LONDON—Significant treatment effect versus placebo of cladribine tablets given to patients with clinically isolated syndrome during the initial treatment period continues to be observed in patients who convert to clinically definite multiple sclerosis (MS) and switch to treatment with a different disease modifying drug (ie, subcutaneous interferon beta-1a), according to data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Giancarlo Comi, MD, Professor of Neurology and Chairman of the Department of Neurology at Vita-Salute San Raffaele University in Milan, Italy, and colleagues reported that patients with clinically isolated syndrome who had been treated with cladribine tablets and who had converted to MS during the Oral Cladribine in Early Multiple Sclerosis (ORACLE-MS) initial treatment period had lower annualized relapse rates during the open-label maintenance period, relative to those patients who had received placebo during the ORACLE-MS initial treatment period.  

The CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study in patients with active MS showed that annualized relapse rates and sustained disability worsening were reduced in patients treated with cladribine tablets annually for two years in short-duration courses, compared with placebo. The efficacy observed in CLARITY was maintained without further active treatment during the CLARITY extension study. In the ORACLE-MS study in patients with a first demyelinating event, cladribine tablets (3.5 mg/kg and 5.25 mg/kg) significantly reduced the risk of conversion to clinically definite MS, compared with placebo. If clinically definite MS occurred in the double-blinded, initial treatment period, patients were treated with subcutaneous interferon beta-1a in an open-label maintenance period.

The present study was designed to assess the annualized relapse rate during the ORACLE-MS open-label maintenance period in patients randomized to cladribine (3.5 mg/kg and 5.25 mg/kg) or placebo in the initial treatment period.

Similar to previous trials, participation in the ORACLE-MS open-label maintenance period was dependent upon the clinical course of the patient’s disease in the initial treatment period. Patients in ORACLE-MS who converted to clinically definite MS (according to Poser criteria) during the initial treatment period entered the open-label maintenance period and were treated with subcutaneous interferon beta-1a (titrated over four weeks up to the dose of 44 μg) administered three times per week.

A total of 109 patients in ORACLE-MS converted to clinically definite MS in the initial treatment period and received at least one dose of interferon beta-1a. The median time on interferon beta-1a was 56.0 weeks. Estimated annualized relapse rates in the open-label maintenance period were 0.14 for patients (n = 25) originally treated with cladribine 3.5 mg/kg, 0.24 for patients (n = 24) originally treated with cladribine 5.25 mg/kg, and 0.42 for patients (n = 60) who originally received placebo in the initial treatment period.

According to the researchers, durable efficacy of cladribine tablets in ORACLE-MS into the open-label maintenance period is consistent with results of the CLARITY and CLARITY extension studies.

This study was sponsored by EMD Serono Inc.

—Glenn S. Williams

LONDON—Significant treatment effect versus placebo of cladribine tablets given to patients with clinically isolated syndrome during the initial treatment period continues to be observed in patients who convert to clinically definite multiple sclerosis (MS) and switch to treatment with a different disease modifying drug (ie, subcutaneous interferon beta-1a), according to data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Giancarlo Comi, MD, Professor of Neurology and Chairman of the Department of Neurology at Vita-Salute San Raffaele University in Milan, Italy, and colleagues reported that patients with clinically isolated syndrome who had been treated with cladribine tablets and who had converted to MS during the Oral Cladribine in Early Multiple Sclerosis (ORACLE-MS) initial treatment period had lower annualized relapse rates during the open-label maintenance period, relative to those patients who had received placebo during the ORACLE-MS initial treatment period.  

The CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study in patients with active MS showed that annualized relapse rates and sustained disability worsening were reduced in patients treated with cladribine tablets annually for two years in short-duration courses, compared with placebo. The efficacy observed in CLARITY was maintained without further active treatment during the CLARITY extension study. In the ORACLE-MS study in patients with a first demyelinating event, cladribine tablets (3.5 mg/kg and 5.25 mg/kg) significantly reduced the risk of conversion to clinically definite MS, compared with placebo. If clinically definite MS occurred in the double-blinded, initial treatment period, patients were treated with subcutaneous interferon beta-1a in an open-label maintenance period.

The present study was designed to assess the annualized relapse rate during the ORACLE-MS open-label maintenance period in patients randomized to cladribine (3.5 mg/kg and 5.25 mg/kg) or placebo in the initial treatment period.

Similar to previous trials, participation in the ORACLE-MS open-label maintenance period was dependent upon the clinical course of the patient’s disease in the initial treatment period. Patients in ORACLE-MS who converted to clinically definite MS (according to Poser criteria) during the initial treatment period entered the open-label maintenance period and were treated with subcutaneous interferon beta-1a (titrated over four weeks up to the dose of 44 μg) administered three times per week.

A total of 109 patients in ORACLE-MS converted to clinically definite MS in the initial treatment period and received at least one dose of interferon beta-1a. The median time on interferon beta-1a was 56.0 weeks. Estimated annualized relapse rates in the open-label maintenance period were 0.14 for patients (n = 25) originally treated with cladribine 3.5 mg/kg, 0.24 for patients (n = 24) originally treated with cladribine 5.25 mg/kg, and 0.42 for patients (n = 60) who originally received placebo in the initial treatment period.

According to the researchers, durable efficacy of cladribine tablets in ORACLE-MS into the open-label maintenance period is consistent with results of the CLARITY and CLARITY extension studies.

This study was sponsored by EMD Serono Inc.

—Glenn S. Williams

LONDON—Significant treatment effect versus placebo of cladribine tablets given to patients with clinically isolated syndrome during the initial treatment period continues to be observed in patients who convert to clinically definite multiple sclerosis (MS) and switch to treatment with a different disease modifying drug (ie, subcutaneous interferon beta-1a), according to data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Giancarlo Comi, MD, Professor of Neurology and Chairman of the Department of Neurology at Vita-Salute San Raffaele University in Milan, Italy, and colleagues reported that patients with clinically isolated syndrome who had been treated with cladribine tablets and who had converted to MS during the Oral Cladribine in Early Multiple Sclerosis (ORACLE-MS) initial treatment period had lower annualized relapse rates during the open-label maintenance period, relative to those patients who had received placebo during the ORACLE-MS initial treatment period.  

The CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study in patients with active MS showed that annualized relapse rates and sustained disability worsening were reduced in patients treated with cladribine tablets annually for two years in short-duration courses, compared with placebo. The efficacy observed in CLARITY was maintained without further active treatment during the CLARITY extension study. In the ORACLE-MS study in patients with a first demyelinating event, cladribine tablets (3.5 mg/kg and 5.25 mg/kg) significantly reduced the risk of conversion to clinically definite MS, compared with placebo. If clinically definite MS occurred in the double-blinded, initial treatment period, patients were treated with subcutaneous interferon beta-1a in an open-label maintenance period.

The present study was designed to assess the annualized relapse rate during the ORACLE-MS open-label maintenance period in patients randomized to cladribine (3.5 mg/kg and 5.25 mg/kg) or placebo in the initial treatment period.

Similar to previous trials, participation in the ORACLE-MS open-label maintenance period was dependent upon the clinical course of the patient’s disease in the initial treatment period. Patients in ORACLE-MS who converted to clinically definite MS (according to Poser criteria) during the initial treatment period entered the open-label maintenance period and were treated with subcutaneous interferon beta-1a (titrated over four weeks up to the dose of 44 μg) administered three times per week.

A total of 109 patients in ORACLE-MS converted to clinically definite MS in the initial treatment period and received at least one dose of interferon beta-1a. The median time on interferon beta-1a was 56.0 weeks. Estimated annualized relapse rates in the open-label maintenance period were 0.14 for patients (n = 25) originally treated with cladribine 3.5 mg/kg, 0.24 for patients (n = 24) originally treated with cladribine 5.25 mg/kg, and 0.42 for patients (n = 60) who originally received placebo in the initial treatment period.

According to the researchers, durable efficacy of cladribine tablets in ORACLE-MS into the open-label maintenance period is consistent with results of the CLARITY and CLARITY extension studies.

This study was sponsored by EMD Serono Inc.

—Glenn S. Williams

In 2014, more people died of drug overdoses than in any other year, and the majority of the deaths involved an opioid. In fact, “more Americans die from drug overdoses than car crashes,” said Sylvia Burwell, HHS secretary, in announcing new actions the department is taking to combat the opioid epidemic.

Related: Call for App to Help Opioid Rehab

The actions build on the HHS Opioid Initiative, launched March 2015, and the National Pain Strategy, the government’s first coordinated plan to reduce the burden of chronic pain in the U.S. The programs focus on 3 priorities: improving opioid prescribing practices, expanding access to medication-assisted treatment, and increasing use of naloxone to reverse overdoses.

Among the changes: SAMHSA finalized a rule to allow practitioners who can prescribe buprenorphine for up to 100 patients for a year or more now to treat up to 275 patients. Practitioners can obtain the waiver for the increase if they have additional credentialing in addiction medicine or addiction psychiatry from a specialty medical board and/or professional society, or practice in a qualified setting.

Related: Lowering Veterans’ Opioid Use and Reducing Overdose Risk

Another important change was to the IHS Prescription Drug Monitoring Program (PDMP) policy. Although many IHS clinicians already use PDMP databases, opioid prescribers and pharmacists will now be required to check state PDMP databases before prescribing or dispensing any opioid for > 7 days. The goal is to help improve pain management care, identify patients who may have a misuse problem, and prevent diversion of drugs. The new policy is effective immediately for > 1,200 clinicians working in IHS federally operated facilities.  The IHS has also announced that it will train hundreds of  law enforcement officers of the Bureau of Indian Affairs on how to use naloxone and provide them with the drug.

The VA is releasing a new policy as well that requires health care providers who prescribe controlled substances to check State PDMPs before prescribing, at least once a year and/or when clinically indicated for renewal or continuation of therapy.

Related: Veterans’ Health and Opioid Safety–Contexts, Risks, and Outreach Implications

President Obama’s budget requests $1.1 billion in new mandatory and discretionary investments over fiscal years 2017 and 2018, to expand access to treatment and prevent opioid misuse and abuse.

In 2014, more people died of drug overdoses than in any other year, and the majority of the deaths involved an opioid. In fact, “more Americans die from drug overdoses than car crashes,” said Sylvia Burwell, HHS secretary, in announcing new actions the department is taking to combat the opioid epidemic.

Related: Call for App to Help Opioid Rehab

The actions build on the HHS Opioid Initiative, launched March 2015, and the National Pain Strategy, the government’s first coordinated plan to reduce the burden of chronic pain in the U.S. The programs focus on 3 priorities: improving opioid prescribing practices, expanding access to medication-assisted treatment, and increasing use of naloxone to reverse overdoses.

Among the changes: SAMHSA finalized a rule to allow practitioners who can prescribe buprenorphine for up to 100 patients for a year or more now to treat up to 275 patients. Practitioners can obtain the waiver for the increase if they have additional credentialing in addiction medicine or addiction psychiatry from a specialty medical board and/or professional society, or practice in a qualified setting.

Related: Lowering Veterans’ Opioid Use and Reducing Overdose Risk

Another important change was to the IHS Prescription Drug Monitoring Program (PDMP) policy. Although many IHS clinicians already use PDMP databases, opioid prescribers and pharmacists will now be required to check state PDMP databases before prescribing or dispensing any opioid for > 7 days. The goal is to help improve pain management care, identify patients who may have a misuse problem, and prevent diversion of drugs. The new policy is effective immediately for > 1,200 clinicians working in IHS federally operated facilities.  The IHS has also announced that it will train hundreds of  law enforcement officers of the Bureau of Indian Affairs on how to use naloxone and provide them with the drug.

The VA is releasing a new policy as well that requires health care providers who prescribe controlled substances to check State PDMPs before prescribing, at least once a year and/or when clinically indicated for renewal or continuation of therapy.

Related: Veterans’ Health and Opioid Safety–Contexts, Risks, and Outreach Implications

President Obama’s budget requests $1.1 billion in new mandatory and discretionary investments over fiscal years 2017 and 2018, to expand access to treatment and prevent opioid misuse and abuse.

In 2014, more people died of drug overdoses than in any other year, and the majority of the deaths involved an opioid. In fact, “more Americans die from drug overdoses than car crashes,” said Sylvia Burwell, HHS secretary, in announcing new actions the department is taking to combat the opioid epidemic.

Related: Call for App to Help Opioid Rehab

The actions build on the HHS Opioid Initiative, launched March 2015, and the National Pain Strategy, the government’s first coordinated plan to reduce the burden of chronic pain in the U.S. The programs focus on 3 priorities: improving opioid prescribing practices, expanding access to medication-assisted treatment, and increasing use of naloxone to reverse overdoses.

Among the changes: SAMHSA finalized a rule to allow practitioners who can prescribe buprenorphine for up to 100 patients for a year or more now to treat up to 275 patients. Practitioners can obtain the waiver for the increase if they have additional credentialing in addiction medicine or addiction psychiatry from a specialty medical board and/or professional society, or practice in a qualified setting.

Related: Lowering Veterans’ Opioid Use and Reducing Overdose Risk

Another important change was to the IHS Prescription Drug Monitoring Program (PDMP) policy. Although many IHS clinicians already use PDMP databases, opioid prescribers and pharmacists will now be required to check state PDMP databases before prescribing or dispensing any opioid for > 7 days. The goal is to help improve pain management care, identify patients who may have a misuse problem, and prevent diversion of drugs. The new policy is effective immediately for > 1,200 clinicians working in IHS federally operated facilities.  The IHS has also announced that it will train hundreds of  law enforcement officers of the Bureau of Indian Affairs on how to use naloxone and provide them with the drug.

The VA is releasing a new policy as well that requires health care providers who prescribe controlled substances to check State PDMPs before prescribing, at least once a year and/or when clinically indicated for renewal or continuation of therapy.

Related: Veterans’ Health and Opioid Safety–Contexts, Risks, and Outreach Implications

President Obama’s budget requests $1.1 billion in new mandatory and discretionary investments over fiscal years 2017 and 2018, to expand access to treatment and prevent opioid misuse and abuse.

Researchers in the lab

Photo by Rhoda Baer

Researchers have developed a metric that uses citation rates to determine the influence of a scientific article.

The team says the metric, known as the Relative Citation Ratio (RCR), measures a scientific publication’s influence in a way that is article-level and field-independent.

George Santangelo, PhD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues described this metric in PLOS Biology.

The researchers noted that citation is the primary mechanism for scientists to recognize the importance of each other’s work, but citation practices vary widely between fields.

RCR incorporates a novel method for field-normalization: the co-citation network. This network is formed from the reference lists of articles that cite the article in question.

For example, if Article X is cited by Article A, Article B, and Article C, the co-citation network of Article X would contain all the articles from the reference lists of Articles A, B, and C. Comparing the citation rate of Article X to the citation rate in the co-citation network allows each article to create its own individualized field.

In addition to using the co-citation network, RCR is also benchmarked to a peer comparison group so that it’s easy to determine the relative impact of an article.

The researchers said this benchmarking step is particularly important as it allows “apples-to-apples” comparisons for groups of papers; eg, comparing research output between similar types of institutions or between developing nations.

To test RCR, Dr Santangelo and his colleagues analyzed 88,835 articles published between 2003 and 2010.

The team said the National Institutes of Health awardees listed as authors of those articles “occupy relatively stable positions of influence across all disciplines.” Furthermore, the values generated by RCR correlated with the opinions of subject matter experts.

Still, the researchers acknowledged that RCR should not be used as a substitute for expert opinion.

“No number can fully represent the impact of an individual work or investigator,” Dr Santangelo said. “Neither RCR nor any other metric can quantitate the underlying value of a study nor measure the importance of making progress in solving a particular problem.”

Dr Santangelo said that, although expert opinion will remain the gold standard, RCR can assist in “the dissemination of a dynamic way to measure the influence of articles on their respective fields.”

A beta version of “iCite,” a web tool for calculating the RCR of articles listed in PubMed, is available at https://icite.od.nih.gov.

Researchers in the lab

Photo by Rhoda Baer

Researchers have developed a metric that uses citation rates to determine the influence of a scientific article.

The team says the metric, known as the Relative Citation Ratio (RCR), measures a scientific publication’s influence in a way that is article-level and field-independent.

George Santangelo, PhD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues described this metric in PLOS Biology.

The researchers noted that citation is the primary mechanism for scientists to recognize the importance of each other’s work, but citation practices vary widely between fields.

RCR incorporates a novel method for field-normalization: the co-citation network. This network is formed from the reference lists of articles that cite the article in question.

For example, if Article X is cited by Article A, Article B, and Article C, the co-citation network of Article X would contain all the articles from the reference lists of Articles A, B, and C. Comparing the citation rate of Article X to the citation rate in the co-citation network allows each article to create its own individualized field.

In addition to using the co-citation network, RCR is also benchmarked to a peer comparison group so that it’s easy to determine the relative impact of an article.

The researchers said this benchmarking step is particularly important as it allows “apples-to-apples” comparisons for groups of papers; eg, comparing research output between similar types of institutions or between developing nations.

To test RCR, Dr Santangelo and his colleagues analyzed 88,835 articles published between 2003 and 2010.

The team said the National Institutes of Health awardees listed as authors of those articles “occupy relatively stable positions of influence across all disciplines.” Furthermore, the values generated by RCR correlated with the opinions of subject matter experts.

Still, the researchers acknowledged that RCR should not be used as a substitute for expert opinion.

“No number can fully represent the impact of an individual work or investigator,” Dr Santangelo said. “Neither RCR nor any other metric can quantitate the underlying value of a study nor measure the importance of making progress in solving a particular problem.”

Dr Santangelo said that, although expert opinion will remain the gold standard, RCR can assist in “the dissemination of a dynamic way to measure the influence of articles on their respective fields.”

A beta version of “iCite,” a web tool for calculating the RCR of articles listed in PubMed, is available at https://icite.od.nih.gov.

Researchers in the lab

Photo by Rhoda Baer

Researchers have developed a metric that uses citation rates to determine the influence of a scientific article.

The team says the metric, known as the Relative Citation Ratio (RCR), measures a scientific publication’s influence in a way that is article-level and field-independent.

George Santangelo, PhD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues described this metric in PLOS Biology.

The researchers noted that citation is the primary mechanism for scientists to recognize the importance of each other’s work, but citation practices vary widely between fields.

RCR incorporates a novel method for field-normalization: the co-citation network. This network is formed from the reference lists of articles that cite the article in question.

For example, if Article X is cited by Article A, Article B, and Article C, the co-citation network of Article X would contain all the articles from the reference lists of Articles A, B, and C. Comparing the citation rate of Article X to the citation rate in the co-citation network allows each article to create its own individualized field.

In addition to using the co-citation network, RCR is also benchmarked to a peer comparison group so that it’s easy to determine the relative impact of an article.

The researchers said this benchmarking step is particularly important as it allows “apples-to-apples” comparisons for groups of papers; eg, comparing research output between similar types of institutions or between developing nations.

To test RCR, Dr Santangelo and his colleagues analyzed 88,835 articles published between 2003 and 2010.

The team said the National Institutes of Health awardees listed as authors of those articles “occupy relatively stable positions of influence across all disciplines.” Furthermore, the values generated by RCR correlated with the opinions of subject matter experts.

Still, the researchers acknowledged that RCR should not be used as a substitute for expert opinion.

“No number can fully represent the impact of an individual work or investigator,” Dr Santangelo said. “Neither RCR nor any other metric can quantitate the underlying value of a study nor measure the importance of making progress in solving a particular problem.”

Dr Santangelo said that, although expert opinion will remain the gold standard, RCR can assist in “the dissemination of a dynamic way to measure the influence of articles on their respective fields.”

A beta version of “iCite,” a web tool for calculating the RCR of articles listed in PubMed, is available at https://icite.od.nih.gov.

Doel nuclear power station

Photo by Rafaël Delaedt

Living near a certain type of nuclear facility may increase a child’s risk of developing acute leukemia, a new study suggests.

The research showed a 2- to 3-fold increased risk of acute leukemia among children living near 1 nuclear facility in Belgium—Mol-Dessel.

However, children who lived near the 3 other Belgian nuclear facilities studied—Doel, Fleurus, and Tihange—had no such increased risk.

Researchers said this study does not confirm a causal relationship between the Mol-Dessel facility and the increased risk of leukemia observed.

However, they did say the facility seems a plausible cause of the increased risk because the data showed significant associations between acute leukemia incidence and 3 surrogate measures of exposure—distance from the facility, prevailing winds, and simulated discharges of the radionuclide Ar-41.

An Van Nieuwenhuyse, MD, PhD, of the Scientific Institute of Public Health in Brussels, Belgium, and colleagues conducted this research and reported the results in the European Journal of Cancer Prevention.

Facilities

The study included 4 nuclear facilities in Belgium—Doel, Mol-Dessel, Fleurus, and Tihange. (The researchers also evaluated a fifth facility, Chooz, but they said it was not possible to draw conclusions regarding this site because the region around it is sparsely populated, which limits the number of cancer cases.)

Doel and Tihange are electricity-generating nuclear power plants that started up in 1975. The nuclear facility at Fleurus has produced radionuclides for medicine and industry since 1971.

The Mol-Dessel facility started up in 1956, and a combination of nuclear activities have taken place there, including scientific and technological research, applied research and metrology, operational waste management, the Belgian Underground Research Laboratory, and the production of fuel assemblies for pressurized-water reactors based on uranium oxide and mixed oxides.

Analysis

The researchers set out to determine whether there was an excess incidence of acute leukemia among children ages 0 to 14 who lived in the vicinity of the aforementioned nuclear facilities. The team analyzed data spanning the period from 2002 to 2008.

For all 4 facilities, the researchers used 2 different measures of surrogate exposure to radionuclide gaseous discharges—residential proximity to the nuclear site and prevailing wind directions.

For the Mol-Dessel site, the researchers also used estimated discharges of the radionuclide Ar-41 as a surrogate measure of exposure.

Results

The data did not show an increased incidence of acute leukemia among children living near the Doel, Tihange, or Fleurus facilities. However, children living within 15 km of the Mol-Dessel site had a significantly increased risk of acute leukemia.

In fact, the researchers said they observed statistically significant associations as a function of distance, prevailing winds, and simulated Ar-41 discharges, which suggests a potential link between acute leukemia incidence and the Mol-Dessel site.

The rate ratios for the Mol-Dessel facility, which were adjusted for age, sex, and socioeconomic status, were:

• 2.70 (95% CI: 1.15–6.33) for children living 0 to 5 km from the site (5 cases of acute leukemia)
• 1.82 (95% CI: 1.02–3.25) for children living 0 to 10 km from the site (11 cases of acute leukemia)
• 1.96 (95% CI: 1.19–3.22) for children living 0 to 15 km from the site (15 cases of acute leukemia)
• 1.09 (95% CI: 0.71–1.61) for children living 0 to 20 km from the site (21 cases of acute leukemia).

The 3 communities lying in the dominant wind direction of the Mol-Dessel nuclear site had rate ratios of 6.81 (95% CI: 2.28–20.32), 4.39 (95% CI: 1.46–13.17), and 3.74 (95% CI: 0.98–14.27).

The researchers calculated P values using Stone’s test, Bithell’s linear risk score test (LRS), and Bithell’s linear risk score test with corresponding ranks as a function of the different measures of surrogate exposure (LRS^r).

All 3 tests showed a significant association between acute leukemia incidence and proximity to the Mol-Dessel site (P<0.01 for all). However, only LRS and LRS^r showed a significant association for wind direction (P=0.01 and 0.03, respectively) and simulated radioactive discharges by Ar-41 (P<0.01 for both).

The researchers noted that, although these results suggest an association between acute childhood leukemia and the Mol-Dessel site, this study had limitations, and more research is needed.

Doel nuclear power station

Photo by Rafaël Delaedt

Living near a certain type of nuclear facility may increase a child’s risk of developing acute leukemia, a new study suggests.

The research showed a 2- to 3-fold increased risk of acute leukemia among children living near 1 nuclear facility in Belgium—Mol-Dessel.

However, children who lived near the 3 other Belgian nuclear facilities studied—Doel, Fleurus, and Tihange—had no such increased risk.

Researchers said this study does not confirm a causal relationship between the Mol-Dessel facility and the increased risk of leukemia observed.

However, they did say the facility seems a plausible cause of the increased risk because the data showed significant associations between acute leukemia incidence and 3 surrogate measures of exposure—distance from the facility, prevailing winds, and simulated discharges of the radionuclide Ar-41.

An Van Nieuwenhuyse, MD, PhD, of the Scientific Institute of Public Health in Brussels, Belgium, and colleagues conducted this research and reported the results in the European Journal of Cancer Prevention.

Facilities

The study included 4 nuclear facilities in Belgium—Doel, Mol-Dessel, Fleurus, and Tihange. (The researchers also evaluated a fifth facility, Chooz, but they said it was not possible to draw conclusions regarding this site because the region around it is sparsely populated, which limits the number of cancer cases.)

Doel and Tihange are electricity-generating nuclear power plants that started up in 1975. The nuclear facility at Fleurus has produced radionuclides for medicine and industry since 1971.

The Mol-Dessel facility started up in 1956, and a combination of nuclear activities have taken place there, including scientific and technological research, applied research and metrology, operational waste management, the Belgian Underground Research Laboratory, and the production of fuel assemblies for pressurized-water reactors based on uranium oxide and mixed oxides.

Analysis

The researchers set out to determine whether there was an excess incidence of acute leukemia among children ages 0 to 14 who lived in the vicinity of the aforementioned nuclear facilities. The team analyzed data spanning the period from 2002 to 2008.

For all 4 facilities, the researchers used 2 different measures of surrogate exposure to radionuclide gaseous discharges—residential proximity to the nuclear site and prevailing wind directions.

For the Mol-Dessel site, the researchers also used estimated discharges of the radionuclide Ar-41 as a surrogate measure of exposure.

Results

The data did not show an increased incidence of acute leukemia among children living near the Doel, Tihange, or Fleurus facilities. However, children living within 15 km of the Mol-Dessel site had a significantly increased risk of acute leukemia.

In fact, the researchers said they observed statistically significant associations as a function of distance, prevailing winds, and simulated Ar-41 discharges, which suggests a potential link between acute leukemia incidence and the Mol-Dessel site.

The rate ratios for the Mol-Dessel facility, which were adjusted for age, sex, and socioeconomic status, were:

• 2.70 (95% CI: 1.15–6.33) for children living 0 to 5 km from the site (5 cases of acute leukemia)
• 1.82 (95% CI: 1.02–3.25) for children living 0 to 10 km from the site (11 cases of acute leukemia)
• 1.96 (95% CI: 1.19–3.22) for children living 0 to 15 km from the site (15 cases of acute leukemia)
• 1.09 (95% CI: 0.71–1.61) for children living 0 to 20 km from the site (21 cases of acute leukemia).

The 3 communities lying in the dominant wind direction of the Mol-Dessel nuclear site had rate ratios of 6.81 (95% CI: 2.28–20.32), 4.39 (95% CI: 1.46–13.17), and 3.74 (95% CI: 0.98–14.27).

The researchers calculated P values using Stone’s test, Bithell’s linear risk score test (LRS), and Bithell’s linear risk score test with corresponding ranks as a function of the different measures of surrogate exposure (LRS^r).

All 3 tests showed a significant association between acute leukemia incidence and proximity to the Mol-Dessel site (P<0.01 for all). However, only LRS and LRS^r showed a significant association for wind direction (P=0.01 and 0.03, respectively) and simulated radioactive discharges by Ar-41 (P<0.01 for both).

The researchers noted that, although these results suggest an association between acute childhood leukemia and the Mol-Dessel site, this study had limitations, and more research is needed.

Doel nuclear power station

Photo by Rafaël Delaedt

Living near a certain type of nuclear facility may increase a child’s risk of developing acute leukemia, a new study suggests.

The research showed a 2- to 3-fold increased risk of acute leukemia among children living near 1 nuclear facility in Belgium—Mol-Dessel.

However, children who lived near the 3 other Belgian nuclear facilities studied—Doel, Fleurus, and Tihange—had no such increased risk.

Researchers said this study does not confirm a causal relationship between the Mol-Dessel facility and the increased risk of leukemia observed.

However, they did say the facility seems a plausible cause of the increased risk because the data showed significant associations between acute leukemia incidence and 3 surrogate measures of exposure—distance from the facility, prevailing winds, and simulated discharges of the radionuclide Ar-41.

An Van Nieuwenhuyse, MD, PhD, of the Scientific Institute of Public Health in Brussels, Belgium, and colleagues conducted this research and reported the results in the European Journal of Cancer Prevention.

Facilities

The study included 4 nuclear facilities in Belgium—Doel, Mol-Dessel, Fleurus, and Tihange. (The researchers also evaluated a fifth facility, Chooz, but they said it was not possible to draw conclusions regarding this site because the region around it is sparsely populated, which limits the number of cancer cases.)

Doel and Tihange are electricity-generating nuclear power plants that started up in 1975. The nuclear facility at Fleurus has produced radionuclides for medicine and industry since 1971.

The Mol-Dessel facility started up in 1956, and a combination of nuclear activities have taken place there, including scientific and technological research, applied research and metrology, operational waste management, the Belgian Underground Research Laboratory, and the production of fuel assemblies for pressurized-water reactors based on uranium oxide and mixed oxides.

Analysis

The researchers set out to determine whether there was an excess incidence of acute leukemia among children ages 0 to 14 who lived in the vicinity of the aforementioned nuclear facilities. The team analyzed data spanning the period from 2002 to 2008.

For all 4 facilities, the researchers used 2 different measures of surrogate exposure to radionuclide gaseous discharges—residential proximity to the nuclear site and prevailing wind directions.

For the Mol-Dessel site, the researchers also used estimated discharges of the radionuclide Ar-41 as a surrogate measure of exposure.

Results

The data did not show an increased incidence of acute leukemia among children living near the Doel, Tihange, or Fleurus facilities. However, children living within 15 km of the Mol-Dessel site had a significantly increased risk of acute leukemia.

In fact, the researchers said they observed statistically significant associations as a function of distance, prevailing winds, and simulated Ar-41 discharges, which suggests a potential link between acute leukemia incidence and the Mol-Dessel site.

The rate ratios for the Mol-Dessel facility, which were adjusted for age, sex, and socioeconomic status, were:

• 2.70 (95% CI: 1.15–6.33) for children living 0 to 5 km from the site (5 cases of acute leukemia)
• 1.82 (95% CI: 1.02–3.25) for children living 0 to 10 km from the site (11 cases of acute leukemia)
• 1.96 (95% CI: 1.19–3.22) for children living 0 to 15 km from the site (15 cases of acute leukemia)
• 1.09 (95% CI: 0.71–1.61) for children living 0 to 20 km from the site (21 cases of acute leukemia).

The 3 communities lying in the dominant wind direction of the Mol-Dessel nuclear site had rate ratios of 6.81 (95% CI: 2.28–20.32), 4.39 (95% CI: 1.46–13.17), and 3.74 (95% CI: 0.98–14.27).

The researchers calculated P values using Stone’s test, Bithell’s linear risk score test (LRS), and Bithell’s linear risk score test with corresponding ranks as a function of the different measures of surrogate exposure (LRS^r).

All 3 tests showed a significant association between acute leukemia incidence and proximity to the Mol-Dessel site (P<0.01 for all). However, only LRS and LRS^r showed a significant association for wind direction (P=0.01 and 0.03, respectively) and simulated radioactive discharges by Ar-41 (P<0.01 for both).

The researchers noted that, although these results suggest an association between acute childhood leukemia and the Mol-Dessel site, this study had limitations, and more research is needed.

Malaria-carrying mosquito

Photo by James Gathany

The World Health Organization (WHO) has certified that Sri Lanka is now free of malaria.

Malaria was on the rise in Sri Lanka in the 1970s and 1980s. So, in the 1990s, the country adjusted its anti-malaria campaign.

The new strategy was to target the malaria parasite as well as the mosquitoes that spread the disease.

Sri Lanka set up mobile malaria clinics in high-transmission areas, which meant that prompt treatment could reduce the parasite reservoir and the possibility of further transmission.

Meanwhile, efforts to enhance surveillance, community engagement, and health education improved the ability of authorities to respond and mobilized popular support for the anti-malaria campaign.

Sri Lanka also received support from partners such as WHO and the Global Fund to Fight AIDS, Tuberculosis and Malaria.

By 2006, Sri Lanka recorded less than 1000 cases of malaria per year. By October 2012, the indigenous cases were down to 0. For the past 3.5 years, no locally transmitted cases have been recorded.

“Sri Lanka’s achievement is truly remarkable,” said Dr Poonam Khetrapal Singh, WHO regional director for Southeast Asia. “In the mid-20th century, it was among the most malaria-affected countries, but now it is malaria-free.”

“This is a testament to the courage and vision of its leaders and signifies the great leaps that can be made when targeted action is taken. It also demonstrates the importance of grass-roots community engagement and a whole-of-society approach when it comes to making dramatic public health gains.”

To maintain elimination and ensure the malaria parasite is not reintroduced to Sri Lanka, the anti-malaria campaign is working closely with local authorities and international partners to maintain surveillance and response capacity and to screen high-risk populations entering the country.

Dr Khetrapal Singh said WHO will continue to support the efforts of Sri Lanka’s health authorities as they relate to malaria, as well as the country’s wider public health mission.

Sri Lanka is the second country in the WHO Southeast Asia region to eliminate malaria—after Maldives.

The announcement that Sri Lanka is malaria-free was made at the Sixty-ninth Session of the WHO Regional Committee for South-East Asia in Colombo, Sri Lanka, in the presence of health ministers and senior health officials from all 11 member states.

Malaria-carrying mosquito

Photo by James Gathany

The World Health Organization (WHO) has certified that Sri Lanka is now free of malaria.

Malaria was on the rise in Sri Lanka in the 1970s and 1980s. So, in the 1990s, the country adjusted its anti-malaria campaign.

The new strategy was to target the malaria parasite as well as the mosquitoes that spread the disease.

Sri Lanka set up mobile malaria clinics in high-transmission areas, which meant that prompt treatment could reduce the parasite reservoir and the possibility of further transmission.

Meanwhile, efforts to enhance surveillance, community engagement, and health education improved the ability of authorities to respond and mobilized popular support for the anti-malaria campaign.

Sri Lanka also received support from partners such as WHO and the Global Fund to Fight AIDS, Tuberculosis and Malaria.

By 2006, Sri Lanka recorded less than 1000 cases of malaria per year. By October 2012, the indigenous cases were down to 0. For the past 3.5 years, no locally transmitted cases have been recorded.

“Sri Lanka’s achievement is truly remarkable,” said Dr Poonam Khetrapal Singh, WHO regional director for Southeast Asia. “In the mid-20th century, it was among the most malaria-affected countries, but now it is malaria-free.”

“This is a testament to the courage and vision of its leaders and signifies the great leaps that can be made when targeted action is taken. It also demonstrates the importance of grass-roots community engagement and a whole-of-society approach when it comes to making dramatic public health gains.”

To maintain elimination and ensure the malaria parasite is not reintroduced to Sri Lanka, the anti-malaria campaign is working closely with local authorities and international partners to maintain surveillance and response capacity and to screen high-risk populations entering the country.

Dr Khetrapal Singh said WHO will continue to support the efforts of Sri Lanka’s health authorities as they relate to malaria, as well as the country’s wider public health mission.

Sri Lanka is the second country in the WHO Southeast Asia region to eliminate malaria—after Maldives.

The announcement that Sri Lanka is malaria-free was made at the Sixty-ninth Session of the WHO Regional Committee for South-East Asia in Colombo, Sri Lanka, in the presence of health ministers and senior health officials from all 11 member states.

Malaria-carrying mosquito

Photo by James Gathany

The World Health Organization (WHO) has certified that Sri Lanka is now free of malaria.

Malaria was on the rise in Sri Lanka in the 1970s and 1980s. So, in the 1990s, the country adjusted its anti-malaria campaign.

The new strategy was to target the malaria parasite as well as the mosquitoes that spread the disease.

Sri Lanka set up mobile malaria clinics in high-transmission areas, which meant that prompt treatment could reduce the parasite reservoir and the possibility of further transmission.

Meanwhile, efforts to enhance surveillance, community engagement, and health education improved the ability of authorities to respond and mobilized popular support for the anti-malaria campaign.

Sri Lanka also received support from partners such as WHO and the Global Fund to Fight AIDS, Tuberculosis and Malaria.

By 2006, Sri Lanka recorded less than 1000 cases of malaria per year. By October 2012, the indigenous cases were down to 0. For the past 3.5 years, no locally transmitted cases have been recorded.

“Sri Lanka’s achievement is truly remarkable,” said Dr Poonam Khetrapal Singh, WHO regional director for Southeast Asia. “In the mid-20th century, it was among the most malaria-affected countries, but now it is malaria-free.”

“This is a testament to the courage and vision of its leaders and signifies the great leaps that can be made when targeted action is taken. It also demonstrates the importance of grass-roots community engagement and a whole-of-society approach when it comes to making dramatic public health gains.”

To maintain elimination and ensure the malaria parasite is not reintroduced to Sri Lanka, the anti-malaria campaign is working closely with local authorities and international partners to maintain surveillance and response capacity and to screen high-risk populations entering the country.

Dr Khetrapal Singh said WHO will continue to support the efforts of Sri Lanka’s health authorities as they relate to malaria, as well as the country’s wider public health mission.

Sri Lanka is the second country in the WHO Southeast Asia region to eliminate malaria—after Maldives.

The announcement that Sri Lanka is malaria-free was made at the Sixty-ninth Session of the WHO Regional Committee for South-East Asia in Colombo, Sri Lanka, in the presence of health ministers and senior health officials from all 11 member states.

Lab mice

Photo by Aaron Logan

Preclinical research suggests that combining a BCL2 inhibitor with a tyrosine kinase inhibitor (TKI) could overcome resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

Investigators found that combining venetoclax and dasatinib increased antitumor activity (when compared to either agent alone) against Ph+ ALL cells in vitro and in a mouse model of the disease.

Jessica Leonard, MD, of Oregon Health & Science University in Portland, and her colleagues reported these findings in Science Translational Medicine.

The researchers said venetoclax and dasatinib demonstrated synergy in vitro, and the combination resulted in a greater degree of apoptosis in Ph+ ALL cells than either agent alone.

The team also observed synergy between venetoclax and cytarabine, dexamethasone, doxorubicin, and vincristine. They said this suggests venetoclax could potentially be used in combination with standard chemotherapy in patients with Ph+ ALL.

The investigators then assessed synergy between venetoclax and other TKIs. Venetoclax demonstrated synergy with imatinib and nilotinib, but the researchers said they saw the most robust synergy when venetoclax was combined with dasatinib or ponatinib.

Further investigation revealed that ponatinib and dasatinib inhibit LYN activity, which impedes STAT5 phosphorylation, which inhibits upregulation of MCL-1.

As upregulation of MCL-1 is a known mechanism of resistance to venetoclax, the researchers believe the addition of either TKI could potentially overcome the development of venetoclax resistance.

Results in a mouse model of Ph+ ALL seemed to support this theory. The researchers injected NSG mice with mononuclear cells from a patient with Ph+ ALL and found that combination treatment with venetoclax and dasatinib prevented engraftment within 90 days in all mice that received the therapy.

In comparison, mice in the control group and those that received single-agent venetoclax engrafted within 60 days. Two of the 5 mice that received dasatinib alone engrafted within 90 days.

In another mouse model, the investigators injected NSG mice with a primary Ph+ ALL sample and found the combination of venetoclax and dasatinib reduced spleen size when compared to no treatment.

In addition, all of the mice that received the combination remained alive during the 4-week treatment period, whereas untreated mice became moribund and were euthanized.

The researchers said these results suggest the combination of dasatinib and venetoclax has the potential to improve the treatment of Ph+ ALL and should be further evaluated for patient care.

Lab mice

Photo by Aaron Logan

Preclinical research suggests that combining a BCL2 inhibitor with a tyrosine kinase inhibitor (TKI) could overcome resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

Investigators found that combining venetoclax and dasatinib increased antitumor activity (when compared to either agent alone) against Ph+ ALL cells in vitro and in a mouse model of the disease.

Jessica Leonard, MD, of Oregon Health & Science University in Portland, and her colleagues reported these findings in Science Translational Medicine.

The researchers said venetoclax and dasatinib demonstrated synergy in vitro, and the combination resulted in a greater degree of apoptosis in Ph+ ALL cells than either agent alone.

The team also observed synergy between venetoclax and cytarabine, dexamethasone, doxorubicin, and vincristine. They said this suggests venetoclax could potentially be used in combination with standard chemotherapy in patients with Ph+ ALL.

The investigators then assessed synergy between venetoclax and other TKIs. Venetoclax demonstrated synergy with imatinib and nilotinib, but the researchers said they saw the most robust synergy when venetoclax was combined with dasatinib or ponatinib.

Further investigation revealed that ponatinib and dasatinib inhibit LYN activity, which impedes STAT5 phosphorylation, which inhibits upregulation of MCL-1.

As upregulation of MCL-1 is a known mechanism of resistance to venetoclax, the researchers believe the addition of either TKI could potentially overcome the development of venetoclax resistance.

Results in a mouse model of Ph+ ALL seemed to support this theory. The researchers injected NSG mice with mononuclear cells from a patient with Ph+ ALL and found that combination treatment with venetoclax and dasatinib prevented engraftment within 90 days in all mice that received the therapy.

In comparison, mice in the control group and those that received single-agent venetoclax engrafted within 60 days. Two of the 5 mice that received dasatinib alone engrafted within 90 days.

In another mouse model, the investigators injected NSG mice with a primary Ph+ ALL sample and found the combination of venetoclax and dasatinib reduced spleen size when compared to no treatment.

In addition, all of the mice that received the combination remained alive during the 4-week treatment period, whereas untreated mice became moribund and were euthanized.

The researchers said these results suggest the combination of dasatinib and venetoclax has the potential to improve the treatment of Ph+ ALL and should be further evaluated for patient care.

Lab mice

Photo by Aaron Logan

Preclinical research suggests that combining a BCL2 inhibitor with a tyrosine kinase inhibitor (TKI) could overcome resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

Investigators found that combining venetoclax and dasatinib increased antitumor activity (when compared to either agent alone) against Ph+ ALL cells in vitro and in a mouse model of the disease.

Jessica Leonard, MD, of Oregon Health & Science University in Portland, and her colleagues reported these findings in Science Translational Medicine.

The researchers said venetoclax and dasatinib demonstrated synergy in vitro, and the combination resulted in a greater degree of apoptosis in Ph+ ALL cells than either agent alone.

The team also observed synergy between venetoclax and cytarabine, dexamethasone, doxorubicin, and vincristine. They said this suggests venetoclax could potentially be used in combination with standard chemotherapy in patients with Ph+ ALL.

The investigators then assessed synergy between venetoclax and other TKIs. Venetoclax demonstrated synergy with imatinib and nilotinib, but the researchers said they saw the most robust synergy when venetoclax was combined with dasatinib or ponatinib.

Further investigation revealed that ponatinib and dasatinib inhibit LYN activity, which impedes STAT5 phosphorylation, which inhibits upregulation of MCL-1.

As upregulation of MCL-1 is a known mechanism of resistance to venetoclax, the researchers believe the addition of either TKI could potentially overcome the development of venetoclax resistance.

Results in a mouse model of Ph+ ALL seemed to support this theory. The researchers injected NSG mice with mononuclear cells from a patient with Ph+ ALL and found that combination treatment with venetoclax and dasatinib prevented engraftment within 90 days in all mice that received the therapy.

In comparison, mice in the control group and those that received single-agent venetoclax engrafted within 60 days. Two of the 5 mice that received dasatinib alone engrafted within 90 days.

In another mouse model, the investigators injected NSG mice with a primary Ph+ ALL sample and found the combination of venetoclax and dasatinib reduced spleen size when compared to no treatment.

In addition, all of the mice that received the combination remained alive during the 4-week treatment period, whereas untreated mice became moribund and were euthanized.

The researchers said these results suggest the combination of dasatinib and venetoclax has the potential to improve the treatment of Ph+ ALL and should be further evaluated for patient care.

More than half of children who are the costliest to cover in the Medicaid program eventually fall out of that category, according to new research.

A retrospective analysis of 48,743 children aged 1-18 years continuously enrolled in Medicaid during 2009-2013 across 10 states who were in the top 5% of all health care spending in 2010 found that from 2011 to 2013, “54.2% fell below the top 5% and did not return to the top 5% in 2011-2013,” Rishi K. Agrawal, MD, of the Ann and Robert Lurie Children’s Hospital, Chicago, and his colleagues wrote in a study published Sept. 15 online in Pediatrics (2016. doi: 10.1542/peds.2016-0682).

© Michael Blann/Thinkstock

Children who were persistently in the top 5% accounted for 32.9% of the cohort and 12.9% of the children who were in the top 5% during 2010 fell out of and returned to the group of highest cost patients in the following 3 years.

“The highest likelihood of subsequent high spending was observed in older children with many chronic conditions, respiratory, or neuromuscular complex chronic conditions, and those who used home health services,” the authors noted. “Decreased likelihood of subsequent high spending was observed with children with hospital or ED [emergency department] use in 2010.”

“Understanding the clinical attributes of children most likely to experience persistent high resource use might help inform clinical approaches to optimize their health,” Dr. Agrawal and associates continued.

They added that previous literature and the authors’ clinical experiences suggest that those with multiple chronic conditions, especially a neuromuscular condition, “are at risk for underuse of primary care,” and without a primary care physician taking charge of overall care coordination, that burden falls on the families.

“Perhaps population health initiatives (e.g., enhanced medical homes or neighborhoods for children with medical complexity, complex care networks) designed to alleviate these specific issues might benefit children who are the most likely to have persistent high resource use,” Dr. Agrawal and his colleagues wrote.

The authors cited no relevant financial disclosures. Jay G. Berry, MD, was supported by the Agency for Healthcare Research and Quality, and Eyal Cohen, MD, was supported as a Harkness Fellow in Health Care Policy and Practice by the Canadian Foundation for Healthcare Improvement and the Commonwealth Fund.

[email protected]

More than half of children who are the costliest to cover in the Medicaid program eventually fall out of that category, according to new research.

A retrospective analysis of 48,743 children aged 1-18 years continuously enrolled in Medicaid during 2009-2013 across 10 states who were in the top 5% of all health care spending in 2010 found that from 2011 to 2013, “54.2% fell below the top 5% and did not return to the top 5% in 2011-2013,” Rishi K. Agrawal, MD, of the Ann and Robert Lurie Children’s Hospital, Chicago, and his colleagues wrote in a study published Sept. 15 online in Pediatrics (2016. doi: 10.1542/peds.2016-0682).

© Michael Blann/Thinkstock

Children who were persistently in the top 5% accounted for 32.9% of the cohort and 12.9% of the children who were in the top 5% during 2010 fell out of and returned to the group of highest cost patients in the following 3 years.

“The highest likelihood of subsequent high spending was observed in older children with many chronic conditions, respiratory, or neuromuscular complex chronic conditions, and those who used home health services,” the authors noted. “Decreased likelihood of subsequent high spending was observed with children with hospital or ED [emergency department] use in 2010.”

“Understanding the clinical attributes of children most likely to experience persistent high resource use might help inform clinical approaches to optimize their health,” Dr. Agrawal and associates continued.

They added that previous literature and the authors’ clinical experiences suggest that those with multiple chronic conditions, especially a neuromuscular condition, “are at risk for underuse of primary care,” and without a primary care physician taking charge of overall care coordination, that burden falls on the families.

“Perhaps population health initiatives (e.g., enhanced medical homes or neighborhoods for children with medical complexity, complex care networks) designed to alleviate these specific issues might benefit children who are the most likely to have persistent high resource use,” Dr. Agrawal and his colleagues wrote.

The authors cited no relevant financial disclosures. Jay G. Berry, MD, was supported by the Agency for Healthcare Research and Quality, and Eyal Cohen, MD, was supported as a Harkness Fellow in Health Care Policy and Practice by the Canadian Foundation for Healthcare Improvement and the Commonwealth Fund.

[email protected]

More than half of children who are the costliest to cover in the Medicaid program eventually fall out of that category, according to new research.

A retrospective analysis of 48,743 children aged 1-18 years continuously enrolled in Medicaid during 2009-2013 across 10 states who were in the top 5% of all health care spending in 2010 found that from 2011 to 2013, “54.2% fell below the top 5% and did not return to the top 5% in 2011-2013,” Rishi K. Agrawal, MD, of the Ann and Robert Lurie Children’s Hospital, Chicago, and his colleagues wrote in a study published Sept. 15 online in Pediatrics (2016. doi: 10.1542/peds.2016-0682).

© Michael Blann/Thinkstock

Children who were persistently in the top 5% accounted for 32.9% of the cohort and 12.9% of the children who were in the top 5% during 2010 fell out of and returned to the group of highest cost patients in the following 3 years.

“The highest likelihood of subsequent high spending was observed in older children with many chronic conditions, respiratory, or neuromuscular complex chronic conditions, and those who used home health services,” the authors noted. “Decreased likelihood of subsequent high spending was observed with children with hospital or ED [emergency department] use in 2010.”

“Understanding the clinical attributes of children most likely to experience persistent high resource use might help inform clinical approaches to optimize their health,” Dr. Agrawal and associates continued.

They added that previous literature and the authors’ clinical experiences suggest that those with multiple chronic conditions, especially a neuromuscular condition, “are at risk for underuse of primary care,” and without a primary care physician taking charge of overall care coordination, that burden falls on the families.

“Perhaps population health initiatives (e.g., enhanced medical homes or neighborhoods for children with medical complexity, complex care networks) designed to alleviate these specific issues might benefit children who are the most likely to have persistent high resource use,” Dr. Agrawal and his colleagues wrote.

The authors cited no relevant financial disclosures. Jay G. Berry, MD, was supported by the Agency for Healthcare Research and Quality, and Eyal Cohen, MD, was supported as a Harkness Fellow in Health Care Policy and Practice by the Canadian Foundation for Healthcare Improvement and the Commonwealth Fund.

[email protected]

The FP diagnosed thrush or candidiasis of the oral mucosa. To make sure it was not just milk, the FP gently drew a tongue blade over the tongue and the white exudate was mostly adherent (milk wipes away rather easily). The tongue blade was then rubbed onto a glass slide and 2 drops of potassium hydroxide (KOH) solution were applied. Microscopic evaluation revealed pseudohyphae and budding yeasts consistent with Candida albicans. (See video on how to perform a KOH preparation.)

Thrush is a common condition in infants with normal immune systems and does not require work-up for immunosuppression if this is the only finding at this age. Of course, thrush is seen in people who are immunosuppressed from various diseases (such as human immunodeficiency virus) and medications (like chemotherapy).

The FP chose to treat the child with oral nystatin suspension 2 mL 4 times a day. The directions were to give 1 mL in each side of the infant’s mouth and to continue this until 48 hours after signs and symptoms resolved. The mother was not having any symptoms or erythema of the nipples, but if she was, a topical antifungal agent (to be washed off before breastfeeding) could be used.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Candidiasis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill;2013:777-781.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP diagnosed thrush or candidiasis of the oral mucosa. To make sure it was not just milk, the FP gently drew a tongue blade over the tongue and the white exudate was mostly adherent (milk wipes away rather easily). The tongue blade was then rubbed onto a glass slide and 2 drops of potassium hydroxide (KOH) solution were applied. Microscopic evaluation revealed pseudohyphae and budding yeasts consistent with Candida albicans. (See video on how to perform a KOH preparation.)

Thrush is a common condition in infants with normal immune systems and does not require work-up for immunosuppression if this is the only finding at this age. Of course, thrush is seen in people who are immunosuppressed from various diseases (such as human immunodeficiency virus) and medications (like chemotherapy).

The FP chose to treat the child with oral nystatin suspension 2 mL 4 times a day. The directions were to give 1 mL in each side of the infant’s mouth and to continue this until 48 hours after signs and symptoms resolved. The mother was not having any symptoms or erythema of the nipples, but if she was, a topical antifungal agent (to be washed off before breastfeeding) could be used.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Candidiasis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill;2013:777-781.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP diagnosed thrush or candidiasis of the oral mucosa. To make sure it was not just milk, the FP gently drew a tongue blade over the tongue and the white exudate was mostly adherent (milk wipes away rather easily). The tongue blade was then rubbed onto a glass slide and 2 drops of potassium hydroxide (KOH) solution were applied. Microscopic evaluation revealed pseudohyphae and budding yeasts consistent with Candida albicans. (See video on how to perform a KOH preparation.)

Thrush is a common condition in infants with normal immune systems and does not require work-up for immunosuppression if this is the only finding at this age. Of course, thrush is seen in people who are immunosuppressed from various diseases (such as human immunodeficiency virus) and medications (like chemotherapy).

The FP chose to treat the child with oral nystatin suspension 2 mL 4 times a day. The directions were to give 1 mL in each side of the infant’s mouth and to continue this until 48 hours after signs and symptoms resolved. The mother was not having any symptoms or erythema of the nipples, but if she was, a topical antifungal agent (to be washed off before breastfeeding) could be used.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Candidiasis. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill;2013:777-781.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

MUNICH – British commercial pilots with insulin-dependent diabetes are flying safely, thanks to a rigorous protocol of hourly blood glucose monitoring during every flight.

Almost every one of the 8,897 readings reported so far has been in the safe “green zone” of 5-15 mmol/L, Julia Hine, MD, said at the annual meeting of the European Association for the Study of Diabetes.

Michele G Sullivan/Frontline Medical News

Only 3.8% fell in the cautionary “amber” range of 4-5 mmol/L or 15-19 mmol/L. Just 0.2% (22) were in the “red” range of below 4 mmol/L or above 20 mmol/L – an occurrence that demands immediate release of airplane control to the copilot.

Reassuringly, only five of those readings occurred during flight, said Dr. Hine of the Royal Surrey County Hospital, England. The rest were taken during the preflight preparation period.

She said the 4-year data confirm that the protocol works, allowing highly skilled professionals to return to their work without compromising personal safety or the safety of those entrusted to their care.

“The testing protocol can be performed safely in the cockpit, with no safety concerns,” Dr. Hine said. “It represents an advance in patient care, showing that insulin-dependent patients can perform complex occupational duties.”

The protocol was instituted in 2012, after a consortium of commercial pilots met with diabetes specialists to create a way for certified pilots to regain their class 1 licenses after a diabetes diagnosis. It’s overseen by the U.K. Civil Aviation Authority and Irish Aviation Authority. Dr. Hine said the U.K. has the largest cadre of certified pilots who have insulin-dependent diabetes in the world. Canada is the only other country with such a program, although, she said, “There are a number of European states that have expressed interest in the program.”

In the United States, a diagnosis of insulin-dependent diabetes currently excludes pilots from flying commercial aircraft. The American Diabetes Association has been lobbying for easing of this strict FAA ban since at least 2014, stating that “the FAA’s blanket ban is not medically justified.” Specifically, the ADA favors a position in which “individual assessment of people with diabetes is the appropriate approach to determining whether a person is qualified to perform certain activities,” according to a statement.

The British protocol requires stringent pre- and in-flight blood sugar monitoring. Levels must be obtained at least 1 hour before reporting for duty and at least 2 hours before commencing a flight.

Blood sugar must be regularly measured during flight at well. For pilots using insulin, levels should be drawn every 2 hours, and for those on oral medications, every 2-4 hours. A final level must be drawn 30 minutes before landing.

Additional testing is required if the pilot experiences any symptoms related to fluctuating blood sugar. All results are read out loud, reported to the copilot and into the plane’s voice data recorder, and recorded in the pilot’s flight data record.

Levels in the amber range require the pilot to take corrective action. For low blood glucose levels, the pilot must consume 10-15 grams of carbohydrate, retest after 30 minutes, and adjust insulin. For high blood glucose levels, the pilot should review insulin dosing and modify carbohydrate intake, then retest in 45 minutes.

Readings in the red range demand immediate action, which includes handing over control of the flight, repeat testing, modifying insulin and carbohydrate intake, and retesting. The pilot may only resume duty when blood glucose returns to a green level.

There is a special protocol for pilots on insulin pumps, which are not guaranteed to function if there is a sudden loss of cabin pressure.

Dr. Hine and her colleague David Russell-Jones, MD, who is the program’s medical director, presented 4 years’ worth of data on 16 of the 26 pilots who have participated in the program. All of these pilots are otherwise healthy men with well-controlled diabetes who were deemed at low risk for glycemic events. They are an average of 40 years old with an average disease duration of 8 years. Their average HbA1c was 53 mmol/l before licensure and 54.8 mmol/l afterwards. All of the pilots have normal renal function, no retinopathy, no changes in blood pressure, and good awareness of hypoglycemia.

Among them, they have accumulated 4,900 flight hours and 8,897 blood glucose readings. Most of the flights (88%) were medium- or short-haul flights of less than 6 hours.

Even though 96% of readings fell into the 5-20 mmol/l green range, the bulk of those readings were in the range of 5-9 mmol/l. There was very little hourly variation in blood glucose levels during flights up to 6 hours, showing that the protocol is effective at establishing stable glycemia.

Right now, the program is in place only for current pilots who have a new diagnosis of diabetes. But, said Dr. Russell-Jones, it may be expanded at some point to encompass people with diabetes who wish to train to become a commercial pilot.

Neither Dr. Hines nor Dr. Russell-Jones reported any financial conflicts.

[email protected]

On Twitter @Alz_Gal

MUNICH – British commercial pilots with insulin-dependent diabetes are flying safely, thanks to a rigorous protocol of hourly blood glucose monitoring during every flight.

Almost every one of the 8,897 readings reported so far has been in the safe “green zone” of 5-15 mmol/L, Julia Hine, MD, said at the annual meeting of the European Association for the Study of Diabetes.

Michele G Sullivan/Frontline Medical News

Only 3.8% fell in the cautionary “amber” range of 4-5 mmol/L or 15-19 mmol/L. Just 0.2% (22) were in the “red” range of below 4 mmol/L or above 20 mmol/L – an occurrence that demands immediate release of airplane control to the copilot.

Reassuringly, only five of those readings occurred during flight, said Dr. Hine of the Royal Surrey County Hospital, England. The rest were taken during the preflight preparation period.

She said the 4-year data confirm that the protocol works, allowing highly skilled professionals to return to their work without compromising personal safety or the safety of those entrusted to their care.

“The testing protocol can be performed safely in the cockpit, with no safety concerns,” Dr. Hine said. “It represents an advance in patient care, showing that insulin-dependent patients can perform complex occupational duties.”

The protocol was instituted in 2012, after a consortium of commercial pilots met with diabetes specialists to create a way for certified pilots to regain their class 1 licenses after a diabetes diagnosis. It’s overseen by the U.K. Civil Aviation Authority and Irish Aviation Authority. Dr. Hine said the U.K. has the largest cadre of certified pilots who have insulin-dependent diabetes in the world. Canada is the only other country with such a program, although, she said, “There are a number of European states that have expressed interest in the program.”

In the United States, a diagnosis of insulin-dependent diabetes currently excludes pilots from flying commercial aircraft. The American Diabetes Association has been lobbying for easing of this strict FAA ban since at least 2014, stating that “the FAA’s blanket ban is not medically justified.” Specifically, the ADA favors a position in which “individual assessment of people with diabetes is the appropriate approach to determining whether a person is qualified to perform certain activities,” according to a statement.

The British protocol requires stringent pre- and in-flight blood sugar monitoring. Levels must be obtained at least 1 hour before reporting for duty and at least 2 hours before commencing a flight.

Blood sugar must be regularly measured during flight at well. For pilots using insulin, levels should be drawn every 2 hours, and for those on oral medications, every 2-4 hours. A final level must be drawn 30 minutes before landing.

Additional testing is required if the pilot experiences any symptoms related to fluctuating blood sugar. All results are read out loud, reported to the copilot and into the plane’s voice data recorder, and recorded in the pilot’s flight data record.

Levels in the amber range require the pilot to take corrective action. For low blood glucose levels, the pilot must consume 10-15 grams of carbohydrate, retest after 30 minutes, and adjust insulin. For high blood glucose levels, the pilot should review insulin dosing and modify carbohydrate intake, then retest in 45 minutes.

Readings in the red range demand immediate action, which includes handing over control of the flight, repeat testing, modifying insulin and carbohydrate intake, and retesting. The pilot may only resume duty when blood glucose returns to a green level.

There is a special protocol for pilots on insulin pumps, which are not guaranteed to function if there is a sudden loss of cabin pressure.

Dr. Hine and her colleague David Russell-Jones, MD, who is the program’s medical director, presented 4 years’ worth of data on 16 of the 26 pilots who have participated in the program. All of these pilots are otherwise healthy men with well-controlled diabetes who were deemed at low risk for glycemic events. They are an average of 40 years old with an average disease duration of 8 years. Their average HbA1c was 53 mmol/l before licensure and 54.8 mmol/l afterwards. All of the pilots have normal renal function, no retinopathy, no changes in blood pressure, and good awareness of hypoglycemia.

Among them, they have accumulated 4,900 flight hours and 8,897 blood glucose readings. Most of the flights (88%) were medium- or short-haul flights of less than 6 hours.

Even though 96% of readings fell into the 5-20 mmol/l green range, the bulk of those readings were in the range of 5-9 mmol/l. There was very little hourly variation in blood glucose levels during flights up to 6 hours, showing that the protocol is effective at establishing stable glycemia.

Right now, the program is in place only for current pilots who have a new diagnosis of diabetes. But, said Dr. Russell-Jones, it may be expanded at some point to encompass people with diabetes who wish to train to become a commercial pilot.

Neither Dr. Hines nor Dr. Russell-Jones reported any financial conflicts.

[email protected]

On Twitter @Alz_Gal

MUNICH – British commercial pilots with insulin-dependent diabetes are flying safely, thanks to a rigorous protocol of hourly blood glucose monitoring during every flight.

Almost every one of the 8,897 readings reported so far has been in the safe “green zone” of 5-15 mmol/L, Julia Hine, MD, said at the annual meeting of the European Association for the Study of Diabetes.

Michele G Sullivan/Frontline Medical News

Only 3.8% fell in the cautionary “amber” range of 4-5 mmol/L or 15-19 mmol/L. Just 0.2% (22) were in the “red” range of below 4 mmol/L or above 20 mmol/L – an occurrence that demands immediate release of airplane control to the copilot.

Reassuringly, only five of those readings occurred during flight, said Dr. Hine of the Royal Surrey County Hospital, England. The rest were taken during the preflight preparation period.

She said the 4-year data confirm that the protocol works, allowing highly skilled professionals to return to their work without compromising personal safety or the safety of those entrusted to their care.

“The testing protocol can be performed safely in the cockpit, with no safety concerns,” Dr. Hine said. “It represents an advance in patient care, showing that insulin-dependent patients can perform complex occupational duties.”

The protocol was instituted in 2012, after a consortium of commercial pilots met with diabetes specialists to create a way for certified pilots to regain their class 1 licenses after a diabetes diagnosis. It’s overseen by the U.K. Civil Aviation Authority and Irish Aviation Authority. Dr. Hine said the U.K. has the largest cadre of certified pilots who have insulin-dependent diabetes in the world. Canada is the only other country with such a program, although, she said, “There are a number of European states that have expressed interest in the program.”

In the United States, a diagnosis of insulin-dependent diabetes currently excludes pilots from flying commercial aircraft. The American Diabetes Association has been lobbying for easing of this strict FAA ban since at least 2014, stating that “the FAA’s blanket ban is not medically justified.” Specifically, the ADA favors a position in which “individual assessment of people with diabetes is the appropriate approach to determining whether a person is qualified to perform certain activities,” according to a statement.

The British protocol requires stringent pre- and in-flight blood sugar monitoring. Levels must be obtained at least 1 hour before reporting for duty and at least 2 hours before commencing a flight.

Blood sugar must be regularly measured during flight at well. For pilots using insulin, levels should be drawn every 2 hours, and for those on oral medications, every 2-4 hours. A final level must be drawn 30 minutes before landing.

Additional testing is required if the pilot experiences any symptoms related to fluctuating blood sugar. All results are read out loud, reported to the copilot and into the plane’s voice data recorder, and recorded in the pilot’s flight data record.

Levels in the amber range require the pilot to take corrective action. For low blood glucose levels, the pilot must consume 10-15 grams of carbohydrate, retest after 30 minutes, and adjust insulin. For high blood glucose levels, the pilot should review insulin dosing and modify carbohydrate intake, then retest in 45 minutes.

Readings in the red range demand immediate action, which includes handing over control of the flight, repeat testing, modifying insulin and carbohydrate intake, and retesting. The pilot may only resume duty when blood glucose returns to a green level.

There is a special protocol for pilots on insulin pumps, which are not guaranteed to function if there is a sudden loss of cabin pressure.

Dr. Hine and her colleague David Russell-Jones, MD, who is the program’s medical director, presented 4 years’ worth of data on 16 of the 26 pilots who have participated in the program. All of these pilots are otherwise healthy men with well-controlled diabetes who were deemed at low risk for glycemic events. They are an average of 40 years old with an average disease duration of 8 years. Their average HbA1c was 53 mmol/l before licensure and 54.8 mmol/l afterwards. All of the pilots have normal renal function, no retinopathy, no changes in blood pressure, and good awareness of hypoglycemia.

Among them, they have accumulated 4,900 flight hours and 8,897 blood glucose readings. Most of the flights (88%) were medium- or short-haul flights of less than 6 hours.

Even though 96% of readings fell into the 5-20 mmol/l green range, the bulk of those readings were in the range of 5-9 mmol/l. There was very little hourly variation in blood glucose levels during flights up to 6 hours, showing that the protocol is effective at establishing stable glycemia.

Right now, the program is in place only for current pilots who have a new diagnosis of diabetes. But, said Dr. Russell-Jones, it may be expanded at some point to encompass people with diabetes who wish to train to become a commercial pilot.

Neither Dr. Hines nor Dr. Russell-Jones reported any financial conflicts.

[email protected]

On Twitter @Alz_Gal

MUNICH – Brain changes suggestive of cerebral microvascular dysfunction are already apparent in patients with prediabetes.

The changes – increased white matter hyperintensities and decreased white matter volume – are even more pronounced in subjects with type 2 diabetes, Marnix van Agtmaal, MD, said at the annual meeting of the European Association for the Study of Diabetes. Patients with frank diabetes also showed an increase in intracranial cerebrospinal fluid – a correlate of the decrease in brain volume, said Dr. van Agtmaal of Maastricht (the Netherlands) University Medical Center.

The changes are probably caused by diabetes-related endothelial dysfunction, he said.

“The brain is highly dependent on properly functioning microcirculation. This is critical, since the brain has high energy demand and no energy reserve. In prediabetes and type 2 diabetes, microvascular endothelial dysfunction occurs. This leads to cerebral hypoperfusion, which in turns causes chronic ischemia. This contributes to small vessel disease leading to brain atrophy and, eventually, cognitive decline and dementia.”

The 2,251 subjects in the analysis were drawn from the Maastricht study, an ongoing observational study of people with type 2 diabetes.

Among the group, 350 had prediabetes, defined as impaired fasting glucose, impaired glucose tolerance, or a combination of the two. Type 2 diabetes was present in 528. The rest had healthy glucose metabolism.

As the cohort progressed from healthy glucose metabolism to prediabetes and then diabetes, they became older (aged 58 years in the healthy group vs. 62 years in the diabetes group), heavier, and displayed worsening cardiovascular risk factors, with increasing systolic blood pressure and progressively poorer lipid profiles. Kidney function was preserved in all patients, however.

The groups were not balanced in terms of sex: 56% of those with healthy glucose metabolism were women, compared with 47% of those with prediabetes and 31% of those with type 2 diabetes.

Dr. van Agtmaal and his colleagues examined white matter hyperintensities, white matter volume, gray matter volume, and intracranial CSF. They conducted three linear regression models: a crude unadjusted model, a partially adjusted model that controlled for age, sex, and intracranial volume; and a fully adjusted model that controlled for those factors, plus systolic blood pressure, lipids, smoking, kidney function, and education.

There was a clear linear association between white matter hyperintensity (WMH) volume and healthy glucose metabolism, prediabetes, and type 2 diabetes. In the crude analysis, the healthy subjects carried about 0.75 mL of WMH. Prediabetic subjects carried about 1.25 mL, and those with diabetes, about 2 mL.

In both the partially and fully adjusted models, this relationship was somewhat attenuated, but it remained significant for both prediabetes and diabetes.

The crude model also found that both diabetes groups had significantly lower white matter volume than did the healthy subjects. In healthy subjects, the mean volume was about 480 mL. This was about 467 mL in those with prediabetes and 466 mL in those with type 2 diabetes. Again, the partially and fully adjusted models slightly attenuated the relationship, but it remained significant in both disease states.

The crude model showed that gray matter was decreased in both prediabetes and type 2 diabetes. In healthy subjects, total gray matter was about 667 mL. In those with prediabetes, it was about 655 mL, and in those with type 2 diabetes, about 645 mL. However, the significant associations disappeared for both diabetes and prediabetes in both adjusted models.

Intracranial CSF was also different among the three groups in the crude model. In the healthy subjects, the total intracranial CSF volume was about 248 mL. In those with prediabetes, it was about 255 mL, and in those with type 2 diabetes, about 270 mL.

The association with prediabetes disappeared in the fully adjusted model – but for type 2 diabetes, it remained strongly significant.

Dr. van Agtmaal has not correlated the imaging findings with any cognitive testing on these subjects but said that study is coming.

“Further analysis will also look at cognitive decline and the development of dementia in the group,” he said. “We also intend to look at associations with other outcomes of cerebral dysfunction, including depression.”

Dr. van Agtmaal had no financial disclosures.

[email protected]

MUNICH – Brain changes suggestive of cerebral microvascular dysfunction are already apparent in patients with prediabetes.

The changes – increased white matter hyperintensities and decreased white matter volume – are even more pronounced in subjects with type 2 diabetes, Marnix van Agtmaal, MD, said at the annual meeting of the European Association for the Study of Diabetes. Patients with frank diabetes also showed an increase in intracranial cerebrospinal fluid – a correlate of the decrease in brain volume, said Dr. van Agtmaal of Maastricht (the Netherlands) University Medical Center.

The changes are probably caused by diabetes-related endothelial dysfunction, he said.

“The brain is highly dependent on properly functioning microcirculation. This is critical, since the brain has high energy demand and no energy reserve. In prediabetes and type 2 diabetes, microvascular endothelial dysfunction occurs. This leads to cerebral hypoperfusion, which in turns causes chronic ischemia. This contributes to small vessel disease leading to brain atrophy and, eventually, cognitive decline and dementia.”

The 2,251 subjects in the analysis were drawn from the Maastricht study, an ongoing observational study of people with type 2 diabetes.

Among the group, 350 had prediabetes, defined as impaired fasting glucose, impaired glucose tolerance, or a combination of the two. Type 2 diabetes was present in 528. The rest had healthy glucose metabolism.

As the cohort progressed from healthy glucose metabolism to prediabetes and then diabetes, they became older (aged 58 years in the healthy group vs. 62 years in the diabetes group), heavier, and displayed worsening cardiovascular risk factors, with increasing systolic blood pressure and progressively poorer lipid profiles. Kidney function was preserved in all patients, however.

The groups were not balanced in terms of sex: 56% of those with healthy glucose metabolism were women, compared with 47% of those with prediabetes and 31% of those with type 2 diabetes.

Dr. van Agtmaal and his colleagues examined white matter hyperintensities, white matter volume, gray matter volume, and intracranial CSF. They conducted three linear regression models: a crude unadjusted model, a partially adjusted model that controlled for age, sex, and intracranial volume; and a fully adjusted model that controlled for those factors, plus systolic blood pressure, lipids, smoking, kidney function, and education.

There was a clear linear association between white matter hyperintensity (WMH) volume and healthy glucose metabolism, prediabetes, and type 2 diabetes. In the crude analysis, the healthy subjects carried about 0.75 mL of WMH. Prediabetic subjects carried about 1.25 mL, and those with diabetes, about 2 mL.

In both the partially and fully adjusted models, this relationship was somewhat attenuated, but it remained significant for both prediabetes and diabetes.

The crude model also found that both diabetes groups had significantly lower white matter volume than did the healthy subjects. In healthy subjects, the mean volume was about 480 mL. This was about 467 mL in those with prediabetes and 466 mL in those with type 2 diabetes. Again, the partially and fully adjusted models slightly attenuated the relationship, but it remained significant in both disease states.

The crude model showed that gray matter was decreased in both prediabetes and type 2 diabetes. In healthy subjects, total gray matter was about 667 mL. In those with prediabetes, it was about 655 mL, and in those with type 2 diabetes, about 645 mL. However, the significant associations disappeared for both diabetes and prediabetes in both adjusted models.

Intracranial CSF was also different among the three groups in the crude model. In the healthy subjects, the total intracranial CSF volume was about 248 mL. In those with prediabetes, it was about 255 mL, and in those with type 2 diabetes, about 270 mL.

The association with prediabetes disappeared in the fully adjusted model – but for type 2 diabetes, it remained strongly significant.

Dr. van Agtmaal has not correlated the imaging findings with any cognitive testing on these subjects but said that study is coming.

“Further analysis will also look at cognitive decline and the development of dementia in the group,” he said. “We also intend to look at associations with other outcomes of cerebral dysfunction, including depression.”

Dr. van Agtmaal had no financial disclosures.

[email protected]

MUNICH – Brain changes suggestive of cerebral microvascular dysfunction are already apparent in patients with prediabetes.

The changes – increased white matter hyperintensities and decreased white matter volume – are even more pronounced in subjects with type 2 diabetes, Marnix van Agtmaal, MD, said at the annual meeting of the European Association for the Study of Diabetes. Patients with frank diabetes also showed an increase in intracranial cerebrospinal fluid – a correlate of the decrease in brain volume, said Dr. van Agtmaal of Maastricht (the Netherlands) University Medical Center.

The changes are probably caused by diabetes-related endothelial dysfunction, he said.

“The brain is highly dependent on properly functioning microcirculation. This is critical, since the brain has high energy demand and no energy reserve. In prediabetes and type 2 diabetes, microvascular endothelial dysfunction occurs. This leads to cerebral hypoperfusion, which in turns causes chronic ischemia. This contributes to small vessel disease leading to brain atrophy and, eventually, cognitive decline and dementia.”

The 2,251 subjects in the analysis were drawn from the Maastricht study, an ongoing observational study of people with type 2 diabetes.

Among the group, 350 had prediabetes, defined as impaired fasting glucose, impaired glucose tolerance, or a combination of the two. Type 2 diabetes was present in 528. The rest had healthy glucose metabolism.

As the cohort progressed from healthy glucose metabolism to prediabetes and then diabetes, they became older (aged 58 years in the healthy group vs. 62 years in the diabetes group), heavier, and displayed worsening cardiovascular risk factors, with increasing systolic blood pressure and progressively poorer lipid profiles. Kidney function was preserved in all patients, however.

The groups were not balanced in terms of sex: 56% of those with healthy glucose metabolism were women, compared with 47% of those with prediabetes and 31% of those with type 2 diabetes.

Dr. van Agtmaal and his colleagues examined white matter hyperintensities, white matter volume, gray matter volume, and intracranial CSF. They conducted three linear regression models: a crude unadjusted model, a partially adjusted model that controlled for age, sex, and intracranial volume; and a fully adjusted model that controlled for those factors, plus systolic blood pressure, lipids, smoking, kidney function, and education.

There was a clear linear association between white matter hyperintensity (WMH) volume and healthy glucose metabolism, prediabetes, and type 2 diabetes. In the crude analysis, the healthy subjects carried about 0.75 mL of WMH. Prediabetic subjects carried about 1.25 mL, and those with diabetes, about 2 mL.

In both the partially and fully adjusted models, this relationship was somewhat attenuated, but it remained significant for both prediabetes and diabetes.

The crude model also found that both diabetes groups had significantly lower white matter volume than did the healthy subjects. In healthy subjects, the mean volume was about 480 mL. This was about 467 mL in those with prediabetes and 466 mL in those with type 2 diabetes. Again, the partially and fully adjusted models slightly attenuated the relationship, but it remained significant in both disease states.

The crude model showed that gray matter was decreased in both prediabetes and type 2 diabetes. In healthy subjects, total gray matter was about 667 mL. In those with prediabetes, it was about 655 mL, and in those with type 2 diabetes, about 645 mL. However, the significant associations disappeared for both diabetes and prediabetes in both adjusted models.

Intracranial CSF was also different among the three groups in the crude model. In the healthy subjects, the total intracranial CSF volume was about 248 mL. In those with prediabetes, it was about 255 mL, and in those with type 2 diabetes, about 270 mL.

The association with prediabetes disappeared in the fully adjusted model – but for type 2 diabetes, it remained strongly significant.

Dr. van Agtmaal has not correlated the imaging findings with any cognitive testing on these subjects but said that study is coming.

“Further analysis will also look at cognitive decline and the development of dementia in the group,” he said. “We also intend to look at associations with other outcomes of cerebral dysfunction, including depression.”

Dr. van Agtmaal had no financial disclosures.

[email protected]