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Post-approval trials for accelerated drugs fall short
New research has revealed shortcomings of post-approval studies for drugs granted accelerated approval in the US.
Researchers found that, for drugs granted accelerated approval from 2009 to 2013, both pre-approval and post-approval trials had limitations in their design and the endpoints used.
“One might expect accelerated approval confirmatory trials to be much more rigorous than the pre-approval trials,” said study author Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“But we found that there were few differences in these key design features of the trials conducted before or after approval.”
Dr Kesselheim and his colleagues reported these findings in JAMA.
The researchers examined pre- and post-approval clinical trials of drugs granted accelerated approval by the US Food and Drug Administration (FDA) between 2009 and 2013.
During that time, the FDA granted 22 drugs accelerated approval for 24 indications (15 of them for hematologic disorders).
Fourteen of the indications were approved on the basis of single-intervention-group studies that enrolled a median of 132 patients.
The FDA ordered 38 post-approval studies to confirm the safety and efficacy of the drugs.
Three years after the last drug’s approval, half of those studies (n=19) were not complete. Eight (42%) of the incomplete studies were either terminated or delayed by more than 1 year.
For 14 of the 24 indications (58%), results from the post-approval studies were not available after a median of 5 years of follow-up.
Study comparison
Published reports were available for 18 of the 19 completed post-approval studies. The characteristics of these studies did not differ much from the 30 pre-approval studies.
There were no statistically significant differences with regard to median patient enrollment (P=0.17), the use of randomized (P=0.31) or double-blind trials (P=0.17), the use of placebo as a comparator (P=0.17), or the lack of a comparator (P=0.21).
However, there was a significant difference in the use of an active comparator (P=0.02), with more post-approval studies using an active comparator.
The researchers also found that 17 of the 18 post-approval trials still used surrogate measures of effect as primary endpoints.
There was no significant difference between pre- and post-approval trials when it came to the use of disease response (P=0.17) or most other surrogate measures (P=0.21) as the trials’ primary endpoint.
The same was true for overall survival (P=0.20), although significantly more post-approval studies used progression-free survival (P=0.001) as a primary endpoint.
“It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes—or even make them worse,” Dr Kesselheim said.
To address these issues and improve the quality of confirmatory studies, Dr Kesselheim suggested the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies.
He also suggested the agency work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug. 
New research has revealed shortcomings of post-approval studies for drugs granted accelerated approval in the US.
Researchers found that, for drugs granted accelerated approval from 2009 to 2013, both pre-approval and post-approval trials had limitations in their design and the endpoints used.
“One might expect accelerated approval confirmatory trials to be much more rigorous than the pre-approval trials,” said study author Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“But we found that there were few differences in these key design features of the trials conducted before or after approval.”
Dr Kesselheim and his colleagues reported these findings in JAMA.
The researchers examined pre- and post-approval clinical trials of drugs granted accelerated approval by the US Food and Drug Administration (FDA) between 2009 and 2013.
During that time, the FDA granted 22 drugs accelerated approval for 24 indications (15 of them for hematologic disorders).
Fourteen of the indications were approved on the basis of single-intervention-group studies that enrolled a median of 132 patients.
The FDA ordered 38 post-approval studies to confirm the safety and efficacy of the drugs.
Three years after the last drug’s approval, half of those studies (n=19) were not complete. Eight (42%) of the incomplete studies were either terminated or delayed by more than 1 year.
For 14 of the 24 indications (58%), results from the post-approval studies were not available after a median of 5 years of follow-up.
Study comparison
Published reports were available for 18 of the 19 completed post-approval studies. The characteristics of these studies did not differ much from the 30 pre-approval studies.
There were no statistically significant differences with regard to median patient enrollment (P=0.17), the use of randomized (P=0.31) or double-blind trials (P=0.17), the use of placebo as a comparator (P=0.17), or the lack of a comparator (P=0.21).
However, there was a significant difference in the use of an active comparator (P=0.02), with more post-approval studies using an active comparator.
The researchers also found that 17 of the 18 post-approval trials still used surrogate measures of effect as primary endpoints.
There was no significant difference between pre- and post-approval trials when it came to the use of disease response (P=0.17) or most other surrogate measures (P=0.21) as the trials’ primary endpoint.
The same was true for overall survival (P=0.20), although significantly more post-approval studies used progression-free survival (P=0.001) as a primary endpoint.
“It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes—or even make them worse,” Dr Kesselheim said.
To address these issues and improve the quality of confirmatory studies, Dr Kesselheim suggested the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies.
He also suggested the agency work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug.
New research has revealed shortcomings of post-approval studies for drugs granted accelerated approval in the US.
Researchers found that, for drugs granted accelerated approval from 2009 to 2013, both pre-approval and post-approval trials had limitations in their design and the endpoints used.
“One might expect accelerated approval confirmatory trials to be much more rigorous than the pre-approval trials,” said study author Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“But we found that there were few differences in these key design features of the trials conducted before or after approval.”
Dr Kesselheim and his colleagues reported these findings in JAMA.
The researchers examined pre- and post-approval clinical trials of drugs granted accelerated approval by the US Food and Drug Administration (FDA) between 2009 and 2013.
During that time, the FDA granted 22 drugs accelerated approval for 24 indications (15 of them for hematologic disorders).
Fourteen of the indications were approved on the basis of single-intervention-group studies that enrolled a median of 132 patients.
The FDA ordered 38 post-approval studies to confirm the safety and efficacy of the drugs.
Three years after the last drug’s approval, half of those studies (n=19) were not complete. Eight (42%) of the incomplete studies were either terminated or delayed by more than 1 year.
For 14 of the 24 indications (58%), results from the post-approval studies were not available after a median of 5 years of follow-up.
Study comparison
Published reports were available for 18 of the 19 completed post-approval studies. The characteristics of these studies did not differ much from the 30 pre-approval studies.
There were no statistically significant differences with regard to median patient enrollment (P=0.17), the use of randomized (P=0.31) or double-blind trials (P=0.17), the use of placebo as a comparator (P=0.17), or the lack of a comparator (P=0.21).
However, there was a significant difference in the use of an active comparator (P=0.02), with more post-approval studies using an active comparator.
The researchers also found that 17 of the 18 post-approval trials still used surrogate measures of effect as primary endpoints.
There was no significant difference between pre- and post-approval trials when it came to the use of disease response (P=0.17) or most other surrogate measures (P=0.21) as the trials’ primary endpoint.
The same was true for overall survival (P=0.20), although significantly more post-approval studies used progression-free survival (P=0.001) as a primary endpoint.
“It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes—or even make them worse,” Dr Kesselheim said.
To address these issues and improve the quality of confirmatory studies, Dr Kesselheim suggested the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies.
He also suggested the agency work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug.
FDA grants drug orphan designation for AML, CMML
The US Food and Drug Administration (FDA) has granted orphan drug designation to H3B-8800 as a treatment for patients with acute myelogenous leukemia (AML) or chronic myelomonocytic leukemia (CMML).
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
About H3B-8800
H3B-8800 is an orally bioavailable small-molecule modulator of wild-type and mutant SF3b complexes. The SF3b complex is a key component of the spliceosome that is found in the cell nucleus and is responsible for the removal of noncoding introns from a transcribed pre-messenger RNA.
Recurrent heterozygous mutations in several core members of the spliceosome (SF3B1, U2AF1, SRSF2, and ZRSR2) have been identified in solid tumor and hematologic malignancies. Mutations in the core spliceosome components lead to aberrant mRNA splicing that may contribute to disease pathogenesis.
Preclinical data have suggested that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in spliceosome-mutant cancer models, including models of AML and CMML. H3B-8800 showed dose-dependent modulation of canonical and aberrant splicing when administered at tolerated doses.
Results from this research were presented at the 2017 AACR Annual Meeting (abstract 1185).
H3B-8800 is currently under investigation in a phase 1 trial of patients with AML, CMML, and myelodysplastic syndromes that may carry mutations in the core spliceosome genes.
H3B-8800 is being developed by H3 Biomedicine Inc.
The US Food and Drug Administration (FDA) has granted orphan drug designation to H3B-8800 as a treatment for patients with acute myelogenous leukemia (AML) or chronic myelomonocytic leukemia (CMML).
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
About H3B-8800
H3B-8800 is an orally bioavailable small-molecule modulator of wild-type and mutant SF3b complexes. The SF3b complex is a key component of the spliceosome that is found in the cell nucleus and is responsible for the removal of noncoding introns from a transcribed pre-messenger RNA.
Recurrent heterozygous mutations in several core members of the spliceosome (SF3B1, U2AF1, SRSF2, and ZRSR2) have been identified in solid tumor and hematologic malignancies. Mutations in the core spliceosome components lead to aberrant mRNA splicing that may contribute to disease pathogenesis.
Preclinical data have suggested that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in spliceosome-mutant cancer models, including models of AML and CMML. H3B-8800 showed dose-dependent modulation of canonical and aberrant splicing when administered at tolerated doses.
Results from this research were presented at the 2017 AACR Annual Meeting (abstract 1185).
H3B-8800 is currently under investigation in a phase 1 trial of patients with AML, CMML, and myelodysplastic syndromes that may carry mutations in the core spliceosome genes.
H3B-8800 is being developed by H3 Biomedicine Inc.
The US Food and Drug Administration (FDA) has granted orphan drug designation to H3B-8800 as a treatment for patients with acute myelogenous leukemia (AML) or chronic myelomonocytic leukemia (CMML).
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
About H3B-8800
H3B-8800 is an orally bioavailable small-molecule modulator of wild-type and mutant SF3b complexes. The SF3b complex is a key component of the spliceosome that is found in the cell nucleus and is responsible for the removal of noncoding introns from a transcribed pre-messenger RNA.
Recurrent heterozygous mutations in several core members of the spliceosome (SF3B1, U2AF1, SRSF2, and ZRSR2) have been identified in solid tumor and hematologic malignancies. Mutations in the core spliceosome components lead to aberrant mRNA splicing that may contribute to disease pathogenesis.
Preclinical data have suggested that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in spliceosome-mutant cancer models, including models of AML and CMML. H3B-8800 showed dose-dependent modulation of canonical and aberrant splicing when administered at tolerated doses.
Results from this research were presented at the 2017 AACR Annual Meeting (abstract 1185).
H3B-8800 is currently under investigation in a phase 1 trial of patients with AML, CMML, and myelodysplastic syndromes that may carry mutations in the core spliceosome genes.
H3B-8800 is being developed by H3 Biomedicine Inc.
FDA allows emergency use of multiplex Zika test
The US Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) for the CII-ArboViroPlex rRT-PCR Test.
It is the first multiplex assay that simultaneously tests for the presence of Zika virus, all serotypes of dengue virus, chikungunya virus, and West Nile virus, as well as a host gene that ensures the accuracy of results.
The EUA does not mean the CII-ArboViroPlex rRT-PCR Test is FDA cleared or approved.
An EUA allows for the use of unapproved medical products in an emergency. The products must be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, or nuclear threat agents, when there are no adequate alternatives.
The EUA for the CII-ArboViroPlex rRT-PCR Test means the test is only authorized as long as circumstances exist to justify the emergency use of in vitro diagnostics for the detection of Zika virus, unless the authorization is terminated or revoked sooner.
About the test
The CII-ArboViroPlex rRT-PCR Test is an assay that detects viral RNA matching Zika virus (ZIKV), dengue virus types 1-4 (DENV), chikungunya virus (CHIKV), and West Nile virus (WNV) with a human housekeeping gene, viral RNA controls, and extraction controls that ensure the integrity of the test from nucleic extraction to the final result.
Named for the 4 arboviruses it targets and the real-time reverse transcription polymerase chain reaction (rRT-PCR) technique it employs, the test can simultaneously detect ZIKV, DENV, CHIKV, and WNV in up to 88 samples of blood in less than 2 hours and ZIKV in urine (collected alongside a patient-matched serum specimen).
The CII-ArboViroPlex rRT-PCR Test was developed by scientists at the Center for Infection and Immunity (CII) at Columbia University’s Mailman School of Public Health in New York, New York. The manufacture of the test will be overseen by CII.
The CII-ArboViroPlex rRT-PCR Test is authorized to be used by laboratories in the US that are certified under the Clinical Laboratory Improvement Amendments of 1988, 42 U.S.C. § 263a, to perform high complexity tests, or by similarly qualified non-US laboratories.
The CII-ArboViroPlex rRT-PCR Test is authorized to be performed with the NucliSENS® easyMag® automated extraction platform (bioMérieux), the RNA UltraSense™ One-Step Quantitative RT-PCR System (Thermo Fisher), and CFX96 Real-Time PCR Detection System (Bio-Rad).
“The ArboViroPlex Test provides an easy and efficient means to simultaneously detect Zika and 3 other mosquito-borne viral infections that may present with similar clinical features,” said Nischay Mishra, of CII.
“The FDA decision to issue the EUA gives clinicians and researchers a powerful tool to diagnose and prevent the spread of Zika,” added W. Ian Lipkin, director of CII.
More information on the CII-ArboViroPlex rRT-PCR Test Virus Kit and other Zika tests granted EUAs can be found on the FDA’s EUA page.
The US Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) for the CII-ArboViroPlex rRT-PCR Test.
It is the first multiplex assay that simultaneously tests for the presence of Zika virus, all serotypes of dengue virus, chikungunya virus, and West Nile virus, as well as a host gene that ensures the accuracy of results.
The EUA does not mean the CII-ArboViroPlex rRT-PCR Test is FDA cleared or approved.
An EUA allows for the use of unapproved medical products in an emergency. The products must be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, or nuclear threat agents, when there are no adequate alternatives.
The EUA for the CII-ArboViroPlex rRT-PCR Test means the test is only authorized as long as circumstances exist to justify the emergency use of in vitro diagnostics for the detection of Zika virus, unless the authorization is terminated or revoked sooner.
About the test
The CII-ArboViroPlex rRT-PCR Test is an assay that detects viral RNA matching Zika virus (ZIKV), dengue virus types 1-4 (DENV), chikungunya virus (CHIKV), and West Nile virus (WNV) with a human housekeeping gene, viral RNA controls, and extraction controls that ensure the integrity of the test from nucleic extraction to the final result.
Named for the 4 arboviruses it targets and the real-time reverse transcription polymerase chain reaction (rRT-PCR) technique it employs, the test can simultaneously detect ZIKV, DENV, CHIKV, and WNV in up to 88 samples of blood in less than 2 hours and ZIKV in urine (collected alongside a patient-matched serum specimen).
The CII-ArboViroPlex rRT-PCR Test was developed by scientists at the Center for Infection and Immunity (CII) at Columbia University’s Mailman School of Public Health in New York, New York. The manufacture of the test will be overseen by CII.
The CII-ArboViroPlex rRT-PCR Test is authorized to be used by laboratories in the US that are certified under the Clinical Laboratory Improvement Amendments of 1988, 42 U.S.C. § 263a, to perform high complexity tests, or by similarly qualified non-US laboratories.
The CII-ArboViroPlex rRT-PCR Test is authorized to be performed with the NucliSENS® easyMag® automated extraction platform (bioMérieux), the RNA UltraSense™ One-Step Quantitative RT-PCR System (Thermo Fisher), and CFX96 Real-Time PCR Detection System (Bio-Rad).
“The ArboViroPlex Test provides an easy and efficient means to simultaneously detect Zika and 3 other mosquito-borne viral infections that may present with similar clinical features,” said Nischay Mishra, of CII.
“The FDA decision to issue the EUA gives clinicians and researchers a powerful tool to diagnose and prevent the spread of Zika,” added W. Ian Lipkin, director of CII.
More information on the CII-ArboViroPlex rRT-PCR Test Virus Kit and other Zika tests granted EUAs can be found on the FDA’s EUA page.
The US Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) for the CII-ArboViroPlex rRT-PCR Test.
It is the first multiplex assay that simultaneously tests for the presence of Zika virus, all serotypes of dengue virus, chikungunya virus, and West Nile virus, as well as a host gene that ensures the accuracy of results.
The EUA does not mean the CII-ArboViroPlex rRT-PCR Test is FDA cleared or approved.
An EUA allows for the use of unapproved medical products in an emergency. The products must be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, or nuclear threat agents, when there are no adequate alternatives.
The EUA for the CII-ArboViroPlex rRT-PCR Test means the test is only authorized as long as circumstances exist to justify the emergency use of in vitro diagnostics for the detection of Zika virus, unless the authorization is terminated or revoked sooner.
About the test
The CII-ArboViroPlex rRT-PCR Test is an assay that detects viral RNA matching Zika virus (ZIKV), dengue virus types 1-4 (DENV), chikungunya virus (CHIKV), and West Nile virus (WNV) with a human housekeeping gene, viral RNA controls, and extraction controls that ensure the integrity of the test from nucleic extraction to the final result.
Named for the 4 arboviruses it targets and the real-time reverse transcription polymerase chain reaction (rRT-PCR) technique it employs, the test can simultaneously detect ZIKV, DENV, CHIKV, and WNV in up to 88 samples of blood in less than 2 hours and ZIKV in urine (collected alongside a patient-matched serum specimen).
The CII-ArboViroPlex rRT-PCR Test was developed by scientists at the Center for Infection and Immunity (CII) at Columbia University’s Mailman School of Public Health in New York, New York. The manufacture of the test will be overseen by CII.
The CII-ArboViroPlex rRT-PCR Test is authorized to be used by laboratories in the US that are certified under the Clinical Laboratory Improvement Amendments of 1988, 42 U.S.C. § 263a, to perform high complexity tests, or by similarly qualified non-US laboratories.
The CII-ArboViroPlex rRT-PCR Test is authorized to be performed with the NucliSENS® easyMag® automated extraction platform (bioMérieux), the RNA UltraSense™ One-Step Quantitative RT-PCR System (Thermo Fisher), and CFX96 Real-Time PCR Detection System (Bio-Rad).
“The ArboViroPlex Test provides an easy and efficient means to simultaneously detect Zika and 3 other mosquito-borne viral infections that may present with similar clinical features,” said Nischay Mishra, of CII.
“The FDA decision to issue the EUA gives clinicians and researchers a powerful tool to diagnose and prevent the spread of Zika,” added W. Ian Lipkin, director of CII.
More information on the CII-ArboViroPlex rRT-PCR Test Virus Kit and other Zika tests granted EUAs can be found on the FDA’s EUA page.
CBO: End of ACA subsidies would mean short-term exit of insurers
Terminating the Affordable Care Act’s cost-sharing reduction payments to insurers would cause a short-term exit by insurers from the individual insurance marketplaces, but the availability of plans is expected to rebound, according to the Congressional Budget Office.
In a new analysis requested by Democratic leadership in the House of Representatives, CBO and staff from the congressional Joint Committee on Taxation (JCT) examined what would happen if the Trump administration announced by the end of August that it would cease to make cost-sharing reduction payments at the end of 2017.
However, insurers would be on the hook to cover the payments no longer provided by the government, which means that “participating insurers would raise premiums of ‘silver’ plans to recover the costs.”
Gross premiums for silver plans “would be 20% higher in 2018 and 25% by 2020,” pushing higher premium tax credits and increasing the federal deficit by $194 billion from 2017 through 2026,” the report states. “Most people would pay net premiums (after accounting for premium tax credits) for nongroup insurance throughout the next decade that were similar to or less than what they would pay otherwise.”
The percentage of people facing a “slight increases” would be higher during the next 2 years, they pointed out.
The number of uninsured would be slightly higher in 2018 (about 1 million more uninsured) but then would be slightly lower starting in 2020 (about 1 million less each year).
Should the administration end cost-sharing reduction payments in 2017, those eligible for tax credits who have annual incomes 200%-400% of the federal poverty level would use their subsidies to purchase either gold or bronze plans, with silver plans going almost exclusively to people eligible for cost-sharing reductions (100%-200% of the poverty line).
Terminating the Affordable Care Act’s cost-sharing reduction payments to insurers would cause a short-term exit by insurers from the individual insurance marketplaces, but the availability of plans is expected to rebound, according to the Congressional Budget Office.
In a new analysis requested by Democratic leadership in the House of Representatives, CBO and staff from the congressional Joint Committee on Taxation (JCT) examined what would happen if the Trump administration announced by the end of August that it would cease to make cost-sharing reduction payments at the end of 2017.
However, insurers would be on the hook to cover the payments no longer provided by the government, which means that “participating insurers would raise premiums of ‘silver’ plans to recover the costs.”
Gross premiums for silver plans “would be 20% higher in 2018 and 25% by 2020,” pushing higher premium tax credits and increasing the federal deficit by $194 billion from 2017 through 2026,” the report states. “Most people would pay net premiums (after accounting for premium tax credits) for nongroup insurance throughout the next decade that were similar to or less than what they would pay otherwise.”
The percentage of people facing a “slight increases” would be higher during the next 2 years, they pointed out.
The number of uninsured would be slightly higher in 2018 (about 1 million more uninsured) but then would be slightly lower starting in 2020 (about 1 million less each year).
Should the administration end cost-sharing reduction payments in 2017, those eligible for tax credits who have annual incomes 200%-400% of the federal poverty level would use their subsidies to purchase either gold or bronze plans, with silver plans going almost exclusively to people eligible for cost-sharing reductions (100%-200% of the poverty line).
Terminating the Affordable Care Act’s cost-sharing reduction payments to insurers would cause a short-term exit by insurers from the individual insurance marketplaces, but the availability of plans is expected to rebound, according to the Congressional Budget Office.
In a new analysis requested by Democratic leadership in the House of Representatives, CBO and staff from the congressional Joint Committee on Taxation (JCT) examined what would happen if the Trump administration announced by the end of August that it would cease to make cost-sharing reduction payments at the end of 2017.
However, insurers would be on the hook to cover the payments no longer provided by the government, which means that “participating insurers would raise premiums of ‘silver’ plans to recover the costs.”
Gross premiums for silver plans “would be 20% higher in 2018 and 25% by 2020,” pushing higher premium tax credits and increasing the federal deficit by $194 billion from 2017 through 2026,” the report states. “Most people would pay net premiums (after accounting for premium tax credits) for nongroup insurance throughout the next decade that were similar to or less than what they would pay otherwise.”
The percentage of people facing a “slight increases” would be higher during the next 2 years, they pointed out.
The number of uninsured would be slightly higher in 2018 (about 1 million more uninsured) but then would be slightly lower starting in 2020 (about 1 million less each year).
Should the administration end cost-sharing reduction payments in 2017, those eligible for tax credits who have annual incomes 200%-400% of the federal poverty level would use their subsidies to purchase either gold or bronze plans, with silver plans going almost exclusively to people eligible for cost-sharing reductions (100%-200% of the poverty line).
Study advances noninvasive prenatal testing for hemophilia
Digital droplet PCR (ddPCR) was an accurate and noninvasive method to detect mutations leading to hemophilia A and B in maternal plasma DNA in 15 at-risk pregnancies of 8 to 42 weeks’ gestation, researchers reported.
Additionally, the researchers showed for the first time that targeted massively parallel sequencing (MPS) accurately detected the clinically important int22h-related inversion mutations in maternal plasma DNA from pregnant hemophilia carriers from three families with the disorder.
As costs of sequencing continue to fall, larger studies of pregnant carriers of F8 int22h-related inversions can help make MPS “an essential part in noninvasive prenatal testing of hemophilia carriers,” Irena Hudecova, PhD, of Li Ka Shing Institute of Health Sciences, Hong Kong, and her associates wrote (Blood. 2017 Jul 20;130[3]:340-7).
Diagnosing hemophilia during pregnancy helps optimize care and allows mothers to make informed decisions about whether to terminate pregnancies. But for male fetuses, invasive testing has been the only option. In a prior small study, researchers used noninvasive microfluidics PCR to detect sequence variants of F8, which encodes factor VIII, and F9, which encodes Factor IX. The assay uses a chip that can accommodate about 9,000 reaction wells, making noninvasive screening much more feasible and affordable. But technical difficulties had precluded detection of int22h-related inversions, the inversion mutations of intron 22 in F8 on chromosome X that affect about half of individuals with severe hemophilia (Blood. 2011 Mar 31;117[13]:3684-91).
For the current study, the researchers first designed family-specific ddPCR assays to test for relevant maternal sequence variants scattered across the F8 and F9 genes. Tests of 15 male singleton fetuses produced three unclassified samples, but no misclassifications.
“Because of the scalability of ddPCR, the protocol performed reliably even in cases with fetal DNA fraction lower than 10%,” the researchers wrote. “When an unclassified result is encountered, one either performs more digital analyses on the sample to accumulate more data points, or when the sample is consumed, one may resort to an additional blood draw, possibly at a later gestational age with higher fetal DNA fraction.”
Next, the investigators used MPS to create detailed fetal haplotype maps of the 7.6-Md region of F8 where int22h-related inversions occur. This approach yielded an “accurate and robust measurement of maternally inherited fetal haplotypes,” they wrote. “Our data suggest it is feasible to apply targeted MPS to interrogate maternally inherited F8 int22h-related inversions, whereas ddPCR [is] an affordable approach for the identification of F8 and F9 sequence variants in maternal plasma.”
The study was funded by the Research Grants Council of the Hong Kong SAR Government and the Vice Chancellor’s One-Off Discretionary Fund of The Chinese University of Hong Kong. Dr. Hudecova reported having no financial disclosures. Several coauthors disclosed patents for plasma nucleic acid analysis and ties to Sequenom, Illumina, Xcelom, and Cirina.
The use of digital droplet PCR for prenatal diagnosis of hemophilia is a major improvement over current invasive methods, such as chorionic villus sampling, amniocentesis, and cordocentesis.
Knowledge of a hemophilia diagnosis before birth provides an opportunity for early hemostatic intervention before procedures such as circumcision are performed, or to prevent morbidity and mortality by cesarean delivery to reduce the risk of intracranial hemorrhage when the birth of a child with severe hemophilia is anticipated. Prenatal testing is also important to ensure hemostatic support for the mother, for whom it may be necessary to prevent bleeding with perinatal anesthesia and/or postpartum bleeding. These prenatal assays depend on knowledge of the mother’s carrier genotype, which is potentially more accurate than factor levels, which may increase with hormone use or the increasing hormone levels of pregnancy and mask carrier diagnosis.
The development of these assays is timely in view of the ongoing My Life, Our Future (MLOF) genome project in hemophilia and underscores the need for carrier testing and genetic counseling of female members from hemophilia kindreds.
Margaret V. Ragni, MD, is with the University of Pittsburgh Medical Center. She reported having no relevant disclosures. These comments are adapted from an accompanying editorial (Blood. 2017 Jul 20;130[3]:240-1).
The use of digital droplet PCR for prenatal diagnosis of hemophilia is a major improvement over current invasive methods, such as chorionic villus sampling, amniocentesis, and cordocentesis.
Knowledge of a hemophilia diagnosis before birth provides an opportunity for early hemostatic intervention before procedures such as circumcision are performed, or to prevent morbidity and mortality by cesarean delivery to reduce the risk of intracranial hemorrhage when the birth of a child with severe hemophilia is anticipated. Prenatal testing is also important to ensure hemostatic support for the mother, for whom it may be necessary to prevent bleeding with perinatal anesthesia and/or postpartum bleeding. These prenatal assays depend on knowledge of the mother’s carrier genotype, which is potentially more accurate than factor levels, which may increase with hormone use or the increasing hormone levels of pregnancy and mask carrier diagnosis.
The development of these assays is timely in view of the ongoing My Life, Our Future (MLOF) genome project in hemophilia and underscores the need for carrier testing and genetic counseling of female members from hemophilia kindreds.
Margaret V. Ragni, MD, is with the University of Pittsburgh Medical Center. She reported having no relevant disclosures. These comments are adapted from an accompanying editorial (Blood. 2017 Jul 20;130[3]:240-1).
The use of digital droplet PCR for prenatal diagnosis of hemophilia is a major improvement over current invasive methods, such as chorionic villus sampling, amniocentesis, and cordocentesis.
Knowledge of a hemophilia diagnosis before birth provides an opportunity for early hemostatic intervention before procedures such as circumcision are performed, or to prevent morbidity and mortality by cesarean delivery to reduce the risk of intracranial hemorrhage when the birth of a child with severe hemophilia is anticipated. Prenatal testing is also important to ensure hemostatic support for the mother, for whom it may be necessary to prevent bleeding with perinatal anesthesia and/or postpartum bleeding. These prenatal assays depend on knowledge of the mother’s carrier genotype, which is potentially more accurate than factor levels, which may increase with hormone use or the increasing hormone levels of pregnancy and mask carrier diagnosis.
The development of these assays is timely in view of the ongoing My Life, Our Future (MLOF) genome project in hemophilia and underscores the need for carrier testing and genetic counseling of female members from hemophilia kindreds.
Margaret V. Ragni, MD, is with the University of Pittsburgh Medical Center. She reported having no relevant disclosures. These comments are adapted from an accompanying editorial (Blood. 2017 Jul 20;130[3]:240-1).
Digital droplet PCR (ddPCR) was an accurate and noninvasive method to detect mutations leading to hemophilia A and B in maternal plasma DNA in 15 at-risk pregnancies of 8 to 42 weeks’ gestation, researchers reported.
Additionally, the researchers showed for the first time that targeted massively parallel sequencing (MPS) accurately detected the clinically important int22h-related inversion mutations in maternal plasma DNA from pregnant hemophilia carriers from three families with the disorder.
As costs of sequencing continue to fall, larger studies of pregnant carriers of F8 int22h-related inversions can help make MPS “an essential part in noninvasive prenatal testing of hemophilia carriers,” Irena Hudecova, PhD, of Li Ka Shing Institute of Health Sciences, Hong Kong, and her associates wrote (Blood. 2017 Jul 20;130[3]:340-7).
Diagnosing hemophilia during pregnancy helps optimize care and allows mothers to make informed decisions about whether to terminate pregnancies. But for male fetuses, invasive testing has been the only option. In a prior small study, researchers used noninvasive microfluidics PCR to detect sequence variants of F8, which encodes factor VIII, and F9, which encodes Factor IX. The assay uses a chip that can accommodate about 9,000 reaction wells, making noninvasive screening much more feasible and affordable. But technical difficulties had precluded detection of int22h-related inversions, the inversion mutations of intron 22 in F8 on chromosome X that affect about half of individuals with severe hemophilia (Blood. 2011 Mar 31;117[13]:3684-91).
For the current study, the researchers first designed family-specific ddPCR assays to test for relevant maternal sequence variants scattered across the F8 and F9 genes. Tests of 15 male singleton fetuses produced three unclassified samples, but no misclassifications.
“Because of the scalability of ddPCR, the protocol performed reliably even in cases with fetal DNA fraction lower than 10%,” the researchers wrote. “When an unclassified result is encountered, one either performs more digital analyses on the sample to accumulate more data points, or when the sample is consumed, one may resort to an additional blood draw, possibly at a later gestational age with higher fetal DNA fraction.”
Next, the investigators used MPS to create detailed fetal haplotype maps of the 7.6-Md region of F8 where int22h-related inversions occur. This approach yielded an “accurate and robust measurement of maternally inherited fetal haplotypes,” they wrote. “Our data suggest it is feasible to apply targeted MPS to interrogate maternally inherited F8 int22h-related inversions, whereas ddPCR [is] an affordable approach for the identification of F8 and F9 sequence variants in maternal plasma.”
The study was funded by the Research Grants Council of the Hong Kong SAR Government and the Vice Chancellor’s One-Off Discretionary Fund of The Chinese University of Hong Kong. Dr. Hudecova reported having no financial disclosures. Several coauthors disclosed patents for plasma nucleic acid analysis and ties to Sequenom, Illumina, Xcelom, and Cirina.
Digital droplet PCR (ddPCR) was an accurate and noninvasive method to detect mutations leading to hemophilia A and B in maternal plasma DNA in 15 at-risk pregnancies of 8 to 42 weeks’ gestation, researchers reported.
Additionally, the researchers showed for the first time that targeted massively parallel sequencing (MPS) accurately detected the clinically important int22h-related inversion mutations in maternal plasma DNA from pregnant hemophilia carriers from three families with the disorder.
As costs of sequencing continue to fall, larger studies of pregnant carriers of F8 int22h-related inversions can help make MPS “an essential part in noninvasive prenatal testing of hemophilia carriers,” Irena Hudecova, PhD, of Li Ka Shing Institute of Health Sciences, Hong Kong, and her associates wrote (Blood. 2017 Jul 20;130[3]:340-7).
Diagnosing hemophilia during pregnancy helps optimize care and allows mothers to make informed decisions about whether to terminate pregnancies. But for male fetuses, invasive testing has been the only option. In a prior small study, researchers used noninvasive microfluidics PCR to detect sequence variants of F8, which encodes factor VIII, and F9, which encodes Factor IX. The assay uses a chip that can accommodate about 9,000 reaction wells, making noninvasive screening much more feasible and affordable. But technical difficulties had precluded detection of int22h-related inversions, the inversion mutations of intron 22 in F8 on chromosome X that affect about half of individuals with severe hemophilia (Blood. 2011 Mar 31;117[13]:3684-91).
For the current study, the researchers first designed family-specific ddPCR assays to test for relevant maternal sequence variants scattered across the F8 and F9 genes. Tests of 15 male singleton fetuses produced three unclassified samples, but no misclassifications.
“Because of the scalability of ddPCR, the protocol performed reliably even in cases with fetal DNA fraction lower than 10%,” the researchers wrote. “When an unclassified result is encountered, one either performs more digital analyses on the sample to accumulate more data points, or when the sample is consumed, one may resort to an additional blood draw, possibly at a later gestational age with higher fetal DNA fraction.”
Next, the investigators used MPS to create detailed fetal haplotype maps of the 7.6-Md region of F8 where int22h-related inversions occur. This approach yielded an “accurate and robust measurement of maternally inherited fetal haplotypes,” they wrote. “Our data suggest it is feasible to apply targeted MPS to interrogate maternally inherited F8 int22h-related inversions, whereas ddPCR [is] an affordable approach for the identification of F8 and F9 sequence variants in maternal plasma.”
The study was funded by the Research Grants Council of the Hong Kong SAR Government and the Vice Chancellor’s One-Off Discretionary Fund of The Chinese University of Hong Kong. Dr. Hudecova reported having no financial disclosures. Several coauthors disclosed patents for plasma nucleic acid analysis and ties to Sequenom, Illumina, Xcelom, and Cirina.
FROM BLOOD
Key clinical point:
Major finding: Digital droplet PCR (ddPCR) detected relevant F8 and F9 gene mutations. Targeted massively parallel sequencing (MPS) determined fetal inheritance of F8 int22h-related inversions, which up to half of individuals with severe hemophilia carry.
Data source: ddPCR of 15 singleton male fetuses from at-risk mothers and MPS of the maternal plasma of pregnant carriers from three hemophilia families.
Disclosures: The study was funded by the Research Grants Council of the Hong Kong SAR Government and the Vice Chancellor’s One-Off Discretionary Fund of The Chinese University of Hong Kong. Dr. Hudecova reported having no financial disclosures. Some of the coauthors disclosed patents for plasma nucleic acid analysis and ties to Sequenom, Illumina, Xcelom, and Cirina.
How many strikes?
(Larissa MacFarquar, Aug. 7 & 14, 2017). It is a very complex question, and one for which there has never been an easy answer, certainly not an answer that can be applied universally. However, my reflex response was “sooner rather than later!”
What prompted my hasty from-the-hip answer is 40-plus years of watching the legal system grind along at a pace that too often fails to take into account the emotional needs of a child’s developing personality. While lawyers file for extensions and wait for slots in dockets bloated with less time-sensitive cases, children float in limbo waiting to hear where their home will be and who will constitute their family.
Even if he is lucky enough to be housed with a single foster home, the odds are that his stays there will be punctuated with returns to his parent as the parent is given one more chance to beat back the demons that have stood in the way of at least an adequate, if not a model, parenthood. The New Yorker article chronicles one such odyssey that spans a mother’s four pregnancies with several fathers.
In the crudest terms, here is the question: “How many strikes does one get before one loses his or her parental rights?” It is a bit easier to make the call when there have been incidents in which a parent’s action or inaction has put the child’s physical health in jeopardy. However, the social workers, physicians, and law enforcement officials who must shoulder the burden of these decisions involving the abusive parent often find themselves in no-win situations. Giving the parent who is suspected of physical abuse having been “just a little heavy handed” one more chance could result in death or life-long impairment.
I suspect the rationale for giving the parent another chance is based on the belief that the biologic family should always be the preferred option; an assumption that can be called into question. While I don’t think these decisions should be made with the strict application of an algorithm, I believe there is more room for evidence-based decision-making. That evidence may not be currently available, but I think we should be asking questions to get that information. For example, for an individual with a specific substance addiction or mental illness with a certain diagnosis, what are the chances of a remedy that will allow that individual to become a functional parent? And how long will it take?
Information like this may be helpful for those folks with the difficult job of deciding when a parent should lose his parental rights in a time course that takes into account the emotional needs of his children.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
(Larissa MacFarquar, Aug. 7 & 14, 2017). It is a very complex question, and one for which there has never been an easy answer, certainly not an answer that can be applied universally. However, my reflex response was “sooner rather than later!”
What prompted my hasty from-the-hip answer is 40-plus years of watching the legal system grind along at a pace that too often fails to take into account the emotional needs of a child’s developing personality. While lawyers file for extensions and wait for slots in dockets bloated with less time-sensitive cases, children float in limbo waiting to hear where their home will be and who will constitute their family.
Even if he is lucky enough to be housed with a single foster home, the odds are that his stays there will be punctuated with returns to his parent as the parent is given one more chance to beat back the demons that have stood in the way of at least an adequate, if not a model, parenthood. The New Yorker article chronicles one such odyssey that spans a mother’s four pregnancies with several fathers.
In the crudest terms, here is the question: “How many strikes does one get before one loses his or her parental rights?” It is a bit easier to make the call when there have been incidents in which a parent’s action or inaction has put the child’s physical health in jeopardy. However, the social workers, physicians, and law enforcement officials who must shoulder the burden of these decisions involving the abusive parent often find themselves in no-win situations. Giving the parent who is suspected of physical abuse having been “just a little heavy handed” one more chance could result in death or life-long impairment.
I suspect the rationale for giving the parent another chance is based on the belief that the biologic family should always be the preferred option; an assumption that can be called into question. While I don’t think these decisions should be made with the strict application of an algorithm, I believe there is more room for evidence-based decision-making. That evidence may not be currently available, but I think we should be asking questions to get that information. For example, for an individual with a specific substance addiction or mental illness with a certain diagnosis, what are the chances of a remedy that will allow that individual to become a functional parent? And how long will it take?
Information like this may be helpful for those folks with the difficult job of deciding when a parent should lose his parental rights in a time course that takes into account the emotional needs of his children.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
(Larissa MacFarquar, Aug. 7 & 14, 2017). It is a very complex question, and one for which there has never been an easy answer, certainly not an answer that can be applied universally. However, my reflex response was “sooner rather than later!”
What prompted my hasty from-the-hip answer is 40-plus years of watching the legal system grind along at a pace that too often fails to take into account the emotional needs of a child’s developing personality. While lawyers file for extensions and wait for slots in dockets bloated with less time-sensitive cases, children float in limbo waiting to hear where their home will be and who will constitute their family.
Even if he is lucky enough to be housed with a single foster home, the odds are that his stays there will be punctuated with returns to his parent as the parent is given one more chance to beat back the demons that have stood in the way of at least an adequate, if not a model, parenthood. The New Yorker article chronicles one such odyssey that spans a mother’s four pregnancies with several fathers.
In the crudest terms, here is the question: “How many strikes does one get before one loses his or her parental rights?” It is a bit easier to make the call when there have been incidents in which a parent’s action or inaction has put the child’s physical health in jeopardy. However, the social workers, physicians, and law enforcement officials who must shoulder the burden of these decisions involving the abusive parent often find themselves in no-win situations. Giving the parent who is suspected of physical abuse having been “just a little heavy handed” one more chance could result in death or life-long impairment.
I suspect the rationale for giving the parent another chance is based on the belief that the biologic family should always be the preferred option; an assumption that can be called into question. While I don’t think these decisions should be made with the strict application of an algorithm, I believe there is more room for evidence-based decision-making. That evidence may not be currently available, but I think we should be asking questions to get that information. For example, for an individual with a specific substance addiction or mental illness with a certain diagnosis, what are the chances of a remedy that will allow that individual to become a functional parent? And how long will it take?
Information like this may be helpful for those folks with the difficult job of deciding when a parent should lose his parental rights in a time course that takes into account the emotional needs of his children.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
Inactivated quadrivalent influenza vaccine safe, effective in 6- to 35-month-olds
MADRID – An intramuscular inactivated quadrivalent influenza vaccine reduced the risk of laboratory-confirmed influenza by up to 69% in previously unvaccinated children aged 6-35 months in a large randomized trial, Stephanie Pepin, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.
The quadrivalent influenza vaccine (QIV) is licensed by the Food and Drug Administration as Fluzone Quadrivalent for use in patients as young as 6 months of age. It contains two A- and two B-lineage influenza strains in order to address the common problem of mismatches between circulating influenza B and the single B-lineage strain included in trivalent vaccines.
The incidence of any laboratory confirmed strain of influenza illness during the period from 14 days post-vaccination to the end of flu season was 4.72% in the QIV group, compared with 9.84% in controls who received placebo, which translated to 52% efficacy. The incidence of influenza from vaccine-similar strains as determined by the Sanger sequencing method was 1.01% in children randomized to QIV, compared with 3.28% with placebo, for a 69% efficacy rate.
The QIV had a safety profile in this young population that was similar to the older licensed trivalent vaccine. The most frequently reported adverse reactions to the QIV were injection site pain, irritability, loss of appetite, abnormal crying, and malaise, each reported in 19%-25% of children after the first injection and in 14%-18% after the second. These were typically mild grade 1 or 2 reactions, which arose in the first 3 days after vaccination and resolved spontaneously 1-3 days later.
The trial was sponsored by Sanofi Pasteur and presented by a company employee.
MADRID – An intramuscular inactivated quadrivalent influenza vaccine reduced the risk of laboratory-confirmed influenza by up to 69% in previously unvaccinated children aged 6-35 months in a large randomized trial, Stephanie Pepin, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.
The quadrivalent influenza vaccine (QIV) is licensed by the Food and Drug Administration as Fluzone Quadrivalent for use in patients as young as 6 months of age. It contains two A- and two B-lineage influenza strains in order to address the common problem of mismatches between circulating influenza B and the single B-lineage strain included in trivalent vaccines.
The incidence of any laboratory confirmed strain of influenza illness during the period from 14 days post-vaccination to the end of flu season was 4.72% in the QIV group, compared with 9.84% in controls who received placebo, which translated to 52% efficacy. The incidence of influenza from vaccine-similar strains as determined by the Sanger sequencing method was 1.01% in children randomized to QIV, compared with 3.28% with placebo, for a 69% efficacy rate.
The QIV had a safety profile in this young population that was similar to the older licensed trivalent vaccine. The most frequently reported adverse reactions to the QIV were injection site pain, irritability, loss of appetite, abnormal crying, and malaise, each reported in 19%-25% of children after the first injection and in 14%-18% after the second. These were typically mild grade 1 or 2 reactions, which arose in the first 3 days after vaccination and resolved spontaneously 1-3 days later.
The trial was sponsored by Sanofi Pasteur and presented by a company employee.
MADRID – An intramuscular inactivated quadrivalent influenza vaccine reduced the risk of laboratory-confirmed influenza by up to 69% in previously unvaccinated children aged 6-35 months in a large randomized trial, Stephanie Pepin, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.
The quadrivalent influenza vaccine (QIV) is licensed by the Food and Drug Administration as Fluzone Quadrivalent for use in patients as young as 6 months of age. It contains two A- and two B-lineage influenza strains in order to address the common problem of mismatches between circulating influenza B and the single B-lineage strain included in trivalent vaccines.
The incidence of any laboratory confirmed strain of influenza illness during the period from 14 days post-vaccination to the end of flu season was 4.72% in the QIV group, compared with 9.84% in controls who received placebo, which translated to 52% efficacy. The incidence of influenza from vaccine-similar strains as determined by the Sanger sequencing method was 1.01% in children randomized to QIV, compared with 3.28% with placebo, for a 69% efficacy rate.
The QIV had a safety profile in this young population that was similar to the older licensed trivalent vaccine. The most frequently reported adverse reactions to the QIV were injection site pain, irritability, loss of appetite, abnormal crying, and malaise, each reported in 19%-25% of children after the first injection and in 14%-18% after the second. These were typically mild grade 1 or 2 reactions, which arose in the first 3 days after vaccination and resolved spontaneously 1-3 days later.
The trial was sponsored by Sanofi Pasteur and presented by a company employee.
AT ESPID 2017
Key clinical point:
Major finding: The intramuscular inactivated influenza vaccine, Fluzone Quadrivalent, reduced the risk of laboratory-confirmed influenza by up to 69% in 6- to 35-month-olds.
Data source: This randomized, multinational, placebo-controlled trial included 5,806 healthy 6- to 35-month-old children.
Disclosures: The study was sponsored by Sanofi Pasteur and presented by a company employee.
Beating your wandering attention
Like many adults, I suspect that I may have been living under the cloud of an undiagnosed case of attention-deficit/hyperactivity disorder (ADHD). What else could explain why my mind wanders during the second hole of my wife’s narrative of her morning golf outing with her friends? Why have I never been in a class or lecture in which after 20 minutes I began wishing I were somewhere else? In my student days, I felt compelled to leave my studies and go to the refrigerator every 15 minutes – even though I wasn’t hungry. Sounds like ADHD to me.
But I know what you are thinking. This guy graduated from medical school, and has been married to the same woman for nearly 50 years. He has no criminal record and has held the same job for more than 40 years. I will admit that my life trajectory is atypical for someone even with a mild case of adult ADHD.
Actually, I don’t really believe that I have an undiagnosed case of ADHD. But I do feel that my attention span is at the short end of the normal spectrum. And I think that by good fortune I stumbled on several strategies that helped me thrive in an academic environment despite my relative attention deficit.
Most noteworthy among those strategies was my habit of listening to heavy metal music with a throbbing beat while I was studying. At my recent college reunion, former classmates whom I hadn’t seen in 50 years reminded me of how often I drove them to quieter study oases with the driving rhythms of the Rolling Stones’ misogynistic anthem “Under My Thumb.”My wife still recalls her amazement the first (and last) time she offered to keep me company while I studied for a pathophysiology exam. She found me hunched over my notes spread out on a coffee table, my knees bouncing to the beat of Joe Cocker crowing the Beatles’ classic “She Came in Through the Bathroom Window” (still one of my all-time favorites). Earbuds hadn’t been invented, and I considered earphones the size of chili bowls too dorky.
I always have assumed that my study habits were just a little weird. But recently I discovered an article describing the work of Alexander Pantelyat, MD, assistant professor of neurology and cofounder of the Johns Hopkins Center for Music and Medicine (“Does Listening to Music Improve Your Focus?” by Heidi Mitchell, Wall Street Journal, July 26, 2017). Dr. Pantelyat notes that the early enthusiasm for playing Mozart to newborns has faded with the understanding that any improvement in learning skills was short-lived. However, he sees some evidence that hearing music of a genre you enjoy may help you focus better than listening to music that you don’t like. He says, “If you enjoy heavy metal, you might be more focused when you listen to it.”
As Dr. Pantelyat cautions, the response to music is highly individual. I generally have not recommended my peculiar study habits to my patients. However, my experience has left me more open-minded when trying to help young people struggling to find a study strategy that works. You may not share my affinity for the Rolling Stones and Joe Cocker, but you have to admit you would rather have your patients listen to their music than take drugs they may not need.
Like many adults, I suspect that I may have been living under the cloud of an undiagnosed case of attention-deficit/hyperactivity disorder (ADHD). What else could explain why my mind wanders during the second hole of my wife’s narrative of her morning golf outing with her friends? Why have I never been in a class or lecture in which after 20 minutes I began wishing I were somewhere else? In my student days, I felt compelled to leave my studies and go to the refrigerator every 15 minutes – even though I wasn’t hungry. Sounds like ADHD to me.
But I know what you are thinking. This guy graduated from medical school, and has been married to the same woman for nearly 50 years. He has no criminal record and has held the same job for more than 40 years. I will admit that my life trajectory is atypical for someone even with a mild case of adult ADHD.
Actually, I don’t really believe that I have an undiagnosed case of ADHD. But I do feel that my attention span is at the short end of the normal spectrum. And I think that by good fortune I stumbled on several strategies that helped me thrive in an academic environment despite my relative attention deficit.
Most noteworthy among those strategies was my habit of listening to heavy metal music with a throbbing beat while I was studying. At my recent college reunion, former classmates whom I hadn’t seen in 50 years reminded me of how often I drove them to quieter study oases with the driving rhythms of the Rolling Stones’ misogynistic anthem “Under My Thumb.”My wife still recalls her amazement the first (and last) time she offered to keep me company while I studied for a pathophysiology exam. She found me hunched over my notes spread out on a coffee table, my knees bouncing to the beat of Joe Cocker crowing the Beatles’ classic “She Came in Through the Bathroom Window” (still one of my all-time favorites). Earbuds hadn’t been invented, and I considered earphones the size of chili bowls too dorky.
I always have assumed that my study habits were just a little weird. But recently I discovered an article describing the work of Alexander Pantelyat, MD, assistant professor of neurology and cofounder of the Johns Hopkins Center for Music and Medicine (“Does Listening to Music Improve Your Focus?” by Heidi Mitchell, Wall Street Journal, July 26, 2017). Dr. Pantelyat notes that the early enthusiasm for playing Mozart to newborns has faded with the understanding that any improvement in learning skills was short-lived. However, he sees some evidence that hearing music of a genre you enjoy may help you focus better than listening to music that you don’t like. He says, “If you enjoy heavy metal, you might be more focused when you listen to it.”
As Dr. Pantelyat cautions, the response to music is highly individual. I generally have not recommended my peculiar study habits to my patients. However, my experience has left me more open-minded when trying to help young people struggling to find a study strategy that works. You may not share my affinity for the Rolling Stones and Joe Cocker, but you have to admit you would rather have your patients listen to their music than take drugs they may not need.
Like many adults, I suspect that I may have been living under the cloud of an undiagnosed case of attention-deficit/hyperactivity disorder (ADHD). What else could explain why my mind wanders during the second hole of my wife’s narrative of her morning golf outing with her friends? Why have I never been in a class or lecture in which after 20 minutes I began wishing I were somewhere else? In my student days, I felt compelled to leave my studies and go to the refrigerator every 15 minutes – even though I wasn’t hungry. Sounds like ADHD to me.
But I know what you are thinking. This guy graduated from medical school, and has been married to the same woman for nearly 50 years. He has no criminal record and has held the same job for more than 40 years. I will admit that my life trajectory is atypical for someone even with a mild case of adult ADHD.
Actually, I don’t really believe that I have an undiagnosed case of ADHD. But I do feel that my attention span is at the short end of the normal spectrum. And I think that by good fortune I stumbled on several strategies that helped me thrive in an academic environment despite my relative attention deficit.
Most noteworthy among those strategies was my habit of listening to heavy metal music with a throbbing beat while I was studying. At my recent college reunion, former classmates whom I hadn’t seen in 50 years reminded me of how often I drove them to quieter study oases with the driving rhythms of the Rolling Stones’ misogynistic anthem “Under My Thumb.”My wife still recalls her amazement the first (and last) time she offered to keep me company while I studied for a pathophysiology exam. She found me hunched over my notes spread out on a coffee table, my knees bouncing to the beat of Joe Cocker crowing the Beatles’ classic “She Came in Through the Bathroom Window” (still one of my all-time favorites). Earbuds hadn’t been invented, and I considered earphones the size of chili bowls too dorky.
I always have assumed that my study habits were just a little weird. But recently I discovered an article describing the work of Alexander Pantelyat, MD, assistant professor of neurology and cofounder of the Johns Hopkins Center for Music and Medicine (“Does Listening to Music Improve Your Focus?” by Heidi Mitchell, Wall Street Journal, July 26, 2017). Dr. Pantelyat notes that the early enthusiasm for playing Mozart to newborns has faded with the understanding that any improvement in learning skills was short-lived. However, he sees some evidence that hearing music of a genre you enjoy may help you focus better than listening to music that you don’t like. He says, “If you enjoy heavy metal, you might be more focused when you listen to it.”
As Dr. Pantelyat cautions, the response to music is highly individual. I generally have not recommended my peculiar study habits to my patients. However, my experience has left me more open-minded when trying to help young people struggling to find a study strategy that works. You may not share my affinity for the Rolling Stones and Joe Cocker, but you have to admit you would rather have your patients listen to their music than take drugs they may not need.
Analysis: Gabapentinoids aren’t the answer to back pain
Treating chronic lower back pain with gabapentinoids carries risks of dizziness, fatigue, and other side effects, but there is little evidence of their efficacy, according to a meta-analysis.
First-line analgesic treatment of chronic lower back pain (CLBP) often brings insufficient relief, leading to second-line treatments with gabapentinoids such as gabapentin (GB) or pregabalin (PG). These drugs are effective for neuropathic pain, but in most cases, CLBP has no clear cause.
Long-term use of gabapentinoids for CLBP has been increasing, but it could carry the risk of side effects. That prompted Harsha Shanthanna, MD, of McMaster University, Hamilton, Ont., and his colleagues to analyze existing research to determine their efficacy and potential harms in the treatment of CLBP.
The authors converted pain relief expressed in numerical rating scale or visual analog scale into a common scale of pain relief.
A meta-analysis of trials that compared GB to placebo found a small reduction in pain in the GB group (mean difference, 0.22 units; 95% confidence interval [CI], –0.51-0.07). No studies compared PG to placebo. Three studies (n = 169) compared PG to an active comparator, and the comparator yielded better improvements in pain (mean difference, 0.42 units; 95% CI, 0.20-0.64). The quality of evidence was rated very low in both PG to comparator and GB to placebo.
No deaths or hospitalizations were reported in the studies. Rates of adverse events were higher in the gabapentinoid groups than in the placebo group, including dizziness (risk ratio, 1.99, 95% CI, 1.17-3.37; number needed to harm, 7), fatigue (RR, 1.85; 95% CI, 1.12-3.05; I2 = 0; NNH, 8), difficulties with mentation (RR, 3.34; 95% CI, 1.54-7.25; NNH, 6), and visual disturbances (RR, 5.72; 95% CI, 1.94-16.91; NNH, 6). The evidence was of very low quality for dizziness and fatigue, low for difficulties with mentation, and moderate with respect to visual disturbances.
Dizziness was more common in PG groups, compared with active comparators (RR, 2.70; 95% CI, 1.25-5.83; NNH, 11), although the quality of evidence was very low.
The study included only a small number of trials, which could lead to issues with heterogeneity, the investigators cautioned.
“Our review demonstrates that there is limited evidence on the use of gabapentinoids in nonspecific CLBP, and the existing evidence in the form of RCTs does not support their use,” the authors concluded.
The study was not funded, and the authors reported having no relevant financial disclosures.
Treating chronic lower back pain with gabapentinoids carries risks of dizziness, fatigue, and other side effects, but there is little evidence of their efficacy, according to a meta-analysis.
First-line analgesic treatment of chronic lower back pain (CLBP) often brings insufficient relief, leading to second-line treatments with gabapentinoids such as gabapentin (GB) or pregabalin (PG). These drugs are effective for neuropathic pain, but in most cases, CLBP has no clear cause.
Long-term use of gabapentinoids for CLBP has been increasing, but it could carry the risk of side effects. That prompted Harsha Shanthanna, MD, of McMaster University, Hamilton, Ont., and his colleagues to analyze existing research to determine their efficacy and potential harms in the treatment of CLBP.
The authors converted pain relief expressed in numerical rating scale or visual analog scale into a common scale of pain relief.
A meta-analysis of trials that compared GB to placebo found a small reduction in pain in the GB group (mean difference, 0.22 units; 95% confidence interval [CI], –0.51-0.07). No studies compared PG to placebo. Three studies (n = 169) compared PG to an active comparator, and the comparator yielded better improvements in pain (mean difference, 0.42 units; 95% CI, 0.20-0.64). The quality of evidence was rated very low in both PG to comparator and GB to placebo.
No deaths or hospitalizations were reported in the studies. Rates of adverse events were higher in the gabapentinoid groups than in the placebo group, including dizziness (risk ratio, 1.99, 95% CI, 1.17-3.37; number needed to harm, 7), fatigue (RR, 1.85; 95% CI, 1.12-3.05; I2 = 0; NNH, 8), difficulties with mentation (RR, 3.34; 95% CI, 1.54-7.25; NNH, 6), and visual disturbances (RR, 5.72; 95% CI, 1.94-16.91; NNH, 6). The evidence was of very low quality for dizziness and fatigue, low for difficulties with mentation, and moderate with respect to visual disturbances.
Dizziness was more common in PG groups, compared with active comparators (RR, 2.70; 95% CI, 1.25-5.83; NNH, 11), although the quality of evidence was very low.
The study included only a small number of trials, which could lead to issues with heterogeneity, the investigators cautioned.
“Our review demonstrates that there is limited evidence on the use of gabapentinoids in nonspecific CLBP, and the existing evidence in the form of RCTs does not support their use,” the authors concluded.
The study was not funded, and the authors reported having no relevant financial disclosures.
Treating chronic lower back pain with gabapentinoids carries risks of dizziness, fatigue, and other side effects, but there is little evidence of their efficacy, according to a meta-analysis.
First-line analgesic treatment of chronic lower back pain (CLBP) often brings insufficient relief, leading to second-line treatments with gabapentinoids such as gabapentin (GB) or pregabalin (PG). These drugs are effective for neuropathic pain, but in most cases, CLBP has no clear cause.
Long-term use of gabapentinoids for CLBP has been increasing, but it could carry the risk of side effects. That prompted Harsha Shanthanna, MD, of McMaster University, Hamilton, Ont., and his colleagues to analyze existing research to determine their efficacy and potential harms in the treatment of CLBP.
The authors converted pain relief expressed in numerical rating scale or visual analog scale into a common scale of pain relief.
A meta-analysis of trials that compared GB to placebo found a small reduction in pain in the GB group (mean difference, 0.22 units; 95% confidence interval [CI], –0.51-0.07). No studies compared PG to placebo. Three studies (n = 169) compared PG to an active comparator, and the comparator yielded better improvements in pain (mean difference, 0.42 units; 95% CI, 0.20-0.64). The quality of evidence was rated very low in both PG to comparator and GB to placebo.
No deaths or hospitalizations were reported in the studies. Rates of adverse events were higher in the gabapentinoid groups than in the placebo group, including dizziness (risk ratio, 1.99, 95% CI, 1.17-3.37; number needed to harm, 7), fatigue (RR, 1.85; 95% CI, 1.12-3.05; I2 = 0; NNH, 8), difficulties with mentation (RR, 3.34; 95% CI, 1.54-7.25; NNH, 6), and visual disturbances (RR, 5.72; 95% CI, 1.94-16.91; NNH, 6). The evidence was of very low quality for dizziness and fatigue, low for difficulties with mentation, and moderate with respect to visual disturbances.
Dizziness was more common in PG groups, compared with active comparators (RR, 2.70; 95% CI, 1.25-5.83; NNH, 11), although the quality of evidence was very low.
The study included only a small number of trials, which could lead to issues with heterogeneity, the investigators cautioned.
“Our review demonstrates that there is limited evidence on the use of gabapentinoids in nonspecific CLBP, and the existing evidence in the form of RCTs does not support their use,” the authors concluded.
The study was not funded, and the authors reported having no relevant financial disclosures.
FROM PLOS MEDICINE
Key clinical point: Gabapentins were little better than placebo for chronic lower back pain, but they posed risks of dizziness and other effects.
Major finding: A meta-analysis of trials that compared gabapentin to placebo found a small reduction in pain in the gabapentin group, but rates of adverse events were higher in the gabapentinoid groups.
Data source: A meta-analysis of 14 randomized, controlled trials.
Disclosures: The study was not funded, and the authors reported having no relevant financial disclosures.
Vitamin D level linked to post-alloSCT relapse risk in myeloma
Patients with myeloid malignancies who have vitamin D deficiency prior to an allogeneic stem cell transplant (alloSCT) are significantly more likely to experience a relapse and have worse overall survival after transplant than patients with adequate vitamin D levels at baseline, investigators have found.
Among 492 patients with lymphoid or myeloid malignancies who had an alloSCT at a single center, those with vitamin D deficiency had a risk of post-transplant relapse that was nearly double the risk of patients with sufficient vitamin D levels. Also, this relapse risk contributed to significantly worse overall survival for the vitamin D–deficient patients, reported Thomas Luft, MD, PhD, and his colleagues from the University of Heidelberg, Germany.
In multivariate analysis, the risk for relapse was limited to patients with myeloid rather than lymphatic disease, they reported in the Journal of Clinical Oncology.
“[O]ur study suggests that VitD deficiency might affect disease control after alloSCT, in particular, in patients allografted for myeloid malignancies. However, the question of whether improving VitD status before alloSCT has an impact on outcome can only be answered by clinical trial,” they wrote.
To see whether pre-transplant vitamin D deficiency – serum levels of 25-hydroxyvitamin D3 less than 20 ng/mL – might have prognostic significance, the investigators looked at a training cohort of 492 patients who underwent alloSCT at their center from 2002 through 2013, and a validation cohort consisting of 398 additional patients with myeloid malignancies treated at the University of Essen, Germany.
Overall survival for the 396 patients (80%) in the training cohort with vitamin D deficiency was significantly worse than for patients with adequate levels (hazard ratio, 1.78; P = .007) in a multivariate analysis adjusted for type of malignancy, disease stage, conditioning intensity, patient age, donor type, and recipient/donor sex match.
Analysis also showed that the excess hazard was accounted for by higher risk of relapse than nonrelapse mortality (HR, 1.96; P = .006).
When the investigators looked at relapse risk by disease type, they found a significantly higher risk among vitamin D–deficient patients with myeloid malignancies (HR, 2.55; P = .014) but not with lymphoid malignancies.
The risk for relapse among patients with myeloid malignancies in the validation cohort was similarly high (HR, 2.60; P = .017).
“The growth inhibitory, pro-differentiation, and pro-apoptotic effects of VitD in vitro are well recognized, and low VitD levels have been shown to enhance clonal proliferation of leukemic cells. Therefore, with regard to treatment before alloSCT but also to conditioning, one might speculate that VitD deficiency facilitates resistance to chemotherapy,” the researchers wrote.
Low vitamin D levels have been associated in other studies with shorter relapse-free and overall survival in patients with acute myeloid leukemia apart from alloSCT.
The researchers recommend clinical trials to explore the possibility that vitamin D supplementation pre-transplant could improve post-transplant outcomes.
The study was supported by a grant from the BLUT Foundation and the European Union’s Seventh Framework Program. Dr. Luft disclosed consulting with Alexion and Jazz Pharmaceuticals, and institutional research funding and travel support from Medac, Neovii, and Jazz.
Patients with myeloid malignancies who have vitamin D deficiency prior to an allogeneic stem cell transplant (alloSCT) are significantly more likely to experience a relapse and have worse overall survival after transplant than patients with adequate vitamin D levels at baseline, investigators have found.
Among 492 patients with lymphoid or myeloid malignancies who had an alloSCT at a single center, those with vitamin D deficiency had a risk of post-transplant relapse that was nearly double the risk of patients with sufficient vitamin D levels. Also, this relapse risk contributed to significantly worse overall survival for the vitamin D–deficient patients, reported Thomas Luft, MD, PhD, and his colleagues from the University of Heidelberg, Germany.
In multivariate analysis, the risk for relapse was limited to patients with myeloid rather than lymphatic disease, they reported in the Journal of Clinical Oncology.
“[O]ur study suggests that VitD deficiency might affect disease control after alloSCT, in particular, in patients allografted for myeloid malignancies. However, the question of whether improving VitD status before alloSCT has an impact on outcome can only be answered by clinical trial,” they wrote.
To see whether pre-transplant vitamin D deficiency – serum levels of 25-hydroxyvitamin D3 less than 20 ng/mL – might have prognostic significance, the investigators looked at a training cohort of 492 patients who underwent alloSCT at their center from 2002 through 2013, and a validation cohort consisting of 398 additional patients with myeloid malignancies treated at the University of Essen, Germany.
Overall survival for the 396 patients (80%) in the training cohort with vitamin D deficiency was significantly worse than for patients with adequate levels (hazard ratio, 1.78; P = .007) in a multivariate analysis adjusted for type of malignancy, disease stage, conditioning intensity, patient age, donor type, and recipient/donor sex match.
Analysis also showed that the excess hazard was accounted for by higher risk of relapse than nonrelapse mortality (HR, 1.96; P = .006).
When the investigators looked at relapse risk by disease type, they found a significantly higher risk among vitamin D–deficient patients with myeloid malignancies (HR, 2.55; P = .014) but not with lymphoid malignancies.
The risk for relapse among patients with myeloid malignancies in the validation cohort was similarly high (HR, 2.60; P = .017).
“The growth inhibitory, pro-differentiation, and pro-apoptotic effects of VitD in vitro are well recognized, and low VitD levels have been shown to enhance clonal proliferation of leukemic cells. Therefore, with regard to treatment before alloSCT but also to conditioning, one might speculate that VitD deficiency facilitates resistance to chemotherapy,” the researchers wrote.
Low vitamin D levels have been associated in other studies with shorter relapse-free and overall survival in patients with acute myeloid leukemia apart from alloSCT.
The researchers recommend clinical trials to explore the possibility that vitamin D supplementation pre-transplant could improve post-transplant outcomes.
The study was supported by a grant from the BLUT Foundation and the European Union’s Seventh Framework Program. Dr. Luft disclosed consulting with Alexion and Jazz Pharmaceuticals, and institutional research funding and travel support from Medac, Neovii, and Jazz.
Patients with myeloid malignancies who have vitamin D deficiency prior to an allogeneic stem cell transplant (alloSCT) are significantly more likely to experience a relapse and have worse overall survival after transplant than patients with adequate vitamin D levels at baseline, investigators have found.
Among 492 patients with lymphoid or myeloid malignancies who had an alloSCT at a single center, those with vitamin D deficiency had a risk of post-transplant relapse that was nearly double the risk of patients with sufficient vitamin D levels. Also, this relapse risk contributed to significantly worse overall survival for the vitamin D–deficient patients, reported Thomas Luft, MD, PhD, and his colleagues from the University of Heidelberg, Germany.
In multivariate analysis, the risk for relapse was limited to patients with myeloid rather than lymphatic disease, they reported in the Journal of Clinical Oncology.
“[O]ur study suggests that VitD deficiency might affect disease control after alloSCT, in particular, in patients allografted for myeloid malignancies. However, the question of whether improving VitD status before alloSCT has an impact on outcome can only be answered by clinical trial,” they wrote.
To see whether pre-transplant vitamin D deficiency – serum levels of 25-hydroxyvitamin D3 less than 20 ng/mL – might have prognostic significance, the investigators looked at a training cohort of 492 patients who underwent alloSCT at their center from 2002 through 2013, and a validation cohort consisting of 398 additional patients with myeloid malignancies treated at the University of Essen, Germany.
Overall survival for the 396 patients (80%) in the training cohort with vitamin D deficiency was significantly worse than for patients with adequate levels (hazard ratio, 1.78; P = .007) in a multivariate analysis adjusted for type of malignancy, disease stage, conditioning intensity, patient age, donor type, and recipient/donor sex match.
Analysis also showed that the excess hazard was accounted for by higher risk of relapse than nonrelapse mortality (HR, 1.96; P = .006).
When the investigators looked at relapse risk by disease type, they found a significantly higher risk among vitamin D–deficient patients with myeloid malignancies (HR, 2.55; P = .014) but not with lymphoid malignancies.
The risk for relapse among patients with myeloid malignancies in the validation cohort was similarly high (HR, 2.60; P = .017).
“The growth inhibitory, pro-differentiation, and pro-apoptotic effects of VitD in vitro are well recognized, and low VitD levels have been shown to enhance clonal proliferation of leukemic cells. Therefore, with regard to treatment before alloSCT but also to conditioning, one might speculate that VitD deficiency facilitates resistance to chemotherapy,” the researchers wrote.
Low vitamin D levels have been associated in other studies with shorter relapse-free and overall survival in patients with acute myeloid leukemia apart from alloSCT.
The researchers recommend clinical trials to explore the possibility that vitamin D supplementation pre-transplant could improve post-transplant outcomes.
The study was supported by a grant from the BLUT Foundation and the European Union’s Seventh Framework Program. Dr. Luft disclosed consulting with Alexion and Jazz Pharmaceuticals, and institutional research funding and travel support from Medac, Neovii, and Jazz.
FROM JCO
Key clinical point: Vitamin D deficiency pre–allogenic stem cell transplant was associated with greater risk of relapse and lower survival for patients with myeloid malignancies.
Major finding: The hazard for relapse among patients with myeloid malignancies and low pre-transplant vitamin D was 2.55 (P = .014), compared with patients with adequate vitamin D.
Data source: Retrospective cohort study of 492 patients with myeloid or lymphoid malignancies, and a validation cohort of 398 patients.
Disclosures: The study was supported by a grant from the BLUT Foundation and the European Union’s Seventh Framework Program. Dr. Luft disclosed consulting with Alexion and Jazz Pharmaceuticals, and institutional research funding and travel support from Medac, Neovii, and Jazz.