Neurology Reviews

People with essential tremor (ET) have nearly three times increased risk of developing dementia, compared with the general population, new research showed.

In a prospective, longitudinal study, incidence of dementia was nearly 20% among older adults with ET. However, the rates were lower than those in adults with Parkinson’s disease.

The study is “the most complete exposition of the longitudinal trajectory of cognitive impairment in an ET cohort,” said the authors, led by Elan D. Louis, MD, MSc, from University of Texas Southwestern Medical Center in Dallas, Texas.

The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
 

Mild Cognitive Impairment Prevalence Nearly Double

For the study, 222 adults with ET with an average age of 79 years at baseline underwent detailed cognitive assessments and were followed for an average of 5 years.

At baseline, 168 people had normal cognitive skills, 35 had mild cognitive impairment (MCI), and 19 had dementia. During the follow-up, 59 individuals developed MCI and 41 developed dementia.

During the follow-up, the cumulative prevalence of dementia was 18.5%, and the average annual conversion rate of MCI to dementia was 12.2% — nearly threefold higher than rates in the general population and roughly one-half the magnitude of those reported for adults with Parkinson’s disease.

The cumulative prevalence of MCI (26.6%) was nearly double that of the general population but less than that in patients with Parkinson’s disease.

“Our data indicate that the prevalence of and conversion rates to dementia in ET fall between those associated with the natural course of aging and the more pronounced rates observed in individuals with Parkinson’s disease,” the researchers wrote in their conference abstract.
 

Far From Trivial

Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, Florida, said, “The days of viewing ET as just a ‘nuisance tremor’ are over. This study shatters the notion that essential tremor is a trivial condition.”

“Moving forward, the research agenda must further elucidate the link between ET and dementia and develop neuroprotective strategies. But this study represents a seismic shift in how we understand essential tremor,” Dr. Lakhan said.

“The benign label no longer applies given the cognitive risks ET patients face. Our clinical practice and communication with patients must adapt accordingly,” he added.

The study was supported by the National Institutes of Health. Drs. Louis and Lakhan had no relevant disclosures.

A version of this article appeared on Medscape.com.

People with essential tremor (ET) have nearly three times increased risk of developing dementia, compared with the general population, new research showed.

In a prospective, longitudinal study, incidence of dementia was nearly 20% among older adults with ET. However, the rates were lower than those in adults with Parkinson’s disease.

The study is “the most complete exposition of the longitudinal trajectory of cognitive impairment in an ET cohort,” said the authors, led by Elan D. Louis, MD, MSc, from University of Texas Southwestern Medical Center in Dallas, Texas.

The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
 

Mild Cognitive Impairment Prevalence Nearly Double

For the study, 222 adults with ET with an average age of 79 years at baseline underwent detailed cognitive assessments and were followed for an average of 5 years.

At baseline, 168 people had normal cognitive skills, 35 had mild cognitive impairment (MCI), and 19 had dementia. During the follow-up, 59 individuals developed MCI and 41 developed dementia.

During the follow-up, the cumulative prevalence of dementia was 18.5%, and the average annual conversion rate of MCI to dementia was 12.2% — nearly threefold higher than rates in the general population and roughly one-half the magnitude of those reported for adults with Parkinson’s disease.

The cumulative prevalence of MCI (26.6%) was nearly double that of the general population but less than that in patients with Parkinson’s disease.

“Our data indicate that the prevalence of and conversion rates to dementia in ET fall between those associated with the natural course of aging and the more pronounced rates observed in individuals with Parkinson’s disease,” the researchers wrote in their conference abstract.
 

Far From Trivial

Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, Florida, said, “The days of viewing ET as just a ‘nuisance tremor’ are over. This study shatters the notion that essential tremor is a trivial condition.”

“Moving forward, the research agenda must further elucidate the link between ET and dementia and develop neuroprotective strategies. But this study represents a seismic shift in how we understand essential tremor,” Dr. Lakhan said.

“The benign label no longer applies given the cognitive risks ET patients face. Our clinical practice and communication with patients must adapt accordingly,” he added.

The study was supported by the National Institutes of Health. Drs. Louis and Lakhan had no relevant disclosures.

A version of this article appeared on Medscape.com.

People with essential tremor (ET) have nearly three times increased risk of developing dementia, compared with the general population, new research showed.

In a prospective, longitudinal study, incidence of dementia was nearly 20% among older adults with ET. However, the rates were lower than those in adults with Parkinson’s disease.

The study is “the most complete exposition of the longitudinal trajectory of cognitive impairment in an ET cohort,” said the authors, led by Elan D. Louis, MD, MSc, from University of Texas Southwestern Medical Center in Dallas, Texas.

The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
 

Mild Cognitive Impairment Prevalence Nearly Double

For the study, 222 adults with ET with an average age of 79 years at baseline underwent detailed cognitive assessments and were followed for an average of 5 years.

At baseline, 168 people had normal cognitive skills, 35 had mild cognitive impairment (MCI), and 19 had dementia. During the follow-up, 59 individuals developed MCI and 41 developed dementia.

During the follow-up, the cumulative prevalence of dementia was 18.5%, and the average annual conversion rate of MCI to dementia was 12.2% — nearly threefold higher than rates in the general population and roughly one-half the magnitude of those reported for adults with Parkinson’s disease.

The cumulative prevalence of MCI (26.6%) was nearly double that of the general population but less than that in patients with Parkinson’s disease.

“Our data indicate that the prevalence of and conversion rates to dementia in ET fall between those associated with the natural course of aging and the more pronounced rates observed in individuals with Parkinson’s disease,” the researchers wrote in their conference abstract.
 

Far From Trivial

Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, Florida, said, “The days of viewing ET as just a ‘nuisance tremor’ are over. This study shatters the notion that essential tremor is a trivial condition.”

“Moving forward, the research agenda must further elucidate the link between ET and dementia and develop neuroprotective strategies. But this study represents a seismic shift in how we understand essential tremor,” Dr. Lakhan said.

“The benign label no longer applies given the cognitive risks ET patients face. Our clinical practice and communication with patients must adapt accordingly,” he added.

The study was supported by the National Institutes of Health. Drs. Louis and Lakhan had no relevant disclosures.

A version of this article appeared on Medscape.com.

President Joe Biden on March 9 signed into law a measure that softened — but did not completely eliminate — a 2024 cut in a key rate used to determine how physicians are paid for treating Medicare patients.

While physician groups hailed the move as partial relief, they say they’ll continue to press for broader changes in the Medicare physician fee schedule.

The Medicare provision was tucked into a larger spending package approved by the US House and Senate.

The American Academy of Family Physicians (AAFP), the American Medical Association (AMA), and other groups have lobbied Congress for months to undo a 3.4% cut in the base rate, or conversion factor, in the physician fee schedule for 2024.

The conversion factor is used in calculations to determine reimbursement for myriad other services. Federal Medicare officials said the cut would mean a 1.25% decrease in overall payments in 2024, compared with 2023.

“With the passage of this legislation, Congress has offset 2.93% of that payment cut,” said Steven P. Furr, MD, AAFP’s president in a statement. “We appreciate this temporary measure but continue to urge Congress to advance comprehensive, long-term Medicare payment reform.”

In a statement, Representative Larry Bucshon, MD (R-IN), said the payment cut could not be completely eliminated because of budget constraints.

The Medicare physician fee schedule covers much of the care clinicians provide to people older than 65 and those with disabilities. It covers about 8000 different types of services, ranging from office visits to surgical procedures, imaging, and tests, according to the Medicare Payment Advisory Commission (MedPAC).

Along with physicians, the fee schedule sets payments for nurse practitioners, physician assistants, podiatrists, physical therapists, psychologists, and other clinicians.

In 2021, the Medicare program and its beneficiaries paid $92.8 billion for services provided by almost 1.3 million clinicians, MedPAC said.
 

Larger Changes Ahead?

Rep. Bucshon is among the physicians serving in the House who are pressing for a permanent revamp of the Medicare physician fee schedule. He cosponsored a bill (HR 2474) that would peg future annual increases in the physician fee schedule to the Medicare Economic Index, which would reflect inflation’s effect.

In April, more than 120 state and national medical groups signed onto an AMA-led letter urging Congress to pass this bill.

The measure is a key priority for the AMA. The organization reached out repeatedly last year to federal officials about it through its own in-house lobbyists, this news organization found through a review of congressional lobbying forms submitted by AMA.

These required disclosure forms reveal how much AMA and other organizations spend each quarter to appeal to members of Congress and federal agencies on specific issues. The disclosure forms do not include a detailed accounting of spending on each issue.

But they do show which issues are priorities for an organization. AMA’s in-house lobbyists reported raising dozens of issues in 2024 within contacts in Congress and federal agencies. These issues included abortion access, maternal health, physician burnout, and potential for bias in clinical use of algorithms, as well as Medicare payment for physicians.

AMA reported spending estimated cost of $20.6 million. (AMA spent $6.7 million in the first quarter, $4.75 million in the second quarter, $3.42 million in the third quarter, and $5.74 million in the fourth quarter.)

In a March 6 statement, Jesse M. Ehrenfeld, MD, MPH, AMA president, urged Congress to turn to more serious consideration of Medicare physician pay beyond short-term tweaks attached to other larger bills.

“As physicians, we are trained to run toward emergencies. We urge Congress to do the same,” Dr. Ehrenfeld said. “We encourage Congress to act if this policy decision is an emergency because — in fact — it is. It is well past time to put an end to stopgap measures that fail to address the underlying causes of the continuing decline in Medicare physician payments.”

There’s bipartisan interest in a revamp of the physician fee schedule amid widespread criticism of the last such overhaul, the Medicare Access and CHIP Reauthorization Act of 2015.

For example, Senate Budget Chairman Sheldon Whitehouse (D-RI) has proposed the creation of a technical advisory committee to improve how Medicare sets the physician fee schedule. The existing fee schedule provides too little money for primary care services and primary care provider pay, contributing to shortages, Sen. Whitehouse said.

Sen. Whitehouse on March 6 held a hearing on ways to beef up US primary care. Among the experts who appeared was Amol Navathe, MD, PhD, of the University of Pennsylvania, Philadelphia, Pennsylvania.

Dr. Navathe said the current Medicare physician fee schedule tilts in favor of procedural services, leading to “underinvestment in cognitive, diagnostic, and supportive services such as primary care.”

In addition, much of what primary care clinicians do, “such as addressing social challenges, is not included in the codes of the fee schedule itself,” said Dr. Navathe, who also serves as the vice chairman of MedPAC.

It’s unclear when Congress will attempt a serious revision to the Medicare physician fee schedule. Lawmakers are unlikely to take on such a major challenge in this election year.

There would be significant opposition and challenges for lawmakers in trying to clear a bill that added an inflation adjustment for what’s already seen as an imperfect physician fee schedule, said Mark E. Miller, PhD, executive vice president of healthcare at the philanthropy Arnold Ventures, which studies how payment decisions affect medical care.

“That bill could cost a lot of money and raise a lot of questions,” Dr. Miller said.

A version of this article appeared on Medscape.com.

President Joe Biden on March 9 signed into law a measure that softened — but did not completely eliminate — a 2024 cut in a key rate used to determine how physicians are paid for treating Medicare patients.

While physician groups hailed the move as partial relief, they say they’ll continue to press for broader changes in the Medicare physician fee schedule.

The Medicare provision was tucked into a larger spending package approved by the US House and Senate.

The American Academy of Family Physicians (AAFP), the American Medical Association (AMA), and other groups have lobbied Congress for months to undo a 3.4% cut in the base rate, or conversion factor, in the physician fee schedule for 2024.

The conversion factor is used in calculations to determine reimbursement for myriad other services. Federal Medicare officials said the cut would mean a 1.25% decrease in overall payments in 2024, compared with 2023.

“With the passage of this legislation, Congress has offset 2.93% of that payment cut,” said Steven P. Furr, MD, AAFP’s president in a statement. “We appreciate this temporary measure but continue to urge Congress to advance comprehensive, long-term Medicare payment reform.”

In a statement, Representative Larry Bucshon, MD (R-IN), said the payment cut could not be completely eliminated because of budget constraints.

The Medicare physician fee schedule covers much of the care clinicians provide to people older than 65 and those with disabilities. It covers about 8000 different types of services, ranging from office visits to surgical procedures, imaging, and tests, according to the Medicare Payment Advisory Commission (MedPAC).

Along with physicians, the fee schedule sets payments for nurse practitioners, physician assistants, podiatrists, physical therapists, psychologists, and other clinicians.

In 2021, the Medicare program and its beneficiaries paid $92.8 billion for services provided by almost 1.3 million clinicians, MedPAC said.
 

Larger Changes Ahead?

Rep. Bucshon is among the physicians serving in the House who are pressing for a permanent revamp of the Medicare physician fee schedule. He cosponsored a bill (HR 2474) that would peg future annual increases in the physician fee schedule to the Medicare Economic Index, which would reflect inflation’s effect.

In April, more than 120 state and national medical groups signed onto an AMA-led letter urging Congress to pass this bill.

The measure is a key priority for the AMA. The organization reached out repeatedly last year to federal officials about it through its own in-house lobbyists, this news organization found through a review of congressional lobbying forms submitted by AMA.

These required disclosure forms reveal how much AMA and other organizations spend each quarter to appeal to members of Congress and federal agencies on specific issues. The disclosure forms do not include a detailed accounting of spending on each issue.

But they do show which issues are priorities for an organization. AMA’s in-house lobbyists reported raising dozens of issues in 2024 within contacts in Congress and federal agencies. These issues included abortion access, maternal health, physician burnout, and potential for bias in clinical use of algorithms, as well as Medicare payment for physicians.

AMA reported spending estimated cost of $20.6 million. (AMA spent $6.7 million in the first quarter, $4.75 million in the second quarter, $3.42 million in the third quarter, and $5.74 million in the fourth quarter.)

In a March 6 statement, Jesse M. Ehrenfeld, MD, MPH, AMA president, urged Congress to turn to more serious consideration of Medicare physician pay beyond short-term tweaks attached to other larger bills.

“As physicians, we are trained to run toward emergencies. We urge Congress to do the same,” Dr. Ehrenfeld said. “We encourage Congress to act if this policy decision is an emergency because — in fact — it is. It is well past time to put an end to stopgap measures that fail to address the underlying causes of the continuing decline in Medicare physician payments.”

There’s bipartisan interest in a revamp of the physician fee schedule amid widespread criticism of the last such overhaul, the Medicare Access and CHIP Reauthorization Act of 2015.

For example, Senate Budget Chairman Sheldon Whitehouse (D-RI) has proposed the creation of a technical advisory committee to improve how Medicare sets the physician fee schedule. The existing fee schedule provides too little money for primary care services and primary care provider pay, contributing to shortages, Sen. Whitehouse said.

Sen. Whitehouse on March 6 held a hearing on ways to beef up US primary care. Among the experts who appeared was Amol Navathe, MD, PhD, of the University of Pennsylvania, Philadelphia, Pennsylvania.

Dr. Navathe said the current Medicare physician fee schedule tilts in favor of procedural services, leading to “underinvestment in cognitive, diagnostic, and supportive services such as primary care.”

In addition, much of what primary care clinicians do, “such as addressing social challenges, is not included in the codes of the fee schedule itself,” said Dr. Navathe, who also serves as the vice chairman of MedPAC.

It’s unclear when Congress will attempt a serious revision to the Medicare physician fee schedule. Lawmakers are unlikely to take on such a major challenge in this election year.

There would be significant opposition and challenges for lawmakers in trying to clear a bill that added an inflation adjustment for what’s already seen as an imperfect physician fee schedule, said Mark E. Miller, PhD, executive vice president of healthcare at the philanthropy Arnold Ventures, which studies how payment decisions affect medical care.

“That bill could cost a lot of money and raise a lot of questions,” Dr. Miller said.

A version of this article appeared on Medscape.com.

President Joe Biden on March 9 signed into law a measure that softened — but did not completely eliminate — a 2024 cut in a key rate used to determine how physicians are paid for treating Medicare patients.

While physician groups hailed the move as partial relief, they say they’ll continue to press for broader changes in the Medicare physician fee schedule.

The Medicare provision was tucked into a larger spending package approved by the US House and Senate.

The American Academy of Family Physicians (AAFP), the American Medical Association (AMA), and other groups have lobbied Congress for months to undo a 3.4% cut in the base rate, or conversion factor, in the physician fee schedule for 2024.

The conversion factor is used in calculations to determine reimbursement for myriad other services. Federal Medicare officials said the cut would mean a 1.25% decrease in overall payments in 2024, compared with 2023.

“With the passage of this legislation, Congress has offset 2.93% of that payment cut,” said Steven P. Furr, MD, AAFP’s president in a statement. “We appreciate this temporary measure but continue to urge Congress to advance comprehensive, long-term Medicare payment reform.”

In a statement, Representative Larry Bucshon, MD (R-IN), said the payment cut could not be completely eliminated because of budget constraints.

The Medicare physician fee schedule covers much of the care clinicians provide to people older than 65 and those with disabilities. It covers about 8000 different types of services, ranging from office visits to surgical procedures, imaging, and tests, according to the Medicare Payment Advisory Commission (MedPAC).

Along with physicians, the fee schedule sets payments for nurse practitioners, physician assistants, podiatrists, physical therapists, psychologists, and other clinicians.

In 2021, the Medicare program and its beneficiaries paid $92.8 billion for services provided by almost 1.3 million clinicians, MedPAC said.
 

Larger Changes Ahead?

Rep. Bucshon is among the physicians serving in the House who are pressing for a permanent revamp of the Medicare physician fee schedule. He cosponsored a bill (HR 2474) that would peg future annual increases in the physician fee schedule to the Medicare Economic Index, which would reflect inflation’s effect.

In April, more than 120 state and national medical groups signed onto an AMA-led letter urging Congress to pass this bill.

The measure is a key priority for the AMA. The organization reached out repeatedly last year to federal officials about it through its own in-house lobbyists, this news organization found through a review of congressional lobbying forms submitted by AMA.

These required disclosure forms reveal how much AMA and other organizations spend each quarter to appeal to members of Congress and federal agencies on specific issues. The disclosure forms do not include a detailed accounting of spending on each issue.

But they do show which issues are priorities for an organization. AMA’s in-house lobbyists reported raising dozens of issues in 2024 within contacts in Congress and federal agencies. These issues included abortion access, maternal health, physician burnout, and potential for bias in clinical use of algorithms, as well as Medicare payment for physicians.

AMA reported spending estimated cost of $20.6 million. (AMA spent $6.7 million in the first quarter, $4.75 million in the second quarter, $3.42 million in the third quarter, and $5.74 million in the fourth quarter.)

In a March 6 statement, Jesse M. Ehrenfeld, MD, MPH, AMA president, urged Congress to turn to more serious consideration of Medicare physician pay beyond short-term tweaks attached to other larger bills.

“As physicians, we are trained to run toward emergencies. We urge Congress to do the same,” Dr. Ehrenfeld said. “We encourage Congress to act if this policy decision is an emergency because — in fact — it is. It is well past time to put an end to stopgap measures that fail to address the underlying causes of the continuing decline in Medicare physician payments.”

There’s bipartisan interest in a revamp of the physician fee schedule amid widespread criticism of the last such overhaul, the Medicare Access and CHIP Reauthorization Act of 2015.

For example, Senate Budget Chairman Sheldon Whitehouse (D-RI) has proposed the creation of a technical advisory committee to improve how Medicare sets the physician fee schedule. The existing fee schedule provides too little money for primary care services and primary care provider pay, contributing to shortages, Sen. Whitehouse said.

Sen. Whitehouse on March 6 held a hearing on ways to beef up US primary care. Among the experts who appeared was Amol Navathe, MD, PhD, of the University of Pennsylvania, Philadelphia, Pennsylvania.

Dr. Navathe said the current Medicare physician fee schedule tilts in favor of procedural services, leading to “underinvestment in cognitive, diagnostic, and supportive services such as primary care.”

In addition, much of what primary care clinicians do, “such as addressing social challenges, is not included in the codes of the fee schedule itself,” said Dr. Navathe, who also serves as the vice chairman of MedPAC.

It’s unclear when Congress will attempt a serious revision to the Medicare physician fee schedule. Lawmakers are unlikely to take on such a major challenge in this election year.

There would be significant opposition and challenges for lawmakers in trying to clear a bill that added an inflation adjustment for what’s already seen as an imperfect physician fee schedule, said Mark E. Miller, PhD, executive vice president of healthcare at the philanthropy Arnold Ventures, which studies how payment decisions affect medical care.

“That bill could cost a lot of money and raise a lot of questions,” Dr. Miller said.

A version of this article appeared on Medscape.com.

Medtronic Neurosurgery has recalled Duet External Drainage and Monitoring System (EDMS) catheter tubing because the catheter may disconnect from the patient line stopcock connectors.

If this happens, potential harm to patients may include infections, cerebrospinal fluid (CSF) leakage, overdrainage of CSF, and abnormality of the ventricles. Uncontrolled overdrainage of CSF could lead to neurological injury or death if the disconnection is undetected.

The Food and Drug Administration has identified this as a Class I recall — the most serious type — due to the risk for serious injury or death. To date, there have been 26 reported injuries and no deaths related to this issue. 

The recall includes 45,176 devices distributed in the United States between May 3, 2021, and January 9, 2024, with model numbers 46913, 46914, 46915, 46916, and 46917.

The Duet EDMS is used for temporary CSF drainage or sampling in patients who have surgery for open descending thoracic aortic aneurysm (TAA) or descending thoraco-abdominal aortic aneurysm (TAAA) or patients who have TAA/TAAA repair surgery and develop symptoms such as paraplegia.

Medtronic has sent an urgent medical device recall letter to all affected customers asking them to identify, quarantine, and return any unused recalled products. 

Customers are also advised to check all Duet EDMS components for damage and ensure that all connections are secure and leak-free. 

If a patient is currently connected to an impacted Duet EDMS and a leak or disconnection is detected, the device should be changed to a new alternative device utilizing a sterile technique. 

It is not recommended that a Duet system device that is connected to a patient and working as intended be removed or replaced.

Customers in the United States with questions about this recall should contact Medtronic at 1-800-874-5797.

A version of this article appeared on Medscape.com.

Medtronic Neurosurgery has recalled Duet External Drainage and Monitoring System (EDMS) catheter tubing because the catheter may disconnect from the patient line stopcock connectors.

If this happens, potential harm to patients may include infections, cerebrospinal fluid (CSF) leakage, overdrainage of CSF, and abnormality of the ventricles. Uncontrolled overdrainage of CSF could lead to neurological injury or death if the disconnection is undetected.

The Food and Drug Administration has identified this as a Class I recall — the most serious type — due to the risk for serious injury or death. To date, there have been 26 reported injuries and no deaths related to this issue. 

The recall includes 45,176 devices distributed in the United States between May 3, 2021, and January 9, 2024, with model numbers 46913, 46914, 46915, 46916, and 46917.

The Duet EDMS is used for temporary CSF drainage or sampling in patients who have surgery for open descending thoracic aortic aneurysm (TAA) or descending thoraco-abdominal aortic aneurysm (TAAA) or patients who have TAA/TAAA repair surgery and develop symptoms such as paraplegia.

Medtronic has sent an urgent medical device recall letter to all affected customers asking them to identify, quarantine, and return any unused recalled products. 

Customers are also advised to check all Duet EDMS components for damage and ensure that all connections are secure and leak-free. 

If a patient is currently connected to an impacted Duet EDMS and a leak or disconnection is detected, the device should be changed to a new alternative device utilizing a sterile technique. 

It is not recommended that a Duet system device that is connected to a patient and working as intended be removed or replaced.

Customers in the United States with questions about this recall should contact Medtronic at 1-800-874-5797.

A version of this article appeared on Medscape.com.

Medtronic Neurosurgery has recalled Duet External Drainage and Monitoring System (EDMS) catheter tubing because the catheter may disconnect from the patient line stopcock connectors.

If this happens, potential harm to patients may include infections, cerebrospinal fluid (CSF) leakage, overdrainage of CSF, and abnormality of the ventricles. Uncontrolled overdrainage of CSF could lead to neurological injury or death if the disconnection is undetected.

The Food and Drug Administration has identified this as a Class I recall — the most serious type — due to the risk for serious injury or death. To date, there have been 26 reported injuries and no deaths related to this issue. 

The recall includes 45,176 devices distributed in the United States between May 3, 2021, and January 9, 2024, with model numbers 46913, 46914, 46915, 46916, and 46917.

The Duet EDMS is used for temporary CSF drainage or sampling in patients who have surgery for open descending thoracic aortic aneurysm (TAA) or descending thoraco-abdominal aortic aneurysm (TAAA) or patients who have TAA/TAAA repair surgery and develop symptoms such as paraplegia.

Medtronic has sent an urgent medical device recall letter to all affected customers asking them to identify, quarantine, and return any unused recalled products. 

Customers are also advised to check all Duet EDMS components for damage and ensure that all connections are secure and leak-free. 

If a patient is currently connected to an impacted Duet EDMS and a leak or disconnection is detected, the device should be changed to a new alternative device utilizing a sterile technique. 

It is not recommended that a Duet system device that is connected to a patient and working as intended be removed or replaced.

Customers in the United States with questions about this recall should contact Medtronic at 1-800-874-5797.

A version of this article appeared on Medscape.com.

Treatment with the investigational monoclonal antibody drug batoclimab significantly improved symptoms in patients with antibody-positive generalized myasthenia gravis, data from a new phase 3 study showed.

After 6 weeks of treatment, patients reported nearly 60% sustained improvement in daily activities and a rapid onset of action from batoclimab, a neonatal crystallizable fragment receptor (FcRn) antagonist.

The clinical effects and the extent of immunoglobulin G (IgG) reduction in this study were similar to those previously reported for efgartigimod and rozanolixizumab, two other FcRn antagonists, the investigators noted, adding that larger studies are needed to better understand the safety profile of batoclimab.

“While most generalized myasthenia gravis patients can achieve good disease control through conventional immunotherapy, there are still unmet needs with this disease,” said study investigator Chongbo Zhao, MD, National Center for Neurological Disorders, Huashan Rare Disease Centre, Department of Neurology, Huashan Hospital of Fudan University, Shanghai, China.

The findings were published online in JAMA Neurology.
 

Unmet Need

A rare chronic disease, myasthenia gravis is caused by autoantibodies that disrupt the neuromuscular junction, most commonly against the nicotinic acetylcholine receptor (AChR). This can cause a variety of symptoms, including difficulty swallowing, chewing, and talking, as well as severe, sometimes life-threatening, muscle weakness.

The estimated global prevalence of myasthenia gravis is 15-25 per 100,000, with cases doubling in the past 20 years.

Treatment for myasthenia gravis typically includes immune-suppressing drugs. But research suggests almost half of patients with generalized myasthenia gravis don’t achieve an adequate response or are intolerant to these treatments, and some therapies are costly or not readily accessible.

“Our treatment goal has evolved from saving patients to improving their quality of life, so we still need to explore safer and more effective novel treatment methods,” Dr. Zhao said.

Batoclimab is a fully humanized monoclonal IgG antibody that binds to FcRn and accelerates clearance of harmful IgG. A phase 2 trial provided preliminary evidence to support the efficacy of this agent in Chinese patients with generalized myasthenia gravis.

The current double-blind phase 3 trial included 132 adult patients (mean age, 44 years; 67% female) of Chinese Han ethnicity with generalized myasthenia gravis at 27 centers in China. Participants had a mean Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 8.4 at baseline, and all but one was positive for AChR or muscle-specific kinase (MuSK) antibodies.

The treatment group received weekly subcutaneous injections of batoclimab at 680 mg for 6 weeks, followed by 4 weeks of observation. The control group received a placebo with the same treatment and follow-up schedule.

All patients received standard of care in addition to the assigned treatment, but changes in dosage and/or dosing frequency were not permitted. Patients received a second cycle if they still required treatment.
 

Bests Placebo

Overall, 90% of participants completed all six doses in cycle 1. The second treatment cycle was conducted in 115 patients, with 88% completing all six doses.

Patients were evaluated at baseline and then weekly for MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite, and the 15-item revised version of the Myasthenia Gravis Quality of Life.

Sustained MG-ADL improvement — the primary outcome — was significantly higher in the batoclimab group compared with placebo (58% vs 31%, respectively; odds ratio, 3.45; P = .001).

While the rate of sustained MG-ADL improvement with batoclimab was lower than that reported for efgartigimod (68%) in a previous trial, that was primarily because of the more stringent definition of sustained MG-ADL improvement (three-point reduction vs two-point reduction from baseline), investigators said.

In the current trial, batoclimab had a rapid onset of action, with scores diverging between the treatment and placebo groups as early as the second week of therapy.

In the second treatment cycle, batoclimab once again outperformed placebo in sustained MG-ADL improvement (63% vs 36%, respectively; P = .002).

Batoclimab also bested placebo on secondary outcomes, including sustained QMG improvement (64% vs 41%; P = .008) and percent of patients achieving minimal symptom expression (25% vs 5%; P = .004).

Results of all subgroup analyses, including by age groups, sex, body weight, body mass index, and MG Foundation of America clinical classification, were consistent with those of the main analysis. The efficacy of batoclimab was also supported by all sensitivity analyses, underscoring the robustness of results.

Batoclimab led to a rapid and sustained reduction in serum AChR antibody levels, with a median reduction of 81% at week 6.
 

Well Tolerated

On discontinuation of batoclimab, serum total IgG returned to a level comparable with the baseline after 4 weeks. Reversibility of the drug’s effect is important considering the risk for infection from prolonged immune suppression, the authors noted.

The rate of peripheral edema was significantly higher in the treatment than in the placebo groups (39% vs 5%), but all cases were mild or moderate and deemed not clinically significant. The treatment group also had higher rates of upper respiratory tract infections (36% vs 22%) and of urinary tract infections (19% vs 15%).

“Although the incidence of upper respiratory tract and urinary tract infections was higher in the batoclimab group numerically, these were mild infections that did not require special treatment, so this is not a concern,” said Dr. Zhao.

Plasma albumin levels in the batoclimab group decreased significantly throughout the treatment cycle, starting at week 1 and reaching a decline of up to 31% at week 6. These levels increased rapidly toward baseline after treatment discontinuation.

High cholesterol levels were noted in the batoclimab group, plateauing by week 6. But levels returned to near baseline levels within 4 weeks after the final dose, and there were no serious related adverse reactions.

The rate of headache was slightly higher in the treatment group (6% vs 5% for placebo). “This finding may seem minor but could potentially translate into improved adherence in daily practice settings,” the authors wrote.

In previous studies, the efficacy of FcRn inhibitors in the Asian population was only examined in subgroup analyses with limited subjects. Finding an effective FcRn antagonist for China and surrounding regions is particularly important “considering the high mortality rate in hospitalized generalized myasthenia gravis patients in China,” the researchers noted.

The trial included only two treatment cycles, although results of an open-label extension trial examining longer-term efficacy of batoclimab should be available by the end of this year, said Dr. Zhao.

The trial was also not designed to investigate long-term safety, particularly infections and cardiovascular events. Only one study subject was negative for AChR or MuSK antibodies, which prevented researchers from assessing the drug’s efficacy in this subpopulation.
 

Questions Remain

Commenting on the study, Fredrik Piehl, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden , said that recent studies of the two other FcRn antagonists were short-term and had limited long-term data. “We don’t know how valuable they may be for continued treatment,” Dr. Piehl said.

It’s also unclear how this new treatment modality compares with existing and emerging drug strategies in terms of the long-term benefit-risk balance, he added.

The rate of adverse events with batoclimab was high compared with placebo in this study and higher than in earlier studies of efgartigimod, Dr. Piehl noted.

“In this study, almost twice as many reported adverse events in the active arm compared with controls, while these differences tended to be smaller in previously reported trials,” he said.

The trial was funded by Nona Biosciences (Suzhou). Dr. Zhao reported being a full-time employee of Nona Biosciences (Suzhou), a subsidiary of Harbour BioMed Inc. He also reported receiving advisory board/consultant fees from Nona Biosciences, Roche, Sanofi, and Zailab outside the submitted work. Dr. Piehl has received research grants from Janssen, Merck KGaA, and UCB; and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche; and preparation of expert witness statement for Novartis.

A version of this article first appeared on Medscape.com.

Treatment with the investigational monoclonal antibody drug batoclimab significantly improved symptoms in patients with antibody-positive generalized myasthenia gravis, data from a new phase 3 study showed.

After 6 weeks of treatment, patients reported nearly 60% sustained improvement in daily activities and a rapid onset of action from batoclimab, a neonatal crystallizable fragment receptor (FcRn) antagonist.

The clinical effects and the extent of immunoglobulin G (IgG) reduction in this study were similar to those previously reported for efgartigimod and rozanolixizumab, two other FcRn antagonists, the investigators noted, adding that larger studies are needed to better understand the safety profile of batoclimab.

“While most generalized myasthenia gravis patients can achieve good disease control through conventional immunotherapy, there are still unmet needs with this disease,” said study investigator Chongbo Zhao, MD, National Center for Neurological Disorders, Huashan Rare Disease Centre, Department of Neurology, Huashan Hospital of Fudan University, Shanghai, China.

The findings were published online in JAMA Neurology.
 

Unmet Need

A rare chronic disease, myasthenia gravis is caused by autoantibodies that disrupt the neuromuscular junction, most commonly against the nicotinic acetylcholine receptor (AChR). This can cause a variety of symptoms, including difficulty swallowing, chewing, and talking, as well as severe, sometimes life-threatening, muscle weakness.

The estimated global prevalence of myasthenia gravis is 15-25 per 100,000, with cases doubling in the past 20 years.

Treatment for myasthenia gravis typically includes immune-suppressing drugs. But research suggests almost half of patients with generalized myasthenia gravis don’t achieve an adequate response or are intolerant to these treatments, and some therapies are costly or not readily accessible.

“Our treatment goal has evolved from saving patients to improving their quality of life, so we still need to explore safer and more effective novel treatment methods,” Dr. Zhao said.

Batoclimab is a fully humanized monoclonal IgG antibody that binds to FcRn and accelerates clearance of harmful IgG. A phase 2 trial provided preliminary evidence to support the efficacy of this agent in Chinese patients with generalized myasthenia gravis.

The current double-blind phase 3 trial included 132 adult patients (mean age, 44 years; 67% female) of Chinese Han ethnicity with generalized myasthenia gravis at 27 centers in China. Participants had a mean Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 8.4 at baseline, and all but one was positive for AChR or muscle-specific kinase (MuSK) antibodies.

The treatment group received weekly subcutaneous injections of batoclimab at 680 mg for 6 weeks, followed by 4 weeks of observation. The control group received a placebo with the same treatment and follow-up schedule.

All patients received standard of care in addition to the assigned treatment, but changes in dosage and/or dosing frequency were not permitted. Patients received a second cycle if they still required treatment.
 

Bests Placebo

Overall, 90% of participants completed all six doses in cycle 1. The second treatment cycle was conducted in 115 patients, with 88% completing all six doses.

Patients were evaluated at baseline and then weekly for MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite, and the 15-item revised version of the Myasthenia Gravis Quality of Life.

Sustained MG-ADL improvement — the primary outcome — was significantly higher in the batoclimab group compared with placebo (58% vs 31%, respectively; odds ratio, 3.45; P = .001).

While the rate of sustained MG-ADL improvement with batoclimab was lower than that reported for efgartigimod (68%) in a previous trial, that was primarily because of the more stringent definition of sustained MG-ADL improvement (three-point reduction vs two-point reduction from baseline), investigators said.

In the current trial, batoclimab had a rapid onset of action, with scores diverging between the treatment and placebo groups as early as the second week of therapy.

In the second treatment cycle, batoclimab once again outperformed placebo in sustained MG-ADL improvement (63% vs 36%, respectively; P = .002).

Batoclimab also bested placebo on secondary outcomes, including sustained QMG improvement (64% vs 41%; P = .008) and percent of patients achieving minimal symptom expression (25% vs 5%; P = .004).

Results of all subgroup analyses, including by age groups, sex, body weight, body mass index, and MG Foundation of America clinical classification, were consistent with those of the main analysis. The efficacy of batoclimab was also supported by all sensitivity analyses, underscoring the robustness of results.

Batoclimab led to a rapid and sustained reduction in serum AChR antibody levels, with a median reduction of 81% at week 6.
 

Well Tolerated

On discontinuation of batoclimab, serum total IgG returned to a level comparable with the baseline after 4 weeks. Reversibility of the drug’s effect is important considering the risk for infection from prolonged immune suppression, the authors noted.

The rate of peripheral edema was significantly higher in the treatment than in the placebo groups (39% vs 5%), but all cases were mild or moderate and deemed not clinically significant. The treatment group also had higher rates of upper respiratory tract infections (36% vs 22%) and of urinary tract infections (19% vs 15%).

“Although the incidence of upper respiratory tract and urinary tract infections was higher in the batoclimab group numerically, these were mild infections that did not require special treatment, so this is not a concern,” said Dr. Zhao.

Plasma albumin levels in the batoclimab group decreased significantly throughout the treatment cycle, starting at week 1 and reaching a decline of up to 31% at week 6. These levels increased rapidly toward baseline after treatment discontinuation.

High cholesterol levels were noted in the batoclimab group, plateauing by week 6. But levels returned to near baseline levels within 4 weeks after the final dose, and there were no serious related adverse reactions.

The rate of headache was slightly higher in the treatment group (6% vs 5% for placebo). “This finding may seem minor but could potentially translate into improved adherence in daily practice settings,” the authors wrote.

In previous studies, the efficacy of FcRn inhibitors in the Asian population was only examined in subgroup analyses with limited subjects. Finding an effective FcRn antagonist for China and surrounding regions is particularly important “considering the high mortality rate in hospitalized generalized myasthenia gravis patients in China,” the researchers noted.

The trial included only two treatment cycles, although results of an open-label extension trial examining longer-term efficacy of batoclimab should be available by the end of this year, said Dr. Zhao.

The trial was also not designed to investigate long-term safety, particularly infections and cardiovascular events. Only one study subject was negative for AChR or MuSK antibodies, which prevented researchers from assessing the drug’s efficacy in this subpopulation.
 

Questions Remain

Commenting on the study, Fredrik Piehl, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden , said that recent studies of the two other FcRn antagonists were short-term and had limited long-term data. “We don’t know how valuable they may be for continued treatment,” Dr. Piehl said.

It’s also unclear how this new treatment modality compares with existing and emerging drug strategies in terms of the long-term benefit-risk balance, he added.

The rate of adverse events with batoclimab was high compared with placebo in this study and higher than in earlier studies of efgartigimod, Dr. Piehl noted.

“In this study, almost twice as many reported adverse events in the active arm compared with controls, while these differences tended to be smaller in previously reported trials,” he said.

The trial was funded by Nona Biosciences (Suzhou). Dr. Zhao reported being a full-time employee of Nona Biosciences (Suzhou), a subsidiary of Harbour BioMed Inc. He also reported receiving advisory board/consultant fees from Nona Biosciences, Roche, Sanofi, and Zailab outside the submitted work. Dr. Piehl has received research grants from Janssen, Merck KGaA, and UCB; and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche; and preparation of expert witness statement for Novartis.

A version of this article first appeared on Medscape.com.

Treatment with the investigational monoclonal antibody drug batoclimab significantly improved symptoms in patients with antibody-positive generalized myasthenia gravis, data from a new phase 3 study showed.

After 6 weeks of treatment, patients reported nearly 60% sustained improvement in daily activities and a rapid onset of action from batoclimab, a neonatal crystallizable fragment receptor (FcRn) antagonist.

The clinical effects and the extent of immunoglobulin G (IgG) reduction in this study were similar to those previously reported for efgartigimod and rozanolixizumab, two other FcRn antagonists, the investigators noted, adding that larger studies are needed to better understand the safety profile of batoclimab.

“While most generalized myasthenia gravis patients can achieve good disease control through conventional immunotherapy, there are still unmet needs with this disease,” said study investigator Chongbo Zhao, MD, National Center for Neurological Disorders, Huashan Rare Disease Centre, Department of Neurology, Huashan Hospital of Fudan University, Shanghai, China.

The findings were published online in JAMA Neurology.
 

Unmet Need

A rare chronic disease, myasthenia gravis is caused by autoantibodies that disrupt the neuromuscular junction, most commonly against the nicotinic acetylcholine receptor (AChR). This can cause a variety of symptoms, including difficulty swallowing, chewing, and talking, as well as severe, sometimes life-threatening, muscle weakness.

The estimated global prevalence of myasthenia gravis is 15-25 per 100,000, with cases doubling in the past 20 years.

Treatment for myasthenia gravis typically includes immune-suppressing drugs. But research suggests almost half of patients with generalized myasthenia gravis don’t achieve an adequate response or are intolerant to these treatments, and some therapies are costly or not readily accessible.

“Our treatment goal has evolved from saving patients to improving their quality of life, so we still need to explore safer and more effective novel treatment methods,” Dr. Zhao said.

Batoclimab is a fully humanized monoclonal IgG antibody that binds to FcRn and accelerates clearance of harmful IgG. A phase 2 trial provided preliminary evidence to support the efficacy of this agent in Chinese patients with generalized myasthenia gravis.

The current double-blind phase 3 trial included 132 adult patients (mean age, 44 years; 67% female) of Chinese Han ethnicity with generalized myasthenia gravis at 27 centers in China. Participants had a mean Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 8.4 at baseline, and all but one was positive for AChR or muscle-specific kinase (MuSK) antibodies.

The treatment group received weekly subcutaneous injections of batoclimab at 680 mg for 6 weeks, followed by 4 weeks of observation. The control group received a placebo with the same treatment and follow-up schedule.

All patients received standard of care in addition to the assigned treatment, but changes in dosage and/or dosing frequency were not permitted. Patients received a second cycle if they still required treatment.
 

Bests Placebo

Overall, 90% of participants completed all six doses in cycle 1. The second treatment cycle was conducted in 115 patients, with 88% completing all six doses.

Patients were evaluated at baseline and then weekly for MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite, and the 15-item revised version of the Myasthenia Gravis Quality of Life.

Sustained MG-ADL improvement — the primary outcome — was significantly higher in the batoclimab group compared with placebo (58% vs 31%, respectively; odds ratio, 3.45; P = .001).

While the rate of sustained MG-ADL improvement with batoclimab was lower than that reported for efgartigimod (68%) in a previous trial, that was primarily because of the more stringent definition of sustained MG-ADL improvement (three-point reduction vs two-point reduction from baseline), investigators said.

In the current trial, batoclimab had a rapid onset of action, with scores diverging between the treatment and placebo groups as early as the second week of therapy.

In the second treatment cycle, batoclimab once again outperformed placebo in sustained MG-ADL improvement (63% vs 36%, respectively; P = .002).

Batoclimab also bested placebo on secondary outcomes, including sustained QMG improvement (64% vs 41%; P = .008) and percent of patients achieving minimal symptom expression (25% vs 5%; P = .004).

Results of all subgroup analyses, including by age groups, sex, body weight, body mass index, and MG Foundation of America clinical classification, were consistent with those of the main analysis. The efficacy of batoclimab was also supported by all sensitivity analyses, underscoring the robustness of results.

Batoclimab led to a rapid and sustained reduction in serum AChR antibody levels, with a median reduction of 81% at week 6.
 

Well Tolerated

On discontinuation of batoclimab, serum total IgG returned to a level comparable with the baseline after 4 weeks. Reversibility of the drug’s effect is important considering the risk for infection from prolonged immune suppression, the authors noted.

The rate of peripheral edema was significantly higher in the treatment than in the placebo groups (39% vs 5%), but all cases were mild or moderate and deemed not clinically significant. The treatment group also had higher rates of upper respiratory tract infections (36% vs 22%) and of urinary tract infections (19% vs 15%).

“Although the incidence of upper respiratory tract and urinary tract infections was higher in the batoclimab group numerically, these were mild infections that did not require special treatment, so this is not a concern,” said Dr. Zhao.

Plasma albumin levels in the batoclimab group decreased significantly throughout the treatment cycle, starting at week 1 and reaching a decline of up to 31% at week 6. These levels increased rapidly toward baseline after treatment discontinuation.

High cholesterol levels were noted in the batoclimab group, plateauing by week 6. But levels returned to near baseline levels within 4 weeks after the final dose, and there were no serious related adverse reactions.

The rate of headache was slightly higher in the treatment group (6% vs 5% for placebo). “This finding may seem minor but could potentially translate into improved adherence in daily practice settings,” the authors wrote.

In previous studies, the efficacy of FcRn inhibitors in the Asian population was only examined in subgroup analyses with limited subjects. Finding an effective FcRn antagonist for China and surrounding regions is particularly important “considering the high mortality rate in hospitalized generalized myasthenia gravis patients in China,” the researchers noted.

The trial included only two treatment cycles, although results of an open-label extension trial examining longer-term efficacy of batoclimab should be available by the end of this year, said Dr. Zhao.

The trial was also not designed to investigate long-term safety, particularly infections and cardiovascular events. Only one study subject was negative for AChR or MuSK antibodies, which prevented researchers from assessing the drug’s efficacy in this subpopulation.
 

Questions Remain

Commenting on the study, Fredrik Piehl, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden , said that recent studies of the two other FcRn antagonists were short-term and had limited long-term data. “We don’t know how valuable they may be for continued treatment,” Dr. Piehl said.

It’s also unclear how this new treatment modality compares with existing and emerging drug strategies in terms of the long-term benefit-risk balance, he added.

The rate of adverse events with batoclimab was high compared with placebo in this study and higher than in earlier studies of efgartigimod, Dr. Piehl noted.

“In this study, almost twice as many reported adverse events in the active arm compared with controls, while these differences tended to be smaller in previously reported trials,” he said.

The trial was funded by Nona Biosciences (Suzhou). Dr. Zhao reported being a full-time employee of Nona Biosciences (Suzhou), a subsidiary of Harbour BioMed Inc. He also reported receiving advisory board/consultant fees from Nona Biosciences, Roche, Sanofi, and Zailab outside the submitted work. Dr. Piehl has received research grants from Janssen, Merck KGaA, and UCB; and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche; and preparation of expert witness statement for Novartis.

A version of this article first appeared on Medscape.com.

TOPLINE:

Obstructive sleep apnea (OSA) is associated with a significantly higher risk for stroke — regardless of continuous positive airway pressure (CPAP) device use — but only in White individuals, new data suggested. The study also found that stroke risk among Black individuals with OSA was lower in those who used CPAP machines vs those who didn›t.

METHODOLOGY:

• Researchers used data on 22,192 people from the Reasons for Geographic and Racial Differences in Stroke study, a US population-based cohort of Black and White individuals with no history of stroke at baseline (mean age, 64 years; 38% Black individuals).
• 11% of overall participants had provider diagnosed OSA at baseline.
• Participants were followed for a mean of 12 years.
• Researchers adjusted for demographic, socioeconomic, and stroke risk factors.

TAKEAWAY: 

• During the follow-up period, 969 participants (4.4%) experienced a stroke.
• After adjusting for confounders, having high OSA risk and diagnosed OSA were associated with higher risks for incident stroke in White individuals (adjusted hazard ratio [aHR], 1.22; 95% CI, 1.01-1.47 and aHR, 1.33; 95% CI, 1.04-1.70, respectively) but not in Black individuals.
• Among those with diagnosed OSA, CPAP use was associated with a higher risk for incident stroke in White individuals (aHR, 1.38; 95% CI, 1.05-1.80) but a lower stroke risk in Black individuals (aHR, 0.36; 95% CI, 0.14-0.90) compared with no CPAP use.Snoring was not associated with incident stroke in either Black or White individuals.
• Snoring was not associated with incident stroke in either Black or White individuals.

IN PRACTICE:

“These results were not what we were expecting to find since Black people have been shown to have a higher risk of stroke and are more likely to have sleep apnea than White people,” lead author Rebecca Robbins, MMSc, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts, said in a news release. “Since it has been shown that Black people have more severe sleep apnea than White people and take longer to be screened and treated than White people, it’s possible that using a CPAP machine provides a greater benefit on reducing stroke risk for Black people.”

SOURCE:

Robbins was the lead and corresponding author of the study. It was published online in Neurology. 

LIMITATIONS:

The current study assessed only self-reported OSA symptoms, risk, diagnosis, and treatment and did not include data on the hours of CPAP usage at night, number of days of treatment, adherence during the follow-up period, and OSA severity. 

DISCLOSURES:

The study was funded by the National Institute of Neurological Disorders and Stroke and the National Institute on Aging. Robbins received consulting income from Sonesta Hotels International, Oura Ring Ltd., Savoir Beds Ltd., Castle Hot Springs, and ByNacht GmbH. The other authors’ disclosures are listed in the original paper.

A version of this article appeared on Medscape.com.

TOPLINE:

Obstructive sleep apnea (OSA) is associated with a significantly higher risk for stroke — regardless of continuous positive airway pressure (CPAP) device use — but only in White individuals, new data suggested. The study also found that stroke risk among Black individuals with OSA was lower in those who used CPAP machines vs those who didn›t.

METHODOLOGY:

• Researchers used data on 22,192 people from the Reasons for Geographic and Racial Differences in Stroke study, a US population-based cohort of Black and White individuals with no history of stroke at baseline (mean age, 64 years; 38% Black individuals).
• 11% of overall participants had provider diagnosed OSA at baseline.
• Participants were followed for a mean of 12 years.
• Researchers adjusted for demographic, socioeconomic, and stroke risk factors.

TAKEAWAY: 

• During the follow-up period, 969 participants (4.4%) experienced a stroke.
• After adjusting for confounders, having high OSA risk and diagnosed OSA were associated with higher risks for incident stroke in White individuals (adjusted hazard ratio [aHR], 1.22; 95% CI, 1.01-1.47 and aHR, 1.33; 95% CI, 1.04-1.70, respectively) but not in Black individuals.
• Among those with diagnosed OSA, CPAP use was associated with a higher risk for incident stroke in White individuals (aHR, 1.38; 95% CI, 1.05-1.80) but a lower stroke risk in Black individuals (aHR, 0.36; 95% CI, 0.14-0.90) compared with no CPAP use.Snoring was not associated with incident stroke in either Black or White individuals.
• Snoring was not associated with incident stroke in either Black or White individuals.

IN PRACTICE:

“These results were not what we were expecting to find since Black people have been shown to have a higher risk of stroke and are more likely to have sleep apnea than White people,” lead author Rebecca Robbins, MMSc, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts, said in a news release. “Since it has been shown that Black people have more severe sleep apnea than White people and take longer to be screened and treated than White people, it’s possible that using a CPAP machine provides a greater benefit on reducing stroke risk for Black people.”

SOURCE:

Robbins was the lead and corresponding author of the study. It was published online in Neurology. 

LIMITATIONS:

The current study assessed only self-reported OSA symptoms, risk, diagnosis, and treatment and did not include data on the hours of CPAP usage at night, number of days of treatment, adherence during the follow-up period, and OSA severity. 

DISCLOSURES:

The study was funded by the National Institute of Neurological Disorders and Stroke and the National Institute on Aging. Robbins received consulting income from Sonesta Hotels International, Oura Ring Ltd., Savoir Beds Ltd., Castle Hot Springs, and ByNacht GmbH. The other authors’ disclosures are listed in the original paper.

A version of this article appeared on Medscape.com.

TOPLINE:

Obstructive sleep apnea (OSA) is associated with a significantly higher risk for stroke — regardless of continuous positive airway pressure (CPAP) device use — but only in White individuals, new data suggested. The study also found that stroke risk among Black individuals with OSA was lower in those who used CPAP machines vs those who didn›t.

METHODOLOGY:

• Researchers used data on 22,192 people from the Reasons for Geographic and Racial Differences in Stroke study, a US population-based cohort of Black and White individuals with no history of stroke at baseline (mean age, 64 years; 38% Black individuals).
• 11% of overall participants had provider diagnosed OSA at baseline.
• Participants were followed for a mean of 12 years.
• Researchers adjusted for demographic, socioeconomic, and stroke risk factors.

TAKEAWAY: 

• During the follow-up period, 969 participants (4.4%) experienced a stroke.
• After adjusting for confounders, having high OSA risk and diagnosed OSA were associated with higher risks for incident stroke in White individuals (adjusted hazard ratio [aHR], 1.22; 95% CI, 1.01-1.47 and aHR, 1.33; 95% CI, 1.04-1.70, respectively) but not in Black individuals.
• Among those with diagnosed OSA, CPAP use was associated with a higher risk for incident stroke in White individuals (aHR, 1.38; 95% CI, 1.05-1.80) but a lower stroke risk in Black individuals (aHR, 0.36; 95% CI, 0.14-0.90) compared with no CPAP use.Snoring was not associated with incident stroke in either Black or White individuals.
• Snoring was not associated with incident stroke in either Black or White individuals.

IN PRACTICE:

“These results were not what we were expecting to find since Black people have been shown to have a higher risk of stroke and are more likely to have sleep apnea than White people,” lead author Rebecca Robbins, MMSc, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts, said in a news release. “Since it has been shown that Black people have more severe sleep apnea than White people and take longer to be screened and treated than White people, it’s possible that using a CPAP machine provides a greater benefit on reducing stroke risk for Black people.”

SOURCE:

Robbins was the lead and corresponding author of the study. It was published online in Neurology. 

LIMITATIONS:

The current study assessed only self-reported OSA symptoms, risk, diagnosis, and treatment and did not include data on the hours of CPAP usage at night, number of days of treatment, adherence during the follow-up period, and OSA severity. 

DISCLOSURES:

The study was funded by the National Institute of Neurological Disorders and Stroke and the National Institute on Aging. Robbins received consulting income from Sonesta Hotels International, Oura Ring Ltd., Savoir Beds Ltd., Castle Hot Springs, and ByNacht GmbH. The other authors’ disclosures are listed in the original paper.

A version of this article appeared on Medscape.com.

Alzheimer’s research is plagued with misconduct and fraud, undermining the progress toward understanding and treating the disease, say investigators who endeavor to expose errors and misleading practices.

The book is yet to be closed, for instance, on whether a 2006 paper by Sylvain Lesne positing amyloid as a major cause of Alzheimer’s was based on fraudulent data. Suspicions about the paper were first raised in late 2021 by Matthew Schrag, MD, PhD, an assistant professor of neurology at Vanderbilt University Medical Center, Nashville, Tennessee.

Dr. Schrag also queried the work of a City University of New York (CUNY) researcher who proposed PT-125 (now simufilam) as a potential anti-amyloid for Alzheimer’s disease. Even though CUNY recently found “egregious” and potentially deliberate misconduct by that researcher, Cassava Sciences is continuing phase 3 trials of simufilam.

Now questions are being raised about work from the lab of Berislav V. Zlokovic, PhD, a prominent neuroscientist at the University of Southern California (USC), Los Angeles, California, and also about studies conducted under the aegis of Domenico Pratico, MD, the director of the Alzheimer’s Center at Temple University in Philadelphia, Pennsylvania.

Alzheimer’s has been a notoriously hard puzzle to solve. Despite decades of research, there are still no effective therapies and disparate theories about potential causes.

Dr. Schrag said he wouldn’t “attribute all the ills in this field” to misconduct, but it “is absolutely a part of the equation.” Some of the papers flagged for integrity issues “have been hugely influential,” he said in an interview. “Some of the labs that we’re talking about have really shaped how we’ve thought about this disease,” he said. “It’s hard to un-ring the bell.”

The fallout from fraud has a wide impact. Taxpayer dollars are wasted in the creation of the fraud and in attempts to replicate the failed experiment. Grad students — the workhorses of labs — waste time trying to repeat studies or may be bullied or intimidated into misconduct, said Elisabeth Bik, PhD, a former Stanford microbiologist who is now a full-time fraud investigator.

And there’s potential harm to patients. “There’s a lot of false hope being given to these people and their families,” Dr. Bik said in an interview.
 

Alzheimer’s Tempts With Big Rewards

There are big rewards for those who publish important papers on Alzheimer’s: More grants, publication in higher-impact journals, larger labs, and potentially, personal enrichment from commercialization of therapies.

“I can see that people are driven to cut corners or even to make up results, or even anything in between, to reach that goal,” said Dr. Bik.

It’s unclear whether misconduct and fraud are on the rise or just being detected more frequently.

“It’s very hard to say,” said Mike Rossner, PhD, president of Image Data Integrity. Institutions hire Dr. Rossner to help ferret out research integrity issues. He told this news organization that it’s likely detection is on the rise, given the increasing number of sleuths like Dr. Bik.

In 2002, Dr. Rossner began to screen all images submitted to the Journal of Clinical Biology in response to the new phenomenon of digital images and the advent of PhotoShop. “Very early on, we started to see problems in digital images that we would not have seen on a glossy printout,” Dr. Rossner said of his time as managing editor of the journal.

From 2002 to 2014, at least 25% of papers had an image that violated guidelines that prohibited the removal of spots or other blemishes (called “beautification”) with PhotoShop, which did not necessarily indicate fraud. They withdrew acceptance for 1% of papers because of image manipulations that affected data interpretation.

Dr. Bik noted that even if there is not a greater percentage of fraudulent papers in Alzheimer’s, “it would still be in absolute numbers a lot of papers that could be fraudulent,” given that Alzheimer’s research is well-funded with federal agencies alone providing $3.7 billion a year.

Images Key to Spotting Issues

Investigative sleuths often use the online forum PubPeer to initially raise questions about papers. The format gives the original authors a chance to comment on or defend their work. While some critiques are about data, most hone in on alleged duplications or manipulations of images, primarily by Western Blots.

The images are key, because “the images are the data,” said Dr. Rossner. “The words are the author’s interpretation of what they see in the images,” he said.

It’s also easier to spot a problem in an image. The raw data or an investigator’s notebooks aren’t needed, and there are artificial intelligence-driven software programs such as Proofig and Image Twin that help investigators spot duplicated images or cases in which an image might have been flipped or otherwise manipulated to make results look better.

Science recently announced that it would be using Proofig to screen images in all papers submitted to its six journals.

Using a screening tool is better than nothing, said Dr. Rossner who still relies on visual inspection, employing contrast or other features in PhotoShop to spot inconsistencies or duplications. But “none of those companies have disclosed how effective they are relative to visual screening, and that to me is very problematic,” he said.

“The tools are not going to catch everything,” said Dr. Bik.

Dr. Schrag agreed. “One of the things that we’re worried about is that a lot of the journals will simply adopt these tools as a screener and assume that that’s going to de-risk their publication portfolio,” he said, noting the high rate of misses.

Artificial Intelligence a Growing Concern

Artificial intelligence (AI) may also accelerate the amount of fraud and add to the difficulty of ferreting it out, said the investigators.

“I’m very worried about AI,” said Dr. Bik. Although AI-generated images and content may be rudimentary today, “next year it’s going to be much better,” she said. Going forward, it may be hard to distinguish between a real dataset and one that has been generated by AI, she said.

“The more closely AI can mimic authentic content, the more difficult it will be for publications to detect intentionally fraudulent submissions,” wrote Dror Kolodkin-Gal, PhD, the founder of Proofig, in an article for the Council of Science Editors.

Dr. Kolodkin-Gal said that AI may be especially prone to misuse by paper mills. Those operations submit fake or shoddy manuscripts to a journal on behalf of researchers seeking publication who pay the mills a fee. The Committee on Publication Ethics reported in 2022 that 2%-46% of papers submitted to journals may be from paper mills.

While it’s unclear whether AI is having any impact now, Dr. Rossner said, “I think I can be pretty confident in saying it is going to be a growing problem” as the tools become more sophisticated.

He sees parallels with the rise of PhotoShop and cites data from the National Institute of Health’s Office of Research Integrity (ORI) showing that in 1990, when PhotoShop was still new, 2% of cases referred to ORI involved image manipulation. By 2007, 70% of cases had image manipulation issues.

Journals, Institutions Need to Step Up More

Fraud may continue apace in part because investigations drag on for years, and in many cases, with a lack of consequences for the perpetrators, said the investigators. And, they say, journals and institutions haven’t devoted enough resources to prevent or investigate misconduct.

“A lot of editors did not even want to investigate because they just didn’t want to believe that there could be fraud in science,” said Dr. Bik of her experiences. “I hope that by now most journals at least should have realized that some proportion of the manuscripts that get sent to their journals is going to be fraud,” she said.

“The bulk of the journals seem like they don’t want to be bothered by this,” agreed Dr. Schrag, adding that “some have gone to great lengths to try to discourage people from bringing forward complaints.”

A big issue is that journals “don’t answer to any higher authority,” said Dr. Schrag. He believes that journals that repeatedly refuse to address integrity issues should be barred from publishing research produced with funds from the National Institutes of Health.

All the investigators said institutions and journals should hire forensic investigators. Relying on unpaid peer reviewers or editors to root out fraud is unrealistic, they said.

“You want to have specialized people with experience and be paid to do that as a full-time job,” said Dr. Bik, who is funded by speaking engagements and receives about $2300 a month through donations to her Patreon account.

Once a potential integrity issue is flagged, there is “an incredible conflict of interest in how these investigations are run,” said Dr. Schrag. “Institutions are asked to investigate their own faculty; they’re asked to investigate themselves.” That “creates the disincentive to move expeditiously,” said Dr. Schrag.

With the space of time, people who have committed fraud can throw out notebooks, delete data from servers, or even PhotoShop original photos so they match the manipulated ones that were submitted, Dr. Bik said.

Institutions could show they are serious about fraud by offering a “central, systematic universal screening of all image data going out of their institutions before submission to a journal,” said Dr. Rossner. But he knows only of a handful that do so. “I think research integrity offices have historically been very reactive, and they need to pivot and become proactive,” said Dr. Rossner.

Dr. Schrag wants to see stronger values within the research enterprise. “You have to build a culture where it’s absolutely anathema at a core level to violate these standards of research integrity,” he said. “We have this notion that we can push the process along faster and get to a grant and get to a paper and get to some short-term goal,” he said. “But the long-term goal in most of these cases is to cure a disease or to understand some biological mysteries. There’s no shortcut to getting there,” said Dr. Schrag.

There have been some high-profile consequences for research integrity failures, such as the 2023 resignation of Stanford University President Marc Tessier-Lavigne in the wake of findings that members of his lab — but not Tessier-Lavigne — engaged in data manipulation.

The process is often opaque, with investigations done in secrecy. “Consequences are not usually revealed, either,” said Dr. Rossner.

Dr. Schrag acknowledges it’s a tough balancing act for institutions to root out bad actors while also ensuring there’s no harm to those who may simply have operated in error.

“But it doesn’t serve anyone’s interest including the people who are accused, in dragging these things out for 5, 6, 8, or 10 years,” he said.

Lesne and Cassava: The Long and Winding Road

The investigations into the Lesne papers and the work underpinning Cassava Sciences’ therapy point to the difficulty of policing integrity and the potential fallout.

Lesne’s signature paper published in Nature in 2006 has been cited some 2300 times and is the fourth most-accessed article of 81,612 articles of a similar age in all journals tracked by Altimetrics.

Dr. Schrag, Dr. Bik, and others wrote to multiple journals asking them to investigate some 25 papers related to simufilam, including a 2012 Journal of Clinical Investigation article by Hoau-Yan Wang, PhD, the CUNY scientist whose work on simufilam has been questioned.

JCI Editor Elizabeth McNally pushed back stating in an editorial in 2022 that they, as whistleblowers, had potential conflicts and that they could be assisting short sellers who were seeking to profit by depressing Cassava’s stock price. Indeed, Dr. Schrag was initially hired by a law firm that was representing short sellers. Ms. McNally said that JCI would start requiring disclosures by whistleblowers.

Dr. Bik urged CUNY to investigate Dr. Wang in 2021 but was rebuffed. Then, in November 2023, a copy of CUNY’s final report on the Wang inquiry was leaked to Science. The university reported that Dr. Wang did not provide any original data or notebooks and that it found “long-standing and egregious misconduct in data management and record keeping by Dr. Wang,” wrote Dr. Bik in a blog post summarizing the investigation.

As of late 2023, 42 papers by Dr. Wang have earned PubPeer posts, seven have been retracted, and five have been marked with an Expression of Concern, wrote Dr. Bik.

Some have called for Cassava to stop its phase 3 studies of simufilam, but the company is proceeding, announcing in November 2023 that they have completed enrollment.

Misconduct Queries Underway at USC and Temple

Meanwhile, Dr. Schrag and Dr. Bik continue sleuthing. They are among a small group of whistleblowers who have filed a complaint with NIH about irregularities in the Zlokovic lab at USC. They allege that images were manipulated in dozens of papers, including some that inform the development of a stroke drug in phase 2 trials.

The inquiry goes well beyond stroke, said Dr. Schrag. Dr. Zlokovic “is one of the most influential scientists on Alzheimer’s scientists in the country,” Dr. Schrag said. The USC scientist is a leader on blood-brain barrier research.

USC is investigating “at some level,” he said. In a statement to this news organization, USC said that it “takes any allegations about research integrity very seriously.” The statement added, “Consistent with federal regulations and USC policies, this review must be kept confidential. As a result, we are unable to provide any further information.”

Mu Yang, PhD, assistant professor of neurobiology at Columbia University Medical Center in New York City, is also working on the Zlokovic investigation.

She calls herself an “accidental sleuth” who fell into the hobby after a graduate student asked her to help replicate a study by Temple University, Philadelphia, Pennsylvania, researcher Dominco Pratico, MD, of Alzheimer’s-like phenotype mice in the Morris Water Maze test. Dr. Yang, who runs the “behavior core” at Columbia — teaching and advising on how to run assays and collect and report data — could see right away that the Pratico data were “too perfect.”

She enlisted maze inventor Richard Morris to join her in a letter of concern to the journals that published Dr. Pratico’s work, all under the aegis of Springer Nature.

The publisher’s integrity team has since retracted four Pratico papers. Three were because of image abnormalities pointed out by Dr. Bik, who worked with Dr. Yang. One was because of “self-plagiarism.”

“The official retraction notes didn’t mention anything about data abnormality being a concern,” said Dr. Yang who says that questionable data is harder to prove than an image duplication or manipulation. And the papers remain available, although dozens of Practico papers have been flagged on PubPeer.

To Dr. Yang, images are the canary in the coalmine. “People don’t just fake western blots but then give real behavior data or give you fake behavior data but give you the most authentic Western Blots,” she said.

Dr. Pratico has now sued a graduate student who was a coauthor on the papers, according to the Philadelphia Inquirer.

The NIH’s ORI has requested that Temple University conduct an investigation, Dr. Yang said.

In a statement to this news organization, Temple said it “does not comment on internal investigations or personnel issues,” but that “allegations of research misconduct are reviewed and investigated centrally through Temple’s Office of the Vice President for Research in accordance with university policy and applicable federal regulations.”

A version of this article appeared on Medscape.com.

Alzheimer’s research is plagued with misconduct and fraud, undermining the progress toward understanding and treating the disease, say investigators who endeavor to expose errors and misleading practices.

The book is yet to be closed, for instance, on whether a 2006 paper by Sylvain Lesne positing amyloid as a major cause of Alzheimer’s was based on fraudulent data. Suspicions about the paper were first raised in late 2021 by Matthew Schrag, MD, PhD, an assistant professor of neurology at Vanderbilt University Medical Center, Nashville, Tennessee.

Dr. Schrag also queried the work of a City University of New York (CUNY) researcher who proposed PT-125 (now simufilam) as a potential anti-amyloid for Alzheimer’s disease. Even though CUNY recently found “egregious” and potentially deliberate misconduct by that researcher, Cassava Sciences is continuing phase 3 trials of simufilam.

Now questions are being raised about work from the lab of Berislav V. Zlokovic, PhD, a prominent neuroscientist at the University of Southern California (USC), Los Angeles, California, and also about studies conducted under the aegis of Domenico Pratico, MD, the director of the Alzheimer’s Center at Temple University in Philadelphia, Pennsylvania.

Alzheimer’s has been a notoriously hard puzzle to solve. Despite decades of research, there are still no effective therapies and disparate theories about potential causes.

Dr. Schrag said he wouldn’t “attribute all the ills in this field” to misconduct, but it “is absolutely a part of the equation.” Some of the papers flagged for integrity issues “have been hugely influential,” he said in an interview. “Some of the labs that we’re talking about have really shaped how we’ve thought about this disease,” he said. “It’s hard to un-ring the bell.”

The fallout from fraud has a wide impact. Taxpayer dollars are wasted in the creation of the fraud and in attempts to replicate the failed experiment. Grad students — the workhorses of labs — waste time trying to repeat studies or may be bullied or intimidated into misconduct, said Elisabeth Bik, PhD, a former Stanford microbiologist who is now a full-time fraud investigator.

And there’s potential harm to patients. “There’s a lot of false hope being given to these people and their families,” Dr. Bik said in an interview.
 

Alzheimer’s Tempts With Big Rewards

There are big rewards for those who publish important papers on Alzheimer’s: More grants, publication in higher-impact journals, larger labs, and potentially, personal enrichment from commercialization of therapies.

“I can see that people are driven to cut corners or even to make up results, or even anything in between, to reach that goal,” said Dr. Bik.

It’s unclear whether misconduct and fraud are on the rise or just being detected more frequently.

“It’s very hard to say,” said Mike Rossner, PhD, president of Image Data Integrity. Institutions hire Dr. Rossner to help ferret out research integrity issues. He told this news organization that it’s likely detection is on the rise, given the increasing number of sleuths like Dr. Bik.

In 2002, Dr. Rossner began to screen all images submitted to the Journal of Clinical Biology in response to the new phenomenon of digital images and the advent of PhotoShop. “Very early on, we started to see problems in digital images that we would not have seen on a glossy printout,” Dr. Rossner said of his time as managing editor of the journal.

From 2002 to 2014, at least 25% of papers had an image that violated guidelines that prohibited the removal of spots or other blemishes (called “beautification”) with PhotoShop, which did not necessarily indicate fraud. They withdrew acceptance for 1% of papers because of image manipulations that affected data interpretation.

Dr. Bik noted that even if there is not a greater percentage of fraudulent papers in Alzheimer’s, “it would still be in absolute numbers a lot of papers that could be fraudulent,” given that Alzheimer’s research is well-funded with federal agencies alone providing $3.7 billion a year.

Images Key to Spotting Issues

Investigative sleuths often use the online forum PubPeer to initially raise questions about papers. The format gives the original authors a chance to comment on or defend their work. While some critiques are about data, most hone in on alleged duplications or manipulations of images, primarily by Western Blots.

The images are key, because “the images are the data,” said Dr. Rossner. “The words are the author’s interpretation of what they see in the images,” he said.

It’s also easier to spot a problem in an image. The raw data or an investigator’s notebooks aren’t needed, and there are artificial intelligence-driven software programs such as Proofig and Image Twin that help investigators spot duplicated images or cases in which an image might have been flipped or otherwise manipulated to make results look better.

Science recently announced that it would be using Proofig to screen images in all papers submitted to its six journals.

Using a screening tool is better than nothing, said Dr. Rossner who still relies on visual inspection, employing contrast or other features in PhotoShop to spot inconsistencies or duplications. But “none of those companies have disclosed how effective they are relative to visual screening, and that to me is very problematic,” he said.

“The tools are not going to catch everything,” said Dr. Bik.

Dr. Schrag agreed. “One of the things that we’re worried about is that a lot of the journals will simply adopt these tools as a screener and assume that that’s going to de-risk their publication portfolio,” he said, noting the high rate of misses.

Artificial Intelligence a Growing Concern

Artificial intelligence (AI) may also accelerate the amount of fraud and add to the difficulty of ferreting it out, said the investigators.

“I’m very worried about AI,” said Dr. Bik. Although AI-generated images and content may be rudimentary today, “next year it’s going to be much better,” she said. Going forward, it may be hard to distinguish between a real dataset and one that has been generated by AI, she said.

“The more closely AI can mimic authentic content, the more difficult it will be for publications to detect intentionally fraudulent submissions,” wrote Dror Kolodkin-Gal, PhD, the founder of Proofig, in an article for the Council of Science Editors.

Dr. Kolodkin-Gal said that AI may be especially prone to misuse by paper mills. Those operations submit fake or shoddy manuscripts to a journal on behalf of researchers seeking publication who pay the mills a fee. The Committee on Publication Ethics reported in 2022 that 2%-46% of papers submitted to journals may be from paper mills.

While it’s unclear whether AI is having any impact now, Dr. Rossner said, “I think I can be pretty confident in saying it is going to be a growing problem” as the tools become more sophisticated.

He sees parallels with the rise of PhotoShop and cites data from the National Institute of Health’s Office of Research Integrity (ORI) showing that in 1990, when PhotoShop was still new, 2% of cases referred to ORI involved image manipulation. By 2007, 70% of cases had image manipulation issues.

Journals, Institutions Need to Step Up More

Fraud may continue apace in part because investigations drag on for years, and in many cases, with a lack of consequences for the perpetrators, said the investigators. And, they say, journals and institutions haven’t devoted enough resources to prevent or investigate misconduct.

“A lot of editors did not even want to investigate because they just didn’t want to believe that there could be fraud in science,” said Dr. Bik of her experiences. “I hope that by now most journals at least should have realized that some proportion of the manuscripts that get sent to their journals is going to be fraud,” she said.

“The bulk of the journals seem like they don’t want to be bothered by this,” agreed Dr. Schrag, adding that “some have gone to great lengths to try to discourage people from bringing forward complaints.”

A big issue is that journals “don’t answer to any higher authority,” said Dr. Schrag. He believes that journals that repeatedly refuse to address integrity issues should be barred from publishing research produced with funds from the National Institutes of Health.

All the investigators said institutions and journals should hire forensic investigators. Relying on unpaid peer reviewers or editors to root out fraud is unrealistic, they said.

“You want to have specialized people with experience and be paid to do that as a full-time job,” said Dr. Bik, who is funded by speaking engagements and receives about $2300 a month through donations to her Patreon account.

Once a potential integrity issue is flagged, there is “an incredible conflict of interest in how these investigations are run,” said Dr. Schrag. “Institutions are asked to investigate their own faculty; they’re asked to investigate themselves.” That “creates the disincentive to move expeditiously,” said Dr. Schrag.

With the space of time, people who have committed fraud can throw out notebooks, delete data from servers, or even PhotoShop original photos so they match the manipulated ones that were submitted, Dr. Bik said.

Institutions could show they are serious about fraud by offering a “central, systematic universal screening of all image data going out of their institutions before submission to a journal,” said Dr. Rossner. But he knows only of a handful that do so. “I think research integrity offices have historically been very reactive, and they need to pivot and become proactive,” said Dr. Rossner.

Dr. Schrag wants to see stronger values within the research enterprise. “You have to build a culture where it’s absolutely anathema at a core level to violate these standards of research integrity,” he said. “We have this notion that we can push the process along faster and get to a grant and get to a paper and get to some short-term goal,” he said. “But the long-term goal in most of these cases is to cure a disease or to understand some biological mysteries. There’s no shortcut to getting there,” said Dr. Schrag.

There have been some high-profile consequences for research integrity failures, such as the 2023 resignation of Stanford University President Marc Tessier-Lavigne in the wake of findings that members of his lab — but not Tessier-Lavigne — engaged in data manipulation.

The process is often opaque, with investigations done in secrecy. “Consequences are not usually revealed, either,” said Dr. Rossner.

Dr. Schrag acknowledges it’s a tough balancing act for institutions to root out bad actors while also ensuring there’s no harm to those who may simply have operated in error.

“But it doesn’t serve anyone’s interest including the people who are accused, in dragging these things out for 5, 6, 8, or 10 years,” he said.

Lesne and Cassava: The Long and Winding Road

The investigations into the Lesne papers and the work underpinning Cassava Sciences’ therapy point to the difficulty of policing integrity and the potential fallout.

Lesne’s signature paper published in Nature in 2006 has been cited some 2300 times and is the fourth most-accessed article of 81,612 articles of a similar age in all journals tracked by Altimetrics.

Dr. Schrag, Dr. Bik, and others wrote to multiple journals asking them to investigate some 25 papers related to simufilam, including a 2012 Journal of Clinical Investigation article by Hoau-Yan Wang, PhD, the CUNY scientist whose work on simufilam has been questioned.

JCI Editor Elizabeth McNally pushed back stating in an editorial in 2022 that they, as whistleblowers, had potential conflicts and that they could be assisting short sellers who were seeking to profit by depressing Cassava’s stock price. Indeed, Dr. Schrag was initially hired by a law firm that was representing short sellers. Ms. McNally said that JCI would start requiring disclosures by whistleblowers.

Dr. Bik urged CUNY to investigate Dr. Wang in 2021 but was rebuffed. Then, in November 2023, a copy of CUNY’s final report on the Wang inquiry was leaked to Science. The university reported that Dr. Wang did not provide any original data or notebooks and that it found “long-standing and egregious misconduct in data management and record keeping by Dr. Wang,” wrote Dr. Bik in a blog post summarizing the investigation.

As of late 2023, 42 papers by Dr. Wang have earned PubPeer posts, seven have been retracted, and five have been marked with an Expression of Concern, wrote Dr. Bik.

Some have called for Cassava to stop its phase 3 studies of simufilam, but the company is proceeding, announcing in November 2023 that they have completed enrollment.

Misconduct Queries Underway at USC and Temple

Meanwhile, Dr. Schrag and Dr. Bik continue sleuthing. They are among a small group of whistleblowers who have filed a complaint with NIH about irregularities in the Zlokovic lab at USC. They allege that images were manipulated in dozens of papers, including some that inform the development of a stroke drug in phase 2 trials.

The inquiry goes well beyond stroke, said Dr. Schrag. Dr. Zlokovic “is one of the most influential scientists on Alzheimer’s scientists in the country,” Dr. Schrag said. The USC scientist is a leader on blood-brain barrier research.

USC is investigating “at some level,” he said. In a statement to this news organization, USC said that it “takes any allegations about research integrity very seriously.” The statement added, “Consistent with federal regulations and USC policies, this review must be kept confidential. As a result, we are unable to provide any further information.”

Mu Yang, PhD, assistant professor of neurobiology at Columbia University Medical Center in New York City, is also working on the Zlokovic investigation.

She calls herself an “accidental sleuth” who fell into the hobby after a graduate student asked her to help replicate a study by Temple University, Philadelphia, Pennsylvania, researcher Dominco Pratico, MD, of Alzheimer’s-like phenotype mice in the Morris Water Maze test. Dr. Yang, who runs the “behavior core” at Columbia — teaching and advising on how to run assays and collect and report data — could see right away that the Pratico data were “too perfect.”

She enlisted maze inventor Richard Morris to join her in a letter of concern to the journals that published Dr. Pratico’s work, all under the aegis of Springer Nature.

The publisher’s integrity team has since retracted four Pratico papers. Three were because of image abnormalities pointed out by Dr. Bik, who worked with Dr. Yang. One was because of “self-plagiarism.”

“The official retraction notes didn’t mention anything about data abnormality being a concern,” said Dr. Yang who says that questionable data is harder to prove than an image duplication or manipulation. And the papers remain available, although dozens of Practico papers have been flagged on PubPeer.

To Dr. Yang, images are the canary in the coalmine. “People don’t just fake western blots but then give real behavior data or give you fake behavior data but give you the most authentic Western Blots,” she said.

Dr. Pratico has now sued a graduate student who was a coauthor on the papers, according to the Philadelphia Inquirer.

The NIH’s ORI has requested that Temple University conduct an investigation, Dr. Yang said.

In a statement to this news organization, Temple said it “does not comment on internal investigations or personnel issues,” but that “allegations of research misconduct are reviewed and investigated centrally through Temple’s Office of the Vice President for Research in accordance with university policy and applicable federal regulations.”

A version of this article appeared on Medscape.com.

Alzheimer’s research is plagued with misconduct and fraud, undermining the progress toward understanding and treating the disease, say investigators who endeavor to expose errors and misleading practices.

The book is yet to be closed, for instance, on whether a 2006 paper by Sylvain Lesne positing amyloid as a major cause of Alzheimer’s was based on fraudulent data. Suspicions about the paper were first raised in late 2021 by Matthew Schrag, MD, PhD, an assistant professor of neurology at Vanderbilt University Medical Center, Nashville, Tennessee.

Dr. Schrag also queried the work of a City University of New York (CUNY) researcher who proposed PT-125 (now simufilam) as a potential anti-amyloid for Alzheimer’s disease. Even though CUNY recently found “egregious” and potentially deliberate misconduct by that researcher, Cassava Sciences is continuing phase 3 trials of simufilam.

Now questions are being raised about work from the lab of Berislav V. Zlokovic, PhD, a prominent neuroscientist at the University of Southern California (USC), Los Angeles, California, and also about studies conducted under the aegis of Domenico Pratico, MD, the director of the Alzheimer’s Center at Temple University in Philadelphia, Pennsylvania.

Alzheimer’s has been a notoriously hard puzzle to solve. Despite decades of research, there are still no effective therapies and disparate theories about potential causes.

Dr. Schrag said he wouldn’t “attribute all the ills in this field” to misconduct, but it “is absolutely a part of the equation.” Some of the papers flagged for integrity issues “have been hugely influential,” he said in an interview. “Some of the labs that we’re talking about have really shaped how we’ve thought about this disease,” he said. “It’s hard to un-ring the bell.”

The fallout from fraud has a wide impact. Taxpayer dollars are wasted in the creation of the fraud and in attempts to replicate the failed experiment. Grad students — the workhorses of labs — waste time trying to repeat studies or may be bullied or intimidated into misconduct, said Elisabeth Bik, PhD, a former Stanford microbiologist who is now a full-time fraud investigator.

And there’s potential harm to patients. “There’s a lot of false hope being given to these people and their families,” Dr. Bik said in an interview.
 

Alzheimer’s Tempts With Big Rewards

There are big rewards for those who publish important papers on Alzheimer’s: More grants, publication in higher-impact journals, larger labs, and potentially, personal enrichment from commercialization of therapies.

“I can see that people are driven to cut corners or even to make up results, or even anything in between, to reach that goal,” said Dr. Bik.

It’s unclear whether misconduct and fraud are on the rise or just being detected more frequently.

“It’s very hard to say,” said Mike Rossner, PhD, president of Image Data Integrity. Institutions hire Dr. Rossner to help ferret out research integrity issues. He told this news organization that it’s likely detection is on the rise, given the increasing number of sleuths like Dr. Bik.

In 2002, Dr. Rossner began to screen all images submitted to the Journal of Clinical Biology in response to the new phenomenon of digital images and the advent of PhotoShop. “Very early on, we started to see problems in digital images that we would not have seen on a glossy printout,” Dr. Rossner said of his time as managing editor of the journal.

From 2002 to 2014, at least 25% of papers had an image that violated guidelines that prohibited the removal of spots or other blemishes (called “beautification”) with PhotoShop, which did not necessarily indicate fraud. They withdrew acceptance for 1% of papers because of image manipulations that affected data interpretation.

Dr. Bik noted that even if there is not a greater percentage of fraudulent papers in Alzheimer’s, “it would still be in absolute numbers a lot of papers that could be fraudulent,” given that Alzheimer’s research is well-funded with federal agencies alone providing $3.7 billion a year.

Images Key to Spotting Issues

Investigative sleuths often use the online forum PubPeer to initially raise questions about papers. The format gives the original authors a chance to comment on or defend their work. While some critiques are about data, most hone in on alleged duplications or manipulations of images, primarily by Western Blots.

The images are key, because “the images are the data,” said Dr. Rossner. “The words are the author’s interpretation of what they see in the images,” he said.

It’s also easier to spot a problem in an image. The raw data or an investigator’s notebooks aren’t needed, and there are artificial intelligence-driven software programs such as Proofig and Image Twin that help investigators spot duplicated images or cases in which an image might have been flipped or otherwise manipulated to make results look better.

Science recently announced that it would be using Proofig to screen images in all papers submitted to its six journals.

Using a screening tool is better than nothing, said Dr. Rossner who still relies on visual inspection, employing contrast or other features in PhotoShop to spot inconsistencies or duplications. But “none of those companies have disclosed how effective they are relative to visual screening, and that to me is very problematic,” he said.

“The tools are not going to catch everything,” said Dr. Bik.

Dr. Schrag agreed. “One of the things that we’re worried about is that a lot of the journals will simply adopt these tools as a screener and assume that that’s going to de-risk their publication portfolio,” he said, noting the high rate of misses.

Artificial Intelligence a Growing Concern

Artificial intelligence (AI) may also accelerate the amount of fraud and add to the difficulty of ferreting it out, said the investigators.

“I’m very worried about AI,” said Dr. Bik. Although AI-generated images and content may be rudimentary today, “next year it’s going to be much better,” she said. Going forward, it may be hard to distinguish between a real dataset and one that has been generated by AI, she said.

“The more closely AI can mimic authentic content, the more difficult it will be for publications to detect intentionally fraudulent submissions,” wrote Dror Kolodkin-Gal, PhD, the founder of Proofig, in an article for the Council of Science Editors.

Dr. Kolodkin-Gal said that AI may be especially prone to misuse by paper mills. Those operations submit fake or shoddy manuscripts to a journal on behalf of researchers seeking publication who pay the mills a fee. The Committee on Publication Ethics reported in 2022 that 2%-46% of papers submitted to journals may be from paper mills.

While it’s unclear whether AI is having any impact now, Dr. Rossner said, “I think I can be pretty confident in saying it is going to be a growing problem” as the tools become more sophisticated.

He sees parallels with the rise of PhotoShop and cites data from the National Institute of Health’s Office of Research Integrity (ORI) showing that in 1990, when PhotoShop was still new, 2% of cases referred to ORI involved image manipulation. By 2007, 70% of cases had image manipulation issues.

Journals, Institutions Need to Step Up More

Fraud may continue apace in part because investigations drag on for years, and in many cases, with a lack of consequences for the perpetrators, said the investigators. And, they say, journals and institutions haven’t devoted enough resources to prevent or investigate misconduct.

“A lot of editors did not even want to investigate because they just didn’t want to believe that there could be fraud in science,” said Dr. Bik of her experiences. “I hope that by now most journals at least should have realized that some proportion of the manuscripts that get sent to their journals is going to be fraud,” she said.

“The bulk of the journals seem like they don’t want to be bothered by this,” agreed Dr. Schrag, adding that “some have gone to great lengths to try to discourage people from bringing forward complaints.”

A big issue is that journals “don’t answer to any higher authority,” said Dr. Schrag. He believes that journals that repeatedly refuse to address integrity issues should be barred from publishing research produced with funds from the National Institutes of Health.

All the investigators said institutions and journals should hire forensic investigators. Relying on unpaid peer reviewers or editors to root out fraud is unrealistic, they said.

“You want to have specialized people with experience and be paid to do that as a full-time job,” said Dr. Bik, who is funded by speaking engagements and receives about $2300 a month through donations to her Patreon account.

Once a potential integrity issue is flagged, there is “an incredible conflict of interest in how these investigations are run,” said Dr. Schrag. “Institutions are asked to investigate their own faculty; they’re asked to investigate themselves.” That “creates the disincentive to move expeditiously,” said Dr. Schrag.

With the space of time, people who have committed fraud can throw out notebooks, delete data from servers, or even PhotoShop original photos so they match the manipulated ones that were submitted, Dr. Bik said.

Institutions could show they are serious about fraud by offering a “central, systematic universal screening of all image data going out of their institutions before submission to a journal,” said Dr. Rossner. But he knows only of a handful that do so. “I think research integrity offices have historically been very reactive, and they need to pivot and become proactive,” said Dr. Rossner.

Dr. Schrag wants to see stronger values within the research enterprise. “You have to build a culture where it’s absolutely anathema at a core level to violate these standards of research integrity,” he said. “We have this notion that we can push the process along faster and get to a grant and get to a paper and get to some short-term goal,” he said. “But the long-term goal in most of these cases is to cure a disease or to understand some biological mysteries. There’s no shortcut to getting there,” said Dr. Schrag.

There have been some high-profile consequences for research integrity failures, such as the 2023 resignation of Stanford University President Marc Tessier-Lavigne in the wake of findings that members of his lab — but not Tessier-Lavigne — engaged in data manipulation.

The process is often opaque, with investigations done in secrecy. “Consequences are not usually revealed, either,” said Dr. Rossner.

Dr. Schrag acknowledges it’s a tough balancing act for institutions to root out bad actors while also ensuring there’s no harm to those who may simply have operated in error.

“But it doesn’t serve anyone’s interest including the people who are accused, in dragging these things out for 5, 6, 8, or 10 years,” he said.

Lesne and Cassava: The Long and Winding Road

The investigations into the Lesne papers and the work underpinning Cassava Sciences’ therapy point to the difficulty of policing integrity and the potential fallout.

Lesne’s signature paper published in Nature in 2006 has been cited some 2300 times and is the fourth most-accessed article of 81,612 articles of a similar age in all journals tracked by Altimetrics.

Dr. Schrag, Dr. Bik, and others wrote to multiple journals asking them to investigate some 25 papers related to simufilam, including a 2012 Journal of Clinical Investigation article by Hoau-Yan Wang, PhD, the CUNY scientist whose work on simufilam has been questioned.

JCI Editor Elizabeth McNally pushed back stating in an editorial in 2022 that they, as whistleblowers, had potential conflicts and that they could be assisting short sellers who were seeking to profit by depressing Cassava’s stock price. Indeed, Dr. Schrag was initially hired by a law firm that was representing short sellers. Ms. McNally said that JCI would start requiring disclosures by whistleblowers.

Dr. Bik urged CUNY to investigate Dr. Wang in 2021 but was rebuffed. Then, in November 2023, a copy of CUNY’s final report on the Wang inquiry was leaked to Science. The university reported that Dr. Wang did not provide any original data or notebooks and that it found “long-standing and egregious misconduct in data management and record keeping by Dr. Wang,” wrote Dr. Bik in a blog post summarizing the investigation.

As of late 2023, 42 papers by Dr. Wang have earned PubPeer posts, seven have been retracted, and five have been marked with an Expression of Concern, wrote Dr. Bik.

Some have called for Cassava to stop its phase 3 studies of simufilam, but the company is proceeding, announcing in November 2023 that they have completed enrollment.

Misconduct Queries Underway at USC and Temple

Meanwhile, Dr. Schrag and Dr. Bik continue sleuthing. They are among a small group of whistleblowers who have filed a complaint with NIH about irregularities in the Zlokovic lab at USC. They allege that images were manipulated in dozens of papers, including some that inform the development of a stroke drug in phase 2 trials.

The inquiry goes well beyond stroke, said Dr. Schrag. Dr. Zlokovic “is one of the most influential scientists on Alzheimer’s scientists in the country,” Dr. Schrag said. The USC scientist is a leader on blood-brain barrier research.

USC is investigating “at some level,” he said. In a statement to this news organization, USC said that it “takes any allegations about research integrity very seriously.” The statement added, “Consistent with federal regulations and USC policies, this review must be kept confidential. As a result, we are unable to provide any further information.”

Mu Yang, PhD, assistant professor of neurobiology at Columbia University Medical Center in New York City, is also working on the Zlokovic investigation.

She calls herself an “accidental sleuth” who fell into the hobby after a graduate student asked her to help replicate a study by Temple University, Philadelphia, Pennsylvania, researcher Dominco Pratico, MD, of Alzheimer’s-like phenotype mice in the Morris Water Maze test. Dr. Yang, who runs the “behavior core” at Columbia — teaching and advising on how to run assays and collect and report data — could see right away that the Pratico data were “too perfect.”

She enlisted maze inventor Richard Morris to join her in a letter of concern to the journals that published Dr. Pratico’s work, all under the aegis of Springer Nature.

The publisher’s integrity team has since retracted four Pratico papers. Three were because of image abnormalities pointed out by Dr. Bik, who worked with Dr. Yang. One was because of “self-plagiarism.”

“The official retraction notes didn’t mention anything about data abnormality being a concern,” said Dr. Yang who says that questionable data is harder to prove than an image duplication or manipulation. And the papers remain available, although dozens of Practico papers have been flagged on PubPeer.

To Dr. Yang, images are the canary in the coalmine. “People don’t just fake western blots but then give real behavior data or give you fake behavior data but give you the most authentic Western Blots,” she said.

Dr. Pratico has now sued a graduate student who was a coauthor on the papers, according to the Philadelphia Inquirer.

The NIH’s ORI has requested that Temple University conduct an investigation, Dr. Yang said.

In a statement to this news organization, Temple said it “does not comment on internal investigations or personnel issues,” but that “allegations of research misconduct are reviewed and investigated centrally through Temple’s Office of the Vice President for Research in accordance with university policy and applicable federal regulations.”

A version of this article appeared on Medscape.com.

Working with medically trained service dogs is associated with a 31% reduction in seizures compared with usual care in treatment-resistant epilepsy, a new study showed.

Investigators speculate that the dogs may ease participants’ stress, leading to a decrease in seizure frequency, although they note this relationship warrants more study.

“Despite the development of numerous antiseizure medications over the past 15 years, up to 30% of people with epilepsy experience persistent seizures,” study author Valérie van Hezik-Wester, MSc, of Erasmus University Rotterdam, Rotterdam, the Netherlands, said in a press release.

The unpredictable nature of seizures is one of the most disabling aspects of epilepsy, Ms. Hezik-Wester added. Seizure dogs are trained to recognize seizures and respond when they occur.

“The tasks that these dogs perform, along with their companionship, may reduce seizure-related anxiety, also potentially reducing seizures caused by stress, the most common trigger for seizures,” she said.

The findings were published online in Neurology.
 

Improve Quality of Life

The study included 25 individuals with medically refractory epilepsy who had an average of two or more seizures per week, with seizure characteristics associated with a high risk for injuries or dysfunction. They also had to be able to care for a service dog.

All were observed under usual care, which included antiseizure medications, neurostimulation devices, and other supportive therapies. Participants could then choose to work with a service dog that had completed socialization and obedience training or be assigned a puppy they would train at home.

The median follow-up was 19 months with usual care and 12 months with the intervention. Participants recorded seizure activity in diaries and completed surveys on seizure severity, quality of life, and well-being every 3 months. Daily seizure counts were converted to obtain cumulative seizure frequencies over 28-day periods.

Of the 25 original participants, six discontinued trial participation before the end of follow-up, four of whom left the study due to difficulty with dog care and training.

Participants receiving usual care reported an average of 115 seizures per 28-day period, while those with trained service dogs recorded 73 seizures in the same period, or a 37% difference between groups.

Researchers found that participants had an average of 31% fewer seizures during the past 3 months when they had seizure dogs, with seven participants achieving a 50%-100% reduction in seizures.

The number of seizure-free days increased from an average of 11 days per 28-day period before receiving a service dog to 15 days after working with a dog.

Scores on the EQ-5D-5L, which measures perceived health problems, decreased on average by 2.5% per consecutive 28-day period with the intervention, reflecting an increase in generic health-related quality of life (0.975; 95% CI, 0.954-0.997).

“These findings show that seizure dogs can help people with epilepsy,” said Ms. van Hezik-Wester. “However, we also found that this partnership with seizure dogs might not be the right fit for everyone, as some people discontinued their participation in this program. More research is needed to better understand which people can benefit from working with seizure dogs.”
 

Enhanced Quality of Life

In an accompanying editorial, Amir Mbonde, MB, and Amy Crepeau, MD, of Mayo Clinic in Phoenix, Arizona, noted the findings add to a growing body of work on the effectiveness of service dogs in reducing seizure frequency.

“In addition to improved seizure control, the EPISODE study demonstrated the benefit of seizure dogs in enhancing the quality of life for patients, a crucial component of comprehensive epilepsy care,” they wrote.

In prior studies, seizure dogs have identified an odor that a person emits before a seizure in up to 97% of people, they noted, adding that this ability “offers immense clinical benefits to people with epilepsy, enhancing their independence, social engagement, employment opportunities, self-confidence, and thus quality of life.”

Study limitations include its small sample size and high attrition rate.

The study was funded by the Netherlands Organization for Health Research and Development and Innovatiefonds Zorgverzekeraars.

A version of this article appeared on Medscape.com.

Working with medically trained service dogs is associated with a 31% reduction in seizures compared with usual care in treatment-resistant epilepsy, a new study showed.

Investigators speculate that the dogs may ease participants’ stress, leading to a decrease in seizure frequency, although they note this relationship warrants more study.

“Despite the development of numerous antiseizure medications over the past 15 years, up to 30% of people with epilepsy experience persistent seizures,” study author Valérie van Hezik-Wester, MSc, of Erasmus University Rotterdam, Rotterdam, the Netherlands, said in a press release.

The unpredictable nature of seizures is one of the most disabling aspects of epilepsy, Ms. Hezik-Wester added. Seizure dogs are trained to recognize seizures and respond when they occur.

“The tasks that these dogs perform, along with their companionship, may reduce seizure-related anxiety, also potentially reducing seizures caused by stress, the most common trigger for seizures,” she said.

The findings were published online in Neurology.
 

Improve Quality of Life

The study included 25 individuals with medically refractory epilepsy who had an average of two or more seizures per week, with seizure characteristics associated with a high risk for injuries or dysfunction. They also had to be able to care for a service dog.

All were observed under usual care, which included antiseizure medications, neurostimulation devices, and other supportive therapies. Participants could then choose to work with a service dog that had completed socialization and obedience training or be assigned a puppy they would train at home.

The median follow-up was 19 months with usual care and 12 months with the intervention. Participants recorded seizure activity in diaries and completed surveys on seizure severity, quality of life, and well-being every 3 months. Daily seizure counts were converted to obtain cumulative seizure frequencies over 28-day periods.

Of the 25 original participants, six discontinued trial participation before the end of follow-up, four of whom left the study due to difficulty with dog care and training.

Participants receiving usual care reported an average of 115 seizures per 28-day period, while those with trained service dogs recorded 73 seizures in the same period, or a 37% difference between groups.

Researchers found that participants had an average of 31% fewer seizures during the past 3 months when they had seizure dogs, with seven participants achieving a 50%-100% reduction in seizures.

The number of seizure-free days increased from an average of 11 days per 28-day period before receiving a service dog to 15 days after working with a dog.

Scores on the EQ-5D-5L, which measures perceived health problems, decreased on average by 2.5% per consecutive 28-day period with the intervention, reflecting an increase in generic health-related quality of life (0.975; 95% CI, 0.954-0.997).

“These findings show that seizure dogs can help people with epilepsy,” said Ms. van Hezik-Wester. “However, we also found that this partnership with seizure dogs might not be the right fit for everyone, as some people discontinued their participation in this program. More research is needed to better understand which people can benefit from working with seizure dogs.”
 

Enhanced Quality of Life

In an accompanying editorial, Amir Mbonde, MB, and Amy Crepeau, MD, of Mayo Clinic in Phoenix, Arizona, noted the findings add to a growing body of work on the effectiveness of service dogs in reducing seizure frequency.

“In addition to improved seizure control, the EPISODE study demonstrated the benefit of seizure dogs in enhancing the quality of life for patients, a crucial component of comprehensive epilepsy care,” they wrote.

In prior studies, seizure dogs have identified an odor that a person emits before a seizure in up to 97% of people, they noted, adding that this ability “offers immense clinical benefits to people with epilepsy, enhancing their independence, social engagement, employment opportunities, self-confidence, and thus quality of life.”

Study limitations include its small sample size and high attrition rate.

The study was funded by the Netherlands Organization for Health Research and Development and Innovatiefonds Zorgverzekeraars.

A version of this article appeared on Medscape.com.

Working with medically trained service dogs is associated with a 31% reduction in seizures compared with usual care in treatment-resistant epilepsy, a new study showed.

Investigators speculate that the dogs may ease participants’ stress, leading to a decrease in seizure frequency, although they note this relationship warrants more study.

“Despite the development of numerous antiseizure medications over the past 15 years, up to 30% of people with epilepsy experience persistent seizures,” study author Valérie van Hezik-Wester, MSc, of Erasmus University Rotterdam, Rotterdam, the Netherlands, said in a press release.

The unpredictable nature of seizures is one of the most disabling aspects of epilepsy, Ms. Hezik-Wester added. Seizure dogs are trained to recognize seizures and respond when they occur.

“The tasks that these dogs perform, along with their companionship, may reduce seizure-related anxiety, also potentially reducing seizures caused by stress, the most common trigger for seizures,” she said.

The findings were published online in Neurology.
 

Improve Quality of Life

The study included 25 individuals with medically refractory epilepsy who had an average of two or more seizures per week, with seizure characteristics associated with a high risk for injuries or dysfunction. They also had to be able to care for a service dog.

All were observed under usual care, which included antiseizure medications, neurostimulation devices, and other supportive therapies. Participants could then choose to work with a service dog that had completed socialization and obedience training or be assigned a puppy they would train at home.

The median follow-up was 19 months with usual care and 12 months with the intervention. Participants recorded seizure activity in diaries and completed surveys on seizure severity, quality of life, and well-being every 3 months. Daily seizure counts were converted to obtain cumulative seizure frequencies over 28-day periods.

Of the 25 original participants, six discontinued trial participation before the end of follow-up, four of whom left the study due to difficulty with dog care and training.

Participants receiving usual care reported an average of 115 seizures per 28-day period, while those with trained service dogs recorded 73 seizures in the same period, or a 37% difference between groups.

Researchers found that participants had an average of 31% fewer seizures during the past 3 months when they had seizure dogs, with seven participants achieving a 50%-100% reduction in seizures.

The number of seizure-free days increased from an average of 11 days per 28-day period before receiving a service dog to 15 days after working with a dog.

Scores on the EQ-5D-5L, which measures perceived health problems, decreased on average by 2.5% per consecutive 28-day period with the intervention, reflecting an increase in generic health-related quality of life (0.975; 95% CI, 0.954-0.997).

“These findings show that seizure dogs can help people with epilepsy,” said Ms. van Hezik-Wester. “However, we also found that this partnership with seizure dogs might not be the right fit for everyone, as some people discontinued their participation in this program. More research is needed to better understand which people can benefit from working with seizure dogs.”
 

Enhanced Quality of Life

In an accompanying editorial, Amir Mbonde, MB, and Amy Crepeau, MD, of Mayo Clinic in Phoenix, Arizona, noted the findings add to a growing body of work on the effectiveness of service dogs in reducing seizure frequency.

“In addition to improved seizure control, the EPISODE study demonstrated the benefit of seizure dogs in enhancing the quality of life for patients, a crucial component of comprehensive epilepsy care,” they wrote.

In prior studies, seizure dogs have identified an odor that a person emits before a seizure in up to 97% of people, they noted, adding that this ability “offers immense clinical benefits to people with epilepsy, enhancing their independence, social engagement, employment opportunities, self-confidence, and thus quality of life.”

Study limitations include its small sample size and high attrition rate.

The study was funded by the Netherlands Organization for Health Research and Development and Innovatiefonds Zorgverzekeraars.

A version of this article appeared on Medscape.com.

A new study provides more evidence that sildenafil (Viagra), which is used to treat erectile dsysfuntion (ED), may help protect against Alzheimer’s disease.

The large real-world analysis of patient data from two databases showed a 30%-54% reduced prevalence in Alzheimer’s disease among patients who took sildenafil (Viagra) than those who did not, after adjusting for potential confounding factors.

This observation was further supported by mechanistic studies showing decreased neurotoxic protein levels in brain cells exposed to the phosphodiesterase type 5 inhibitor (PDE5i).

“Our findings provide further weight to repurposing this existing FDA-approved drug as a novel treatment for Alzheimer’s, which is in great need of new therapies,” Feixiong Cheng, PhD, director of the Cleveland Clinic Genome Center, who led the research, said in a news release. 

“We used artificial intelligence to integrate data across multiple domains which all indicated sildenafil’s potential against this devastating neurological disease,” Dr. Cheng noted. 

The study was published online in the Journal of Alzheimer’s Disease.
 

Neuroprotective?

Using real-world patient data from the MarketScan Medicare Supplemental database (2012-2017) and the Clinformatics database (2007-2020), the researchers conducted propensity score-stratified analyses after adjusting for gender, age, race, and comorbidities. 

They searched for all individuals with pharmacy claims for sildenafil or four comparator drugs — bumetanide, furosemide, spironolactone, and nifedipine. Results showed that sildenafil use was associated with reduced likelihood of Alzheimer’s disease relative to the control drugs. 

For example, sildenafil use was associated with a 54% reduced incidence of Alzheimer’s disease in MarketScan (hazard ratio [HR], 0.46; 95% CI, 0.32-0.66) and a 30% reduced prevalence of Alzheimer’s disease in Clinformatics (HR, 0.70; 95% CI, 0.49-1.00) compared with spironolactone.

The findings support a study published earlier this year that found a potential protective effect of PDE5i treatment on Alzheimer’s disease risk.

However, this research and the current study are contradicted by another paper published in Brain Communications in late 2022 which showed no such link between ED meds and reduced Alzheimer’s disease risk.

The investigators also found that sildenafil reduces tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic Alzheimer’s disease patient induced pluripotent stem cell (iPSC)-derived neurons. 

They further demonstrated through RNA-sequencing data analysis that sildenafil specifically targets Alzheimer’s disease related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in Alzheimer’s disease.

“We believe our findings provide the evidence needed for clinical trials to further examine the potential effectiveness of sildenafil in patients with Alzheimer’s disease,” Dr. Cheng said. 

The study was primarily supported by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Cheng had no relevant disclosures. 

A version of this article appeared on Medscape.com.

A new study provides more evidence that sildenafil (Viagra), which is used to treat erectile dsysfuntion (ED), may help protect against Alzheimer’s disease.

The large real-world analysis of patient data from two databases showed a 30%-54% reduced prevalence in Alzheimer’s disease among patients who took sildenafil (Viagra) than those who did not, after adjusting for potential confounding factors.

This observation was further supported by mechanistic studies showing decreased neurotoxic protein levels in brain cells exposed to the phosphodiesterase type 5 inhibitor (PDE5i).

“Our findings provide further weight to repurposing this existing FDA-approved drug as a novel treatment for Alzheimer’s, which is in great need of new therapies,” Feixiong Cheng, PhD, director of the Cleveland Clinic Genome Center, who led the research, said in a news release. 

“We used artificial intelligence to integrate data across multiple domains which all indicated sildenafil’s potential against this devastating neurological disease,” Dr. Cheng noted. 

The study was published online in the Journal of Alzheimer’s Disease.
 

Neuroprotective?

Using real-world patient data from the MarketScan Medicare Supplemental database (2012-2017) and the Clinformatics database (2007-2020), the researchers conducted propensity score-stratified analyses after adjusting for gender, age, race, and comorbidities. 

They searched for all individuals with pharmacy claims for sildenafil or four comparator drugs — bumetanide, furosemide, spironolactone, and nifedipine. Results showed that sildenafil use was associated with reduced likelihood of Alzheimer’s disease relative to the control drugs. 

For example, sildenafil use was associated with a 54% reduced incidence of Alzheimer’s disease in MarketScan (hazard ratio [HR], 0.46; 95% CI, 0.32-0.66) and a 30% reduced prevalence of Alzheimer’s disease in Clinformatics (HR, 0.70; 95% CI, 0.49-1.00) compared with spironolactone.

The findings support a study published earlier this year that found a potential protective effect of PDE5i treatment on Alzheimer’s disease risk.

However, this research and the current study are contradicted by another paper published in Brain Communications in late 2022 which showed no such link between ED meds and reduced Alzheimer’s disease risk.

The investigators also found that sildenafil reduces tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic Alzheimer’s disease patient induced pluripotent stem cell (iPSC)-derived neurons. 

They further demonstrated through RNA-sequencing data analysis that sildenafil specifically targets Alzheimer’s disease related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in Alzheimer’s disease.

“We believe our findings provide the evidence needed for clinical trials to further examine the potential effectiveness of sildenafil in patients with Alzheimer’s disease,” Dr. Cheng said. 

The study was primarily supported by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Cheng had no relevant disclosures. 

A version of this article appeared on Medscape.com.

A new study provides more evidence that sildenafil (Viagra), which is used to treat erectile dsysfuntion (ED), may help protect against Alzheimer’s disease.

The large real-world analysis of patient data from two databases showed a 30%-54% reduced prevalence in Alzheimer’s disease among patients who took sildenafil (Viagra) than those who did not, after adjusting for potential confounding factors.

This observation was further supported by mechanistic studies showing decreased neurotoxic protein levels in brain cells exposed to the phosphodiesterase type 5 inhibitor (PDE5i).

“Our findings provide further weight to repurposing this existing FDA-approved drug as a novel treatment for Alzheimer’s, which is in great need of new therapies,” Feixiong Cheng, PhD, director of the Cleveland Clinic Genome Center, who led the research, said in a news release. 

“We used artificial intelligence to integrate data across multiple domains which all indicated sildenafil’s potential against this devastating neurological disease,” Dr. Cheng noted. 

The study was published online in the Journal of Alzheimer’s Disease.
 

Neuroprotective?

Using real-world patient data from the MarketScan Medicare Supplemental database (2012-2017) and the Clinformatics database (2007-2020), the researchers conducted propensity score-stratified analyses after adjusting for gender, age, race, and comorbidities. 

They searched for all individuals with pharmacy claims for sildenafil or four comparator drugs — bumetanide, furosemide, spironolactone, and nifedipine. Results showed that sildenafil use was associated with reduced likelihood of Alzheimer’s disease relative to the control drugs. 

For example, sildenafil use was associated with a 54% reduced incidence of Alzheimer’s disease in MarketScan (hazard ratio [HR], 0.46; 95% CI, 0.32-0.66) and a 30% reduced prevalence of Alzheimer’s disease in Clinformatics (HR, 0.70; 95% CI, 0.49-1.00) compared with spironolactone.

The findings support a study published earlier this year that found a potential protective effect of PDE5i treatment on Alzheimer’s disease risk.

However, this research and the current study are contradicted by another paper published in Brain Communications in late 2022 which showed no such link between ED meds and reduced Alzheimer’s disease risk.

The investigators also found that sildenafil reduces tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic Alzheimer’s disease patient induced pluripotent stem cell (iPSC)-derived neurons. 

They further demonstrated through RNA-sequencing data analysis that sildenafil specifically targets Alzheimer’s disease related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in Alzheimer’s disease.

“We believe our findings provide the evidence needed for clinical trials to further examine the potential effectiveness of sildenafil in patients with Alzheimer’s disease,” Dr. Cheng said. 

The study was primarily supported by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Cheng had no relevant disclosures. 

A version of this article appeared on Medscape.com.

WEST PALM BEACH, FLORIDA — Patient-reported outcomes (PROs) define the issues that matter to the patient, but their potential in multiple sclerosis (MS) is likely to remain unfulfilled until barriers, including a lack of incentives, are addressed systematically, according to experts participating in a symposium at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

These barriers include a lack of consensus on how and which PROs to collect, lack of a systematic method of interpreting the meaning of PRO changes, and lack of reimbursement for the time to collect PRO data and enter it into the medical record, according to Robert McBurney, PhD, president of the nonprofit Accelerated Cure Project for Multiple Sclerosis, Washington.
 

Potentially Useful Clinical Information

PROs can identify hidden symptoms of MS as well as provide information on the relative importance of the standard measures of disease progression, such as disability, but at the current time “these are rarely captured or used in shared decision-making to guide treatment,” Dr. McBurney said.

A reasonable analogy can be made between MS and musculoskeletal diseases, such as arthritis, according to Dr. McBurney. In both, not all patients experience the burden of disease in the same way, whether measured with traditional laboratory or imaging evidence of disease activity or by PROs that capture anxiety, depression, and specific impairments affecting activities of daily living.

Yet, the Centers for Medicare and Medicaid Services (CMS) is now mandating the entry of PRO data for the reimbursement of some forms of orthopedic surgery, while MS is lagging behind, according to Dr. McBurney.

The difference between orthopedics and MS is evidence submitted to CMS showing that improvement in PROs matter for patient outcome and well-being. Dr. McBurney argued that the same type of data is lacking for MS.

More well-designed clinical trials are needed to confirm that beneficial effects on PROs can improve patient outcomes, but Dr. McBurney suggested that PRO data from the many MS patient registries might be an easier first step. He reported that 24 of 43 MS registries around the globe are now capturing PRO data.

Unfortunately, the AXON registry, which is managed by the American Academy of Neurology, is not one of them, Dr. McBurney said. This is not an oversight. Dr. McBurney explained that the first effort to add PROs to data collected by AXON was initiated more than 5 years ago, but several complications thwarted the process. A new effort has been recently scheduled.

By developing data showing that PROs matter, AAN “might lead the charge” for establishing the collection of PRO data as a standard of care and eliciting reimbursement from third-party payers for doing so, Dr. McBurney said. Nevertheless, he cautioned that validated methodology for collecting PRO data and identifying clinically meaningful changes in scores will be fundamental to PRO utility.
 

A Path Forward

In the best circumstance, PRO data captured at a patient visit would be analogous to a lab test. Just as blood tests generate data in the context of normative ranges for a dozen or more parameters, the PRO data could be displayed with the same type of context, allowing physicians and patients to see a specific PRO measure displayed against a normative range so results are easily interpreted, according to Dr. McBurney.

But, again, there are barriers. Numerous validated sets of PROs are available with no consensus on which might serve as a standard. While Dr. McBurney singled out the SymptoMScreen tool as one that is already recommended by the MS Data Alliance, a nonprofit organization supported by the European Charcot Foundation to transform real-world MS data into evidence suitable for MS care, he acknowledged it is just one of many options.

“The SymptoMScreen has been used in several clinical studies and it is relatively simple to use,” Dr. McBurney said. Even if there is no single “best” instrument for measuring PROs, a standard might move the process forward.

The president of the European Charcot Foundation, Giancarlo Comi, MD, agreed that PROs are almost certainly coming to the routine management of MS as each of the current barriers described by Dr. McBurney are addressed. He said that PROs are particularly important in managing progressive MS, for which he thinks that traditional biomarkers, such as brain images, are particularly poor at capturing the burden of disease.

“The EMA [European Medicines Agency] and the FDA [Food and Drug Administration] are both very interested in using PROs to evaluate treatments in MS,” he said.

PROs might be incorporated into routine care by clinicians convinced that they help in guiding treatment choices, but Dr. McBurney and Dr. Comi agreed that some approach, including financial incentives, to encourage clinicians to capture and record PROs is probably needed before they are used routinely.

Dr. McBurney reports no potential conflicts of interest. Dr. Comi reports financial relationships with Almirall, Celgene, Genzyme, Hoffman-LaRoche, Janssen, Merck, Novartis, and Sanofi.

WEST PALM BEACH, FLORIDA — Patient-reported outcomes (PROs) define the issues that matter to the patient, but their potential in multiple sclerosis (MS) is likely to remain unfulfilled until barriers, including a lack of incentives, are addressed systematically, according to experts participating in a symposium at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

These barriers include a lack of consensus on how and which PROs to collect, lack of a systematic method of interpreting the meaning of PRO changes, and lack of reimbursement for the time to collect PRO data and enter it into the medical record, according to Robert McBurney, PhD, president of the nonprofit Accelerated Cure Project for Multiple Sclerosis, Washington.
 

Potentially Useful Clinical Information

PROs can identify hidden symptoms of MS as well as provide information on the relative importance of the standard measures of disease progression, such as disability, but at the current time “these are rarely captured or used in shared decision-making to guide treatment,” Dr. McBurney said.

A reasonable analogy can be made between MS and musculoskeletal diseases, such as arthritis, according to Dr. McBurney. In both, not all patients experience the burden of disease in the same way, whether measured with traditional laboratory or imaging evidence of disease activity or by PROs that capture anxiety, depression, and specific impairments affecting activities of daily living.

Yet, the Centers for Medicare and Medicaid Services (CMS) is now mandating the entry of PRO data for the reimbursement of some forms of orthopedic surgery, while MS is lagging behind, according to Dr. McBurney.

The difference between orthopedics and MS is evidence submitted to CMS showing that improvement in PROs matter for patient outcome and well-being. Dr. McBurney argued that the same type of data is lacking for MS.

More well-designed clinical trials are needed to confirm that beneficial effects on PROs can improve patient outcomes, but Dr. McBurney suggested that PRO data from the many MS patient registries might be an easier first step. He reported that 24 of 43 MS registries around the globe are now capturing PRO data.

Unfortunately, the AXON registry, which is managed by the American Academy of Neurology, is not one of them, Dr. McBurney said. This is not an oversight. Dr. McBurney explained that the first effort to add PROs to data collected by AXON was initiated more than 5 years ago, but several complications thwarted the process. A new effort has been recently scheduled.

By developing data showing that PROs matter, AAN “might lead the charge” for establishing the collection of PRO data as a standard of care and eliciting reimbursement from third-party payers for doing so, Dr. McBurney said. Nevertheless, he cautioned that validated methodology for collecting PRO data and identifying clinically meaningful changes in scores will be fundamental to PRO utility.
 

A Path Forward

In the best circumstance, PRO data captured at a patient visit would be analogous to a lab test. Just as blood tests generate data in the context of normative ranges for a dozen or more parameters, the PRO data could be displayed with the same type of context, allowing physicians and patients to see a specific PRO measure displayed against a normative range so results are easily interpreted, according to Dr. McBurney.

But, again, there are barriers. Numerous validated sets of PROs are available with no consensus on which might serve as a standard. While Dr. McBurney singled out the SymptoMScreen tool as one that is already recommended by the MS Data Alliance, a nonprofit organization supported by the European Charcot Foundation to transform real-world MS data into evidence suitable for MS care, he acknowledged it is just one of many options.

“The SymptoMScreen has been used in several clinical studies and it is relatively simple to use,” Dr. McBurney said. Even if there is no single “best” instrument for measuring PROs, a standard might move the process forward.

The president of the European Charcot Foundation, Giancarlo Comi, MD, agreed that PROs are almost certainly coming to the routine management of MS as each of the current barriers described by Dr. McBurney are addressed. He said that PROs are particularly important in managing progressive MS, for which he thinks that traditional biomarkers, such as brain images, are particularly poor at capturing the burden of disease.

“The EMA [European Medicines Agency] and the FDA [Food and Drug Administration] are both very interested in using PROs to evaluate treatments in MS,” he said.

PROs might be incorporated into routine care by clinicians convinced that they help in guiding treatment choices, but Dr. McBurney and Dr. Comi agreed that some approach, including financial incentives, to encourage clinicians to capture and record PROs is probably needed before they are used routinely.

Dr. McBurney reports no potential conflicts of interest. Dr. Comi reports financial relationships with Almirall, Celgene, Genzyme, Hoffman-LaRoche, Janssen, Merck, Novartis, and Sanofi.

WEST PALM BEACH, FLORIDA — Patient-reported outcomes (PROs) define the issues that matter to the patient, but their potential in multiple sclerosis (MS) is likely to remain unfulfilled until barriers, including a lack of incentives, are addressed systematically, according to experts participating in a symposium at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

These barriers include a lack of consensus on how and which PROs to collect, lack of a systematic method of interpreting the meaning of PRO changes, and lack of reimbursement for the time to collect PRO data and enter it into the medical record, according to Robert McBurney, PhD, president of the nonprofit Accelerated Cure Project for Multiple Sclerosis, Washington.
 

Potentially Useful Clinical Information

PROs can identify hidden symptoms of MS as well as provide information on the relative importance of the standard measures of disease progression, such as disability, but at the current time “these are rarely captured or used in shared decision-making to guide treatment,” Dr. McBurney said.

A reasonable analogy can be made between MS and musculoskeletal diseases, such as arthritis, according to Dr. McBurney. In both, not all patients experience the burden of disease in the same way, whether measured with traditional laboratory or imaging evidence of disease activity or by PROs that capture anxiety, depression, and specific impairments affecting activities of daily living.

Yet, the Centers for Medicare and Medicaid Services (CMS) is now mandating the entry of PRO data for the reimbursement of some forms of orthopedic surgery, while MS is lagging behind, according to Dr. McBurney.

The difference between orthopedics and MS is evidence submitted to CMS showing that improvement in PROs matter for patient outcome and well-being. Dr. McBurney argued that the same type of data is lacking for MS.

More well-designed clinical trials are needed to confirm that beneficial effects on PROs can improve patient outcomes, but Dr. McBurney suggested that PRO data from the many MS patient registries might be an easier first step. He reported that 24 of 43 MS registries around the globe are now capturing PRO data.

Unfortunately, the AXON registry, which is managed by the American Academy of Neurology, is not one of them, Dr. McBurney said. This is not an oversight. Dr. McBurney explained that the first effort to add PROs to data collected by AXON was initiated more than 5 years ago, but several complications thwarted the process. A new effort has been recently scheduled.

By developing data showing that PROs matter, AAN “might lead the charge” for establishing the collection of PRO data as a standard of care and eliciting reimbursement from third-party payers for doing so, Dr. McBurney said. Nevertheless, he cautioned that validated methodology for collecting PRO data and identifying clinically meaningful changes in scores will be fundamental to PRO utility.
 

A Path Forward

In the best circumstance, PRO data captured at a patient visit would be analogous to a lab test. Just as blood tests generate data in the context of normative ranges for a dozen or more parameters, the PRO data could be displayed with the same type of context, allowing physicians and patients to see a specific PRO measure displayed against a normative range so results are easily interpreted, according to Dr. McBurney.

But, again, there are barriers. Numerous validated sets of PROs are available with no consensus on which might serve as a standard. While Dr. McBurney singled out the SymptoMScreen tool as one that is already recommended by the MS Data Alliance, a nonprofit organization supported by the European Charcot Foundation to transform real-world MS data into evidence suitable for MS care, he acknowledged it is just one of many options.

“The SymptoMScreen has been used in several clinical studies and it is relatively simple to use,” Dr. McBurney said. Even if there is no single “best” instrument for measuring PROs, a standard might move the process forward.

The president of the European Charcot Foundation, Giancarlo Comi, MD, agreed that PROs are almost certainly coming to the routine management of MS as each of the current barriers described by Dr. McBurney are addressed. He said that PROs are particularly important in managing progressive MS, for which he thinks that traditional biomarkers, such as brain images, are particularly poor at capturing the burden of disease.

“The EMA [European Medicines Agency] and the FDA [Food and Drug Administration] are both very interested in using PROs to evaluate treatments in MS,” he said.

PROs might be incorporated into routine care by clinicians convinced that they help in guiding treatment choices, but Dr. McBurney and Dr. Comi agreed that some approach, including financial incentives, to encourage clinicians to capture and record PROs is probably needed before they are used routinely.

Dr. McBurney reports no potential conflicts of interest. Dr. Comi reports financial relationships with Almirall, Celgene, Genzyme, Hoffman-LaRoche, Janssen, Merck, Novartis, and Sanofi.

WEST PALM BEACH, FLORIDA — When evaluated at 3 or 12 months, serum neurofilament light chain (sNfL) levels were predictive of new or enlarging T2 lesions in patients with multiple sclerosis (MS) regardless of treatment assignment, according to new substudy data from the ASCLEPIOS I/II trials presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

There are numerous studies supporting sNfL as a prognostic biomarker in MS, but a series of preplanned ASCLEPIOS substudies provided an opportunity to evaluate its predictive value across different therapies, according to Thomas P. Leist, MD, PhD, division chief, Multiple Sclerosis/Neuroimmunology, Thomas Jefferson University, Philadelphia, Pennsylvania.

These data “support the use of a single sNfL threshold to prognosticate disease activity in patients with relapsing-remitting MS on a disease-modifying therapy,” Dr. Leist reported.

When those with elevated sNfL levels, defined as being above the median (≥ 9.3 pg/mL), at 3 months were compared with those with lower sNfL levels (< 9.3 pg/mL), the on-treatment annualized rate of new or enlarging T2 lesions was 2.2-fold (P < .001) greater. When measured at 12 months, the annualized rate was 3.6-fold greater (P < .001).

These differences in annualized rates for higher sNfL levels at 3 months (3.67 vs 1.69) and 12 months (4.90 vs 1.37) were independent of assigned therapy.

The ASCLEPIOS I/II trials compared the injectable anti-CD20 monoclonal antibody ofatumumab to teriflunomide, an oral inhibitor of pyrimidine synthesis, using a double-dummy, double-blind protocol. In the two trials that were published together (N Engl J Med. 2020 Aug 6;383[6]:546-557. doi: 10.1056/NEJMoa1917246), the annualized relapse rate was about 50% lower for ofatumumab (P < .001 in both trials). Other markers of activity, such as new lesions on T1- and T2-weighted imaging as well as sNfL levels, all favored ofatumumab numerically even if not all the secondary measures reached statistical significance.
 

Is sNfL Relevant Independent of Treatment?

In this preplanned substudy, the question was whether sNfL levels over the course of early follow-up were prognostic regardless of treatment assignment. This was not only shown for the study population overall but for several important subpopulations, such as those defined by race and ethnicity and body mass index (BMI). Of the 1892 patients enrolled in the two ASCLEPIOS trials, baseline sNfL data collection, which was part of the study protocol, was available for 1746 (92.8%).

Nearly 90% of the patients enrolled in the ASCLEPIOS trials were White with the remainder nearly evenly split between Black, Asian, and other, a category that included unknown race. In all groups, the annualized mean rate of new or enlarging T2 lesions was more than double among those with a sNfL above the mean versus those below the mean.

While these results were based on an above-or-below mean sNfL threshold, “future work should evaluate how this single sNfL threshold could be optimized with a specific target and population in mind,” according to the lead investigator on this analysis, Silvia R. Delgado, MD, a professor in the Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.

The BMI analysis also supported the same idea. Anne H. Cross, MD, Washington University School of Medicine, St. Louis, Missouri, who led this work, concluded that a single sNfL threshold was prognostic for all groups studied, “including those defined by BMI and age.”
 

Optimal sNfL Threshold May Not Be Defined

Like Dr. Leist, Dr. Cross emphasized that while these data suggest that sNfL is a useful prognostic indicator in patients on treatment regardless of the treatment they are receiving, these subanalyses “support further work on the optimization of sNfL.” The potential for a more clinically useful threshold to define elevated sNfL has not been ruled out.

Although Daniel Ontaneda, MD, PhD, an associate professor of neurology, Cleveland Clinic, Cleveland, Ohio, did not review these data in detail, he agreed that evidence showing sNfL levels to be consistently prognostic regardless of background therapy is potentially important new information. Dr. Ontaneda, the chair of this year’s ACTRIMS conference, said that progress in defining new biomarkers for RRMS, such as sNfL, is needed and potentially clinically meaningful.

However, asked if evaluating sNfL after a specific time on therapy, such as 3 months, would be helpful to clinicians guiding therapy, Dr. Ontaneda said, “This is a different question.” He said a separate set of studies will be needed to confirm that acting on sNfL levels can improve outcomes.

Dr. Leist reported financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Janssen, Sanofi, and Novartis, which was the sponsor of the ASCLEPIOS trials. Dr. Salvado has financial relationships with EMD Serono and Novartis. Dr. Cross has financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Horizon, Novartis, Octave, and TG Therapeutics. Dr. Ontaneda reports no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — When evaluated at 3 or 12 months, serum neurofilament light chain (sNfL) levels were predictive of new or enlarging T2 lesions in patients with multiple sclerosis (MS) regardless of treatment assignment, according to new substudy data from the ASCLEPIOS I/II trials presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

There are numerous studies supporting sNfL as a prognostic biomarker in MS, but a series of preplanned ASCLEPIOS substudies provided an opportunity to evaluate its predictive value across different therapies, according to Thomas P. Leist, MD, PhD, division chief, Multiple Sclerosis/Neuroimmunology, Thomas Jefferson University, Philadelphia, Pennsylvania.

These data “support the use of a single sNfL threshold to prognosticate disease activity in patients with relapsing-remitting MS on a disease-modifying therapy,” Dr. Leist reported.

When those with elevated sNfL levels, defined as being above the median (≥ 9.3 pg/mL), at 3 months were compared with those with lower sNfL levels (< 9.3 pg/mL), the on-treatment annualized rate of new or enlarging T2 lesions was 2.2-fold (P < .001) greater. When measured at 12 months, the annualized rate was 3.6-fold greater (P < .001).

These differences in annualized rates for higher sNfL levels at 3 months (3.67 vs 1.69) and 12 months (4.90 vs 1.37) were independent of assigned therapy.

The ASCLEPIOS I/II trials compared the injectable anti-CD20 monoclonal antibody ofatumumab to teriflunomide, an oral inhibitor of pyrimidine synthesis, using a double-dummy, double-blind protocol. In the two trials that were published together (N Engl J Med. 2020 Aug 6;383[6]:546-557. doi: 10.1056/NEJMoa1917246), the annualized relapse rate was about 50% lower for ofatumumab (P < .001 in both trials). Other markers of activity, such as new lesions on T1- and T2-weighted imaging as well as sNfL levels, all favored ofatumumab numerically even if not all the secondary measures reached statistical significance.
 

Is sNfL Relevant Independent of Treatment?

In this preplanned substudy, the question was whether sNfL levels over the course of early follow-up were prognostic regardless of treatment assignment. This was not only shown for the study population overall but for several important subpopulations, such as those defined by race and ethnicity and body mass index (BMI). Of the 1892 patients enrolled in the two ASCLEPIOS trials, baseline sNfL data collection, which was part of the study protocol, was available for 1746 (92.8%).

Nearly 90% of the patients enrolled in the ASCLEPIOS trials were White with the remainder nearly evenly split between Black, Asian, and other, a category that included unknown race. In all groups, the annualized mean rate of new or enlarging T2 lesions was more than double among those with a sNfL above the mean versus those below the mean.

While these results were based on an above-or-below mean sNfL threshold, “future work should evaluate how this single sNfL threshold could be optimized with a specific target and population in mind,” according to the lead investigator on this analysis, Silvia R. Delgado, MD, a professor in the Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.

The BMI analysis also supported the same idea. Anne H. Cross, MD, Washington University School of Medicine, St. Louis, Missouri, who led this work, concluded that a single sNfL threshold was prognostic for all groups studied, “including those defined by BMI and age.”
 

Optimal sNfL Threshold May Not Be Defined

Like Dr. Leist, Dr. Cross emphasized that while these data suggest that sNfL is a useful prognostic indicator in patients on treatment regardless of the treatment they are receiving, these subanalyses “support further work on the optimization of sNfL.” The potential for a more clinically useful threshold to define elevated sNfL has not been ruled out.

Although Daniel Ontaneda, MD, PhD, an associate professor of neurology, Cleveland Clinic, Cleveland, Ohio, did not review these data in detail, he agreed that evidence showing sNfL levels to be consistently prognostic regardless of background therapy is potentially important new information. Dr. Ontaneda, the chair of this year’s ACTRIMS conference, said that progress in defining new biomarkers for RRMS, such as sNfL, is needed and potentially clinically meaningful.

However, asked if evaluating sNfL after a specific time on therapy, such as 3 months, would be helpful to clinicians guiding therapy, Dr. Ontaneda said, “This is a different question.” He said a separate set of studies will be needed to confirm that acting on sNfL levels can improve outcomes.

Dr. Leist reported financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Janssen, Sanofi, and Novartis, which was the sponsor of the ASCLEPIOS trials. Dr. Salvado has financial relationships with EMD Serono and Novartis. Dr. Cross has financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Horizon, Novartis, Octave, and TG Therapeutics. Dr. Ontaneda reports no potential conflicts of interest.

WEST PALM BEACH, FLORIDA — When evaluated at 3 or 12 months, serum neurofilament light chain (sNfL) levels were predictive of new or enlarging T2 lesions in patients with multiple sclerosis (MS) regardless of treatment assignment, according to new substudy data from the ASCLEPIOS I/II trials presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

There are numerous studies supporting sNfL as a prognostic biomarker in MS, but a series of preplanned ASCLEPIOS substudies provided an opportunity to evaluate its predictive value across different therapies, according to Thomas P. Leist, MD, PhD, division chief, Multiple Sclerosis/Neuroimmunology, Thomas Jefferson University, Philadelphia, Pennsylvania.

These data “support the use of a single sNfL threshold to prognosticate disease activity in patients with relapsing-remitting MS on a disease-modifying therapy,” Dr. Leist reported.

When those with elevated sNfL levels, defined as being above the median (≥ 9.3 pg/mL), at 3 months were compared with those with lower sNfL levels (< 9.3 pg/mL), the on-treatment annualized rate of new or enlarging T2 lesions was 2.2-fold (P < .001) greater. When measured at 12 months, the annualized rate was 3.6-fold greater (P < .001).

These differences in annualized rates for higher sNfL levels at 3 months (3.67 vs 1.69) and 12 months (4.90 vs 1.37) were independent of assigned therapy.

The ASCLEPIOS I/II trials compared the injectable anti-CD20 monoclonal antibody ofatumumab to teriflunomide, an oral inhibitor of pyrimidine synthesis, using a double-dummy, double-blind protocol. In the two trials that were published together (N Engl J Med. 2020 Aug 6;383[6]:546-557. doi: 10.1056/NEJMoa1917246), the annualized relapse rate was about 50% lower for ofatumumab (P < .001 in both trials). Other markers of activity, such as new lesions on T1- and T2-weighted imaging as well as sNfL levels, all favored ofatumumab numerically even if not all the secondary measures reached statistical significance.
 

Is sNfL Relevant Independent of Treatment?

In this preplanned substudy, the question was whether sNfL levels over the course of early follow-up were prognostic regardless of treatment assignment. This was not only shown for the study population overall but for several important subpopulations, such as those defined by race and ethnicity and body mass index (BMI). Of the 1892 patients enrolled in the two ASCLEPIOS trials, baseline sNfL data collection, which was part of the study protocol, was available for 1746 (92.8%).

Nearly 90% of the patients enrolled in the ASCLEPIOS trials were White with the remainder nearly evenly split between Black, Asian, and other, a category that included unknown race. In all groups, the annualized mean rate of new or enlarging T2 lesions was more than double among those with a sNfL above the mean versus those below the mean.

While these results were based on an above-or-below mean sNfL threshold, “future work should evaluate how this single sNfL threshold could be optimized with a specific target and population in mind,” according to the lead investigator on this analysis, Silvia R. Delgado, MD, a professor in the Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.

The BMI analysis also supported the same idea. Anne H. Cross, MD, Washington University School of Medicine, St. Louis, Missouri, who led this work, concluded that a single sNfL threshold was prognostic for all groups studied, “including those defined by BMI and age.”
 

Optimal sNfL Threshold May Not Be Defined

Like Dr. Leist, Dr. Cross emphasized that while these data suggest that sNfL is a useful prognostic indicator in patients on treatment regardless of the treatment they are receiving, these subanalyses “support further work on the optimization of sNfL.” The potential for a more clinically useful threshold to define elevated sNfL has not been ruled out.

Although Daniel Ontaneda, MD, PhD, an associate professor of neurology, Cleveland Clinic, Cleveland, Ohio, did not review these data in detail, he agreed that evidence showing sNfL levels to be consistently prognostic regardless of background therapy is potentially important new information. Dr. Ontaneda, the chair of this year’s ACTRIMS conference, said that progress in defining new biomarkers for RRMS, such as sNfL, is needed and potentially clinically meaningful.

However, asked if evaluating sNfL after a specific time on therapy, such as 3 months, would be helpful to clinicians guiding therapy, Dr. Ontaneda said, “This is a different question.” He said a separate set of studies will be needed to confirm that acting on sNfL levels can improve outcomes.

Dr. Leist reported financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Janssen, Sanofi, and Novartis, which was the sponsor of the ASCLEPIOS trials. Dr. Salvado has financial relationships with EMD Serono and Novartis. Dr. Cross has financial relationships with Biogen, Bristol-Myers Squibb, EMD Serono, Genentech/Roche, Horizon, Novartis, Octave, and TG Therapeutics. Dr. Ontaneda reports no potential conflicts of interest.