Researchers say they have determined the 3-dimensional, atomic structure of GPR56, an adhesion G protein-coupled receptor (aGPCR) linked to the development of several diseases, including acute myeloid leukemia (AML).

The team also engineered a molecule that can turn off GPR56, laying the groundwork for the development of treatments that target diseases mediated by GPR56 and other aGPCRs.

“Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combatting diseases influenced by aGPCRs,” said study author Gabriel Salzman, an MD/PhD student at the University of Chicago in Illinois.

Salzman and his colleagues detailed their work in the journal Neuron.

Over the past several years, researchers have discovered that aGPCRs play a range of biological roles, many of which are closely linked to human diseases.

aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space. However, a structural foundation for understanding the function of these extracellular regions has been lacking. And researchers didn’t know if these regions could be targeted for therapeutic intervention.

The focus of the current study is GPR56 (also known as ADGRG1), an aGPCR that has established biological roles in muscle cell development, neurodevelopment, and several cancers, including AML.

The researchers engineered a monobody molecule that binds to the extracellular region of GPR56 and causes intracellular signaling to decrease. They said this establishes that it’s possible to change the function of aGPCRs by targeting their extracellular regions with pharmaceuticals.

The team also determined the structure of the entire extracellular region of GPR56 at an atomic level, the first such structural description of any aGPCR. In doing so, they identified a unique protein domain called PLL, which, if deleted, corresponds to a naturally occurring variant of GPR56.

The researchers went on to show that deleting the PLL domain led to increased signaling, further supporting the concept that extracellular regions govern cell signaling.

Bioinformatics analysis also revealed a particular position in the PLL domain that is highly conserved across species, often a telltale sign of biological importance.

The researchers believe that understanding the biological roles played by aGPCR extracellular regions will give scientists more tools to develop treatments for diseases influenced by these protein receptors.

For example, recent studies have shown that AML therapy may benefit from GPR56 inhibition. And this study suggests a monobody like the one created by Salzman’s team might be useful in that respect.

“Our discovery that aGPCR extracellular regions regulate function in a multifaceted and complex manner provides important guidelines for developing therapeutics for diverse diseases in which aGPCRs play important roles,” Salzman said.

Researchers say they have determined the 3-dimensional, atomic structure of GPR56, an adhesion G protein-coupled receptor (aGPCR) linked to the development of several diseases, including acute myeloid leukemia (AML).

The team also engineered a molecule that can turn off GPR56, laying the groundwork for the development of treatments that target diseases mediated by GPR56 and other aGPCRs.

“Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combatting diseases influenced by aGPCRs,” said study author Gabriel Salzman, an MD/PhD student at the University of Chicago in Illinois.

Salzman and his colleagues detailed their work in the journal Neuron.

Over the past several years, researchers have discovered that aGPCRs play a range of biological roles, many of which are closely linked to human diseases.

aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space. However, a structural foundation for understanding the function of these extracellular regions has been lacking. And researchers didn’t know if these regions could be targeted for therapeutic intervention.

The focus of the current study is GPR56 (also known as ADGRG1), an aGPCR that has established biological roles in muscle cell development, neurodevelopment, and several cancers, including AML.

The researchers engineered a monobody molecule that binds to the extracellular region of GPR56 and causes intracellular signaling to decrease. They said this establishes that it’s possible to change the function of aGPCRs by targeting their extracellular regions with pharmaceuticals.

The team also determined the structure of the entire extracellular region of GPR56 at an atomic level, the first such structural description of any aGPCR. In doing so, they identified a unique protein domain called PLL, which, if deleted, corresponds to a naturally occurring variant of GPR56.

The researchers went on to show that deleting the PLL domain led to increased signaling, further supporting the concept that extracellular regions govern cell signaling.

Bioinformatics analysis also revealed a particular position in the PLL domain that is highly conserved across species, often a telltale sign of biological importance.

The researchers believe that understanding the biological roles played by aGPCR extracellular regions will give scientists more tools to develop treatments for diseases influenced by these protein receptors.

For example, recent studies have shown that AML therapy may benefit from GPR56 inhibition. And this study suggests a monobody like the one created by Salzman’s team might be useful in that respect.

“Our discovery that aGPCR extracellular regions regulate function in a multifaceted and complex manner provides important guidelines for developing therapeutics for diverse diseases in which aGPCRs play important roles,” Salzman said.

Researchers say they have determined the 3-dimensional, atomic structure of GPR56, an adhesion G protein-coupled receptor (aGPCR) linked to the development of several diseases, including acute myeloid leukemia (AML).

The team also engineered a molecule that can turn off GPR56, laying the groundwork for the development of treatments that target diseases mediated by GPR56 and other aGPCRs.

“Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combatting diseases influenced by aGPCRs,” said study author Gabriel Salzman, an MD/PhD student at the University of Chicago in Illinois.

Salzman and his colleagues detailed their work in the journal Neuron.

Over the past several years, researchers have discovered that aGPCRs play a range of biological roles, many of which are closely linked to human diseases.

aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space. However, a structural foundation for understanding the function of these extracellular regions has been lacking. And researchers didn’t know if these regions could be targeted for therapeutic intervention.

The focus of the current study is GPR56 (also known as ADGRG1), an aGPCR that has established biological roles in muscle cell development, neurodevelopment, and several cancers, including AML.

The researchers engineered a monobody molecule that binds to the extracellular region of GPR56 and causes intracellular signaling to decrease. They said this establishes that it’s possible to change the function of aGPCRs by targeting their extracellular regions with pharmaceuticals.

The team also determined the structure of the entire extracellular region of GPR56 at an atomic level, the first such structural description of any aGPCR. In doing so, they identified a unique protein domain called PLL, which, if deleted, corresponds to a naturally occurring variant of GPR56.

The researchers went on to show that deleting the PLL domain led to increased signaling, further supporting the concept that extracellular regions govern cell signaling.

Bioinformatics analysis also revealed a particular position in the PLL domain that is highly conserved across species, often a telltale sign of biological importance.

The researchers believe that understanding the biological roles played by aGPCR extracellular regions will give scientists more tools to develop treatments for diseases influenced by these protein receptors.

For example, recent studies have shown that AML therapy may benefit from GPR56 inhibition. And this study suggests a monobody like the one created by Salzman’s team might be useful in that respect.

“Our discovery that aGPCR extracellular regions regulate function in a multifaceted and complex manner provides important guidelines for developing therapeutics for diverse diseases in which aGPCRs play important roles,” Salzman said.

The US Food and Drug Administration (FDA) has granted fast track designation to an investigational malaria vaccine.

Sanaria® PfSPZ Vaccine is composed of live but weakened Plasmodium falciparum sporozoites and is being developed by Sanaria, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Trials of Sanaria® PfSPZ Vaccine

In a phase 1 study published in Science in 2013, 80% of patients who received higher doses of Sanaria® PfSPZ Vaccine were protected from malaria at 3 weeks after vaccination.

In another phase 1 study published in Nature Medicine in 2016, 4 doses of the vaccine protected 73% of subjects from malaria at 3 weeks and 55% of subjects at 21 weeks.

Five of the subjects without parasitemia at 21 weeks were exposed to malaria-carrying mosquitoes again at 59 weeks, and none developed parasitemia.

To date, 1165 volunteers have received Sanaria’s PfSPZ-based products in more than 2 dozen clinical trials in the US, Europe, and Africa.

Clinical trials are in progress in Tanzania, Kenya, Mali, Burkina Faso, Germany, and the US, and are intended to begin soon in Equatorial Guinea.

The US Food and Drug Administration (FDA) has granted fast track designation to an investigational malaria vaccine.

Sanaria® PfSPZ Vaccine is composed of live but weakened Plasmodium falciparum sporozoites and is being developed by Sanaria, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Trials of Sanaria® PfSPZ Vaccine

In a phase 1 study published in Science in 2013, 80% of patients who received higher doses of Sanaria® PfSPZ Vaccine were protected from malaria at 3 weeks after vaccination.

In another phase 1 study published in Nature Medicine in 2016, 4 doses of the vaccine protected 73% of subjects from malaria at 3 weeks and 55% of subjects at 21 weeks.

Five of the subjects without parasitemia at 21 weeks were exposed to malaria-carrying mosquitoes again at 59 weeks, and none developed parasitemia.

To date, 1165 volunteers have received Sanaria’s PfSPZ-based products in more than 2 dozen clinical trials in the US, Europe, and Africa.

Clinical trials are in progress in Tanzania, Kenya, Mali, Burkina Faso, Germany, and the US, and are intended to begin soon in Equatorial Guinea.

The US Food and Drug Administration (FDA) has granted fast track designation to an investigational malaria vaccine.

Sanaria® PfSPZ Vaccine is composed of live but weakened Plasmodium falciparum sporozoites and is being developed by Sanaria, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Trials of Sanaria® PfSPZ Vaccine

In a phase 1 study published in Science in 2013, 80% of patients who received higher doses of Sanaria® PfSPZ Vaccine were protected from malaria at 3 weeks after vaccination.

In another phase 1 study published in Nature Medicine in 2016, 4 doses of the vaccine protected 73% of subjects from malaria at 3 weeks and 55% of subjects at 21 weeks.

Five of the subjects without parasitemia at 21 weeks were exposed to malaria-carrying mosquitoes again at 59 weeks, and none developed parasitemia.

To date, 1165 volunteers have received Sanaria’s PfSPZ-based products in more than 2 dozen clinical trials in the US, Europe, and Africa.

Clinical trials are in progress in Tanzania, Kenya, Mali, Burkina Faso, Germany, and the US, and are intended to begin soon in Equatorial Guinea.

Drugs intended to treat high blood pressure might also be effective for treating cerebral malaria, according to preclinical research published in the Journal of Clinical Investigation.

Researchers tested these drugs—angiotensin II (Ang II) receptor modulators—in mice.

In an initial experiment, 2 of the drugs—losartan and CGP-42112A—reduced the incidence of cerebral malaria.

In another experiment, 2 other Ang II receptor modulators—irbesartan and compound 21 (C21)—were each combined with the antimalarial chloroquine.

Both combinations improved survival in mice with cerebral malaria when compared to chloroquine alone.

“About 1 in 5 patients with cerebral malaria die within 48 hours of being admitted to the hospital—the time it takes for the parasite-killing drug to take effect,” said study author Ana Rodriguez, PhD, of NYU Langone Medical Center in New York.

“If we could add a drug that stopped hemorrhages during that window, it would buy time and save lives.”

With this research, Dr Rodriguez and her colleagues showed that Ang II receptor modulators inhibit the activation of beta-catenin, a protein that plays a key role in cerebral malaria.

The team found that when Plasmodium falciparum–infected red blood cells rupture over human brain microvascular endothelial cells, this activates beta-catenin, which mediates the disruption of interendothelial junctions.

But inhibiting the activation of beta-catenin with Ang II receptor modulators protects endothelial cells from this disruption.

The researchers demonstrated this by infecting mice with P berghei ANKA, treating them with losartan or CGP-42112A, and monitoring them for neurological symptoms.

Seventy-five percent of control mice developed cerebral malaria, compared to 13.3% of mice treated with losartan and 28.5% treated with CGP-42112A.

In another experiment, the researchers treated malaria-infected mice with chloroquine, alone or in combination with irbesartan or C21, only after neurological signs were evident.

The team observed an increase in survival for mice treated with irbesartan or C21. The survival rate was 18% for the mice treated only with chloroquine, 65% for mice given irbesartan, and 73% percent for mice treated with C21.

The researchers also found that mice treated with irbesartan or C21 experienced fewer, smaller hemorrhages. And, in most cases, these mice fully recovered.

Dr Rodriguez and her colleagues said the next steps for this research will be to investigate the exact molecules coming from ruptured P falciparum–infected red blood cells that signal to beta-catenin in vessel walls, and to conduct trials that test the effects of Ang II receptor modulators in patients with cerebral malaria.

Drugs intended to treat high blood pressure might also be effective for treating cerebral malaria, according to preclinical research published in the Journal of Clinical Investigation.

Researchers tested these drugs—angiotensin II (Ang II) receptor modulators—in mice.

In an initial experiment, 2 of the drugs—losartan and CGP-42112A—reduced the incidence of cerebral malaria.

In another experiment, 2 other Ang II receptor modulators—irbesartan and compound 21 (C21)—were each combined with the antimalarial chloroquine.

Both combinations improved survival in mice with cerebral malaria when compared to chloroquine alone.

“About 1 in 5 patients with cerebral malaria die within 48 hours of being admitted to the hospital—the time it takes for the parasite-killing drug to take effect,” said study author Ana Rodriguez, PhD, of NYU Langone Medical Center in New York.

“If we could add a drug that stopped hemorrhages during that window, it would buy time and save lives.”

With this research, Dr Rodriguez and her colleagues showed that Ang II receptor modulators inhibit the activation of beta-catenin, a protein that plays a key role in cerebral malaria.

The team found that when Plasmodium falciparum–infected red blood cells rupture over human brain microvascular endothelial cells, this activates beta-catenin, which mediates the disruption of interendothelial junctions.

But inhibiting the activation of beta-catenin with Ang II receptor modulators protects endothelial cells from this disruption.

The researchers demonstrated this by infecting mice with P berghei ANKA, treating them with losartan or CGP-42112A, and monitoring them for neurological symptoms.

Seventy-five percent of control mice developed cerebral malaria, compared to 13.3% of mice treated with losartan and 28.5% treated with CGP-42112A.

In another experiment, the researchers treated malaria-infected mice with chloroquine, alone or in combination with irbesartan or C21, only after neurological signs were evident.

The team observed an increase in survival for mice treated with irbesartan or C21. The survival rate was 18% for the mice treated only with chloroquine, 65% for mice given irbesartan, and 73% percent for mice treated with C21.

The researchers also found that mice treated with irbesartan or C21 experienced fewer, smaller hemorrhages. And, in most cases, these mice fully recovered.

Dr Rodriguez and her colleagues said the next steps for this research will be to investigate the exact molecules coming from ruptured P falciparum–infected red blood cells that signal to beta-catenin in vessel walls, and to conduct trials that test the effects of Ang II receptor modulators in patients with cerebral malaria.

Drugs intended to treat high blood pressure might also be effective for treating cerebral malaria, according to preclinical research published in the Journal of Clinical Investigation.

Researchers tested these drugs—angiotensin II (Ang II) receptor modulators—in mice.

In an initial experiment, 2 of the drugs—losartan and CGP-42112A—reduced the incidence of cerebral malaria.

In another experiment, 2 other Ang II receptor modulators—irbesartan and compound 21 (C21)—were each combined with the antimalarial chloroquine.

Both combinations improved survival in mice with cerebral malaria when compared to chloroquine alone.

“About 1 in 5 patients with cerebral malaria die within 48 hours of being admitted to the hospital—the time it takes for the parasite-killing drug to take effect,” said study author Ana Rodriguez, PhD, of NYU Langone Medical Center in New York.

“If we could add a drug that stopped hemorrhages during that window, it would buy time and save lives.”

With this research, Dr Rodriguez and her colleagues showed that Ang II receptor modulators inhibit the activation of beta-catenin, a protein that plays a key role in cerebral malaria.

The team found that when Plasmodium falciparum–infected red blood cells rupture over human brain microvascular endothelial cells, this activates beta-catenin, which mediates the disruption of interendothelial junctions.

But inhibiting the activation of beta-catenin with Ang II receptor modulators protects endothelial cells from this disruption.

The researchers demonstrated this by infecting mice with P berghei ANKA, treating them with losartan or CGP-42112A, and monitoring them for neurological symptoms.

Seventy-five percent of control mice developed cerebral malaria, compared to 13.3% of mice treated with losartan and 28.5% treated with CGP-42112A.

In another experiment, the researchers treated malaria-infected mice with chloroquine, alone or in combination with irbesartan or C21, only after neurological signs were evident.

The team observed an increase in survival for mice treated with irbesartan or C21. The survival rate was 18% for the mice treated only with chloroquine, 65% for mice given irbesartan, and 73% percent for mice treated with C21.

The researchers also found that mice treated with irbesartan or C21 experienced fewer, smaller hemorrhages. And, in most cases, these mice fully recovered.

Dr Rodriguez and her colleagues said the next steps for this research will be to investigate the exact molecules coming from ruptured P falciparum–infected red blood cells that signal to beta-catenin in vessel walls, and to conduct trials that test the effects of Ang II receptor modulators in patients with cerebral malaria.

COLUMBUS, OHIO – The disparity in amputation rates between blacks and non-Hispanic whites in Chicago was higher than the national average and up to five times greater on the predominantly black South Side than on the predominantly white North Side of the city.

The reasons for this disparity are unclear, but a recent study of white and black Chicagoans has shown that the rates at which the races self-report claudication do not differ, suggesting that better utilization of public health resources in the black community could potentially reduce this disparity.

Reporting at the annual meeting of the Midwestern Vascular Surgery Society, lead investigator Samantha Minc, MD, of Rush University in Chicago, said the difference in amputation rates may be traced to later recognition of disease in nonwhites.

“Possible reasons for late recognition of disease include lack of access to care, communication issues with doctors, education issues, or the patient and/or caregiver and primary care provider having difficulty accessing specialists,” Dr. Minc said. “Another often-cited explanation for the late recognition is the possibility of differences in disease symptom manifestations in nonwhites, which is what we chose to study.”

Investigators from Rush University analyzed data from a combined cohort of Chicago residents age 65 years and older from two studies of aging: The Rush Memory and Aging Project and the Minority Aging Research Study.

Because of the segregated nature of Chicago – the North Side is mostly white, the South Side mostly black and the West Side mostly Hispanic – prior research has coupled census data with the Illinois Department of Public Health database to analyze care patterns. This data showed that the disparity in amputation rates among groups in Chicago was higher than the national average and up to five times greater on the South Side, compared with the North, Dr. Minc said.

The latest study matched blacks and whites from both studies 1:2 based on age, education, gender, and length of follow-up. In all, a cohort of 2,487 subjects was generated: 801 blacks and 1,686 non-Hispanic whites. Among blacks, 6.5% reported claudication at baseline, compared with 5.9% of whites, and at any point of the study 19.5% of blacks and 19.6% of non-Hispanic whites reported claudication, differences that were not statistically significant.

Blacks did have higher rates of diabetes, 27% vs. 12.6%, were more likely to have used tobacco, more likely to be female, and were slightly younger on average, but other demographic factors – such as income or rates of congestive heart failure and coronary artery disease – were not significantly different, Dr. Minc said.

The study findings will inform the Chicago Department of Public Health’s Healthy Chicago 2.0 initiative to reduce the disparity in amputation rates between whites and blacks by 10% by 2020.

Dr. Minc acknowledged limitations of the study, among them that participants were volunteers, aged 65 years and older, and 72% female, that Hispanics were excluded, and that the use of the Modified Rose/World Health Organization questionnaire to detect claudication is “specific, but not very sensitive.”

“Our findings suggest that the delay in recognition in disease in nonwhites is not due to a racial differences in disease manifestation or symptomatology and that addressing socioeconomic issues, such as access to care, communication, and education may reduce the racial disparity in amputation rates,” Dr. Minc said. “Public health resources should focus on early recognition of the disease in higher-risk groups to decrease this disparity.”

Dr. Minc and her coauthors had no relationships to disclose.

COLUMBUS, OHIO – The disparity in amputation rates between blacks and non-Hispanic whites in Chicago was higher than the national average and up to five times greater on the predominantly black South Side than on the predominantly white North Side of the city.

The reasons for this disparity are unclear, but a recent study of white and black Chicagoans has shown that the rates at which the races self-report claudication do not differ, suggesting that better utilization of public health resources in the black community could potentially reduce this disparity.

Reporting at the annual meeting of the Midwestern Vascular Surgery Society, lead investigator Samantha Minc, MD, of Rush University in Chicago, said the difference in amputation rates may be traced to later recognition of disease in nonwhites.

“Possible reasons for late recognition of disease include lack of access to care, communication issues with doctors, education issues, or the patient and/or caregiver and primary care provider having difficulty accessing specialists,” Dr. Minc said. “Another often-cited explanation for the late recognition is the possibility of differences in disease symptom manifestations in nonwhites, which is what we chose to study.”

Investigators from Rush University analyzed data from a combined cohort of Chicago residents age 65 years and older from two studies of aging: The Rush Memory and Aging Project and the Minority Aging Research Study.

Because of the segregated nature of Chicago – the North Side is mostly white, the South Side mostly black and the West Side mostly Hispanic – prior research has coupled census data with the Illinois Department of Public Health database to analyze care patterns. This data showed that the disparity in amputation rates among groups in Chicago was higher than the national average and up to five times greater on the South Side, compared with the North, Dr. Minc said.

The latest study matched blacks and whites from both studies 1:2 based on age, education, gender, and length of follow-up. In all, a cohort of 2,487 subjects was generated: 801 blacks and 1,686 non-Hispanic whites. Among blacks, 6.5% reported claudication at baseline, compared with 5.9% of whites, and at any point of the study 19.5% of blacks and 19.6% of non-Hispanic whites reported claudication, differences that were not statistically significant.

Blacks did have higher rates of diabetes, 27% vs. 12.6%, were more likely to have used tobacco, more likely to be female, and were slightly younger on average, but other demographic factors – such as income or rates of congestive heart failure and coronary artery disease – were not significantly different, Dr. Minc said.

The study findings will inform the Chicago Department of Public Health’s Healthy Chicago 2.0 initiative to reduce the disparity in amputation rates between whites and blacks by 10% by 2020.

Dr. Minc acknowledged limitations of the study, among them that participants were volunteers, aged 65 years and older, and 72% female, that Hispanics were excluded, and that the use of the Modified Rose/World Health Organization questionnaire to detect claudication is “specific, but not very sensitive.”

“Our findings suggest that the delay in recognition in disease in nonwhites is not due to a racial differences in disease manifestation or symptomatology and that addressing socioeconomic issues, such as access to care, communication, and education may reduce the racial disparity in amputation rates,” Dr. Minc said. “Public health resources should focus on early recognition of the disease in higher-risk groups to decrease this disparity.”

Dr. Minc and her coauthors had no relationships to disclose.

COLUMBUS, OHIO – The disparity in amputation rates between blacks and non-Hispanic whites in Chicago was higher than the national average and up to five times greater on the predominantly black South Side than on the predominantly white North Side of the city.

The reasons for this disparity are unclear, but a recent study of white and black Chicagoans has shown that the rates at which the races self-report claudication do not differ, suggesting that better utilization of public health resources in the black community could potentially reduce this disparity.

Reporting at the annual meeting of the Midwestern Vascular Surgery Society, lead investigator Samantha Minc, MD, of Rush University in Chicago, said the difference in amputation rates may be traced to later recognition of disease in nonwhites.

“Possible reasons for late recognition of disease include lack of access to care, communication issues with doctors, education issues, or the patient and/or caregiver and primary care provider having difficulty accessing specialists,” Dr. Minc said. “Another often-cited explanation for the late recognition is the possibility of differences in disease symptom manifestations in nonwhites, which is what we chose to study.”

Investigators from Rush University analyzed data from a combined cohort of Chicago residents age 65 years and older from two studies of aging: The Rush Memory and Aging Project and the Minority Aging Research Study.

Because of the segregated nature of Chicago – the North Side is mostly white, the South Side mostly black and the West Side mostly Hispanic – prior research has coupled census data with the Illinois Department of Public Health database to analyze care patterns. This data showed that the disparity in amputation rates among groups in Chicago was higher than the national average and up to five times greater on the South Side, compared with the North, Dr. Minc said.

The latest study matched blacks and whites from both studies 1:2 based on age, education, gender, and length of follow-up. In all, a cohort of 2,487 subjects was generated: 801 blacks and 1,686 non-Hispanic whites. Among blacks, 6.5% reported claudication at baseline, compared with 5.9% of whites, and at any point of the study 19.5% of blacks and 19.6% of non-Hispanic whites reported claudication, differences that were not statistically significant.

Blacks did have higher rates of diabetes, 27% vs. 12.6%, were more likely to have used tobacco, more likely to be female, and were slightly younger on average, but other demographic factors – such as income or rates of congestive heart failure and coronary artery disease – were not significantly different, Dr. Minc said.

The study findings will inform the Chicago Department of Public Health’s Healthy Chicago 2.0 initiative to reduce the disparity in amputation rates between whites and blacks by 10% by 2020.

Dr. Minc acknowledged limitations of the study, among them that participants were volunteers, aged 65 years and older, and 72% female, that Hispanics were excluded, and that the use of the Modified Rose/World Health Organization questionnaire to detect claudication is “specific, but not very sensitive.”

“Our findings suggest that the delay in recognition in disease in nonwhites is not due to a racial differences in disease manifestation or symptomatology and that addressing socioeconomic issues, such as access to care, communication, and education may reduce the racial disparity in amputation rates,” Dr. Minc said. “Public health resources should focus on early recognition of the disease in higher-risk groups to decrease this disparity.”

Dr. Minc and her coauthors had no relationships to disclose.

The Food and Drug Administration approved an extended-release combination of canagliflozin and metformin for first-line use as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes, according to Janssen Pharmaceuticals.

Once-daily Invokamet XR combines canagliflozin (Invokana) and an extended-release formulation of metformin. Studies in healthy adults have shown that Invokamet XR results in the same levels of canagliflozin and metformin in the body as when corresponding dosages of the two medicines are administered as separate tablets.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

Phase III studies showed that using canagliflozin and metformin lowered blood sugar and, in prespecified secondary endpoints, was linked to greater reductions in body weight and systolic blood pressure.

Invokamet XR is available with 50 mg or 150 mg of canagliflozin, and 500 mg or 1,000 mg of extended-release metformin. Invokamet XR contains a boxed warning regarding the risk of lactic acidosis.

Read the full company statement here.

llaubach@frontlinemedcom.com

The Food and Drug Administration approved an extended-release combination of canagliflozin and metformin for first-line use as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes, according to Janssen Pharmaceuticals.

Once-daily Invokamet XR combines canagliflozin (Invokana) and an extended-release formulation of metformin. Studies in healthy adults have shown that Invokamet XR results in the same levels of canagliflozin and metformin in the body as when corresponding dosages of the two medicines are administered as separate tablets.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

Phase III studies showed that using canagliflozin and metformin lowered blood sugar and, in prespecified secondary endpoints, was linked to greater reductions in body weight and systolic blood pressure.

Invokamet XR is available with 50 mg or 150 mg of canagliflozin, and 500 mg or 1,000 mg of extended-release metformin. Invokamet XR contains a boxed warning regarding the risk of lactic acidosis.

Read the full company statement here.

llaubach@frontlinemedcom.com

The Food and Drug Administration approved an extended-release combination of canagliflozin and metformin for first-line use as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes, according to Janssen Pharmaceuticals.

Once-daily Invokamet XR combines canagliflozin (Invokana) and an extended-release formulation of metformin. Studies in healthy adults have shown that Invokamet XR results in the same levels of canagliflozin and metformin in the body as when corresponding dosages of the two medicines are administered as separate tablets.

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

Phase III studies showed that using canagliflozin and metformin lowered blood sugar and, in prespecified secondary endpoints, was linked to greater reductions in body weight and systolic blood pressure.

Invokamet XR is available with 50 mg or 150 mg of canagliflozin, and 500 mg or 1,000 mg of extended-release metformin. Invokamet XR contains a boxed warning regarding the risk of lactic acidosis.

Read the full company statement here.

llaubach@frontlinemedcom.com

LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.

Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.

“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.

Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.

Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.

Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.

Versus interferon beta-1a

The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.

In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.

Versus fingolimod

The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.

“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.

Versus natalizumab

The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.

Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.

 

A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.

Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.

Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.

LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.

Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.

“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.

Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.

Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.

Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.

Versus interferon beta-1a

The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.

In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.

Versus fingolimod

The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.

“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.

Versus natalizumab

The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.

Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.

 

A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.

Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.

Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.

LONDON – Real-world data show that the disease-modifying multiple sclerosis drug alemtuzumab is as effective as natalizumab for preventing relapse and disability progression in patients with relapsing-remitting multiple sclerosis.

Three separate analyses of data involving more than 4,000 patients included in the MSBase Registry and from seven European MS centers showed that alemtuzumab (Lemtrada) was also more effective than subcutaneous interferon beta-1a (IFN beta-1a; Rebif) and fingolimod (Gilenya) for relapse prevention.

“We have seen that alemtuzumab is superior to IFN beta-1a subcutaneous administration in suppressing relapse activity and, in patients with a perilously high level of relapse activity, also in suppressing the probability of reaching disability progression and increasing the probability of reaching disability regression,” Tomas Kalincik, MD, said at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Furthermore, “alemtuzumab was superior to fingolimod in suppressing annualized relapse rates, and comparable to natalizumab (Tysabri) in controlling relapse activity and limiting the probability of disability progression,” said Dr. Kalincik of the University of Melbourne.

Head-to-head trials of MS therapies are lacking, so the aim of the observational study was to compare the treatment effectiveness of alemtuzumab versus natalizumab, IFN beta-1a, and fingolimod. Specifically, the aim was to look at the annualized relapse rate (ARR), cumulative hazard of relapses, and 6-month Expanded Disability Scale Score (EDSS) progression and regression. Propensity score matching was used to make the comparisons between alemtuzumab and the other MS treatments.

Patient data were retrospectively taken from the MSbase database, which includes prospectively collected data from more than 41,000 patients with MS treated at 119 centers in 35 countries. For inclusion in the present analysis, patients had to have definite relapsing-remitting multiple sclerosis, a baseline EDSS of 0-5.5, age of 65 years or younger, and duration of MS of 10 years or less, as well as one or more relapses in the previous year. Patients also needed to have a minimum follow-up of 12 months before and 6 months after they started treatment, and a minimum of two post-baseline visits that were 6 months apart.

Of 15,763 patients with definite MS who commenced treatment with one of the four MS therapies being considered, 4,332 met all the inclusion criteria. Of these, 189 were treated with alemtuzumab, 1,160 with natalizumab, 2,155 with IFN beta-1a, and 828 with fingolimod. Dr. Kalincik noted that the alemtuzumab patient data were combined from seven European MS centers and not the MSBase database.

Versus interferon beta-1a

The first data analysis involved 124 alemtuzumab-treated patients and 219 IFN beta-1a-treated patients with 5 years’ follow-up. Compared with IFN beta-1a, alemtuzumab was associated with an overall lower 5-year ARR of 0.2 versus 0.5 (P less than .001). The annual relapse rates by each individual year were also all significantly lower with alemtuzumab, and the cumulative hazard ratio (HR) of relapses was 0.42 (P less than .001), indicating an almost 60% reduction in relapses over time.

In terms of disability progression, alemtuzumab did not show an advantage over IFN beta-1a, which is in contrast to the findings of its pivotal trials, Dr. Kalincik observed. However, alemtuzumab was found to have an advantage over IFN beta-1a therapy in a secondary analysis if patients had highly active disease, defined as either three or more relapses over a 2-year period or two or more relapses over a 1-year period. The HR for confirmed disability progression was 0.64 (P = .016). Patients with on-treatment relapses within the previous year also fared better if treated with alemtuzumab, with a HR of 3.9 (P = .028) for confirmed disability regression.

Versus fingolimod

The second data analysis involved 114 alemtuzumab-treated patients and 195 fingolimod-treated patients with 3 years’ follow-up. When compared with fingolimod, there was again a much lower ARR overall (0.15 vs. 0.3; P less than .001) at 3 years, and at years 1, 2, and 3 individually (P less than .05). There was a nonsignificant 40% reduction in the relapse rate over time.

“For the disability outcomes, we haven’t seen any statistically significant difference, neither between the 6-month confirmed disability progression nor the 6-month confirmed disability regression,” Dr. Kalincik reported.

Versus natalizumab

The third and final analysis involved 138 alemtuzumab-treated patients and 223 natalizumab-treated patients with 4 years’ follow-up. There were no significant differences found in either the ARR overall (0.2 for both treatments; P = .8) or by follow-up year, and the cumulative hazard of relapses was the same.

Although there was no significant difference in confirmed disability progression at 6 months between the two treatments, there was a significant difference observed for the confirmed 6-month disability regression that favored natalizumab during the first year of treatment, Dr. Kalincik said. After 1 year, this potential advantage disappeared, he observed.

 

A large number of sensitivity analyses were performed and “largely confirm” the outcomes of the primary analyses.

Limitations include the lack of MRI data, and it was not possible to evaluate the relative safety of treatments.

Dr. Kalincik disclosed ties with Roche, Genzyme, Novartis, Merck, Biogen, WebMD Global, Sanofi, Teva, and BioCSL.

PORTLAND, OR—Higher serum levels of polychlorinated biphenyls (PCBs) are associated with increased risk of Parkinson’s disease in two independent study populations, according to research presented at the Fourth World Parkinson Congress.

Samuel Goldman, MD, MPH, Principal Investigator of Neurology at San Francisco Veterans Affairs Medical Center and Associate Professor of Neurology at the University of California San Francisco, and colleagues investigated whether recently observed associations of serum PCBs and Parkinson’s disease replicate in an independent study population.


PCBs are persistent environmental pollutants that are detectable in most people despite a worldwide ban on their production that has been in place for more than 20 years. PCBs cause selective dopaminergic toxicity in animal models, but have been minimally studied in Parkinson’s disease, the researchers said.

The investigators recently reported a significantly increased risk of Parkinson’s disease associated with higher levels of serum PCBs in a case–control study of Alaska Native people. In the present study, they investigated this association in a demographically dissimilar study population.

They identified people with Parkinson’s disease within the Agricultural Health Study, a cohort of pesticide applicators and their spouses in Iowa and North Carolina. They also randomly selected controls matched for age, sex, and state. They confirmed Parkinson’s disease diagnoses by in-person neurologist evaluation and consensus review. PCB congeners 118, 138, 153, and 180 were measured as ng/g lipid in serum using gas chromatography-mass spectroscopy. To assess dose-response, the researchers constructed quartiles for each congener and for the sum of congeners. The used logistic regression, adjusting for age, gender, and state, to calculate odds ratios.

Ninety-seven people with Parkinson’s disease and 113 controls were included in the study. About 25% of the participants were women. Mean age was 69. Parkinson’s disease was associated with higher levels of PCBs. A significant dose-response was seen across quartiles. Participants in the second, third, and fourth quartiles of total PCB levels had a 1.7-, 2.4-, and 2.7-fold greater risk of Parkinson’s disease, respectively, compared with participants in the lowest quartile of total PCB levels. Odds ratios were similar in the Agricultural Heath Study and the Alaska study. In both studies, PCB levels correlated positively with age but not with disease duration, which argues against reverse causation, the researchers said.

—Jake Remaly

PORTLAND, OR—Higher serum levels of polychlorinated biphenyls (PCBs) are associated with increased risk of Parkinson’s disease in two independent study populations, according to research presented at the Fourth World Parkinson Congress.

Samuel Goldman, MD, MPH, Principal Investigator of Neurology at San Francisco Veterans Affairs Medical Center and Associate Professor of Neurology at the University of California San Francisco, and colleagues investigated whether recently observed associations of serum PCBs and Parkinson’s disease replicate in an independent study population.


PCBs are persistent environmental pollutants that are detectable in most people despite a worldwide ban on their production that has been in place for more than 20 years. PCBs cause selective dopaminergic toxicity in animal models, but have been minimally studied in Parkinson’s disease, the researchers said.

The investigators recently reported a significantly increased risk of Parkinson’s disease associated with higher levels of serum PCBs in a case–control study of Alaska Native people. In the present study, they investigated this association in a demographically dissimilar study population.

They identified people with Parkinson’s disease within the Agricultural Health Study, a cohort of pesticide applicators and their spouses in Iowa and North Carolina. They also randomly selected controls matched for age, sex, and state. They confirmed Parkinson’s disease diagnoses by in-person neurologist evaluation and consensus review. PCB congeners 118, 138, 153, and 180 were measured as ng/g lipid in serum using gas chromatography-mass spectroscopy. To assess dose-response, the researchers constructed quartiles for each congener and for the sum of congeners. The used logistic regression, adjusting for age, gender, and state, to calculate odds ratios.

Ninety-seven people with Parkinson’s disease and 113 controls were included in the study. About 25% of the participants were women. Mean age was 69. Parkinson’s disease was associated with higher levels of PCBs. A significant dose-response was seen across quartiles. Participants in the second, third, and fourth quartiles of total PCB levels had a 1.7-, 2.4-, and 2.7-fold greater risk of Parkinson’s disease, respectively, compared with participants in the lowest quartile of total PCB levels. Odds ratios were similar in the Agricultural Heath Study and the Alaska study. In both studies, PCB levels correlated positively with age but not with disease duration, which argues against reverse causation, the researchers said.

—Jake Remaly

PORTLAND, OR—Higher serum levels of polychlorinated biphenyls (PCBs) are associated with increased risk of Parkinson’s disease in two independent study populations, according to research presented at the Fourth World Parkinson Congress.

Samuel Goldman, MD, MPH, Principal Investigator of Neurology at San Francisco Veterans Affairs Medical Center and Associate Professor of Neurology at the University of California San Francisco, and colleagues investigated whether recently observed associations of serum PCBs and Parkinson’s disease replicate in an independent study population.


PCBs are persistent environmental pollutants that are detectable in most people despite a worldwide ban on their production that has been in place for more than 20 years. PCBs cause selective dopaminergic toxicity in animal models, but have been minimally studied in Parkinson’s disease, the researchers said.

The investigators recently reported a significantly increased risk of Parkinson’s disease associated with higher levels of serum PCBs in a case–control study of Alaska Native people. In the present study, they investigated this association in a demographically dissimilar study population.

They identified people with Parkinson’s disease within the Agricultural Health Study, a cohort of pesticide applicators and their spouses in Iowa and North Carolina. They also randomly selected controls matched for age, sex, and state. They confirmed Parkinson’s disease diagnoses by in-person neurologist evaluation and consensus review. PCB congeners 118, 138, 153, and 180 were measured as ng/g lipid in serum using gas chromatography-mass spectroscopy. To assess dose-response, the researchers constructed quartiles for each congener and for the sum of congeners. The used logistic regression, adjusting for age, gender, and state, to calculate odds ratios.

Ninety-seven people with Parkinson’s disease and 113 controls were included in the study. About 25% of the participants were women. Mean age was 69. Parkinson’s disease was associated with higher levels of PCBs. A significant dose-response was seen across quartiles. Participants in the second, third, and fourth quartiles of total PCB levels had a 1.7-, 2.4-, and 2.7-fold greater risk of Parkinson’s disease, respectively, compared with participants in the lowest quartile of total PCB levels. Odds ratios were similar in the Agricultural Heath Study and the Alaska study. In both studies, PCB levels correlated positively with age but not with disease duration, which argues against reverse causation, the researchers said.

—Jake Remaly

PORTLAND, OR—High doses of transdermal nicotine failed to improve off motor symptoms in patients with Parkinson’s disease, according to trial results presented at the Fourth World Parkinson Congress. Nicotine may have provided benefit on secondary outcome measures, researchers said.

Gabriel Villafane, MD, a neurologist at Henri Mondor University Hospital in Créteil, France, and colleagues conducted the Nicopark2 Study, a single-blind, controlled, randomized trial to evaluate the effect of high doses of transdermal nicotine (approximately 90 mg per day) on motor symptoms in Parkinson’s disease.

Cigarette smoking is associated with a dose-dependent reduction in risk of Parkinson’s disease. Nicotine’s effect on motor symptoms in Parkinson’s disease is controversial. Seven of eight open-label studies suggested that nicotine improves motor symptoms, but four placebo-controlled studies were negative.

The investigators enrolled 40 patients with Parkinson’s disease in the study. Eligible patients were nonsmokers age 35 to 70 with a Hoehn and Yahr off stage of four or less and a Hoehn and Yahr on stage of three or less. Patients had received levodopa treatment for at least three years. Exclusion criteria included neurosurgery, psychiatric disease, and symptomatic orthostatic hypotension.

The primary outcome was mean difference between groups in change of Unified Parkinson’s Disease Rating Scale off motor score from baseline to week 39 on blinded video rating.

Twenty patients were randomized to receive transdermal nicotine, and 20 patients were randomized to a control group. The change in motor score between groups was not statistically significant. Change in quality of life assessed by the Parkinson’s Disease Questionnaire was not statistically significant. At 39 weeks, a reduction in levodopa doses, a reduction in dyskinesias, and an improvement in activities of daily living were observed in the nicotine group, the researchers said.

Adverse events occurred in more patients the nicotine group than in the control group. They included worsening of parkinsonism (30% vs 5%), cutaneous reactions (35% vs 5%), gastrointestinal complaints (65% vs 15%), hypotension (25% vs 5%), insomnia (25% vs 5%), and nervousness and anxiety (20% vs 0%). Ten patients in the nicotine group had a serious adverse event, compared with three patients in the control group.

—Jake Remaly

PORTLAND, OR—High doses of transdermal nicotine failed to improve off motor symptoms in patients with Parkinson’s disease, according to trial results presented at the Fourth World Parkinson Congress. Nicotine may have provided benefit on secondary outcome measures, researchers said.

Gabriel Villafane, MD, a neurologist at Henri Mondor University Hospital in Créteil, France, and colleagues conducted the Nicopark2 Study, a single-blind, controlled, randomized trial to evaluate the effect of high doses of transdermal nicotine (approximately 90 mg per day) on motor symptoms in Parkinson’s disease.

Cigarette smoking is associated with a dose-dependent reduction in risk of Parkinson’s disease. Nicotine’s effect on motor symptoms in Parkinson’s disease is controversial. Seven of eight open-label studies suggested that nicotine improves motor symptoms, but four placebo-controlled studies were negative.

The investigators enrolled 40 patients with Parkinson’s disease in the study. Eligible patients were nonsmokers age 35 to 70 with a Hoehn and Yahr off stage of four or less and a Hoehn and Yahr on stage of three or less. Patients had received levodopa treatment for at least three years. Exclusion criteria included neurosurgery, psychiatric disease, and symptomatic orthostatic hypotension.

The primary outcome was mean difference between groups in change of Unified Parkinson’s Disease Rating Scale off motor score from baseline to week 39 on blinded video rating.

Twenty patients were randomized to receive transdermal nicotine, and 20 patients were randomized to a control group. The change in motor score between groups was not statistically significant. Change in quality of life assessed by the Parkinson’s Disease Questionnaire was not statistically significant. At 39 weeks, a reduction in levodopa doses, a reduction in dyskinesias, and an improvement in activities of daily living were observed in the nicotine group, the researchers said.

Adverse events occurred in more patients the nicotine group than in the control group. They included worsening of parkinsonism (30% vs 5%), cutaneous reactions (35% vs 5%), gastrointestinal complaints (65% vs 15%), hypotension (25% vs 5%), insomnia (25% vs 5%), and nervousness and anxiety (20% vs 0%). Ten patients in the nicotine group had a serious adverse event, compared with three patients in the control group.

—Jake Remaly

PORTLAND, OR—High doses of transdermal nicotine failed to improve off motor symptoms in patients with Parkinson’s disease, according to trial results presented at the Fourth World Parkinson Congress. Nicotine may have provided benefit on secondary outcome measures, researchers said.

Gabriel Villafane, MD, a neurologist at Henri Mondor University Hospital in Créteil, France, and colleagues conducted the Nicopark2 Study, a single-blind, controlled, randomized trial to evaluate the effect of high doses of transdermal nicotine (approximately 90 mg per day) on motor symptoms in Parkinson’s disease.

Cigarette smoking is associated with a dose-dependent reduction in risk of Parkinson’s disease. Nicotine’s effect on motor symptoms in Parkinson’s disease is controversial. Seven of eight open-label studies suggested that nicotine improves motor symptoms, but four placebo-controlled studies were negative.

The investigators enrolled 40 patients with Parkinson’s disease in the study. Eligible patients were nonsmokers age 35 to 70 with a Hoehn and Yahr off stage of four or less and a Hoehn and Yahr on stage of three or less. Patients had received levodopa treatment for at least three years. Exclusion criteria included neurosurgery, psychiatric disease, and symptomatic orthostatic hypotension.

The primary outcome was mean difference between groups in change of Unified Parkinson’s Disease Rating Scale off motor score from baseline to week 39 on blinded video rating.

Twenty patients were randomized to receive transdermal nicotine, and 20 patients were randomized to a control group. The change in motor score between groups was not statistically significant. Change in quality of life assessed by the Parkinson’s Disease Questionnaire was not statistically significant. At 39 weeks, a reduction in levodopa doses, a reduction in dyskinesias, and an improvement in activities of daily living were observed in the nicotine group, the researchers said.

Adverse events occurred in more patients the nicotine group than in the control group. They included worsening of parkinsonism (30% vs 5%), cutaneous reactions (35% vs 5%), gastrointestinal complaints (65% vs 15%), hypotension (25% vs 5%), insomnia (25% vs 5%), and nervousness and anxiety (20% vs 0%). Ten patients in the nicotine group had a serious adverse event, compared with three patients in the control group.

—Jake Remaly

Clinical outcomes of surgery and patient-reported outcomes of function, disability, and health status are two different measures of surgical success.

A large study of patients who had bariatric surgery showed that patient-reported outcomes were correlated with long-term weight loss but not with short-term complication rates. In addition, obesity-specific patient-reported quality of life scores were associated with a reduction in medications required for the treatment of obesity-related conditions.

“Clinical outcomes, such as perioperative morbidity and mortality, are commonly used to benchmark hospital performance,” reported Jennifer F. Waljee, MD, and her associates at the University of Michigan, Ann Arbor (Ann Surg. 2016. doi: 10.1097/SLA.0000000000001852).

“However, for many surgical procedures, such as bariatric surgery ... complications may be rare, and may not entirely reflect treatment effectiveness. Alternatively, patient-reported measures of function, disability, and health status may offer a unique and more reliable assessment of provider quality and performance,” she explained. Yet despite growing interest in using patient-reported measures, many important questions regarding their accuracy, applicability, and clinical utility remain. The purpose of this study was, therefore, to evaluate how patient-reported quality of life measures compared to short-term and long-term clinical outcomes in patients who underwent bariatric surgery.

 

©Vasilis Varsakelis/fotolia.com

The majority of the study’s 11,420 participants were female (79.8%), were white (84.1%), and underwent Roux-en-Y laparoscopic gastric bypass (56.8%). For each study participant, both short-term and long-term clinical outcome measures were obtained from medical board review. Short-term clinical outcomes were defined as the rate of perioperative complications within 30 days of bariatric surgery. Percent excess weight loss at 1 year post surgery was used as a long-term clinical outcome.

In addition, two patient-reported outcomes were collected: an overall health-related quality of life score called the Health and Activities Limitations Index (HALex) and an obesity-specific quality of life score, the Bariatric Quality of Life (BQL) index, which measures well-being, social and physical functioning, and obesity-related symptoms.

Multivariate and linear regression models demonstrated that short-term complication rates were not correlated to the overall patient-reported quality of life score (P = .32) or to the obesity-specific BQL score (P = .74).

However, the long-term measure of excess weight loss at 1 year post surgery was significantly associated with both overall and obesity-specific patient-reported measures of health-related quality of life (P less than .002 and P less than .001 respectively).

Moreover, scores indicating improved quality of life were associated with greater weight loss.

Finally, comorbidity resolution, estimated by the reduction in the use of medications taken to treat conditions related to obesity, was significantly associated with the obesity-specific measure, BQL, but not the overall quality of life measure, HALex.

“In conclusion, [patient-reported outcomes] are distinct from clinical outcomes,” investigators wrote. Patient-reported outcomes “provide an opportunity for improved population-based cost-effectiveness analyses using outcomes germane to procedures performed for symptomatology and improving QOL,” they added.

The Agency for Healthcare Research and Quality supported the research. The investigators reported having no disclosures.

jcraig@frontlinemedcom.com

On Twitter @jessnicolecraig

Clinical outcomes of surgery and patient-reported outcomes of function, disability, and health status are two different measures of surgical success.

A large study of patients who had bariatric surgery showed that patient-reported outcomes were correlated with long-term weight loss but not with short-term complication rates. In addition, obesity-specific patient-reported quality of life scores were associated with a reduction in medications required for the treatment of obesity-related conditions.

“Clinical outcomes, such as perioperative morbidity and mortality, are commonly used to benchmark hospital performance,” reported Jennifer F. Waljee, MD, and her associates at the University of Michigan, Ann Arbor (Ann Surg. 2016. doi: 10.1097/SLA.0000000000001852).

“However, for many surgical procedures, such as bariatric surgery ... complications may be rare, and may not entirely reflect treatment effectiveness. Alternatively, patient-reported measures of function, disability, and health status may offer a unique and more reliable assessment of provider quality and performance,” she explained. Yet despite growing interest in using patient-reported measures, many important questions regarding their accuracy, applicability, and clinical utility remain. The purpose of this study was, therefore, to evaluate how patient-reported quality of life measures compared to short-term and long-term clinical outcomes in patients who underwent bariatric surgery.

 

©Vasilis Varsakelis/fotolia.com

The majority of the study’s 11,420 participants were female (79.8%), were white (84.1%), and underwent Roux-en-Y laparoscopic gastric bypass (56.8%). For each study participant, both short-term and long-term clinical outcome measures were obtained from medical board review. Short-term clinical outcomes were defined as the rate of perioperative complications within 30 days of bariatric surgery. Percent excess weight loss at 1 year post surgery was used as a long-term clinical outcome.

In addition, two patient-reported outcomes were collected: an overall health-related quality of life score called the Health and Activities Limitations Index (HALex) and an obesity-specific quality of life score, the Bariatric Quality of Life (BQL) index, which measures well-being, social and physical functioning, and obesity-related symptoms.

Multivariate and linear regression models demonstrated that short-term complication rates were not correlated to the overall patient-reported quality of life score (P = .32) or to the obesity-specific BQL score (P = .74).

However, the long-term measure of excess weight loss at 1 year post surgery was significantly associated with both overall and obesity-specific patient-reported measures of health-related quality of life (P less than .002 and P less than .001 respectively).

Moreover, scores indicating improved quality of life were associated with greater weight loss.

Finally, comorbidity resolution, estimated by the reduction in the use of medications taken to treat conditions related to obesity, was significantly associated with the obesity-specific measure, BQL, but not the overall quality of life measure, HALex.

“In conclusion, [patient-reported outcomes] are distinct from clinical outcomes,” investigators wrote. Patient-reported outcomes “provide an opportunity for improved population-based cost-effectiveness analyses using outcomes germane to procedures performed for symptomatology and improving QOL,” they added.

The Agency for Healthcare Research and Quality supported the research. The investigators reported having no disclosures.

jcraig@frontlinemedcom.com

On Twitter @jessnicolecraig

Clinical outcomes of surgery and patient-reported outcomes of function, disability, and health status are two different measures of surgical success.

A large study of patients who had bariatric surgery showed that patient-reported outcomes were correlated with long-term weight loss but not with short-term complication rates. In addition, obesity-specific patient-reported quality of life scores were associated with a reduction in medications required for the treatment of obesity-related conditions.

“Clinical outcomes, such as perioperative morbidity and mortality, are commonly used to benchmark hospital performance,” reported Jennifer F. Waljee, MD, and her associates at the University of Michigan, Ann Arbor (Ann Surg. 2016. doi: 10.1097/SLA.0000000000001852).

“However, for many surgical procedures, such as bariatric surgery ... complications may be rare, and may not entirely reflect treatment effectiveness. Alternatively, patient-reported measures of function, disability, and health status may offer a unique and more reliable assessment of provider quality and performance,” she explained. Yet despite growing interest in using patient-reported measures, many important questions regarding their accuracy, applicability, and clinical utility remain. The purpose of this study was, therefore, to evaluate how patient-reported quality of life measures compared to short-term and long-term clinical outcomes in patients who underwent bariatric surgery.

 

©Vasilis Varsakelis/fotolia.com

The majority of the study’s 11,420 participants were female (79.8%), were white (84.1%), and underwent Roux-en-Y laparoscopic gastric bypass (56.8%). For each study participant, both short-term and long-term clinical outcome measures were obtained from medical board review. Short-term clinical outcomes were defined as the rate of perioperative complications within 30 days of bariatric surgery. Percent excess weight loss at 1 year post surgery was used as a long-term clinical outcome.

In addition, two patient-reported outcomes were collected: an overall health-related quality of life score called the Health and Activities Limitations Index (HALex) and an obesity-specific quality of life score, the Bariatric Quality of Life (BQL) index, which measures well-being, social and physical functioning, and obesity-related symptoms.

Multivariate and linear regression models demonstrated that short-term complication rates were not correlated to the overall patient-reported quality of life score (P = .32) or to the obesity-specific BQL score (P = .74).

However, the long-term measure of excess weight loss at 1 year post surgery was significantly associated with both overall and obesity-specific patient-reported measures of health-related quality of life (P less than .002 and P less than .001 respectively).

Moreover, scores indicating improved quality of life were associated with greater weight loss.

Finally, comorbidity resolution, estimated by the reduction in the use of medications taken to treat conditions related to obesity, was significantly associated with the obesity-specific measure, BQL, but not the overall quality of life measure, HALex.

“In conclusion, [patient-reported outcomes] are distinct from clinical outcomes,” investigators wrote. Patient-reported outcomes “provide an opportunity for improved population-based cost-effectiveness analyses using outcomes germane to procedures performed for symptomatology and improving QOL,” they added.

The Agency for Healthcare Research and Quality supported the research. The investigators reported having no disclosures.

jcraig@frontlinemedcom.com

On Twitter @jessnicolecraig

The search is on for clinical trial participants to help verify whether two genetically based vaccines that lowered Zika virus viremia in infected primates will be effective in humans.

Although much is still unknown about the pathogenesis, immunity, and transmission of the flavivirus, its devastating effects mean developing a vaccine is imperative, wrote Kimberly A. Dowd, PhD, a virologist at the National Institute of Allergy and Infectious Diseases, and her colleagues in a paper published online in Science.

©Aunt_Spray/Thinkstock

According to Dr. Dowd and her coauthors, the quickest path to a Zika vaccine is to start with what is already known about flaviviruses and to avoid unnecessary bureaucracy.

“Advantages of DNA vaccines include the ability to rapidly test multiple candidate antigen designs, rapidly produce GMP material, and established safety profile in humans, and a relatively straightforward regulatory pathway into clinical evaluation,” Dr. Dowd and her colleagues wrote. The study details the results of two Zika vaccine candidates tested in primates. The clinical trial will now test these vaccines’ efficacy in humans (Science. 2016 Sept 22. doi: 10.1126/science.aai3197).

Starting with insights gained from DNA-based testing for a West Nile virus vaccine that showed vaccine-elicited neutralizing antibodies are associated with protection from flavivirus-mediated disease, and data showing that a single vaccine antigen will protect against all strains of Zika virus, Dr. Dowd and her coinvestigators developed two DNA-based vaccines that successfully bound to Zika subviral particles in infected mice. Then they tested the vaccines in rhesus macaques.

Six animals were injected with either 1 mg of VRC5283 at 0 and 4 weeks. Another six were injected with 4 mg of either VRC5283 or VRC5288 at 0 or 4 weeks. Another six were injected with a single 1-mg dose of VRC5288 at week 0. After the initial DNA dose, all animals were found to have detectable binding and neutralizing antibody activity, peaking at week 3. Compared with controls given the CMV-immediate early-promoter–containing vector VRC8400, all study animals had a significantly higher neutralizing antibody response (P = .022). The group given the single dose of VRC5288 had significantly lower neutralizing antibody titers, compared with macaques given two doses of either vaccine (P = .022).

Across the groups given two doses of either vaccine, there were no significant differences between titer levels, suggesting that both vaccine candidates elicit substantial Zika virus–specific neutralizing antibodies in primates. More to the point was that 8 weeks after immunization, when all animals in the study were challenged subcutaneously with the virus, viremia levels in the 18 total macaques given two doses of either amount and of either vaccine were undetectable in all but 1. Compared with controls, that had peak viral loads on day 3 or 4, the six animals given one dose of 1 mg VRC5288 were viremic on day 3, but at a significantly reduced rate (P = .041).

Taking into account one animal in the VRC5288 two-dose 4-mg group that had viral load blips above background on days 3 and 7, as well as the lowest titer levels of all the test animals, the investigators determined that 70% protection from Zika virus viremia would be possible if certain titer levels could be achieved.

Whether waning or incomplete immunity could lead to enhanced flavivirus disease is a concern when developing correct vaccination dosage, the investigators said. However, despite some breakthrough infection in the group given the single 1 mg dose of VRC5288, the animals’ illness remained subclinical, there were no signs of replication, and their viremia levels were lower than in unvaccinated controls.

Now, all eyes are on how the vaccines compare with one another while researchers try to establish an adequate serologic correlate of sterilizing immunity in humans. According to Dr. Dowd and her colleagues, the phase I trial is being designed in parallel with other trials looking into a purified, protein-based whole-inactivated Zika virus vaccine, as well as other antigens, delivery methods, and combination vaccines.

The multipronged approach improves the likelihood that enough immunogenicity data can be gathered and translated into a successful intervention for the women of child-bearing age most affected by the Zika virus, and the general population at large, Dr. Dowd and her colleagues concluded.

The research was supported by intramural funding from the National Institute of Allergy and Infectious Diseases; start-up funding from the department of diagnostic medicine and pathobiology, College of Veterinary Medicine, Kansas State University; and federal funds from the Frederick National Laboratory for Cancer Research, NIH. One of the coauthors also reported funding from Leidos Biomedical Research.

 

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

The search is on for clinical trial participants to help verify whether two genetically based vaccines that lowered Zika virus viremia in infected primates will be effective in humans.

Although much is still unknown about the pathogenesis, immunity, and transmission of the flavivirus, its devastating effects mean developing a vaccine is imperative, wrote Kimberly A. Dowd, PhD, a virologist at the National Institute of Allergy and Infectious Diseases, and her colleagues in a paper published online in Science.

©Aunt_Spray/Thinkstock

According to Dr. Dowd and her coauthors, the quickest path to a Zika vaccine is to start with what is already known about flaviviruses and to avoid unnecessary bureaucracy.

“Advantages of DNA vaccines include the ability to rapidly test multiple candidate antigen designs, rapidly produce GMP material, and established safety profile in humans, and a relatively straightforward regulatory pathway into clinical evaluation,” Dr. Dowd and her colleagues wrote. The study details the results of two Zika vaccine candidates tested in primates. The clinical trial will now test these vaccines’ efficacy in humans (Science. 2016 Sept 22. doi: 10.1126/science.aai3197).

Starting with insights gained from DNA-based testing for a West Nile virus vaccine that showed vaccine-elicited neutralizing antibodies are associated with protection from flavivirus-mediated disease, and data showing that a single vaccine antigen will protect against all strains of Zika virus, Dr. Dowd and her coinvestigators developed two DNA-based vaccines that successfully bound to Zika subviral particles in infected mice. Then they tested the vaccines in rhesus macaques.

Six animals were injected with either 1 mg of VRC5283 at 0 and 4 weeks. Another six were injected with 4 mg of either VRC5283 or VRC5288 at 0 or 4 weeks. Another six were injected with a single 1-mg dose of VRC5288 at week 0. After the initial DNA dose, all animals were found to have detectable binding and neutralizing antibody activity, peaking at week 3. Compared with controls given the CMV-immediate early-promoter–containing vector VRC8400, all study animals had a significantly higher neutralizing antibody response (P = .022). The group given the single dose of VRC5288 had significantly lower neutralizing antibody titers, compared with macaques given two doses of either vaccine (P = .022).

Across the groups given two doses of either vaccine, there were no significant differences between titer levels, suggesting that both vaccine candidates elicit substantial Zika virus–specific neutralizing antibodies in primates. More to the point was that 8 weeks after immunization, when all animals in the study were challenged subcutaneously with the virus, viremia levels in the 18 total macaques given two doses of either amount and of either vaccine were undetectable in all but 1. Compared with controls, that had peak viral loads on day 3 or 4, the six animals given one dose of 1 mg VRC5288 were viremic on day 3, but at a significantly reduced rate (P = .041).

Taking into account one animal in the VRC5288 two-dose 4-mg group that had viral load blips above background on days 3 and 7, as well as the lowest titer levels of all the test animals, the investigators determined that 70% protection from Zika virus viremia would be possible if certain titer levels could be achieved.

Whether waning or incomplete immunity could lead to enhanced flavivirus disease is a concern when developing correct vaccination dosage, the investigators said. However, despite some breakthrough infection in the group given the single 1 mg dose of VRC5288, the animals’ illness remained subclinical, there were no signs of replication, and their viremia levels were lower than in unvaccinated controls.

Now, all eyes are on how the vaccines compare with one another while researchers try to establish an adequate serologic correlate of sterilizing immunity in humans. According to Dr. Dowd and her colleagues, the phase I trial is being designed in parallel with other trials looking into a purified, protein-based whole-inactivated Zika virus vaccine, as well as other antigens, delivery methods, and combination vaccines.

The multipronged approach improves the likelihood that enough immunogenicity data can be gathered and translated into a successful intervention for the women of child-bearing age most affected by the Zika virus, and the general population at large, Dr. Dowd and her colleagues concluded.

The research was supported by intramural funding from the National Institute of Allergy and Infectious Diseases; start-up funding from the department of diagnostic medicine and pathobiology, College of Veterinary Medicine, Kansas State University; and federal funds from the Frederick National Laboratory for Cancer Research, NIH. One of the coauthors also reported funding from Leidos Biomedical Research.

 

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

The search is on for clinical trial participants to help verify whether two genetically based vaccines that lowered Zika virus viremia in infected primates will be effective in humans.

Although much is still unknown about the pathogenesis, immunity, and transmission of the flavivirus, its devastating effects mean developing a vaccine is imperative, wrote Kimberly A. Dowd, PhD, a virologist at the National Institute of Allergy and Infectious Diseases, and her colleagues in a paper published online in Science.

©Aunt_Spray/Thinkstock

According to Dr. Dowd and her coauthors, the quickest path to a Zika vaccine is to start with what is already known about flaviviruses and to avoid unnecessary bureaucracy.

“Advantages of DNA vaccines include the ability to rapidly test multiple candidate antigen designs, rapidly produce GMP material, and established safety profile in humans, and a relatively straightforward regulatory pathway into clinical evaluation,” Dr. Dowd and her colleagues wrote. The study details the results of two Zika vaccine candidates tested in primates. The clinical trial will now test these vaccines’ efficacy in humans (Science. 2016 Sept 22. doi: 10.1126/science.aai3197).

Starting with insights gained from DNA-based testing for a West Nile virus vaccine that showed vaccine-elicited neutralizing antibodies are associated with protection from flavivirus-mediated disease, and data showing that a single vaccine antigen will protect against all strains of Zika virus, Dr. Dowd and her coinvestigators developed two DNA-based vaccines that successfully bound to Zika subviral particles in infected mice. Then they tested the vaccines in rhesus macaques.

Six animals were injected with either 1 mg of VRC5283 at 0 and 4 weeks. Another six were injected with 4 mg of either VRC5283 or VRC5288 at 0 or 4 weeks. Another six were injected with a single 1-mg dose of VRC5288 at week 0. After the initial DNA dose, all animals were found to have detectable binding and neutralizing antibody activity, peaking at week 3. Compared with controls given the CMV-immediate early-promoter–containing vector VRC8400, all study animals had a significantly higher neutralizing antibody response (P = .022). The group given the single dose of VRC5288 had significantly lower neutralizing antibody titers, compared with macaques given two doses of either vaccine (P = .022).

Across the groups given two doses of either vaccine, there were no significant differences between titer levels, suggesting that both vaccine candidates elicit substantial Zika virus–specific neutralizing antibodies in primates. More to the point was that 8 weeks after immunization, when all animals in the study were challenged subcutaneously with the virus, viremia levels in the 18 total macaques given two doses of either amount and of either vaccine were undetectable in all but 1. Compared with controls, that had peak viral loads on day 3 or 4, the six animals given one dose of 1 mg VRC5288 were viremic on day 3, but at a significantly reduced rate (P = .041).

Taking into account one animal in the VRC5288 two-dose 4-mg group that had viral load blips above background on days 3 and 7, as well as the lowest titer levels of all the test animals, the investigators determined that 70% protection from Zika virus viremia would be possible if certain titer levels could be achieved.

Whether waning or incomplete immunity could lead to enhanced flavivirus disease is a concern when developing correct vaccination dosage, the investigators said. However, despite some breakthrough infection in the group given the single 1 mg dose of VRC5288, the animals’ illness remained subclinical, there were no signs of replication, and their viremia levels were lower than in unvaccinated controls.

Now, all eyes are on how the vaccines compare with one another while researchers try to establish an adequate serologic correlate of sterilizing immunity in humans. According to Dr. Dowd and her colleagues, the phase I trial is being designed in parallel with other trials looking into a purified, protein-based whole-inactivated Zika virus vaccine, as well as other antigens, delivery methods, and combination vaccines.

The multipronged approach improves the likelihood that enough immunogenicity data can be gathered and translated into a successful intervention for the women of child-bearing age most affected by the Zika virus, and the general population at large, Dr. Dowd and her colleagues concluded.

The research was supported by intramural funding from the National Institute of Allergy and Infectious Diseases; start-up funding from the department of diagnostic medicine and pathobiology, College of Veterinary Medicine, Kansas State University; and federal funds from the Frederick National Laboratory for Cancer Research, NIH. One of the coauthors also reported funding from Leidos Biomedical Research.

 

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight