BALTIMORE—Deep brain stimulation (DBS) of the subthalamic nucleus, along with optimal drug therapy (ODT), produces clinically meaningful improvements in clinician-assessed motor control for at least five years in patients with early-stage Parkinson’s disease, according to a prospective pilot study. If the findings are confirmed in a phase III trial that has been approved, DBS may become a valuable method to achieve long-term improvement in motor skills in patients with Parkinson’s disease.

Mallory Hacker, PhD, Research Assistant Professor of Neurology at Vanderbilt University in Nashville, presented the latest results of a subanalysis of a randomized, controlled, single-blind clinical trial at the 141st Annual Meeting of the American Neurological Association.

The pilot trial included 30 patients with Parkinson’s disease between ages 50 and 75 and demonstrated the safety and benefit of DBS in conjunction with ODT—which includes drugs such as carbidopa–levodopa, pramipexole, ropinirole, and selegiline—compared with ODT alone in improving motor scores of the patients through two years. The latest subanalysis of the trial data examined the effect of DBS for at least five years.

The subanalysis included 28 patients: 14 in the DBS and ODT group and 14 in the ODT-only group. Both groups were predominantly male and were similar in age (about 61) at baseline. Motor control was assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III (clinician assessed) and the Hoehn and Yahr scale.

Over the five-year period, mean UPDRS motor scores progressively worsened for the ODT group, but improved for patients who received DBS. Compared with patients who received ODT only, patients who received DBS plus ODT had UPDRS improvements of 4.6 points at 1.5 years, 5.8 points at two years, 8.9 points at four years, and 10.1 points at five years.

“These results demonstrate that subthalamic nucleus DBS applied in early-stage Parkinson’s disease may provide long-term, clinically meaningful improvement in motor function over standard clinical therapy,” Dr. Hacker said.

The exact mechanism of DBS is still unknown, but evidence suggests that synaptic plasticity is involved. Results from the pilot trial led to FDA approval of a large-scale, multicenter clinical trial. Participants will be implanted with a DBS device and will receive ODT. Some subjects will be randomized to receive DBS during the first two years, along with ODT, and the remainder will receive ODT only. In the following two years, all subjects will receive DBS and ODT.

—Brian Hoyle

BALTIMORE—Deep brain stimulation (DBS) of the subthalamic nucleus, along with optimal drug therapy (ODT), produces clinically meaningful improvements in clinician-assessed motor control for at least five years in patients with early-stage Parkinson’s disease, according to a prospective pilot study. If the findings are confirmed in a phase III trial that has been approved, DBS may become a valuable method to achieve long-term improvement in motor skills in patients with Parkinson’s disease.

Mallory Hacker, PhD, Research Assistant Professor of Neurology at Vanderbilt University in Nashville, presented the latest results of a subanalysis of a randomized, controlled, single-blind clinical trial at the 141st Annual Meeting of the American Neurological Association.

The pilot trial included 30 patients with Parkinson’s disease between ages 50 and 75 and demonstrated the safety and benefit of DBS in conjunction with ODT—which includes drugs such as carbidopa–levodopa, pramipexole, ropinirole, and selegiline—compared with ODT alone in improving motor scores of the patients through two years. The latest subanalysis of the trial data examined the effect of DBS for at least five years.

The subanalysis included 28 patients: 14 in the DBS and ODT group and 14 in the ODT-only group. Both groups were predominantly male and were similar in age (about 61) at baseline. Motor control was assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III (clinician assessed) and the Hoehn and Yahr scale.

Over the five-year period, mean UPDRS motor scores progressively worsened for the ODT group, but improved for patients who received DBS. Compared with patients who received ODT only, patients who received DBS plus ODT had UPDRS improvements of 4.6 points at 1.5 years, 5.8 points at two years, 8.9 points at four years, and 10.1 points at five years.

“These results demonstrate that subthalamic nucleus DBS applied in early-stage Parkinson’s disease may provide long-term, clinically meaningful improvement in motor function over standard clinical therapy,” Dr. Hacker said.

The exact mechanism of DBS is still unknown, but evidence suggests that synaptic plasticity is involved. Results from the pilot trial led to FDA approval of a large-scale, multicenter clinical trial. Participants will be implanted with a DBS device and will receive ODT. Some subjects will be randomized to receive DBS during the first two years, along with ODT, and the remainder will receive ODT only. In the following two years, all subjects will receive DBS and ODT.

—Brian Hoyle

BALTIMORE—Deep brain stimulation (DBS) of the subthalamic nucleus, along with optimal drug therapy (ODT), produces clinically meaningful improvements in clinician-assessed motor control for at least five years in patients with early-stage Parkinson’s disease, according to a prospective pilot study. If the findings are confirmed in a phase III trial that has been approved, DBS may become a valuable method to achieve long-term improvement in motor skills in patients with Parkinson’s disease.

Mallory Hacker, PhD, Research Assistant Professor of Neurology at Vanderbilt University in Nashville, presented the latest results of a subanalysis of a randomized, controlled, single-blind clinical trial at the 141st Annual Meeting of the American Neurological Association.

The pilot trial included 30 patients with Parkinson’s disease between ages 50 and 75 and demonstrated the safety and benefit of DBS in conjunction with ODT—which includes drugs such as carbidopa–levodopa, pramipexole, ropinirole, and selegiline—compared with ODT alone in improving motor scores of the patients through two years. The latest subanalysis of the trial data examined the effect of DBS for at least five years.

The subanalysis included 28 patients: 14 in the DBS and ODT group and 14 in the ODT-only group. Both groups were predominantly male and were similar in age (about 61) at baseline. Motor control was assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III (clinician assessed) and the Hoehn and Yahr scale.

Over the five-year period, mean UPDRS motor scores progressively worsened for the ODT group, but improved for patients who received DBS. Compared with patients who received ODT only, patients who received DBS plus ODT had UPDRS improvements of 4.6 points at 1.5 years, 5.8 points at two years, 8.9 points at four years, and 10.1 points at five years.

“These results demonstrate that subthalamic nucleus DBS applied in early-stage Parkinson’s disease may provide long-term, clinically meaningful improvement in motor function over standard clinical therapy,” Dr. Hacker said.

The exact mechanism of DBS is still unknown, but evidence suggests that synaptic plasticity is involved. Results from the pilot trial led to FDA approval of a large-scale, multicenter clinical trial. Participants will be implanted with a DBS device and will receive ODT. Some subjects will be randomized to receive DBS during the first two years, along with ODT, and the remainder will receive ODT only. In the following two years, all subjects will receive DBS and ODT.

—Brian Hoyle

The rare p.G411S mutation of PINK1 greatly increases the risk of early-onset Parkinson’s disease, even if present in only one allele, according to a genetic association study published online ahead of print November 2 in Brain. By reducing kinase activity towards ubiquitin, the mutation impairs the elimination of damaged mitochondria from cells.

Previous data had indicated that mutations in both PINK1 alleles confer a risk of early-onset Parkinson’s disease (age younger than 45). Genetic studies had suggested that a single mutated PINK1 allele also might increase the risk of developing the disease.

Wolfdieter Springer, PhD, Associate Professor of Neuroscience at Mayo Clinic in Jacksonville, Florida, and colleagues examined DNA samples from 2,560 patients with Parkinson’s disease and 2,145 controls from the United States, Poland, Norway, Ireland, and Sweden. Patients were included in the study irrespective of age at disease onset. The controls included the patients’ spouses and caregivers, as well as unrelated individuals. Dr. Springer and colleagues also searched the literature for previous studies that identified or excluded PINK1 p.G411S mutations in cases of Parkinson’s disease and controls.

The investigators found PINK1 p.G411S substitution in 19 cases (0.74%) and five control subjects (0.23%), indicating a significant association with an intermediate effect size between heterozygous PINK1 p.G411S carrier status and Parkinson’s disease (odds ratio [OR], 2.92). The median age at disease onset was significantly lower in the 19 cases carrying PINK1 p.G411S than in noncarrier cases (59 vs 64). When the researchers combined their data with those of six studies that they had identified in the literature review, the increased risk of Parkinson’s disease associated with the p.G411S mutation remained evident (OR, 2.89).

Levels of PINK1 protein, which helps selectively eliminate damaged mitochondria from cells, were similar in p.G411S heterozygous cells and in wild-type controls. Levels of p-Ser65-Ub, a marker of mitochondrial stress, were persistently lower, however, and were significantly reduced at later time points. In a HeLa cell model, the researchers observed that p.G411S overexpressing cells had reduced p-Ser65-Ub levels, compared with PINK1 wild-type cells. Furthermore, p.G411S showed strongly reduced kinase activity towards ubiquitin, compared with PINK1 wild-type. Coexpression of p.G411S along with PINK1 wild-type significantly impaired ubiquitin phosphorylation.

“Genetic analyses, as well as functional, cell-based and structural, computational characterization, for the first time provided evidence for a partial dominant-negative function of the heterozygous PINK1 p.G411S mutation that confers a markedly increased risk for Parkinson’s disease,” said Dr. Springer. “The low frequency of homozygote p.G411S carriers may be due to the rarity of the mutation or could indicate [that] it is particularly damaging or clinically manifests with an alternate phenotypic presentation. Replication of our genetic association in other case–control series and further clinical studies is now warranted.”

—Erik Greb

Suggested Reading

Puschmann A, Fiesel FC, Caulfield TR, et al. Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism. Brain. 2016 Nov 2 [Epub ahead of print].

The rare p.G411S mutation of PINK1 greatly increases the risk of early-onset Parkinson’s disease, even if present in only one allele, according to a genetic association study published online ahead of print November 2 in Brain. By reducing kinase activity towards ubiquitin, the mutation impairs the elimination of damaged mitochondria from cells.

Previous data had indicated that mutations in both PINK1 alleles confer a risk of early-onset Parkinson’s disease (age younger than 45). Genetic studies had suggested that a single mutated PINK1 allele also might increase the risk of developing the disease.

Wolfdieter Springer, PhD, Associate Professor of Neuroscience at Mayo Clinic in Jacksonville, Florida, and colleagues examined DNA samples from 2,560 patients with Parkinson’s disease and 2,145 controls from the United States, Poland, Norway, Ireland, and Sweden. Patients were included in the study irrespective of age at disease onset. The controls included the patients’ spouses and caregivers, as well as unrelated individuals. Dr. Springer and colleagues also searched the literature for previous studies that identified or excluded PINK1 p.G411S mutations in cases of Parkinson’s disease and controls.

The investigators found PINK1 p.G411S substitution in 19 cases (0.74%) and five control subjects (0.23%), indicating a significant association with an intermediate effect size between heterozygous PINK1 p.G411S carrier status and Parkinson’s disease (odds ratio [OR], 2.92). The median age at disease onset was significantly lower in the 19 cases carrying PINK1 p.G411S than in noncarrier cases (59 vs 64). When the researchers combined their data with those of six studies that they had identified in the literature review, the increased risk of Parkinson’s disease associated with the p.G411S mutation remained evident (OR, 2.89).

Levels of PINK1 protein, which helps selectively eliminate damaged mitochondria from cells, were similar in p.G411S heterozygous cells and in wild-type controls. Levels of p-Ser65-Ub, a marker of mitochondrial stress, were persistently lower, however, and were significantly reduced at later time points. In a HeLa cell model, the researchers observed that p.G411S overexpressing cells had reduced p-Ser65-Ub levels, compared with PINK1 wild-type cells. Furthermore, p.G411S showed strongly reduced kinase activity towards ubiquitin, compared with PINK1 wild-type. Coexpression of p.G411S along with PINK1 wild-type significantly impaired ubiquitin phosphorylation.

“Genetic analyses, as well as functional, cell-based and structural, computational characterization, for the first time provided evidence for a partial dominant-negative function of the heterozygous PINK1 p.G411S mutation that confers a markedly increased risk for Parkinson’s disease,” said Dr. Springer. “The low frequency of homozygote p.G411S carriers may be due to the rarity of the mutation or could indicate [that] it is particularly damaging or clinically manifests with an alternate phenotypic presentation. Replication of our genetic association in other case–control series and further clinical studies is now warranted.”

—Erik Greb

Suggested Reading

Puschmann A, Fiesel FC, Caulfield TR, et al. Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism. Brain. 2016 Nov 2 [Epub ahead of print].

The rare p.G411S mutation of PINK1 greatly increases the risk of early-onset Parkinson’s disease, even if present in only one allele, according to a genetic association study published online ahead of print November 2 in Brain. By reducing kinase activity towards ubiquitin, the mutation impairs the elimination of damaged mitochondria from cells.

Previous data had indicated that mutations in both PINK1 alleles confer a risk of early-onset Parkinson’s disease (age younger than 45). Genetic studies had suggested that a single mutated PINK1 allele also might increase the risk of developing the disease.

Wolfdieter Springer, PhD, Associate Professor of Neuroscience at Mayo Clinic in Jacksonville, Florida, and colleagues examined DNA samples from 2,560 patients with Parkinson’s disease and 2,145 controls from the United States, Poland, Norway, Ireland, and Sweden. Patients were included in the study irrespective of age at disease onset. The controls included the patients’ spouses and caregivers, as well as unrelated individuals. Dr. Springer and colleagues also searched the literature for previous studies that identified or excluded PINK1 p.G411S mutations in cases of Parkinson’s disease and controls.

The investigators found PINK1 p.G411S substitution in 19 cases (0.74%) and five control subjects (0.23%), indicating a significant association with an intermediate effect size between heterozygous PINK1 p.G411S carrier status and Parkinson’s disease (odds ratio [OR], 2.92). The median age at disease onset was significantly lower in the 19 cases carrying PINK1 p.G411S than in noncarrier cases (59 vs 64). When the researchers combined their data with those of six studies that they had identified in the literature review, the increased risk of Parkinson’s disease associated with the p.G411S mutation remained evident (OR, 2.89).

Levels of PINK1 protein, which helps selectively eliminate damaged mitochondria from cells, were similar in p.G411S heterozygous cells and in wild-type controls. Levels of p-Ser65-Ub, a marker of mitochondrial stress, were persistently lower, however, and were significantly reduced at later time points. In a HeLa cell model, the researchers observed that p.G411S overexpressing cells had reduced p-Ser65-Ub levels, compared with PINK1 wild-type cells. Furthermore, p.G411S showed strongly reduced kinase activity towards ubiquitin, compared with PINK1 wild-type. Coexpression of p.G411S along with PINK1 wild-type significantly impaired ubiquitin phosphorylation.

“Genetic analyses, as well as functional, cell-based and structural, computational characterization, for the first time provided evidence for a partial dominant-negative function of the heterozygous PINK1 p.G411S mutation that confers a markedly increased risk for Parkinson’s disease,” said Dr. Springer. “The low frequency of homozygote p.G411S carriers may be due to the rarity of the mutation or could indicate [that] it is particularly damaging or clinically manifests with an alternate phenotypic presentation. Replication of our genetic association in other case–control series and further clinical studies is now warranted.”

—Erik Greb

Suggested Reading

Puschmann A, Fiesel FC, Caulfield TR, et al. Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism. Brain. 2016 Nov 2 [Epub ahead of print].

NEW ORLEANS – Treatment with autologous bone marrow cells can avert amputation in selected patients who have critical limb ischemia and are not candidates for revascularization surgery, based on results from the randomized phase III MOBILE trial.

Critical limb ischemia, the end stage of peripheral arterial disease, accounts for more than 53,000 major limb amputations in the United States annually, noted principal investigator Dr. Michael P. Murphy, director of the Vascular and Cardiac Center for Adult Stem Cell Therapy at Indiana University, Indianapolis.

In the trial, investigators randomized 155 affected limbs (in 152 patients) 3:1 to receive double-blinded treatment with injections of concentrated autologous bone marrow aspirate or placebo.

Amputation-free survival 1 year after treatment, the trial’s primary endpoint, was not significantly better in the aspirate group than in the placebo group, according to the researchers. However, the aspirate reduced the risk of major amputation by 73% in the subgroup with less severe (Rutherford class 4) disease and by 67% in the subgroup of patients who did not have diabetes.

“Personally, I would recommend cell therapy for my Rutherford 4 patients and my nondiabetic Rutherford 5 patients,” Dr. Murphy said. “And one would say even for the Rutherford 5 diabetics, there were no safety concerns and there is hope for improvement rather than amputation – it might be worth the roll of the dice.”

The investigators are preparing a manuscript based on the full data and working with Biomet, the trial sponsor, to apply for Food and Drug Administration approval of the product for the treatment of critical limb ischemia, he said.

Lessons learned

A session attendee asked whether stronger demonstration of benefit in a larger trial is needed to justify the use and cost of such new cellular therapies.

“If we could go back and do it all over again, we would do things differently knowing what we know now,” Dr. Murphy replied, noting that the investigators had to stick to a trial design created more than a decade ago.

“We discovered that the event rate in patients with critical limb ischemia in the control group is actually 30% and not 40% because medical management has changed,” he said. “Secondly, we would do a 1:1 randomization and most likely would increase our sample size to 200, and we probably would have seen a difference overall. That difference overall would have been provided by, of course, increasing the Rutherford 4 and Rutherford 5 nondiabetics, which would overshadow the increased amputation rate in the diabetic group.”

“I think from this [experience], we can launch a much larger study, if there were funding for it, and look at autologous versus allogeneic cells in this domain,” Dr. Murphy concluded.
 

Identifying patients who benefit

Session panelist Roberto Bolli, MD, chief of the division of cardiovascular medicine at the University of Louisville (Ky.), commended the MOBILE trial for its study design and prespecified subgroup analyses.

“The whole problem we are coping with, not just in this trial, but in other studies, is that patients are different and some patients may respond better than others, or some patients may not respond at all. And really, we still don’t understand why some patients respond or not – it may have to do with their immune system, their regenerative capacity, as well as the type of cells that are being used,” he said.

“Even though it was in its entirety a negative study, it’s very important because it identified a possible target for future trials, which is patients without diabetes in Rutherford class 4, which may benefit from therapy,” Dr. Bolli concluded.
 

Trial details

Patients were enrolled in MOBILE from 24 U.S. centers. All had critical limb ischemia, were ineligible for revascularization, had an ankle-brachial index of less than 0.60 or a toe-brachial index of less than 0.40, and had Rutherford 4 disease (rest pain) or Rutherford 5 disease (tissue loss).

They received concentrated autologous bone marrow aspirate or placebo by intramuscular injection at 35-40 sites in the affected limb.

Results showed that the groups did not differ significantly with respect to the rates of adverse events or serious adverse events overall, Dr. Murphy reported. The aspirate group had lower rates of respiratory failure and fever; they also had a higher rate of anemia (68.9% vs. 36.1%, P less than .001) as expected, from the aspiration procedure, but with no associated complications.

The 1-year rate of amputation-free survival events, reflecting both major amputations and death, was lower with the aspirate, at 20.2%, than with placebo, at 30.5%, but not significantly so (P = .224). Findings were similar for major amputation in the entire trial population (16.0% vs. 22.2%, P = .392). However, this outcome was less common with the aspirate among patients with Rutherford 4 disease (7.7% vs. 26.3%, P = .041) and nondiabetic patients (10.0% vs. 27.7%, P = .046).

“Looking at these data, it became apparent to us that the Rutherford 5 diabetic was the outlying group,” said Dr. Murphy, who disclosed that he had no relevant conflicts of interest.

Considering all other patients – Rutherford 4 regardless of diabetes status and nondiabetic Rutherford 5 – the aspirate was associated with a dramatically lower rate of amputation compared with the placebo (9.6% vs. 26.7%, P = .021; hazard ratio, 0.33). In this subset, the number needed to treat with bone marrow aspirate to prevent a single amputation was just 6.

The aspirate and placebo groups did not differ with respect to ankle-brachial index, toe-brachial index, or 6-minute walk test distance in the entire trial population. Transcutaneous oxygen pressure (TcP02), an indicator of microvascular perfusion in the subcutaneous tissue of the ischemic limb, increased by 59% in the aspirate group but by only 7% in the placebo group.

NEW ORLEANS – Treatment with autologous bone marrow cells can avert amputation in selected patients who have critical limb ischemia and are not candidates for revascularization surgery, based on results from the randomized phase III MOBILE trial.

Critical limb ischemia, the end stage of peripheral arterial disease, accounts for more than 53,000 major limb amputations in the United States annually, noted principal investigator Dr. Michael P. Murphy, director of the Vascular and Cardiac Center for Adult Stem Cell Therapy at Indiana University, Indianapolis.

In the trial, investigators randomized 155 affected limbs (in 152 patients) 3:1 to receive double-blinded treatment with injections of concentrated autologous bone marrow aspirate or placebo.

Amputation-free survival 1 year after treatment, the trial’s primary endpoint, was not significantly better in the aspirate group than in the placebo group, according to the researchers. However, the aspirate reduced the risk of major amputation by 73% in the subgroup with less severe (Rutherford class 4) disease and by 67% in the subgroup of patients who did not have diabetes.

“Personally, I would recommend cell therapy for my Rutherford 4 patients and my nondiabetic Rutherford 5 patients,” Dr. Murphy said. “And one would say even for the Rutherford 5 diabetics, there were no safety concerns and there is hope for improvement rather than amputation – it might be worth the roll of the dice.”

The investigators are preparing a manuscript based on the full data and working with Biomet, the trial sponsor, to apply for Food and Drug Administration approval of the product for the treatment of critical limb ischemia, he said.

Lessons learned

A session attendee asked whether stronger demonstration of benefit in a larger trial is needed to justify the use and cost of such new cellular therapies.

“If we could go back and do it all over again, we would do things differently knowing what we know now,” Dr. Murphy replied, noting that the investigators had to stick to a trial design created more than a decade ago.

“We discovered that the event rate in patients with critical limb ischemia in the control group is actually 30% and not 40% because medical management has changed,” he said. “Secondly, we would do a 1:1 randomization and most likely would increase our sample size to 200, and we probably would have seen a difference overall. That difference overall would have been provided by, of course, increasing the Rutherford 4 and Rutherford 5 nondiabetics, which would overshadow the increased amputation rate in the diabetic group.”

“I think from this [experience], we can launch a much larger study, if there were funding for it, and look at autologous versus allogeneic cells in this domain,” Dr. Murphy concluded.
 

Identifying patients who benefit

Session panelist Roberto Bolli, MD, chief of the division of cardiovascular medicine at the University of Louisville (Ky.), commended the MOBILE trial for its study design and prespecified subgroup analyses.

“The whole problem we are coping with, not just in this trial, but in other studies, is that patients are different and some patients may respond better than others, or some patients may not respond at all. And really, we still don’t understand why some patients respond or not – it may have to do with their immune system, their regenerative capacity, as well as the type of cells that are being used,” he said.

“Even though it was in its entirety a negative study, it’s very important because it identified a possible target for future trials, which is patients without diabetes in Rutherford class 4, which may benefit from therapy,” Dr. Bolli concluded.
 

Trial details

Patients were enrolled in MOBILE from 24 U.S. centers. All had critical limb ischemia, were ineligible for revascularization, had an ankle-brachial index of less than 0.60 or a toe-brachial index of less than 0.40, and had Rutherford 4 disease (rest pain) or Rutherford 5 disease (tissue loss).

They received concentrated autologous bone marrow aspirate or placebo by intramuscular injection at 35-40 sites in the affected limb.

Results showed that the groups did not differ significantly with respect to the rates of adverse events or serious adverse events overall, Dr. Murphy reported. The aspirate group had lower rates of respiratory failure and fever; they also had a higher rate of anemia (68.9% vs. 36.1%, P less than .001) as expected, from the aspiration procedure, but with no associated complications.

The 1-year rate of amputation-free survival events, reflecting both major amputations and death, was lower with the aspirate, at 20.2%, than with placebo, at 30.5%, but not significantly so (P = .224). Findings were similar for major amputation in the entire trial population (16.0% vs. 22.2%, P = .392). However, this outcome was less common with the aspirate among patients with Rutherford 4 disease (7.7% vs. 26.3%, P = .041) and nondiabetic patients (10.0% vs. 27.7%, P = .046).

“Looking at these data, it became apparent to us that the Rutherford 5 diabetic was the outlying group,” said Dr. Murphy, who disclosed that he had no relevant conflicts of interest.

Considering all other patients – Rutherford 4 regardless of diabetes status and nondiabetic Rutherford 5 – the aspirate was associated with a dramatically lower rate of amputation compared with the placebo (9.6% vs. 26.7%, P = .021; hazard ratio, 0.33). In this subset, the number needed to treat with bone marrow aspirate to prevent a single amputation was just 6.

The aspirate and placebo groups did not differ with respect to ankle-brachial index, toe-brachial index, or 6-minute walk test distance in the entire trial population. Transcutaneous oxygen pressure (TcP02), an indicator of microvascular perfusion in the subcutaneous tissue of the ischemic limb, increased by 59% in the aspirate group but by only 7% in the placebo group.

NEW ORLEANS – Treatment with autologous bone marrow cells can avert amputation in selected patients who have critical limb ischemia and are not candidates for revascularization surgery, based on results from the randomized phase III MOBILE trial.

Critical limb ischemia, the end stage of peripheral arterial disease, accounts for more than 53,000 major limb amputations in the United States annually, noted principal investigator Dr. Michael P. Murphy, director of the Vascular and Cardiac Center for Adult Stem Cell Therapy at Indiana University, Indianapolis.

In the trial, investigators randomized 155 affected limbs (in 152 patients) 3:1 to receive double-blinded treatment with injections of concentrated autologous bone marrow aspirate or placebo.

Amputation-free survival 1 year after treatment, the trial’s primary endpoint, was not significantly better in the aspirate group than in the placebo group, according to the researchers. However, the aspirate reduced the risk of major amputation by 73% in the subgroup with less severe (Rutherford class 4) disease and by 67% in the subgroup of patients who did not have diabetes.

“Personally, I would recommend cell therapy for my Rutherford 4 patients and my nondiabetic Rutherford 5 patients,” Dr. Murphy said. “And one would say even for the Rutherford 5 diabetics, there were no safety concerns and there is hope for improvement rather than amputation – it might be worth the roll of the dice.”

The investigators are preparing a manuscript based on the full data and working with Biomet, the trial sponsor, to apply for Food and Drug Administration approval of the product for the treatment of critical limb ischemia, he said.

Lessons learned

A session attendee asked whether stronger demonstration of benefit in a larger trial is needed to justify the use and cost of such new cellular therapies.

“If we could go back and do it all over again, we would do things differently knowing what we know now,” Dr. Murphy replied, noting that the investigators had to stick to a trial design created more than a decade ago.

“We discovered that the event rate in patients with critical limb ischemia in the control group is actually 30% and not 40% because medical management has changed,” he said. “Secondly, we would do a 1:1 randomization and most likely would increase our sample size to 200, and we probably would have seen a difference overall. That difference overall would have been provided by, of course, increasing the Rutherford 4 and Rutherford 5 nondiabetics, which would overshadow the increased amputation rate in the diabetic group.”

“I think from this [experience], we can launch a much larger study, if there were funding for it, and look at autologous versus allogeneic cells in this domain,” Dr. Murphy concluded.
 

Identifying patients who benefit

Session panelist Roberto Bolli, MD, chief of the division of cardiovascular medicine at the University of Louisville (Ky.), commended the MOBILE trial for its study design and prespecified subgroup analyses.

“The whole problem we are coping with, not just in this trial, but in other studies, is that patients are different and some patients may respond better than others, or some patients may not respond at all. And really, we still don’t understand why some patients respond or not – it may have to do with their immune system, their regenerative capacity, as well as the type of cells that are being used,” he said.

“Even though it was in its entirety a negative study, it’s very important because it identified a possible target for future trials, which is patients without diabetes in Rutherford class 4, which may benefit from therapy,” Dr. Bolli concluded.
 

Trial details

Patients were enrolled in MOBILE from 24 U.S. centers. All had critical limb ischemia, were ineligible for revascularization, had an ankle-brachial index of less than 0.60 or a toe-brachial index of less than 0.40, and had Rutherford 4 disease (rest pain) or Rutherford 5 disease (tissue loss).

They received concentrated autologous bone marrow aspirate or placebo by intramuscular injection at 35-40 sites in the affected limb.

Results showed that the groups did not differ significantly with respect to the rates of adverse events or serious adverse events overall, Dr. Murphy reported. The aspirate group had lower rates of respiratory failure and fever; they also had a higher rate of anemia (68.9% vs. 36.1%, P less than .001) as expected, from the aspiration procedure, but with no associated complications.

The 1-year rate of amputation-free survival events, reflecting both major amputations and death, was lower with the aspirate, at 20.2%, than with placebo, at 30.5%, but not significantly so (P = .224). Findings were similar for major amputation in the entire trial population (16.0% vs. 22.2%, P = .392). However, this outcome was less common with the aspirate among patients with Rutherford 4 disease (7.7% vs. 26.3%, P = .041) and nondiabetic patients (10.0% vs. 27.7%, P = .046).

“Looking at these data, it became apparent to us that the Rutherford 5 diabetic was the outlying group,” said Dr. Murphy, who disclosed that he had no relevant conflicts of interest.

Considering all other patients – Rutherford 4 regardless of diabetes status and nondiabetic Rutherford 5 – the aspirate was associated with a dramatically lower rate of amputation compared with the placebo (9.6% vs. 26.7%, P = .021; hazard ratio, 0.33). In this subset, the number needed to treat with bone marrow aspirate to prevent a single amputation was just 6.

The aspirate and placebo groups did not differ with respect to ankle-brachial index, toe-brachial index, or 6-minute walk test distance in the entire trial population. Transcutaneous oxygen pressure (TcP02), an indicator of microvascular perfusion in the subcutaneous tissue of the ischemic limb, increased by 59% in the aspirate group but by only 7% in the placebo group.

NEW ORLEANS – HeartMate 3, the latest left ventricular assist device in the HeartMate line, appears to have solved the problem of pump thrombosis, a complication that has dogged ventricular pumps since the issue leapt into medical awareness about 3 years ago (New Engl J Med. 2014 Jan 2;370:33-40).

During 6 months of follow-up, none of 152 heart failure patients assigned to receive a HeartMate 3 left ventricular assist device (LVAD) developed suspected or confirmed pump thrombosis, compared with 14 patients (10%) having pump thrombosis out of 138 recipients of the prior-generation HeartMate II LVAD who served as the control group for the study.

Mitchel L. Zoler/Frontline Medical News

Mitchel L. Zoler/Frontline Medical News

NEW ORLEANS – HeartMate 3, the latest left ventricular assist device in the HeartMate line, appears to have solved the problem of pump thrombosis, a complication that has dogged ventricular pumps since the issue leapt into medical awareness about 3 years ago (New Engl J Med. 2014 Jan 2;370:33-40).

During 6 months of follow-up, none of 152 heart failure patients assigned to receive a HeartMate 3 left ventricular assist device (LVAD) developed suspected or confirmed pump thrombosis, compared with 14 patients (10%) having pump thrombosis out of 138 recipients of the prior-generation HeartMate II LVAD who served as the control group for the study.

Mitchel L. Zoler/Frontline Medical News

Mitchel L. Zoler/Frontline Medical News

NEW ORLEANS – HeartMate 3, the latest left ventricular assist device in the HeartMate line, appears to have solved the problem of pump thrombosis, a complication that has dogged ventricular pumps since the issue leapt into medical awareness about 3 years ago (New Engl J Med. 2014 Jan 2;370:33-40).

During 6 months of follow-up, none of 152 heart failure patients assigned to receive a HeartMate 3 left ventricular assist device (LVAD) developed suspected or confirmed pump thrombosis, compared with 14 patients (10%) having pump thrombosis out of 138 recipients of the prior-generation HeartMate II LVAD who served as the control group for the study.

Mitchel L. Zoler/Frontline Medical News

Mitchel L. Zoler/Frontline Medical News

Click here to download the PDF. 

Click here to download the PDF. 

Click here to download the PDF. 

BOSTON – As part of the push to create value-based care across the specialties, hepatologists should consider medical homes for their patients, such as those with cirrhosis, according to experts.

“Cirrhosis is a chronic condition, highly symptomatic, and occurs in highly comorbid individuals. Treating them in a medical home scenario means we can offer services that we don’t otherwise do, but which are associated with better outcomes for our patients,” Fasiha Kanwal, MD, of the department of medicine at Baylor College of Medicine, Houston, said in a panel presentation at the annual meeting of the American Association for the Study of Liver Diseases.

[email protected]

On Twitter @whitneymcknight

BOSTON – As part of the push to create value-based care across the specialties, hepatologists should consider medical homes for their patients, such as those with cirrhosis, according to experts.

“Cirrhosis is a chronic condition, highly symptomatic, and occurs in highly comorbid individuals. Treating them in a medical home scenario means we can offer services that we don’t otherwise do, but which are associated with better outcomes for our patients,” Fasiha Kanwal, MD, of the department of medicine at Baylor College of Medicine, Houston, said in a panel presentation at the annual meeting of the American Association for the Study of Liver Diseases.

[email protected]

On Twitter @whitneymcknight

BOSTON – As part of the push to create value-based care across the specialties, hepatologists should consider medical homes for their patients, such as those with cirrhosis, according to experts.

“Cirrhosis is a chronic condition, highly symptomatic, and occurs in highly comorbid individuals. Treating them in a medical home scenario means we can offer services that we don’t otherwise do, but which are associated with better outcomes for our patients,” Fasiha Kanwal, MD, of the department of medicine at Baylor College of Medicine, Houston, said in a panel presentation at the annual meeting of the American Association for the Study of Liver Diseases.

[email protected]

On Twitter @whitneymcknight

SAN FRANCISCO – Gifted children are far too commonly misunderstood, mislabeled, and misdiagnosed, leading to a mismatch between their needs and others’ perceptions of their needs, Dan Peters, PhD, a licensed psychologist and executive director of the Summit Center in the greater San Francisco and Los Angeles areas, explained at the annual meeting of the American Academy of Pediatrics.

Too often, one or more of these children’s health, developmental, social-emotional or learning needs are overlooked, or they receive an inappropriate mental health, developmental and/or learning disorder diagnosis. In fact, many of the risk factors for giftedness resemble those of other conditions: underachievement, difficulties with peers, social isolation, power struggles, perfectionism, anxiety, and depression.

Further, those who are culturally or linguistically diverse may not be recognized if a non-English first language obscures their performance ability or their socioeconomic status or lack of resources and enrichment opportunities leads them to be overlooked. It’s therefore important that practitioners understand what giftedness actually is and the characteristics gifted children might exhibit.

Understanding giftedness

A simple definition of giftedness is demonstrating a performance or the capacity for performance that significantly exceeds age or grade-level expectations, according to one school district’s gifted and talented education program.

A more involved description provided by the Columbus Group in 1991 defines giftedness as an “asynchronous development in which advanced cognitive abilities and heightened intensity combine to create inner experiences and awareness that are qualitatively different from the norm.” This asynchrony increases with higher intellectual capacity, they wrote. “The uniqueness of the gifted renders them vulnerable and requires modifications in parenting, teaching, and counseling in order for them to develop optimally.”

The level of a child’s giftedness makes a difference in their needs as well; these levels include advanced learners (IQ of 120-129), moderately gifted (130-144), highly gifted (145-159), exceptionally gifted (160-179), and profoundly gifted (180 and greater). Different spheres of giftedness can include intellectual ability, creative or productive thinking, leadership ability, and visual or performing arts. Consider the list of common characteristics of gifted children that Dr. Peters provided:

• Rapid learners.
• Strong memory.
• Large vocabulary.
• Advanced comprehension of nuances.
• Largely self-taught.
• Unusual emotional depth.
• Abstract/complex/logical/insightful thinking.
• Idealism and a sense of justice.
• Intense feelings and reactions.
• Highly sensitive.
• Long attention span and persistence.
• Preoccupied with own thoughts.
• Impatient with self and others’ inabilities and slowness.
• Asks probing questions (able to go beyond what is taught).
• Wide range of interests.
• Highly developed curiosity.
• Interest in experimenting and doing things differently.
• Divergent thinking.
• Keen and unusual sense of humor.

Dr. Peters cited Kazimierz Dabrowski, MD, PhD, a Polish psychiatrist of the mid-20th century, as explaining the sensitivity and intensity experienced by many gifted individuals in terms of overexcitabilities – a “greater capacity to be stimulated by and respond to external and internal stimuli.”

“Overexcitability permeates a gifted person’s existence and gives energy to their intelligence, talents, and personality,” Dr. Peters explained of Dabrowski’s ideas. This enhancement manifests in psychomotor terms as a strong drive, a lot of energy or movement, or extended bouts of activity. Intellectually, gifted children have an “insatiable curiosity, and voracious appetite and capacity for intellectual effort and stimulation,” Dr. Peters said. They may have heightened sensual experience in seeing, smelling, tasting, touching, or hearing, and they have an active imaginary and fantasy life. They also exhibit a capacity for great emotional depth and empathy – they deeply feel their own and others’ emotions.

How giftedness can be misdiagnosed

It is the combination of these very characteristics that can lead gifted children to receive an inappropriate mental or developmental diagnosis instead of being recognized as gifted.

“By current estimates, at any given time, approximately 11%-20% of children in the United States have a behavioral or emotional disorder as defined in the DSM-5,” Dr. Peters cited. Further, one study found that diagnoses of attention-deficit/hyperactivity disorder have increased 66% between 2000 and 2010, with 90% of those children taking psychostimulant medications – yet a study in the Journal of Health Economics estimated that one in five children diagnosed with ADHD are probably misdiagnosed and are receiving those medications.

Other incorrect diagnoses besides ADHD that gifted youth may commonly receive include anger diagnoses, ideational or anxiety disorders, developmental and personality disorders, mood disorders, and learning disorders.
 

Twice exceptionalism (2e)

Even more challenging are twice exceptional children, or 2e, those who are both gifted and have a learning or emotional disability or challenge. Common dual diagnoses in gifted children include anxiety disorders, depression (or existential depression), sleep disorders (such as nightmares, night terrors, or sleep walking), allergies, asthma, ADHD, oppositional-defiant disorder, obsessive-compulsive personality disorder, autism spectrum disorder, nonverbal learning disability, social/pragmatic communication disorder, and learning disorders such as dyslexia, dyscalculia, central auditory processing disorder, or sensory-motor integration disorder.

“It’s very complex. What happens is, a lot of people think you’re either gifted or not,” Dr. Peters said. “In the classroom, sometimes the advanced ability overshadows the weakness and so we get a lot of readers with an IQ of 130-150 and reading at the 50% percentile, and everyone says they’re fine, but they’re dyslexic.”

Other times, the weakness overshadows the strength, and sometimes they’re right in the middle where neither their giftedness nor their disability is recognized or addressed, Peters said. 2e children are very difficult to diagnose but also at higher risk for difficulties if one or both (or more) of their diagnoses are missed.

Maximizing gifted children’s developmental potential

Pediatricians have an opportunity to support gifted children by recognizing and accepting them for who they are, while also acknowledging that they want to feel “normal,” and therefore need extra reassurance and support from adults. Pediatricians should seek information about giftedness and 2e children from state and national gifted organizations, and, in the office, frame conversations with families and children’s differential diagnoses in terms of a child’s giftedness. If a pediatrician is themself gifted, they may be “a supportive and kindred spirit” to the child, Dr. Peters said.

In daily life, as well, gifted children need to be accepted for who they are, provided opportunities to be with their intellectual and academic peers, and provided challenges in their areas of strength, interests, or passions. Parents and teachers should follow their lead in learning: Keep up the pace for those who want to learn fast, and go deeper for those who want slower, more in-depth learning. Adults also need to understand their intensities and sensitivities and lead with their strengths in discussions.

Dr. Peters reported no disclosures.

SAN FRANCISCO – Gifted children are far too commonly misunderstood, mislabeled, and misdiagnosed, leading to a mismatch between their needs and others’ perceptions of their needs, Dan Peters, PhD, a licensed psychologist and executive director of the Summit Center in the greater San Francisco and Los Angeles areas, explained at the annual meeting of the American Academy of Pediatrics.

Too often, one or more of these children’s health, developmental, social-emotional or learning needs are overlooked, or they receive an inappropriate mental health, developmental and/or learning disorder diagnosis. In fact, many of the risk factors for giftedness resemble those of other conditions: underachievement, difficulties with peers, social isolation, power struggles, perfectionism, anxiety, and depression.

Further, those who are culturally or linguistically diverse may not be recognized if a non-English first language obscures their performance ability or their socioeconomic status or lack of resources and enrichment opportunities leads them to be overlooked. It’s therefore important that practitioners understand what giftedness actually is and the characteristics gifted children might exhibit.

Understanding giftedness

A simple definition of giftedness is demonstrating a performance or the capacity for performance that significantly exceeds age or grade-level expectations, according to one school district’s gifted and talented education program.

A more involved description provided by the Columbus Group in 1991 defines giftedness as an “asynchronous development in which advanced cognitive abilities and heightened intensity combine to create inner experiences and awareness that are qualitatively different from the norm.” This asynchrony increases with higher intellectual capacity, they wrote. “The uniqueness of the gifted renders them vulnerable and requires modifications in parenting, teaching, and counseling in order for them to develop optimally.”

The level of a child’s giftedness makes a difference in their needs as well; these levels include advanced learners (IQ of 120-129), moderately gifted (130-144), highly gifted (145-159), exceptionally gifted (160-179), and profoundly gifted (180 and greater). Different spheres of giftedness can include intellectual ability, creative or productive thinking, leadership ability, and visual or performing arts. Consider the list of common characteristics of gifted children that Dr. Peters provided:

• Rapid learners.
• Strong memory.
• Large vocabulary.
• Advanced comprehension of nuances.
• Largely self-taught.
• Unusual emotional depth.
• Abstract/complex/logical/insightful thinking.
• Idealism and a sense of justice.
• Intense feelings and reactions.
• Highly sensitive.
• Long attention span and persistence.
• Preoccupied with own thoughts.
• Impatient with self and others’ inabilities and slowness.
• Asks probing questions (able to go beyond what is taught).
• Wide range of interests.
• Highly developed curiosity.
• Interest in experimenting and doing things differently.
• Divergent thinking.
• Keen and unusual sense of humor.

Dr. Peters cited Kazimierz Dabrowski, MD, PhD, a Polish psychiatrist of the mid-20th century, as explaining the sensitivity and intensity experienced by many gifted individuals in terms of overexcitabilities – a “greater capacity to be stimulated by and respond to external and internal stimuli.”

“Overexcitability permeates a gifted person’s existence and gives energy to their intelligence, talents, and personality,” Dr. Peters explained of Dabrowski’s ideas. This enhancement manifests in psychomotor terms as a strong drive, a lot of energy or movement, or extended bouts of activity. Intellectually, gifted children have an “insatiable curiosity, and voracious appetite and capacity for intellectual effort and stimulation,” Dr. Peters said. They may have heightened sensual experience in seeing, smelling, tasting, touching, or hearing, and they have an active imaginary and fantasy life. They also exhibit a capacity for great emotional depth and empathy – they deeply feel their own and others’ emotions.

How giftedness can be misdiagnosed

It is the combination of these very characteristics that can lead gifted children to receive an inappropriate mental or developmental diagnosis instead of being recognized as gifted.

“By current estimates, at any given time, approximately 11%-20% of children in the United States have a behavioral or emotional disorder as defined in the DSM-5,” Dr. Peters cited. Further, one study found that diagnoses of attention-deficit/hyperactivity disorder have increased 66% between 2000 and 2010, with 90% of those children taking psychostimulant medications – yet a study in the Journal of Health Economics estimated that one in five children diagnosed with ADHD are probably misdiagnosed and are receiving those medications.

Other incorrect diagnoses besides ADHD that gifted youth may commonly receive include anger diagnoses, ideational or anxiety disorders, developmental and personality disorders, mood disorders, and learning disorders.
 

Twice exceptionalism (2e)

Even more challenging are twice exceptional children, or 2e, those who are both gifted and have a learning or emotional disability or challenge. Common dual diagnoses in gifted children include anxiety disorders, depression (or existential depression), sleep disorders (such as nightmares, night terrors, or sleep walking), allergies, asthma, ADHD, oppositional-defiant disorder, obsessive-compulsive personality disorder, autism spectrum disorder, nonverbal learning disability, social/pragmatic communication disorder, and learning disorders such as dyslexia, dyscalculia, central auditory processing disorder, or sensory-motor integration disorder.

“It’s very complex. What happens is, a lot of people think you’re either gifted or not,” Dr. Peters said. “In the classroom, sometimes the advanced ability overshadows the weakness and so we get a lot of readers with an IQ of 130-150 and reading at the 50% percentile, and everyone says they’re fine, but they’re dyslexic.”

Other times, the weakness overshadows the strength, and sometimes they’re right in the middle where neither their giftedness nor their disability is recognized or addressed, Peters said. 2e children are very difficult to diagnose but also at higher risk for difficulties if one or both (or more) of their diagnoses are missed.

Maximizing gifted children’s developmental potential

Pediatricians have an opportunity to support gifted children by recognizing and accepting them for who they are, while also acknowledging that they want to feel “normal,” and therefore need extra reassurance and support from adults. Pediatricians should seek information about giftedness and 2e children from state and national gifted organizations, and, in the office, frame conversations with families and children’s differential diagnoses in terms of a child’s giftedness. If a pediatrician is themself gifted, they may be “a supportive and kindred spirit” to the child, Dr. Peters said.

In daily life, as well, gifted children need to be accepted for who they are, provided opportunities to be with their intellectual and academic peers, and provided challenges in their areas of strength, interests, or passions. Parents and teachers should follow their lead in learning: Keep up the pace for those who want to learn fast, and go deeper for those who want slower, more in-depth learning. Adults also need to understand their intensities and sensitivities and lead with their strengths in discussions.

Dr. Peters reported no disclosures.

SAN FRANCISCO – Gifted children are far too commonly misunderstood, mislabeled, and misdiagnosed, leading to a mismatch between their needs and others’ perceptions of their needs, Dan Peters, PhD, a licensed psychologist and executive director of the Summit Center in the greater San Francisco and Los Angeles areas, explained at the annual meeting of the American Academy of Pediatrics.

Too often, one or more of these children’s health, developmental, social-emotional or learning needs are overlooked, or they receive an inappropriate mental health, developmental and/or learning disorder diagnosis. In fact, many of the risk factors for giftedness resemble those of other conditions: underachievement, difficulties with peers, social isolation, power struggles, perfectionism, anxiety, and depression.

Further, those who are culturally or linguistically diverse may not be recognized if a non-English first language obscures their performance ability or their socioeconomic status or lack of resources and enrichment opportunities leads them to be overlooked. It’s therefore important that practitioners understand what giftedness actually is and the characteristics gifted children might exhibit.

Understanding giftedness

A simple definition of giftedness is demonstrating a performance or the capacity for performance that significantly exceeds age or grade-level expectations, according to one school district’s gifted and talented education program.

A more involved description provided by the Columbus Group in 1991 defines giftedness as an “asynchronous development in which advanced cognitive abilities and heightened intensity combine to create inner experiences and awareness that are qualitatively different from the norm.” This asynchrony increases with higher intellectual capacity, they wrote. “The uniqueness of the gifted renders them vulnerable and requires modifications in parenting, teaching, and counseling in order for them to develop optimally.”

The level of a child’s giftedness makes a difference in their needs as well; these levels include advanced learners (IQ of 120-129), moderately gifted (130-144), highly gifted (145-159), exceptionally gifted (160-179), and profoundly gifted (180 and greater). Different spheres of giftedness can include intellectual ability, creative or productive thinking, leadership ability, and visual or performing arts. Consider the list of common characteristics of gifted children that Dr. Peters provided:

• Rapid learners.
• Strong memory.
• Large vocabulary.
• Advanced comprehension of nuances.
• Largely self-taught.
• Unusual emotional depth.
• Abstract/complex/logical/insightful thinking.
• Idealism and a sense of justice.
• Intense feelings and reactions.
• Highly sensitive.
• Long attention span and persistence.
• Preoccupied with own thoughts.
• Impatient with self and others’ inabilities and slowness.
• Asks probing questions (able to go beyond what is taught).
• Wide range of interests.
• Highly developed curiosity.
• Interest in experimenting and doing things differently.
• Divergent thinking.
• Keen and unusual sense of humor.

Dr. Peters cited Kazimierz Dabrowski, MD, PhD, a Polish psychiatrist of the mid-20th century, as explaining the sensitivity and intensity experienced by many gifted individuals in terms of overexcitabilities – a “greater capacity to be stimulated by and respond to external and internal stimuli.”

“Overexcitability permeates a gifted person’s existence and gives energy to their intelligence, talents, and personality,” Dr. Peters explained of Dabrowski’s ideas. This enhancement manifests in psychomotor terms as a strong drive, a lot of energy or movement, or extended bouts of activity. Intellectually, gifted children have an “insatiable curiosity, and voracious appetite and capacity for intellectual effort and stimulation,” Dr. Peters said. They may have heightened sensual experience in seeing, smelling, tasting, touching, or hearing, and they have an active imaginary and fantasy life. They also exhibit a capacity for great emotional depth and empathy – they deeply feel their own and others’ emotions.

How giftedness can be misdiagnosed

It is the combination of these very characteristics that can lead gifted children to receive an inappropriate mental or developmental diagnosis instead of being recognized as gifted.

“By current estimates, at any given time, approximately 11%-20% of children in the United States have a behavioral or emotional disorder as defined in the DSM-5,” Dr. Peters cited. Further, one study found that diagnoses of attention-deficit/hyperactivity disorder have increased 66% between 2000 and 2010, with 90% of those children taking psychostimulant medications – yet a study in the Journal of Health Economics estimated that one in five children diagnosed with ADHD are probably misdiagnosed and are receiving those medications.

Other incorrect diagnoses besides ADHD that gifted youth may commonly receive include anger diagnoses, ideational or anxiety disorders, developmental and personality disorders, mood disorders, and learning disorders.
 

Twice exceptionalism (2e)

Even more challenging are twice exceptional children, or 2e, those who are both gifted and have a learning or emotional disability or challenge. Common dual diagnoses in gifted children include anxiety disorders, depression (or existential depression), sleep disorders (such as nightmares, night terrors, or sleep walking), allergies, asthma, ADHD, oppositional-defiant disorder, obsessive-compulsive personality disorder, autism spectrum disorder, nonverbal learning disability, social/pragmatic communication disorder, and learning disorders such as dyslexia, dyscalculia, central auditory processing disorder, or sensory-motor integration disorder.

“It’s very complex. What happens is, a lot of people think you’re either gifted or not,” Dr. Peters said. “In the classroom, sometimes the advanced ability overshadows the weakness and so we get a lot of readers with an IQ of 130-150 and reading at the 50% percentile, and everyone says they’re fine, but they’re dyslexic.”

Other times, the weakness overshadows the strength, and sometimes they’re right in the middle where neither their giftedness nor their disability is recognized or addressed, Peters said. 2e children are very difficult to diagnose but also at higher risk for difficulties if one or both (or more) of their diagnoses are missed.

Maximizing gifted children’s developmental potential

Pediatricians have an opportunity to support gifted children by recognizing and accepting them for who they are, while also acknowledging that they want to feel “normal,” and therefore need extra reassurance and support from adults. Pediatricians should seek information about giftedness and 2e children from state and national gifted organizations, and, in the office, frame conversations with families and children’s differential diagnoses in terms of a child’s giftedness. If a pediatrician is themself gifted, they may be “a supportive and kindred spirit” to the child, Dr. Peters said.

In daily life, as well, gifted children need to be accepted for who they are, provided opportunities to be with their intellectual and academic peers, and provided challenges in their areas of strength, interests, or passions. Parents and teachers should follow their lead in learning: Keep up the pace for those who want to learn fast, and go deeper for those who want slower, more in-depth learning. Adults also need to understand their intensities and sensitivities and lead with their strengths in discussions.

Dr. Peters reported no disclosures.

NEW ORLEANS – Oral iron supplementation was declared ineffective for the treatment of iron deficiency in patients with heart failure with reduced ejection fraction in one major randomized trial while intravenous ferric carboxymaltose improved exercise capacity and quality of life in another study presented at the American Heart Association scientific sessions.

Iron deficiency is present in roughly half of patients with heart failure with reduced ejection fraction (HFrEF). In affected patients it’s associated with diminished functional capacity and poor quality of life, and is an independent predictor of mortality. Thus, it has emerged as a potential therapeutic target in HFrEF.

[email protected]


 

NEW ORLEANS – Oral iron supplementation was declared ineffective for the treatment of iron deficiency in patients with heart failure with reduced ejection fraction in one major randomized trial while intravenous ferric carboxymaltose improved exercise capacity and quality of life in another study presented at the American Heart Association scientific sessions.

Iron deficiency is present in roughly half of patients with heart failure with reduced ejection fraction (HFrEF). In affected patients it’s associated with diminished functional capacity and poor quality of life, and is an independent predictor of mortality. Thus, it has emerged as a potential therapeutic target in HFrEF.

[email protected]


 

NEW ORLEANS – Oral iron supplementation was declared ineffective for the treatment of iron deficiency in patients with heart failure with reduced ejection fraction in one major randomized trial while intravenous ferric carboxymaltose improved exercise capacity and quality of life in another study presented at the American Heart Association scientific sessions.

Iron deficiency is present in roughly half of patients with heart failure with reduced ejection fraction (HFrEF). In affected patients it’s associated with diminished functional capacity and poor quality of life, and is an independent predictor of mortality. Thus, it has emerged as a potential therapeutic target in HFrEF.

[email protected]


 

BOSTON – Though criteria for insurance approval for direct-acting antivirals (DAAs) for hepatitis C virus (HCV) are loosening, many patients are still denied by both public and private carriers. Providers and patients should know that it’s worthwhile to appeal these denials; 78.1% (115 of 145) of initial DAA denials were approved on appeal, according to a recent study.

Jane Giang, PharmD, a clinical pharmacist at the University of North Carolina Health System, Chapel Hill, worked with colleagues to conduct a retrospective study of patients at her facility who were prescribed a DAA for HCV between October 2014 and April 2016.

Dr. Giang, in a video interview at the annual meeting of the American Association for the Study of Liver Diseases, said that she works alongside physicians in her clinic to craft appeals, tailoring appeal letters to individual patients’ circumstances.

[email protected]

On Twitter@karioakes

BOSTON – Though criteria for insurance approval for direct-acting antivirals (DAAs) for hepatitis C virus (HCV) are loosening, many patients are still denied by both public and private carriers. Providers and patients should know that it’s worthwhile to appeal these denials; 78.1% (115 of 145) of initial DAA denials were approved on appeal, according to a recent study.

Jane Giang, PharmD, a clinical pharmacist at the University of North Carolina Health System, Chapel Hill, worked with colleagues to conduct a retrospective study of patients at her facility who were prescribed a DAA for HCV between October 2014 and April 2016.

Dr. Giang, in a video interview at the annual meeting of the American Association for the Study of Liver Diseases, said that she works alongside physicians in her clinic to craft appeals, tailoring appeal letters to individual patients’ circumstances.

[email protected]

On Twitter@karioakes

BOSTON – Though criteria for insurance approval for direct-acting antivirals (DAAs) for hepatitis C virus (HCV) are loosening, many patients are still denied by both public and private carriers. Providers and patients should know that it’s worthwhile to appeal these denials; 78.1% (115 of 145) of initial DAA denials were approved on appeal, according to a recent study.

Jane Giang, PharmD, a clinical pharmacist at the University of North Carolina Health System, Chapel Hill, worked with colleagues to conduct a retrospective study of patients at her facility who were prescribed a DAA for HCV between October 2014 and April 2016.

Dr. Giang, in a video interview at the annual meeting of the American Association for the Study of Liver Diseases, said that she works alongside physicians in her clinic to craft appeals, tailoring appeal letters to individual patients’ circumstances.

[email protected]

On Twitter@karioakes

CORONADO, CALIF. – Among advanced cancer patients with bowel obstruction, surgery was not an independent predictor of the ability to eat at discharge or survival within 90 days of consultation, results from a long-term retrospective study showed.

“I think this represents the complexity in treating these patients,” lead study author Brian D. Badgwell, MD, said at the annual meeting of the Western Surgical Association. “We need future studies to identify the optimal outcome measures.”

[email protected]

CORONADO, CALIF. – Among advanced cancer patients with bowel obstruction, surgery was not an independent predictor of the ability to eat at discharge or survival within 90 days of consultation, results from a long-term retrospective study showed.

“I think this represents the complexity in treating these patients,” lead study author Brian D. Badgwell, MD, said at the annual meeting of the Western Surgical Association. “We need future studies to identify the optimal outcome measures.”

[email protected]

CORONADO, CALIF. – Among advanced cancer patients with bowel obstruction, surgery was not an independent predictor of the ability to eat at discharge or survival within 90 days of consultation, results from a long-term retrospective study showed.

“I think this represents the complexity in treating these patients,” lead study author Brian D. Badgwell, MD, said at the annual meeting of the Western Surgical Association. “We need future studies to identify the optimal outcome measures.”

[email protected]