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Method could make injectable drugs safer
Photo by Bill Branson
A new drug-making technique could reduce the risk of hemolysis, thrombosis, and other serious side effects that can occur with injectable drugs, according to researchers.
The team used the technique to remove potentially harmful additives—surfactants—from 12 common injectable drugs.
Jonathan F. Lovell, PhD, of University at Buffalo in New York, and his colleagues described the technique in Nature Communications.
Pharmaceutical companies use surfactants to dissolve a medicine into a liquid solution, making it suitable for injection. Unfortunately, solutions loaded with surfactants and other nonessential ingredients may increase the risk of thrombosis, hemolysis, anaphylactic shock, and other side effects.
Researchers have tried to address this problem in two ways, each with varying degrees of success.
Some have taken the “top-down” approach, in which they shrink drug particles to nanoscale sizes to eliminate excess additives. While promising, the method doesn’t work well with injectable medicine because the drug particles are still too large to safely inject.
Other researchers have worked from the “bottom up,” using nanotechnology to build new drugs from scratch. This can yield the desired results, but developing new drug formulations takes years, and drugs are coupled with new additives that can produce new side effects.
The technique described in Nature Communications differs from both of these approaches.
Dr Lovell and his colleagues dissolved 12 drugs—vitamin K1, cyclosporine, cabazitaxel, and others—one at a time into a surfactant called Pluronic. Then, by lowering the solution’s temperature to 4° C, they were able to remove the excess Pluronic via a membrane.
The end result was drugs that contain 100 to 1000 times less excess additives.
“For the drugs we looked at, this is as close as anyone has gotten to introducing pure, injectable medicine into the body,” Dr Lovell said. “Essentially, it’s a new way to package drugs.”
The findings are significant, he said, because they show that many injectable drug formulations may be improved through an easy-to-adopt process. He and his colleagues are now working to refine the method further. 
Photo by Bill Branson
A new drug-making technique could reduce the risk of hemolysis, thrombosis, and other serious side effects that can occur with injectable drugs, according to researchers.
The team used the technique to remove potentially harmful additives—surfactants—from 12 common injectable drugs.
Jonathan F. Lovell, PhD, of University at Buffalo in New York, and his colleagues described the technique in Nature Communications.
Pharmaceutical companies use surfactants to dissolve a medicine into a liquid solution, making it suitable for injection. Unfortunately, solutions loaded with surfactants and other nonessential ingredients may increase the risk of thrombosis, hemolysis, anaphylactic shock, and other side effects.
Researchers have tried to address this problem in two ways, each with varying degrees of success.
Some have taken the “top-down” approach, in which they shrink drug particles to nanoscale sizes to eliminate excess additives. While promising, the method doesn’t work well with injectable medicine because the drug particles are still too large to safely inject.
Other researchers have worked from the “bottom up,” using nanotechnology to build new drugs from scratch. This can yield the desired results, but developing new drug formulations takes years, and drugs are coupled with new additives that can produce new side effects.
The technique described in Nature Communications differs from both of these approaches.
Dr Lovell and his colleagues dissolved 12 drugs—vitamin K1, cyclosporine, cabazitaxel, and others—one at a time into a surfactant called Pluronic. Then, by lowering the solution’s temperature to 4° C, they were able to remove the excess Pluronic via a membrane.
The end result was drugs that contain 100 to 1000 times less excess additives.
“For the drugs we looked at, this is as close as anyone has gotten to introducing pure, injectable medicine into the body,” Dr Lovell said. “Essentially, it’s a new way to package drugs.”
The findings are significant, he said, because they show that many injectable drug formulations may be improved through an easy-to-adopt process. He and his colleagues are now working to refine the method further.
Photo by Bill Branson
A new drug-making technique could reduce the risk of hemolysis, thrombosis, and other serious side effects that can occur with injectable drugs, according to researchers.
The team used the technique to remove potentially harmful additives—surfactants—from 12 common injectable drugs.
Jonathan F. Lovell, PhD, of University at Buffalo in New York, and his colleagues described the technique in Nature Communications.
Pharmaceutical companies use surfactants to dissolve a medicine into a liquid solution, making it suitable for injection. Unfortunately, solutions loaded with surfactants and other nonessential ingredients may increase the risk of thrombosis, hemolysis, anaphylactic shock, and other side effects.
Researchers have tried to address this problem in two ways, each with varying degrees of success.
Some have taken the “top-down” approach, in which they shrink drug particles to nanoscale sizes to eliminate excess additives. While promising, the method doesn’t work well with injectable medicine because the drug particles are still too large to safely inject.
Other researchers have worked from the “bottom up,” using nanotechnology to build new drugs from scratch. This can yield the desired results, but developing new drug formulations takes years, and drugs are coupled with new additives that can produce new side effects.
The technique described in Nature Communications differs from both of these approaches.
Dr Lovell and his colleagues dissolved 12 drugs—vitamin K1, cyclosporine, cabazitaxel, and others—one at a time into a surfactant called Pluronic. Then, by lowering the solution’s temperature to 4° C, they were able to remove the excess Pluronic via a membrane.
The end result was drugs that contain 100 to 1000 times less excess additives.
“For the drugs we looked at, this is as close as anyone has gotten to introducing pure, injectable medicine into the body,” Dr Lovell said. “Essentially, it’s a new way to package drugs.”
The findings are significant, he said, because they show that many injectable drug formulations may be improved through an easy-to-adopt process. He and his colleagues are now working to refine the method further.
Mutation in mice may have affected research results
Researchers say they have discovered a mutation in a subline of C57BL/6 mice that could compromise results from previous studies.
“We found an unexpected mutation with potentially important consequences in strains of mice that had been separately engineered in labs in California and Japan,” said Shiv Pillai, MD, PhD, of The Ragon Institute of MGH, MIT and Harvard in Cambridge, Massachusetts.
“[W]e traced the problem to a subline of B6 mice from one specific company that have been sold in Asia, North America, Europe, and Israel. We have notified this company—Harlan Laboratories, which is now part of Envigo—of our findings, and they have been very responsive and will use approaches we have provided to check all of their colonies.”
Dr Pillai and his colleagues described their discovery of the mutation in Cell Reports.
The team noted that, in immunological studies, mutant mice are backcrossed for many generations into B6 mice so that all genes other than the mutant gene are derived from the B6 strain. This allows the comparison of data from laboratories in different parts of the world and simplifies creating mice with mutations in several genes.
A 2009 study out of Dr Pillai’s lab showed that 2 strains of mice engineered to lack the Siae or Cmah genes—both of which code for enzymes involved with sialic acid proteins—also had significant defects in the development of B cells, which were assumed to be the result of the knockout genes.
However, when Siae-deficient mice were further backcrossed with a different group of C57BL/6 mice, the result was a strain of Siae-knockout mice that did not have the B-cell development defects. A newly engineered strain of mice with a different Siae mutation also had normal B-cell development.
Detailed genetic sequencing of the first knockout line revealed a previously unsuspected mutation in a gene called Dock2, located on a chromosome 11, instead of chromosome 9 where Siae is located.
The same mutation was previously reported in 2 colonies of a different knockout mouse developed in Japan.
Dr Pillai’s team also found the Dock2 mutation in a completely different group of mice from the University of California, San Diego—where their Siae-mutant strain had been developed—and realized that 3 different engineered strains with the same unwanted mutation had probably acquired it from a common source. The team eventually traced it back to a subline of C57BL/6 mice from Harlan/Envigo.
Since most research papers using C57BL/6 mice or other such “background” strains do not indicate the specific subline, the researchers said they have no way of knowing how many studies might be affected by their findings.
But they hope the publication of these results will alert other research teams to the potential need to review their results.
“While embryonic stem cells from C57BL/6 mice have recently become available, which allows the generation of knockout strains with less backcrossing, B6 mice are used for many different kinds of experiments, including as controls,” Dr Pillai said.
“Researchers who have used them need to re-genotype the mice to look for the Dock2 mutation and, if they find it, check to see whether their results are preserved if the Dock2 mutation is bred out.”
Researchers say they have discovered a mutation in a subline of C57BL/6 mice that could compromise results from previous studies.
“We found an unexpected mutation with potentially important consequences in strains of mice that had been separately engineered in labs in California and Japan,” said Shiv Pillai, MD, PhD, of The Ragon Institute of MGH, MIT and Harvard in Cambridge, Massachusetts.
“[W]e traced the problem to a subline of B6 mice from one specific company that have been sold in Asia, North America, Europe, and Israel. We have notified this company—Harlan Laboratories, which is now part of Envigo—of our findings, and they have been very responsive and will use approaches we have provided to check all of their colonies.”
Dr Pillai and his colleagues described their discovery of the mutation in Cell Reports.
The team noted that, in immunological studies, mutant mice are backcrossed for many generations into B6 mice so that all genes other than the mutant gene are derived from the B6 strain. This allows the comparison of data from laboratories in different parts of the world and simplifies creating mice with mutations in several genes.
A 2009 study out of Dr Pillai’s lab showed that 2 strains of mice engineered to lack the Siae or Cmah genes—both of which code for enzymes involved with sialic acid proteins—also had significant defects in the development of B cells, which were assumed to be the result of the knockout genes.
However, when Siae-deficient mice were further backcrossed with a different group of C57BL/6 mice, the result was a strain of Siae-knockout mice that did not have the B-cell development defects. A newly engineered strain of mice with a different Siae mutation also had normal B-cell development.
Detailed genetic sequencing of the first knockout line revealed a previously unsuspected mutation in a gene called Dock2, located on a chromosome 11, instead of chromosome 9 where Siae is located.
The same mutation was previously reported in 2 colonies of a different knockout mouse developed in Japan.
Dr Pillai’s team also found the Dock2 mutation in a completely different group of mice from the University of California, San Diego—where their Siae-mutant strain had been developed—and realized that 3 different engineered strains with the same unwanted mutation had probably acquired it from a common source. The team eventually traced it back to a subline of C57BL/6 mice from Harlan/Envigo.
Since most research papers using C57BL/6 mice or other such “background” strains do not indicate the specific subline, the researchers said they have no way of knowing how many studies might be affected by their findings.
But they hope the publication of these results will alert other research teams to the potential need to review their results.
“While embryonic stem cells from C57BL/6 mice have recently become available, which allows the generation of knockout strains with less backcrossing, B6 mice are used for many different kinds of experiments, including as controls,” Dr Pillai said.
“Researchers who have used them need to re-genotype the mice to look for the Dock2 mutation and, if they find it, check to see whether their results are preserved if the Dock2 mutation is bred out.”
Researchers say they have discovered a mutation in a subline of C57BL/6 mice that could compromise results from previous studies.
“We found an unexpected mutation with potentially important consequences in strains of mice that had been separately engineered in labs in California and Japan,” said Shiv Pillai, MD, PhD, of The Ragon Institute of MGH, MIT and Harvard in Cambridge, Massachusetts.
“[W]e traced the problem to a subline of B6 mice from one specific company that have been sold in Asia, North America, Europe, and Israel. We have notified this company—Harlan Laboratories, which is now part of Envigo—of our findings, and they have been very responsive and will use approaches we have provided to check all of their colonies.”
Dr Pillai and his colleagues described their discovery of the mutation in Cell Reports.
The team noted that, in immunological studies, mutant mice are backcrossed for many generations into B6 mice so that all genes other than the mutant gene are derived from the B6 strain. This allows the comparison of data from laboratories in different parts of the world and simplifies creating mice with mutations in several genes.
A 2009 study out of Dr Pillai’s lab showed that 2 strains of mice engineered to lack the Siae or Cmah genes—both of which code for enzymes involved with sialic acid proteins—also had significant defects in the development of B cells, which were assumed to be the result of the knockout genes.
However, when Siae-deficient mice were further backcrossed with a different group of C57BL/6 mice, the result was a strain of Siae-knockout mice that did not have the B-cell development defects. A newly engineered strain of mice with a different Siae mutation also had normal B-cell development.
Detailed genetic sequencing of the first knockout line revealed a previously unsuspected mutation in a gene called Dock2, located on a chromosome 11, instead of chromosome 9 where Siae is located.
The same mutation was previously reported in 2 colonies of a different knockout mouse developed in Japan.
Dr Pillai’s team also found the Dock2 mutation in a completely different group of mice from the University of California, San Diego—where their Siae-mutant strain had been developed—and realized that 3 different engineered strains with the same unwanted mutation had probably acquired it from a common source. The team eventually traced it back to a subline of C57BL/6 mice from Harlan/Envigo.
Since most research papers using C57BL/6 mice or other such “background” strains do not indicate the specific subline, the researchers said they have no way of knowing how many studies might be affected by their findings.
But they hope the publication of these results will alert other research teams to the potential need to review their results.
“While embryonic stem cells from C57BL/6 mice have recently become available, which allows the generation of knockout strains with less backcrossing, B6 mice are used for many different kinds of experiments, including as controls,” Dr Pillai said.
“Researchers who have used them need to re-genotype the mice to look for the Dock2 mutation and, if they find it, check to see whether their results are preserved if the Dock2 mutation is bred out.”
Breast cancer drug could treat AML
(below) palbociclib treatment
Images courtesy of Iris Uras
and Vetmeduni Vienna
Palbociclib, a CDK4/6 kinase inhibitor approved to treat breast cancer, could also be used to treat acute myeloid leukemia (AML), according to research published in Blood.
The drug induced apoptosis in FLT3-mutant AML cells and inhibited tumor growth in mouse models of FLT3-ITD+ AML.
Palbociclib also demonstrated synergy with a range of FLT3 inhibitors.
The researchers said these results can be explained by the fact that CDK6 is “absolutely required” for the viability of FLT3-dependent leukemic cells and FLT3-ITD-induced leukemogenesis.
“We found a novel therapeutic window that attacks the dependency of a cancer cell on its growth regulator,” said study author Iris Uras, PhD, of Vetmeduni Vienna in Austria.
Dr Uras and her colleagues first found that palbociclib acts specifically on FLT3-ITD+ AML cells, inhibiting their viability in a dose-dependent manner. Palbociclib induced cell-cycle arrest and apoptosis in these cells.
Palbociclib also arrested tumor growth in mouse models of FLT3-ITD+ AML, significantly decreasing tumor size when compared to untreated controls (P<0.05).
Further investigation revealed that CDK6—but not CDK4—directly regulates FLT3 expression.
CDK6 acts as a transcriptional regulator of FLT3 and the serine threonine kinase PIM1, which also plays a role in leukemogenesis. As palbociclib inhibits CDK6, it downregulates FLT3 and reduces PIM1 transcription.
To build upon these findings, the researchers tested palbociclib in combination with FLT3 inhibitors.
They observed “pronounced in vitro synergy” between palbociclib and TCS-359, tandutinib, and quizartinib in FLT3-ITD+ AML cell lines and samples from patients with FLT3-ITD+ AML.
“We are attacking FLT3 from two sides there—blocking its expression and inhibiting its activity,” Dr Uras said. “A combination therapy could be a breakthrough for many patients suffering from leukemia.”
(below) palbociclib treatment
Images courtesy of Iris Uras
and Vetmeduni Vienna
Palbociclib, a CDK4/6 kinase inhibitor approved to treat breast cancer, could also be used to treat acute myeloid leukemia (AML), according to research published in Blood.
The drug induced apoptosis in FLT3-mutant AML cells and inhibited tumor growth in mouse models of FLT3-ITD+ AML.
Palbociclib also demonstrated synergy with a range of FLT3 inhibitors.
The researchers said these results can be explained by the fact that CDK6 is “absolutely required” for the viability of FLT3-dependent leukemic cells and FLT3-ITD-induced leukemogenesis.
“We found a novel therapeutic window that attacks the dependency of a cancer cell on its growth regulator,” said study author Iris Uras, PhD, of Vetmeduni Vienna in Austria.
Dr Uras and her colleagues first found that palbociclib acts specifically on FLT3-ITD+ AML cells, inhibiting their viability in a dose-dependent manner. Palbociclib induced cell-cycle arrest and apoptosis in these cells.
Palbociclib also arrested tumor growth in mouse models of FLT3-ITD+ AML, significantly decreasing tumor size when compared to untreated controls (P<0.05).
Further investigation revealed that CDK6—but not CDK4—directly regulates FLT3 expression.
CDK6 acts as a transcriptional regulator of FLT3 and the serine threonine kinase PIM1, which also plays a role in leukemogenesis. As palbociclib inhibits CDK6, it downregulates FLT3 and reduces PIM1 transcription.
To build upon these findings, the researchers tested palbociclib in combination with FLT3 inhibitors.
They observed “pronounced in vitro synergy” between palbociclib and TCS-359, tandutinib, and quizartinib in FLT3-ITD+ AML cell lines and samples from patients with FLT3-ITD+ AML.
“We are attacking FLT3 from two sides there—blocking its expression and inhibiting its activity,” Dr Uras said. “A combination therapy could be a breakthrough for many patients suffering from leukemia.”
(below) palbociclib treatment
Images courtesy of Iris Uras
and Vetmeduni Vienna
Palbociclib, a CDK4/6 kinase inhibitor approved to treat breast cancer, could also be used to treat acute myeloid leukemia (AML), according to research published in Blood.
The drug induced apoptosis in FLT3-mutant AML cells and inhibited tumor growth in mouse models of FLT3-ITD+ AML.
Palbociclib also demonstrated synergy with a range of FLT3 inhibitors.
The researchers said these results can be explained by the fact that CDK6 is “absolutely required” for the viability of FLT3-dependent leukemic cells and FLT3-ITD-induced leukemogenesis.
“We found a novel therapeutic window that attacks the dependency of a cancer cell on its growth regulator,” said study author Iris Uras, PhD, of Vetmeduni Vienna in Austria.
Dr Uras and her colleagues first found that palbociclib acts specifically on FLT3-ITD+ AML cells, inhibiting their viability in a dose-dependent manner. Palbociclib induced cell-cycle arrest and apoptosis in these cells.
Palbociclib also arrested tumor growth in mouse models of FLT3-ITD+ AML, significantly decreasing tumor size when compared to untreated controls (P<0.05).
Further investigation revealed that CDK6—but not CDK4—directly regulates FLT3 expression.
CDK6 acts as a transcriptional regulator of FLT3 and the serine threonine kinase PIM1, which also plays a role in leukemogenesis. As palbociclib inhibits CDK6, it downregulates FLT3 and reduces PIM1 transcription.
To build upon these findings, the researchers tested palbociclib in combination with FLT3 inhibitors.
They observed “pronounced in vitro synergy” between palbociclib and TCS-359, tandutinib, and quizartinib in FLT3-ITD+ AML cell lines and samples from patients with FLT3-ITD+ AML.
“We are attacking FLT3 from two sides there—blocking its expression and inhibiting its activity,” Dr Uras said. “A combination therapy could be a breakthrough for many patients suffering from leukemia.”
FDA: No oral ketoconazole for skin, nail fungus
The Food and Drug Administration is warning health care professionals not to prescribe oral ketoconazole for patients with fungal infections of the skin and nails, because of "the risks of serious liver damage, adrenal gland problems, and harmful interactions with other medicines that outweigh its benefit in treating these conditions."
The advisory, issued on May 19, points out that oral ketoconazole (Nizoral) is no longer approved for treating nail or skin fungal infections. Topical forms of ketoconazole have not been associated with liver damage, adrenal problems, or drug interactions, the advisory adds.
"Health care professionals should use ketoconazole tablets only to treat serious fungal infections when no other antifungal therapies are available," according to the FDA. "Skin and nail fungal infections in otherwise healthy persons are not life-threatening, and so the risks associated with oral ketoconazole outweigh the benefits. Other treatment options are available over-the-counter and by prescription, but are also associated with risks that should be weighed against their benefits."
The advisory updates one issued in July 2013 when the drug's label was changed to reflect these safety concerns, including dropping the nail and skin infections from the approved indications. Since then, the FDA has received one report of a patient who died of liver failure associated with oral ketoconazole used to treat nail fungus. Furthermore, a survey of office-based physicians found that in the 18 months ending in June 2015, "skin and nail fungal infections were the only diagnoses cited for the use of oral ketoconazole."
Serious adverse events associated with oral ketoconazole should be reported to the FDA's MedWatch program online or call 800-332-1088.
The Food and Drug Administration is warning health care professionals not to prescribe oral ketoconazole for patients with fungal infections of the skin and nails, because of "the risks of serious liver damage, adrenal gland problems, and harmful interactions with other medicines that outweigh its benefit in treating these conditions."
The advisory, issued on May 19, points out that oral ketoconazole (Nizoral) is no longer approved for treating nail or skin fungal infections. Topical forms of ketoconazole have not been associated with liver damage, adrenal problems, or drug interactions, the advisory adds.
"Health care professionals should use ketoconazole tablets only to treat serious fungal infections when no other antifungal therapies are available," according to the FDA. "Skin and nail fungal infections in otherwise healthy persons are not life-threatening, and so the risks associated with oral ketoconazole outweigh the benefits. Other treatment options are available over-the-counter and by prescription, but are also associated with risks that should be weighed against their benefits."
The advisory updates one issued in July 2013 when the drug's label was changed to reflect these safety concerns, including dropping the nail and skin infections from the approved indications. Since then, the FDA has received one report of a patient who died of liver failure associated with oral ketoconazole used to treat nail fungus. Furthermore, a survey of office-based physicians found that in the 18 months ending in June 2015, "skin and nail fungal infections were the only diagnoses cited for the use of oral ketoconazole."
Serious adverse events associated with oral ketoconazole should be reported to the FDA's MedWatch program online or call 800-332-1088.
The Food and Drug Administration is warning health care professionals not to prescribe oral ketoconazole for patients with fungal infections of the skin and nails, because of "the risks of serious liver damage, adrenal gland problems, and harmful interactions with other medicines that outweigh its benefit in treating these conditions."
The advisory, issued on May 19, points out that oral ketoconazole (Nizoral) is no longer approved for treating nail or skin fungal infections. Topical forms of ketoconazole have not been associated with liver damage, adrenal problems, or drug interactions, the advisory adds.
"Health care professionals should use ketoconazole tablets only to treat serious fungal infections when no other antifungal therapies are available," according to the FDA. "Skin and nail fungal infections in otherwise healthy persons are not life-threatening, and so the risks associated with oral ketoconazole outweigh the benefits. Other treatment options are available over-the-counter and by prescription, but are also associated with risks that should be weighed against their benefits."
The advisory updates one issued in July 2013 when the drug's label was changed to reflect these safety concerns, including dropping the nail and skin infections from the approved indications. Since then, the FDA has received one report of a patient who died of liver failure associated with oral ketoconazole used to treat nail fungus. Furthermore, a survey of office-based physicians found that in the 18 months ending in June 2015, "skin and nail fungal infections were the only diagnoses cited for the use of oral ketoconazole."
Serious adverse events associated with oral ketoconazole should be reported to the FDA's MedWatch program online or call 800-332-1088.
Hepatitis A and B combo vaccinations remain effective after 15 years
Young adults who received a combined hepatitis A and B vaccination at age 12-15 years maintained immunity after 15 years, making a booster shot unnecessary, according to Dr. Jiri Beran of the Vaccination and Travel Medicine Centre, Hradec Kralove, Czech Republic, and associates.
Study participants received either a 2-dose adult formulation or a 3-dose pediatric formulation. Of the 162 participants included in the 15-year follow-up, all were seropositive for anti–hepatitis A vaccine antibodies, 81.1% of those who received the two-dose vaccination had anti–hepatitis B antibodies, and 81.8% of those who received the three-dose vaccination had anti–hepatitis B antibodies.
In a subsequent hepatitis B vaccine challenge, all of 8 participants who received the two-dose vaccination and 10 of 11 participants who received the three-dose vaccination developed an anamnastic response. No side effects inconsistent with previous experience were observed.
“The present study confirms that the combined hepatitis A and B vaccine is equally immunogenic and safe in adolescents when administered as the standard three-dose pediatric regimen or as two doses of the adult strength vacciwne,” the investigators said.
Find the full study in Vaccine (doi: 10.1016/j.vaccine.2016.04.033).
Young adults who received a combined hepatitis A and B vaccination at age 12-15 years maintained immunity after 15 years, making a booster shot unnecessary, according to Dr. Jiri Beran of the Vaccination and Travel Medicine Centre, Hradec Kralove, Czech Republic, and associates.
Study participants received either a 2-dose adult formulation or a 3-dose pediatric formulation. Of the 162 participants included in the 15-year follow-up, all were seropositive for anti–hepatitis A vaccine antibodies, 81.1% of those who received the two-dose vaccination had anti–hepatitis B antibodies, and 81.8% of those who received the three-dose vaccination had anti–hepatitis B antibodies.
In a subsequent hepatitis B vaccine challenge, all of 8 participants who received the two-dose vaccination and 10 of 11 participants who received the three-dose vaccination developed an anamnastic response. No side effects inconsistent with previous experience were observed.
“The present study confirms that the combined hepatitis A and B vaccine is equally immunogenic and safe in adolescents when administered as the standard three-dose pediatric regimen or as two doses of the adult strength vacciwne,” the investigators said.
Find the full study in Vaccine (doi: 10.1016/j.vaccine.2016.04.033).
Young adults who received a combined hepatitis A and B vaccination at age 12-15 years maintained immunity after 15 years, making a booster shot unnecessary, according to Dr. Jiri Beran of the Vaccination and Travel Medicine Centre, Hradec Kralove, Czech Republic, and associates.
Study participants received either a 2-dose adult formulation or a 3-dose pediatric formulation. Of the 162 participants included in the 15-year follow-up, all were seropositive for anti–hepatitis A vaccine antibodies, 81.1% of those who received the two-dose vaccination had anti–hepatitis B antibodies, and 81.8% of those who received the three-dose vaccination had anti–hepatitis B antibodies.
In a subsequent hepatitis B vaccine challenge, all of 8 participants who received the two-dose vaccination and 10 of 11 participants who received the three-dose vaccination developed an anamnastic response. No side effects inconsistent with previous experience were observed.
“The present study confirms that the combined hepatitis A and B vaccine is equally immunogenic and safe in adolescents when administered as the standard three-dose pediatric regimen or as two doses of the adult strength vacciwne,” the investigators said.
Find the full study in Vaccine (doi: 10.1016/j.vaccine.2016.04.033).
FROM VACCINE
Hepatitis B vaccine in infancy provides long-term protection into adolescence
Pediatric doses of hepatitis B vaccine can provide long-term protection against hepatitis B up to 15-16 years, and also can produce strong immune memory, according to Dr. Olivier Van Der Meeren of GlaxoSmithKline Vaccines, Wavre, Belgium, and his associates.
The researchers looked at 303 healthy adolescents who had received three doses of monovalent pediatric hepatitis B vaccine (containing 10 mcg hepatitis B surface antigen, HBsAg) in infancy. Of the 293 patients analyzed, 71% were seropositive (anti-HBs antibodies greater than or equal to 6.2 mIU/mL) before the challenge dose and 65% remained seroprotected (anti-HBs antibodies greater than or equal to 10 mIU/mL) after challenge. One month after the challenge dose, the percentage of seroprotected subjects increased to 99%, and 91% of those patients had anti-HBs antibody concentrations greater than or equal to 100 mIU/mL.
The study also looked at safety and reactogenicity. The researchers stated that it was well tolerated, with pain and fatigue the most frequently reported adverse effects.
“Despite declining levels of circulating anti-HBs antibodies, the vast majority of subjects in our study were able to mount a rapid and robust anamnestic response after a challenge dose (more than 150-fold increase in GMC [geometric mean concentration]) regardless of their pre-challenge serostatus,” the researchers concluded. “This confirms that maintaining anti-HBs antibody concentrations greater than 10 mIU/mL may not be essential for protection against clinically significant breakthrough hepatitis B infection.”
Find the study in Vaccine (doi:10.1016/j.vaccine.2016.04.013).
Pediatric doses of hepatitis B vaccine can provide long-term protection against hepatitis B up to 15-16 years, and also can produce strong immune memory, according to Dr. Olivier Van Der Meeren of GlaxoSmithKline Vaccines, Wavre, Belgium, and his associates.
The researchers looked at 303 healthy adolescents who had received three doses of monovalent pediatric hepatitis B vaccine (containing 10 mcg hepatitis B surface antigen, HBsAg) in infancy. Of the 293 patients analyzed, 71% were seropositive (anti-HBs antibodies greater than or equal to 6.2 mIU/mL) before the challenge dose and 65% remained seroprotected (anti-HBs antibodies greater than or equal to 10 mIU/mL) after challenge. One month after the challenge dose, the percentage of seroprotected subjects increased to 99%, and 91% of those patients had anti-HBs antibody concentrations greater than or equal to 100 mIU/mL.
The study also looked at safety and reactogenicity. The researchers stated that it was well tolerated, with pain and fatigue the most frequently reported adverse effects.
“Despite declining levels of circulating anti-HBs antibodies, the vast majority of subjects in our study were able to mount a rapid and robust anamnestic response after a challenge dose (more than 150-fold increase in GMC [geometric mean concentration]) regardless of their pre-challenge serostatus,” the researchers concluded. “This confirms that maintaining anti-HBs antibody concentrations greater than 10 mIU/mL may not be essential for protection against clinically significant breakthrough hepatitis B infection.”
Find the study in Vaccine (doi:10.1016/j.vaccine.2016.04.013).
Pediatric doses of hepatitis B vaccine can provide long-term protection against hepatitis B up to 15-16 years, and also can produce strong immune memory, according to Dr. Olivier Van Der Meeren of GlaxoSmithKline Vaccines, Wavre, Belgium, and his associates.
The researchers looked at 303 healthy adolescents who had received three doses of monovalent pediatric hepatitis B vaccine (containing 10 mcg hepatitis B surface antigen, HBsAg) in infancy. Of the 293 patients analyzed, 71% were seropositive (anti-HBs antibodies greater than or equal to 6.2 mIU/mL) before the challenge dose and 65% remained seroprotected (anti-HBs antibodies greater than or equal to 10 mIU/mL) after challenge. One month after the challenge dose, the percentage of seroprotected subjects increased to 99%, and 91% of those patients had anti-HBs antibody concentrations greater than or equal to 100 mIU/mL.
The study also looked at safety and reactogenicity. The researchers stated that it was well tolerated, with pain and fatigue the most frequently reported adverse effects.
“Despite declining levels of circulating anti-HBs antibodies, the vast majority of subjects in our study were able to mount a rapid and robust anamnestic response after a challenge dose (more than 150-fold increase in GMC [geometric mean concentration]) regardless of their pre-challenge serostatus,” the researchers concluded. “This confirms that maintaining anti-HBs antibody concentrations greater than 10 mIU/mL may not be essential for protection against clinically significant breakthrough hepatitis B infection.”
Find the study in Vaccine (doi:10.1016/j.vaccine.2016.04.013).
FROM VACCINE
Medical errors: Caring for the second victim (you)
Diabetic foot ulcers linked to cognitive decline
Among patients with type 2 diabetes, those with foot ulcers show cognitive impairment across all domains when compared with those without, according to a report published in Diabetes Care.
In what they described as one of the first studies to examine cognitive function in people with diabetic foot ulcers, researchers found that these patients “remember less, have decreased ability to concentrate, and more difficulty with learning, less inhibition, slower cognitive and psychomotor responses, and less verbal fluency” than patients with diabetes that does not include foot involvement.
Although this study had a cross-sectional design that precluded drawing conclusions about causality, an analysis that estimated the participants’ premorbid and postmorbid cognitive abilities suggested that people with diabetic foot ulcers had experienced a recent significant cognitive decline, while those without foot ulcers had not, said Rachel Natovich, Ph.D., of the department of public health, Ben-Gurion University of the Negev, Be’er Sheva (Israel) and the Endocrinology Institute, Sheba Medical Center, Ramat Gan (Israel) and her associates. These findings indicate that patients with diabetic foot ulcers – the very patients who face the greatest self-treatment challenges – are the ones who have the weakest cognitive resources to do so, they noted.
The investigators examined this issue after noting that recent consensus guidelines require patients with diabetic foot ulcers to take on even more self-management than is already required for the diabetes. This demands “applying complex cognitive abilities in learning, understanding, and remembering new information; planning and initiating self-care practices; adopting behavioral changes that involve psychomotor abilities; and maintaining these behaviors while controlling and repressing impulses.” So Dr. Natovich and her associates assessed whether the cognitive profile of patients who have diabetic foot problems differs from that of patients who don’t, using a case-control study design.
The 194 study participants were aged 45-75 years. The 99 subjects who had at least one diabetic foot ulcer (cases) were matched for age and duration of diabetes with 95 subjects who did not (controls). All underwent a comprehensive battery of neuropsychological tests assessing general intelligence, short- and long-term memory, attention and concentration, psychomotor efficiency, reaction time, executive function, nonverbal IQ, visual-motor speed, coordination, capacity for learning, verbal production, semantic memory, and language. All were also assessed for depression via the Patient Health Questionnaire.
After scores were standardized according to the expected performance by age and education level, patients with diabetic foot ulcers showed significantly lower scores in all the domains tested, compared with the patients without foot ulcers. This difference persisted after the data were adjusted to account for possible confounding factors such as smoking status, hemoglobin A1c level, presence or absence of depressive symptoms, and presence or absence of macrovascular disease (Diab Care. 2016 May. doi:10.2337/dc15-2838).
The estimated premorbid cognitive function was similar between the two study groups, but current cognitive function declined significantly in the patients with foot ulcers while remaining relatively constant in the patients without foot ulcers. Prospective studies are needed to explore the timing of cognitive decline and the possibility of causation, Dr. Natovich and her associates said.
The study results “highlight the importance of focusing on cognitive functioning, a less-studied area in diabetic foot research,” they added.
“We feel that it is important to screen the cognitive status of these patients regularly and to take cognitive abilities into consideration in treatment-planning recommendations and follow-up.”
Among patients with type 2 diabetes, those with foot ulcers show cognitive impairment across all domains when compared with those without, according to a report published in Diabetes Care.
In what they described as one of the first studies to examine cognitive function in people with diabetic foot ulcers, researchers found that these patients “remember less, have decreased ability to concentrate, and more difficulty with learning, less inhibition, slower cognitive and psychomotor responses, and less verbal fluency” than patients with diabetes that does not include foot involvement.
Although this study had a cross-sectional design that precluded drawing conclusions about causality, an analysis that estimated the participants’ premorbid and postmorbid cognitive abilities suggested that people with diabetic foot ulcers had experienced a recent significant cognitive decline, while those without foot ulcers had not, said Rachel Natovich, Ph.D., of the department of public health, Ben-Gurion University of the Negev, Be’er Sheva (Israel) and the Endocrinology Institute, Sheba Medical Center, Ramat Gan (Israel) and her associates. These findings indicate that patients with diabetic foot ulcers – the very patients who face the greatest self-treatment challenges – are the ones who have the weakest cognitive resources to do so, they noted.
The investigators examined this issue after noting that recent consensus guidelines require patients with diabetic foot ulcers to take on even more self-management than is already required for the diabetes. This demands “applying complex cognitive abilities in learning, understanding, and remembering new information; planning and initiating self-care practices; adopting behavioral changes that involve psychomotor abilities; and maintaining these behaviors while controlling and repressing impulses.” So Dr. Natovich and her associates assessed whether the cognitive profile of patients who have diabetic foot problems differs from that of patients who don’t, using a case-control study design.
The 194 study participants were aged 45-75 years. The 99 subjects who had at least one diabetic foot ulcer (cases) were matched for age and duration of diabetes with 95 subjects who did not (controls). All underwent a comprehensive battery of neuropsychological tests assessing general intelligence, short- and long-term memory, attention and concentration, psychomotor efficiency, reaction time, executive function, nonverbal IQ, visual-motor speed, coordination, capacity for learning, verbal production, semantic memory, and language. All were also assessed for depression via the Patient Health Questionnaire.
After scores were standardized according to the expected performance by age and education level, patients with diabetic foot ulcers showed significantly lower scores in all the domains tested, compared with the patients without foot ulcers. This difference persisted after the data were adjusted to account for possible confounding factors such as smoking status, hemoglobin A1c level, presence or absence of depressive symptoms, and presence or absence of macrovascular disease (Diab Care. 2016 May. doi:10.2337/dc15-2838).
The estimated premorbid cognitive function was similar between the two study groups, but current cognitive function declined significantly in the patients with foot ulcers while remaining relatively constant in the patients without foot ulcers. Prospective studies are needed to explore the timing of cognitive decline and the possibility of causation, Dr. Natovich and her associates said.
The study results “highlight the importance of focusing on cognitive functioning, a less-studied area in diabetic foot research,” they added.
“We feel that it is important to screen the cognitive status of these patients regularly and to take cognitive abilities into consideration in treatment-planning recommendations and follow-up.”
Among patients with type 2 diabetes, those with foot ulcers show cognitive impairment across all domains when compared with those without, according to a report published in Diabetes Care.
In what they described as one of the first studies to examine cognitive function in people with diabetic foot ulcers, researchers found that these patients “remember less, have decreased ability to concentrate, and more difficulty with learning, less inhibition, slower cognitive and psychomotor responses, and less verbal fluency” than patients with diabetes that does not include foot involvement.
Although this study had a cross-sectional design that precluded drawing conclusions about causality, an analysis that estimated the participants’ premorbid and postmorbid cognitive abilities suggested that people with diabetic foot ulcers had experienced a recent significant cognitive decline, while those without foot ulcers had not, said Rachel Natovich, Ph.D., of the department of public health, Ben-Gurion University of the Negev, Be’er Sheva (Israel) and the Endocrinology Institute, Sheba Medical Center, Ramat Gan (Israel) and her associates. These findings indicate that patients with diabetic foot ulcers – the very patients who face the greatest self-treatment challenges – are the ones who have the weakest cognitive resources to do so, they noted.
The investigators examined this issue after noting that recent consensus guidelines require patients with diabetic foot ulcers to take on even more self-management than is already required for the diabetes. This demands “applying complex cognitive abilities in learning, understanding, and remembering new information; planning and initiating self-care practices; adopting behavioral changes that involve psychomotor abilities; and maintaining these behaviors while controlling and repressing impulses.” So Dr. Natovich and her associates assessed whether the cognitive profile of patients who have diabetic foot problems differs from that of patients who don’t, using a case-control study design.
The 194 study participants were aged 45-75 years. The 99 subjects who had at least one diabetic foot ulcer (cases) were matched for age and duration of diabetes with 95 subjects who did not (controls). All underwent a comprehensive battery of neuropsychological tests assessing general intelligence, short- and long-term memory, attention and concentration, psychomotor efficiency, reaction time, executive function, nonverbal IQ, visual-motor speed, coordination, capacity for learning, verbal production, semantic memory, and language. All were also assessed for depression via the Patient Health Questionnaire.
After scores were standardized according to the expected performance by age and education level, patients with diabetic foot ulcers showed significantly lower scores in all the domains tested, compared with the patients without foot ulcers. This difference persisted after the data were adjusted to account for possible confounding factors such as smoking status, hemoglobin A1c level, presence or absence of depressive symptoms, and presence or absence of macrovascular disease (Diab Care. 2016 May. doi:10.2337/dc15-2838).
The estimated premorbid cognitive function was similar between the two study groups, but current cognitive function declined significantly in the patients with foot ulcers while remaining relatively constant in the patients without foot ulcers. Prospective studies are needed to explore the timing of cognitive decline and the possibility of causation, Dr. Natovich and her associates said.
The study results “highlight the importance of focusing on cognitive functioning, a less-studied area in diabetic foot research,” they added.
“We feel that it is important to screen the cognitive status of these patients regularly and to take cognitive abilities into consideration in treatment-planning recommendations and follow-up.”
FROM DIABETES CARE
Key clinical point: Among patients with type 2 diabetes, those with foot ulcers show cognitive impairment, compared with those who don’t have foot ulcers.
Major finding: Ninety-nine patients with at least one diabetic foot showed significantly lower scores in all cognitive domains tested compared with the 95 patients without foot ulcers.
Data source: A cross-sectional case-control study comparing cognitive performance between 99 patients with and 95 patients without diabetic foot ulcers.
Disclosures: No sponsor of this study was identified. Dr. Natovich and her associates reported having no relevant disclosures.
Elective induction of labor at 39 (vs 41) weeks: Caveats and considerations
Tasked with tackling the literature on the subject and debating the question of whether or not it is best to electively induce labor in women with low-risk pregnancies at 39 weeks (vs at 41 weeks after expectant management), Errol Norwitz, MD, PhD, Chairman of the Department of Obstetrics and Gynecology and Professor at Tufts University School of Medicine in Boston, Massachusetts, and Charles Lockwood, MD, Senior Vice President at the University of South Florida (USF) and Dean of the USF Health Morsani College of Medicine in Tampa came to the same conclusion: Elective induction of labor (eIOL) at 39 weeks is superior to expectant management when it comes to fetal outcomes.
In addition, they both agreed that complication rates to the mother (ie, number of cesarean deliveries [CDs]) would not be increased, and possibly even reduced, with eIOL at 39 weeks versus 41 weeks. Dr. Norwitz postulated that, with IOL there is no increase in CD rate in multiparous women and nulliparous women with a favorable cervical exam but that there likely could be an increase in the CD rate for nulliparous women with an unfavorable cervical exam.
The finding that eIOL at 39 weeks is better than at 41 weeks for the infant is likely due to a bigger baby size past 39 weeks (with more traumatic deliveries) and higher rates of postmaturity complications, said Dr. Lockwood. And for the mother, eIOL at 39 weeks can reduce risks—of preeclampsia, abruption, sepsis, and others—the presenters pointed out.
Arriving at their conclusions: The dataDr. Norwitz explained the challenge before them in this unusual “debate.” “In ObGyn we all read the same literature but we often come away with very different takes as to what the implications are and how we incorporate this into our management algorithms. Instead of taking a pro/con approach, with one assigned to ‘yes’ and the other assigned to ‘no,’ and selectively picking out the literature to support our positions, what we did was we each went away, read the literature, synthesized it, and tried to answer this question for ourselves.”
Dr. Norwitz, who is widely published and known for his research on the causes and prevention of preeclampsia and preterm labor, examined and presented the published literature for benefit and harms to the fetus and mother in continuing pregnancy past 39 weeks.
Dr. Lockwood also examined the literature, including a large population cohort of about 1.27 million women that examined CD rates, perinatal mortality, and neonatal and maternal outcomes of eIOL at 39 weeks versus expectant management.1 He presented, however, that the best evidence to compare the question at hand would be a randomized clinical trial comparing specifically eIOL at 39 weeks versus expectant management, with IOL at 41 weeks. To be powered to detect a difference in perinatal and maternal mortality, this trial would need to include 2.2 to 12.6 million women, he maintained. “When empirical evidence doesn’t exist, the only alternative is some kind of other modeling,” he said. Therefore, he and a team of researchers conducted a Monte Carlo microsimulation modeling decision analysis, taking into account “all outcomes and all preferences that we possibly could cull from the literature.”
Which women actually could benefit from eIOL at 39 weeks?Women with high-risk pregnancies were not included in this debate or considered. Dr. Norwitz clearly defined his case patient at the outset as a 22-year-old G1 at 39 0/7 weeks who has had an uncomplicated pregnancy but is now complaining of decreased fetal movement and tells you that she is worried because her sister lost her baby at 40 weeks to stillbirth. She specifically asks, “Doctor, why can’t you induce my labor now?”
What counseling a patient about the risks/benefits of eIOL at 39 weeks would requireTwo fundamentals would need to be ensured. The first: precise gestational dating. Dr. Norwitz pointed out that menstrual history can be inaccurate, especially in women with irregular cycles, who are taking hormonal contraception, or who have intermenstrual bleeding. “Early dating ultrasound is the best way to date pregnancies and probably should be done routinely,” although it is not currently standard of care in the United States, he said.
The second fundamental: a true induction of labor process, not one that involves “stopping at 5 PM,” said Dr. Lockwood.
“Although Dr. Lockwood’s 5-PM statement was made tongue-in-cheek,” said Dr. Norwitz after the debate, “he certainly was implying that a genuine effort should be made to effect a vaginal delivery—that is, giving the most effective cervical ripening agents, allowing enough time to pass, and defining clearly the criteria for failed IOL. You shouldn’t just throw the towel in at 5 PM because you want to go home.”
Cost implicationsElectively inducing labor in all women with low-risk pregnancies at 39 weeks is a strategy with unknown cost implications, and the cost difference between this strategy and expectant management up to 41 weeks is not known.
“We need to be sure that we understand the cost implications of these strategies, which of course would need to be balanced against the potential perinatal and maternal morbidity and fetal death,” said Dr. Lockwood.
The meaning of “elective”Dr. Norwitz also made the point postdebate that the American College of Obstetricians and Gynecologists (ACOG) does not support elective IOL prior to 39 weeks’ gestation. “The key term here is ‘elective,’" he said, "which refers to a delivery without a clear medical or obstetric indication. ACOG does support delivery prior to 39 weeks’ gestation, there just needs to be an appropriate indication.”
1. Stock SJ, Ferguson E, Duffy A, Ford I, Chalmers J, Norman JE. Outcomes of elective induction of labour compared with expectant management: population based study. BMJ. 2012;344:e2838.
Tasked with tackling the literature on the subject and debating the question of whether or not it is best to electively induce labor in women with low-risk pregnancies at 39 weeks (vs at 41 weeks after expectant management), Errol Norwitz, MD, PhD, Chairman of the Department of Obstetrics and Gynecology and Professor at Tufts University School of Medicine in Boston, Massachusetts, and Charles Lockwood, MD, Senior Vice President at the University of South Florida (USF) and Dean of the USF Health Morsani College of Medicine in Tampa came to the same conclusion: Elective induction of labor (eIOL) at 39 weeks is superior to expectant management when it comes to fetal outcomes.
In addition, they both agreed that complication rates to the mother (ie, number of cesarean deliveries [CDs]) would not be increased, and possibly even reduced, with eIOL at 39 weeks versus 41 weeks. Dr. Norwitz postulated that, with IOL there is no increase in CD rate in multiparous women and nulliparous women with a favorable cervical exam but that there likely could be an increase in the CD rate for nulliparous women with an unfavorable cervical exam.
The finding that eIOL at 39 weeks is better than at 41 weeks for the infant is likely due to a bigger baby size past 39 weeks (with more traumatic deliveries) and higher rates of postmaturity complications, said Dr. Lockwood. And for the mother, eIOL at 39 weeks can reduce risks—of preeclampsia, abruption, sepsis, and others—the presenters pointed out.
Arriving at their conclusions: The dataDr. Norwitz explained the challenge before them in this unusual “debate.” “In ObGyn we all read the same literature but we often come away with very different takes as to what the implications are and how we incorporate this into our management algorithms. Instead of taking a pro/con approach, with one assigned to ‘yes’ and the other assigned to ‘no,’ and selectively picking out the literature to support our positions, what we did was we each went away, read the literature, synthesized it, and tried to answer this question for ourselves.”
Dr. Norwitz, who is widely published and known for his research on the causes and prevention of preeclampsia and preterm labor, examined and presented the published literature for benefit and harms to the fetus and mother in continuing pregnancy past 39 weeks.
Dr. Lockwood also examined the literature, including a large population cohort of about 1.27 million women that examined CD rates, perinatal mortality, and neonatal and maternal outcomes of eIOL at 39 weeks versus expectant management.1 He presented, however, that the best evidence to compare the question at hand would be a randomized clinical trial comparing specifically eIOL at 39 weeks versus expectant management, with IOL at 41 weeks. To be powered to detect a difference in perinatal and maternal mortality, this trial would need to include 2.2 to 12.6 million women, he maintained. “When empirical evidence doesn’t exist, the only alternative is some kind of other modeling,” he said. Therefore, he and a team of researchers conducted a Monte Carlo microsimulation modeling decision analysis, taking into account “all outcomes and all preferences that we possibly could cull from the literature.”
Which women actually could benefit from eIOL at 39 weeks?Women with high-risk pregnancies were not included in this debate or considered. Dr. Norwitz clearly defined his case patient at the outset as a 22-year-old G1 at 39 0/7 weeks who has had an uncomplicated pregnancy but is now complaining of decreased fetal movement and tells you that she is worried because her sister lost her baby at 40 weeks to stillbirth. She specifically asks, “Doctor, why can’t you induce my labor now?”
What counseling a patient about the risks/benefits of eIOL at 39 weeks would requireTwo fundamentals would need to be ensured. The first: precise gestational dating. Dr. Norwitz pointed out that menstrual history can be inaccurate, especially in women with irregular cycles, who are taking hormonal contraception, or who have intermenstrual bleeding. “Early dating ultrasound is the best way to date pregnancies and probably should be done routinely,” although it is not currently standard of care in the United States, he said.
The second fundamental: a true induction of labor process, not one that involves “stopping at 5 PM,” said Dr. Lockwood.
“Although Dr. Lockwood’s 5-PM statement was made tongue-in-cheek,” said Dr. Norwitz after the debate, “he certainly was implying that a genuine effort should be made to effect a vaginal delivery—that is, giving the most effective cervical ripening agents, allowing enough time to pass, and defining clearly the criteria for failed IOL. You shouldn’t just throw the towel in at 5 PM because you want to go home.”
Cost implicationsElectively inducing labor in all women with low-risk pregnancies at 39 weeks is a strategy with unknown cost implications, and the cost difference between this strategy and expectant management up to 41 weeks is not known.
“We need to be sure that we understand the cost implications of these strategies, which of course would need to be balanced against the potential perinatal and maternal morbidity and fetal death,” said Dr. Lockwood.
The meaning of “elective”Dr. Norwitz also made the point postdebate that the American College of Obstetricians and Gynecologists (ACOG) does not support elective IOL prior to 39 weeks’ gestation. “The key term here is ‘elective,’" he said, "which refers to a delivery without a clear medical or obstetric indication. ACOG does support delivery prior to 39 weeks’ gestation, there just needs to be an appropriate indication.”
Tasked with tackling the literature on the subject and debating the question of whether or not it is best to electively induce labor in women with low-risk pregnancies at 39 weeks (vs at 41 weeks after expectant management), Errol Norwitz, MD, PhD, Chairman of the Department of Obstetrics and Gynecology and Professor at Tufts University School of Medicine in Boston, Massachusetts, and Charles Lockwood, MD, Senior Vice President at the University of South Florida (USF) and Dean of the USF Health Morsani College of Medicine in Tampa came to the same conclusion: Elective induction of labor (eIOL) at 39 weeks is superior to expectant management when it comes to fetal outcomes.
In addition, they both agreed that complication rates to the mother (ie, number of cesarean deliveries [CDs]) would not be increased, and possibly even reduced, with eIOL at 39 weeks versus 41 weeks. Dr. Norwitz postulated that, with IOL there is no increase in CD rate in multiparous women and nulliparous women with a favorable cervical exam but that there likely could be an increase in the CD rate for nulliparous women with an unfavorable cervical exam.
The finding that eIOL at 39 weeks is better than at 41 weeks for the infant is likely due to a bigger baby size past 39 weeks (with more traumatic deliveries) and higher rates of postmaturity complications, said Dr. Lockwood. And for the mother, eIOL at 39 weeks can reduce risks—of preeclampsia, abruption, sepsis, and others—the presenters pointed out.
Arriving at their conclusions: The dataDr. Norwitz explained the challenge before them in this unusual “debate.” “In ObGyn we all read the same literature but we often come away with very different takes as to what the implications are and how we incorporate this into our management algorithms. Instead of taking a pro/con approach, with one assigned to ‘yes’ and the other assigned to ‘no,’ and selectively picking out the literature to support our positions, what we did was we each went away, read the literature, synthesized it, and tried to answer this question for ourselves.”
Dr. Norwitz, who is widely published and known for his research on the causes and prevention of preeclampsia and preterm labor, examined and presented the published literature for benefit and harms to the fetus and mother in continuing pregnancy past 39 weeks.
Dr. Lockwood also examined the literature, including a large population cohort of about 1.27 million women that examined CD rates, perinatal mortality, and neonatal and maternal outcomes of eIOL at 39 weeks versus expectant management.1 He presented, however, that the best evidence to compare the question at hand would be a randomized clinical trial comparing specifically eIOL at 39 weeks versus expectant management, with IOL at 41 weeks. To be powered to detect a difference in perinatal and maternal mortality, this trial would need to include 2.2 to 12.6 million women, he maintained. “When empirical evidence doesn’t exist, the only alternative is some kind of other modeling,” he said. Therefore, he and a team of researchers conducted a Monte Carlo microsimulation modeling decision analysis, taking into account “all outcomes and all preferences that we possibly could cull from the literature.”
Which women actually could benefit from eIOL at 39 weeks?Women with high-risk pregnancies were not included in this debate or considered. Dr. Norwitz clearly defined his case patient at the outset as a 22-year-old G1 at 39 0/7 weeks who has had an uncomplicated pregnancy but is now complaining of decreased fetal movement and tells you that she is worried because her sister lost her baby at 40 weeks to stillbirth. She specifically asks, “Doctor, why can’t you induce my labor now?”
What counseling a patient about the risks/benefits of eIOL at 39 weeks would requireTwo fundamentals would need to be ensured. The first: precise gestational dating. Dr. Norwitz pointed out that menstrual history can be inaccurate, especially in women with irregular cycles, who are taking hormonal contraception, or who have intermenstrual bleeding. “Early dating ultrasound is the best way to date pregnancies and probably should be done routinely,” although it is not currently standard of care in the United States, he said.
The second fundamental: a true induction of labor process, not one that involves “stopping at 5 PM,” said Dr. Lockwood.
“Although Dr. Lockwood’s 5-PM statement was made tongue-in-cheek,” said Dr. Norwitz after the debate, “he certainly was implying that a genuine effort should be made to effect a vaginal delivery—that is, giving the most effective cervical ripening agents, allowing enough time to pass, and defining clearly the criteria for failed IOL. You shouldn’t just throw the towel in at 5 PM because you want to go home.”
Cost implicationsElectively inducing labor in all women with low-risk pregnancies at 39 weeks is a strategy with unknown cost implications, and the cost difference between this strategy and expectant management up to 41 weeks is not known.
“We need to be sure that we understand the cost implications of these strategies, which of course would need to be balanced against the potential perinatal and maternal morbidity and fetal death,” said Dr. Lockwood.
The meaning of “elective”Dr. Norwitz also made the point postdebate that the American College of Obstetricians and Gynecologists (ACOG) does not support elective IOL prior to 39 weeks’ gestation. “The key term here is ‘elective,’" he said, "which refers to a delivery without a clear medical or obstetric indication. ACOG does support delivery prior to 39 weeks’ gestation, there just needs to be an appropriate indication.”
1. Stock SJ, Ferguson E, Duffy A, Ford I, Chalmers J, Norman JE. Outcomes of elective induction of labour compared with expectant management: population based study. BMJ. 2012;344:e2838.
1. Stock SJ, Ferguson E, Duffy A, Ford I, Chalmers J, Norman JE. Outcomes of elective induction of labour compared with expectant management: population based study. BMJ. 2012;344:e2838.
General surgeons getting less vascular training
Vascular surgery fellow case logs reflect an increase in endovascular interventions, but general surgery residents may be missing out on training opportunities, according to a study of national case data.
In addition, general surgery residents saw a decrease in open vascular surgery cases, which was not reflected among the vascular surgery fellows, according to Dr. Rose C. Pedersen and colleagues in the department of surgery, Kaiser Permanente Los Angeles Medical Center. The report was published online in Annals of Vascular Surgery (doi: 10.1016/j.avsg.2016.02.008).
The paper was originally presented at the 2105 annual meeting of the Southern California Vascular Society. The study reports findings of a review of the Accreditation Council for Graduate Medical Education national case log reports from 2001 to 2012.
During that period, the number of general surgery residents increased from 1,021 to 1,098, while the number of vascular surgery fellows increased from 96 to 121. The total number of vascular cases logged by the vascular fellows significantly increased by 161%, from an average of 298 cases to 762 cases over the time period assessed. During that same period, vascular cases done by general surgery residents significantly decreased by 40%, from an average of 186 to 116 cases.
In terms of open cases. vascular fellows saw a significant 43% decrease in open abdominal aortic aneurysm (AAA) cases, going from 26 to 15, and a slight but significant increase in carotid endarterectomy cases logged (44 to 49). Hemodialysis access and major amputations also both increased significantly. A decreases in open surgery for peripheral obstructive disease was small and not significant.
General surgery residents saw decreases in all open surgery areas over the time period: AAA cases fell significantly by 78% (9 cases to 2 cases); carotid endarterectomies decreased significantly from 23 to 12 cases; and surgery for peripheral obstructive disease fell significantly from 21 to 8). Hemodialysis access cases and major amputations both decreased as well, but not significantly.
Endovascular cases increased from 2001 to 2012 for both vascular fellows and general surgery residents. Vascular fellows saw endovascular AAA repair significantly increase from an average of 17 to 46 cases, while those for general surgery residents rosed from roughly 1 to 3 cases. Similarly, endovascular interventions for peripheral obstructive disease significantly increased for vascular fellows from 17 to 85, and from 1.3 to 4 for general surgery residents.
“The contemporary management of abdominal aortic aneurysmal diseases and peripheral obstructive diseases has been particularly changed by endovascular therapies that have been adopted into the training experience of vascular surgery fellows, but not those of general surgery residents. Open surgery experience has decreased overall for general surgery residents in all major categories, a change not seen in vascular fellows,” the researchers concluded.
The authors reported no relevant disclosures.
Vascular surgical practice has evolved with the introduction of minimally invasive technology and advancement of endovascular techniques, and as such, the training of the vascular surgical specialist too has evolved. This article highlights the effect of these technological advancements on the vascular surgical fellowship training experience and points out the effect of this embracing of endovascular techniques by academic centers in their general surgery trainee vascular surgical experience. Open operative case numbers are declining and endovascular case numbers are increasing significantly.
As traditionally performed open procedures are being substituted for endovascular repairs, the open operative experience for vascular surgery trainees is declining or staying stable at the expense of the general surgery resident experience. Open cases (open aneurysm repairs, aortofemoral artery bypasses, visceral artery bypasses, carotid endarterectomies), because they are performed infrequently now, have become fellow cases.
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Dr. Erica L. Mitchell |
Endovascular cases, which have increased over 300%-400%, too are essentially fellow cases (or in 0+5 programs, which are not discussed in this manuscript, vascular surgery resident cases) because the endovascular skill set does not appear to translate or transfer (and therefore is not considered relevant to the general surgery resident planning on a fellowship or career in the traditional surgical specialties) into open and laparoscopic skills desired by general surgery trainees.
Unfortunately, this open to endovascular operative experience shift will only increase with the introduction and early adoption (in academic centers) of complex endovascular techniques for the management of complex obstructive and aneurysmal arterial disease. A review of case log data for 0+5 and 5+2 residents completing programs in 2014-2015 reveals the operative experience and continued decline in open operative case numbers and increases in endovascular case numbers.
Vascular surgery training programs and their faculties have a responsibility to make sure the operative experience of general surgery residents is a worthwhile one. We, the faculty, need to keep encouraging general surgery residents to come to the operating room, even if they are not the primary surgeons. To make this worthwhile for them (because residents will not come to the operating room if there is nothing to be gained for themselves), we have to let them participate in the case somehow. One of the most critical aspects of a vascular surgical procedure is the operative exposure.
Having the general surgery residents participate in the vascular exposure is not only formative to their understanding of surgical anatomy, and applicable to all aspects of surgical practice, it is also critical to trainee development of decision making, judgment, and situational awareness. These exposures can and should be logged, using the e-code, to receive ACGME case log credit for vascular surgical procedures. E-codes, additionally, allow more than one resident to take credit for an arterial exposure and repair. We must also encourage trainees to come to the angio suite, while these cases, on the outset do not seem relevant to general surgery training, they do provide the learner with a greater appreciation of the complexity of vascular anatomy.
Importantly, as long as we continue to train vascular surgery specialists via the traditional 5+2 paradigm, we must keep general surgery residents, rotating through our services, interested and engaged in the management of vascular diseases. The simplest way to engage them is to make them feel relevant and to make them feel relevant they have to participate, both inside and outside of the operating room. It is, after all, our duty as surgical educators and advocates for our specialty to train the next generation of vascular surgical specialists!
Dr. Erica L. Mitchell is professor of surgery, program director for vascular surgery, and vice-chair of quality, department of surgery, Oregon Health & Science University, Portland. She is an associate medical editor of Vascular Specialist.
Vascular surgical practice has evolved with the introduction of minimally invasive technology and advancement of endovascular techniques, and as such, the training of the vascular surgical specialist too has evolved. This article highlights the effect of these technological advancements on the vascular surgical fellowship training experience and points out the effect of this embracing of endovascular techniques by academic centers in their general surgery trainee vascular surgical experience. Open operative case numbers are declining and endovascular case numbers are increasing significantly.
As traditionally performed open procedures are being substituted for endovascular repairs, the open operative experience for vascular surgery trainees is declining or staying stable at the expense of the general surgery resident experience. Open cases (open aneurysm repairs, aortofemoral artery bypasses, visceral artery bypasses, carotid endarterectomies), because they are performed infrequently now, have become fellow cases.
|
Dr. Erica L. Mitchell |
Endovascular cases, which have increased over 300%-400%, too are essentially fellow cases (or in 0+5 programs, which are not discussed in this manuscript, vascular surgery resident cases) because the endovascular skill set does not appear to translate or transfer (and therefore is not considered relevant to the general surgery resident planning on a fellowship or career in the traditional surgical specialties) into open and laparoscopic skills desired by general surgery trainees.
Unfortunately, this open to endovascular operative experience shift will only increase with the introduction and early adoption (in academic centers) of complex endovascular techniques for the management of complex obstructive and aneurysmal arterial disease. A review of case log data for 0+5 and 5+2 residents completing programs in 2014-2015 reveals the operative experience and continued decline in open operative case numbers and increases in endovascular case numbers.
Vascular surgery training programs and their faculties have a responsibility to make sure the operative experience of general surgery residents is a worthwhile one. We, the faculty, need to keep encouraging general surgery residents to come to the operating room, even if they are not the primary surgeons. To make this worthwhile for them (because residents will not come to the operating room if there is nothing to be gained for themselves), we have to let them participate in the case somehow. One of the most critical aspects of a vascular surgical procedure is the operative exposure.
Having the general surgery residents participate in the vascular exposure is not only formative to their understanding of surgical anatomy, and applicable to all aspects of surgical practice, it is also critical to trainee development of decision making, judgment, and situational awareness. These exposures can and should be logged, using the e-code, to receive ACGME case log credit for vascular surgical procedures. E-codes, additionally, allow more than one resident to take credit for an arterial exposure and repair. We must also encourage trainees to come to the angio suite, while these cases, on the outset do not seem relevant to general surgery training, they do provide the learner with a greater appreciation of the complexity of vascular anatomy.
Importantly, as long as we continue to train vascular surgery specialists via the traditional 5+2 paradigm, we must keep general surgery residents, rotating through our services, interested and engaged in the management of vascular diseases. The simplest way to engage them is to make them feel relevant and to make them feel relevant they have to participate, both inside and outside of the operating room. It is, after all, our duty as surgical educators and advocates for our specialty to train the next generation of vascular surgical specialists!
Dr. Erica L. Mitchell is professor of surgery, program director for vascular surgery, and vice-chair of quality, department of surgery, Oregon Health & Science University, Portland. She is an associate medical editor of Vascular Specialist.
Vascular surgical practice has evolved with the introduction of minimally invasive technology and advancement of endovascular techniques, and as such, the training of the vascular surgical specialist too has evolved. This article highlights the effect of these technological advancements on the vascular surgical fellowship training experience and points out the effect of this embracing of endovascular techniques by academic centers in their general surgery trainee vascular surgical experience. Open operative case numbers are declining and endovascular case numbers are increasing significantly.
As traditionally performed open procedures are being substituted for endovascular repairs, the open operative experience for vascular surgery trainees is declining or staying stable at the expense of the general surgery resident experience. Open cases (open aneurysm repairs, aortofemoral artery bypasses, visceral artery bypasses, carotid endarterectomies), because they are performed infrequently now, have become fellow cases.
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Dr. Erica L. Mitchell |
Endovascular cases, which have increased over 300%-400%, too are essentially fellow cases (or in 0+5 programs, which are not discussed in this manuscript, vascular surgery resident cases) because the endovascular skill set does not appear to translate or transfer (and therefore is not considered relevant to the general surgery resident planning on a fellowship or career in the traditional surgical specialties) into open and laparoscopic skills desired by general surgery trainees.
Unfortunately, this open to endovascular operative experience shift will only increase with the introduction and early adoption (in academic centers) of complex endovascular techniques for the management of complex obstructive and aneurysmal arterial disease. A review of case log data for 0+5 and 5+2 residents completing programs in 2014-2015 reveals the operative experience and continued decline in open operative case numbers and increases in endovascular case numbers.
Vascular surgery training programs and their faculties have a responsibility to make sure the operative experience of general surgery residents is a worthwhile one. We, the faculty, need to keep encouraging general surgery residents to come to the operating room, even if they are not the primary surgeons. To make this worthwhile for them (because residents will not come to the operating room if there is nothing to be gained for themselves), we have to let them participate in the case somehow. One of the most critical aspects of a vascular surgical procedure is the operative exposure.
Having the general surgery residents participate in the vascular exposure is not only formative to their understanding of surgical anatomy, and applicable to all aspects of surgical practice, it is also critical to trainee development of decision making, judgment, and situational awareness. These exposures can and should be logged, using the e-code, to receive ACGME case log credit for vascular surgical procedures. E-codes, additionally, allow more than one resident to take credit for an arterial exposure and repair. We must also encourage trainees to come to the angio suite, while these cases, on the outset do not seem relevant to general surgery training, they do provide the learner with a greater appreciation of the complexity of vascular anatomy.
Importantly, as long as we continue to train vascular surgery specialists via the traditional 5+2 paradigm, we must keep general surgery residents, rotating through our services, interested and engaged in the management of vascular diseases. The simplest way to engage them is to make them feel relevant and to make them feel relevant they have to participate, both inside and outside of the operating room. It is, after all, our duty as surgical educators and advocates for our specialty to train the next generation of vascular surgical specialists!
Dr. Erica L. Mitchell is professor of surgery, program director for vascular surgery, and vice-chair of quality, department of surgery, Oregon Health & Science University, Portland. She is an associate medical editor of Vascular Specialist.
Vascular surgery fellow case logs reflect an increase in endovascular interventions, but general surgery residents may be missing out on training opportunities, according to a study of national case data.
In addition, general surgery residents saw a decrease in open vascular surgery cases, which was not reflected among the vascular surgery fellows, according to Dr. Rose C. Pedersen and colleagues in the department of surgery, Kaiser Permanente Los Angeles Medical Center. The report was published online in Annals of Vascular Surgery (doi: 10.1016/j.avsg.2016.02.008).
The paper was originally presented at the 2105 annual meeting of the Southern California Vascular Society. The study reports findings of a review of the Accreditation Council for Graduate Medical Education national case log reports from 2001 to 2012.
During that period, the number of general surgery residents increased from 1,021 to 1,098, while the number of vascular surgery fellows increased from 96 to 121. The total number of vascular cases logged by the vascular fellows significantly increased by 161%, from an average of 298 cases to 762 cases over the time period assessed. During that same period, vascular cases done by general surgery residents significantly decreased by 40%, from an average of 186 to 116 cases.
In terms of open cases. vascular fellows saw a significant 43% decrease in open abdominal aortic aneurysm (AAA) cases, going from 26 to 15, and a slight but significant increase in carotid endarterectomy cases logged (44 to 49). Hemodialysis access and major amputations also both increased significantly. A decreases in open surgery for peripheral obstructive disease was small and not significant.
General surgery residents saw decreases in all open surgery areas over the time period: AAA cases fell significantly by 78% (9 cases to 2 cases); carotid endarterectomies decreased significantly from 23 to 12 cases; and surgery for peripheral obstructive disease fell significantly from 21 to 8). Hemodialysis access cases and major amputations both decreased as well, but not significantly.
Endovascular cases increased from 2001 to 2012 for both vascular fellows and general surgery residents. Vascular fellows saw endovascular AAA repair significantly increase from an average of 17 to 46 cases, while those for general surgery residents rosed from roughly 1 to 3 cases. Similarly, endovascular interventions for peripheral obstructive disease significantly increased for vascular fellows from 17 to 85, and from 1.3 to 4 for general surgery residents.
“The contemporary management of abdominal aortic aneurysmal diseases and peripheral obstructive diseases has been particularly changed by endovascular therapies that have been adopted into the training experience of vascular surgery fellows, but not those of general surgery residents. Open surgery experience has decreased overall for general surgery residents in all major categories, a change not seen in vascular fellows,” the researchers concluded.
The authors reported no relevant disclosures.
Vascular surgery fellow case logs reflect an increase in endovascular interventions, but general surgery residents may be missing out on training opportunities, according to a study of national case data.
In addition, general surgery residents saw a decrease in open vascular surgery cases, which was not reflected among the vascular surgery fellows, according to Dr. Rose C. Pedersen and colleagues in the department of surgery, Kaiser Permanente Los Angeles Medical Center. The report was published online in Annals of Vascular Surgery (doi: 10.1016/j.avsg.2016.02.008).
The paper was originally presented at the 2105 annual meeting of the Southern California Vascular Society. The study reports findings of a review of the Accreditation Council for Graduate Medical Education national case log reports from 2001 to 2012.
During that period, the number of general surgery residents increased from 1,021 to 1,098, while the number of vascular surgery fellows increased from 96 to 121. The total number of vascular cases logged by the vascular fellows significantly increased by 161%, from an average of 298 cases to 762 cases over the time period assessed. During that same period, vascular cases done by general surgery residents significantly decreased by 40%, from an average of 186 to 116 cases.
In terms of open cases. vascular fellows saw a significant 43% decrease in open abdominal aortic aneurysm (AAA) cases, going from 26 to 15, and a slight but significant increase in carotid endarterectomy cases logged (44 to 49). Hemodialysis access and major amputations also both increased significantly. A decreases in open surgery for peripheral obstructive disease was small and not significant.
General surgery residents saw decreases in all open surgery areas over the time period: AAA cases fell significantly by 78% (9 cases to 2 cases); carotid endarterectomies decreased significantly from 23 to 12 cases; and surgery for peripheral obstructive disease fell significantly from 21 to 8). Hemodialysis access cases and major amputations both decreased as well, but not significantly.
Endovascular cases increased from 2001 to 2012 for both vascular fellows and general surgery residents. Vascular fellows saw endovascular AAA repair significantly increase from an average of 17 to 46 cases, while those for general surgery residents rosed from roughly 1 to 3 cases. Similarly, endovascular interventions for peripheral obstructive disease significantly increased for vascular fellows from 17 to 85, and from 1.3 to 4 for general surgery residents.
“The contemporary management of abdominal aortic aneurysmal diseases and peripheral obstructive diseases has been particularly changed by endovascular therapies that have been adopted into the training experience of vascular surgery fellows, but not those of general surgery residents. Open surgery experience has decreased overall for general surgery residents in all major categories, a change not seen in vascular fellows,” the researchers concluded.
The authors reported no relevant disclosures.
FROM ANNALS OF VASCULAR SURGERY
