according to a report published online Dec. 6 in the New England Journal of Medicine.

Microarray analysis is more productive in such cases chiefly because it can be used on nonviable tissue, even on macerated tissue, with some success, said Dr. Uma M. Reddy of the National Institute of Child Health and Human Development, Bethesda, Md., and her associates.

Until now, only two small studies, involving only 44 stillbirths in all, have assessed the usefulness of microarray testing to identify a cause in stillbirths.

The investigators performed a population-based study of genetic findings in cases of stillbirth using data from the Stillbirth Collaborative Research Network, a racially and ethnically diverse cohort drawn from five geographic catchment areas in the United States. They assessed 532 stillbirths (from 524 pregnancies) that occurred at 59 hospitals during 2006-2008.

Standard karyotyping was attempted on fetal tissue, placental tissue, cord blood, fetal muscle, and/or fetal liver, and results were obtained in 375 (71%) of these stillbirths. A total of 31 were classified as abnormal, with findings including trisomy 21, trisomy 18, trisomy 13, monosomy X, and other sex-chromosome abnormalities.

When microarray testing was performed on the same samples, results were obtained in 465 (87.4%) of the stillbirths, which is a significantly greater yield than that obtained with karyotyping. "We thus were able to obtain a result in 90 more cases (24% more) than we would have done using karyotype analysis alone," the researchers said.

Microarray testing showed no "benign" or "probably benign" chromosomal abnormalities in these stillbirths. It showed aneuploidy in 32, other pathogenic variants in 12, and variants "of unknown significance" in 25.

"Microarray analysis provided improved detection of genomic abnormalities, as compared with karyotype analysis (8.3% vs. 5.8%), a 41.9% increase. ... When we included variants of unknown significance in this comparison, we observed an even greater detection of abnormalities with the use of microarray analysis, as compared with karyotype analysis (13% vs. 5.8%), a 122.6% increase," Dr. Reddy and her colleagues said.

"Of the 157 stillbirths for which karyotype analysis failed to provide a definitive result, 79.6% yielded a definitive microarray result: 73.9% were normal or probably benign, and 5.7% were abnormal," they noted.

Looked at another way, karyotyping either failed altogether or produced normal results in 41% of the 44 stillbirths in which microarray testing demonstrated aneuploidy or a known pathogenic chromosomal variant (N. Engl. J. Med. 2012 Dec. 6 [doi:10.1056/NEJMoa1201569]).

The investigators also performed a subgroup analysis of the 443 antepartum stillbirths in this series. As with the entire study cohort, microarray analysis detected more abnormalities (8.8%) in this subgroup than did karyotyping (6.5%), representing a 35% increase in diagnostic yield.

In a subgroup analysis of the 472 stillbirths in which postmortem examinations were conducted, microarray analysis also detected more abnormalities (29.9%) than did karyotyping (19.4%), which represents a 54% increase in diagnostic yield.

In addition, the microarray technique, but not karyotyping, identified three stillbirths with abnormalities on chromosome 22q11.2, a region that is known to be disrupted in DiGeorge syndrome (also known as velocardiofacial syndrome). One of these fetuses was found to have multiple cardiopulmonary, facial, skeletal, urogenital, and thymic anomalies on postmortem examination.

This result suggests that genomic imbalances in the 22q11.2 region may be associated with stillbirth as well as with DiGeorge syndrome. Identifying such variations in cases of stillbirth would be important so that parental studies can be performed. The risk of recurrence of DiGeorge syndrome in subsequent pregnancies can vary from less than 0.1% in genotypically normal parents to 50% if one parent has a deletion, Dr. Reddy and her associates said.

In another eight stillbirths, the microarray method, but not karyotyping, also identified variations "of unknown significance" in the region of chromosome 19p13.3. This region is known to harbor frequent variations that are not yet understood. No congenital anomalies were present in these eight cases on postmortem examination, but there were "substantially abnormal" placental findings, including chronic deciduitis, villous infarction, chronic cytomegalovirus villitis, and abruption.

Chromosomal variations in this region previously have been associated with disease but not with stillbirth, so the variation identified on microarray testing in these eight stillbirths may be benign or may confer a risk of stillbirth; further research should supply the answer, the investigators said.

This study was supported by NICHD. Dr. Reddy reported no potential financial conflicts of interest, and her associates reported numerous ties to industry sources.

Chromosomal microarray testing is equivalent to standard karyotype testing for prenatal diagnosis of common aneuploidies, and it provides additional clinically relevant information that karyotyping cannot, according to a report published online Dec. 6 in the New England Journal of Medicine.

In a study comparing the yields between these two techniques for routine detection of fetal disorders among more than 4,000 pregnant women, microarray testing identified important genetic anomalies missed by karyotyping in 1.7% of pregnancies with the usual indications for diagnostic testing (such as advanced maternal age) and 6% of cases in which ultrasound had revealed an anomaly.

"These data indicate a benefit to chromosomal microarray analysis as a standard part of prenatal testing, bearing in mind that, as with karyotyping, the detection of variants of uncertain clinical significance presents a challenge for counseling and cause [patients] anxiety," said Dr. Ronald J. Wapner of Columbia University Medical Center, New York, and his associates.

In fact, if microarray testing proves to have a similar yield of positive results in confirmation studies, "offering invasive testing and microarray analysis to all pregnant women would seem to be appropriate. This is consistent with the recommendations of the American Congress of Obstetricians and Gynecologists, who suggest that all women, regardless of their risk, should be offered the option of invasive testing," they noted.

Until now, microarray testing has been assessed as a method for prenatal diagnosis only in small studies of pregnancies with a high likelihood of chromosomal abnormalities, such as those in which the fetus is known to have structural anomalies. But it was not known whether the technique would reliably detect all the chromosomal abnormalities that are identified by standard karyotyping, let alone whether it would detect additional chromosomal abnormalities.

"We conducted a large, prospective study of prenatal diagnostic samples to assess, in blinded fashion, the ability of microarray analysis to diagnose common chromosome abnormalities and to gauge the extent of additional information provided by microarray analysis as compared with standard karyotyping," Dr. Wapner and his associates wrote.

They screened 6,537 women with singleton pregnancies who presented to 29 prenatal diagnostic centers for either chorionic villus sampling (CVS) or amniocentesis in 2008-2011. They then enrolled 4,406 of these women who had indications such as advanced maternal age, a positive result on aneuploidy screening, or fetal structural anomalies detected on ultrasound, and who had adequate samples from CVS (2,275 pregnancies) or amniocentesis (2,131 pregnancies).

Microarray testing was successful in 4,340 (98.8%) of these cases. Fifty-eight of these were then excluded because the samples showed mosaicism on karyotyping.

Standard karyotyping identified common autosomal aneuploidies in 7.4% of the remaining 4,282 samples and sex-chromosome aneuploidies in another 1.3%. Microarray testing also identified all of these aneuploidies. Moreover, the microarray method indicated that another eight of the CVS samples showed probable mosaicism.

More important, microarray analysis identified clinically significant segmental aneuploidies that had not been detected on karyotyping. Overall, 2% of the samples that showed normal karyotypes were found to have clinically significant copy-number variants on microarray testing, the investigators said (N. Engl. J. Med. 2012;367:2175-84).

In the subgroup of 755 samples from pregnancies with suspected growth or structural anomalies, 6% showed clinically relevant findings on microarray that were not detected on karyotyping.

Similarly, in the subgroup of 1,966 pregnancies that didn’t show anomalies on ultrasound but were referred for prenatal testing because of advanced maternal age, microarray analysis detected chromosomal abnormalities in 1.7% that were not detected on karyotyping.

Microarray testing also flagged 130 cases that were normal on karyotyping but showed chromosomal abnormalities "of uncertain significance." In 36 of these, the findings were judged to be "probably benign"; the remaining 94 cases were referred to an expert committee so their clinical relevance could be adjudicated. The committee judged 61 of these cases to be concerning enough that the patient should be informed of the chromosomal abnormality.

However, during the interval since the inception of this study 5 years ago, researchers have made considerable progress in determining whether most of these "uncertain" findings are either benign or clinically significant. If the currently available data had been used to adjudicate these 94 samples, only 56 would have been judged as "of uncertain significance," while 30 would have been categorized as clearly pathogenic and 8 as probably benign.

"With this additional information, the pathogenicity of only 1.5% of copy-number variants detected on microarray in karyotypically normal samples remains ‘uncertain,’ and this number should continue to fall as additional experience is acquired," Dr. Wapner and his associates said.

They added that they are following the offspring from the pregnancies in which copy-number variants were discovered, to establish what, if any, phenotypes develop. They are particularly interested in linking specific chromosomal abnormalities with later diagnoses of developmental delay.

This study was supported by the National Institute of Child Health and Human Development. Agilent Technologies and Affymetrix donated the microarrays and reagents used in the study, and Integrated Genetics was reimbursed for the costs of handling samples and managing cytogenetic data. Dr. Wapner reported no potential financial conflicts of interest, and his associates reported numerous ties to industry sources.

Chromosomal microarray testing is equivalent to standard karyotype testing for prenatal diagnosis of common aneuploidies, and it provides additional clinically relevant information that karyotyping cannot, according to a report published online Dec. 6 in the New England Journal of Medicine.

In a study comparing the yields between these two techniques for routine detection of fetal disorders among more than 4,000 pregnant women, microarray testing identified important genetic anomalies missed by karyotyping in 1.7% of pregnancies with the usual indications for diagnostic testing (such as advanced maternal age) and 6% of cases in which ultrasound had revealed an anomaly.

"These data indicate a benefit to chromosomal microarray analysis as a standard part of prenatal testing, bearing in mind that, as with karyotyping, the detection of variants of uncertain clinical significance presents a challenge for counseling and cause [patients] anxiety," said Dr. Ronald J. Wapner of Columbia University Medical Center, New York, and his associates.

In fact, if microarray testing proves to have a similar yield of positive results in confirmation studies, "offering invasive testing and microarray analysis to all pregnant women would seem to be appropriate. This is consistent with the recommendations of the American Congress of Obstetricians and Gynecologists, who suggest that all women, regardless of their risk, should be offered the option of invasive testing," they noted.

Until now, microarray testing has been assessed as a method for prenatal diagnosis only in small studies of pregnancies with a high likelihood of chromosomal abnormalities, such as those in which the fetus is known to have structural anomalies. But it was not known whether the technique would reliably detect all the chromosomal abnormalities that are identified by standard karyotyping, let alone whether it would detect additional chromosomal abnormalities.

"We conducted a large, prospective study of prenatal diagnostic samples to assess, in blinded fashion, the ability of microarray analysis to diagnose common chromosome abnormalities and to gauge the extent of additional information provided by microarray analysis as compared with standard karyotyping," Dr. Wapner and his associates wrote.

They screened 6,537 women with singleton pregnancies who presented to 29 prenatal diagnostic centers for either chorionic villus sampling (CVS) or amniocentesis in 2008-2011. They then enrolled 4,406 of these women who had indications such as advanced maternal age, a positive result on aneuploidy screening, or fetal structural anomalies detected on ultrasound, and who had adequate samples from CVS (2,275 pregnancies) or amniocentesis (2,131 pregnancies).

Microarray testing was successful in 4,340 (98.8%) of these cases. Fifty-eight of these were then excluded because the samples showed mosaicism on karyotyping.

Standard karyotyping identified common autosomal aneuploidies in 7.4% of the remaining 4,282 samples and sex-chromosome aneuploidies in another 1.3%. Microarray testing also identified all of these aneuploidies. Moreover, the microarray method indicated that another eight of the CVS samples showed probable mosaicism.

More important, microarray analysis identified clinically significant segmental aneuploidies that had not been detected on karyotyping. Overall, 2% of the samples that showed normal karyotypes were found to have clinically significant copy-number variants on microarray testing, the investigators said (N. Engl. J. Med. 2012;367:2175-84).

In the subgroup of 755 samples from pregnancies with suspected growth or structural anomalies, 6% showed clinically relevant findings on microarray that were not detected on karyotyping.

Similarly, in the subgroup of 1,966 pregnancies that didn’t show anomalies on ultrasound but were referred for prenatal testing because of advanced maternal age, microarray analysis detected chromosomal abnormalities in 1.7% that were not detected on karyotyping.

Microarray testing also flagged 130 cases that were normal on karyotyping but showed chromosomal abnormalities "of uncertain significance." In 36 of these, the findings were judged to be "probably benign"; the remaining 94 cases were referred to an expert committee so their clinical relevance could be adjudicated. The committee judged 61 of these cases to be concerning enough that the patient should be informed of the chromosomal abnormality.

However, during the interval since the inception of this study 5 years ago, researchers have made considerable progress in determining whether most of these "uncertain" findings are either benign or clinically significant. If the currently available data had been used to adjudicate these 94 samples, only 56 would have been judged as "of uncertain significance," while 30 would have been categorized as clearly pathogenic and 8 as probably benign.

"With this additional information, the pathogenicity of only 1.5% of copy-number variants detected on microarray in karyotypically normal samples remains ‘uncertain,’ and this number should continue to fall as additional experience is acquired," Dr. Wapner and his associates said.

They added that they are following the offspring from the pregnancies in which copy-number variants were discovered, to establish what, if any, phenotypes develop. They are particularly interested in linking specific chromosomal abnormalities with later diagnoses of developmental delay.

This study was supported by the National Institute of Child Health and Human Development. Agilent Technologies and Affymetrix donated the microarrays and reagents used in the study, and Integrated Genetics was reimbursed for the costs of handling samples and managing cytogenetic data. Dr. Wapner reported no potential financial conflicts of interest, and his associates reported numerous ties to industry sources.

Chromosomal microarray testing is equivalent to standard karyotype testing for prenatal diagnosis of common aneuploidies, and it provides additional clinically relevant information that karyotyping cannot, according to a report published online Dec. 6 in the New England Journal of Medicine.

In a study comparing the yields between these two techniques for routine detection of fetal disorders among more than 4,000 pregnant women, microarray testing identified important genetic anomalies missed by karyotyping in 1.7% of pregnancies with the usual indications for diagnostic testing (such as advanced maternal age) and 6% of cases in which ultrasound had revealed an anomaly.

"These data indicate a benefit to chromosomal microarray analysis as a standard part of prenatal testing, bearing in mind that, as with karyotyping, the detection of variants of uncertain clinical significance presents a challenge for counseling and cause [patients] anxiety," said Dr. Ronald J. Wapner of Columbia University Medical Center, New York, and his associates.

In fact, if microarray testing proves to have a similar yield of positive results in confirmation studies, "offering invasive testing and microarray analysis to all pregnant women would seem to be appropriate. This is consistent with the recommendations of the American Congress of Obstetricians and Gynecologists, who suggest that all women, regardless of their risk, should be offered the option of invasive testing," they noted.

Until now, microarray testing has been assessed as a method for prenatal diagnosis only in small studies of pregnancies with a high likelihood of chromosomal abnormalities, such as those in which the fetus is known to have structural anomalies. But it was not known whether the technique would reliably detect all the chromosomal abnormalities that are identified by standard karyotyping, let alone whether it would detect additional chromosomal abnormalities.

"We conducted a large, prospective study of prenatal diagnostic samples to assess, in blinded fashion, the ability of microarray analysis to diagnose common chromosome abnormalities and to gauge the extent of additional information provided by microarray analysis as compared with standard karyotyping," Dr. Wapner and his associates wrote.

They screened 6,537 women with singleton pregnancies who presented to 29 prenatal diagnostic centers for either chorionic villus sampling (CVS) or amniocentesis in 2008-2011. They then enrolled 4,406 of these women who had indications such as advanced maternal age, a positive result on aneuploidy screening, or fetal structural anomalies detected on ultrasound, and who had adequate samples from CVS (2,275 pregnancies) or amniocentesis (2,131 pregnancies).

Microarray testing was successful in 4,340 (98.8%) of these cases. Fifty-eight of these were then excluded because the samples showed mosaicism on karyotyping.

Standard karyotyping identified common autosomal aneuploidies in 7.4% of the remaining 4,282 samples and sex-chromosome aneuploidies in another 1.3%. Microarray testing also identified all of these aneuploidies. Moreover, the microarray method indicated that another eight of the CVS samples showed probable mosaicism.

More important, microarray analysis identified clinically significant segmental aneuploidies that had not been detected on karyotyping. Overall, 2% of the samples that showed normal karyotypes were found to have clinically significant copy-number variants on microarray testing, the investigators said (N. Engl. J. Med. 2012;367:2175-84).

In the subgroup of 755 samples from pregnancies with suspected growth or structural anomalies, 6% showed clinically relevant findings on microarray that were not detected on karyotyping.

Similarly, in the subgroup of 1,966 pregnancies that didn’t show anomalies on ultrasound but were referred for prenatal testing because of advanced maternal age, microarray analysis detected chromosomal abnormalities in 1.7% that were not detected on karyotyping.

Microarray testing also flagged 130 cases that were normal on karyotyping but showed chromosomal abnormalities "of uncertain significance." In 36 of these, the findings were judged to be "probably benign"; the remaining 94 cases were referred to an expert committee so their clinical relevance could be adjudicated. The committee judged 61 of these cases to be concerning enough that the patient should be informed of the chromosomal abnormality.

However, during the interval since the inception of this study 5 years ago, researchers have made considerable progress in determining whether most of these "uncertain" findings are either benign or clinically significant. If the currently available data had been used to adjudicate these 94 samples, only 56 would have been judged as "of uncertain significance," while 30 would have been categorized as clearly pathogenic and 8 as probably benign.

"With this additional information, the pathogenicity of only 1.5% of copy-number variants detected on microarray in karyotypically normal samples remains ‘uncertain,’ and this number should continue to fall as additional experience is acquired," Dr. Wapner and his associates said.

They added that they are following the offspring from the pregnancies in which copy-number variants were discovered, to establish what, if any, phenotypes develop. They are particularly interested in linking specific chromosomal abnormalities with later diagnoses of developmental delay.

This study was supported by the National Institute of Child Health and Human Development. Agilent Technologies and Affymetrix donated the microarrays and reagents used in the study, and Integrated Genetics was reimbursed for the costs of handling samples and managing cytogenetic data. Dr. Wapner reported no potential financial conflicts of interest, and his associates reported numerous ties to industry sources.

For older men with a urinary tract infection, taking antibiotics for more than 1 week does not reduce the rate of either early or late recurrence, compared with taking the drugs for 1 week, according to a report published online Dec. 3 in Archives of Internal Medicine.

Moreover, the longer course of antibiotics appeared to raise the risk of developing a Clostridium difficile infection in this retrospective observational study of 33,336 male outpatients, said Dr. Dimitri M. Drekonja of the Minneapolis Veterans Affairs Health Care System and his associates.

The study findings indicate that randomized clinical trials are needed to directly assess the benefits and harms of shorter-duration vs. longer-duration antibiotic therapy for male UTI, "to guide optimal management for this common condition," Dr. Drekonja and his colleagues noted.

The investigators used a national Veterans Affairs database to assess the effect of treatment duration on outcomes, because no study to date has evaluated the adequacy of a 7-day course of antibiotics in men as compared to a 10- or 14-day course. "The optimal treatment duration for UTI in men is unknown," they said.

For this study, the investigators searched the database for outpatient visits associated with ICD-9 codes for acute UTI and a concurrent prescription for a UTI-related antimicrobial during a single year. They identified 33,336 index cases, as well as 1,772 early recurrences (within 30 days of an index case) and 4,041 late recurrences (more than 30 days after an index case).

The mean patient age was 68 years, and comorbidities were common. The study subjects also frequently had medical conditions that predisposed them to UTI, including diabetes (35%), prostate hypertrophy (33%), and a history of prior UTI (31%).

The most commonly used agents for index cases were ciprofloxacin (63%); trimethoprim-sulfamethoxazole (27%); nitrofurantoin (6%); amoxicillin, either alone or in combination with clavulanic acid (6%); and levofloxacin (4%). Some index cases were treated with multiple antibiotics.

In a univariate analysis, rates of early recurrence were not significantly different between patients who received shorter-duration therapy (3.9%) and patients who received longer-duration therapy (4.2%).This was true in the study population as a whole and when the data were broken down by individual antibiotics.

This lack of difference in early recurrence rates persisted in a multivariate analysis, the investigators said (Arch. Intern. Med. 2012 Dec. 3 [doi: 10.1001/2013.jamainternmend.829]).

In a univariate analysis, longer duration of antibiotic therapy not only failed to cut the rate of late recurrences, but increased them slightly. Late recurrence rates were 11% in patients who received longer-duration therapy and 8.4% in those who received shorter-duration therapy. This small difference persisted in a multivariate analysis.

However, since this was an observational study, residual confounding could account for the failure to demonstrate a clinical benefit with longer duration of antibiotic therapy. "For instance, patients at increased risk for recurrence because of some unmeasured factor (e.g., catheter use) may have been overrepresented in the group that received longer-duration treatment," Dr. Drekonja and his associates said.

That is why they called for randomized clinical trials of the issue.

The researchers also examined whether longer duration of antibiotic therapy was associated with a higher rate of C. difficile infection than short-term antibiotic therapy. There was a slight increase in C. difficile infection in a univariate analysis (0.5% with long-duration vs. 0.3% with short-duration treatment), but that difference lost statistical significance in a multivariate analysis.

"Together, our findings suggest that longer-duration treatment for male UTI in the outpatient setting is not associated with a reduction in early or late recurrence and may be associated with an increase in subsequent C. difficile infection," they said.

This study was supported by the Minneapolis Veterans Affairs Health Care System. Dr. Drekonja reported no financial conflicts of interest. One of his associates reported ties to Merck, Rochester Medical, and Syntiron.

For older men with a urinary tract infection, taking antibiotics for more than 1 week does not reduce the rate of either early or late recurrence, compared with taking the drugs for 1 week, according to a report published online Dec. 3 in Archives of Internal Medicine.

Moreover, the longer course of antibiotics appeared to raise the risk of developing a Clostridium difficile infection in this retrospective observational study of 33,336 male outpatients, said Dr. Dimitri M. Drekonja of the Minneapolis Veterans Affairs Health Care System and his associates.

The study findings indicate that randomized clinical trials are needed to directly assess the benefits and harms of shorter-duration vs. longer-duration antibiotic therapy for male UTI, "to guide optimal management for this common condition," Dr. Drekonja and his colleagues noted.

The investigators used a national Veterans Affairs database to assess the effect of treatment duration on outcomes, because no study to date has evaluated the adequacy of a 7-day course of antibiotics in men as compared to a 10- or 14-day course. "The optimal treatment duration for UTI in men is unknown," they said.

For this study, the investigators searched the database for outpatient visits associated with ICD-9 codes for acute UTI and a concurrent prescription for a UTI-related antimicrobial during a single year. They identified 33,336 index cases, as well as 1,772 early recurrences (within 30 days of an index case) and 4,041 late recurrences (more than 30 days after an index case).

The mean patient age was 68 years, and comorbidities were common. The study subjects also frequently had medical conditions that predisposed them to UTI, including diabetes (35%), prostate hypertrophy (33%), and a history of prior UTI (31%).

The most commonly used agents for index cases were ciprofloxacin (63%); trimethoprim-sulfamethoxazole (27%); nitrofurantoin (6%); amoxicillin, either alone or in combination with clavulanic acid (6%); and levofloxacin (4%). Some index cases were treated with multiple antibiotics.

In a univariate analysis, rates of early recurrence were not significantly different between patients who received shorter-duration therapy (3.9%) and patients who received longer-duration therapy (4.2%).This was true in the study population as a whole and when the data were broken down by individual antibiotics.

This lack of difference in early recurrence rates persisted in a multivariate analysis, the investigators said (Arch. Intern. Med. 2012 Dec. 3 [doi: 10.1001/2013.jamainternmend.829]).

In a univariate analysis, longer duration of antibiotic therapy not only failed to cut the rate of late recurrences, but increased them slightly. Late recurrence rates were 11% in patients who received longer-duration therapy and 8.4% in those who received shorter-duration therapy. This small difference persisted in a multivariate analysis.

However, since this was an observational study, residual confounding could account for the failure to demonstrate a clinical benefit with longer duration of antibiotic therapy. "For instance, patients at increased risk for recurrence because of some unmeasured factor (e.g., catheter use) may have been overrepresented in the group that received longer-duration treatment," Dr. Drekonja and his associates said.

That is why they called for randomized clinical trials of the issue.

The researchers also examined whether longer duration of antibiotic therapy was associated with a higher rate of C. difficile infection than short-term antibiotic therapy. There was a slight increase in C. difficile infection in a univariate analysis (0.5% with long-duration vs. 0.3% with short-duration treatment), but that difference lost statistical significance in a multivariate analysis.

"Together, our findings suggest that longer-duration treatment for male UTI in the outpatient setting is not associated with a reduction in early or late recurrence and may be associated with an increase in subsequent C. difficile infection," they said.

This study was supported by the Minneapolis Veterans Affairs Health Care System. Dr. Drekonja reported no financial conflicts of interest. One of his associates reported ties to Merck, Rochester Medical, and Syntiron.

For older men with a urinary tract infection, taking antibiotics for more than 1 week does not reduce the rate of either early or late recurrence, compared with taking the drugs for 1 week, according to a report published online Dec. 3 in Archives of Internal Medicine.

Moreover, the longer course of antibiotics appeared to raise the risk of developing a Clostridium difficile infection in this retrospective observational study of 33,336 male outpatients, said Dr. Dimitri M. Drekonja of the Minneapolis Veterans Affairs Health Care System and his associates.

The study findings indicate that randomized clinical trials are needed to directly assess the benefits and harms of shorter-duration vs. longer-duration antibiotic therapy for male UTI, "to guide optimal management for this common condition," Dr. Drekonja and his colleagues noted.

The investigators used a national Veterans Affairs database to assess the effect of treatment duration on outcomes, because no study to date has evaluated the adequacy of a 7-day course of antibiotics in men as compared to a 10- or 14-day course. "The optimal treatment duration for UTI in men is unknown," they said.

For this study, the investigators searched the database for outpatient visits associated with ICD-9 codes for acute UTI and a concurrent prescription for a UTI-related antimicrobial during a single year. They identified 33,336 index cases, as well as 1,772 early recurrences (within 30 days of an index case) and 4,041 late recurrences (more than 30 days after an index case).

The mean patient age was 68 years, and comorbidities were common. The study subjects also frequently had medical conditions that predisposed them to UTI, including diabetes (35%), prostate hypertrophy (33%), and a history of prior UTI (31%).

The most commonly used agents for index cases were ciprofloxacin (63%); trimethoprim-sulfamethoxazole (27%); nitrofurantoin (6%); amoxicillin, either alone or in combination with clavulanic acid (6%); and levofloxacin (4%). Some index cases were treated with multiple antibiotics.

In a univariate analysis, rates of early recurrence were not significantly different between patients who received shorter-duration therapy (3.9%) and patients who received longer-duration therapy (4.2%).This was true in the study population as a whole and when the data were broken down by individual antibiotics.

This lack of difference in early recurrence rates persisted in a multivariate analysis, the investigators said (Arch. Intern. Med. 2012 Dec. 3 [doi: 10.1001/2013.jamainternmend.829]).

In a univariate analysis, longer duration of antibiotic therapy not only failed to cut the rate of late recurrences, but increased them slightly. Late recurrence rates were 11% in patients who received longer-duration therapy and 8.4% in those who received shorter-duration therapy. This small difference persisted in a multivariate analysis.

However, since this was an observational study, residual confounding could account for the failure to demonstrate a clinical benefit with longer duration of antibiotic therapy. "For instance, patients at increased risk for recurrence because of some unmeasured factor (e.g., catheter use) may have been overrepresented in the group that received longer-duration treatment," Dr. Drekonja and his associates said.

That is why they called for randomized clinical trials of the issue.

The researchers also examined whether longer duration of antibiotic therapy was associated with a higher rate of C. difficile infection than short-term antibiotic therapy. There was a slight increase in C. difficile infection in a univariate analysis (0.5% with long-duration vs. 0.3% with short-duration treatment), but that difference lost statistical significance in a multivariate analysis.

"Together, our findings suggest that longer-duration treatment for male UTI in the outpatient setting is not associated with a reduction in early or late recurrence and may be associated with an increase in subsequent C. difficile infection," they said.

This study was supported by the Minneapolis Veterans Affairs Health Care System. Dr. Drekonja reported no financial conflicts of interest. One of his associates reported ties to Merck, Rochester Medical, and Syntiron.

A nationally representative survey of more than 10,000 adolescents and their parents found "no compelling evidence for either misuse or overuse of psychotropic medications," according to a report published online Dec. 3 in Archives of Pediatrics and Adolescent Medicine.

Only 2.5% of these youths who had no DSM-IV diagnosis reported psychotropic use during the preceding year, and the clear majority of them had severe impairment or suicidality that warranted the treatment, said Kathleen R. Merikangas, Ph.D., of the National Institute of Mental Health, Bethesda, Md., and her associates.

Far from confirming concerns about inappropriate prescribing of psychotropic medications in the pediatric population, these study findings suggest that the agents are in fact underused and that mental health disorders are underrecognized in children and adolescents, the investigators said.

The "substantial" controversy over this issue has been generated chiefly by "anecdotal reports, studies of small unrepresentative clinical samples, and secondary analyses of large databases on prescription drug use that lack detailed clinical information about individual patients," Dr. Merikangas and her colleagues said.

"To our knowledge, no previous study has examined patterns of specific classes of psychotropic medication use among youth across a full range of common mental disorders and service sectors in a large nationally representative sample of adolescents," they added.

Their study drew on data from the National Comorbidity Survey Adolescent Supplement, a survey of 10,123 youths aged 13-18 years across the United States who were interviewed directly in 2001-2004 regarding their use of mental health services and medications during the preceding year. This included a household sample of 879 subjects and a school sample of 9,244. Parents or their surrogates were interviewed separately via written questionnaire, providing information on the subjects’ sociodemographic status, development, and physical and mental health.

The mean age of the study population was 15.2 years, and it was equally divided between boys and girls. The sample was predominantly (65.6%) non-Hispanic white. Most of the adolescents’ parents (85%) had completed at least a high school education, and 78.6% of the subjects lived with either married or cohabiting parents.

The interviewers administered a modified version of the World Health Organization Composite International Diagnostic Interview, which generated DSM-IV diagnoses for mood, anxiety, eating, behavior, and substance use disorders. The subjects and their parents also detailed the use of psychotropic medication for behavioral or emotional problems during the preceding year. The drugs were categorized in broad classes as antidepressants, stimulants, anxiolytics, mood stabilizers, or antipsychotics.

Overall, 24.9% of the study subjects said they had received mental health services during the past year.

Only 2.5% of adolescents without a DSM-IV diagnosis had been given psychotropic medications, and the clear majority of them "had evidence of psychological distress or impairment reflected in a lifetime history of mental disorders, subthreshold conditions, or developmental disorders," the investigators said (Arch. Pediatr. Adolesc. Med. 2012 Dec. 3 [doi:10.1001/jamapediatrics.2013.431]).

The clear majority of adolescents who reported using psychotropics, "particularly those who received treatment in specialty mental health settings, had a mental disorder with severe consequences and impairment, functional impairment, suicidality, or associated behavioral and developmental difficulties. When neurodevelopmental disorders, lifetime history, and subthreshold conditions are considered, there are few youths treated with psychotropic medications who did not have a serious behavioral, cognitive, or emotional disturbance," they noted.

Even among adolescents with a DSM-IV disorder, only 14.2% said they had been treated with a psychotropic medication.

The disorder with the highest prevalence of medication use was attention-deficit/hyperactivity disorder; 31% of the subjects with ADHD reported using psychotropics, as did 19.7% of those with mood disorders, 19.3% of those with eating disorders, 19.3% of those with behavior disorders, 14.4% of those with substance use disorders, and 11.6% of those with anxiety disorders.

The prevalence rates of use of the strongest psychotropic agents in particular were "very low." Only 1% of subjects with DSM-IV disorders used antipsychotics, only 0.7% used mood stabilizers, and only 1.3% used anxiolytics.

"The highest rates of psychotropic medication use were observed among those with a developmental disorder/autism (42%) or self-reported suicidality (27.1%)," Dr. Merikangas and her associates said.

Antidepressants were used primarily by subjects with depression or bipolar disorder, and less often by those with anxiety disorders. "Only 1.3% of those with no DSM-IV disorder reported antidepressant use during the past year," the researchers said.

Similarly, stimulants were used primarily by subjects with ADHD, though a small proportion (6%) of youth with other behavior disorders used stimulants. "Only 0.8% of those without a DSM-IV disorder reported stimulant use," they noted.

The proportion of subjects who used antipsychotics was "very small." Only 2% of subjects with developmental disorders or learning disabilities, 1.7% with bipolar disorder, and 1.8% with behavioral disorders used the drugs. And among subjects without a DSM-IV disorder, "only 0.1% ... reported antipsychotic prescriptions."

In addition to the low overall rates of use of psychotropic drugs, this robust correlation between specific disorders and individual medications "should also diminish criticism of medication misuse," Dr. Merikangas and her colleagues said.

Instead, clinicians should be concerned about underrecognition of mental health disorders and underuse of appropriate psychotropics in this patient population. For example, "despite unequivocal experimental evidence of efficacy, a substantial majority of adolescents with ADHD did not receive stimulants in the past year. Even among those who were treated in the specialty mental health sector, only about one-third of adolescents with ADHD received stimulants," they said.

This study was supported by the Intramural Research Program of the National Institute of Mental Health. No financial conflicts of interest were reported.

A nationally representative survey of more than 10,000 adolescents and their parents found "no compelling evidence for either misuse or overuse of psychotropic medications," according to a report published online Dec. 3 in Archives of Pediatrics and Adolescent Medicine.

Only 2.5% of these youths who had no DSM-IV diagnosis reported psychotropic use during the preceding year, and the clear majority of them had severe impairment or suicidality that warranted the treatment, said Kathleen R. Merikangas, Ph.D., of the National Institute of Mental Health, Bethesda, Md., and her associates.

Far from confirming concerns about inappropriate prescribing of psychotropic medications in the pediatric population, these study findings suggest that the agents are in fact underused and that mental health disorders are underrecognized in children and adolescents, the investigators said.

The "substantial" controversy over this issue has been generated chiefly by "anecdotal reports, studies of small unrepresentative clinical samples, and secondary analyses of large databases on prescription drug use that lack detailed clinical information about individual patients," Dr. Merikangas and her colleagues said.

"To our knowledge, no previous study has examined patterns of specific classes of psychotropic medication use among youth across a full range of common mental disorders and service sectors in a large nationally representative sample of adolescents," they added.

Their study drew on data from the National Comorbidity Survey Adolescent Supplement, a survey of 10,123 youths aged 13-18 years across the United States who were interviewed directly in 2001-2004 regarding their use of mental health services and medications during the preceding year. This included a household sample of 879 subjects and a school sample of 9,244. Parents or their surrogates were interviewed separately via written questionnaire, providing information on the subjects’ sociodemographic status, development, and physical and mental health.

The mean age of the study population was 15.2 years, and it was equally divided between boys and girls. The sample was predominantly (65.6%) non-Hispanic white. Most of the adolescents’ parents (85%) had completed at least a high school education, and 78.6% of the subjects lived with either married or cohabiting parents.

The interviewers administered a modified version of the World Health Organization Composite International Diagnostic Interview, which generated DSM-IV diagnoses for mood, anxiety, eating, behavior, and substance use disorders. The subjects and their parents also detailed the use of psychotropic medication for behavioral or emotional problems during the preceding year. The drugs were categorized in broad classes as antidepressants, stimulants, anxiolytics, mood stabilizers, or antipsychotics.

Overall, 24.9% of the study subjects said they had received mental health services during the past year.

Only 2.5% of adolescents without a DSM-IV diagnosis had been given psychotropic medications, and the clear majority of them "had evidence of psychological distress or impairment reflected in a lifetime history of mental disorders, subthreshold conditions, or developmental disorders," the investigators said (Arch. Pediatr. Adolesc. Med. 2012 Dec. 3 [doi:10.1001/jamapediatrics.2013.431]).

The clear majority of adolescents who reported using psychotropics, "particularly those who received treatment in specialty mental health settings, had a mental disorder with severe consequences and impairment, functional impairment, suicidality, or associated behavioral and developmental difficulties. When neurodevelopmental disorders, lifetime history, and subthreshold conditions are considered, there are few youths treated with psychotropic medications who did not have a serious behavioral, cognitive, or emotional disturbance," they noted.

Even among adolescents with a DSM-IV disorder, only 14.2% said they had been treated with a psychotropic medication.

The disorder with the highest prevalence of medication use was attention-deficit/hyperactivity disorder; 31% of the subjects with ADHD reported using psychotropics, as did 19.7% of those with mood disorders, 19.3% of those with eating disorders, 19.3% of those with behavior disorders, 14.4% of those with substance use disorders, and 11.6% of those with anxiety disorders.

The prevalence rates of use of the strongest psychotropic agents in particular were "very low." Only 1% of subjects with DSM-IV disorders used antipsychotics, only 0.7% used mood stabilizers, and only 1.3% used anxiolytics.

"The highest rates of psychotropic medication use were observed among those with a developmental disorder/autism (42%) or self-reported suicidality (27.1%)," Dr. Merikangas and her associates said.

Antidepressants were used primarily by subjects with depression or bipolar disorder, and less often by those with anxiety disorders. "Only 1.3% of those with no DSM-IV disorder reported antidepressant use during the past year," the researchers said.

Similarly, stimulants were used primarily by subjects with ADHD, though a small proportion (6%) of youth with other behavior disorders used stimulants. "Only 0.8% of those without a DSM-IV disorder reported stimulant use," they noted.

The proportion of subjects who used antipsychotics was "very small." Only 2% of subjects with developmental disorders or learning disabilities, 1.7% with bipolar disorder, and 1.8% with behavioral disorders used the drugs. And among subjects without a DSM-IV disorder, "only 0.1% ... reported antipsychotic prescriptions."

In addition to the low overall rates of use of psychotropic drugs, this robust correlation between specific disorders and individual medications "should also diminish criticism of medication misuse," Dr. Merikangas and her colleagues said.

Instead, clinicians should be concerned about underrecognition of mental health disorders and underuse of appropriate psychotropics in this patient population. For example, "despite unequivocal experimental evidence of efficacy, a substantial majority of adolescents with ADHD did not receive stimulants in the past year. Even among those who were treated in the specialty mental health sector, only about one-third of adolescents with ADHD received stimulants," they said.

This study was supported by the Intramural Research Program of the National Institute of Mental Health. No financial conflicts of interest were reported.

A nationally representative survey of more than 10,000 adolescents and their parents found "no compelling evidence for either misuse or overuse of psychotropic medications," according to a report published online Dec. 3 in Archives of Pediatrics and Adolescent Medicine.

Only 2.5% of these youths who had no DSM-IV diagnosis reported psychotropic use during the preceding year, and the clear majority of them had severe impairment or suicidality that warranted the treatment, said Kathleen R. Merikangas, Ph.D., of the National Institute of Mental Health, Bethesda, Md., and her associates.

Far from confirming concerns about inappropriate prescribing of psychotropic medications in the pediatric population, these study findings suggest that the agents are in fact underused and that mental health disorders are underrecognized in children and adolescents, the investigators said.

The "substantial" controversy over this issue has been generated chiefly by "anecdotal reports, studies of small unrepresentative clinical samples, and secondary analyses of large databases on prescription drug use that lack detailed clinical information about individual patients," Dr. Merikangas and her colleagues said.

"To our knowledge, no previous study has examined patterns of specific classes of psychotropic medication use among youth across a full range of common mental disorders and service sectors in a large nationally representative sample of adolescents," they added.

Their study drew on data from the National Comorbidity Survey Adolescent Supplement, a survey of 10,123 youths aged 13-18 years across the United States who were interviewed directly in 2001-2004 regarding their use of mental health services and medications during the preceding year. This included a household sample of 879 subjects and a school sample of 9,244. Parents or their surrogates were interviewed separately via written questionnaire, providing information on the subjects’ sociodemographic status, development, and physical and mental health.

The mean age of the study population was 15.2 years, and it was equally divided between boys and girls. The sample was predominantly (65.6%) non-Hispanic white. Most of the adolescents’ parents (85%) had completed at least a high school education, and 78.6% of the subjects lived with either married or cohabiting parents.

The interviewers administered a modified version of the World Health Organization Composite International Diagnostic Interview, which generated DSM-IV diagnoses for mood, anxiety, eating, behavior, and substance use disorders. The subjects and their parents also detailed the use of psychotropic medication for behavioral or emotional problems during the preceding year. The drugs were categorized in broad classes as antidepressants, stimulants, anxiolytics, mood stabilizers, or antipsychotics.

Overall, 24.9% of the study subjects said they had received mental health services during the past year.

Only 2.5% of adolescents without a DSM-IV diagnosis had been given psychotropic medications, and the clear majority of them "had evidence of psychological distress or impairment reflected in a lifetime history of mental disorders, subthreshold conditions, or developmental disorders," the investigators said (Arch. Pediatr. Adolesc. Med. 2012 Dec. 3 [doi:10.1001/jamapediatrics.2013.431]).

The clear majority of adolescents who reported using psychotropics, "particularly those who received treatment in specialty mental health settings, had a mental disorder with severe consequences and impairment, functional impairment, suicidality, or associated behavioral and developmental difficulties. When neurodevelopmental disorders, lifetime history, and subthreshold conditions are considered, there are few youths treated with psychotropic medications who did not have a serious behavioral, cognitive, or emotional disturbance," they noted.

Even among adolescents with a DSM-IV disorder, only 14.2% said they had been treated with a psychotropic medication.

The disorder with the highest prevalence of medication use was attention-deficit/hyperactivity disorder; 31% of the subjects with ADHD reported using psychotropics, as did 19.7% of those with mood disorders, 19.3% of those with eating disorders, 19.3% of those with behavior disorders, 14.4% of those with substance use disorders, and 11.6% of those with anxiety disorders.

The prevalence rates of use of the strongest psychotropic agents in particular were "very low." Only 1% of subjects with DSM-IV disorders used antipsychotics, only 0.7% used mood stabilizers, and only 1.3% used anxiolytics.

"The highest rates of psychotropic medication use were observed among those with a developmental disorder/autism (42%) or self-reported suicidality (27.1%)," Dr. Merikangas and her associates said.

Antidepressants were used primarily by subjects with depression or bipolar disorder, and less often by those with anxiety disorders. "Only 1.3% of those with no DSM-IV disorder reported antidepressant use during the past year," the researchers said.

Similarly, stimulants were used primarily by subjects with ADHD, though a small proportion (6%) of youth with other behavior disorders used stimulants. "Only 0.8% of those without a DSM-IV disorder reported stimulant use," they noted.

The proportion of subjects who used antipsychotics was "very small." Only 2% of subjects with developmental disorders or learning disabilities, 1.7% with bipolar disorder, and 1.8% with behavioral disorders used the drugs. And among subjects without a DSM-IV disorder, "only 0.1% ... reported antipsychotic prescriptions."

In addition to the low overall rates of use of psychotropic drugs, this robust correlation between specific disorders and individual medications "should also diminish criticism of medication misuse," Dr. Merikangas and her colleagues said.

Instead, clinicians should be concerned about underrecognition of mental health disorders and underuse of appropriate psychotropics in this patient population. For example, "despite unequivocal experimental evidence of efficacy, a substantial majority of adolescents with ADHD did not receive stimulants in the past year. Even among those who were treated in the specialty mental health sector, only about one-third of adolescents with ADHD received stimulants," they said.

This study was supported by the Intramural Research Program of the National Institute of Mental Health. No financial conflicts of interest were reported.

Videocapsule endoscopy’s success at identifying the cause of obscure gastrointestinal bleeding was found to be associated with markedly different clinical factors in two separate studies published in the December issue of Clinical Gastroenterology and Hepatology.

Capsule endoscopy allows visualization of the entire small bowel. Knowing which factors are associated with positive findings on capsule endoscopy would allow more appropriate patient selection for the procedure. This in turn would improve its diagnostic yield and maximize resource utilization.

Unfortunately, no single factor was found to accurately predict the success of this form of endoscopy in patients who presented with obscure gastrointestinal bleeding (OGIB) and who had negative or ambiguous findings on upper and lower endoscopies. In fact, the two studies identified entirely different predictors.

In the first study, Dr. Neal C. Shahidi and his associates at the University of British Columbia, Vancouver, reviewed the records of all 698 capsule endoscopies performed at St. Paul’s Hospital in 2001-2011 for the indication of OGIB. Mean patient age was 63 years, and the cohort was equally composed of men and women.

Approximately 48% of these study subjects presented with overt bleeding: hematemesis, hematochezia, or melena. The other 52% presented with occult bleeding evidenced by a positive fecal occult blood test (28%), iron deficiency anemia (21%), or an acute drop in hemoglobin (3%). No causes for the bleeding were identified on conventional esophagogastroduodenoscopy, intraoperative enteroscopy, or colonoscopy.

In approximately 4% of cases, capsule endoscopy failed for technical reasons, including limited visualization because of excessive debris, failure of the videocapsule to enter the small bowel within the procedure time, or inadequate viewing of the small bowel.

Capsule endoscopy definitively identified the cause of the bleeding – ulcerations/erosions, masses, vascular lesions, or visible blood – in 42% of these cases. Most were localized to the small bowel, although 18% were found in the stomach or cecum.

Even though the investigators "rigorously assessed" symptoms, other clinical factors, and patient characteristics such as smoking status, alcohol consumption, and a variety of comorbid conditions, the only factors found to be significantly associated with positive findings on capsule endoscopy were a high number of esophagogastroduodenoscopies leading up to the procedure (odds ratio 1.17), an increase in the need for transfusions (3-9 transfusions, OR 1.70; 10 or more, OR 2.72), and the presence of comorbid connective-tissue disease (OR 2.24).

This is the first report in the literature linking connective-tissue disease with positive findings on capsule endoscopy. There were 41 patients with rheumatoid arthritis, polymyalgia rheumatica, scleroderma, or other connective-tissue disorders in this series.

The increased frequency of positive capsule endoscopy in this subgroup of patients may be due in part to their predisposition to vascular lesions. Alternatively, connective-tissue disease may simply be a marker for the regular use of NSAIDs, Dr. Shahidi and his associates said.

Regarding the association with an increasing need for transfusions, "it is acceptable to presume that a patient’s transfusion requirements may be a marker for ongoing or severe pathology within the gastrointestinal tract," they noted.

Similarly, more frequent esophagogastroduodenoscopies may be another marker for ongoing GI bleeding, "as patients who continue to experience significant bleeding may undergo more endoscopic assessment," they added.

In the second study, Dr. Lucie Lepileur of the University of Rouen (France) and her colleagues reviewed the records on 911 capsule endoscopies performed for OGIB at two university referral centers during 2004-2010.

All the study subjects had undergone upper and lower endoscopies that were deemed negative or insufficient to explain their symptoms. A total of 41% presented with overt bleeding, chiefly melena and hematochezia, and the remaining 59% had occult bleeding.

Capsule endoscopy failed for technical reasons in approximately 1% of the cohort. It permitted a definitive diagnosis in 56%, including 203 angioectasias, 88 ulcerations, 70 tumors, 24 varices, and 6 diverticula of the small bowel. The procedure also identified lesions in the esophagus or stomach and the colon.

In another 8% of patients, capsule endoscopy revealed signs of suspected recent bleeding such as residual blood, clots, or red spots, but didn’t identify a specific lesion. The procedure failed to reveal any possible source of bleeding in the remaining 35% of cases.

The only factors found to be significantly associated with positive findings on capsule endoscopy were a history of overt bleeding (OR 3.8), male gender (OR 1.4), age of more than 60 years (OR 1.4), and inpatient status (OR 1.3). Conversely, female gender was the only factor found to be predictive of a nondiagnostic procedure.

The link with advanced age "can easily be explained by the more frequent occurrence of angioectasia in the elderly, which was the main bleeding lesion found in our series," Dr. Lepileur and her colleagues wrote.

The link with inpatient status likely reflects the more fragile health or more critical bleeding among patients who are hospitalized than among outpatients.

The finding that capsule endoscopy is more fruitful in men and less so in women suggests that the cause of chronic blood loss among women may be gynecologic rather than gastrointestinal in nature, the researchers said.

Neither Dr. Shahidi nor Dr. Lepileur reported any potential financial conflicts of interest.

Videocapsule endoscopy’s success at identifying the cause of obscure gastrointestinal bleeding was found to be associated with markedly different clinical factors in two separate studies published in the December issue of Clinical Gastroenterology and Hepatology.

Capsule endoscopy allows visualization of the entire small bowel. Knowing which factors are associated with positive findings on capsule endoscopy would allow more appropriate patient selection for the procedure. This in turn would improve its diagnostic yield and maximize resource utilization.

Unfortunately, no single factor was found to accurately predict the success of this form of endoscopy in patients who presented with obscure gastrointestinal bleeding (OGIB) and who had negative or ambiguous findings on upper and lower endoscopies. In fact, the two studies identified entirely different predictors.

In the first study, Dr. Neal C. Shahidi and his associates at the University of British Columbia, Vancouver, reviewed the records of all 698 capsule endoscopies performed at St. Paul’s Hospital in 2001-2011 for the indication of OGIB. Mean patient age was 63 years, and the cohort was equally composed of men and women.

Approximately 48% of these study subjects presented with overt bleeding: hematemesis, hematochezia, or melena. The other 52% presented with occult bleeding evidenced by a positive fecal occult blood test (28%), iron deficiency anemia (21%), or an acute drop in hemoglobin (3%). No causes for the bleeding were identified on conventional esophagogastroduodenoscopy, intraoperative enteroscopy, or colonoscopy.

In approximately 4% of cases, capsule endoscopy failed for technical reasons, including limited visualization because of excessive debris, failure of the videocapsule to enter the small bowel within the procedure time, or inadequate viewing of the small bowel.

Capsule endoscopy definitively identified the cause of the bleeding – ulcerations/erosions, masses, vascular lesions, or visible blood – in 42% of these cases. Most were localized to the small bowel, although 18% were found in the stomach or cecum.

Even though the investigators "rigorously assessed" symptoms, other clinical factors, and patient characteristics such as smoking status, alcohol consumption, and a variety of comorbid conditions, the only factors found to be significantly associated with positive findings on capsule endoscopy were a high number of esophagogastroduodenoscopies leading up to the procedure (odds ratio 1.17), an increase in the need for transfusions (3-9 transfusions, OR 1.70; 10 or more, OR 2.72), and the presence of comorbid connective-tissue disease (OR 2.24).

This is the first report in the literature linking connective-tissue disease with positive findings on capsule endoscopy. There were 41 patients with rheumatoid arthritis, polymyalgia rheumatica, scleroderma, or other connective-tissue disorders in this series.

The increased frequency of positive capsule endoscopy in this subgroup of patients may be due in part to their predisposition to vascular lesions. Alternatively, connective-tissue disease may simply be a marker for the regular use of NSAIDs, Dr. Shahidi and his associates said.

Regarding the association with an increasing need for transfusions, "it is acceptable to presume that a patient’s transfusion requirements may be a marker for ongoing or severe pathology within the gastrointestinal tract," they noted.

Similarly, more frequent esophagogastroduodenoscopies may be another marker for ongoing GI bleeding, "as patients who continue to experience significant bleeding may undergo more endoscopic assessment," they added.

In the second study, Dr. Lucie Lepileur of the University of Rouen (France) and her colleagues reviewed the records on 911 capsule endoscopies performed for OGIB at two university referral centers during 2004-2010.

All the study subjects had undergone upper and lower endoscopies that were deemed negative or insufficient to explain their symptoms. A total of 41% presented with overt bleeding, chiefly melena and hematochezia, and the remaining 59% had occult bleeding.

Capsule endoscopy failed for technical reasons in approximately 1% of the cohort. It permitted a definitive diagnosis in 56%, including 203 angioectasias, 88 ulcerations, 70 tumors, 24 varices, and 6 diverticula of the small bowel. The procedure also identified lesions in the esophagus or stomach and the colon.

In another 8% of patients, capsule endoscopy revealed signs of suspected recent bleeding such as residual blood, clots, or red spots, but didn’t identify a specific lesion. The procedure failed to reveal any possible source of bleeding in the remaining 35% of cases.

The only factors found to be significantly associated with positive findings on capsule endoscopy were a history of overt bleeding (OR 3.8), male gender (OR 1.4), age of more than 60 years (OR 1.4), and inpatient status (OR 1.3). Conversely, female gender was the only factor found to be predictive of a nondiagnostic procedure.

The link with advanced age "can easily be explained by the more frequent occurrence of angioectasia in the elderly, which was the main bleeding lesion found in our series," Dr. Lepileur and her colleagues wrote.

The link with inpatient status likely reflects the more fragile health or more critical bleeding among patients who are hospitalized than among outpatients.

The finding that capsule endoscopy is more fruitful in men and less so in women suggests that the cause of chronic blood loss among women may be gynecologic rather than gastrointestinal in nature, the researchers said.

Neither Dr. Shahidi nor Dr. Lepileur reported any potential financial conflicts of interest.

Videocapsule endoscopy’s success at identifying the cause of obscure gastrointestinal bleeding was found to be associated with markedly different clinical factors in two separate studies published in the December issue of Clinical Gastroenterology and Hepatology.

Capsule endoscopy allows visualization of the entire small bowel. Knowing which factors are associated with positive findings on capsule endoscopy would allow more appropriate patient selection for the procedure. This in turn would improve its diagnostic yield and maximize resource utilization.

Unfortunately, no single factor was found to accurately predict the success of this form of endoscopy in patients who presented with obscure gastrointestinal bleeding (OGIB) and who had negative or ambiguous findings on upper and lower endoscopies. In fact, the two studies identified entirely different predictors.

In the first study, Dr. Neal C. Shahidi and his associates at the University of British Columbia, Vancouver, reviewed the records of all 698 capsule endoscopies performed at St. Paul’s Hospital in 2001-2011 for the indication of OGIB. Mean patient age was 63 years, and the cohort was equally composed of men and women.

Approximately 48% of these study subjects presented with overt bleeding: hematemesis, hematochezia, or melena. The other 52% presented with occult bleeding evidenced by a positive fecal occult blood test (28%), iron deficiency anemia (21%), or an acute drop in hemoglobin (3%). No causes for the bleeding were identified on conventional esophagogastroduodenoscopy, intraoperative enteroscopy, or colonoscopy.

In approximately 4% of cases, capsule endoscopy failed for technical reasons, including limited visualization because of excessive debris, failure of the videocapsule to enter the small bowel within the procedure time, or inadequate viewing of the small bowel.

Capsule endoscopy definitively identified the cause of the bleeding – ulcerations/erosions, masses, vascular lesions, or visible blood – in 42% of these cases. Most were localized to the small bowel, although 18% were found in the stomach or cecum.

Even though the investigators "rigorously assessed" symptoms, other clinical factors, and patient characteristics such as smoking status, alcohol consumption, and a variety of comorbid conditions, the only factors found to be significantly associated with positive findings on capsule endoscopy were a high number of esophagogastroduodenoscopies leading up to the procedure (odds ratio 1.17), an increase in the need for transfusions (3-9 transfusions, OR 1.70; 10 or more, OR 2.72), and the presence of comorbid connective-tissue disease (OR 2.24).

This is the first report in the literature linking connective-tissue disease with positive findings on capsule endoscopy. There were 41 patients with rheumatoid arthritis, polymyalgia rheumatica, scleroderma, or other connective-tissue disorders in this series.

The increased frequency of positive capsule endoscopy in this subgroup of patients may be due in part to their predisposition to vascular lesions. Alternatively, connective-tissue disease may simply be a marker for the regular use of NSAIDs, Dr. Shahidi and his associates said.

Regarding the association with an increasing need for transfusions, "it is acceptable to presume that a patient’s transfusion requirements may be a marker for ongoing or severe pathology within the gastrointestinal tract," they noted.

Similarly, more frequent esophagogastroduodenoscopies may be another marker for ongoing GI bleeding, "as patients who continue to experience significant bleeding may undergo more endoscopic assessment," they added.

In the second study, Dr. Lucie Lepileur of the University of Rouen (France) and her colleagues reviewed the records on 911 capsule endoscopies performed for OGIB at two university referral centers during 2004-2010.

All the study subjects had undergone upper and lower endoscopies that were deemed negative or insufficient to explain their symptoms. A total of 41% presented with overt bleeding, chiefly melena and hematochezia, and the remaining 59% had occult bleeding.

Capsule endoscopy failed for technical reasons in approximately 1% of the cohort. It permitted a definitive diagnosis in 56%, including 203 angioectasias, 88 ulcerations, 70 tumors, 24 varices, and 6 diverticula of the small bowel. The procedure also identified lesions in the esophagus or stomach and the colon.

In another 8% of patients, capsule endoscopy revealed signs of suspected recent bleeding such as residual blood, clots, or red spots, but didn’t identify a specific lesion. The procedure failed to reveal any possible source of bleeding in the remaining 35% of cases.

The only factors found to be significantly associated with positive findings on capsule endoscopy were a history of overt bleeding (OR 3.8), male gender (OR 1.4), age of more than 60 years (OR 1.4), and inpatient status (OR 1.3). Conversely, female gender was the only factor found to be predictive of a nondiagnostic procedure.

The link with advanced age "can easily be explained by the more frequent occurrence of angioectasia in the elderly, which was the main bleeding lesion found in our series," Dr. Lepileur and her colleagues wrote.

The link with inpatient status likely reflects the more fragile health or more critical bleeding among patients who are hospitalized than among outpatients.

The finding that capsule endoscopy is more fruitful in men and less so in women suggests that the cause of chronic blood loss among women may be gynecologic rather than gastrointestinal in nature, the researchers said.

Neither Dr. Shahidi nor Dr. Lepileur reported any potential financial conflicts of interest.

Empiric acid suppression with the "PPI test," widely used to assess whether upper-GI symptoms are due to gastroesophageal reflux disease, actually performs poorly as a predictor of GERD, Dr. Peter Bytzer and his colleagues wrote in the December issue of Clinical Gastroenterology and Hepatology.

Typically, clinicians perform a PPI test to diagnose GERD without the need for endoscopy. They give patients a 2-week course of a proton pump inhibitor and then determine whether the brief treatment ameliorated upper GI symptoms. If so, the symptoms are assumed to be acid related, said Dr. Bytzer of Copenhagen University and his associates.

But in their study, such a PPI test "showed a disappointingly low validity" for diagnosing GERD, and couldn’t reliably distinguish between reflux esophagitis and nonerosive reflux disease. Even when combined with a clinical diagnosis made by a primary care physician, a clinical diagnosis made by a gastroenterologist, or the results of a detailed diagnostic questionnaire, the outcome of a PPI test didn’t add reliable information allowing clinicians to separate patients who had GERD from those who did not, the researchers said (Clin. Gastroenterol. Hepatol. 2012 [doi:10.1016/j.cgh.2012.06.030]).

Dr. Bytzer and his colleagues analyzed data originally collected in the DIAMOND clinical trial, an international study that found the Reflux Disease Questionnaire to be useful in diagnosing GERD among patients who consulted primary care physicians because of frequent upper GI symptoms. The DIAMOND study results indicated that unlike the Reflux Disease Questionnaire, PPI testing had very limited diagnostic value.

Dr. Bytzer and his associates performed more detailed analyses of the data, using different combinations of three main symptoms (heartburn, central chest pain, and dysphagia or regurgitation); different definitions of "PPI response"; and assessments of various subgroups of patients, all in the hope of improving the diagnostic yield of PPI testing. They compared the diagnostic usefulness of PPI testing against state-of-the-art comprehensive diagnostic work-ups for GERD in 299 of the DIAMOND study subjects.

"This large database provides the best platform so far to test whether there are better approaches for scoring a test of PPI therapy," the investigators noted.

All of the subjects underwent endoscopy with concomitant wireless esophageal pH monitoring and symptom assessment. They then completed the detailed Reflux Disease Questionnaire, and participated in a 2-week PPI test using esomeprazole (Nexium), during which they recorded GI symptoms in a diary.

A total of 69% of the patients who did have GERD showed a positive response to the PPI test. This means that 31% of the study participants with GERD were not identified by PPI testing.

Moreover, 51% of the patients who did not have GERD also showed a positive response to the PPI test, the investigators said.

Both patients who had GERD and patients who did not reported that their symptom response to acid suppression increased over the course of the first 5-6 days of treatment and then leveled off for the remaining 8-9 days.

The PPI test performed only marginally better across various subgroups of patients, such as those with GERD plus reflux esophagitis (as compared with patients who had GERD but no reflux esophagitis) or those whose physicians were certain of their GERD diagnosis (compared with patients whose physicians were uncertain about their GERD diagnosis).

For example, 48% of the study participants whose physicians predicted that they had GERD showed a positive response on PPI testing – a rate that was nearly identical to the 47% of study subjects whose physicians predicted that they had some disorder other than GERD.

Similarly, the PPI test performed only marginally better when different symptom combinations and different definitions of "PPI response" were assessed.

"In line with other researchers, we found that ... the clinical value of [the PPI test] is very limited," Dr. Bytzer and his colleagues said.

This study was funded by AstraZeneca. Dr. Bytzer reported ties to AstraZeneca, Boehringer Ingelheim, Eisai, Nycomed, Reckitt Benckiser, Takeda, and Wyeth, and his associates reported ties to numerous industry sources, including employment by AstraZeneca.

Empiric acid suppression with the "PPI test," widely used to assess whether upper-GI symptoms are due to gastroesophageal reflux disease, actually performs poorly as a predictor of GERD, Dr. Peter Bytzer and his colleagues wrote in the December issue of Clinical Gastroenterology and Hepatology.

Typically, clinicians perform a PPI test to diagnose GERD without the need for endoscopy. They give patients a 2-week course of a proton pump inhibitor and then determine whether the brief treatment ameliorated upper GI symptoms. If so, the symptoms are assumed to be acid related, said Dr. Bytzer of Copenhagen University and his associates.

But in their study, such a PPI test "showed a disappointingly low validity" for diagnosing GERD, and couldn’t reliably distinguish between reflux esophagitis and nonerosive reflux disease. Even when combined with a clinical diagnosis made by a primary care physician, a clinical diagnosis made by a gastroenterologist, or the results of a detailed diagnostic questionnaire, the outcome of a PPI test didn’t add reliable information allowing clinicians to separate patients who had GERD from those who did not, the researchers said (Clin. Gastroenterol. Hepatol. 2012 [doi:10.1016/j.cgh.2012.06.030]).

Dr. Bytzer and his colleagues analyzed data originally collected in the DIAMOND clinical trial, an international study that found the Reflux Disease Questionnaire to be useful in diagnosing GERD among patients who consulted primary care physicians because of frequent upper GI symptoms. The DIAMOND study results indicated that unlike the Reflux Disease Questionnaire, PPI testing had very limited diagnostic value.

Dr. Bytzer and his associates performed more detailed analyses of the data, using different combinations of three main symptoms (heartburn, central chest pain, and dysphagia or regurgitation); different definitions of "PPI response"; and assessments of various subgroups of patients, all in the hope of improving the diagnostic yield of PPI testing. They compared the diagnostic usefulness of PPI testing against state-of-the-art comprehensive diagnostic work-ups for GERD in 299 of the DIAMOND study subjects.

"This large database provides the best platform so far to test whether there are better approaches for scoring a test of PPI therapy," the investigators noted.

All of the subjects underwent endoscopy with concomitant wireless esophageal pH monitoring and symptom assessment. They then completed the detailed Reflux Disease Questionnaire, and participated in a 2-week PPI test using esomeprazole (Nexium), during which they recorded GI symptoms in a diary.

A total of 69% of the patients who did have GERD showed a positive response to the PPI test. This means that 31% of the study participants with GERD were not identified by PPI testing.

Moreover, 51% of the patients who did not have GERD also showed a positive response to the PPI test, the investigators said.

Both patients who had GERD and patients who did not reported that their symptom response to acid suppression increased over the course of the first 5-6 days of treatment and then leveled off for the remaining 8-9 days.

The PPI test performed only marginally better across various subgroups of patients, such as those with GERD plus reflux esophagitis (as compared with patients who had GERD but no reflux esophagitis) or those whose physicians were certain of their GERD diagnosis (compared with patients whose physicians were uncertain about their GERD diagnosis).

For example, 48% of the study participants whose physicians predicted that they had GERD showed a positive response on PPI testing – a rate that was nearly identical to the 47% of study subjects whose physicians predicted that they had some disorder other than GERD.

Similarly, the PPI test performed only marginally better when different symptom combinations and different definitions of "PPI response" were assessed.

"In line with other researchers, we found that ... the clinical value of [the PPI test] is very limited," Dr. Bytzer and his colleagues said.

This study was funded by AstraZeneca. Dr. Bytzer reported ties to AstraZeneca, Boehringer Ingelheim, Eisai, Nycomed, Reckitt Benckiser, Takeda, and Wyeth, and his associates reported ties to numerous industry sources, including employment by AstraZeneca.

Empiric acid suppression with the "PPI test," widely used to assess whether upper-GI symptoms are due to gastroesophageal reflux disease, actually performs poorly as a predictor of GERD, Dr. Peter Bytzer and his colleagues wrote in the December issue of Clinical Gastroenterology and Hepatology.

Typically, clinicians perform a PPI test to diagnose GERD without the need for endoscopy. They give patients a 2-week course of a proton pump inhibitor and then determine whether the brief treatment ameliorated upper GI symptoms. If so, the symptoms are assumed to be acid related, said Dr. Bytzer of Copenhagen University and his associates.

But in their study, such a PPI test "showed a disappointingly low validity" for diagnosing GERD, and couldn’t reliably distinguish between reflux esophagitis and nonerosive reflux disease. Even when combined with a clinical diagnosis made by a primary care physician, a clinical diagnosis made by a gastroenterologist, or the results of a detailed diagnostic questionnaire, the outcome of a PPI test didn’t add reliable information allowing clinicians to separate patients who had GERD from those who did not, the researchers said (Clin. Gastroenterol. Hepatol. 2012 [doi:10.1016/j.cgh.2012.06.030]).

Dr. Bytzer and his colleagues analyzed data originally collected in the DIAMOND clinical trial, an international study that found the Reflux Disease Questionnaire to be useful in diagnosing GERD among patients who consulted primary care physicians because of frequent upper GI symptoms. The DIAMOND study results indicated that unlike the Reflux Disease Questionnaire, PPI testing had very limited diagnostic value.

Dr. Bytzer and his associates performed more detailed analyses of the data, using different combinations of three main symptoms (heartburn, central chest pain, and dysphagia or regurgitation); different definitions of "PPI response"; and assessments of various subgroups of patients, all in the hope of improving the diagnostic yield of PPI testing. They compared the diagnostic usefulness of PPI testing against state-of-the-art comprehensive diagnostic work-ups for GERD in 299 of the DIAMOND study subjects.

"This large database provides the best platform so far to test whether there are better approaches for scoring a test of PPI therapy," the investigators noted.

All of the subjects underwent endoscopy with concomitant wireless esophageal pH monitoring and symptom assessment. They then completed the detailed Reflux Disease Questionnaire, and participated in a 2-week PPI test using esomeprazole (Nexium), during which they recorded GI symptoms in a diary.

A total of 69% of the patients who did have GERD showed a positive response to the PPI test. This means that 31% of the study participants with GERD were not identified by PPI testing.

Moreover, 51% of the patients who did not have GERD also showed a positive response to the PPI test, the investigators said.

Both patients who had GERD and patients who did not reported that their symptom response to acid suppression increased over the course of the first 5-6 days of treatment and then leveled off for the remaining 8-9 days.

The PPI test performed only marginally better across various subgroups of patients, such as those with GERD plus reflux esophagitis (as compared with patients who had GERD but no reflux esophagitis) or those whose physicians were certain of their GERD diagnosis (compared with patients whose physicians were uncertain about their GERD diagnosis).

For example, 48% of the study participants whose physicians predicted that they had GERD showed a positive response on PPI testing – a rate that was nearly identical to the 47% of study subjects whose physicians predicted that they had some disorder other than GERD.

Similarly, the PPI test performed only marginally better when different symptom combinations and different definitions of "PPI response" were assessed.

"In line with other researchers, we found that ... the clinical value of [the PPI test] is very limited," Dr. Bytzer and his colleagues said.

This study was funded by AstraZeneca. Dr. Bytzer reported ties to AstraZeneca, Boehringer Ingelheim, Eisai, Nycomed, Reckitt Benckiser, Takeda, and Wyeth, and his associates reported ties to numerous industry sources, including employment by AstraZeneca.

Two large observational "real-world" studies of two different treatments for heart failure failed to confirm the results of clinical trials of those treatments, leaving clinicians to wonder which study findings to trust, according to separate reports in the Nov. 28 issue of JAMA.

In one report, aldosterone antagonists failed to improve mortality or reduce CV readmissions in patients who had heart failure with decreased ejection fraction, after clinical trials had indicated the agents would do so. In another report, renin-angiotensin system antagonists did reduce mortality in patients who had HF with preserved ejection fraction, after clinical trials had indicated the drugs would not do so.

Both research groups called for additional study to clarify the discrepant results.

In the first study, investigators noted that "landmark clinical trials" had shown the aldosterone antagonists spironolactone and eplerenone cut mortality by up to 30% and readmissions for HF by nearly 40% among patients who had heart failure accompanied by reduced ejection fraction. Yet even though these drugs are now recommended for such patients, physicians have been slow to comply.

This may be due in part to uncertainty about the safety and effectiveness of aldosterone antagonists under real-world conditions, where many patients – the elderly, those with diabetes or chronic kidney disease, and those already using other medications predisposing them to hyperkalemia – fall outside the strict inclusion criteria used in clinical trial populations, said Dr. Adrian F. Hernandez of Duke Clinical Research Institute, Durham, N.C., and his associates.

Dr. Hernandez and his colleagues used data from the Get With The Guidelines–HF registry and the Medicare claims database to assess the drugs’ effectiveness in 5,887 patients aged 65 and older who had been discharged from 246 U.S. hospitals with a diagnosis of HF with decreased left ventricular ejection fraction in 2005-2009 and who were eligible for treatment with aldosterone antagonists. Only 1,070 of the study subjects received a prescription for the drugs at discharge.

After 3 years, there were no significant differences in all-cause mortality or in readmission for cardiovascular disorders between patients who were given aldosterone antagonists and patients who were not, the researchers said (JAMA 2012;308:2097-107).

On the down side, treated patients did show a higher rate of rehospitalization for hyperkalemia, usually during the first few weeks after initiating therapy with aldosterone antagonists.

This study wasn’t designed to determine why the results contradicted the "impressive benefits of aldosterone antagonist therapy" reported in "pivotal" efficacy trials as well as in a systematic review of randomized clinical trials of the therapy. But the researchers suggested that it’s possible the drugs have limited effectiveness in older patients in clinical practice, possibly because they may not adhere to treatment as well as subjects in intensely monitored clinical trials.

"Our findings highlight the importance of conducting clinical trials that can be easily generalized to real-world practice and in which the most vulnerable patient groups are well represented," Dr. Hernandez and his colleagues said.

Moreover, "developing protocols and systems that encourage optimal use and monitoring of aldosterone antagonist therapy may help to ensure that the effectiveness of this therapy in clinical practice approaches the efficacy achieved in clinical trials."

The investigators added that in their study, aldosterone antagonists did reduce the rate of rehospitalization for HF, which indicates that further study is needed to clarify the benefits and risks of therapy.

The second JAMA report involved the use of renin-angiotensin system (RAS) antagonists, which includes ACE inhibitors and angiotensin-receptor blockers, for patients who have heart failure with preserved ejection fraction. Three randomized clinical trials had concluded that the agents failed to improve outcomes in such patients, but those trials were marred by flaws such as selection bias, underpowering, and high crossover rates, said Dr. Lars H. Lund of the Karolinska Institutet, Stockholm, and his associates.

Dr. Lund and his colleagues used data from the Swedish Heart Failure Registry to examine RAS antagonists’ effectiveness in a large, unselected patient population. Their main analysis included 16,216 patients from 77 hospitals and 84 primary care outpatient clinics, of whom 77% received RAS antagonists and 23% did not.

Patients who took the drugs showed a 1-year crude survival of 86%, compared with only 69% for patients who didn’t take them. Five-year survival was 55% and 32%, respectively, the investigators said (JAMA 2012;308:2108-117).

The researchers also developed propensity scores using 43 clinically relevant variables at baseline so they could construct age-matched and propensity-matched groups of 3,329 patients who received the drugs at hospital discharge and 3,329 who did not. In this analysis, 1-year survival was 77% for the treated patients vs. 72% for the untreated, and 5-year survival was 36% vs 34%, respectively. These differences were statistically significant and confirmed that the result of the main analysis was accurate, Dr. Lund and his associates said.

They performed one further consistency analysis to affirm their findings, and found a dose-response relationship: the greater the use of RAS antagonists, the greater the reduction in mortality.

Taken together, these findings suggest that RAS antagonists may be beneficial for patients who have HF with preserved ejection fraction, "but this should be confirmed in an appropriately powered randomized trial," they added.

Dr. Hernandez’s study was funded by the Agency for Healthcare Research and Quality; he reported ties to Amylin Pharmaceutical, Johnson & Johnson, AstraZeneca, Corthera, and Sanofi-Aventis, and his associates reported ties to numerous industry sources.

Dr. Lund’s study was funded by the Swedish National Board of Health and Welfare, the Swedish Association of Local Authorities and Regions, the Swedish Society of Cardiology, the Swedish Heart-Lung Foundation, and Astra-Zeneca; he reported ties to AstraZeneca, Thoratec, and HeartWare.

Two large observational "real-world" studies of two different treatments for heart failure failed to confirm the results of clinical trials of those treatments, leaving clinicians to wonder which study findings to trust, according to separate reports in the Nov. 28 issue of JAMA.

In one report, aldosterone antagonists failed to improve mortality or reduce CV readmissions in patients who had heart failure with decreased ejection fraction, after clinical trials had indicated the agents would do so. In another report, renin-angiotensin system antagonists did reduce mortality in patients who had HF with preserved ejection fraction, after clinical trials had indicated the drugs would not do so.

Both research groups called for additional study to clarify the discrepant results.

In the first study, investigators noted that "landmark clinical trials" had shown the aldosterone antagonists spironolactone and eplerenone cut mortality by up to 30% and readmissions for HF by nearly 40% among patients who had heart failure accompanied by reduced ejection fraction. Yet even though these drugs are now recommended for such patients, physicians have been slow to comply.

This may be due in part to uncertainty about the safety and effectiveness of aldosterone antagonists under real-world conditions, where many patients – the elderly, those with diabetes or chronic kidney disease, and those already using other medications predisposing them to hyperkalemia – fall outside the strict inclusion criteria used in clinical trial populations, said Dr. Adrian F. Hernandez of Duke Clinical Research Institute, Durham, N.C., and his associates.

Dr. Hernandez and his colleagues used data from the Get With The Guidelines–HF registry and the Medicare claims database to assess the drugs’ effectiveness in 5,887 patients aged 65 and older who had been discharged from 246 U.S. hospitals with a diagnosis of HF with decreased left ventricular ejection fraction in 2005-2009 and who were eligible for treatment with aldosterone antagonists. Only 1,070 of the study subjects received a prescription for the drugs at discharge.

After 3 years, there were no significant differences in all-cause mortality or in readmission for cardiovascular disorders between patients who were given aldosterone antagonists and patients who were not, the researchers said (JAMA 2012;308:2097-107).

On the down side, treated patients did show a higher rate of rehospitalization for hyperkalemia, usually during the first few weeks after initiating therapy with aldosterone antagonists.

This study wasn’t designed to determine why the results contradicted the "impressive benefits of aldosterone antagonist therapy" reported in "pivotal" efficacy trials as well as in a systematic review of randomized clinical trials of the therapy. But the researchers suggested that it’s possible the drugs have limited effectiveness in older patients in clinical practice, possibly because they may not adhere to treatment as well as subjects in intensely monitored clinical trials.

"Our findings highlight the importance of conducting clinical trials that can be easily generalized to real-world practice and in which the most vulnerable patient groups are well represented," Dr. Hernandez and his colleagues said.

Moreover, "developing protocols and systems that encourage optimal use and monitoring of aldosterone antagonist therapy may help to ensure that the effectiveness of this therapy in clinical practice approaches the efficacy achieved in clinical trials."

The investigators added that in their study, aldosterone antagonists did reduce the rate of rehospitalization for HF, which indicates that further study is needed to clarify the benefits and risks of therapy.

The second JAMA report involved the use of renin-angiotensin system (RAS) antagonists, which includes ACE inhibitors and angiotensin-receptor blockers, for patients who have heart failure with preserved ejection fraction. Three randomized clinical trials had concluded that the agents failed to improve outcomes in such patients, but those trials were marred by flaws such as selection bias, underpowering, and high crossover rates, said Dr. Lars H. Lund of the Karolinska Institutet, Stockholm, and his associates.

Dr. Lund and his colleagues used data from the Swedish Heart Failure Registry to examine RAS antagonists’ effectiveness in a large, unselected patient population. Their main analysis included 16,216 patients from 77 hospitals and 84 primary care outpatient clinics, of whom 77% received RAS antagonists and 23% did not.

Patients who took the drugs showed a 1-year crude survival of 86%, compared with only 69% for patients who didn’t take them. Five-year survival was 55% and 32%, respectively, the investigators said (JAMA 2012;308:2108-117).

The researchers also developed propensity scores using 43 clinically relevant variables at baseline so they could construct age-matched and propensity-matched groups of 3,329 patients who received the drugs at hospital discharge and 3,329 who did not. In this analysis, 1-year survival was 77% for the treated patients vs. 72% for the untreated, and 5-year survival was 36% vs 34%, respectively. These differences were statistically significant and confirmed that the result of the main analysis was accurate, Dr. Lund and his associates said.

They performed one further consistency analysis to affirm their findings, and found a dose-response relationship: the greater the use of RAS antagonists, the greater the reduction in mortality.

Taken together, these findings suggest that RAS antagonists may be beneficial for patients who have HF with preserved ejection fraction, "but this should be confirmed in an appropriately powered randomized trial," they added.

Dr. Hernandez’s study was funded by the Agency for Healthcare Research and Quality; he reported ties to Amylin Pharmaceutical, Johnson & Johnson, AstraZeneca, Corthera, and Sanofi-Aventis, and his associates reported ties to numerous industry sources.

Dr. Lund’s study was funded by the Swedish National Board of Health and Welfare, the Swedish Association of Local Authorities and Regions, the Swedish Society of Cardiology, the Swedish Heart-Lung Foundation, and Astra-Zeneca; he reported ties to AstraZeneca, Thoratec, and HeartWare.

Two large observational "real-world" studies of two different treatments for heart failure failed to confirm the results of clinical trials of those treatments, leaving clinicians to wonder which study findings to trust, according to separate reports in the Nov. 28 issue of JAMA.

In one report, aldosterone antagonists failed to improve mortality or reduce CV readmissions in patients who had heart failure with decreased ejection fraction, after clinical trials had indicated the agents would do so. In another report, renin-angiotensin system antagonists did reduce mortality in patients who had HF with preserved ejection fraction, after clinical trials had indicated the drugs would not do so.

Both research groups called for additional study to clarify the discrepant results.

In the first study, investigators noted that "landmark clinical trials" had shown the aldosterone antagonists spironolactone and eplerenone cut mortality by up to 30% and readmissions for HF by nearly 40% among patients who had heart failure accompanied by reduced ejection fraction. Yet even though these drugs are now recommended for such patients, physicians have been slow to comply.

This may be due in part to uncertainty about the safety and effectiveness of aldosterone antagonists under real-world conditions, where many patients – the elderly, those with diabetes or chronic kidney disease, and those already using other medications predisposing them to hyperkalemia – fall outside the strict inclusion criteria used in clinical trial populations, said Dr. Adrian F. Hernandez of Duke Clinical Research Institute, Durham, N.C., and his associates.

Dr. Hernandez and his colleagues used data from the Get With The Guidelines–HF registry and the Medicare claims database to assess the drugs’ effectiveness in 5,887 patients aged 65 and older who had been discharged from 246 U.S. hospitals with a diagnosis of HF with decreased left ventricular ejection fraction in 2005-2009 and who were eligible for treatment with aldosterone antagonists. Only 1,070 of the study subjects received a prescription for the drugs at discharge.

After 3 years, there were no significant differences in all-cause mortality or in readmission for cardiovascular disorders between patients who were given aldosterone antagonists and patients who were not, the researchers said (JAMA 2012;308:2097-107).

On the down side, treated patients did show a higher rate of rehospitalization for hyperkalemia, usually during the first few weeks after initiating therapy with aldosterone antagonists.

This study wasn’t designed to determine why the results contradicted the "impressive benefits of aldosterone antagonist therapy" reported in "pivotal" efficacy trials as well as in a systematic review of randomized clinical trials of the therapy. But the researchers suggested that it’s possible the drugs have limited effectiveness in older patients in clinical practice, possibly because they may not adhere to treatment as well as subjects in intensely monitored clinical trials.

"Our findings highlight the importance of conducting clinical trials that can be easily generalized to real-world practice and in which the most vulnerable patient groups are well represented," Dr. Hernandez and his colleagues said.

Moreover, "developing protocols and systems that encourage optimal use and monitoring of aldosterone antagonist therapy may help to ensure that the effectiveness of this therapy in clinical practice approaches the efficacy achieved in clinical trials."

The investigators added that in their study, aldosterone antagonists did reduce the rate of rehospitalization for HF, which indicates that further study is needed to clarify the benefits and risks of therapy.

The second JAMA report involved the use of renin-angiotensin system (RAS) antagonists, which includes ACE inhibitors and angiotensin-receptor blockers, for patients who have heart failure with preserved ejection fraction. Three randomized clinical trials had concluded that the agents failed to improve outcomes in such patients, but those trials were marred by flaws such as selection bias, underpowering, and high crossover rates, said Dr. Lars H. Lund of the Karolinska Institutet, Stockholm, and his associates.

Dr. Lund and his colleagues used data from the Swedish Heart Failure Registry to examine RAS antagonists’ effectiveness in a large, unselected patient population. Their main analysis included 16,216 patients from 77 hospitals and 84 primary care outpatient clinics, of whom 77% received RAS antagonists and 23% did not.

Patients who took the drugs showed a 1-year crude survival of 86%, compared with only 69% for patients who didn’t take them. Five-year survival was 55% and 32%, respectively, the investigators said (JAMA 2012;308:2108-117).

The researchers also developed propensity scores using 43 clinically relevant variables at baseline so they could construct age-matched and propensity-matched groups of 3,329 patients who received the drugs at hospital discharge and 3,329 who did not. In this analysis, 1-year survival was 77% for the treated patients vs. 72% for the untreated, and 5-year survival was 36% vs 34%, respectively. These differences were statistically significant and confirmed that the result of the main analysis was accurate, Dr. Lund and his associates said.

They performed one further consistency analysis to affirm their findings, and found a dose-response relationship: the greater the use of RAS antagonists, the greater the reduction in mortality.

Taken together, these findings suggest that RAS antagonists may be beneficial for patients who have HF with preserved ejection fraction, "but this should be confirmed in an appropriately powered randomized trial," they added.

Dr. Hernandez’s study was funded by the Agency for Healthcare Research and Quality; he reported ties to Amylin Pharmaceutical, Johnson & Johnson, AstraZeneca, Corthera, and Sanofi-Aventis, and his associates reported ties to numerous industry sources.

Dr. Lund’s study was funded by the Swedish National Board of Health and Welfare, the Swedish Association of Local Authorities and Regions, the Swedish Society of Cardiology, the Swedish Heart-Lung Foundation, and Astra-Zeneca; he reported ties to AstraZeneca, Thoratec, and HeartWare.

The odds of a child developing pertussis increase as the interval since he or she received the fifth and final dose of the DTaP vaccine increases, according to a report published in the November 28, 2012 issue of JAMA.

This pattern indicates a progressive waning of vaccine effectiveness every year after completion of the vaccine series, which would explain the recently noted surge in pertussis cases among 7- to 10-year-olds in at least 34 states, said Lara K. Misegades, Ph.D., of the Meningitis and Vaccine Preventable Disease Branch of the Centers for Disease Control and Prevention and her associates.

These are the findings of "the first large-scale assessment of the U.S. five-dose DTaP schedule conducted in the setting of a mature vaccination program and allowing for a comparison of fully vaccinated and unvaccinated children." Together with the findings of previous studies that used different methods to examine this issue, the results "suggest that waning of immunity following DTaP vaccination may have resulted in a much larger pool of susceptible individuals" than previously realized.

"In periods of increased pertussis transmission, the burden of disease attributable to the vaccinated but susceptible population is high," Dr. Misegades and her colleagues noted.

The investigators examined the durability of the protection provided by the DTaP vaccine by using a case-control study design to compare pertussis incidence between fully vaccinated and unvaccinated children aged 4-10 years who were living in California during the 2010 pertussis epidemic there. The study population comprised 682 cases who developed confirmed, probable, or suspected pertussis and 2,016 controls who did not, enrolled from the offices of 265 clinicians.

All the vaccinated children had received their first three doses before the age of 1 year, a fourth dose at 1-2 years of age, and a fifth dose at 4-6 years of age.

Compared with controls, children who developed pertussis had a lower chance of having received all five doses of DTaP, with an odds ratio of 0.11. This finding was not unexpected.

When the study subjects were categorized by time since completion of the vaccine series, using unvaccinated subjects as the reference group, those who developed pertussis were less likely to have received their fifth dose within the preceding 12 months. The rate of pertussis was 2.8% among children who had received their final dose of vaccine during the previous year, compared with 17.6% among children who had received their final dose of vaccine more than 1 year previously, the investigators said (JAMA 2012;308:2126-32).

This association not only persisted but became stronger with increasing time since receipt of the final vaccine dose, so that vaccine effectiveness declined further with each succeeding year.

To adjust for a possible misclassification bias, which is inherent in all case-control studies, a secondary analysis was performed using only cases of confirmed pertussis, excluding cases of probable or suspected pertussis. The results "did not change appreciably," indicating that the data were not affected by misclassification bias.

These findings, together with those of previous studies using different methods of analysis, "have raised concerns about the current U.S. pertussis vaccine program and may prompt consideration of alternative schedules. Options include delaying administration of the fifth DTaP dose or administering the Tdap booster at earlier than 11 years of age," Dr. Misegades and her associates said.

"These issues will require careful and ongoing review of the epidemiology and vaccine program nationwide. Ultimately, improved control of pertussis may require a vaccine that provides longer duration of protection or differently affects transmission in the community," they added.

No financial conflicts of interest were reported.

The odds of a child developing pertussis increase as the interval since he or she received the fifth and final dose of the DTaP vaccine increases, according to a report published in the November 28, 2012 issue of JAMA.

This pattern indicates a progressive waning of vaccine effectiveness every year after completion of the vaccine series, which would explain the recently noted surge in pertussis cases among 7- to 10-year-olds in at least 34 states, said Lara K. Misegades, Ph.D., of the Meningitis and Vaccine Preventable Disease Branch of the Centers for Disease Control and Prevention and her associates.

These are the findings of "the first large-scale assessment of the U.S. five-dose DTaP schedule conducted in the setting of a mature vaccination program and allowing for a comparison of fully vaccinated and unvaccinated children." Together with the findings of previous studies that used different methods to examine this issue, the results "suggest that waning of immunity following DTaP vaccination may have resulted in a much larger pool of susceptible individuals" than previously realized.

"In periods of increased pertussis transmission, the burden of disease attributable to the vaccinated but susceptible population is high," Dr. Misegades and her colleagues noted.

The investigators examined the durability of the protection provided by the DTaP vaccine by using a case-control study design to compare pertussis incidence between fully vaccinated and unvaccinated children aged 4-10 years who were living in California during the 2010 pertussis epidemic there. The study population comprised 682 cases who developed confirmed, probable, or suspected pertussis and 2,016 controls who did not, enrolled from the offices of 265 clinicians.

All the vaccinated children had received their first three doses before the age of 1 year, a fourth dose at 1-2 years of age, and a fifth dose at 4-6 years of age.

Compared with controls, children who developed pertussis had a lower chance of having received all five doses of DTaP, with an odds ratio of 0.11. This finding was not unexpected.

When the study subjects were categorized by time since completion of the vaccine series, using unvaccinated subjects as the reference group, those who developed pertussis were less likely to have received their fifth dose within the preceding 12 months. The rate of pertussis was 2.8% among children who had received their final dose of vaccine during the previous year, compared with 17.6% among children who had received their final dose of vaccine more than 1 year previously, the investigators said (JAMA 2012;308:2126-32).

This association not only persisted but became stronger with increasing time since receipt of the final vaccine dose, so that vaccine effectiveness declined further with each succeeding year.

To adjust for a possible misclassification bias, which is inherent in all case-control studies, a secondary analysis was performed using only cases of confirmed pertussis, excluding cases of probable or suspected pertussis. The results "did not change appreciably," indicating that the data were not affected by misclassification bias.

These findings, together with those of previous studies using different methods of analysis, "have raised concerns about the current U.S. pertussis vaccine program and may prompt consideration of alternative schedules. Options include delaying administration of the fifth DTaP dose or administering the Tdap booster at earlier than 11 years of age," Dr. Misegades and her associates said.

"These issues will require careful and ongoing review of the epidemiology and vaccine program nationwide. Ultimately, improved control of pertussis may require a vaccine that provides longer duration of protection or differently affects transmission in the community," they added.

No financial conflicts of interest were reported.

The odds of a child developing pertussis increase as the interval since he or she received the fifth and final dose of the DTaP vaccine increases, according to a report published in the November 28, 2012 issue of JAMA.

This pattern indicates a progressive waning of vaccine effectiveness every year after completion of the vaccine series, which would explain the recently noted surge in pertussis cases among 7- to 10-year-olds in at least 34 states, said Lara K. Misegades, Ph.D., of the Meningitis and Vaccine Preventable Disease Branch of the Centers for Disease Control and Prevention and her associates.

These are the findings of "the first large-scale assessment of the U.S. five-dose DTaP schedule conducted in the setting of a mature vaccination program and allowing for a comparison of fully vaccinated and unvaccinated children." Together with the findings of previous studies that used different methods to examine this issue, the results "suggest that waning of immunity following DTaP vaccination may have resulted in a much larger pool of susceptible individuals" than previously realized.

"In periods of increased pertussis transmission, the burden of disease attributable to the vaccinated but susceptible population is high," Dr. Misegades and her colleagues noted.

The investigators examined the durability of the protection provided by the DTaP vaccine by using a case-control study design to compare pertussis incidence between fully vaccinated and unvaccinated children aged 4-10 years who were living in California during the 2010 pertussis epidemic there. The study population comprised 682 cases who developed confirmed, probable, or suspected pertussis and 2,016 controls who did not, enrolled from the offices of 265 clinicians.

All the vaccinated children had received their first three doses before the age of 1 year, a fourth dose at 1-2 years of age, and a fifth dose at 4-6 years of age.

Compared with controls, children who developed pertussis had a lower chance of having received all five doses of DTaP, with an odds ratio of 0.11. This finding was not unexpected.

When the study subjects were categorized by time since completion of the vaccine series, using unvaccinated subjects as the reference group, those who developed pertussis were less likely to have received their fifth dose within the preceding 12 months. The rate of pertussis was 2.8% among children who had received their final dose of vaccine during the previous year, compared with 17.6% among children who had received their final dose of vaccine more than 1 year previously, the investigators said (JAMA 2012;308:2126-32).

This association not only persisted but became stronger with increasing time since receipt of the final vaccine dose, so that vaccine effectiveness declined further with each succeeding year.

To adjust for a possible misclassification bias, which is inherent in all case-control studies, a secondary analysis was performed using only cases of confirmed pertussis, excluding cases of probable or suspected pertussis. The results "did not change appreciably," indicating that the data were not affected by misclassification bias.

These findings, together with those of previous studies using different methods of analysis, "have raised concerns about the current U.S. pertussis vaccine program and may prompt consideration of alternative schedules. Options include delaying administration of the fifth DTaP dose or administering the Tdap booster at earlier than 11 years of age," Dr. Misegades and her associates said.

"These issues will require careful and ongoing review of the epidemiology and vaccine program nationwide. Ultimately, improved control of pertussis may require a vaccine that provides longer duration of protection or differently affects transmission in the community," they added.

No financial conflicts of interest were reported.

A change in Medicare policy regarding payments for consultations vs. office visits had the unintended consequence of raising overall costs the first year it was implemented, according to a report published online in Archives of Internal Medicine.

Prior to 2010, the Medicare Physician Fee Schedule provided higher payments for consultations than for office visits at every level of complexity. For example, in 2009 Medicare paid $124.79 on average for a consultation of medium complexity, compared with $91.97 for a new patient office visit and $61.31 for an established patient office visit of similar complexity.

thinkstockphotos.com

Since primary care physicians billed primarily for office visits and specialists billed primarily for consultations, this resulted in a large discrepancy in reimbursement between primary and specialist physicians for doing similarly complex work, according to Zirui Song, Ph.D., of the department of health care policy, Harvard Medical School, Boston, and his associates.

With the fee schedule for calendar 2010, the Centers for Medicare and Medicaid Services eliminated payments for consultations altogether, so that all outpatient physician encounters would be billed as office visits, and simultaneously raised the fees for office visits. The change was designed specifically to be budget-neutral for the Medicare program.

Dr. Song and his colleagues assessed the effects of this policy change on Medicare payments in 2010. They used data from a sample of 2.2 million Medicare beneficiaries who had a diagnosis related to diabetes or cardiovascular conditions, or prescriptions for any cardiovascular or cholesterol-reducing drugs, and who were seen as outpatients in 2007 through the end of 2010.

During 2010, payments for consultations decreased an average of $18.52 per beneficiary per quarter.

However, payments for new patient office visits rose by $13.64 per beneficiary per quarter and payments for established patient office visits rose by $15.08 per beneficiary per quarter. This represents an increase of 131% in the number of new patient office visits billed to Medicare and an increase of 12% in the number of established patient office visits billed to Medicare, compared with the preceding year.

"On net, spending on all physician encounters was higher by $10.20 per beneficiary per quarter after the policy" for an increase of 6.5%, Dr. Song and his associates said (Arch. Intern. Med. 2012 [doi:10.1001/jamainternmend.2013.1125]).

The volume of patient encounters did not increase during this period, the researchers found. Rather, it appears that "an increase in the intensity of coding" was responsible for approximately one-third of the 6.5% rise, while the fee increase for office visits was responsible for the other two-thirds.

The income gap between specialists and primary care physicians did narrow somewhat after this policy change was implemented. Primary care physicians accounted for a slightly greater proportion (58%) of the rise in spending than did specialists (42%), the researchers noted.

They added that this study pertained only to Medicare payments for outpatient encounters, and did not address all other physician services. "The overall discrepancy in Medicare payments" between primary care and specialist physicians "derives largely from procedural services, which this policy does not address," Dr. Song and his colleagues said.

Similarly, this study examined only the policy’s effect on the first year after implementation, and these results may not be generalizable to longer term effects, they said.

This study was supported by The Commonwealth Fund, the National Institute on Aging, and the National Bureau of Economic Research. The investigators reported no relevant financial conflicts of interest.

A change in Medicare policy regarding payments for consultations vs. office visits had the unintended consequence of raising overall costs the first year it was implemented, according to a report published online in Archives of Internal Medicine.

Prior to 2010, the Medicare Physician Fee Schedule provided higher payments for consultations than for office visits at every level of complexity. For example, in 2009 Medicare paid $124.79 on average for a consultation of medium complexity, compared with $91.97 for a new patient office visit and $61.31 for an established patient office visit of similar complexity.

thinkstockphotos.com

Since primary care physicians billed primarily for office visits and specialists billed primarily for consultations, this resulted in a large discrepancy in reimbursement between primary and specialist physicians for doing similarly complex work, according to Zirui Song, Ph.D., of the department of health care policy, Harvard Medical School, Boston, and his associates.

With the fee schedule for calendar 2010, the Centers for Medicare and Medicaid Services eliminated payments for consultations altogether, so that all outpatient physician encounters would be billed as office visits, and simultaneously raised the fees for office visits. The change was designed specifically to be budget-neutral for the Medicare program.

Dr. Song and his colleagues assessed the effects of this policy change on Medicare payments in 2010. They used data from a sample of 2.2 million Medicare beneficiaries who had a diagnosis related to diabetes or cardiovascular conditions, or prescriptions for any cardiovascular or cholesterol-reducing drugs, and who were seen as outpatients in 2007 through the end of 2010.

During 2010, payments for consultations decreased an average of $18.52 per beneficiary per quarter.

However, payments for new patient office visits rose by $13.64 per beneficiary per quarter and payments for established patient office visits rose by $15.08 per beneficiary per quarter. This represents an increase of 131% in the number of new patient office visits billed to Medicare and an increase of 12% in the number of established patient office visits billed to Medicare, compared with the preceding year.

"On net, spending on all physician encounters was higher by $10.20 per beneficiary per quarter after the policy" for an increase of 6.5%, Dr. Song and his associates said (Arch. Intern. Med. 2012 [doi:10.1001/jamainternmend.2013.1125]).

The volume of patient encounters did not increase during this period, the researchers found. Rather, it appears that "an increase in the intensity of coding" was responsible for approximately one-third of the 6.5% rise, while the fee increase for office visits was responsible for the other two-thirds.

The income gap between specialists and primary care physicians did narrow somewhat after this policy change was implemented. Primary care physicians accounted for a slightly greater proportion (58%) of the rise in spending than did specialists (42%), the researchers noted.

They added that this study pertained only to Medicare payments for outpatient encounters, and did not address all other physician services. "The overall discrepancy in Medicare payments" between primary care and specialist physicians "derives largely from procedural services, which this policy does not address," Dr. Song and his colleagues said.

Similarly, this study examined only the policy’s effect on the first year after implementation, and these results may not be generalizable to longer term effects, they said.

This study was supported by The Commonwealth Fund, the National Institute on Aging, and the National Bureau of Economic Research. The investigators reported no relevant financial conflicts of interest.

A change in Medicare policy regarding payments for consultations vs. office visits had the unintended consequence of raising overall costs the first year it was implemented, according to a report published online in Archives of Internal Medicine.

Prior to 2010, the Medicare Physician Fee Schedule provided higher payments for consultations than for office visits at every level of complexity. For example, in 2009 Medicare paid $124.79 on average for a consultation of medium complexity, compared with $91.97 for a new patient office visit and $61.31 for an established patient office visit of similar complexity.

thinkstockphotos.com

Since primary care physicians billed primarily for office visits and specialists billed primarily for consultations, this resulted in a large discrepancy in reimbursement between primary and specialist physicians for doing similarly complex work, according to Zirui Song, Ph.D., of the department of health care policy, Harvard Medical School, Boston, and his associates.

With the fee schedule for calendar 2010, the Centers for Medicare and Medicaid Services eliminated payments for consultations altogether, so that all outpatient physician encounters would be billed as office visits, and simultaneously raised the fees for office visits. The change was designed specifically to be budget-neutral for the Medicare program.

Dr. Song and his colleagues assessed the effects of this policy change on Medicare payments in 2010. They used data from a sample of 2.2 million Medicare beneficiaries who had a diagnosis related to diabetes or cardiovascular conditions, or prescriptions for any cardiovascular or cholesterol-reducing drugs, and who were seen as outpatients in 2007 through the end of 2010.

During 2010, payments for consultations decreased an average of $18.52 per beneficiary per quarter.

However, payments for new patient office visits rose by $13.64 per beneficiary per quarter and payments for established patient office visits rose by $15.08 per beneficiary per quarter. This represents an increase of 131% in the number of new patient office visits billed to Medicare and an increase of 12% in the number of established patient office visits billed to Medicare, compared with the preceding year.

"On net, spending on all physician encounters was higher by $10.20 per beneficiary per quarter after the policy" for an increase of 6.5%, Dr. Song and his associates said (Arch. Intern. Med. 2012 [doi:10.1001/jamainternmend.2013.1125]).

The volume of patient encounters did not increase during this period, the researchers found. Rather, it appears that "an increase in the intensity of coding" was responsible for approximately one-third of the 6.5% rise, while the fee increase for office visits was responsible for the other two-thirds.

The income gap between specialists and primary care physicians did narrow somewhat after this policy change was implemented. Primary care physicians accounted for a slightly greater proportion (58%) of the rise in spending than did specialists (42%), the researchers noted.

They added that this study pertained only to Medicare payments for outpatient encounters, and did not address all other physician services. "The overall discrepancy in Medicare payments" between primary care and specialist physicians "derives largely from procedural services, which this policy does not address," Dr. Song and his colleagues said.

Similarly, this study examined only the policy’s effect on the first year after implementation, and these results may not be generalizable to longer term effects, they said.

This study was supported by The Commonwealth Fund, the National Institute on Aging, and the National Bureau of Economic Research. The investigators reported no relevant financial conflicts of interest.

For patients who undergo elective repair of abdominal aortic aneurysm, long-term mortality is not significantly different between those who have endovascular surgery and those who have open surgery, according to a report published online Nov. 22 in the New England Journal of Medicine.

Perioperative survival was superior with the endovascular approach, and that advantage lasted for up to 3 years. But from that point on, survival was similar between patients who had undergone endovascular repair and those who had undergone open repair, said Dr. Frank A. Lederle of the Veterans Affairs Medical Center, Minneapolis, Minn., and his associates.

Three large, randomized clinical trials compared the two surgical approaches: the United Kingdom Endovascular Repair 1 (EVAR 1) trial, the Dutch Randomized Endovascular Aneurysm Management (DREAM) trial, and the Open versus Endovascular Repair (OVER) Veterans Affairs Cooperative Study in the United States. All three studies initially showed a survival advantage with the endovascular procedure in the perioperative period. But longer follow-up in the EVAR 1 and DREAM studies suggested that this advantage was lost at approximately 2 years, due to an excess in late deaths among patients who had undergone endovascular repair.

Dr. Lederle and his colleagues now report the long-term findings of the OVER trial, and they also found that at approximately 3 years, the survival curves between the two study groups converged.

The OVER trial was conducted at 42 VA medical centers across the country and involved 881 patients. The mean patient age was 70 years, and, as is typical in VA cohorts, 99% of the subjects were male.

All patients had abdominal aortic aneurysms with a maximal external diameter of at least 5 cm, an associated iliac-artery aneurysm with a maximum diameter of at least 3 cm, or a maximal diameter of at least 4.5 cm plus either rapid enlargement or a saccular appearance on radiography and CT examination.

A total of 444 study subjects were randomly assigned to endovascular repair and 437 to open repair. They were followed for up to 9 years (mean follow-up, 5.2 years). During that time, there were 146 deaths in each group.

All-cause mortality was significantly lower in the endovascular group at 2 years, but that difference was only of borderline significance at 3 years and disappeared completely thereafter. Similarly, the restricted mean survival was no different between the two groups at 5 years and at 9 years (N. Engl. J. Med. 2012;367:1988-97 [doi:10.1056/NEJMoa1207481]).

The time to a second therapeutic procedure or death was similar between the two groups, as were the number of hospitalizations after the initial repair, the number of secondary therapeutic procedures needed, and postoperative quality of life.

The most likely explanation for the convergence of the survival curves over time is that the frailest patients in the open-repair group died soon after that rigorous procedure, while the frailest patients in the endovascular-repair group survived that less invasive surgery but succumbed within a year or two, Dr. Lederle and his associates said.

When the data were analyzed according to patient age, an interesting result emerged: Patients younger than age 70 had better survival with endovascular than with open repair, while patients older than age 70 had better survival with open than with endovascular repair. This was surprising, given that "much of the early enthusiasm for endovascular repair focused on the expected advantage among old or infirm patients who were not good candidates for open repair," they noted.

Even though the rate of late ruptures was higher for the endovascular approach, it was still a very low rate, "with only six ruptures during 4,576 patient-years of follow-up." Moreover, four of these six late ruptures occurred in elderly patients, three of whom didn’t adhere to the recommended follow-up.

"We therefore consider endovascular repair to be a reasonable option in patients younger than 70 years of age who are likely to adhere to medical advice," Dr. Lederle and his colleagues said.

Nevertheless, endovascular repair "does not yet offer a long-term advantage over open repair, particularly among older patients, for whom such an advantage was originally expected," they noted.

This study was supported by the Department of Veterans Affairs Office of Research and Development. Dr. Lederle reported no financial conflicts of interest; one of his associates reported ties to Abbott, Cook, Covidien, Gore, and Endologix.

For patients who undergo elective repair of abdominal aortic aneurysm, long-term mortality is not significantly different between those who have endovascular surgery and those who have open surgery, according to a report published online Nov. 22 in the New England Journal of Medicine.

Perioperative survival was superior with the endovascular approach, and that advantage lasted for up to 3 years. But from that point on, survival was similar between patients who had undergone endovascular repair and those who had undergone open repair, said Dr. Frank A. Lederle of the Veterans Affairs Medical Center, Minneapolis, Minn., and his associates.

Three large, randomized clinical trials compared the two surgical approaches: the United Kingdom Endovascular Repair 1 (EVAR 1) trial, the Dutch Randomized Endovascular Aneurysm Management (DREAM) trial, and the Open versus Endovascular Repair (OVER) Veterans Affairs Cooperative Study in the United States. All three studies initially showed a survival advantage with the endovascular procedure in the perioperative period. But longer follow-up in the EVAR 1 and DREAM studies suggested that this advantage was lost at approximately 2 years, due to an excess in late deaths among patients who had undergone endovascular repair.

Dr. Lederle and his colleagues now report the long-term findings of the OVER trial, and they also found that at approximately 3 years, the survival curves between the two study groups converged.

The OVER trial was conducted at 42 VA medical centers across the country and involved 881 patients. The mean patient age was 70 years, and, as is typical in VA cohorts, 99% of the subjects were male.

All patients had abdominal aortic aneurysms with a maximal external diameter of at least 5 cm, an associated iliac-artery aneurysm with a maximum diameter of at least 3 cm, or a maximal diameter of at least 4.5 cm plus either rapid enlargement or a saccular appearance on radiography and CT examination.

A total of 444 study subjects were randomly assigned to endovascular repair and 437 to open repair. They were followed for up to 9 years (mean follow-up, 5.2 years). During that time, there were 146 deaths in each group.

All-cause mortality was significantly lower in the endovascular group at 2 years, but that difference was only of borderline significance at 3 years and disappeared completely thereafter. Similarly, the restricted mean survival was no different between the two groups at 5 years and at 9 years (N. Engl. J. Med. 2012;367:1988-97 [doi:10.1056/NEJMoa1207481]).

The time to a second therapeutic procedure or death was similar between the two groups, as were the number of hospitalizations after the initial repair, the number of secondary therapeutic procedures needed, and postoperative quality of life.

The most likely explanation for the convergence of the survival curves over time is that the frailest patients in the open-repair group died soon after that rigorous procedure, while the frailest patients in the endovascular-repair group survived that less invasive surgery but succumbed within a year or two, Dr. Lederle and his associates said.

When the data were analyzed according to patient age, an interesting result emerged: Patients younger than age 70 had better survival with endovascular than with open repair, while patients older than age 70 had better survival with open than with endovascular repair. This was surprising, given that "much of the early enthusiasm for endovascular repair focused on the expected advantage among old or infirm patients who were not good candidates for open repair," they noted.

Even though the rate of late ruptures was higher for the endovascular approach, it was still a very low rate, "with only six ruptures during 4,576 patient-years of follow-up." Moreover, four of these six late ruptures occurred in elderly patients, three of whom didn’t adhere to the recommended follow-up.

"We therefore consider endovascular repair to be a reasonable option in patients younger than 70 years of age who are likely to adhere to medical advice," Dr. Lederle and his colleagues said.

Nevertheless, endovascular repair "does not yet offer a long-term advantage over open repair, particularly among older patients, for whom such an advantage was originally expected," they noted.

This study was supported by the Department of Veterans Affairs Office of Research and Development. Dr. Lederle reported no financial conflicts of interest; one of his associates reported ties to Abbott, Cook, Covidien, Gore, and Endologix.

For patients who undergo elective repair of abdominal aortic aneurysm, long-term mortality is not significantly different between those who have endovascular surgery and those who have open surgery, according to a report published online Nov. 22 in the New England Journal of Medicine.

Perioperative survival was superior with the endovascular approach, and that advantage lasted for up to 3 years. But from that point on, survival was similar between patients who had undergone endovascular repair and those who had undergone open repair, said Dr. Frank A. Lederle of the Veterans Affairs Medical Center, Minneapolis, Minn., and his associates.

Three large, randomized clinical trials compared the two surgical approaches: the United Kingdom Endovascular Repair 1 (EVAR 1) trial, the Dutch Randomized Endovascular Aneurysm Management (DREAM) trial, and the Open versus Endovascular Repair (OVER) Veterans Affairs Cooperative Study in the United States. All three studies initially showed a survival advantage with the endovascular procedure in the perioperative period. But longer follow-up in the EVAR 1 and DREAM studies suggested that this advantage was lost at approximately 2 years, due to an excess in late deaths among patients who had undergone endovascular repair.

Dr. Lederle and his colleagues now report the long-term findings of the OVER trial, and they also found that at approximately 3 years, the survival curves between the two study groups converged.

The OVER trial was conducted at 42 VA medical centers across the country and involved 881 patients. The mean patient age was 70 years, and, as is typical in VA cohorts, 99% of the subjects were male.

All patients had abdominal aortic aneurysms with a maximal external diameter of at least 5 cm, an associated iliac-artery aneurysm with a maximum diameter of at least 3 cm, or a maximal diameter of at least 4.5 cm plus either rapid enlargement or a saccular appearance on radiography and CT examination.

A total of 444 study subjects were randomly assigned to endovascular repair and 437 to open repair. They were followed for up to 9 years (mean follow-up, 5.2 years). During that time, there were 146 deaths in each group.

All-cause mortality was significantly lower in the endovascular group at 2 years, but that difference was only of borderline significance at 3 years and disappeared completely thereafter. Similarly, the restricted mean survival was no different between the two groups at 5 years and at 9 years (N. Engl. J. Med. 2012;367:1988-97 [doi:10.1056/NEJMoa1207481]).

The time to a second therapeutic procedure or death was similar between the two groups, as were the number of hospitalizations after the initial repair, the number of secondary therapeutic procedures needed, and postoperative quality of life.

The most likely explanation for the convergence of the survival curves over time is that the frailest patients in the open-repair group died soon after that rigorous procedure, while the frailest patients in the endovascular-repair group survived that less invasive surgery but succumbed within a year or two, Dr. Lederle and his associates said.

When the data were analyzed according to patient age, an interesting result emerged: Patients younger than age 70 had better survival with endovascular than with open repair, while patients older than age 70 had better survival with open than with endovascular repair. This was surprising, given that "much of the early enthusiasm for endovascular repair focused on the expected advantage among old or infirm patients who were not good candidates for open repair," they noted.

Even though the rate of late ruptures was higher for the endovascular approach, it was still a very low rate, "with only six ruptures during 4,576 patient-years of follow-up." Moreover, four of these six late ruptures occurred in elderly patients, three of whom didn’t adhere to the recommended follow-up.

"We therefore consider endovascular repair to be a reasonable option in patients younger than 70 years of age who are likely to adhere to medical advice," Dr. Lederle and his colleagues said.

Nevertheless, endovascular repair "does not yet offer a long-term advantage over open repair, particularly among older patients, for whom such an advantage was originally expected," they noted.

This study was supported by the Department of Veterans Affairs Office of Research and Development. Dr. Lederle reported no financial conflicts of interest; one of his associates reported ties to Abbott, Cook, Covidien, Gore, and Endologix.