One in four patients at an urban diabetes center reported underusing insulin because of concerns about cost, according to a survey of patients with type 1 or type 2 diabetes mellitus who were recently prescribed the drug.

“These results highlight an urgent need to address affordability of insulin,” lead author Darby Herkert of Yale College in New Haven, Conn., and her coauthors wrote in a study published online in JAMA Internal Medicine.

In the survey of 199 diabetes patients who had an outpatient visit at the Yale Diabetes Center between June and August 2017, 25.5% reported cost-related insulin underuse. Only 60.8% of those patients discussed the prohibitive costs with their clinician, and 29.4% changed insulin types because of high prices. Patients who reported insulin underuse were also more likely to have poorer glycemic control than patients who did not, at a rate of 43.1% versus 28.1% (odds ratio, 2.96; 95% confidence interval, 1.14-8.16; P = .03).

The authors noted potential limitations in their study, including focusing on patients of just one treatment center and the inability to establish a causal relationship between cost-related underuse and poor glycemic control. Nonetheless, they strongly encouraged asking diabetes patients about potential cost issues; they also stressed the need for larger forces to step in and guarantee insulin’s availability. “Insulin is a life-saving, essential medicine, and most patients cannot act as price-sensitive buyers. Regulators and the medical community need to intervene to ensure that insulin is affordable to patients who need it,” they wrote.

This study was supported by the Global Health Field Experiences Award, the Yale College Fellowship for Research in Global Health Studies, and the Global Health Field Experiences Seed Funding Award. The corresponding author reported receiving funding from the Centers of Medicare and Medicaid Services to develop publicly reported quality measures. Another author reported receiving support from Health Action International and Alosa Health. No other disclosures were reported.

SOURCE: Herkert D et al. JAMA Internal Medicine. 2018 Dec 3. doi: 10.1001/jamainternmed.2018.5008.

One in four patients at an urban diabetes center reported underusing insulin because of concerns about cost, according to a survey of patients with type 1 or type 2 diabetes mellitus who were recently prescribed the drug.

“These results highlight an urgent need to address affordability of insulin,” lead author Darby Herkert of Yale College in New Haven, Conn., and her coauthors wrote in a study published online in JAMA Internal Medicine.

In the survey of 199 diabetes patients who had an outpatient visit at the Yale Diabetes Center between June and August 2017, 25.5% reported cost-related insulin underuse. Only 60.8% of those patients discussed the prohibitive costs with their clinician, and 29.4% changed insulin types because of high prices. Patients who reported insulin underuse were also more likely to have poorer glycemic control than patients who did not, at a rate of 43.1% versus 28.1% (odds ratio, 2.96; 95% confidence interval, 1.14-8.16; P = .03).

The authors noted potential limitations in their study, including focusing on patients of just one treatment center and the inability to establish a causal relationship between cost-related underuse and poor glycemic control. Nonetheless, they strongly encouraged asking diabetes patients about potential cost issues; they also stressed the need for larger forces to step in and guarantee insulin’s availability. “Insulin is a life-saving, essential medicine, and most patients cannot act as price-sensitive buyers. Regulators and the medical community need to intervene to ensure that insulin is affordable to patients who need it,” they wrote.

This study was supported by the Global Health Field Experiences Award, the Yale College Fellowship for Research in Global Health Studies, and the Global Health Field Experiences Seed Funding Award. The corresponding author reported receiving funding from the Centers of Medicare and Medicaid Services to develop publicly reported quality measures. Another author reported receiving support from Health Action International and Alosa Health. No other disclosures were reported.

SOURCE: Herkert D et al. JAMA Internal Medicine. 2018 Dec 3. doi: 10.1001/jamainternmed.2018.5008.

One in four patients at an urban diabetes center reported underusing insulin because of concerns about cost, according to a survey of patients with type 1 or type 2 diabetes mellitus who were recently prescribed the drug.

“These results highlight an urgent need to address affordability of insulin,” lead author Darby Herkert of Yale College in New Haven, Conn., and her coauthors wrote in a study published online in JAMA Internal Medicine.

In the survey of 199 diabetes patients who had an outpatient visit at the Yale Diabetes Center between June and August 2017, 25.5% reported cost-related insulin underuse. Only 60.8% of those patients discussed the prohibitive costs with their clinician, and 29.4% changed insulin types because of high prices. Patients who reported insulin underuse were also more likely to have poorer glycemic control than patients who did not, at a rate of 43.1% versus 28.1% (odds ratio, 2.96; 95% confidence interval, 1.14-8.16; P = .03).

The authors noted potential limitations in their study, including focusing on patients of just one treatment center and the inability to establish a causal relationship between cost-related underuse and poor glycemic control. Nonetheless, they strongly encouraged asking diabetes patients about potential cost issues; they also stressed the need for larger forces to step in and guarantee insulin’s availability. “Insulin is a life-saving, essential medicine, and most patients cannot act as price-sensitive buyers. Regulators and the medical community need to intervene to ensure that insulin is affordable to patients who need it,” they wrote.

This study was supported by the Global Health Field Experiences Award, the Yale College Fellowship for Research in Global Health Studies, and the Global Health Field Experiences Seed Funding Award. The corresponding author reported receiving funding from the Centers of Medicare and Medicaid Services to develop publicly reported quality measures. Another author reported receiving support from Health Action International and Alosa Health. No other disclosures were reported.

SOURCE: Herkert D et al. JAMA Internal Medicine. 2018 Dec 3. doi: 10.1001/jamainternmed.2018.5008.

SAN DIEGO – Lower-than-usual doses of rituximab may be sufficient in patients with acquired thrombotic thrombocytopenic purpura (TTP), results of a recent pilot safety and efficacy study suggest.

Patients receiving just 100 mg/week for 4 weeks had rates of relapse and exacerbation that were favorable, compared with historical controls, according to investigator Jeffrey I. Zwicker, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston. He presented the findings at the annual meeting of the American Society of Hematology.

However, the low-dose treatment was not without side effects, according to Dr. Zwicker, who described one case of acute respiratory failure out of the 19 patients enrolled in the ART (Adjuvant Rituximab in TTP) study.

“The likely benefit is cost savings, rather than less toxicity,” Dr. Zwicker said of the low-dose rituximab regimen.

Out of 19 patients enrolled in ART, 18 were eligible to receive the study treatment, which included low-dose rituximab plus standard plasma exchange and corticosteroids.

Following this initial therapy, all patients had a response, defined as a platelet count 150,000/mcL or greater for 2 consecutive days, with a median time to response of 5 days.

There were two exacerbations (12%) at 30 days after stopping plasma exchange and no cases of refractory TTP, which compared favorably to historical controls, Dr. Zwicker said.

The rate of relapse at 2 years was 28%, which again compared favorably with a historical control data repository in which the rate of relapse at 2 years was 51%.

One patient in the study suffered a case of acute respiratory failure requiring intubation during the third rituximab infusion and was ultimately placed on extracorporeal membrane oxygenation.

“The patient did survive, but this is just a reminder that there are potential side effects, even with lower doses of rituximab,” Dr. Zwicker said.

A few other serious adverse events – including central line infection and bacteremia in one patient – were more likely related to the plasma exchange, he added.

These results with low-dose rituximab are consistent with findings that rituximab 375 mg/m² for four doses reduces the incidence of exacerbation and refractory disease and prevents or delays relapses, according to Dr. Zwicker and his coinvestigators, including J. Evan Sadler, MD, PhD, of Washington University, St. Louis, who initiated the study.

The typical TTP regimen of rituximab 375 mg/m² for four weekly doses is borrowed from protocols for B-cell lymphomas; however, the B-cell mass in nonmalignant disease is likely to be much less than in lymphoproliferative disorders, Dr. Zwicker told attendees.

“The benefit, principally, of lower-dose rituximab is saving of thousands upon thousands of dollars,” Dr. Zwicker said.

This is not the only data set to suggest a potential role for lower-dose rituximab, he added, noting that a recently published retrospective analysis showed “fairly similar” treatment-free survival rates for standard rituximab and a reduced-dose regimen. There also are case series in other autoimmune cytopenias, namely idiopathic thrombocytopenic purpura and pure red cell aplasia, that provide evidence in support of low-dose rituximab, he added.

Dr. Zwicker reported research funding with Incyte and Quercegen, and consultancy with Parexel. Dr. Sadler reported consultancy with Ablynx.

SOURCE: Zwicker JI et al. ASH 2018, Abstract 374.

SAN DIEGO – Lower-than-usual doses of rituximab may be sufficient in patients with acquired thrombotic thrombocytopenic purpura (TTP), results of a recent pilot safety and efficacy study suggest.

Patients receiving just 100 mg/week for 4 weeks had rates of relapse and exacerbation that were favorable, compared with historical controls, according to investigator Jeffrey I. Zwicker, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston. He presented the findings at the annual meeting of the American Society of Hematology.

However, the low-dose treatment was not without side effects, according to Dr. Zwicker, who described one case of acute respiratory failure out of the 19 patients enrolled in the ART (Adjuvant Rituximab in TTP) study.

“The likely benefit is cost savings, rather than less toxicity,” Dr. Zwicker said of the low-dose rituximab regimen.

Out of 19 patients enrolled in ART, 18 were eligible to receive the study treatment, which included low-dose rituximab plus standard plasma exchange and corticosteroids.

Following this initial therapy, all patients had a response, defined as a platelet count 150,000/mcL or greater for 2 consecutive days, with a median time to response of 5 days.

There were two exacerbations (12%) at 30 days after stopping plasma exchange and no cases of refractory TTP, which compared favorably to historical controls, Dr. Zwicker said.

The rate of relapse at 2 years was 28%, which again compared favorably with a historical control data repository in which the rate of relapse at 2 years was 51%.

One patient in the study suffered a case of acute respiratory failure requiring intubation during the third rituximab infusion and was ultimately placed on extracorporeal membrane oxygenation.

“The patient did survive, but this is just a reminder that there are potential side effects, even with lower doses of rituximab,” Dr. Zwicker said.

A few other serious adverse events – including central line infection and bacteremia in one patient – were more likely related to the plasma exchange, he added.

These results with low-dose rituximab are consistent with findings that rituximab 375 mg/m² for four doses reduces the incidence of exacerbation and refractory disease and prevents or delays relapses, according to Dr. Zwicker and his coinvestigators, including J. Evan Sadler, MD, PhD, of Washington University, St. Louis, who initiated the study.

The typical TTP regimen of rituximab 375 mg/m² for four weekly doses is borrowed from protocols for B-cell lymphomas; however, the B-cell mass in nonmalignant disease is likely to be much less than in lymphoproliferative disorders, Dr. Zwicker told attendees.

“The benefit, principally, of lower-dose rituximab is saving of thousands upon thousands of dollars,” Dr. Zwicker said.

This is not the only data set to suggest a potential role for lower-dose rituximab, he added, noting that a recently published retrospective analysis showed “fairly similar” treatment-free survival rates for standard rituximab and a reduced-dose regimen. There also are case series in other autoimmune cytopenias, namely idiopathic thrombocytopenic purpura and pure red cell aplasia, that provide evidence in support of low-dose rituximab, he added.

Dr. Zwicker reported research funding with Incyte and Quercegen, and consultancy with Parexel. Dr. Sadler reported consultancy with Ablynx.

SOURCE: Zwicker JI et al. ASH 2018, Abstract 374.

SAN DIEGO – Lower-than-usual doses of rituximab may be sufficient in patients with acquired thrombotic thrombocytopenic purpura (TTP), results of a recent pilot safety and efficacy study suggest.

Patients receiving just 100 mg/week for 4 weeks had rates of relapse and exacerbation that were favorable, compared with historical controls, according to investigator Jeffrey I. Zwicker, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston. He presented the findings at the annual meeting of the American Society of Hematology.

However, the low-dose treatment was not without side effects, according to Dr. Zwicker, who described one case of acute respiratory failure out of the 19 patients enrolled in the ART (Adjuvant Rituximab in TTP) study.

“The likely benefit is cost savings, rather than less toxicity,” Dr. Zwicker said of the low-dose rituximab regimen.

Out of 19 patients enrolled in ART, 18 were eligible to receive the study treatment, which included low-dose rituximab plus standard plasma exchange and corticosteroids.

Following this initial therapy, all patients had a response, defined as a platelet count 150,000/mcL or greater for 2 consecutive days, with a median time to response of 5 days.

There were two exacerbations (12%) at 30 days after stopping plasma exchange and no cases of refractory TTP, which compared favorably to historical controls, Dr. Zwicker said.

The rate of relapse at 2 years was 28%, which again compared favorably with a historical control data repository in which the rate of relapse at 2 years was 51%.

One patient in the study suffered a case of acute respiratory failure requiring intubation during the third rituximab infusion and was ultimately placed on extracorporeal membrane oxygenation.

“The patient did survive, but this is just a reminder that there are potential side effects, even with lower doses of rituximab,” Dr. Zwicker said.

A few other serious adverse events – including central line infection and bacteremia in one patient – were more likely related to the plasma exchange, he added.

These results with low-dose rituximab are consistent with findings that rituximab 375 mg/m² for four doses reduces the incidence of exacerbation and refractory disease and prevents or delays relapses, according to Dr. Zwicker and his coinvestigators, including J. Evan Sadler, MD, PhD, of Washington University, St. Louis, who initiated the study.

The typical TTP regimen of rituximab 375 mg/m² for four weekly doses is borrowed from protocols for B-cell lymphomas; however, the B-cell mass in nonmalignant disease is likely to be much less than in lymphoproliferative disorders, Dr. Zwicker told attendees.

“The benefit, principally, of lower-dose rituximab is saving of thousands upon thousands of dollars,” Dr. Zwicker said.

This is not the only data set to suggest a potential role for lower-dose rituximab, he added, noting that a recently published retrospective analysis showed “fairly similar” treatment-free survival rates for standard rituximab and a reduced-dose regimen. There also are case series in other autoimmune cytopenias, namely idiopathic thrombocytopenic purpura and pure red cell aplasia, that provide evidence in support of low-dose rituximab, he added.

Dr. Zwicker reported research funding with Incyte and Quercegen, and consultancy with Parexel. Dr. Sadler reported consultancy with Ablynx.

SOURCE: Zwicker JI et al. ASH 2018, Abstract 374.

CHICAGO – Phased withdrawal of guideline-directed medical therapy in patients who seemed to have recovered from dilated cardiomyopathy resulted in relapses in 40% of patients within 6 months in the TRED-HF trial.

Bruce Jancin/MDedge News

The clinical implications of this small pilot randomized trial are clear: “Withdrawal of therapy should not usually be attempted, at least until we can predict who’s going to relapse and who’s not,” Brian P. Halliday, MD, PhD, said at the American Heart Association scientific sessions.

“Improvement in function represents remission rather than permanent recovery for many patients,” added Dr. Halliday of Imperial College London.

The study was performed to address a question that arises with increasing frequency in clinical practice as a result of the impressive advances in heart failure therapy in recent years, he said. “Patients frequently come to us in clinic and ask us, ‘Do I need to continue to take these medications forever?’ They’re frequently young, and they want to know if they really need to be subject to 40 or 50 years of medication. Some are concerned about side effects, others are interested in pregnancy, and then there is the financial cost.”

Simultaneously published in The Lancet, TRED-HF was a single-center, open-label study of 51 patients who had prior dilated cardiomyopathy (DCM) and a median left ventricular ejection fraction (LVEF) of 25% at the time of diagnosis 4.9 years earlier and who subsequently recovered in response to therapy. That is, they became symptom-free with an LVEF greater than 50%, a normal left ventricular end diastolic volume index, and a reassuringly low median N-terminal pro b-type natriuretic peptide (NP-pro-BNP) level of 72 ng/L.

For the study, 25 patients were randomized to phased withdrawal of their heart failure drugs over a 16-week period: First they reduced or stopped loop diuretics, then mineralocorticoid antagonists, then beta-blockers, and finally their ACE inhibitor or angiotensin receptor blocker. The other 26 participants continued therapy during the first 6 months of the study, then 25 of the 26 crossed over to phased withdrawal. The outlier didn’t cross over because of atrial fibrillation.

The primary endpoint was relapse of DCM within 6 months of the start of the study. Relapse was defined as either a drop in LVEF of more than 10% to a level below 50%, at least a doubling of NT-pro-BNP to greater than 400 ng/L, clinical evidence of heart failure, or a greater than 10% increase in LV end diastolic volume as assessed by cardiac MRI.
 

The results

During the first half of the study, 11 of 25 patients (44%) relapsed during or after medication withdrawal. None of the controls relapsed. In the crossover phase, 9 of 25 patients (35%) relapsed in response to treatment withdrawal. Of the 20 patients who relapsed, 13 did so within 16 weeks of beginning medication withdrawal. Indeed, most patients relapsed within 8 weeks of their last medication. Ten of the twenty fulfilled multiple criteria for relapse.

Medication withdrawal was accompanied not only by a mean 9.5% reduction in LVEF, compared with baseline, but by a 15.4-bpm rise in heart rate, a 7.0–mm Hg increase in diastolic blood pressure, and 5.1-point deterioration in Kansas City Cardiomyopathy Questionnaire scores, demonstrating that what happened off treatment was true DCM recurrence and not simply an imaging artifact.

Experts react

Designated discussant Jane E. Wilcox, MD, commented, “Currently, in 2018, we have no true signature of recovery. These patients are indeed in cardiac remission and have an indefinite indication for continuing their evidence-based medical therapy without interruption.”

Bruce Jancin/MDedge News

“The clinical implication here is, I think, we should TRED-lightly,” quipped Dr. Wilcox of Northwestern University in Chicago.

Her own research indicates that even patients who have recovered their LVEF and no longer seem to have a heart failure phenotype still have an abnormal myocardial substrate as evidenced by persistent dysfunctional cardiac mechanics on echocardiography. Nonetheless, she remains optimistic.

“I don’t think [TRED-HF] squelches the future of myocardial recovery. I think it actually invigorates the field for an assessment of genomics, proteomics, and metabolomics looking for that true signature of cardiac recovery,” she said.

Donald Lloyd-Jones, MD, who chaired a press conference where Dr. Halliday presented the TRED-HF results, complimented the investigators for tackling what he termed “an incredibly important clinical question that comes up all the time.”

“I really want to commend the investigators for taking on what, on its face, might be an ethically challenging question by taking treatment away when we don’t know what the answer is likely to be. But they really checked all the boxes to make sure this was done in a very safe and monitored way, so that even though the outcome was what it turned out to be, the harm to patients was minimalized,” said Dr. Lloyd-Jones, professor and chair of the department of preventive medicine and director of the Northwestern University Clinical and Translational Sciences Institute, Chicago.

“No patient wants to be on more medication than they need to be, but I think for the time being this class of patients is going to have to be maintained on medications until we understand a little more,” Dr. Lloyd-Jones concluded.

Dr. Halliday reported having no financial conflicts regarding the study, funded by the British Heart Foundation.

bjancin@mdedge.com

SOURCE: Halliday BP. AHA scientific sessions, Abstract 18621. Simulpub The Lancet. 2018 Nov 11. doi: 10.1016/S0140-6736(18)32484-X.

CHICAGO – Phased withdrawal of guideline-directed medical therapy in patients who seemed to have recovered from dilated cardiomyopathy resulted in relapses in 40% of patients within 6 months in the TRED-HF trial.

Bruce Jancin/MDedge News

The clinical implications of this small pilot randomized trial are clear: “Withdrawal of therapy should not usually be attempted, at least until we can predict who’s going to relapse and who’s not,” Brian P. Halliday, MD, PhD, said at the American Heart Association scientific sessions.

“Improvement in function represents remission rather than permanent recovery for many patients,” added Dr. Halliday of Imperial College London.

The study was performed to address a question that arises with increasing frequency in clinical practice as a result of the impressive advances in heart failure therapy in recent years, he said. “Patients frequently come to us in clinic and ask us, ‘Do I need to continue to take these medications forever?’ They’re frequently young, and they want to know if they really need to be subject to 40 or 50 years of medication. Some are concerned about side effects, others are interested in pregnancy, and then there is the financial cost.”

Simultaneously published in The Lancet, TRED-HF was a single-center, open-label study of 51 patients who had prior dilated cardiomyopathy (DCM) and a median left ventricular ejection fraction (LVEF) of 25% at the time of diagnosis 4.9 years earlier and who subsequently recovered in response to therapy. That is, they became symptom-free with an LVEF greater than 50%, a normal left ventricular end diastolic volume index, and a reassuringly low median N-terminal pro b-type natriuretic peptide (NP-pro-BNP) level of 72 ng/L.

For the study, 25 patients were randomized to phased withdrawal of their heart failure drugs over a 16-week period: First they reduced or stopped loop diuretics, then mineralocorticoid antagonists, then beta-blockers, and finally their ACE inhibitor or angiotensin receptor blocker. The other 26 participants continued therapy during the first 6 months of the study, then 25 of the 26 crossed over to phased withdrawal. The outlier didn’t cross over because of atrial fibrillation.

The primary endpoint was relapse of DCM within 6 months of the start of the study. Relapse was defined as either a drop in LVEF of more than 10% to a level below 50%, at least a doubling of NT-pro-BNP to greater than 400 ng/L, clinical evidence of heart failure, or a greater than 10% increase in LV end diastolic volume as assessed by cardiac MRI.
 

The results

During the first half of the study, 11 of 25 patients (44%) relapsed during or after medication withdrawal. None of the controls relapsed. In the crossover phase, 9 of 25 patients (35%) relapsed in response to treatment withdrawal. Of the 20 patients who relapsed, 13 did so within 16 weeks of beginning medication withdrawal. Indeed, most patients relapsed within 8 weeks of their last medication. Ten of the twenty fulfilled multiple criteria for relapse.

Medication withdrawal was accompanied not only by a mean 9.5% reduction in LVEF, compared with baseline, but by a 15.4-bpm rise in heart rate, a 7.0–mm Hg increase in diastolic blood pressure, and 5.1-point deterioration in Kansas City Cardiomyopathy Questionnaire scores, demonstrating that what happened off treatment was true DCM recurrence and not simply an imaging artifact.

Experts react

Designated discussant Jane E. Wilcox, MD, commented, “Currently, in 2018, we have no true signature of recovery. These patients are indeed in cardiac remission and have an indefinite indication for continuing their evidence-based medical therapy without interruption.”

Bruce Jancin/MDedge News

“The clinical implication here is, I think, we should TRED-lightly,” quipped Dr. Wilcox of Northwestern University in Chicago.

Her own research indicates that even patients who have recovered their LVEF and no longer seem to have a heart failure phenotype still have an abnormal myocardial substrate as evidenced by persistent dysfunctional cardiac mechanics on echocardiography. Nonetheless, she remains optimistic.

“I don’t think [TRED-HF] squelches the future of myocardial recovery. I think it actually invigorates the field for an assessment of genomics, proteomics, and metabolomics looking for that true signature of cardiac recovery,” she said.

Donald Lloyd-Jones, MD, who chaired a press conference where Dr. Halliday presented the TRED-HF results, complimented the investigators for tackling what he termed “an incredibly important clinical question that comes up all the time.”

“I really want to commend the investigators for taking on what, on its face, might be an ethically challenging question by taking treatment away when we don’t know what the answer is likely to be. But they really checked all the boxes to make sure this was done in a very safe and monitored way, so that even though the outcome was what it turned out to be, the harm to patients was minimalized,” said Dr. Lloyd-Jones, professor and chair of the department of preventive medicine and director of the Northwestern University Clinical and Translational Sciences Institute, Chicago.

“No patient wants to be on more medication than they need to be, but I think for the time being this class of patients is going to have to be maintained on medications until we understand a little more,” Dr. Lloyd-Jones concluded.

Dr. Halliday reported having no financial conflicts regarding the study, funded by the British Heart Foundation.

bjancin@mdedge.com

SOURCE: Halliday BP. AHA scientific sessions, Abstract 18621. Simulpub The Lancet. 2018 Nov 11. doi: 10.1016/S0140-6736(18)32484-X.

CHICAGO – Phased withdrawal of guideline-directed medical therapy in patients who seemed to have recovered from dilated cardiomyopathy resulted in relapses in 40% of patients within 6 months in the TRED-HF trial.

Bruce Jancin/MDedge News

The clinical implications of this small pilot randomized trial are clear: “Withdrawal of therapy should not usually be attempted, at least until we can predict who’s going to relapse and who’s not,” Brian P. Halliday, MD, PhD, said at the American Heart Association scientific sessions.

“Improvement in function represents remission rather than permanent recovery for many patients,” added Dr. Halliday of Imperial College London.

The study was performed to address a question that arises with increasing frequency in clinical practice as a result of the impressive advances in heart failure therapy in recent years, he said. “Patients frequently come to us in clinic and ask us, ‘Do I need to continue to take these medications forever?’ They’re frequently young, and they want to know if they really need to be subject to 40 or 50 years of medication. Some are concerned about side effects, others are interested in pregnancy, and then there is the financial cost.”

Simultaneously published in The Lancet, TRED-HF was a single-center, open-label study of 51 patients who had prior dilated cardiomyopathy (DCM) and a median left ventricular ejection fraction (LVEF) of 25% at the time of diagnosis 4.9 years earlier and who subsequently recovered in response to therapy. That is, they became symptom-free with an LVEF greater than 50%, a normal left ventricular end diastolic volume index, and a reassuringly low median N-terminal pro b-type natriuretic peptide (NP-pro-BNP) level of 72 ng/L.

For the study, 25 patients were randomized to phased withdrawal of their heart failure drugs over a 16-week period: First they reduced or stopped loop diuretics, then mineralocorticoid antagonists, then beta-blockers, and finally their ACE inhibitor or angiotensin receptor blocker. The other 26 participants continued therapy during the first 6 months of the study, then 25 of the 26 crossed over to phased withdrawal. The outlier didn’t cross over because of atrial fibrillation.

The primary endpoint was relapse of DCM within 6 months of the start of the study. Relapse was defined as either a drop in LVEF of more than 10% to a level below 50%, at least a doubling of NT-pro-BNP to greater than 400 ng/L, clinical evidence of heart failure, or a greater than 10% increase in LV end diastolic volume as assessed by cardiac MRI.
 

The results

During the first half of the study, 11 of 25 patients (44%) relapsed during or after medication withdrawal. None of the controls relapsed. In the crossover phase, 9 of 25 patients (35%) relapsed in response to treatment withdrawal. Of the 20 patients who relapsed, 13 did so within 16 weeks of beginning medication withdrawal. Indeed, most patients relapsed within 8 weeks of their last medication. Ten of the twenty fulfilled multiple criteria for relapse.

Medication withdrawal was accompanied not only by a mean 9.5% reduction in LVEF, compared with baseline, but by a 15.4-bpm rise in heart rate, a 7.0–mm Hg increase in diastolic blood pressure, and 5.1-point deterioration in Kansas City Cardiomyopathy Questionnaire scores, demonstrating that what happened off treatment was true DCM recurrence and not simply an imaging artifact.

Experts react

Designated discussant Jane E. Wilcox, MD, commented, “Currently, in 2018, we have no true signature of recovery. These patients are indeed in cardiac remission and have an indefinite indication for continuing their evidence-based medical therapy without interruption.”

Bruce Jancin/MDedge News

“The clinical implication here is, I think, we should TRED-lightly,” quipped Dr. Wilcox of Northwestern University in Chicago.

Her own research indicates that even patients who have recovered their LVEF and no longer seem to have a heart failure phenotype still have an abnormal myocardial substrate as evidenced by persistent dysfunctional cardiac mechanics on echocardiography. Nonetheless, she remains optimistic.

“I don’t think [TRED-HF] squelches the future of myocardial recovery. I think it actually invigorates the field for an assessment of genomics, proteomics, and metabolomics looking for that true signature of cardiac recovery,” she said.

Donald Lloyd-Jones, MD, who chaired a press conference where Dr. Halliday presented the TRED-HF results, complimented the investigators for tackling what he termed “an incredibly important clinical question that comes up all the time.”

“I really want to commend the investigators for taking on what, on its face, might be an ethically challenging question by taking treatment away when we don’t know what the answer is likely to be. But they really checked all the boxes to make sure this was done in a very safe and monitored way, so that even though the outcome was what it turned out to be, the harm to patients was minimalized,” said Dr. Lloyd-Jones, professor and chair of the department of preventive medicine and director of the Northwestern University Clinical and Translational Sciences Institute, Chicago.

“No patient wants to be on more medication than they need to be, but I think for the time being this class of patients is going to have to be maintained on medications until we understand a little more,” Dr. Lloyd-Jones concluded.

Dr. Halliday reported having no financial conflicts regarding the study, funded by the British Heart Foundation.

bjancin@mdedge.com

SOURCE: Halliday BP. AHA scientific sessions, Abstract 18621. Simulpub The Lancet. 2018 Nov 11. doi: 10.1016/S0140-6736(18)32484-X.

SAN DIEGO – A newly developed personalized model that “harnesses the power of artificial intelligence” to predict overall survival and transformation to acute myeloid leukemia (AML) in patients with myelodysplastic syndromes outperforms both the original and revised International Prognostic Scoring Systems (IPSS, IPSS-R), according to Aziz Nazha, MD.

The machine learning model, which was built using clinical and genomic data derived from myelodysplastic syndrome (MDS) patients diagnosed according to 2008 World Health Organization criteria, incorporates information beyond that included in the IPSS and IPSS-R, and provides patient-specific survival probabilities at different time points, Dr. Nazha of Cleveland Clinic reported during a press briefing at the annual meeting of the American Society of Hematology.

The model was developed in a combined training cohort of 1,471 patients from the Cleveland Clinic and Munich Leukemia Laboratory and was validated in a separate cohort of 831 patients from the Moffitt Cancer Center in Tampa, Fla.

The concordance index – a measure for comparing the accuracy of the various models – was 0.80 for overall survival (OS), and 0.78 for AML transformation vs. 0.66 and 0.73, respectively, for IPSS, and 0.67 and 0.73, respectively, for IPSS-R, Dr. Nazha said. The new “geno-clinical” model also outperformed mutations-only analysis, mutations plus cytogenetics analysis, and mutations plus cytogenetics plus age analyses for both OS and AML transformation.

Adding mutational variant allelic frequency did not significantly improve prediction accuracy, he noted.

Dr. Nazha and his colleagues are developing a web application tool that can be used to run the trained model to calculate patient-specific, time-specific OS and AML transformation probabilities. He discussed the new model and its implications for personalized prognosis and treatment in this video interview.

Improved risk assessment helps patients understand their disease and “establish expectations about their journey with their disease,” and it is also extremely important for treating physicians, he said.

“All of our consensus guidelines and treatment recommendations are based on risk,” he explained, noting that the approach varies greatly for higher- and lower-risk patients.

This model represents a potential new focus on “personalized prediction” in addition to the increasing focus on personalized treatment and takes into account the heterogeneous outcomes seen in patients with MDS, he said.

Dr. Nazha reported consultancy for Karyopharma and Tolero, and data-monitoring committee membership for MEI.

sworcester@mdedge.com

SOURCE: Nazha A et al. ASH 2018, Abstract 793.

SAN DIEGO – A newly developed personalized model that “harnesses the power of artificial intelligence” to predict overall survival and transformation to acute myeloid leukemia (AML) in patients with myelodysplastic syndromes outperforms both the original and revised International Prognostic Scoring Systems (IPSS, IPSS-R), according to Aziz Nazha, MD.

The machine learning model, which was built using clinical and genomic data derived from myelodysplastic syndrome (MDS) patients diagnosed according to 2008 World Health Organization criteria, incorporates information beyond that included in the IPSS and IPSS-R, and provides patient-specific survival probabilities at different time points, Dr. Nazha of Cleveland Clinic reported during a press briefing at the annual meeting of the American Society of Hematology.

The model was developed in a combined training cohort of 1,471 patients from the Cleveland Clinic and Munich Leukemia Laboratory and was validated in a separate cohort of 831 patients from the Moffitt Cancer Center in Tampa, Fla.

The concordance index – a measure for comparing the accuracy of the various models – was 0.80 for overall survival (OS), and 0.78 for AML transformation vs. 0.66 and 0.73, respectively, for IPSS, and 0.67 and 0.73, respectively, for IPSS-R, Dr. Nazha said. The new “geno-clinical” model also outperformed mutations-only analysis, mutations plus cytogenetics analysis, and mutations plus cytogenetics plus age analyses for both OS and AML transformation.

Adding mutational variant allelic frequency did not significantly improve prediction accuracy, he noted.

Dr. Nazha and his colleagues are developing a web application tool that can be used to run the trained model to calculate patient-specific, time-specific OS and AML transformation probabilities. He discussed the new model and its implications for personalized prognosis and treatment in this video interview.

Improved risk assessment helps patients understand their disease and “establish expectations about their journey with their disease,” and it is also extremely important for treating physicians, he said.

“All of our consensus guidelines and treatment recommendations are based on risk,” he explained, noting that the approach varies greatly for higher- and lower-risk patients.

This model represents a potential new focus on “personalized prediction” in addition to the increasing focus on personalized treatment and takes into account the heterogeneous outcomes seen in patients with MDS, he said.

Dr. Nazha reported consultancy for Karyopharma and Tolero, and data-monitoring committee membership for MEI.

sworcester@mdedge.com

SOURCE: Nazha A et al. ASH 2018, Abstract 793.

SAN DIEGO – A newly developed personalized model that “harnesses the power of artificial intelligence” to predict overall survival and transformation to acute myeloid leukemia (AML) in patients with myelodysplastic syndromes outperforms both the original and revised International Prognostic Scoring Systems (IPSS, IPSS-R), according to Aziz Nazha, MD.

The machine learning model, which was built using clinical and genomic data derived from myelodysplastic syndrome (MDS) patients diagnosed according to 2008 World Health Organization criteria, incorporates information beyond that included in the IPSS and IPSS-R, and provides patient-specific survival probabilities at different time points, Dr. Nazha of Cleveland Clinic reported during a press briefing at the annual meeting of the American Society of Hematology.

The model was developed in a combined training cohort of 1,471 patients from the Cleveland Clinic and Munich Leukemia Laboratory and was validated in a separate cohort of 831 patients from the Moffitt Cancer Center in Tampa, Fla.

The concordance index – a measure for comparing the accuracy of the various models – was 0.80 for overall survival (OS), and 0.78 for AML transformation vs. 0.66 and 0.73, respectively, for IPSS, and 0.67 and 0.73, respectively, for IPSS-R, Dr. Nazha said. The new “geno-clinical” model also outperformed mutations-only analysis, mutations plus cytogenetics analysis, and mutations plus cytogenetics plus age analyses for both OS and AML transformation.

Adding mutational variant allelic frequency did not significantly improve prediction accuracy, he noted.

Dr. Nazha and his colleagues are developing a web application tool that can be used to run the trained model to calculate patient-specific, time-specific OS and AML transformation probabilities. He discussed the new model and its implications for personalized prognosis and treatment in this video interview.

Improved risk assessment helps patients understand their disease and “establish expectations about their journey with their disease,” and it is also extremely important for treating physicians, he said.

“All of our consensus guidelines and treatment recommendations are based on risk,” he explained, noting that the approach varies greatly for higher- and lower-risk patients.

This model represents a potential new focus on “personalized prediction” in addition to the increasing focus on personalized treatment and takes into account the heterogeneous outcomes seen in patients with MDS, he said.

Dr. Nazha reported consultancy for Karyopharma and Tolero, and data-monitoring committee membership for MEI.

sworcester@mdedge.com

SOURCE: Nazha A et al. ASH 2018, Abstract 793.

Comorbidity between headaches with a range of physical conditions that have been associated with adult migraine demonstrates that multimorbidity occurs early in development. This according to a recent study that examined the associations between headaches and migraine with physical and mental disorders in a large pediatric registry. The study included 9,329 youth aged 8-21 years from the Philadelphia Neurodevelopmental Cohort. Physical conditions, including headache, were ascertained from electronic medical records and in-person interviews. Modified International Classification of Headache Disorders (ICHD-II) criteria were used to classify migraine symptoms. Forty-two other physical conditions were classified into 14 classes of medical disorders. Researchers found:

• Lifetime prevalence of any headache was 45.5%, and of migraine was 22.6%.
• Any headache was associated with a broad range of physical disorders, attention-deficit/hyperactivity disorder (odds ratio [OR] 1.2), and behavior disorders (1.3).
• Youth with migraine had greater odds of specific physical conditions and mental disorders, including respiratory, neurologic/central nervous system, developmental, anxiety, behavior, and mood disorders than those with non-migraine headache (OR ranged from 1.3 to 1.9).

Lateef T, He J-P, Nelson K, et al. Physical–mental comorbidity of pediatric migraine in the Philadelphia Neurodevelopmental Cohort. [Published online ahead of print October 29, 2018]. J Pediatr. doi:10.1016/j.jpeds.2018.09.033.

Comorbidity between headaches with a range of physical conditions that have been associated with adult migraine demonstrates that multimorbidity occurs early in development. This according to a recent study that examined the associations between headaches and migraine with physical and mental disorders in a large pediatric registry. The study included 9,329 youth aged 8-21 years from the Philadelphia Neurodevelopmental Cohort. Physical conditions, including headache, were ascertained from electronic medical records and in-person interviews. Modified International Classification of Headache Disorders (ICHD-II) criteria were used to classify migraine symptoms. Forty-two other physical conditions were classified into 14 classes of medical disorders. Researchers found:

• Lifetime prevalence of any headache was 45.5%, and of migraine was 22.6%.
• Any headache was associated with a broad range of physical disorders, attention-deficit/hyperactivity disorder (odds ratio [OR] 1.2), and behavior disorders (1.3).
• Youth with migraine had greater odds of specific physical conditions and mental disorders, including respiratory, neurologic/central nervous system, developmental, anxiety, behavior, and mood disorders than those with non-migraine headache (OR ranged from 1.3 to 1.9).

Lateef T, He J-P, Nelson K, et al. Physical–mental comorbidity of pediatric migraine in the Philadelphia Neurodevelopmental Cohort. [Published online ahead of print October 29, 2018]. J Pediatr. doi:10.1016/j.jpeds.2018.09.033.

Comorbidity between headaches with a range of physical conditions that have been associated with adult migraine demonstrates that multimorbidity occurs early in development. This according to a recent study that examined the associations between headaches and migraine with physical and mental disorders in a large pediatric registry. The study included 9,329 youth aged 8-21 years from the Philadelphia Neurodevelopmental Cohort. Physical conditions, including headache, were ascertained from electronic medical records and in-person interviews. Modified International Classification of Headache Disorders (ICHD-II) criteria were used to classify migraine symptoms. Forty-two other physical conditions were classified into 14 classes of medical disorders. Researchers found:

• Lifetime prevalence of any headache was 45.5%, and of migraine was 22.6%.
• Any headache was associated with a broad range of physical disorders, attention-deficit/hyperactivity disorder (odds ratio [OR] 1.2), and behavior disorders (1.3).
• Youth with migraine had greater odds of specific physical conditions and mental disorders, including respiratory, neurologic/central nervous system, developmental, anxiety, behavior, and mood disorders than those with non-migraine headache (OR ranged from 1.3 to 1.9).

Lateef T, He J-P, Nelson K, et al. Physical–mental comorbidity of pediatric migraine in the Philadelphia Neurodevelopmental Cohort. [Published online ahead of print October 29, 2018]. J Pediatr. doi:10.1016/j.jpeds.2018.09.033.

Recent findings suggest an abnormal sensory integration for spatial orientation in vestibular migraine (VM), related to daily dizziness in these patients. Researchers investigated the effect of static head tilts on errors of upright perception in a group of 27 patients with VM in comparison with a group of 27 healthy controls. Perception of upright was measured in a dark room using a subjective visual vertical (SVV) paradigm at 3 head tilt positions (upright, ±20°). VM patients were also surveyed about the quality of their dizziness and spatial symptoms during daily activities. Researchers found:

• In the upright head position, SVV errors were within the normal range for VM patients and healthy controls (within 2° from true vertical).
• During the static head tilts of 20° to the right, VM patients showed larger SVV errors consistent with overestimation of the tilt magnitude (ie, as if they felt further tilted toward the right side) (VM: −3.21° ± 0.93 vs control: 0.52° ± 0.70).
• During the head tilt to the left, SVV errors in VM patients did not differ significantly from controls (VM: 0.77° ± 1.05 vs control: −0.04° ± 0.68).

Winnick A, Sadeghpour S, Otero-Millan J, Chang T-P, Kheradmand A. Errors of upright perception in patients with vestibular migraine. [Published online ahead of print October 30, 2018]. Front Neurol. doi:10.3389/fneur.2018.00892.

Recent findings suggest an abnormal sensory integration for spatial orientation in vestibular migraine (VM), related to daily dizziness in these patients. Researchers investigated the effect of static head tilts on errors of upright perception in a group of 27 patients with VM in comparison with a group of 27 healthy controls. Perception of upright was measured in a dark room using a subjective visual vertical (SVV) paradigm at 3 head tilt positions (upright, ±20°). VM patients were also surveyed about the quality of their dizziness and spatial symptoms during daily activities. Researchers found:

• In the upright head position, SVV errors were within the normal range for VM patients and healthy controls (within 2° from true vertical).
• During the static head tilts of 20° to the right, VM patients showed larger SVV errors consistent with overestimation of the tilt magnitude (ie, as if they felt further tilted toward the right side) (VM: −3.21° ± 0.93 vs control: 0.52° ± 0.70).
• During the head tilt to the left, SVV errors in VM patients did not differ significantly from controls (VM: 0.77° ± 1.05 vs control: −0.04° ± 0.68).

Winnick A, Sadeghpour S, Otero-Millan J, Chang T-P, Kheradmand A. Errors of upright perception in patients with vestibular migraine. [Published online ahead of print October 30, 2018]. Front Neurol. doi:10.3389/fneur.2018.00892.

Recent findings suggest an abnormal sensory integration for spatial orientation in vestibular migraine (VM), related to daily dizziness in these patients. Researchers investigated the effect of static head tilts on errors of upright perception in a group of 27 patients with VM in comparison with a group of 27 healthy controls. Perception of upright was measured in a dark room using a subjective visual vertical (SVV) paradigm at 3 head tilt positions (upright, ±20°). VM patients were also surveyed about the quality of their dizziness and spatial symptoms during daily activities. Researchers found:

• In the upright head position, SVV errors were within the normal range for VM patients and healthy controls (within 2° from true vertical).
• During the static head tilts of 20° to the right, VM patients showed larger SVV errors consistent with overestimation of the tilt magnitude (ie, as if they felt further tilted toward the right side) (VM: −3.21° ± 0.93 vs control: 0.52° ± 0.70).
• During the head tilt to the left, SVV errors in VM patients did not differ significantly from controls (VM: 0.77° ± 1.05 vs control: −0.04° ± 0.68).

Winnick A, Sadeghpour S, Otero-Millan J, Chang T-P, Kheradmand A. Errors of upright perception in patients with vestibular migraine. [Published online ahead of print October 30, 2018]. Front Neurol. doi:10.3389/fneur.2018.00892.

Migraine with aura was associated with increased risk of incident atrial fibrillation (AF), according to a recent study, and this may potentially lead to ischemic strokes. In the Atherosclerosis Risk in Communities (ARIC) study, a longitudinal, community-based cohort study, participants were interviewed for migraine history between 1993 and 1995 and were followed for incident AF through 2013. AF was adjudicated using electrocardiographs (ECGs), discharge codes, and death certificates. Researchers found:

• Of 11,939 participants assessed for headache and without prior AF or stroke, 426 reported migraines with visual aura, 1090 with migraine without visual aura, 1018 non-migraine headache, and 9405 no headache.
• Over a 20-year follow-up period, incident AF was noted in 232 (15%) of 1516 with migraine and 1623 (17%) of 9405 without headache.
• After adjustment for multiple confounders, migraine with visual aura was associated with increased risk of AF compared to no headache (hazard ratio 1.30) as well as when compared to migraine without visual aura (hazard ratio 1.39).
• The data suggest that AF may be a potential mediator of migraine with visual aura–stroke risk.

Sen S, Androulakis XM, Duda V, et al. Migraine with visual aura a risk factor for incident atrial fibrillation. A cohort study. [Published online ahead of print November 14, 2018]. Neurology. doi:10.1212/WNL.0000000000006650.

Migraine with aura was associated with increased risk of incident atrial fibrillation (AF), according to a recent study, and this may potentially lead to ischemic strokes. In the Atherosclerosis Risk in Communities (ARIC) study, a longitudinal, community-based cohort study, participants were interviewed for migraine history between 1993 and 1995 and were followed for incident AF through 2013. AF was adjudicated using electrocardiographs (ECGs), discharge codes, and death certificates. Researchers found:

• Of 11,939 participants assessed for headache and without prior AF or stroke, 426 reported migraines with visual aura, 1090 with migraine without visual aura, 1018 non-migraine headache, and 9405 no headache.
• Over a 20-year follow-up period, incident AF was noted in 232 (15%) of 1516 with migraine and 1623 (17%) of 9405 without headache.
• After adjustment for multiple confounders, migraine with visual aura was associated with increased risk of AF compared to no headache (hazard ratio 1.30) as well as when compared to migraine without visual aura (hazard ratio 1.39).
• The data suggest that AF may be a potential mediator of migraine with visual aura–stroke risk.

Sen S, Androulakis XM, Duda V, et al. Migraine with visual aura a risk factor for incident atrial fibrillation. A cohort study. [Published online ahead of print November 14, 2018]. Neurology. doi:10.1212/WNL.0000000000006650.

Migraine with aura was associated with increased risk of incident atrial fibrillation (AF), according to a recent study, and this may potentially lead to ischemic strokes. In the Atherosclerosis Risk in Communities (ARIC) study, a longitudinal, community-based cohort study, participants were interviewed for migraine history between 1993 and 1995 and were followed for incident AF through 2013. AF was adjudicated using electrocardiographs (ECGs), discharge codes, and death certificates. Researchers found:

• Of 11,939 participants assessed for headache and without prior AF or stroke, 426 reported migraines with visual aura, 1090 with migraine without visual aura, 1018 non-migraine headache, and 9405 no headache.
• Over a 20-year follow-up period, incident AF was noted in 232 (15%) of 1516 with migraine and 1623 (17%) of 9405 without headache.
• After adjustment for multiple confounders, migraine with visual aura was associated with increased risk of AF compared to no headache (hazard ratio 1.30) as well as when compared to migraine without visual aura (hazard ratio 1.39).
• The data suggest that AF may be a potential mediator of migraine with visual aura–stroke risk.

Sen S, Androulakis XM, Duda V, et al. Migraine with visual aura a risk factor for incident atrial fibrillation. A cohort study. [Published online ahead of print November 14, 2018]. Neurology. doi:10.1212/WNL.0000000000006650.

NEW ORLEANS – Seizure frequency increased during pregnancy for 53% of women with frontal lobe epilepsy, based on a study reported by Paula E. Voinescu, MD, PhD, at the annual meeting of the American Epilepsy Society.

Jacob Remaly/MDedge News

The single center study included data on 76 pregnancies in women with focal epilepsy –17 of them in patients with frontal lobe epilepsy – and 38 pregnancies in women with generalized epilepsy. Seizures were more frequent during pregnancy, compared with baseline, in 5.5% of women with generalized epilepsy, 22.6% of women with focal epilepsies, and 53.0% of women with frontal lobe epilepsy, said Dr. Voinescu, lead author of the study and a neurologist at Brigham and Women’s Hospital in Boston.

“Frontal lobe epilepsy is known to be difficult to manage in general and often resistant to therapy, but it isn’t clear why the seizures got worse among pregnant women because the levels of medication in their blood was considered adequate. Until more research provides treatment guidance, doctors should carefully monitor their pregnant patients who have focal epilepsy to see if their seizures increase despite adequate blood levels and then adjust their medication if necessary,” she advised. “As we know from other research, seizures during pregnancy can increase the risk of distress and neurodevelopmental delays for the baby, as well as the risk of miscarriage.”

For the study, Dr. Voinescu and her colleagues analyzed prospectively collected clinical data from 99 pregnant women followed at Brigham and Women’s Hospital between 2013 and 2018.

The researchers excluded patients with abortions, seizure onset during pregnancy, poorly defined preconception seizure frequency, nonepileptic seizures, antiepileptic drug (AED) noncompliance, and pregnancies that were enrolled in other studies. The investigators documented patients’ seizure types and AED regimens and recorded seizure frequency during the 9 months before conception, during pregnancy, and 9 months postpartum. The researchers summed all seizures for each individual for each interval. They defined seizure frequency worsening as any increase above the preconception baseline, and evaluated differences between focal and generalized epilepsy and between frontal lobe and other focal epilepsies.

Increased seizure activity tended to occur in women on more than one AED, according to Dr. Voinescu. In women with frontal lobe epilepsy, seizure worsening during pregnancy was most likely to begin in the second trimester.

The gap in seizure frequency between the groups narrowed in the 9-month postpartum period. Seizures were more frequent during the postpartum period, compared with baseline, in 12.12% of women with generalized epilepsy, 20.14% of women with focal epilepsies, and 20.00% of women with frontal lobe epilepsy.

Future analyses will evaluate the influence of AED type and concentration and specific timing on seizure control during pregnancy and the postpartum period, Dr. Voinescu said. Future studies should also include measures of sleep, which may be a contributory mechanism to the differences found between these epilepsy types.

Dr. Voinescu reported receiving funding from the American Brain Foundation, the American Epilepsy Society, and the Epilepsy Foundation through the Susan Spencer Clinical Research Fellowship.

jremaly@mdedge.com

SOURCE: Voinescu PE et al. AES 2018, Abstract 3.236.

NEW ORLEANS – Seizure frequency increased during pregnancy for 53% of women with frontal lobe epilepsy, based on a study reported by Paula E. Voinescu, MD, PhD, at the annual meeting of the American Epilepsy Society.

Jacob Remaly/MDedge News

The single center study included data on 76 pregnancies in women with focal epilepsy –17 of them in patients with frontal lobe epilepsy – and 38 pregnancies in women with generalized epilepsy. Seizures were more frequent during pregnancy, compared with baseline, in 5.5% of women with generalized epilepsy, 22.6% of women with focal epilepsies, and 53.0% of women with frontal lobe epilepsy, said Dr. Voinescu, lead author of the study and a neurologist at Brigham and Women’s Hospital in Boston.

“Frontal lobe epilepsy is known to be difficult to manage in general and often resistant to therapy, but it isn’t clear why the seizures got worse among pregnant women because the levels of medication in their blood was considered adequate. Until more research provides treatment guidance, doctors should carefully monitor their pregnant patients who have focal epilepsy to see if their seizures increase despite adequate blood levels and then adjust their medication if necessary,” she advised. “As we know from other research, seizures during pregnancy can increase the risk of distress and neurodevelopmental delays for the baby, as well as the risk of miscarriage.”

For the study, Dr. Voinescu and her colleagues analyzed prospectively collected clinical data from 99 pregnant women followed at Brigham and Women’s Hospital between 2013 and 2018.

The researchers excluded patients with abortions, seizure onset during pregnancy, poorly defined preconception seizure frequency, nonepileptic seizures, antiepileptic drug (AED) noncompliance, and pregnancies that were enrolled in other studies. The investigators documented patients’ seizure types and AED regimens and recorded seizure frequency during the 9 months before conception, during pregnancy, and 9 months postpartum. The researchers summed all seizures for each individual for each interval. They defined seizure frequency worsening as any increase above the preconception baseline, and evaluated differences between focal and generalized epilepsy and between frontal lobe and other focal epilepsies.

Increased seizure activity tended to occur in women on more than one AED, according to Dr. Voinescu. In women with frontal lobe epilepsy, seizure worsening during pregnancy was most likely to begin in the second trimester.

The gap in seizure frequency between the groups narrowed in the 9-month postpartum period. Seizures were more frequent during the postpartum period, compared with baseline, in 12.12% of women with generalized epilepsy, 20.14% of women with focal epilepsies, and 20.00% of women with frontal lobe epilepsy.

Future analyses will evaluate the influence of AED type and concentration and specific timing on seizure control during pregnancy and the postpartum period, Dr. Voinescu said. Future studies should also include measures of sleep, which may be a contributory mechanism to the differences found between these epilepsy types.

Dr. Voinescu reported receiving funding from the American Brain Foundation, the American Epilepsy Society, and the Epilepsy Foundation through the Susan Spencer Clinical Research Fellowship.

jremaly@mdedge.com

SOURCE: Voinescu PE et al. AES 2018, Abstract 3.236.

NEW ORLEANS – Seizure frequency increased during pregnancy for 53% of women with frontal lobe epilepsy, based on a study reported by Paula E. Voinescu, MD, PhD, at the annual meeting of the American Epilepsy Society.

Jacob Remaly/MDedge News

The single center study included data on 76 pregnancies in women with focal epilepsy –17 of them in patients with frontal lobe epilepsy – and 38 pregnancies in women with generalized epilepsy. Seizures were more frequent during pregnancy, compared with baseline, in 5.5% of women with generalized epilepsy, 22.6% of women with focal epilepsies, and 53.0% of women with frontal lobe epilepsy, said Dr. Voinescu, lead author of the study and a neurologist at Brigham and Women’s Hospital in Boston.

“Frontal lobe epilepsy is known to be difficult to manage in general and often resistant to therapy, but it isn’t clear why the seizures got worse among pregnant women because the levels of medication in their blood was considered adequate. Until more research provides treatment guidance, doctors should carefully monitor their pregnant patients who have focal epilepsy to see if their seizures increase despite adequate blood levels and then adjust their medication if necessary,” she advised. “As we know from other research, seizures during pregnancy can increase the risk of distress and neurodevelopmental delays for the baby, as well as the risk of miscarriage.”

For the study, Dr. Voinescu and her colleagues analyzed prospectively collected clinical data from 99 pregnant women followed at Brigham and Women’s Hospital between 2013 and 2018.

The researchers excluded patients with abortions, seizure onset during pregnancy, poorly defined preconception seizure frequency, nonepileptic seizures, antiepileptic drug (AED) noncompliance, and pregnancies that were enrolled in other studies. The investigators documented patients’ seizure types and AED regimens and recorded seizure frequency during the 9 months before conception, during pregnancy, and 9 months postpartum. The researchers summed all seizures for each individual for each interval. They defined seizure frequency worsening as any increase above the preconception baseline, and evaluated differences between focal and generalized epilepsy and between frontal lobe and other focal epilepsies.

Increased seizure activity tended to occur in women on more than one AED, according to Dr. Voinescu. In women with frontal lobe epilepsy, seizure worsening during pregnancy was most likely to begin in the second trimester.

The gap in seizure frequency between the groups narrowed in the 9-month postpartum period. Seizures were more frequent during the postpartum period, compared with baseline, in 12.12% of women with generalized epilepsy, 20.14% of women with focal epilepsies, and 20.00% of women with frontal lobe epilepsy.

Future analyses will evaluate the influence of AED type and concentration and specific timing on seizure control during pregnancy and the postpartum period, Dr. Voinescu said. Future studies should also include measures of sleep, which may be a contributory mechanism to the differences found between these epilepsy types.

Dr. Voinescu reported receiving funding from the American Brain Foundation, the American Epilepsy Society, and the Epilepsy Foundation through the Susan Spencer Clinical Research Fellowship.

jremaly@mdedge.com

SOURCE: Voinescu PE et al. AES 2018, Abstract 3.236.

Recent years have seen dramatic increases in the prevalences of chronic diseases such as type 1 diabetes,¹ gastroesophageal reflux disease,² asthma,³ inflammatory bowel disease,⁴ and, notably, obesity.⁵ I propose the hypothesis that much of this increase may be due to loss of diversity in the bacteria that make our guts their home.⁶ While multiple causes contribute, much of the blame may be attributed to the use—and overuse—of antibiotics.

FAT AND GETTING FATTER

Today, nearly 40% of US adults are obese, and nearly three-fourths are either obese or overweight.⁷ More alarming, the prevalence of obesity is also high and getting higher in children and adolescents,⁸ having increased from 10.0% in 1988–1994 to 17.8% in 2013–2016.

And not just in the United States. Trends in weight have been going up around the world, with a lag of about 30 years between developing countries and industrialized countries.5

OUR BACTERIA, OURSELVES

I believe that the bacteria we carry are not random, but rather have coevolved along with us, passed down from generation to generation in a state of dynamic equilibrium between microbes and host. Evidence supporting this comes from a study by Ochman et al,⁹ who analyzed the DNA from fecal samples from different hominid species (including Homo sapiens) and found that the phylogenic relationships among the bacteria mirrored those among the apes.

Interacting with each other and with us in complex ways, our bacteria are a diverse community to which we can apply the term microbiome. They are acquired in a standard, choreographed process,¹⁰ and their composition comes to resemble that of adults by the age of 3.¹¹

Before modern times, microbes were transferred from mother to child during vaginal birth, from the mother’s breast during nursing, through skin-to-skin contact, and from the mother’s mouth by kissing. Now, widespread cesarean delivery, bottle-feeding, extensive bathing (especially with antibacterial soaps), and especially the use of antibiotics have changed the human ecology and altered transmission and maintenance of ancestral microbes, which affects the composition of the microbiota. The microbes, both good and bad, that are usually acquired early in life are especially important, since they affect a developmentally critical stage.¹²

Loss of microbial diversity in the mother appears to be cumulative over succeeding generations.¹³ For example, in a study in Japanese families, Urita et al¹⁴ found a decline in the prevalence of Helicobacter pylori colonization from 68.7% in the first generation to 43.4% in the second generation and 12.5% in the third. Clemente et al¹⁵ studied the intestinal microbiota in a previously uncontacted group of Yanomami people in the Amazon jungle and found they had the highest diversity of bacteria ever reported in a human group. By comparison, the research team calculated that we in the United States have already lost 50% of our microbial diversity, and 2 other groups, the Guahibo (another Amerindian group) and rural Malawians, were in between. More recent studies are confirming these observations.^16,17

 

 

USE AND OVERUSE OF ANTIBIOTICS

More than 73 billion antibiotic doses are prescribed worldwide yearly,¹⁸ or about 10 doses for every man, woman, and child on Earth, and the numbers are rising. In the United States 262 million courses were prescribed in 2011, or 842 per 1,000 population.¹⁹ Children receive a mean of 2.7 courses by age 2, and 10.9 by age 10. More than 50% of women receive antibiotics during pregnancy or perinatally. This is in addition to an unknown level of exposure from agricultural use of antibiotics.

Repeated antibiotic exposure is common in early life, varies widely by country, and is often not medically justified.²⁰ In the United States, antibiotic use varies by region, with the heaviest use in the South.^19,21 It also varies widely among prescribers.²² Jones et al²³ examined antibiotic prescribing for acute respiratory infections in US veterans and found that the top 10% of physicians gave an antibiotic more than 90% of the time. Physicians in Sweden prescribe about 60% fewer antibiotics than we do in the United States.^21,24

Observational data indicate that people who receive antibiotics have a higher risk of chronic diseases later in life, eg:

• Type 2 diabetes (odds ratio 1.21, 95% confidence interval 1.19–1.23 with 2 to 4 courses, and odds ratio 1.53 (1.50–1.55) with 5 or more courses, up to 15 years after²⁵
• Obesity: US states with the highest prevalence of antibiotic use also have the highest prevalence of obesity²⁶
• Kidney stones: prior antibiotic exposure in a large UK study was associated with increased kidney stone risk, for exposures up to 5 years earlier.²⁷

The meat industry has exploited the weight effect for decades, adding subtherapeutic doses of antibiotics to animals’ feed to make them gain weight.²8

FINDINGS FROM STUDIES IN MICE

Laboratory studies of the relationship between antibiotic exposure and disease phenotypes in mice have yielded interesting findings.

Mice exposed to antibiotics had more body fat at 10 weeks (32.0%) than control mice (22.9%).²⁹

Low-dose penicillin, started at birth, induces long-lasting effects on the expression of genes involved in immunity and enhances the effect of a high-fat diet in terms of weight gain.³⁰ If the antibiotic exposure is limited to early life, the effect on the microbiota is transient, but the mice still gain weight. If the microbiota from the mice who received penicillin is transferred to germ-free mice, the recipients also become fat, indicating that the bacteria, not the antibiotics per se, cause the weight gain.

In other experiments,³¹ a series of short, therapeutic doses of antibiotics early in life modeled after those given to children to treat their acute infections caused long-term changes in the composition of the microbiome and in metabolism.

A single course of a macrolide antibiotic also had long-term effects on the microbial population and on the host’s ileal gene expression, T-cell populations, and secretory immunoglobulin A expression.³² These effects were seen only in mice that had a microbiome to begin with, not in germ-free mice, indicating that the antibiotics had their effect through the changes in the microbiome, not directly. But when germ-free mice received a fecal transplant of an impaired microbiome, it was sufficient to affect immunity.

In nonobese diabetic mice, treatment with antibiotics early in life altered the gut microbiome and its metabolic capacities, intestinal gene expression, and T-cell populations, accelerating the onset of type 1 diabetes.³³

In a study in Danish children,³⁴ the likelihood of inflammatory bowel disease increased with early-life antibiotic exposure: the more courses the child received, the greater the likelihood of disease. This observation led researchers to wonder if an antibiotic-altered microbiome affects the outcome of inflammatory bowel disease in the next generation.³⁵ Germ-free female mice who received microbiota from mice who had received antibiotics passed the altered microbiome to their pups. Mice lacking the gene for interleukin 10 are genetically susceptible to colitis, and when this experiment was done in mice lacking this gene, the offspring developed markedly more colitis. This indicated the mothers could pass down their altered microbiome to the next generation and that it would affect their risk of disease.

WHAT CAN WE DO?

All physicians must adhere to the principles of antibiotic stewardship,³⁶ not only to prevent the development of resistant strains of pathogens and the overgrowth of potentially dangerous species such as Clostridium difficile, but also, possibly, to prevent the loss of diversity in the human microbiome and thus discourage the development of chronic diseases.

In the future, as we discover more about the microbiome and the optimal mix of bacteria to carry, this information may find practical application in medicine. A pediatrician, for example, may want to analyze a child’s microbiome and, if it is abnormal, administer specific organisms to reshape it.

Recent years have seen dramatic increases in the prevalences of chronic diseases such as type 1 diabetes,¹ gastroesophageal reflux disease,² asthma,³ inflammatory bowel disease,⁴ and, notably, obesity.⁵ I propose the hypothesis that much of this increase may be due to loss of diversity in the bacteria that make our guts their home.⁶ While multiple causes contribute, much of the blame may be attributed to the use—and overuse—of antibiotics.

FAT AND GETTING FATTER

Today, nearly 40% of US adults are obese, and nearly three-fourths are either obese or overweight.⁷ More alarming, the prevalence of obesity is also high and getting higher in children and adolescents,⁸ having increased from 10.0% in 1988–1994 to 17.8% in 2013–2016.

And not just in the United States. Trends in weight have been going up around the world, with a lag of about 30 years between developing countries and industrialized countries.5

OUR BACTERIA, OURSELVES

I believe that the bacteria we carry are not random, but rather have coevolved along with us, passed down from generation to generation in a state of dynamic equilibrium between microbes and host. Evidence supporting this comes from a study by Ochman et al,⁹ who analyzed the DNA from fecal samples from different hominid species (including Homo sapiens) and found that the phylogenic relationships among the bacteria mirrored those among the apes.

Interacting with each other and with us in complex ways, our bacteria are a diverse community to which we can apply the term microbiome. They are acquired in a standard, choreographed process,¹⁰ and their composition comes to resemble that of adults by the age of 3.¹¹

Before modern times, microbes were transferred from mother to child during vaginal birth, from the mother’s breast during nursing, through skin-to-skin contact, and from the mother’s mouth by kissing. Now, widespread cesarean delivery, bottle-feeding, extensive bathing (especially with antibacterial soaps), and especially the use of antibiotics have changed the human ecology and altered transmission and maintenance of ancestral microbes, which affects the composition of the microbiota. The microbes, both good and bad, that are usually acquired early in life are especially important, since they affect a developmentally critical stage.¹²

Loss of microbial diversity in the mother appears to be cumulative over succeeding generations.¹³ For example, in a study in Japanese families, Urita et al¹⁴ found a decline in the prevalence of Helicobacter pylori colonization from 68.7% in the first generation to 43.4% in the second generation and 12.5% in the third. Clemente et al¹⁵ studied the intestinal microbiota in a previously uncontacted group of Yanomami people in the Amazon jungle and found they had the highest diversity of bacteria ever reported in a human group. By comparison, the research team calculated that we in the United States have already lost 50% of our microbial diversity, and 2 other groups, the Guahibo (another Amerindian group) and rural Malawians, were in between. More recent studies are confirming these observations.^16,17

 

 

USE AND OVERUSE OF ANTIBIOTICS

More than 73 billion antibiotic doses are prescribed worldwide yearly,¹⁸ or about 10 doses for every man, woman, and child on Earth, and the numbers are rising. In the United States 262 million courses were prescribed in 2011, or 842 per 1,000 population.¹⁹ Children receive a mean of 2.7 courses by age 2, and 10.9 by age 10. More than 50% of women receive antibiotics during pregnancy or perinatally. This is in addition to an unknown level of exposure from agricultural use of antibiotics.

Repeated antibiotic exposure is common in early life, varies widely by country, and is often not medically justified.²⁰ In the United States, antibiotic use varies by region, with the heaviest use in the South.^19,21 It also varies widely among prescribers.²² Jones et al²³ examined antibiotic prescribing for acute respiratory infections in US veterans and found that the top 10% of physicians gave an antibiotic more than 90% of the time. Physicians in Sweden prescribe about 60% fewer antibiotics than we do in the United States.^21,24

Observational data indicate that people who receive antibiotics have a higher risk of chronic diseases later in life, eg:

• Type 2 diabetes (odds ratio 1.21, 95% confidence interval 1.19–1.23 with 2 to 4 courses, and odds ratio 1.53 (1.50–1.55) with 5 or more courses, up to 15 years after²⁵
• Obesity: US states with the highest prevalence of antibiotic use also have the highest prevalence of obesity²⁶
• Kidney stones: prior antibiotic exposure in a large UK study was associated with increased kidney stone risk, for exposures up to 5 years earlier.²⁷

The meat industry has exploited the weight effect for decades, adding subtherapeutic doses of antibiotics to animals’ feed to make them gain weight.²8

FINDINGS FROM STUDIES IN MICE

Laboratory studies of the relationship between antibiotic exposure and disease phenotypes in mice have yielded interesting findings.

Mice exposed to antibiotics had more body fat at 10 weeks (32.0%) than control mice (22.9%).²⁹

Low-dose penicillin, started at birth, induces long-lasting effects on the expression of genes involved in immunity and enhances the effect of a high-fat diet in terms of weight gain.³⁰ If the antibiotic exposure is limited to early life, the effect on the microbiota is transient, but the mice still gain weight. If the microbiota from the mice who received penicillin is transferred to germ-free mice, the recipients also become fat, indicating that the bacteria, not the antibiotics per se, cause the weight gain.

In other experiments,³¹ a series of short, therapeutic doses of antibiotics early in life modeled after those given to children to treat their acute infections caused long-term changes in the composition of the microbiome and in metabolism.

A single course of a macrolide antibiotic also had long-term effects on the microbial population and on the host’s ileal gene expression, T-cell populations, and secretory immunoglobulin A expression.³² These effects were seen only in mice that had a microbiome to begin with, not in germ-free mice, indicating that the antibiotics had their effect through the changes in the microbiome, not directly. But when germ-free mice received a fecal transplant of an impaired microbiome, it was sufficient to affect immunity.

In nonobese diabetic mice, treatment with antibiotics early in life altered the gut microbiome and its metabolic capacities, intestinal gene expression, and T-cell populations, accelerating the onset of type 1 diabetes.³³

In a study in Danish children,³⁴ the likelihood of inflammatory bowel disease increased with early-life antibiotic exposure: the more courses the child received, the greater the likelihood of disease. This observation led researchers to wonder if an antibiotic-altered microbiome affects the outcome of inflammatory bowel disease in the next generation.³⁵ Germ-free female mice who received microbiota from mice who had received antibiotics passed the altered microbiome to their pups. Mice lacking the gene for interleukin 10 are genetically susceptible to colitis, and when this experiment was done in mice lacking this gene, the offspring developed markedly more colitis. This indicated the mothers could pass down their altered microbiome to the next generation and that it would affect their risk of disease.

WHAT CAN WE DO?

All physicians must adhere to the principles of antibiotic stewardship,³⁶ not only to prevent the development of resistant strains of pathogens and the overgrowth of potentially dangerous species such as Clostridium difficile, but also, possibly, to prevent the loss of diversity in the human microbiome and thus discourage the development of chronic diseases.

In the future, as we discover more about the microbiome and the optimal mix of bacteria to carry, this information may find practical application in medicine. A pediatrician, for example, may want to analyze a child’s microbiome and, if it is abnormal, administer specific organisms to reshape it.

Recent years have seen dramatic increases in the prevalences of chronic diseases such as type 1 diabetes,¹ gastroesophageal reflux disease,² asthma,³ inflammatory bowel disease,⁴ and, notably, obesity.⁵ I propose the hypothesis that much of this increase may be due to loss of diversity in the bacteria that make our guts their home.⁶ While multiple causes contribute, much of the blame may be attributed to the use—and overuse—of antibiotics.

FAT AND GETTING FATTER

Today, nearly 40% of US adults are obese, and nearly three-fourths are either obese or overweight.⁷ More alarming, the prevalence of obesity is also high and getting higher in children and adolescents,⁸ having increased from 10.0% in 1988–1994 to 17.8% in 2013–2016.

And not just in the United States. Trends in weight have been going up around the world, with a lag of about 30 years between developing countries and industrialized countries.5

OUR BACTERIA, OURSELVES

I believe that the bacteria we carry are not random, but rather have coevolved along with us, passed down from generation to generation in a state of dynamic equilibrium between microbes and host. Evidence supporting this comes from a study by Ochman et al,⁹ who analyzed the DNA from fecal samples from different hominid species (including Homo sapiens) and found that the phylogenic relationships among the bacteria mirrored those among the apes.

Interacting with each other and with us in complex ways, our bacteria are a diverse community to which we can apply the term microbiome. They are acquired in a standard, choreographed process,¹⁰ and their composition comes to resemble that of adults by the age of 3.¹¹

Before modern times, microbes were transferred from mother to child during vaginal birth, from the mother’s breast during nursing, through skin-to-skin contact, and from the mother’s mouth by kissing. Now, widespread cesarean delivery, bottle-feeding, extensive bathing (especially with antibacterial soaps), and especially the use of antibiotics have changed the human ecology and altered transmission and maintenance of ancestral microbes, which affects the composition of the microbiota. The microbes, both good and bad, that are usually acquired early in life are especially important, since they affect a developmentally critical stage.¹²

Loss of microbial diversity in the mother appears to be cumulative over succeeding generations.¹³ For example, in a study in Japanese families, Urita et al¹⁴ found a decline in the prevalence of Helicobacter pylori colonization from 68.7% in the first generation to 43.4% in the second generation and 12.5% in the third. Clemente et al¹⁵ studied the intestinal microbiota in a previously uncontacted group of Yanomami people in the Amazon jungle and found they had the highest diversity of bacteria ever reported in a human group. By comparison, the research team calculated that we in the United States have already lost 50% of our microbial diversity, and 2 other groups, the Guahibo (another Amerindian group) and rural Malawians, were in between. More recent studies are confirming these observations.^16,17

 

 

USE AND OVERUSE OF ANTIBIOTICS

More than 73 billion antibiotic doses are prescribed worldwide yearly,¹⁸ or about 10 doses for every man, woman, and child on Earth, and the numbers are rising. In the United States 262 million courses were prescribed in 2011, or 842 per 1,000 population.¹⁹ Children receive a mean of 2.7 courses by age 2, and 10.9 by age 10. More than 50% of women receive antibiotics during pregnancy or perinatally. This is in addition to an unknown level of exposure from agricultural use of antibiotics.

Repeated antibiotic exposure is common in early life, varies widely by country, and is often not medically justified.²⁰ In the United States, antibiotic use varies by region, with the heaviest use in the South.^19,21 It also varies widely among prescribers.²² Jones et al²³ examined antibiotic prescribing for acute respiratory infections in US veterans and found that the top 10% of physicians gave an antibiotic more than 90% of the time. Physicians in Sweden prescribe about 60% fewer antibiotics than we do in the United States.^21,24

Observational data indicate that people who receive antibiotics have a higher risk of chronic diseases later in life, eg:

• Type 2 diabetes (odds ratio 1.21, 95% confidence interval 1.19–1.23 with 2 to 4 courses, and odds ratio 1.53 (1.50–1.55) with 5 or more courses, up to 15 years after²⁵
• Obesity: US states with the highest prevalence of antibiotic use also have the highest prevalence of obesity²⁶
• Kidney stones: prior antibiotic exposure in a large UK study was associated with increased kidney stone risk, for exposures up to 5 years earlier.²⁷

The meat industry has exploited the weight effect for decades, adding subtherapeutic doses of antibiotics to animals’ feed to make them gain weight.²8

FINDINGS FROM STUDIES IN MICE

Laboratory studies of the relationship between antibiotic exposure and disease phenotypes in mice have yielded interesting findings.

Mice exposed to antibiotics had more body fat at 10 weeks (32.0%) than control mice (22.9%).²⁹

Low-dose penicillin, started at birth, induces long-lasting effects on the expression of genes involved in immunity and enhances the effect of a high-fat diet in terms of weight gain.³⁰ If the antibiotic exposure is limited to early life, the effect on the microbiota is transient, but the mice still gain weight. If the microbiota from the mice who received penicillin is transferred to germ-free mice, the recipients also become fat, indicating that the bacteria, not the antibiotics per se, cause the weight gain.

In other experiments,³¹ a series of short, therapeutic doses of antibiotics early in life modeled after those given to children to treat their acute infections caused long-term changes in the composition of the microbiome and in metabolism.

A single course of a macrolide antibiotic also had long-term effects on the microbial population and on the host’s ileal gene expression, T-cell populations, and secretory immunoglobulin A expression.³² These effects were seen only in mice that had a microbiome to begin with, not in germ-free mice, indicating that the antibiotics had their effect through the changes in the microbiome, not directly. But when germ-free mice received a fecal transplant of an impaired microbiome, it was sufficient to affect immunity.

In nonobese diabetic mice, treatment with antibiotics early in life altered the gut microbiome and its metabolic capacities, intestinal gene expression, and T-cell populations, accelerating the onset of type 1 diabetes.³³

In a study in Danish children,³⁴ the likelihood of inflammatory bowel disease increased with early-life antibiotic exposure: the more courses the child received, the greater the likelihood of disease. This observation led researchers to wonder if an antibiotic-altered microbiome affects the outcome of inflammatory bowel disease in the next generation.³⁵ Germ-free female mice who received microbiota from mice who had received antibiotics passed the altered microbiome to their pups. Mice lacking the gene for interleukin 10 are genetically susceptible to colitis, and when this experiment was done in mice lacking this gene, the offspring developed markedly more colitis. This indicated the mothers could pass down their altered microbiome to the next generation and that it would affect their risk of disease.

WHAT CAN WE DO?

All physicians must adhere to the principles of antibiotic stewardship,³⁶ not only to prevent the development of resistant strains of pathogens and the overgrowth of potentially dangerous species such as Clostridium difficile, but also, possibly, to prevent the loss of diversity in the human microbiome and thus discourage the development of chronic diseases.

In the future, as we discover more about the microbiome and the optimal mix of bacteria to carry, this information may find practical application in medicine. A pediatrician, for example, may want to analyze a child’s microbiome and, if it is abnormal, administer specific organisms to reshape it.

The SVS Executive Board has announced that all Active SVS members in good standing will now be considered Fellows of the Society for Vascular Surgery™ (FSVS™). The trademarked designation is one of the benefits of SVS membership and is a public acknowledgement that a surgeon has met the high standards required by the SVS of its members and has shown and professional commitment to the field of vascular surgery. Active members in good standing may add the initials FSVS™ after their name in any usage, such as signature lines, letterhead, door signage and so on. Distinguished Fellows also may use the trademarked designation of DFSVS™. Read the official announcement here.

The SVS Executive Board has announced that all Active SVS members in good standing will now be considered Fellows of the Society for Vascular Surgery™ (FSVS™). The trademarked designation is one of the benefits of SVS membership and is a public acknowledgement that a surgeon has met the high standards required by the SVS of its members and has shown and professional commitment to the field of vascular surgery. Active members in good standing may add the initials FSVS™ after their name in any usage, such as signature lines, letterhead, door signage and so on. Distinguished Fellows also may use the trademarked designation of DFSVS™. Read the official announcement here.

The SVS Executive Board has announced that all Active SVS members in good standing will now be considered Fellows of the Society for Vascular Surgery™ (FSVS™). The trademarked designation is one of the benefits of SVS membership and is a public acknowledgement that a surgeon has met the high standards required by the SVS of its members and has shown and professional commitment to the field of vascular surgery. Active members in good standing may add the initials FSVS™ after their name in any usage, such as signature lines, letterhead, door signage and so on. Distinguished Fellows also may use the trademarked designation of DFSVS™. Read the official announcement here.