MDedge Neurology

Reducing exposure to air pollution may slow brain aging and reduce the risk of dementia, new research reveals. The findings have implications for individual behaviors, such as avoiding areas with poor air quality, but they also have implications for public policy, said study investigator, Xinhui Wang, PhD, assistant professor of research neurology, department of neurology, University of Southern California, Los Angeles.

“Controlling air quality has great benefits not only for the short-term, for example for pulmonary function or very broadly mortality, but can impact brain function and slow memory function decline and in the long run may reduce dementia cases.”

The findings were presented at the 2021 Alzheimer’s Association International Conference.
 

New approach

Previous research examining the impact of reducing air pollution, which has primarily examined respiratory illnesses and mortality, showed it is beneficial. However, no previous studies have examined the impact of improved air quality on cognitive function.

The current study used a subset of participants from the Women’s Health Initiative Memory Study-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO), which evaluated whether postmenopausal women derive cognitive benefit from hormone therapy.

The analysis included 2,232 community-dwelling older women aged 74-92 (mean age, 81.5 years) who did not have dementia at study enrollment.

Researchers obtained measures of participants’ annual cognitive function from 2008 to 2018. These measures included general cognitive status assessed using the Telephone Interview for Cognitive Status-modified (TICSm) and episodic memory assessed by the telephone-based California Verbal Learning Test (CVLT).

The investigators used complex geographical covariates to estimate exposure to fine particulate matter (PM_2.5) and nitrogen dioxide (NO₂), in areas where individual participants lived from 1996 to 2012. The investigators averaged measures over 3-year periods immediately preceding (recent exposure) and 10 years prior to (remote exposure) enrollment, then calculated individual-level improvements in air quality as the reduction from remote to recent exposures.

The researchers examined pollution exposure and cognitive outcomes at different times to determine causation.

“Maybe the relationship isn’t causal and is just an association, so we tried to separate the timeframe for exposure and outcome and make sure the exposure was before we measured the outcome,” said Dr. Wang.

The investigators adjusted for multiple sociodemographic, lifestyle, and clinical characteristics.
 

Reduced dementia risk

The analysis showed air quality improved significantly for both PM_2.5 and NO₂ before study enrollment. “For almost 95% of the subjects in our study, air quality improved over the 10 years,” said Dr. Wang.

During a median follow-up of 6.2 years, there was a significant decline in cognitive status and episodic memory in study participants, which makes sense, said Dr. Wang, because cognitive function naturally declines with age.

However, a 10% improvement in air quality PM_2.5 and NO₂ resulted in a respective 14% and 26% decreased risk for dementia. This translates into a level of risk seen in women 2 to 3 years younger.

Greater air quality improvement was associated with slower decline in both general cognitive status and episodic memory.

“Participants all declined in cognitive function, but living in areas with the greatest air quality improvement slowed this decline,” said Dr. Wang.

“Whether you look at global cognitive function or memory-specific function, and whether you look at PM_2.5 or NO₂, slower decline was in the range of someone who is 1-2 years younger.”

The associations did not significantly differ by age, region, education, APOE ε4 genotypes, or cardiovascular risk factors.

Patients concerned about cognitive decline can take steps to avoid exposure to pollution by wearing a mask; avoiding heavy traffic, fires, and smoke; or moving to an area with better air quality, said Dr. Wang.

“But our study mainly tried to provide some evidence for policymakers and regulators,” she added.

Another study carried out by the same investigators suggests pollution may affect various cognitive functions differently. This analysis used the same cohort, timeframe, and air quality improvement indicators as the first study but examined the association with specific cognitive domains, including episodic memory, working memory, attention/executive function, and language.

The investigators found women living in locations with greater PM_2.5 improvement performed better on tests of episodic memory (P = .002), working memory (P = .01) and attention/executive function (P = .01), but not language. Findings were similar for improved NO₂.

When looking at air quality improvement and trajectory slopes of decline across cognitive functions, only the association between improved NO₂ and slower episodic memory decline was statistically significant (P < 0.001). “The other domains were marginal or not significant,” said Dr. Wang.

“This suggests that brain regions are impacted differently,” she said, adding that various brain areas oversee different cognitive functions.
 

Important policy implications

Commenting on the research, Rebecca Edelmayer, PhD, senior director of scientific engagement, Alzheimer’s Association, said she welcomes new research on environmental factors that affect Alzheimer’s disease.

Whereas previous studies have linked longterm air pollution exposure to accumulation of Alzheimer’s disease-related brain plaques and increased risk of dementia, “these newer studies provide some of the first evidence to suggest that actually reducing pollution is associated with lower risk of all-cause dementia,” said Dr. Edelmayer.

Individuals can control some factors that contribute to dementia risk, such as exercise, diet, and physical activity, but it’s more difficult for them to control exposure to smog and pollution, she said.

“This is probably going to require changes to policy from federal and local governments and businesses, to start addressing the need to improve air quality to help reduce risk for dementia.”

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

Reducing exposure to air pollution may slow brain aging and reduce the risk of dementia, new research reveals. The findings have implications for individual behaviors, such as avoiding areas with poor air quality, but they also have implications for public policy, said study investigator, Xinhui Wang, PhD, assistant professor of research neurology, department of neurology, University of Southern California, Los Angeles.

“Controlling air quality has great benefits not only for the short-term, for example for pulmonary function or very broadly mortality, but can impact brain function and slow memory function decline and in the long run may reduce dementia cases.”

The findings were presented at the 2021 Alzheimer’s Association International Conference.
 

New approach

Previous research examining the impact of reducing air pollution, which has primarily examined respiratory illnesses and mortality, showed it is beneficial. However, no previous studies have examined the impact of improved air quality on cognitive function.

The current study used a subset of participants from the Women’s Health Initiative Memory Study-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO), which evaluated whether postmenopausal women derive cognitive benefit from hormone therapy.

The analysis included 2,232 community-dwelling older women aged 74-92 (mean age, 81.5 years) who did not have dementia at study enrollment.

Researchers obtained measures of participants’ annual cognitive function from 2008 to 2018. These measures included general cognitive status assessed using the Telephone Interview for Cognitive Status-modified (TICSm) and episodic memory assessed by the telephone-based California Verbal Learning Test (CVLT).

The investigators used complex geographical covariates to estimate exposure to fine particulate matter (PM_2.5) and nitrogen dioxide (NO₂), in areas where individual participants lived from 1996 to 2012. The investigators averaged measures over 3-year periods immediately preceding (recent exposure) and 10 years prior to (remote exposure) enrollment, then calculated individual-level improvements in air quality as the reduction from remote to recent exposures.

The researchers examined pollution exposure and cognitive outcomes at different times to determine causation.

“Maybe the relationship isn’t causal and is just an association, so we tried to separate the timeframe for exposure and outcome and make sure the exposure was before we measured the outcome,” said Dr. Wang.

The investigators adjusted for multiple sociodemographic, lifestyle, and clinical characteristics.
 

Reduced dementia risk

The analysis showed air quality improved significantly for both PM_2.5 and NO₂ before study enrollment. “For almost 95% of the subjects in our study, air quality improved over the 10 years,” said Dr. Wang.

During a median follow-up of 6.2 years, there was a significant decline in cognitive status and episodic memory in study participants, which makes sense, said Dr. Wang, because cognitive function naturally declines with age.

However, a 10% improvement in air quality PM_2.5 and NO₂ resulted in a respective 14% and 26% decreased risk for dementia. This translates into a level of risk seen in women 2 to 3 years younger.

Greater air quality improvement was associated with slower decline in both general cognitive status and episodic memory.

“Participants all declined in cognitive function, but living in areas with the greatest air quality improvement slowed this decline,” said Dr. Wang.

“Whether you look at global cognitive function or memory-specific function, and whether you look at PM_2.5 or NO₂, slower decline was in the range of someone who is 1-2 years younger.”

The associations did not significantly differ by age, region, education, APOE ε4 genotypes, or cardiovascular risk factors.

Patients concerned about cognitive decline can take steps to avoid exposure to pollution by wearing a mask; avoiding heavy traffic, fires, and smoke; or moving to an area with better air quality, said Dr. Wang.

“But our study mainly tried to provide some evidence for policymakers and regulators,” she added.

Another study carried out by the same investigators suggests pollution may affect various cognitive functions differently. This analysis used the same cohort, timeframe, and air quality improvement indicators as the first study but examined the association with specific cognitive domains, including episodic memory, working memory, attention/executive function, and language.

The investigators found women living in locations with greater PM_2.5 improvement performed better on tests of episodic memory (P = .002), working memory (P = .01) and attention/executive function (P = .01), but not language. Findings were similar for improved NO₂.

When looking at air quality improvement and trajectory slopes of decline across cognitive functions, only the association between improved NO₂ and slower episodic memory decline was statistically significant (P < 0.001). “The other domains were marginal or not significant,” said Dr. Wang.

“This suggests that brain regions are impacted differently,” she said, adding that various brain areas oversee different cognitive functions.
 

Important policy implications

Commenting on the research, Rebecca Edelmayer, PhD, senior director of scientific engagement, Alzheimer’s Association, said she welcomes new research on environmental factors that affect Alzheimer’s disease.

Whereas previous studies have linked longterm air pollution exposure to accumulation of Alzheimer’s disease-related brain plaques and increased risk of dementia, “these newer studies provide some of the first evidence to suggest that actually reducing pollution is associated with lower risk of all-cause dementia,” said Dr. Edelmayer.

Individuals can control some factors that contribute to dementia risk, such as exercise, diet, and physical activity, but it’s more difficult for them to control exposure to smog and pollution, she said.

“This is probably going to require changes to policy from federal and local governments and businesses, to start addressing the need to improve air quality to help reduce risk for dementia.”

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

Reducing exposure to air pollution may slow brain aging and reduce the risk of dementia, new research reveals. The findings have implications for individual behaviors, such as avoiding areas with poor air quality, but they also have implications for public policy, said study investigator, Xinhui Wang, PhD, assistant professor of research neurology, department of neurology, University of Southern California, Los Angeles.

“Controlling air quality has great benefits not only for the short-term, for example for pulmonary function or very broadly mortality, but can impact brain function and slow memory function decline and in the long run may reduce dementia cases.”

The findings were presented at the 2021 Alzheimer’s Association International Conference.
 

New approach

Previous research examining the impact of reducing air pollution, which has primarily examined respiratory illnesses and mortality, showed it is beneficial. However, no previous studies have examined the impact of improved air quality on cognitive function.

The current study used a subset of participants from the Women’s Health Initiative Memory Study-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO), which evaluated whether postmenopausal women derive cognitive benefit from hormone therapy.

The analysis included 2,232 community-dwelling older women aged 74-92 (mean age, 81.5 years) who did not have dementia at study enrollment.

Researchers obtained measures of participants’ annual cognitive function from 2008 to 2018. These measures included general cognitive status assessed using the Telephone Interview for Cognitive Status-modified (TICSm) and episodic memory assessed by the telephone-based California Verbal Learning Test (CVLT).

The investigators used complex geographical covariates to estimate exposure to fine particulate matter (PM_2.5) and nitrogen dioxide (NO₂), in areas where individual participants lived from 1996 to 2012. The investigators averaged measures over 3-year periods immediately preceding (recent exposure) and 10 years prior to (remote exposure) enrollment, then calculated individual-level improvements in air quality as the reduction from remote to recent exposures.

The researchers examined pollution exposure and cognitive outcomes at different times to determine causation.

“Maybe the relationship isn’t causal and is just an association, so we tried to separate the timeframe for exposure and outcome and make sure the exposure was before we measured the outcome,” said Dr. Wang.

The investigators adjusted for multiple sociodemographic, lifestyle, and clinical characteristics.
 

Reduced dementia risk

The analysis showed air quality improved significantly for both PM_2.5 and NO₂ before study enrollment. “For almost 95% of the subjects in our study, air quality improved over the 10 years,” said Dr. Wang.

During a median follow-up of 6.2 years, there was a significant decline in cognitive status and episodic memory in study participants, which makes sense, said Dr. Wang, because cognitive function naturally declines with age.

However, a 10% improvement in air quality PM_2.5 and NO₂ resulted in a respective 14% and 26% decreased risk for dementia. This translates into a level of risk seen in women 2 to 3 years younger.

Greater air quality improvement was associated with slower decline in both general cognitive status and episodic memory.

“Participants all declined in cognitive function, but living in areas with the greatest air quality improvement slowed this decline,” said Dr. Wang.

“Whether you look at global cognitive function or memory-specific function, and whether you look at PM_2.5 or NO₂, slower decline was in the range of someone who is 1-2 years younger.”

The associations did not significantly differ by age, region, education, APOE ε4 genotypes, or cardiovascular risk factors.

Patients concerned about cognitive decline can take steps to avoid exposure to pollution by wearing a mask; avoiding heavy traffic, fires, and smoke; or moving to an area with better air quality, said Dr. Wang.

“But our study mainly tried to provide some evidence for policymakers and regulators,” she added.

Another study carried out by the same investigators suggests pollution may affect various cognitive functions differently. This analysis used the same cohort, timeframe, and air quality improvement indicators as the first study but examined the association with specific cognitive domains, including episodic memory, working memory, attention/executive function, and language.

The investigators found women living in locations with greater PM_2.5 improvement performed better on tests of episodic memory (P = .002), working memory (P = .01) and attention/executive function (P = .01), but not language. Findings were similar for improved NO₂.

When looking at air quality improvement and trajectory slopes of decline across cognitive functions, only the association between improved NO₂ and slower episodic memory decline was statistically significant (P < 0.001). “The other domains were marginal or not significant,” said Dr. Wang.

“This suggests that brain regions are impacted differently,” she said, adding that various brain areas oversee different cognitive functions.
 

Important policy implications

Commenting on the research, Rebecca Edelmayer, PhD, senior director of scientific engagement, Alzheimer’s Association, said she welcomes new research on environmental factors that affect Alzheimer’s disease.

Whereas previous studies have linked longterm air pollution exposure to accumulation of Alzheimer’s disease-related brain plaques and increased risk of dementia, “these newer studies provide some of the first evidence to suggest that actually reducing pollution is associated with lower risk of all-cause dementia,” said Dr. Edelmayer.

Individuals can control some factors that contribute to dementia risk, such as exercise, diet, and physical activity, but it’s more difficult for them to control exposure to smog and pollution, she said.

“This is probably going to require changes to policy from federal and local governments and businesses, to start addressing the need to improve air quality to help reduce risk for dementia.”

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

An expert panel has released the first recommendations on the appropriate use of aducanumab (Aduhelm), the controversial anti-amyloid drug that was approved by the U.S. Food and Drug Administration in June for adults with early Alzheimer’s disease.

“There are incredible gaps between the FDA label and what most of us in the field feel needs to happen in terms of detailed guidance on using this drug,” said panel member Alireza Atri, MD, PhD, director of the Banner Sun Health Research Institute (Banner Health) in Sun City, Arizona.

“This is a first-in-class drug where the vast majority of clinicians have no experience with it, and patients and their caregivers are already asking for it, and there are some really important conversations to be had – not only about who may qualify to begin with and also about potential effectiveness and safety,” Dr. Atri added.

The aducanumab recommendations were published online July 27 in the Journal of Prevention of Alzheimer’s Disease to coincide with their presentation at the 2021 Alzheimer’s Association International Conference.

A separate article outlining the key recommendations was published in Alzheimer’s and Dementia: Translational Research and Clinical Interventions.
 

Patient-centered focus

The panel recommends that aducanumab only be used for patients with clinical features similar to those of the patients who took part in the clinical trials that led to the drug’s approval – patients with mild cognitive impairment (MCI) due to Alzheimer’s disease and mild Alzheimer’s disease dementia who have brain amyloid, as confirmed on amyloid positron-emission tomography (PET) or with cerebrospinal fluid (CSF) findings consistent with Alzheimer’s disease.

“You’re giving a drug that’s been approved on accelerated status for lowering amyloid, so amyloid status needs to be verified either by an amyloid PET scan or spinal fluid,” said Dr. Atri.

The panel also recommends that patients under consideration for aducanumab treatment have no psychiatric problems; that they be medically stable with no cardiovascular or cardiopulmonary conditions; that they are not taking anticoagulants; that they have no organ failure; and that they have no active cancer except for low-grade basal and squamous cell carcinomas. Current treatment with cholinesterase inhibitors and memantine is acceptable.

Dr. Atri noted that the prescribing label for the drug provides “broad strokes about titration.” The panel recommends that the drug be titrated to the highest dose to maximize opportunity for efficacy.

Monthly infusions should begin with a dose of 1 mg/kg for the first and second infusions. They should be increased to 3 mg/kg for infusions three and four and to 6 mg/kg for the fifth and sixth infusions. The intended dose of 10 mg/kg should be administered on the seventh infusion. The target dose level of 10 mg/kg should then be continued for the foreseeable future, the panel notes.

Safety monitoring is critically important. The panel recommends structured monitoring for amyloid-related imaging abnormalities of the effusion (ARIA-E) or hemorrhagic (ARIA-H) type. Patients should undergo MRI at least 1 year before aducanumab treatment is initiated or at baseline if there are any suggestions of a focal brain event since the last MRI. MRI should again be conducted before the fifth, seventh, and 12th infusions.

The panel says the “best practice” for providing aducanumab therapy is to adopt a patient-centered focus.
 

‘Not a cure’

“There should be comprehensive discussions and clear communication with the patient and care partner regarding the requirements for therapy, the expected outcome of therapy, potential risks and side effects, and the required safety monitoring, as well as uncertainties regarding individual responses and benefits,” said Dr. Atri.

“Patients need to know that this is not a cure. It’s not going to actually make their cognition better, but by removing amyloid, there is a reasonable chance it’s going to slow down clinical decline,” he added.

“You could have two identical twins who would qualify, and when you have this discussion with them, based on the risk and reward calculus, one may reasonably decide, ‘this is not for me,’ and that’s really important,” Dr. Atri added.

He cautioned that these initial recommendations are “a starting point, not a finishing point,” and will be updated as needed.

“This paper takes no stance on advocating for this treatment. But now that it’s available, let’s put up some guardrails and use it appropriately and safety,” Dr. Atri said.

“Clinicians are requesting clarity and more specific information about the appropriate use of this new treatment,” Rebecca Edelmayer, PhD, senior director of scientific engagement, the Alzheimer’s Association, said in an interview.

These first appropriate-use recommendations are “a first step and will certainly evolve over time as the medication is prescribed,” Dr. Edelmayer said.

The research had no specific funding. Dr. Atri has received honoraria for consulting; participating in independent data safety monitoring boards; providing educational lectures, programs, and materials; or serving on advisory boards for AbbVie, Acadia, Allergan, the Alzheimer’s Association, Axovant, AZ Therapies, Biogen, Grifols, Harvard Medical School Graduate Continuing Education, JOMDD, Lundbeck, Merck, Roche/Genentech, Novo Nordisk, Sunovion, and Suven. Dr. Edelmayer has disclosed no relevant financial relationships.

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

An expert panel has released the first recommendations on the appropriate use of aducanumab (Aduhelm), the controversial anti-amyloid drug that was approved by the U.S. Food and Drug Administration in June for adults with early Alzheimer’s disease.

“There are incredible gaps between the FDA label and what most of us in the field feel needs to happen in terms of detailed guidance on using this drug,” said panel member Alireza Atri, MD, PhD, director of the Banner Sun Health Research Institute (Banner Health) in Sun City, Arizona.

“This is a first-in-class drug where the vast majority of clinicians have no experience with it, and patients and their caregivers are already asking for it, and there are some really important conversations to be had – not only about who may qualify to begin with and also about potential effectiveness and safety,” Dr. Atri added.

The aducanumab recommendations were published online July 27 in the Journal of Prevention of Alzheimer’s Disease to coincide with their presentation at the 2021 Alzheimer’s Association International Conference.

A separate article outlining the key recommendations was published in Alzheimer’s and Dementia: Translational Research and Clinical Interventions.
 

Patient-centered focus

The panel recommends that aducanumab only be used for patients with clinical features similar to those of the patients who took part in the clinical trials that led to the drug’s approval – patients with mild cognitive impairment (MCI) due to Alzheimer’s disease and mild Alzheimer’s disease dementia who have brain amyloid, as confirmed on amyloid positron-emission tomography (PET) or with cerebrospinal fluid (CSF) findings consistent with Alzheimer’s disease.

“You’re giving a drug that’s been approved on accelerated status for lowering amyloid, so amyloid status needs to be verified either by an amyloid PET scan or spinal fluid,” said Dr. Atri.

The panel also recommends that patients under consideration for aducanumab treatment have no psychiatric problems; that they be medically stable with no cardiovascular or cardiopulmonary conditions; that they are not taking anticoagulants; that they have no organ failure; and that they have no active cancer except for low-grade basal and squamous cell carcinomas. Current treatment with cholinesterase inhibitors and memantine is acceptable.

Dr. Atri noted that the prescribing label for the drug provides “broad strokes about titration.” The panel recommends that the drug be titrated to the highest dose to maximize opportunity for efficacy.

Monthly infusions should begin with a dose of 1 mg/kg for the first and second infusions. They should be increased to 3 mg/kg for infusions three and four and to 6 mg/kg for the fifth and sixth infusions. The intended dose of 10 mg/kg should be administered on the seventh infusion. The target dose level of 10 mg/kg should then be continued for the foreseeable future, the panel notes.

Safety monitoring is critically important. The panel recommends structured monitoring for amyloid-related imaging abnormalities of the effusion (ARIA-E) or hemorrhagic (ARIA-H) type. Patients should undergo MRI at least 1 year before aducanumab treatment is initiated or at baseline if there are any suggestions of a focal brain event since the last MRI. MRI should again be conducted before the fifth, seventh, and 12th infusions.

The panel says the “best practice” for providing aducanumab therapy is to adopt a patient-centered focus.
 

‘Not a cure’

“There should be comprehensive discussions and clear communication with the patient and care partner regarding the requirements for therapy, the expected outcome of therapy, potential risks and side effects, and the required safety monitoring, as well as uncertainties regarding individual responses and benefits,” said Dr. Atri.

“Patients need to know that this is not a cure. It’s not going to actually make their cognition better, but by removing amyloid, there is a reasonable chance it’s going to slow down clinical decline,” he added.

“You could have two identical twins who would qualify, and when you have this discussion with them, based on the risk and reward calculus, one may reasonably decide, ‘this is not for me,’ and that’s really important,” Dr. Atri added.

He cautioned that these initial recommendations are “a starting point, not a finishing point,” and will be updated as needed.

“This paper takes no stance on advocating for this treatment. But now that it’s available, let’s put up some guardrails and use it appropriately and safety,” Dr. Atri said.

“Clinicians are requesting clarity and more specific information about the appropriate use of this new treatment,” Rebecca Edelmayer, PhD, senior director of scientific engagement, the Alzheimer’s Association, said in an interview.

These first appropriate-use recommendations are “a first step and will certainly evolve over time as the medication is prescribed,” Dr. Edelmayer said.

The research had no specific funding. Dr. Atri has received honoraria for consulting; participating in independent data safety monitoring boards; providing educational lectures, programs, and materials; or serving on advisory boards for AbbVie, Acadia, Allergan, the Alzheimer’s Association, Axovant, AZ Therapies, Biogen, Grifols, Harvard Medical School Graduate Continuing Education, JOMDD, Lundbeck, Merck, Roche/Genentech, Novo Nordisk, Sunovion, and Suven. Dr. Edelmayer has disclosed no relevant financial relationships.

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

An expert panel has released the first recommendations on the appropriate use of aducanumab (Aduhelm), the controversial anti-amyloid drug that was approved by the U.S. Food and Drug Administration in June for adults with early Alzheimer’s disease.

“There are incredible gaps between the FDA label and what most of us in the field feel needs to happen in terms of detailed guidance on using this drug,” said panel member Alireza Atri, MD, PhD, director of the Banner Sun Health Research Institute (Banner Health) in Sun City, Arizona.

“This is a first-in-class drug where the vast majority of clinicians have no experience with it, and patients and their caregivers are already asking for it, and there are some really important conversations to be had – not only about who may qualify to begin with and also about potential effectiveness and safety,” Dr. Atri added.

The aducanumab recommendations were published online July 27 in the Journal of Prevention of Alzheimer’s Disease to coincide with their presentation at the 2021 Alzheimer’s Association International Conference.

A separate article outlining the key recommendations was published in Alzheimer’s and Dementia: Translational Research and Clinical Interventions.
 

Patient-centered focus

The panel recommends that aducanumab only be used for patients with clinical features similar to those of the patients who took part in the clinical trials that led to the drug’s approval – patients with mild cognitive impairment (MCI) due to Alzheimer’s disease and mild Alzheimer’s disease dementia who have brain amyloid, as confirmed on amyloid positron-emission tomography (PET) or with cerebrospinal fluid (CSF) findings consistent with Alzheimer’s disease.

“You’re giving a drug that’s been approved on accelerated status for lowering amyloid, so amyloid status needs to be verified either by an amyloid PET scan or spinal fluid,” said Dr. Atri.

The panel also recommends that patients under consideration for aducanumab treatment have no psychiatric problems; that they be medically stable with no cardiovascular or cardiopulmonary conditions; that they are not taking anticoagulants; that they have no organ failure; and that they have no active cancer except for low-grade basal and squamous cell carcinomas. Current treatment with cholinesterase inhibitors and memantine is acceptable.

Dr. Atri noted that the prescribing label for the drug provides “broad strokes about titration.” The panel recommends that the drug be titrated to the highest dose to maximize opportunity for efficacy.

Monthly infusions should begin with a dose of 1 mg/kg for the first and second infusions. They should be increased to 3 mg/kg for infusions three and four and to 6 mg/kg for the fifth and sixth infusions. The intended dose of 10 mg/kg should be administered on the seventh infusion. The target dose level of 10 mg/kg should then be continued for the foreseeable future, the panel notes.

Safety monitoring is critically important. The panel recommends structured monitoring for amyloid-related imaging abnormalities of the effusion (ARIA-E) or hemorrhagic (ARIA-H) type. Patients should undergo MRI at least 1 year before aducanumab treatment is initiated or at baseline if there are any suggestions of a focal brain event since the last MRI. MRI should again be conducted before the fifth, seventh, and 12th infusions.

The panel says the “best practice” for providing aducanumab therapy is to adopt a patient-centered focus.
 

‘Not a cure’

“There should be comprehensive discussions and clear communication with the patient and care partner regarding the requirements for therapy, the expected outcome of therapy, potential risks and side effects, and the required safety monitoring, as well as uncertainties regarding individual responses and benefits,” said Dr. Atri.

“Patients need to know that this is not a cure. It’s not going to actually make their cognition better, but by removing amyloid, there is a reasonable chance it’s going to slow down clinical decline,” he added.

“You could have two identical twins who would qualify, and when you have this discussion with them, based on the risk and reward calculus, one may reasonably decide, ‘this is not for me,’ and that’s really important,” Dr. Atri added.

He cautioned that these initial recommendations are “a starting point, not a finishing point,” and will be updated as needed.

“This paper takes no stance on advocating for this treatment. But now that it’s available, let’s put up some guardrails and use it appropriately and safety,” Dr. Atri said.

“Clinicians are requesting clarity and more specific information about the appropriate use of this new treatment,” Rebecca Edelmayer, PhD, senior director of scientific engagement, the Alzheimer’s Association, said in an interview.

These first appropriate-use recommendations are “a first step and will certainly evolve over time as the medication is prescribed,” Dr. Edelmayer said.

The research had no specific funding. Dr. Atri has received honoraria for consulting; participating in independent data safety monitoring boards; providing educational lectures, programs, and materials; or serving on advisory boards for AbbVie, Acadia, Allergan, the Alzheimer’s Association, Axovant, AZ Therapies, Biogen, Grifols, Harvard Medical School Graduate Continuing Education, JOMDD, Lundbeck, Merck, Roche/Genentech, Novo Nordisk, Sunovion, and Suven. Dr. Edelmayer has disclosed no relevant financial relationships.

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

When used for appropriate patients, MRI imaging is helpful in congenital melanocytic nevus (CMN) management and may help predict neurologic outcomes or drive neurosurgical intervention, results from a small multi-institutional study showed.

“The majority of congenital nevi are considered low risk for cutaneous and/or systemic complications,” Holly Neale said at the annual meeting of the Society for Pediatric Dermatology. “However, a subset of children born with higher-risk congenital nevi require close monitoring, as some features of congenital nevi have been associated with cutaneous melanoma, central nervous system melanoma, melanin in the brain or spine, and structural irregularities in the brain or spine. It’s important to understand which congenital nevi are considered higher risk in order to guide management and counseling decisions.”

One major management decision is to do a screening magnetic resonance image of the CNS to evaluate for neurologic involvement, said Ms. Neale, a fourth-year medical student at the University of Massachusetts, Worcester. Prior studies have shown that congenital nevi that are bigger than 20 cm, posterior axial location, and having more than one congenital nevus may predict CNS abnormalities, while recent guidelines from experts in the field suggest that any child with more than one congenital nevus at birth undergo screening MRI.

“However, guidelines are evolving, and more data is required to better understand the CNS abnormalities and patient outcomes for children with congenital nevi,” said Ms. Neale, who spent the past year as a pediatric dermatology research fellow at Massachusetts General Hospital, Boston.

To address this knowledge gap, she and colleagues at the University of Massachusetts, Massachusetts General Hospital, and Boston Children’s Hospital performed a retrospective chart review between Jan. 1, 2009, and Dec. 31, 2019, of individuals ages 18 and younger who had an MRI of the brain or spine with at least one dermatologist-diagnosed nevus as identified via key words in the medical record. Of the 909 patients screened, 46 met inclusion criteria, evenly split between males and females.

The most common location of the largest nevus was the trunk (in 41% of patients), followed by lesions that spanned multiple regions. More than one-third of patients had giant nevi (greater than 40 cm).

“The majority of images were considered nonconcerning, which includes normal, benign, or other findings such as trauma related, infectious, or orthopedic, which we did not classify as abnormal as it did not guide our study question,” Ms. Neale said. Specifically, 8% of spine images and 27% of brain images were considered “concerning,” defined as any finding that prompted further workup or monitoring, which includes findings concerning for melanin.

The most common brain finding was melanin (in eight children), and one child with brain melanin also had findings suggestive of melanin in the thoracic spine. The most common finding in spine MRIs was fatty filum (in four children), requiring intervention for tethering in only one individual. No cases of cutaneous melanoma developed during the study period, and only one patient with abnormal imaging had CNS melanoma, which was fatal.

All patients with findings suggestive of CNS melanin had more than four nevi present at birth, which is in line with current imaging screening guidelines. In addition, children with concerning imaging had higher rates of death, neurodevelopmental problems, seizures, and neurosurgery, compared with their counterparts with unremarkable imaging findings. Describing preliminary analyses, Ms. Neale said that a chi square analysis was performed to test statistical significance of these differences, “and neurosurgery was the only variable that children with concerning imaging were significantly more likely to experience, although sample size limits detection for the other variables.”

The authors concluded that MRI is a helpful tool when used in the appropriate clinical context for the management of congenital nevi. “As more children undergo imaging, we may discover more nonmelanin abnormalities,” she said.

Joseph M. Lam, MD, who was asked to comment on the study, said that the increased risk of CNS melanin in patients with larger lesions and in those with multiple lesions confirms previous reports.

“It is interesting to note that some patients with nonconcerning imaging results still had neurodevelopmental problems and seizures, albeit at a lower rate than those with concerning imaging results,” said Dr. Lam, a pediatric dermatologist at British Columbia Children’s Hospital, Vancouver. “The lack of a control group for comparison of rates of neurological sequelae, such as NDP, seizures and nonmelanin structural anomalies, limits the generalizability of the findings. However, this is a nice study that helps us understand better the CNS anomalies in CMN.”

Ms. Neale acknowledged certain limitations of the study, including the lack of a control group without CMN, the small number of patients, the potential for referral bias, and its retrospective design. Also, the proximity of the study period does not allow for chronic follow-up and detection of the development of melanoma or other problems in the future.

Ms. Neale and associates reported having no relevant financial disclosures. Dr. Lam disclosed that he has received speaker fees from Pierre Fabre.

[email protected]

When used for appropriate patients, MRI imaging is helpful in congenital melanocytic nevus (CMN) management and may help predict neurologic outcomes or drive neurosurgical intervention, results from a small multi-institutional study showed.

“The majority of congenital nevi are considered low risk for cutaneous and/or systemic complications,” Holly Neale said at the annual meeting of the Society for Pediatric Dermatology. “However, a subset of children born with higher-risk congenital nevi require close monitoring, as some features of congenital nevi have been associated with cutaneous melanoma, central nervous system melanoma, melanin in the brain or spine, and structural irregularities in the brain or spine. It’s important to understand which congenital nevi are considered higher risk in order to guide management and counseling decisions.”

One major management decision is to do a screening magnetic resonance image of the CNS to evaluate for neurologic involvement, said Ms. Neale, a fourth-year medical student at the University of Massachusetts, Worcester. Prior studies have shown that congenital nevi that are bigger than 20 cm, posterior axial location, and having more than one congenital nevus may predict CNS abnormalities, while recent guidelines from experts in the field suggest that any child with more than one congenital nevus at birth undergo screening MRI.

“However, guidelines are evolving, and more data is required to better understand the CNS abnormalities and patient outcomes for children with congenital nevi,” said Ms. Neale, who spent the past year as a pediatric dermatology research fellow at Massachusetts General Hospital, Boston.

To address this knowledge gap, she and colleagues at the University of Massachusetts, Massachusetts General Hospital, and Boston Children’s Hospital performed a retrospective chart review between Jan. 1, 2009, and Dec. 31, 2019, of individuals ages 18 and younger who had an MRI of the brain or spine with at least one dermatologist-diagnosed nevus as identified via key words in the medical record. Of the 909 patients screened, 46 met inclusion criteria, evenly split between males and females.

The most common location of the largest nevus was the trunk (in 41% of patients), followed by lesions that spanned multiple regions. More than one-third of patients had giant nevi (greater than 40 cm).

“The majority of images were considered nonconcerning, which includes normal, benign, or other findings such as trauma related, infectious, or orthopedic, which we did not classify as abnormal as it did not guide our study question,” Ms. Neale said. Specifically, 8% of spine images and 27% of brain images were considered “concerning,” defined as any finding that prompted further workup or monitoring, which includes findings concerning for melanin.

The most common brain finding was melanin (in eight children), and one child with brain melanin also had findings suggestive of melanin in the thoracic spine. The most common finding in spine MRIs was fatty filum (in four children), requiring intervention for tethering in only one individual. No cases of cutaneous melanoma developed during the study period, and only one patient with abnormal imaging had CNS melanoma, which was fatal.

All patients with findings suggestive of CNS melanin had more than four nevi present at birth, which is in line with current imaging screening guidelines. In addition, children with concerning imaging had higher rates of death, neurodevelopmental problems, seizures, and neurosurgery, compared with their counterparts with unremarkable imaging findings. Describing preliminary analyses, Ms. Neale said that a chi square analysis was performed to test statistical significance of these differences, “and neurosurgery was the only variable that children with concerning imaging were significantly more likely to experience, although sample size limits detection for the other variables.”

The authors concluded that MRI is a helpful tool when used in the appropriate clinical context for the management of congenital nevi. “As more children undergo imaging, we may discover more nonmelanin abnormalities,” she said.

Joseph M. Lam, MD, who was asked to comment on the study, said that the increased risk of CNS melanin in patients with larger lesions and in those with multiple lesions confirms previous reports.

“It is interesting to note that some patients with nonconcerning imaging results still had neurodevelopmental problems and seizures, albeit at a lower rate than those with concerning imaging results,” said Dr. Lam, a pediatric dermatologist at British Columbia Children’s Hospital, Vancouver. “The lack of a control group for comparison of rates of neurological sequelae, such as NDP, seizures and nonmelanin structural anomalies, limits the generalizability of the findings. However, this is a nice study that helps us understand better the CNS anomalies in CMN.”

Ms. Neale acknowledged certain limitations of the study, including the lack of a control group without CMN, the small number of patients, the potential for referral bias, and its retrospective design. Also, the proximity of the study period does not allow for chronic follow-up and detection of the development of melanoma or other problems in the future.

Ms. Neale and associates reported having no relevant financial disclosures. Dr. Lam disclosed that he has received speaker fees from Pierre Fabre.

[email protected]

When used for appropriate patients, MRI imaging is helpful in congenital melanocytic nevus (CMN) management and may help predict neurologic outcomes or drive neurosurgical intervention, results from a small multi-institutional study showed.

“The majority of congenital nevi are considered low risk for cutaneous and/or systemic complications,” Holly Neale said at the annual meeting of the Society for Pediatric Dermatology. “However, a subset of children born with higher-risk congenital nevi require close monitoring, as some features of congenital nevi have been associated with cutaneous melanoma, central nervous system melanoma, melanin in the brain or spine, and structural irregularities in the brain or spine. It’s important to understand which congenital nevi are considered higher risk in order to guide management and counseling decisions.”

One major management decision is to do a screening magnetic resonance image of the CNS to evaluate for neurologic involvement, said Ms. Neale, a fourth-year medical student at the University of Massachusetts, Worcester. Prior studies have shown that congenital nevi that are bigger than 20 cm, posterior axial location, and having more than one congenital nevus may predict CNS abnormalities, while recent guidelines from experts in the field suggest that any child with more than one congenital nevus at birth undergo screening MRI.

“However, guidelines are evolving, and more data is required to better understand the CNS abnormalities and patient outcomes for children with congenital nevi,” said Ms. Neale, who spent the past year as a pediatric dermatology research fellow at Massachusetts General Hospital, Boston.

To address this knowledge gap, she and colleagues at the University of Massachusetts, Massachusetts General Hospital, and Boston Children’s Hospital performed a retrospective chart review between Jan. 1, 2009, and Dec. 31, 2019, of individuals ages 18 and younger who had an MRI of the brain or spine with at least one dermatologist-diagnosed nevus as identified via key words in the medical record. Of the 909 patients screened, 46 met inclusion criteria, evenly split between males and females.

The most common location of the largest nevus was the trunk (in 41% of patients), followed by lesions that spanned multiple regions. More than one-third of patients had giant nevi (greater than 40 cm).

“The majority of images were considered nonconcerning, which includes normal, benign, or other findings such as trauma related, infectious, or orthopedic, which we did not classify as abnormal as it did not guide our study question,” Ms. Neale said. Specifically, 8% of spine images and 27% of brain images were considered “concerning,” defined as any finding that prompted further workup or monitoring, which includes findings concerning for melanin.

The most common brain finding was melanin (in eight children), and one child with brain melanin also had findings suggestive of melanin in the thoracic spine. The most common finding in spine MRIs was fatty filum (in four children), requiring intervention for tethering in only one individual. No cases of cutaneous melanoma developed during the study period, and only one patient with abnormal imaging had CNS melanoma, which was fatal.

All patients with findings suggestive of CNS melanin had more than four nevi present at birth, which is in line with current imaging screening guidelines. In addition, children with concerning imaging had higher rates of death, neurodevelopmental problems, seizures, and neurosurgery, compared with their counterparts with unremarkable imaging findings. Describing preliminary analyses, Ms. Neale said that a chi square analysis was performed to test statistical significance of these differences, “and neurosurgery was the only variable that children with concerning imaging were significantly more likely to experience, although sample size limits detection for the other variables.”

The authors concluded that MRI is a helpful tool when used in the appropriate clinical context for the management of congenital nevi. “As more children undergo imaging, we may discover more nonmelanin abnormalities,” she said.

Joseph M. Lam, MD, who was asked to comment on the study, said that the increased risk of CNS melanin in patients with larger lesions and in those with multiple lesions confirms previous reports.

“It is interesting to note that some patients with nonconcerning imaging results still had neurodevelopmental problems and seizures, albeit at a lower rate than those with concerning imaging results,” said Dr. Lam, a pediatric dermatologist at British Columbia Children’s Hospital, Vancouver. “The lack of a control group for comparison of rates of neurological sequelae, such as NDP, seizures and nonmelanin structural anomalies, limits the generalizability of the findings. However, this is a nice study that helps us understand better the CNS anomalies in CMN.”

Ms. Neale acknowledged certain limitations of the study, including the lack of a control group without CMN, the small number of patients, the potential for referral bias, and its retrospective design. Also, the proximity of the study period does not allow for chronic follow-up and detection of the development of melanoma or other problems in the future.

Ms. Neale and associates reported having no relevant financial disclosures. Dr. Lam disclosed that he has received speaker fees from Pierre Fabre.

[email protected]

Occipital nerve stimulation may help safely prevent attacks of medically intractable chronic cluster headache, according to a new study.

Medically intractable chronic cluster headaches are unilateral headaches that cause excruciating pain during attacks, which may happen as frequently as eight times per day. They are refractory to, or intolerant of, preventive medications typically used in chronic cluster headaches.

In a randomized controlled trial of patients with medically intractable chronic cluster headache, occipital nerve stimulation (ONS) was found to offer relief by reducing the frequency of attacks.

“ONS was associated with a major, rapid, and sustained improvement of severe and long-lasting medically intractable chronic cluster headache, both at high and low intensity,” Leopoldine A. Wilbrink, MD, of Leiden (the Netherlands) University Medical Centre, and coauthors wrote in their paper.

The findings were published online.

The multicenter, randomized, double-blind, phase 3 clinical trial was carried out at seven hospitals in the Netherlands, Belgium, Germany, and Hungary. A total of 150 patients with suspected medically intractable chronic cluster headache were enrolled between October 2010 and December 2017, and observed for 12 weeks at baseline. Of those initially enrolled, 131 patients with at least four medically intractable chronic cluster headache attacks per week and a history of nonresponsiveness to at least three standard preventive medications were randomly allocated to one of two groups: Sixty-five patients received 24 weeks of ONS at high intensity (100% intensity, or the intensity 10% below the threshold of discomfort as reported by the patient) while 66 received low-intensity (30%) ONS. At 25-48 weeks, the patients received open-label ONS.
 

Safe and well tolerated

“Because ONS causes paraesthesia, preventing masked comparison versus placebo, we compared high-intensity versus low-intensity ONS, which are hypothesised to cause similar paraesthesia, but with different efficacy,” wrote Dr. Wilbrink and colleagues.

From baseline to weeks 21-24, the median weekly mean attack frequencies decreased to 7.38 (95% confidence interval [CI]: 2.5-18.5, P < .0001). A median decrease in 5.21 attacks per week (–11.18 to –0.19, P < .0001) was observed.

The 100% ONS group saw a decrease in mean attack frequency from 17.58 at baseline (range, 9.83-29.33) to 9.5 (3-21.25) at 21-24 weeks with a median change of –4.08 (–11.92 to –0.25). In the 30% ONS group, the mean attack frequency decreased from 15 (9.25 to 22.33) to 6.75 (1.5-16.5) with a median change of –6.5 (–10.83 to –0.08).

At weeks 21-24, the difference in median weekly mean attack frequency between the groups was –2.42 (–5.17 to 3.33).

The authors stated that, in both groups, ONS was “safe and well tolerated.” A total of 129 adverse events were reported in the 100% ONS group and 95 in the 30% ONS group, of which 17 and 9 were considered serious, respectively. The serious adverse events required a short hospital stay to resolve minor hardware issues. The adverse events most frequently observed were local pain, impaired wound healing, neck stiffness, and hardware damage.
 

Low intensity stimulation may be best

“The main limitation of the study comes from the difficulty in defining the electrical dose, which was not constant across patients within each group, but individually adjusted depending on the perception of the ONS-induced paraesthesia,” Denys Fontaine, MD, and Michel Lanteri-Minet, MD, both from Université Cote D’Azur in France, wrote in an accompanying editorial.

Given that the primary outcome did not differ significantly between the treatment groups, the editorialists stated that “the lowest stimulation intensity that induces paraesthesia is sufficient to obtain an effect in the patients who respond. Increasing the electrical dose or intensity does not seem to bring better efficacy and might even induce discomfort (painful paraesthesia or shock-like sensations) that might substantially reduce the tolerance of this approach.”

While the trial did not provide convincing evidence of high intensity ONS in medically intractable chronic cluster headache, the editorialists are otherwise optimistic about the findings: “… considering the significant difference between baseline and the end of the randomised stimulation phase in both groups (about half of the patients showed a 50% decrease in attack frequency), the findings of this study support the favourable results of previous real-world studies, and indicate that a substantial proportion of patients with intractable chronic cluster headache, although not all, could have their condition substantially improved by ONS.” Dr. Fontaine and Dr. Lanteri-Minet added that they hope that “these data will help health authorities to recognise the efficacy of ONS and consider its approval for use in patients with intractable chronic cluster headache.”

Priorities for future research in this area should “focus on optimising stimulation protocols and disentangling the underlying mechanism of action,” Dr. Wilbrink and colleagues wrote.

The study was funded by the Spinoza 2009 Lifetime Scientific Research Achievement Premium, the Netherlands Organisation for Scientific Research, the Dutch Ministry of Health (as part of a national provisional reimbursement program for promising new treatments), the NutsOhra Foundation from the Dutch Health Insurance Companies, and an unrestricted grant from Medtronic, all to Dr. Ferrari.

Occipital nerve stimulation may help safely prevent attacks of medically intractable chronic cluster headache, according to a new study.

Medically intractable chronic cluster headaches are unilateral headaches that cause excruciating pain during attacks, which may happen as frequently as eight times per day. They are refractory to, or intolerant of, preventive medications typically used in chronic cluster headaches.

In a randomized controlled trial of patients with medically intractable chronic cluster headache, occipital nerve stimulation (ONS) was found to offer relief by reducing the frequency of attacks.

“ONS was associated with a major, rapid, and sustained improvement of severe and long-lasting medically intractable chronic cluster headache, both at high and low intensity,” Leopoldine A. Wilbrink, MD, of Leiden (the Netherlands) University Medical Centre, and coauthors wrote in their paper.

The findings were published online.

The multicenter, randomized, double-blind, phase 3 clinical trial was carried out at seven hospitals in the Netherlands, Belgium, Germany, and Hungary. A total of 150 patients with suspected medically intractable chronic cluster headache were enrolled between October 2010 and December 2017, and observed for 12 weeks at baseline. Of those initially enrolled, 131 patients with at least four medically intractable chronic cluster headache attacks per week and a history of nonresponsiveness to at least three standard preventive medications were randomly allocated to one of two groups: Sixty-five patients received 24 weeks of ONS at high intensity (100% intensity, or the intensity 10% below the threshold of discomfort as reported by the patient) while 66 received low-intensity (30%) ONS. At 25-48 weeks, the patients received open-label ONS.
 

Safe and well tolerated

“Because ONS causes paraesthesia, preventing masked comparison versus placebo, we compared high-intensity versus low-intensity ONS, which are hypothesised to cause similar paraesthesia, but with different efficacy,” wrote Dr. Wilbrink and colleagues.

From baseline to weeks 21-24, the median weekly mean attack frequencies decreased to 7.38 (95% confidence interval [CI]: 2.5-18.5, P < .0001). A median decrease in 5.21 attacks per week (–11.18 to –0.19, P < .0001) was observed.

The 100% ONS group saw a decrease in mean attack frequency from 17.58 at baseline (range, 9.83-29.33) to 9.5 (3-21.25) at 21-24 weeks with a median change of –4.08 (–11.92 to –0.25). In the 30% ONS group, the mean attack frequency decreased from 15 (9.25 to 22.33) to 6.75 (1.5-16.5) with a median change of –6.5 (–10.83 to –0.08).

At weeks 21-24, the difference in median weekly mean attack frequency between the groups was –2.42 (–5.17 to 3.33).

The authors stated that, in both groups, ONS was “safe and well tolerated.” A total of 129 adverse events were reported in the 100% ONS group and 95 in the 30% ONS group, of which 17 and 9 were considered serious, respectively. The serious adverse events required a short hospital stay to resolve minor hardware issues. The adverse events most frequently observed were local pain, impaired wound healing, neck stiffness, and hardware damage.
 

Low intensity stimulation may be best

“The main limitation of the study comes from the difficulty in defining the electrical dose, which was not constant across patients within each group, but individually adjusted depending on the perception of the ONS-induced paraesthesia,” Denys Fontaine, MD, and Michel Lanteri-Minet, MD, both from Université Cote D’Azur in France, wrote in an accompanying editorial.

Given that the primary outcome did not differ significantly between the treatment groups, the editorialists stated that “the lowest stimulation intensity that induces paraesthesia is sufficient to obtain an effect in the patients who respond. Increasing the electrical dose or intensity does not seem to bring better efficacy and might even induce discomfort (painful paraesthesia or shock-like sensations) that might substantially reduce the tolerance of this approach.”

While the trial did not provide convincing evidence of high intensity ONS in medically intractable chronic cluster headache, the editorialists are otherwise optimistic about the findings: “… considering the significant difference between baseline and the end of the randomised stimulation phase in both groups (about half of the patients showed a 50% decrease in attack frequency), the findings of this study support the favourable results of previous real-world studies, and indicate that a substantial proportion of patients with intractable chronic cluster headache, although not all, could have their condition substantially improved by ONS.” Dr. Fontaine and Dr. Lanteri-Minet added that they hope that “these data will help health authorities to recognise the efficacy of ONS and consider its approval for use in patients with intractable chronic cluster headache.”

Priorities for future research in this area should “focus on optimising stimulation protocols and disentangling the underlying mechanism of action,” Dr. Wilbrink and colleagues wrote.

The study was funded by the Spinoza 2009 Lifetime Scientific Research Achievement Premium, the Netherlands Organisation for Scientific Research, the Dutch Ministry of Health (as part of a national provisional reimbursement program for promising new treatments), the NutsOhra Foundation from the Dutch Health Insurance Companies, and an unrestricted grant from Medtronic, all to Dr. Ferrari.

Occipital nerve stimulation may help safely prevent attacks of medically intractable chronic cluster headache, according to a new study.

Medically intractable chronic cluster headaches are unilateral headaches that cause excruciating pain during attacks, which may happen as frequently as eight times per day. They are refractory to, or intolerant of, preventive medications typically used in chronic cluster headaches.

In a randomized controlled trial of patients with medically intractable chronic cluster headache, occipital nerve stimulation (ONS) was found to offer relief by reducing the frequency of attacks.

“ONS was associated with a major, rapid, and sustained improvement of severe and long-lasting medically intractable chronic cluster headache, both at high and low intensity,” Leopoldine A. Wilbrink, MD, of Leiden (the Netherlands) University Medical Centre, and coauthors wrote in their paper.

The findings were published online.

The multicenter, randomized, double-blind, phase 3 clinical trial was carried out at seven hospitals in the Netherlands, Belgium, Germany, and Hungary. A total of 150 patients with suspected medically intractable chronic cluster headache were enrolled between October 2010 and December 2017, and observed for 12 weeks at baseline. Of those initially enrolled, 131 patients with at least four medically intractable chronic cluster headache attacks per week and a history of nonresponsiveness to at least three standard preventive medications were randomly allocated to one of two groups: Sixty-five patients received 24 weeks of ONS at high intensity (100% intensity, or the intensity 10% below the threshold of discomfort as reported by the patient) while 66 received low-intensity (30%) ONS. At 25-48 weeks, the patients received open-label ONS.
 

Safe and well tolerated

“Because ONS causes paraesthesia, preventing masked comparison versus placebo, we compared high-intensity versus low-intensity ONS, which are hypothesised to cause similar paraesthesia, but with different efficacy,” wrote Dr. Wilbrink and colleagues.

From baseline to weeks 21-24, the median weekly mean attack frequencies decreased to 7.38 (95% confidence interval [CI]: 2.5-18.5, P < .0001). A median decrease in 5.21 attacks per week (–11.18 to –0.19, P < .0001) was observed.

The 100% ONS group saw a decrease in mean attack frequency from 17.58 at baseline (range, 9.83-29.33) to 9.5 (3-21.25) at 21-24 weeks with a median change of –4.08 (–11.92 to –0.25). In the 30% ONS group, the mean attack frequency decreased from 15 (9.25 to 22.33) to 6.75 (1.5-16.5) with a median change of –6.5 (–10.83 to –0.08).

At weeks 21-24, the difference in median weekly mean attack frequency between the groups was –2.42 (–5.17 to 3.33).

The authors stated that, in both groups, ONS was “safe and well tolerated.” A total of 129 adverse events were reported in the 100% ONS group and 95 in the 30% ONS group, of which 17 and 9 were considered serious, respectively. The serious adverse events required a short hospital stay to resolve minor hardware issues. The adverse events most frequently observed were local pain, impaired wound healing, neck stiffness, and hardware damage.
 

Low intensity stimulation may be best

“The main limitation of the study comes from the difficulty in defining the electrical dose, which was not constant across patients within each group, but individually adjusted depending on the perception of the ONS-induced paraesthesia,” Denys Fontaine, MD, and Michel Lanteri-Minet, MD, both from Université Cote D’Azur in France, wrote in an accompanying editorial.

Given that the primary outcome did not differ significantly between the treatment groups, the editorialists stated that “the lowest stimulation intensity that induces paraesthesia is sufficient to obtain an effect in the patients who respond. Increasing the electrical dose or intensity does not seem to bring better efficacy and might even induce discomfort (painful paraesthesia or shock-like sensations) that might substantially reduce the tolerance of this approach.”

While the trial did not provide convincing evidence of high intensity ONS in medically intractable chronic cluster headache, the editorialists are otherwise optimistic about the findings: “… considering the significant difference between baseline and the end of the randomised stimulation phase in both groups (about half of the patients showed a 50% decrease in attack frequency), the findings of this study support the favourable results of previous real-world studies, and indicate that a substantial proportion of patients with intractable chronic cluster headache, although not all, could have their condition substantially improved by ONS.” Dr. Fontaine and Dr. Lanteri-Minet added that they hope that “these data will help health authorities to recognise the efficacy of ONS and consider its approval for use in patients with intractable chronic cluster headache.”

Priorities for future research in this area should “focus on optimising stimulation protocols and disentangling the underlying mechanism of action,” Dr. Wilbrink and colleagues wrote.

The study was funded by the Spinoza 2009 Lifetime Scientific Research Achievement Premium, the Netherlands Organisation for Scientific Research, the Dutch Ministry of Health (as part of a national provisional reimbursement program for promising new treatments), the NutsOhra Foundation from the Dutch Health Insurance Companies, and an unrestricted grant from Medtronic, all to Dr. Ferrari.

When Jerry Gardner, MD, and a junior colleague received the acceptance notification for their abstract to be presented at Digestive Diseases Week® (DDW) 2021, a clause in the mandatory participation agreement gave Dr. Gardner pause. It required his colleague, as the submitting author, to completely accept any and all legal responsibility for any claims that might arise out of their presentation.

VladKol/Getty Images

The clause was a red flag to Dr. Gardner, president of Science for Organizations, a Mill Valley, Calif.–based consulting firm. The gastroenterologist and former head of the digestive diseases branch at the National Institute of Diabetes and Digestive and Kidney Diseases – who has made hundreds of presentations and had participated in DDW for 40 years – had never encountered such a broad indemnity clause.

This news organization investigated just how risky it is to make a presentation at a conference – more than a dozen professional societies were contacted. Although DDW declined to discuss its agreement, Houston health care attorney Rachel V. Rose said that Dr. Gardner was smart to be cautious. “I would not sign that agreement. I have never seen anything that broad and all encompassing,” she said.

The DDW requirement “means that participants must put themselves at great potential financial risk in order to present their work,” Dr. Gardner said. He added that he and his colleague would not have submitted an abstract had they known about the indemnification clause up front.

Dr. Gardner advised his colleague not to sign the DDW agreement. She did not, and both missed the meeting.
 

Speakers ‘have to be careful’

Dr. Gardner may be an exception. How many doctors are willing to forgo a presentation because of a concern about something in an agreement?

John Mandrola, MD, said he operates under the assumption that if he does not sign the agreement, then he won’t be able to give his presentation. He admits that he generally just signs them and is careful with his presentations. “I’ve never really paid much attention to them,” said Dr. Mandrola, a cardiac electrophysiologist in Louisville, Ky., and chief cardiology correspondent for Medscape.

Not everyone takes that approach. “I do think that people read them, but they also take them with a grain of salt,” said E. Magnus Ohman, MBBS, professor of medicine at Duke University, Durham, N.C. He said he’s pragmatic and regards the agreements as a necessary evil in a litigious nation. Speakers “have to be careful, obviously,” Dr. Ohman said in an interview.

Some argue that the requirements are not only fair but also understandable. David Johnson, MD, a former president of the American College of Gastroenterology, said he has never had questions about agreements for meetings he has been involved with. “To me, this is not anything other than standard operating procedure,” he said.

Presenters participate by invitation, noted Dr. Johnson, a professor of medicine and chief of gastroenterology at the Eastern Virginia Medical School, Norfolk, who is a contributor to this news organization. “If they stand up and do something egregious, I would concur that the society should not be liable,” he said.
 

Big asks, big secrecy

Even for those who generally agree with Dr. Johnson’s position, it may be hard to completely understand what’s at stake without an attorney.

Although many declined to discuss their policies, a handful of professional societies provided their agreements for review. In general, the agreements appear to offer broad protection and rights to the organizers and large liability exposure for the participants. Participants are charged with a wide range of responsibilities, such as ensuring against copyright violations and intellectual property infringement, and that they also agree to unlimited use of their presentations and their name and likeness.

The American Academy of Neurology, which held its meeting virtually in 2021, required participants to indemnify the organization against all “losses, expenses, damages, or liabilities,” including “reasonable attorneys’ fees.” Federal employees, however, could opt out of indemnification.

The American Society of Clinical Oncology said that it does not usually require indemnification from its meeting participants. However, a spokesperson noted that ASCO did require participants at its 2021 virtual meeting to abide by the terms of use for content posted to the ASCO website. Those terms specify that users agree to indemnify ASCO from damages related to posts.

The American Psychiatric Association said it does not require any indemnification but did not make its agreement available. The American Academy of Pediatrics also said it did not require indemnification but would not share its agreement.

An American Diabetes Association spokesperson said that “every association is different in what they ask or require from speakers,” but would not share its requirements.

The American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, the American College of Physicians, and the Endocrine Society all declined to participate.

The organizations that withheld agreements “probably don’t want anybody picking apart their documents,” said Kyle Claussen, CEO of the Resolve Physician Agency, which reviews employment contracts and other contracts for physicians. “The more fair a document, the more likely they would be willing to disclose that, because they have nothing to hide,” he said.
 

‘It’s all on you’

Requiring indemnification for any and all aspects of a presentation appears to be increasingly common, said the attorneys interviewed for this article. As organizations repackage meeting presentations for sale, they put the content further out into the world and for a longer period, which increases liability exposure.

“If I’m the attorney for DDW, I certainly think I’d want to have this in place,” said Mr. Claussen.

“It’s good business sense for them because it reduces their risk,” said Courtney H. A. Thompson, an attorney with Fredrikson & Byron in Minneapolis, who advises regional and national corporations and ad agencies on advertising, marketing, and trademark law. She also works with clients who speak at meetings and who thus encounter meeting agreements.

Ms. Thompson said indemnity clauses have become fairly common over the past decade, especially as more companies and organizations have sought to protect trademarks, copyrights, and intellectual property and to minimize litigation costs.

A conference organizer “doesn’t want a third party to come after them for intellectual property, privacy, or publicity right infringement based on the participation of the customer or, in this case, the speaker,” said Ms. Thompson.

The agreements also reflect America’s litigation-prone culture.

Dean Fanelli, a patent attorney in the Washington, D.C., office of Cooley LLP, said the agreements he’s been asked to sign as a speaker increasingly seem “overly lawyerly.”

Two decades ago, a speaker might have been asked to sign a paragraph or a one-page form. Now “they often look more like formalized legal agreements,” Mr. Fanelli told this news organization.

The DDW agreement, for instance, ran four pages and contained 21 detailed clauses.

The increasingly complicated agreements “are a little over the top,” said Mr. Fanelli. But as an attorney who works with clients in the pharmaceutical industry, he said he understands that meeting organizers want to protect their rights.

DDW’s main indemnification clause requires the participant to indemnify DDW and its agents, directors, and employees “against any and all claims, demands, causes of action, losses, damages, liabilities, costs, and expenses,” including attorneys’ fees “arising out of a claim, action or proceeding” based on a breach or “alleged breach” by the participant.

“You’re releasing this information to them and then you’re also giving them blanket indemnity back, saying if there’s any type of intellectual property violation on your end – if you’ve included any type of work that’s protected, if this causes any problems – it’s all on you,” said Mr. Claussen.
 

Other potential pitfalls

Aside from indemnification, participation agreements can contain other potentially worrisome clauses, including onerous terms for cancellation and reuse of content without remuneration.

DDW requires royalty-free licensing of a speaker’s content; the organization can reproduce it in perpetuity without royalties. Many organizations have such a clause in their agreements, including the AAN and the American College of Cardiology.

ASCO’s general authorization form for meeting participants requires that they assign to ASCO rights to their content “perpetually, irrevocably, worldwide and royalty free.” Participants can contact the organization if they seek to opt out, but it’s not clear whether ASCO grants such requests.

Participants in the upcoming American Heart Association annual meeting can deny permission to record their presentation. But if they allow recording and do not agree to assign all rights and copyright ownership to the AHA, the work will be excluded from publication in the meeting program, e-posters, and the meeting supplement in Circulation.

Mr. Claussen said granting royalty-free rights presents a conundrum. Having content reproduced in various formats “might be better for your personal brand,” but it’s not likely to result in any direct compensation and could increase liability exposure, he said.
 

How presenters must prepare

Mr. Claussen and Ms. Rose said speakers should be vigilant about their own rights and responsibilities, including ensuring that they do not violate copyrights or infringe on intellectual property rights.

“I would recommend that folks be meticulous about what is in their slide deck and materials,” said Ms. Thompson. He said that presenters should be sure they have the right to share material. Technologies crawl the internet seeking out infringement, which often leads to cease and desist letters from attorneys, she said.

It’s better to head off such a letter, Ms. Thompson said. “You need to defend it whether or not it’s a viable claim,” and that can be costly, she said.

Both Ms. Thompson and Mr. Fanelli also warn about disclosing anything that might be considered a trade secret. Many agreements prohibit presenters from engaging in commercial promotion, but if a talk includes information about a drug or device, the manufacturer will want to review the presentation before it’s made public, said Mr. Fanelli.

Many organizations prohibit attendees from photographing, recording, or tweeting at meetings and often require speakers to warn the audience about doing so. DDW goes further by holding presenters liable if someone violates the rule.

“That’s a huge problem,” said Dr. Mandrola. He noted that although it might be easy to police journalists attending a meeting, “it seems hard to enforce that rule amongst just regular attendees.”
 

Accept or negotiate?

Individuals who submit work to an organization might feel they must sign an agreement as is, especially if they are looking to advance their career or expand knowledge by presenting work at a meeting. But some attorneys said it might be possible to negotiate with meeting organizers.

“My personal opinion is that it never hurts to ask,” said Ms. Thompson. If she were speaking at a legal conference, she would mark up a contract and “see what happens.” The more times pushback is accepted – say, if it works with three out of five speaking engagements – the more it reduces overall liability exposure.

Mr. Fanelli, however, said that although he always reads over an agreement, he typically signs without negotiating. “I don’t usually worry about it because I’m just trying to talk at a particular seminar,” he said.

Prospective presenters “have to weigh that balance – do you want to talk at a seminar, or are you concerned about the legal issues?” said Mr. Fanelli.

If in doubt, talk with a lawyer.

“If you ever have a question on whether or not you should consult an attorney, the answer is always yes,” said Mr. Claussen. It would be “an ounce of prevention,” especially if it’s just a short agreement, he said.

Dr. Ohman, however, said that he believed “it would be fairly costly” and potentially unwieldy. “You can’t litigate everything in life,” he added.

As for Dr. Gardner, he said he would not be as likely to attend DDW in the future if he has to agree to cover any and all liability. “I can’t conceive of ever agreeing to personally indemnify DDW in order to make a presentation at the annual meeting,” he said.

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

When Jerry Gardner, MD, and a junior colleague received the acceptance notification for their abstract to be presented at Digestive Diseases Week® (DDW) 2021, a clause in the mandatory participation agreement gave Dr. Gardner pause. It required his colleague, as the submitting author, to completely accept any and all legal responsibility for any claims that might arise out of their presentation.

VladKol/Getty Images

The clause was a red flag to Dr. Gardner, president of Science for Organizations, a Mill Valley, Calif.–based consulting firm. The gastroenterologist and former head of the digestive diseases branch at the National Institute of Diabetes and Digestive and Kidney Diseases – who has made hundreds of presentations and had participated in DDW for 40 years – had never encountered such a broad indemnity clause.

This news organization investigated just how risky it is to make a presentation at a conference – more than a dozen professional societies were contacted. Although DDW declined to discuss its agreement, Houston health care attorney Rachel V. Rose said that Dr. Gardner was smart to be cautious. “I would not sign that agreement. I have never seen anything that broad and all encompassing,” she said.

The DDW requirement “means that participants must put themselves at great potential financial risk in order to present their work,” Dr. Gardner said. He added that he and his colleague would not have submitted an abstract had they known about the indemnification clause up front.

Dr. Gardner advised his colleague not to sign the DDW agreement. She did not, and both missed the meeting.
 

Speakers ‘have to be careful’

Dr. Gardner may be an exception. How many doctors are willing to forgo a presentation because of a concern about something in an agreement?

John Mandrola, MD, said he operates under the assumption that if he does not sign the agreement, then he won’t be able to give his presentation. He admits that he generally just signs them and is careful with his presentations. “I’ve never really paid much attention to them,” said Dr. Mandrola, a cardiac electrophysiologist in Louisville, Ky., and chief cardiology correspondent for Medscape.

Not everyone takes that approach. “I do think that people read them, but they also take them with a grain of salt,” said E. Magnus Ohman, MBBS, professor of medicine at Duke University, Durham, N.C. He said he’s pragmatic and regards the agreements as a necessary evil in a litigious nation. Speakers “have to be careful, obviously,” Dr. Ohman said in an interview.

Some argue that the requirements are not only fair but also understandable. David Johnson, MD, a former president of the American College of Gastroenterology, said he has never had questions about agreements for meetings he has been involved with. “To me, this is not anything other than standard operating procedure,” he said.

Presenters participate by invitation, noted Dr. Johnson, a professor of medicine and chief of gastroenterology at the Eastern Virginia Medical School, Norfolk, who is a contributor to this news organization. “If they stand up and do something egregious, I would concur that the society should not be liable,” he said.
 

Big asks, big secrecy

Even for those who generally agree with Dr. Johnson’s position, it may be hard to completely understand what’s at stake without an attorney.

Although many declined to discuss their policies, a handful of professional societies provided their agreements for review. In general, the agreements appear to offer broad protection and rights to the organizers and large liability exposure for the participants. Participants are charged with a wide range of responsibilities, such as ensuring against copyright violations and intellectual property infringement, and that they also agree to unlimited use of their presentations and their name and likeness.

The American Academy of Neurology, which held its meeting virtually in 2021, required participants to indemnify the organization against all “losses, expenses, damages, or liabilities,” including “reasonable attorneys’ fees.” Federal employees, however, could opt out of indemnification.

The American Society of Clinical Oncology said that it does not usually require indemnification from its meeting participants. However, a spokesperson noted that ASCO did require participants at its 2021 virtual meeting to abide by the terms of use for content posted to the ASCO website. Those terms specify that users agree to indemnify ASCO from damages related to posts.

The American Psychiatric Association said it does not require any indemnification but did not make its agreement available. The American Academy of Pediatrics also said it did not require indemnification but would not share its agreement.

An American Diabetes Association spokesperson said that “every association is different in what they ask or require from speakers,” but would not share its requirements.

The American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, the American College of Physicians, and the Endocrine Society all declined to participate.

The organizations that withheld agreements “probably don’t want anybody picking apart their documents,” said Kyle Claussen, CEO of the Resolve Physician Agency, which reviews employment contracts and other contracts for physicians. “The more fair a document, the more likely they would be willing to disclose that, because they have nothing to hide,” he said.
 

‘It’s all on you’

Requiring indemnification for any and all aspects of a presentation appears to be increasingly common, said the attorneys interviewed for this article. As organizations repackage meeting presentations for sale, they put the content further out into the world and for a longer period, which increases liability exposure.

“If I’m the attorney for DDW, I certainly think I’d want to have this in place,” said Mr. Claussen.

“It’s good business sense for them because it reduces their risk,” said Courtney H. A. Thompson, an attorney with Fredrikson & Byron in Minneapolis, who advises regional and national corporations and ad agencies on advertising, marketing, and trademark law. She also works with clients who speak at meetings and who thus encounter meeting agreements.

Ms. Thompson said indemnity clauses have become fairly common over the past decade, especially as more companies and organizations have sought to protect trademarks, copyrights, and intellectual property and to minimize litigation costs.

A conference organizer “doesn’t want a third party to come after them for intellectual property, privacy, or publicity right infringement based on the participation of the customer or, in this case, the speaker,” said Ms. Thompson.

The agreements also reflect America’s litigation-prone culture.

Dean Fanelli, a patent attorney in the Washington, D.C., office of Cooley LLP, said the agreements he’s been asked to sign as a speaker increasingly seem “overly lawyerly.”

Two decades ago, a speaker might have been asked to sign a paragraph or a one-page form. Now “they often look more like formalized legal agreements,” Mr. Fanelli told this news organization.

The DDW agreement, for instance, ran four pages and contained 21 detailed clauses.

The increasingly complicated agreements “are a little over the top,” said Mr. Fanelli. But as an attorney who works with clients in the pharmaceutical industry, he said he understands that meeting organizers want to protect their rights.

DDW’s main indemnification clause requires the participant to indemnify DDW and its agents, directors, and employees “against any and all claims, demands, causes of action, losses, damages, liabilities, costs, and expenses,” including attorneys’ fees “arising out of a claim, action or proceeding” based on a breach or “alleged breach” by the participant.

“You’re releasing this information to them and then you’re also giving them blanket indemnity back, saying if there’s any type of intellectual property violation on your end – if you’ve included any type of work that’s protected, if this causes any problems – it’s all on you,” said Mr. Claussen.
 

Other potential pitfalls

Aside from indemnification, participation agreements can contain other potentially worrisome clauses, including onerous terms for cancellation and reuse of content without remuneration.

DDW requires royalty-free licensing of a speaker’s content; the organization can reproduce it in perpetuity without royalties. Many organizations have such a clause in their agreements, including the AAN and the American College of Cardiology.

ASCO’s general authorization form for meeting participants requires that they assign to ASCO rights to their content “perpetually, irrevocably, worldwide and royalty free.” Participants can contact the organization if they seek to opt out, but it’s not clear whether ASCO grants such requests.

Participants in the upcoming American Heart Association annual meeting can deny permission to record their presentation. But if they allow recording and do not agree to assign all rights and copyright ownership to the AHA, the work will be excluded from publication in the meeting program, e-posters, and the meeting supplement in Circulation.

Mr. Claussen said granting royalty-free rights presents a conundrum. Having content reproduced in various formats “might be better for your personal brand,” but it’s not likely to result in any direct compensation and could increase liability exposure, he said.
 

How presenters must prepare

Mr. Claussen and Ms. Rose said speakers should be vigilant about their own rights and responsibilities, including ensuring that they do not violate copyrights or infringe on intellectual property rights.

“I would recommend that folks be meticulous about what is in their slide deck and materials,” said Ms. Thompson. He said that presenters should be sure they have the right to share material. Technologies crawl the internet seeking out infringement, which often leads to cease and desist letters from attorneys, she said.

It’s better to head off such a letter, Ms. Thompson said. “You need to defend it whether or not it’s a viable claim,” and that can be costly, she said.

Both Ms. Thompson and Mr. Fanelli also warn about disclosing anything that might be considered a trade secret. Many agreements prohibit presenters from engaging in commercial promotion, but if a talk includes information about a drug or device, the manufacturer will want to review the presentation before it’s made public, said Mr. Fanelli.

Many organizations prohibit attendees from photographing, recording, or tweeting at meetings and often require speakers to warn the audience about doing so. DDW goes further by holding presenters liable if someone violates the rule.

“That’s a huge problem,” said Dr. Mandrola. He noted that although it might be easy to police journalists attending a meeting, “it seems hard to enforce that rule amongst just regular attendees.”
 

Accept or negotiate?

Individuals who submit work to an organization might feel they must sign an agreement as is, especially if they are looking to advance their career or expand knowledge by presenting work at a meeting. But some attorneys said it might be possible to negotiate with meeting organizers.

“My personal opinion is that it never hurts to ask,” said Ms. Thompson. If she were speaking at a legal conference, she would mark up a contract and “see what happens.” The more times pushback is accepted – say, if it works with three out of five speaking engagements – the more it reduces overall liability exposure.

Mr. Fanelli, however, said that although he always reads over an agreement, he typically signs without negotiating. “I don’t usually worry about it because I’m just trying to talk at a particular seminar,” he said.

Prospective presenters “have to weigh that balance – do you want to talk at a seminar, or are you concerned about the legal issues?” said Mr. Fanelli.

If in doubt, talk with a lawyer.

“If you ever have a question on whether or not you should consult an attorney, the answer is always yes,” said Mr. Claussen. It would be “an ounce of prevention,” especially if it’s just a short agreement, he said.

Dr. Ohman, however, said that he believed “it would be fairly costly” and potentially unwieldy. “You can’t litigate everything in life,” he added.

As for Dr. Gardner, he said he would not be as likely to attend DDW in the future if he has to agree to cover any and all liability. “I can’t conceive of ever agreeing to personally indemnify DDW in order to make a presentation at the annual meeting,” he said.

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

When Jerry Gardner, MD, and a junior colleague received the acceptance notification for their abstract to be presented at Digestive Diseases Week® (DDW) 2021, a clause in the mandatory participation agreement gave Dr. Gardner pause. It required his colleague, as the submitting author, to completely accept any and all legal responsibility for any claims that might arise out of their presentation.

VladKol/Getty Images

The clause was a red flag to Dr. Gardner, president of Science for Organizations, a Mill Valley, Calif.–based consulting firm. The gastroenterologist and former head of the digestive diseases branch at the National Institute of Diabetes and Digestive and Kidney Diseases – who has made hundreds of presentations and had participated in DDW for 40 years – had never encountered such a broad indemnity clause.

This news organization investigated just how risky it is to make a presentation at a conference – more than a dozen professional societies were contacted. Although DDW declined to discuss its agreement, Houston health care attorney Rachel V. Rose said that Dr. Gardner was smart to be cautious. “I would not sign that agreement. I have never seen anything that broad and all encompassing,” she said.

The DDW requirement “means that participants must put themselves at great potential financial risk in order to present their work,” Dr. Gardner said. He added that he and his colleague would not have submitted an abstract had they known about the indemnification clause up front.

Dr. Gardner advised his colleague not to sign the DDW agreement. She did not, and both missed the meeting.
 

Speakers ‘have to be careful’

Dr. Gardner may be an exception. How many doctors are willing to forgo a presentation because of a concern about something in an agreement?

John Mandrola, MD, said he operates under the assumption that if he does not sign the agreement, then he won’t be able to give his presentation. He admits that he generally just signs them and is careful with his presentations. “I’ve never really paid much attention to them,” said Dr. Mandrola, a cardiac electrophysiologist in Louisville, Ky., and chief cardiology correspondent for Medscape.

Not everyone takes that approach. “I do think that people read them, but they also take them with a grain of salt,” said E. Magnus Ohman, MBBS, professor of medicine at Duke University, Durham, N.C. He said he’s pragmatic and regards the agreements as a necessary evil in a litigious nation. Speakers “have to be careful, obviously,” Dr. Ohman said in an interview.

Some argue that the requirements are not only fair but also understandable. David Johnson, MD, a former president of the American College of Gastroenterology, said he has never had questions about agreements for meetings he has been involved with. “To me, this is not anything other than standard operating procedure,” he said.

Presenters participate by invitation, noted Dr. Johnson, a professor of medicine and chief of gastroenterology at the Eastern Virginia Medical School, Norfolk, who is a contributor to this news organization. “If they stand up and do something egregious, I would concur that the society should not be liable,” he said.
 

Big asks, big secrecy

Even for those who generally agree with Dr. Johnson’s position, it may be hard to completely understand what’s at stake without an attorney.

Although many declined to discuss their policies, a handful of professional societies provided their agreements for review. In general, the agreements appear to offer broad protection and rights to the organizers and large liability exposure for the participants. Participants are charged with a wide range of responsibilities, such as ensuring against copyright violations and intellectual property infringement, and that they also agree to unlimited use of their presentations and their name and likeness.

The American Academy of Neurology, which held its meeting virtually in 2021, required participants to indemnify the organization against all “losses, expenses, damages, or liabilities,” including “reasonable attorneys’ fees.” Federal employees, however, could opt out of indemnification.

The American Society of Clinical Oncology said that it does not usually require indemnification from its meeting participants. However, a spokesperson noted that ASCO did require participants at its 2021 virtual meeting to abide by the terms of use for content posted to the ASCO website. Those terms specify that users agree to indemnify ASCO from damages related to posts.

The American Psychiatric Association said it does not require any indemnification but did not make its agreement available. The American Academy of Pediatrics also said it did not require indemnification but would not share its agreement.

An American Diabetes Association spokesperson said that “every association is different in what they ask or require from speakers,” but would not share its requirements.

The American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, the American College of Physicians, and the Endocrine Society all declined to participate.

The organizations that withheld agreements “probably don’t want anybody picking apart their documents,” said Kyle Claussen, CEO of the Resolve Physician Agency, which reviews employment contracts and other contracts for physicians. “The more fair a document, the more likely they would be willing to disclose that, because they have nothing to hide,” he said.
 

‘It’s all on you’

Requiring indemnification for any and all aspects of a presentation appears to be increasingly common, said the attorneys interviewed for this article. As organizations repackage meeting presentations for sale, they put the content further out into the world and for a longer period, which increases liability exposure.

“If I’m the attorney for DDW, I certainly think I’d want to have this in place,” said Mr. Claussen.

“It’s good business sense for them because it reduces their risk,” said Courtney H. A. Thompson, an attorney with Fredrikson & Byron in Minneapolis, who advises regional and national corporations and ad agencies on advertising, marketing, and trademark law. She also works with clients who speak at meetings and who thus encounter meeting agreements.

Ms. Thompson said indemnity clauses have become fairly common over the past decade, especially as more companies and organizations have sought to protect trademarks, copyrights, and intellectual property and to minimize litigation costs.

A conference organizer “doesn’t want a third party to come after them for intellectual property, privacy, or publicity right infringement based on the participation of the customer or, in this case, the speaker,” said Ms. Thompson.

The agreements also reflect America’s litigation-prone culture.

Dean Fanelli, a patent attorney in the Washington, D.C., office of Cooley LLP, said the agreements he’s been asked to sign as a speaker increasingly seem “overly lawyerly.”

Two decades ago, a speaker might have been asked to sign a paragraph or a one-page form. Now “they often look more like formalized legal agreements,” Mr. Fanelli told this news organization.

The DDW agreement, for instance, ran four pages and contained 21 detailed clauses.

The increasingly complicated agreements “are a little over the top,” said Mr. Fanelli. But as an attorney who works with clients in the pharmaceutical industry, he said he understands that meeting organizers want to protect their rights.

DDW’s main indemnification clause requires the participant to indemnify DDW and its agents, directors, and employees “against any and all claims, demands, causes of action, losses, damages, liabilities, costs, and expenses,” including attorneys’ fees “arising out of a claim, action or proceeding” based on a breach or “alleged breach” by the participant.

“You’re releasing this information to them and then you’re also giving them blanket indemnity back, saying if there’s any type of intellectual property violation on your end – if you’ve included any type of work that’s protected, if this causes any problems – it’s all on you,” said Mr. Claussen.
 

Other potential pitfalls

Aside from indemnification, participation agreements can contain other potentially worrisome clauses, including onerous terms for cancellation and reuse of content without remuneration.

DDW requires royalty-free licensing of a speaker’s content; the organization can reproduce it in perpetuity without royalties. Many organizations have such a clause in their agreements, including the AAN and the American College of Cardiology.

ASCO’s general authorization form for meeting participants requires that they assign to ASCO rights to their content “perpetually, irrevocably, worldwide and royalty free.” Participants can contact the organization if they seek to opt out, but it’s not clear whether ASCO grants such requests.

Participants in the upcoming American Heart Association annual meeting can deny permission to record their presentation. But if they allow recording and do not agree to assign all rights and copyright ownership to the AHA, the work will be excluded from publication in the meeting program, e-posters, and the meeting supplement in Circulation.

Mr. Claussen said granting royalty-free rights presents a conundrum. Having content reproduced in various formats “might be better for your personal brand,” but it’s not likely to result in any direct compensation and could increase liability exposure, he said.
 

How presenters must prepare

Mr. Claussen and Ms. Rose said speakers should be vigilant about their own rights and responsibilities, including ensuring that they do not violate copyrights or infringe on intellectual property rights.

“I would recommend that folks be meticulous about what is in their slide deck and materials,” said Ms. Thompson. He said that presenters should be sure they have the right to share material. Technologies crawl the internet seeking out infringement, which often leads to cease and desist letters from attorneys, she said.

It’s better to head off such a letter, Ms. Thompson said. “You need to defend it whether or not it’s a viable claim,” and that can be costly, she said.

Both Ms. Thompson and Mr. Fanelli also warn about disclosing anything that might be considered a trade secret. Many agreements prohibit presenters from engaging in commercial promotion, but if a talk includes information about a drug or device, the manufacturer will want to review the presentation before it’s made public, said Mr. Fanelli.

Many organizations prohibit attendees from photographing, recording, or tweeting at meetings and often require speakers to warn the audience about doing so. DDW goes further by holding presenters liable if someone violates the rule.

“That’s a huge problem,” said Dr. Mandrola. He noted that although it might be easy to police journalists attending a meeting, “it seems hard to enforce that rule amongst just regular attendees.”
 

Accept or negotiate?

Individuals who submit work to an organization might feel they must sign an agreement as is, especially if they are looking to advance their career or expand knowledge by presenting work at a meeting. But some attorneys said it might be possible to negotiate with meeting organizers.

“My personal opinion is that it never hurts to ask,” said Ms. Thompson. If she were speaking at a legal conference, she would mark up a contract and “see what happens.” The more times pushback is accepted – say, if it works with three out of five speaking engagements – the more it reduces overall liability exposure.

Mr. Fanelli, however, said that although he always reads over an agreement, he typically signs without negotiating. “I don’t usually worry about it because I’m just trying to talk at a particular seminar,” he said.

Prospective presenters “have to weigh that balance – do you want to talk at a seminar, or are you concerned about the legal issues?” said Mr. Fanelli.

If in doubt, talk with a lawyer.

“If you ever have a question on whether or not you should consult an attorney, the answer is always yes,” said Mr. Claussen. It would be “an ounce of prevention,” especially if it’s just a short agreement, he said.

Dr. Ohman, however, said that he believed “it would be fairly costly” and potentially unwieldy. “You can’t litigate everything in life,” he added.

As for Dr. Gardner, he said he would not be as likely to attend DDW in the future if he has to agree to cover any and all liability. “I can’t conceive of ever agreeing to personally indemnify DDW in order to make a presentation at the annual meeting,” he said.

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

A dyadic telehealth intervention to help people with dementia and their caregivers can achieve outcomes similar to those of traditional, in-person approaches. The program combines information, education, and skills training to help participants overcome specific challenges.

“It focuses on individualized problem solving and is tailored to the needs of the person. The focus is not just on educating caregivers, but working on strategies to maintain independence in the person with dementia and support them to remain active and engaged,” said Kate Laver, PhD, who presented the study at the annual meeting of the Alzheimer’s Association International Conference. Dr. Laver is an associate professor in the College of Medicine and Public Health at Flinders University in Adelaide, South Australia.

The program is called Care of Persons with Dementia in Their Environments (COPE), and has previously been demonstrated to improve outcomes when conducted through in-person home visits. Over a maximum of ten sessions in 4 months, COPE employs occupational therapists and individuals with nursing skills to identify environmental stressors that can be modified to reduce sensory, physical, and cognitive demands. It also looks for comorbidities in the person with dementia that could be contributing to poor functioning. The goal of COPE is to encourage the person with dementia to reengage in daily activities, and to reduce caregiver burden as a result.

In a 2020 study, Dr. Laver and colleagues showed that COPE is noninferior when delivered by telehealth compared with in-person delivery. They randomized 63 caregiver-patient dyads to telehealth or home visit delivery of the COPE program. Sixty percent of the persons with dementia were male, and the mean caregiver time was 32 months.

Similar improvements in outcomes were seen in both groups, with no statistically significant differences for the primary outcome of change in Caregiver Mastery Index score at 4 months (mean difference, 0.09; 95% confidence interval, –1.26 to 1.45). Similar changes were also seen in the Perceived Change Scale, which is a 13-item caregiver questionnaire that covers day-to-day care challenges, including feeling overwhelmed or upset, sleeping patterns, and availability of personal time.

Not surprisingly, telehealth implementation led to reduced mean travel time (77.2 minutes vs. 255.9 minutes; P < .0001). The face-to-face time was shorter in the telehealth group (308 vs. 337 minutes), though the difference was not statistically significant. Dr. Laver noted that the consent rate was high at 75%, but there were some missed sessions.
 

Lessons learned

During the presentation, Dr. Laver emphasized some lessons learned from conversion to a telehealth model. These included providing a tablet and stand on loan, a user guide with pictures, and an initial on-site training session. The first two sessions were conducted on site to do an in-person demonstration and to assess the participants and the home environment.

She noted that it was important to have an IT support person on call to help participants use the provided tablet if needed, though this was rarely used.

“Although few people (at the time) had their own devices, they were able to quickly master videoconferencing. We felt that it was important to ensure that the first couple of consultations were in person – this enabled the therapist to develop rapport, practice use of videoconferencing, and get a good idea of the person’s environment and relationship with the person with dementia,” said Dr. Laver.

She noted that telehealth can be more efficient, and even preferred, during times like the COVID-19 pandemic, as well as in rural settings. But home visits will always be needed. “They are important for developing rapport and enabling a comprehensive assessment of the person with dementia, relationships, and environment. They are also preferred by some caregivers,” said Dr. Laver.

The demonstration of equivalence to in-person delivery was welcome, said Ingo Kilimann, MD, who comoderated the session where Dr. Laver presented. “We have to bring help to the families where they are, and not just tell them where they can get the help, because some people are just not able to actually come to some specialists’ centers. So it’s very important information that it does work,” said Dr. Kilimann, who is a dementia neurologist and head of the memory clinic at the The German Center for Neurodegenerative Diseases in Bonn.

He added that mixing of on-site and remote sessions is a good model. “I think that is the way to be most effective – to have someone in person at the person with dementia’s house, and then have online support for the rest of the time, and then it can be as successful as a total in-person intervention,” said Dr. Kilimann.

Dr. Laver had no relevant financial disclosures.

A dyadic telehealth intervention to help people with dementia and their caregivers can achieve outcomes similar to those of traditional, in-person approaches. The program combines information, education, and skills training to help participants overcome specific challenges.

“It focuses on individualized problem solving and is tailored to the needs of the person. The focus is not just on educating caregivers, but working on strategies to maintain independence in the person with dementia and support them to remain active and engaged,” said Kate Laver, PhD, who presented the study at the annual meeting of the Alzheimer’s Association International Conference. Dr. Laver is an associate professor in the College of Medicine and Public Health at Flinders University in Adelaide, South Australia.

The program is called Care of Persons with Dementia in Their Environments (COPE), and has previously been demonstrated to improve outcomes when conducted through in-person home visits. Over a maximum of ten sessions in 4 months, COPE employs occupational therapists and individuals with nursing skills to identify environmental stressors that can be modified to reduce sensory, physical, and cognitive demands. It also looks for comorbidities in the person with dementia that could be contributing to poor functioning. The goal of COPE is to encourage the person with dementia to reengage in daily activities, and to reduce caregiver burden as a result.

In a 2020 study, Dr. Laver and colleagues showed that COPE is noninferior when delivered by telehealth compared with in-person delivery. They randomized 63 caregiver-patient dyads to telehealth or home visit delivery of the COPE program. Sixty percent of the persons with dementia were male, and the mean caregiver time was 32 months.

Similar improvements in outcomes were seen in both groups, with no statistically significant differences for the primary outcome of change in Caregiver Mastery Index score at 4 months (mean difference, 0.09; 95% confidence interval, –1.26 to 1.45). Similar changes were also seen in the Perceived Change Scale, which is a 13-item caregiver questionnaire that covers day-to-day care challenges, including feeling overwhelmed or upset, sleeping patterns, and availability of personal time.

Not surprisingly, telehealth implementation led to reduced mean travel time (77.2 minutes vs. 255.9 minutes; P < .0001). The face-to-face time was shorter in the telehealth group (308 vs. 337 minutes), though the difference was not statistically significant. Dr. Laver noted that the consent rate was high at 75%, but there were some missed sessions.
 

Lessons learned

During the presentation, Dr. Laver emphasized some lessons learned from conversion to a telehealth model. These included providing a tablet and stand on loan, a user guide with pictures, and an initial on-site training session. The first two sessions were conducted on site to do an in-person demonstration and to assess the participants and the home environment.

She noted that it was important to have an IT support person on call to help participants use the provided tablet if needed, though this was rarely used.

“Although few people (at the time) had their own devices, they were able to quickly master videoconferencing. We felt that it was important to ensure that the first couple of consultations were in person – this enabled the therapist to develop rapport, practice use of videoconferencing, and get a good idea of the person’s environment and relationship with the person with dementia,” said Dr. Laver.

She noted that telehealth can be more efficient, and even preferred, during times like the COVID-19 pandemic, as well as in rural settings. But home visits will always be needed. “They are important for developing rapport and enabling a comprehensive assessment of the person with dementia, relationships, and environment. They are also preferred by some caregivers,” said Dr. Laver.

The demonstration of equivalence to in-person delivery was welcome, said Ingo Kilimann, MD, who comoderated the session where Dr. Laver presented. “We have to bring help to the families where they are, and not just tell them where they can get the help, because some people are just not able to actually come to some specialists’ centers. So it’s very important information that it does work,” said Dr. Kilimann, who is a dementia neurologist and head of the memory clinic at the The German Center for Neurodegenerative Diseases in Bonn.

He added that mixing of on-site and remote sessions is a good model. “I think that is the way to be most effective – to have someone in person at the person with dementia’s house, and then have online support for the rest of the time, and then it can be as successful as a total in-person intervention,” said Dr. Kilimann.

Dr. Laver had no relevant financial disclosures.

A dyadic telehealth intervention to help people with dementia and their caregivers can achieve outcomes similar to those of traditional, in-person approaches. The program combines information, education, and skills training to help participants overcome specific challenges.

“It focuses on individualized problem solving and is tailored to the needs of the person. The focus is not just on educating caregivers, but working on strategies to maintain independence in the person with dementia and support them to remain active and engaged,” said Kate Laver, PhD, who presented the study at the annual meeting of the Alzheimer’s Association International Conference. Dr. Laver is an associate professor in the College of Medicine and Public Health at Flinders University in Adelaide, South Australia.

The program is called Care of Persons with Dementia in Their Environments (COPE), and has previously been demonstrated to improve outcomes when conducted through in-person home visits. Over a maximum of ten sessions in 4 months, COPE employs occupational therapists and individuals with nursing skills to identify environmental stressors that can be modified to reduce sensory, physical, and cognitive demands. It also looks for comorbidities in the person with dementia that could be contributing to poor functioning. The goal of COPE is to encourage the person with dementia to reengage in daily activities, and to reduce caregiver burden as a result.

In a 2020 study, Dr. Laver and colleagues showed that COPE is noninferior when delivered by telehealth compared with in-person delivery. They randomized 63 caregiver-patient dyads to telehealth or home visit delivery of the COPE program. Sixty percent of the persons with dementia were male, and the mean caregiver time was 32 months.

Similar improvements in outcomes were seen in both groups, with no statistically significant differences for the primary outcome of change in Caregiver Mastery Index score at 4 months (mean difference, 0.09; 95% confidence interval, –1.26 to 1.45). Similar changes were also seen in the Perceived Change Scale, which is a 13-item caregiver questionnaire that covers day-to-day care challenges, including feeling overwhelmed or upset, sleeping patterns, and availability of personal time.

Not surprisingly, telehealth implementation led to reduced mean travel time (77.2 minutes vs. 255.9 minutes; P < .0001). The face-to-face time was shorter in the telehealth group (308 vs. 337 minutes), though the difference was not statistically significant. Dr. Laver noted that the consent rate was high at 75%, but there were some missed sessions.
 

Lessons learned

During the presentation, Dr. Laver emphasized some lessons learned from conversion to a telehealth model. These included providing a tablet and stand on loan, a user guide with pictures, and an initial on-site training session. The first two sessions were conducted on site to do an in-person demonstration and to assess the participants and the home environment.

She noted that it was important to have an IT support person on call to help participants use the provided tablet if needed, though this was rarely used.

“Although few people (at the time) had their own devices, they were able to quickly master videoconferencing. We felt that it was important to ensure that the first couple of consultations were in person – this enabled the therapist to develop rapport, practice use of videoconferencing, and get a good idea of the person’s environment and relationship with the person with dementia,” said Dr. Laver.

She noted that telehealth can be more efficient, and even preferred, during times like the COVID-19 pandemic, as well as in rural settings. But home visits will always be needed. “They are important for developing rapport and enabling a comprehensive assessment of the person with dementia, relationships, and environment. They are also preferred by some caregivers,” said Dr. Laver.

The demonstration of equivalence to in-person delivery was welcome, said Ingo Kilimann, MD, who comoderated the session where Dr. Laver presented. “We have to bring help to the families where they are, and not just tell them where they can get the help, because some people are just not able to actually come to some specialists’ centers. So it’s very important information that it does work,” said Dr. Kilimann, who is a dementia neurologist and head of the memory clinic at the The German Center for Neurodegenerative Diseases in Bonn.

He added that mixing of on-site and remote sessions is a good model. “I think that is the way to be most effective – to have someone in person at the person with dementia’s house, and then have online support for the rest of the time, and then it can be as successful as a total in-person intervention,” said Dr. Kilimann.

Dr. Laver had no relevant financial disclosures.

When a child presents with café au lait macules, when is genetic testing for neurofibromatosis type 1 (NF1) advised?

According to Peter Kannu, MB, ChB, DCH, PhD, a definitive diagnosis of NF1 can be made in most children using National Institutes of Health criteria published in 1988, which include the presence of two of the following:

• Six or more café au lait macules over 5 mm in diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals
• Two or more neurofibromas of any type or one plexiform neurofibroma
• Freckling in the axillary or inguinal regions
• Two or more Lisch nodules
• Optic glioma
• A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis
• Having a first-degree relative with NF1

For example, in the case of an 8-year-old child who presents with multiple café au lait macules, axillary and inguinal freckling, Lisch nodules, and an optic glioma, “the diagnosis is secure and genetic testing is not going to change clinical management or surveillance,” Dr. Kannu, a clinical geneticist at the University of Alberta, Edmonton, said during the annual meeting of the Society for Pediatric Dermatology. “The only reason for genetic testing in this situation is so that we know the mutation in order to inform reproductive risk counseling in the future.”

However, while a diagnosis of NF1 may be suspected in a 6- to 12-month-old presenting with only café au lait macules, “the diagnosis is not secure because the clinical criteria cannot be met. In this situation, a genetic test can speed up the diagnosis,” he added. “Or, if the test is negative, it can decrease your suspicion for NF1 and you wouldn’t refer the child on to an NF1 screening clinic for intensive surveillance.”

Dr. Kannu based his remarks largely on his 5 years working at the multidisciplinary Genodermatoses Clinic at the Hospital for Sick Children, Toronto. Founded in 2015, the clinic is a “one-stop shop” designed to reduce the wait time for diagnosis and management and the number of hospital visits. The team – composed of a dermatologist, medical geneticist, genetic counselor, residents, and fellows – meets to review the charts of each patient before the appointment, and decides on a preliminary management plan. All children are then seen by one of the trainees in the clinic who devises a differential diagnosis that is presented to staff physicians, at which point genetic testing is decided on. A genetics counselor handles follow-up for those who do have genetic testing.

In 2018, Dr. Kannu and colleagues conducted an informal review of 300 patients who had been seen in the clinic. The mean age at referral was about 6 years, 51% were female, and the top three referral sources were pediatricians (51%), dermatologists (18%), and family physicians (18%). Of the 300 children, 84 (28%) were confirmed to have a diagnosis of NF1. Two patients were diagnosed with NF2 and 5% of the total cohort was diagnosed with mosaic NF1 (MNF1), “which is higher than what you would expect based on the incidence of MNF1 in the literature,” he said.

He separates genetic tests for NF1 into one of two categories: Conventional testing, which is offered by most labs in North America; and comprehensive testing, which is offered by the medical genomics lab at the University of Alabama at Birmingham. Conventional testing focuses on the exons, “the protein coding regions of the gene where most of the mutations lie,” he said. “The test also sequences about 20 base pairs or so of the intron exon boundary and may pick up some intronic mutations. But this test will not detect anything that’s hidden deep in the intronic region.”

Comprehensive testing, meanwhile, checks for mutations in both introns and exons.

Dr. Kannu and colleagues published a case of a paraspinal ganglioneuroma in the proband of a large family with mild cutaneous manifestations of NF1, carrying a deep NF1 intronic mutation. “The clinicians were suspicious that this was NF1, rightly so. The diagnosis was only confirmed after we sent samples to the University of Alabama lab where the deep intronic mutation was found,” he said.

The other situation where conventional genetic testing may be negative is in the case of MNF1, where there “are mutations in some cells but not all cells,” Dr. Kannu explained. “It may only be present in the melanocytes of the skin but not present in the lymphocytes in the blood. Mosaicism is characterized by the regional distribution of pigmentary or other NF1 associated findings. Mosaicism may be detected in the blood if it’s more than 20%. Anything less than that is not detected with conventional genetic testing using DNA from blood and requires extracting DNA from a punch biopsy sample of a café au lait macule.”

The differential diagnosis of café au lait macules includes several conditions associated mutations in the RAS pathway. “Neurofibromin is a key signal of molecules which regulates the activation of RAS,” Dr. Kannu said. “A close binding partner of NF1 is SPRED 1. We know that mutations in this gene cause Legius syndrome, a condition which presents with multiple café au lait macules.”

Two key receptors in the RAS pathway include EGFR and KITL, he continued. Mutations in the EGFR receptor cause a rare condition known as neonatal skin and bowel disease, while mutations in the KITL receptor cause familial progressive hyperpigmentation with or without hypopigmentation. “Looking into the pathway and focusing downstream of RAS, we have genes such as RAF and CBL, which are mutated in Noonan syndrome,” he said. “Further along in the pathway you have mutations in PTEN, which cause Cowden syndrome, and mutations in TSC1 and TSC2, which cause tuberous sclerosis. Mutations in any of these genes can also present with café au lait macules.”

During a question-and-answer session Dr. Kannu was asked to comment about revised diagnostic criteria for NF1 based on an international consensus recommendation, such as changes in the eye that require a formal opthalmologic examination, which were recently published.

“We are understanding more about the phenotype,” he said. “If you fulfill diagnostic criteria for NF1, the main reasons for doing genetic testing are, one, if the family wants to know that information, and two, it informs our reproductive risk counseling. Genotype-phenotype correlations do exist in NF1 but they’re not very robust, so that information is not clinically useful.”

Dr. Kannu disclosed that he has been an advisory board member for Ipsen, Novartis, and Alexion. He has also been a primary investigator for QED and Clementia.

[email protected]

When a child presents with café au lait macules, when is genetic testing for neurofibromatosis type 1 (NF1) advised?

According to Peter Kannu, MB, ChB, DCH, PhD, a definitive diagnosis of NF1 can be made in most children using National Institutes of Health criteria published in 1988, which include the presence of two of the following:

• Six or more café au lait macules over 5 mm in diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals
• Two or more neurofibromas of any type or one plexiform neurofibroma
• Freckling in the axillary or inguinal regions
• Two or more Lisch nodules
• Optic glioma
• A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis
• Having a first-degree relative with NF1

For example, in the case of an 8-year-old child who presents with multiple café au lait macules, axillary and inguinal freckling, Lisch nodules, and an optic glioma, “the diagnosis is secure and genetic testing is not going to change clinical management or surveillance,” Dr. Kannu, a clinical geneticist at the University of Alberta, Edmonton, said during the annual meeting of the Society for Pediatric Dermatology. “The only reason for genetic testing in this situation is so that we know the mutation in order to inform reproductive risk counseling in the future.”

However, while a diagnosis of NF1 may be suspected in a 6- to 12-month-old presenting with only café au lait macules, “the diagnosis is not secure because the clinical criteria cannot be met. In this situation, a genetic test can speed up the diagnosis,” he added. “Or, if the test is negative, it can decrease your suspicion for NF1 and you wouldn’t refer the child on to an NF1 screening clinic for intensive surveillance.”

Dr. Kannu based his remarks largely on his 5 years working at the multidisciplinary Genodermatoses Clinic at the Hospital for Sick Children, Toronto. Founded in 2015, the clinic is a “one-stop shop” designed to reduce the wait time for diagnosis and management and the number of hospital visits. The team – composed of a dermatologist, medical geneticist, genetic counselor, residents, and fellows – meets to review the charts of each patient before the appointment, and decides on a preliminary management plan. All children are then seen by one of the trainees in the clinic who devises a differential diagnosis that is presented to staff physicians, at which point genetic testing is decided on. A genetics counselor handles follow-up for those who do have genetic testing.

In 2018, Dr. Kannu and colleagues conducted an informal review of 300 patients who had been seen in the clinic. The mean age at referral was about 6 years, 51% were female, and the top three referral sources were pediatricians (51%), dermatologists (18%), and family physicians (18%). Of the 300 children, 84 (28%) were confirmed to have a diagnosis of NF1. Two patients were diagnosed with NF2 and 5% of the total cohort was diagnosed with mosaic NF1 (MNF1), “which is higher than what you would expect based on the incidence of MNF1 in the literature,” he said.

He separates genetic tests for NF1 into one of two categories: Conventional testing, which is offered by most labs in North America; and comprehensive testing, which is offered by the medical genomics lab at the University of Alabama at Birmingham. Conventional testing focuses on the exons, “the protein coding regions of the gene where most of the mutations lie,” he said. “The test also sequences about 20 base pairs or so of the intron exon boundary and may pick up some intronic mutations. But this test will not detect anything that’s hidden deep in the intronic region.”

Comprehensive testing, meanwhile, checks for mutations in both introns and exons.

Dr. Kannu and colleagues published a case of a paraspinal ganglioneuroma in the proband of a large family with mild cutaneous manifestations of NF1, carrying a deep NF1 intronic mutation. “The clinicians were suspicious that this was NF1, rightly so. The diagnosis was only confirmed after we sent samples to the University of Alabama lab where the deep intronic mutation was found,” he said.

The other situation where conventional genetic testing may be negative is in the case of MNF1, where there “are mutations in some cells but not all cells,” Dr. Kannu explained. “It may only be present in the melanocytes of the skin but not present in the lymphocytes in the blood. Mosaicism is characterized by the regional distribution of pigmentary or other NF1 associated findings. Mosaicism may be detected in the blood if it’s more than 20%. Anything less than that is not detected with conventional genetic testing using DNA from blood and requires extracting DNA from a punch biopsy sample of a café au lait macule.”

The differential diagnosis of café au lait macules includes several conditions associated mutations in the RAS pathway. “Neurofibromin is a key signal of molecules which regulates the activation of RAS,” Dr. Kannu said. “A close binding partner of NF1 is SPRED 1. We know that mutations in this gene cause Legius syndrome, a condition which presents with multiple café au lait macules.”

Two key receptors in the RAS pathway include EGFR and KITL, he continued. Mutations in the EGFR receptor cause a rare condition known as neonatal skin and bowel disease, while mutations in the KITL receptor cause familial progressive hyperpigmentation with or without hypopigmentation. “Looking into the pathway and focusing downstream of RAS, we have genes such as RAF and CBL, which are mutated in Noonan syndrome,” he said. “Further along in the pathway you have mutations in PTEN, which cause Cowden syndrome, and mutations in TSC1 and TSC2, which cause tuberous sclerosis. Mutations in any of these genes can also present with café au lait macules.”

During a question-and-answer session Dr. Kannu was asked to comment about revised diagnostic criteria for NF1 based on an international consensus recommendation, such as changes in the eye that require a formal opthalmologic examination, which were recently published.

“We are understanding more about the phenotype,” he said. “If you fulfill diagnostic criteria for NF1, the main reasons for doing genetic testing are, one, if the family wants to know that information, and two, it informs our reproductive risk counseling. Genotype-phenotype correlations do exist in NF1 but they’re not very robust, so that information is not clinically useful.”

Dr. Kannu disclosed that he has been an advisory board member for Ipsen, Novartis, and Alexion. He has also been a primary investigator for QED and Clementia.

[email protected]

When a child presents with café au lait macules, when is genetic testing for neurofibromatosis type 1 (NF1) advised?

According to Peter Kannu, MB, ChB, DCH, PhD, a definitive diagnosis of NF1 can be made in most children using National Institutes of Health criteria published in 1988, which include the presence of two of the following:

• Six or more café au lait macules over 5 mm in diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals
• Two or more neurofibromas of any type or one plexiform neurofibroma
• Freckling in the axillary or inguinal regions
• Two or more Lisch nodules
• Optic glioma
• A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis
• Having a first-degree relative with NF1

For example, in the case of an 8-year-old child who presents with multiple café au lait macules, axillary and inguinal freckling, Lisch nodules, and an optic glioma, “the diagnosis is secure and genetic testing is not going to change clinical management or surveillance,” Dr. Kannu, a clinical geneticist at the University of Alberta, Edmonton, said during the annual meeting of the Society for Pediatric Dermatology. “The only reason for genetic testing in this situation is so that we know the mutation in order to inform reproductive risk counseling in the future.”

However, while a diagnosis of NF1 may be suspected in a 6- to 12-month-old presenting with only café au lait macules, “the diagnosis is not secure because the clinical criteria cannot be met. In this situation, a genetic test can speed up the diagnosis,” he added. “Or, if the test is negative, it can decrease your suspicion for NF1 and you wouldn’t refer the child on to an NF1 screening clinic for intensive surveillance.”

Dr. Kannu based his remarks largely on his 5 years working at the multidisciplinary Genodermatoses Clinic at the Hospital for Sick Children, Toronto. Founded in 2015, the clinic is a “one-stop shop” designed to reduce the wait time for diagnosis and management and the number of hospital visits. The team – composed of a dermatologist, medical geneticist, genetic counselor, residents, and fellows – meets to review the charts of each patient before the appointment, and decides on a preliminary management plan. All children are then seen by one of the trainees in the clinic who devises a differential diagnosis that is presented to staff physicians, at which point genetic testing is decided on. A genetics counselor handles follow-up for those who do have genetic testing.

In 2018, Dr. Kannu and colleagues conducted an informal review of 300 patients who had been seen in the clinic. The mean age at referral was about 6 years, 51% were female, and the top three referral sources were pediatricians (51%), dermatologists (18%), and family physicians (18%). Of the 300 children, 84 (28%) were confirmed to have a diagnosis of NF1. Two patients were diagnosed with NF2 and 5% of the total cohort was diagnosed with mosaic NF1 (MNF1), “which is higher than what you would expect based on the incidence of MNF1 in the literature,” he said.

He separates genetic tests for NF1 into one of two categories: Conventional testing, which is offered by most labs in North America; and comprehensive testing, which is offered by the medical genomics lab at the University of Alabama at Birmingham. Conventional testing focuses on the exons, “the protein coding regions of the gene where most of the mutations lie,” he said. “The test also sequences about 20 base pairs or so of the intron exon boundary and may pick up some intronic mutations. But this test will not detect anything that’s hidden deep in the intronic region.”

Comprehensive testing, meanwhile, checks for mutations in both introns and exons.

Dr. Kannu and colleagues published a case of a paraspinal ganglioneuroma in the proband of a large family with mild cutaneous manifestations of NF1, carrying a deep NF1 intronic mutation. “The clinicians were suspicious that this was NF1, rightly so. The diagnosis was only confirmed after we sent samples to the University of Alabama lab where the deep intronic mutation was found,” he said.

The other situation where conventional genetic testing may be negative is in the case of MNF1, where there “are mutations in some cells but not all cells,” Dr. Kannu explained. “It may only be present in the melanocytes of the skin but not present in the lymphocytes in the blood. Mosaicism is characterized by the regional distribution of pigmentary or other NF1 associated findings. Mosaicism may be detected in the blood if it’s more than 20%. Anything less than that is not detected with conventional genetic testing using DNA from blood and requires extracting DNA from a punch biopsy sample of a café au lait macule.”

The differential diagnosis of café au lait macules includes several conditions associated mutations in the RAS pathway. “Neurofibromin is a key signal of molecules which regulates the activation of RAS,” Dr. Kannu said. “A close binding partner of NF1 is SPRED 1. We know that mutations in this gene cause Legius syndrome, a condition which presents with multiple café au lait macules.”

Two key receptors in the RAS pathway include EGFR and KITL, he continued. Mutations in the EGFR receptor cause a rare condition known as neonatal skin and bowel disease, while mutations in the KITL receptor cause familial progressive hyperpigmentation with or without hypopigmentation. “Looking into the pathway and focusing downstream of RAS, we have genes such as RAF and CBL, which are mutated in Noonan syndrome,” he said. “Further along in the pathway you have mutations in PTEN, which cause Cowden syndrome, and mutations in TSC1 and TSC2, which cause tuberous sclerosis. Mutations in any of these genes can also present with café au lait macules.”

During a question-and-answer session Dr. Kannu was asked to comment about revised diagnostic criteria for NF1 based on an international consensus recommendation, such as changes in the eye that require a formal opthalmologic examination, which were recently published.

“We are understanding more about the phenotype,” he said. “If you fulfill diagnostic criteria for NF1, the main reasons for doing genetic testing are, one, if the family wants to know that information, and two, it informs our reproductive risk counseling. Genotype-phenotype correlations do exist in NF1 but they’re not very robust, so that information is not clinically useful.”

Dr. Kannu disclosed that he has been an advisory board member for Ipsen, Novartis, and Alexion. He has also been a primary investigator for QED and Clementia.

[email protected]

For the sixth consecutive year, the Mayo Clinic in Rochester, Minn., claimed the No. 1 spot in the annual honor roll of best hospitals published July 27 by U.S. News & World Report.
 

This year’s expanded report debuts new ratings for seven “important procedures and conditions to help patients, in consultation with their doctors, narrow down their choice of hospital based on the specific type of care they need,” Ben Harder, managing editor and chief of health analysis, said in a news release.

With new ratings for myocardial infarction, stroke, hip fracture, and back surgery (spinal fusion), the report now ranks 17 procedures and conditions.

Also new to the 2021 report, which marks the 32nd edition, is a look at racial disparities in health care and the inclusion of health equity measures alongside the hospital rankings.

The new measures examine whether the patients each hospital has treated reflect the racial and ethnic diversity of the surrounding community, among other aspects of health equity.

“At roughly four out of five hospitals, we found that the community’s minority residents were underrepresented among patients receiving services such as joint replacement, cancer surgery and common heart procedures,” Mr. Harder said.

“Against this backdrop, however, we found important exceptions – hospitals that provide care to a disproportionate share of their community’s minority residents. These metrics are just a beginning; we aim to expand on our measurement of health equity in the future,” Mr. Harder added.

Mayo and Cleveland Clinic remain tops

Following the Mayo Clinic, the Cleveland Clinic once again takes the No. 2 spot in the magazine’s latest annual honor roll of best hospitals, which highlights hospitals that deliver exceptional treatment across multiple areas of care.

UCLA Medical Center, Los Angeles, holds the No. 3 spot in 2021. In 2020, UCLA Medical Center and New York–Presbyterian Hospital–Columbia and Cornell, New York, sat in a tie at No. 4.

In 2021, Johns Hopkins Hospital, Baltimore, which held the No. 3 spot in 2020, drops to No. 4, while Massachusetts General Hospital in Boston takes the No. 5 spot, up from No. 6 in 2020.

Rounding out the top 10 (in order) are Cedars-Sinai Medical Center, Los Angeles; New York–Presbyterian Hospital–Columbia and Cornell, New York; NYU Langone Hospitals, New York; UCSF Medical Center, San Francisco; and Northwestern Memorial Hospital, Chicago.
 

2021-2022 Best Hospitals honor roll

1. Mayo Clinic, Rochester, Minn.

2. Cleveland Clinic, Cleveland

3. UCLA Medical Center, Los Angeles

4. Johns Hopkins Hospital, Baltimore

5. Massachusetts General Hospital, Boston

6. Cedars-Sinai Medical Center, San Francisco

7. New York–Presbyterian Hospital–Columbia and Cornell, New York

8. NYU Langone Hospitals, New York

9. UCSF Medical Center, San Francisco

10. Northwestern Memorial Hospital, Chicago

11. University of Michigan Hospitals–Michigan Medicine, Ann Arbor.

12. Stanford Health Care–Stanford Hospital, Palo Alto, Calif.

13. Hospitals of the University of Pennsylvania–Penn Presbyterian, Philadelphia

14. Brigham and Women’s Hospital, Boston

15. Mayo Clinic–Phoenix, Phoenix

16. Houston Methodist Hospital, Houston

17. (tie) Barnes-Jewish Hospital, St. Louis

17. (tie) Mount Sinai Hospital, New York Rush University Medical Center, Chicago

19. Rush University Medical Center, Chicago

20. Vanderbilt University Medical Center, Nashville, Tenn.

For the 2021-2022 rankings and ratings, the magazine compared more than 4,750 hospitals nationwide in 15 specialties and 17 procedures and conditions.

At least 2,039 hospitals received a high performance rating in at least one of the services rated; 11 hospitals received high performance in all 17. A total of 175 hospitals were nationally ranked in at least one specialty

For specialty rankings, the University of Texas MD Anderson Cancer Center continues to hold the No. 1 spot in cancer care, the Hospital for Special Surgery continues to be No. 1 in orthopedics, and the Cleveland Clinic continues to be No. 1 in cardiology and heart surgery.
 

Top five for cancer

1. University of Texas MD Anderson Cancer Center, Houston

2. Memorial Sloan Kettering Cancer Center, New York

3. Mayo Clinic, Rochester, Minn.

4. Dana-Farber/Brigham & Women’s Cancer Center, Boston

5. Cleveland Clinic, Cleveland

Top five for cardiology and heart surgery

1. Cleveland Clinic, Cleveland

2. Mayo Clinic, Rochester, Minn.

3. Cedars-Sinai Medical Center, Los Angeles

4. New York–Presbyterian Hospital–Columbia and Cornell, New York

5. NYU Langone Hospitals, New York

Top five for orthopedics

1. Hospital for Special Surgery, New York

2. Mayo Clinic, Rochester, Minn.

3. Cedars-Sinai Medical Center, Los Angeles

4. NYU Langone Orthopedic Hospital, New York

5. UCLA Medical Center, Los Angeles

The magazine noted that data for the 2021-2022 Best Hospitals rankings and ratings were not affected by the COVID-19 pandemic, which began after the end of the data collection period.

The methodologies used in determining the rankings are based largely on objective measures, such as risk-adjusted survival, discharge-to-home rates, volume, and quality of nursing, among other care-related indicators.

The full report is available online.

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

For the sixth consecutive year, the Mayo Clinic in Rochester, Minn., claimed the No. 1 spot in the annual honor roll of best hospitals published July 27 by U.S. News & World Report.
 

This year’s expanded report debuts new ratings for seven “important procedures and conditions to help patients, in consultation with their doctors, narrow down their choice of hospital based on the specific type of care they need,” Ben Harder, managing editor and chief of health analysis, said in a news release.

With new ratings for myocardial infarction, stroke, hip fracture, and back surgery (spinal fusion), the report now ranks 17 procedures and conditions.

Also new to the 2021 report, which marks the 32nd edition, is a look at racial disparities in health care and the inclusion of health equity measures alongside the hospital rankings.

The new measures examine whether the patients each hospital has treated reflect the racial and ethnic diversity of the surrounding community, among other aspects of health equity.

“At roughly four out of five hospitals, we found that the community’s minority residents were underrepresented among patients receiving services such as joint replacement, cancer surgery and common heart procedures,” Mr. Harder said.

“Against this backdrop, however, we found important exceptions – hospitals that provide care to a disproportionate share of their community’s minority residents. These metrics are just a beginning; we aim to expand on our measurement of health equity in the future,” Mr. Harder added.

Mayo and Cleveland Clinic remain tops

Following the Mayo Clinic, the Cleveland Clinic once again takes the No. 2 spot in the magazine’s latest annual honor roll of best hospitals, which highlights hospitals that deliver exceptional treatment across multiple areas of care.

UCLA Medical Center, Los Angeles, holds the No. 3 spot in 2021. In 2020, UCLA Medical Center and New York–Presbyterian Hospital–Columbia and Cornell, New York, sat in a tie at No. 4.

In 2021, Johns Hopkins Hospital, Baltimore, which held the No. 3 spot in 2020, drops to No. 4, while Massachusetts General Hospital in Boston takes the No. 5 spot, up from No. 6 in 2020.

Rounding out the top 10 (in order) are Cedars-Sinai Medical Center, Los Angeles; New York–Presbyterian Hospital–Columbia and Cornell, New York; NYU Langone Hospitals, New York; UCSF Medical Center, San Francisco; and Northwestern Memorial Hospital, Chicago.
 

2021-2022 Best Hospitals honor roll

1. Mayo Clinic, Rochester, Minn.

2. Cleveland Clinic, Cleveland

3. UCLA Medical Center, Los Angeles

4. Johns Hopkins Hospital, Baltimore

5. Massachusetts General Hospital, Boston

6. Cedars-Sinai Medical Center, San Francisco

7. New York–Presbyterian Hospital–Columbia and Cornell, New York

8. NYU Langone Hospitals, New York

9. UCSF Medical Center, San Francisco

10. Northwestern Memorial Hospital, Chicago

11. University of Michigan Hospitals–Michigan Medicine, Ann Arbor.

12. Stanford Health Care–Stanford Hospital, Palo Alto, Calif.

13. Hospitals of the University of Pennsylvania–Penn Presbyterian, Philadelphia

14. Brigham and Women’s Hospital, Boston

15. Mayo Clinic–Phoenix, Phoenix

16. Houston Methodist Hospital, Houston

17. (tie) Barnes-Jewish Hospital, St. Louis

17. (tie) Mount Sinai Hospital, New York Rush University Medical Center, Chicago

19. Rush University Medical Center, Chicago

20. Vanderbilt University Medical Center, Nashville, Tenn.

For the 2021-2022 rankings and ratings, the magazine compared more than 4,750 hospitals nationwide in 15 specialties and 17 procedures and conditions.

At least 2,039 hospitals received a high performance rating in at least one of the services rated; 11 hospitals received high performance in all 17. A total of 175 hospitals were nationally ranked in at least one specialty

For specialty rankings, the University of Texas MD Anderson Cancer Center continues to hold the No. 1 spot in cancer care, the Hospital for Special Surgery continues to be No. 1 in orthopedics, and the Cleveland Clinic continues to be No. 1 in cardiology and heart surgery.
 

Top five for cancer

1. University of Texas MD Anderson Cancer Center, Houston

2. Memorial Sloan Kettering Cancer Center, New York

3. Mayo Clinic, Rochester, Minn.

4. Dana-Farber/Brigham & Women’s Cancer Center, Boston

5. Cleveland Clinic, Cleveland

Top five for cardiology and heart surgery

1. Cleveland Clinic, Cleveland

2. Mayo Clinic, Rochester, Minn.

3. Cedars-Sinai Medical Center, Los Angeles

4. New York–Presbyterian Hospital–Columbia and Cornell, New York

5. NYU Langone Hospitals, New York

Top five for orthopedics

1. Hospital for Special Surgery, New York

2. Mayo Clinic, Rochester, Minn.

3. Cedars-Sinai Medical Center, Los Angeles

4. NYU Langone Orthopedic Hospital, New York

5. UCLA Medical Center, Los Angeles

The magazine noted that data for the 2021-2022 Best Hospitals rankings and ratings were not affected by the COVID-19 pandemic, which began after the end of the data collection period.

The methodologies used in determining the rankings are based largely on objective measures, such as risk-adjusted survival, discharge-to-home rates, volume, and quality of nursing, among other care-related indicators.

The full report is available online.

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

For the sixth consecutive year, the Mayo Clinic in Rochester, Minn., claimed the No. 1 spot in the annual honor roll of best hospitals published July 27 by U.S. News & World Report.
 

This year’s expanded report debuts new ratings for seven “important procedures and conditions to help patients, in consultation with their doctors, narrow down their choice of hospital based on the specific type of care they need,” Ben Harder, managing editor and chief of health analysis, said in a news release.

With new ratings for myocardial infarction, stroke, hip fracture, and back surgery (spinal fusion), the report now ranks 17 procedures and conditions.

Also new to the 2021 report, which marks the 32nd edition, is a look at racial disparities in health care and the inclusion of health equity measures alongside the hospital rankings.

The new measures examine whether the patients each hospital has treated reflect the racial and ethnic diversity of the surrounding community, among other aspects of health equity.

“At roughly four out of five hospitals, we found that the community’s minority residents were underrepresented among patients receiving services such as joint replacement, cancer surgery and common heart procedures,” Mr. Harder said.

“Against this backdrop, however, we found important exceptions – hospitals that provide care to a disproportionate share of their community’s minority residents. These metrics are just a beginning; we aim to expand on our measurement of health equity in the future,” Mr. Harder added.

Mayo and Cleveland Clinic remain tops

Following the Mayo Clinic, the Cleveland Clinic once again takes the No. 2 spot in the magazine’s latest annual honor roll of best hospitals, which highlights hospitals that deliver exceptional treatment across multiple areas of care.

UCLA Medical Center, Los Angeles, holds the No. 3 spot in 2021. In 2020, UCLA Medical Center and New York–Presbyterian Hospital–Columbia and Cornell, New York, sat in a tie at No. 4.

In 2021, Johns Hopkins Hospital, Baltimore, which held the No. 3 spot in 2020, drops to No. 4, while Massachusetts General Hospital in Boston takes the No. 5 spot, up from No. 6 in 2020.

Rounding out the top 10 (in order) are Cedars-Sinai Medical Center, Los Angeles; New York–Presbyterian Hospital–Columbia and Cornell, New York; NYU Langone Hospitals, New York; UCSF Medical Center, San Francisco; and Northwestern Memorial Hospital, Chicago.
 

2021-2022 Best Hospitals honor roll

1. Mayo Clinic, Rochester, Minn.

2. Cleveland Clinic, Cleveland

3. UCLA Medical Center, Los Angeles

4. Johns Hopkins Hospital, Baltimore

5. Massachusetts General Hospital, Boston

6. Cedars-Sinai Medical Center, San Francisco

7. New York–Presbyterian Hospital–Columbia and Cornell, New York

8. NYU Langone Hospitals, New York

9. UCSF Medical Center, San Francisco

10. Northwestern Memorial Hospital, Chicago

11. University of Michigan Hospitals–Michigan Medicine, Ann Arbor.

12. Stanford Health Care–Stanford Hospital, Palo Alto, Calif.

13. Hospitals of the University of Pennsylvania–Penn Presbyterian, Philadelphia

14. Brigham and Women’s Hospital, Boston

15. Mayo Clinic–Phoenix, Phoenix

16. Houston Methodist Hospital, Houston

17. (tie) Barnes-Jewish Hospital, St. Louis

17. (tie) Mount Sinai Hospital, New York Rush University Medical Center, Chicago

19. Rush University Medical Center, Chicago

20. Vanderbilt University Medical Center, Nashville, Tenn.

For the 2021-2022 rankings and ratings, the magazine compared more than 4,750 hospitals nationwide in 15 specialties and 17 procedures and conditions.

At least 2,039 hospitals received a high performance rating in at least one of the services rated; 11 hospitals received high performance in all 17. A total of 175 hospitals were nationally ranked in at least one specialty

For specialty rankings, the University of Texas MD Anderson Cancer Center continues to hold the No. 1 spot in cancer care, the Hospital for Special Surgery continues to be No. 1 in orthopedics, and the Cleveland Clinic continues to be No. 1 in cardiology and heart surgery.
 

Top five for cancer

1. University of Texas MD Anderson Cancer Center, Houston

2. Memorial Sloan Kettering Cancer Center, New York

3. Mayo Clinic, Rochester, Minn.

4. Dana-Farber/Brigham & Women’s Cancer Center, Boston

5. Cleveland Clinic, Cleveland

Top five for cardiology and heart surgery

1. Cleveland Clinic, Cleveland

2. Mayo Clinic, Rochester, Minn.

3. Cedars-Sinai Medical Center, Los Angeles

4. New York–Presbyterian Hospital–Columbia and Cornell, New York

5. NYU Langone Hospitals, New York

Top five for orthopedics

1. Hospital for Special Surgery, New York

2. Mayo Clinic, Rochester, Minn.

3. Cedars-Sinai Medical Center, Los Angeles

4. NYU Langone Orthopedic Hospital, New York

5. UCLA Medical Center, Los Angeles

The magazine noted that data for the 2021-2022 Best Hospitals rankings and ratings were not affected by the COVID-19 pandemic, which began after the end of the data collection period.

The methodologies used in determining the rankings are based largely on objective measures, such as risk-adjusted survival, discharge-to-home rates, volume, and quality of nursing, among other care-related indicators.

The full report is available online.

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

As COVID-19 cases, hospitalizations, and deaths mount again across the country, the American Medical Association (AMA), the American Nursing Association, and 54 other medical and allied healthcare associations released a joint statement calling on “all health care and long-term care employers” to require their workers to receive the COVID-19 vaccine.

This injunction, issued July 26, covers everyone in healthcare, Emanuel Ezekiel, MD, PhD, chair of the department of medical ethics and health policy at the University of Pennsylvania, Philadelphia, and the organizer of the joint statement, said in an interview.

That includes not only hospitals, but also physician offices, ambulatory surgery centers, home care agencies, skilled nursing facilities, pharmacies, laboratories, and imaging centers, he said.

The exhortation to get vaccinated also extends to federal and state healthcare facilities, including those of the military health system — TRICARE and the Department of Veterans Affairs — which instituted a mandate the same day.

The American Hospital Association (AHA) and other hospital groups recently said they supported hospitals and health systems that required their personnel to get vaccinated. Several dozen healthcare organizations have already done so, including some of the nation’s largest health systems.

A substantial fraction of U.S. healthcare workers have not yet gotten vaccinated, although how many are unvaccinated is unclear. An analysis by WebMD and Medscape Medical News estimated that 25% of hospital workers who had contact with patients were unvaccinated at the end of May.

More than 38% of nursing workers were not fully vaccinated by July 11, according to an analysis of Centers for Medicare & Medicaid Services data by LeadingAge, which was cited by the Washington Post. And more than 40% of nursing home employees have not been fully vaccinated, according to the Centers for Disease Control and Prevention.

The joint statement did not give any indication of how many employees of physician practices have failed to get COVID shots. However, a recent AMA survey shows that 96% of physicians have been fully vaccinated.
 

Ethical commitment

The main reason for vaccine mandates, according to the healthcare associations’ statement, is “the ethical commitment to put patients as well as residents of long-term care facilities first and take all steps necessary to ensure their health and well-being.”

In addition, the statement noted, vaccination can protect healthcare workers and their families from getting COVID-19.

The statement also pointed out that many healthcare and long-term care organizations already require vaccinations for influenza, hepatitis B, and pertussis.

Workers who have certain medical conditions should be exempt from the vaccination mandates, the statement added.

While recognizing the “historical mistrust of health care institutions” among some healthcare workers, the statement said, “We must continue to address workers’ concerns, engage with marginalized populations, and work with trusted messengers to improve vaccine acceptance.”

There has been some skepticism about the legality of requiring healthcare workers to get vaccinated as a condition of employment, partly because the U.S. Food and Drug Administration has not yet fully authorized any of the COVID-19 vaccines.

But in June, a federal judge turned down a legal challenge to Houston Methodist’s vaccination mandate.

“It is critical that all people in the health care workforce get vaccinated against COVID-19 for the safety of our patients and our colleagues. With more than 300 million doses administered in the United States and nearly 4 billion doses administered worldwide, we know the vaccines are safe and highly effective at preventing severe illness and death from COVID-19.

“Increased vaccinations among health care personnel will not only reduce the spread of COVID-19 but also reduce the harmful toll this virus is taking within the health care workforce and those we are striving to serve,” Susan Bailey, MD, immediate past president of the AMA, said in a news release.

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

As COVID-19 cases, hospitalizations, and deaths mount again across the country, the American Medical Association (AMA), the American Nursing Association, and 54 other medical and allied healthcare associations released a joint statement calling on “all health care and long-term care employers” to require their workers to receive the COVID-19 vaccine.

This injunction, issued July 26, covers everyone in healthcare, Emanuel Ezekiel, MD, PhD, chair of the department of medical ethics and health policy at the University of Pennsylvania, Philadelphia, and the organizer of the joint statement, said in an interview.

That includes not only hospitals, but also physician offices, ambulatory surgery centers, home care agencies, skilled nursing facilities, pharmacies, laboratories, and imaging centers, he said.

The exhortation to get vaccinated also extends to federal and state healthcare facilities, including those of the military health system — TRICARE and the Department of Veterans Affairs — which instituted a mandate the same day.

The American Hospital Association (AHA) and other hospital groups recently said they supported hospitals and health systems that required their personnel to get vaccinated. Several dozen healthcare organizations have already done so, including some of the nation’s largest health systems.

A substantial fraction of U.S. healthcare workers have not yet gotten vaccinated, although how many are unvaccinated is unclear. An analysis by WebMD and Medscape Medical News estimated that 25% of hospital workers who had contact with patients were unvaccinated at the end of May.

More than 38% of nursing workers were not fully vaccinated by July 11, according to an analysis of Centers for Medicare & Medicaid Services data by LeadingAge, which was cited by the Washington Post. And more than 40% of nursing home employees have not been fully vaccinated, according to the Centers for Disease Control and Prevention.

The joint statement did not give any indication of how many employees of physician practices have failed to get COVID shots. However, a recent AMA survey shows that 96% of physicians have been fully vaccinated.
 

Ethical commitment

The main reason for vaccine mandates, according to the healthcare associations’ statement, is “the ethical commitment to put patients as well as residents of long-term care facilities first and take all steps necessary to ensure their health and well-being.”

In addition, the statement noted, vaccination can protect healthcare workers and their families from getting COVID-19.

The statement also pointed out that many healthcare and long-term care organizations already require vaccinations for influenza, hepatitis B, and pertussis.

Workers who have certain medical conditions should be exempt from the vaccination mandates, the statement added.

While recognizing the “historical mistrust of health care institutions” among some healthcare workers, the statement said, “We must continue to address workers’ concerns, engage with marginalized populations, and work with trusted messengers to improve vaccine acceptance.”

There has been some skepticism about the legality of requiring healthcare workers to get vaccinated as a condition of employment, partly because the U.S. Food and Drug Administration has not yet fully authorized any of the COVID-19 vaccines.

But in June, a federal judge turned down a legal challenge to Houston Methodist’s vaccination mandate.

“It is critical that all people in the health care workforce get vaccinated against COVID-19 for the safety of our patients and our colleagues. With more than 300 million doses administered in the United States and nearly 4 billion doses administered worldwide, we know the vaccines are safe and highly effective at preventing severe illness and death from COVID-19.

“Increased vaccinations among health care personnel will not only reduce the spread of COVID-19 but also reduce the harmful toll this virus is taking within the health care workforce and those we are striving to serve,” Susan Bailey, MD, immediate past president of the AMA, said in a news release.

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

As COVID-19 cases, hospitalizations, and deaths mount again across the country, the American Medical Association (AMA), the American Nursing Association, and 54 other medical and allied healthcare associations released a joint statement calling on “all health care and long-term care employers” to require their workers to receive the COVID-19 vaccine.

This injunction, issued July 26, covers everyone in healthcare, Emanuel Ezekiel, MD, PhD, chair of the department of medical ethics and health policy at the University of Pennsylvania, Philadelphia, and the organizer of the joint statement, said in an interview.

That includes not only hospitals, but also physician offices, ambulatory surgery centers, home care agencies, skilled nursing facilities, pharmacies, laboratories, and imaging centers, he said.

The exhortation to get vaccinated also extends to federal and state healthcare facilities, including those of the military health system — TRICARE and the Department of Veterans Affairs — which instituted a mandate the same day.

The American Hospital Association (AHA) and other hospital groups recently said they supported hospitals and health systems that required their personnel to get vaccinated. Several dozen healthcare organizations have already done so, including some of the nation’s largest health systems.

A substantial fraction of U.S. healthcare workers have not yet gotten vaccinated, although how many are unvaccinated is unclear. An analysis by WebMD and Medscape Medical News estimated that 25% of hospital workers who had contact with patients were unvaccinated at the end of May.

More than 38% of nursing workers were not fully vaccinated by July 11, according to an analysis of Centers for Medicare & Medicaid Services data by LeadingAge, which was cited by the Washington Post. And more than 40% of nursing home employees have not been fully vaccinated, according to the Centers for Disease Control and Prevention.

The joint statement did not give any indication of how many employees of physician practices have failed to get COVID shots. However, a recent AMA survey shows that 96% of physicians have been fully vaccinated.
 

Ethical commitment

The main reason for vaccine mandates, according to the healthcare associations’ statement, is “the ethical commitment to put patients as well as residents of long-term care facilities first and take all steps necessary to ensure their health and well-being.”

In addition, the statement noted, vaccination can protect healthcare workers and their families from getting COVID-19.

The statement also pointed out that many healthcare and long-term care organizations already require vaccinations for influenza, hepatitis B, and pertussis.

Workers who have certain medical conditions should be exempt from the vaccination mandates, the statement added.

While recognizing the “historical mistrust of health care institutions” among some healthcare workers, the statement said, “We must continue to address workers’ concerns, engage with marginalized populations, and work with trusted messengers to improve vaccine acceptance.”

There has been some skepticism about the legality of requiring healthcare workers to get vaccinated as a condition of employment, partly because the U.S. Food and Drug Administration has not yet fully authorized any of the COVID-19 vaccines.

But in June, a federal judge turned down a legal challenge to Houston Methodist’s vaccination mandate.

“It is critical that all people in the health care workforce get vaccinated against COVID-19 for the safety of our patients and our colleagues. With more than 300 million doses administered in the United States and nearly 4 billion doses administered worldwide, we know the vaccines are safe and highly effective at preventing severe illness and death from COVID-19.

“Increased vaccinations among health care personnel will not only reduce the spread of COVID-19 but also reduce the harmful toll this virus is taking within the health care workforce and those we are striving to serve,” Susan Bailey, MD, immediate past president of the AMA, said in a news release.

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

I don’t see anyone under 18. After all, I’m not a child neurologist.

People will occasionally argue with this policy, claiming that it’s too rigid. Why not 17½? I know that some adult neurologists do see teenagers.

But not me. It’s easier to just have a solid line and stick by it.

So, by habit, I often note someone’s birthday on the schedule to make sure they’re old enough to see me. And, over the years, this has made me realize the passage of time more than a lot of things.

Not much changes in my office. I’ve been in the same building since 2013, had the same furniture for longer, and the same staff since 2004. So it’s easy to lose track of how long I’ve been doing this.

But when I started out I didn’t see anyone born after 1979. Today that’s crept up to 2003. How the hell did that happen?

With that came the even more sobering realization that my kids are now all old enough to be my patients.

Time flies by in this world. You do the same thing day in and day out, and suddenly you’re 20 years older and starting to think about retirement.

We all see ourselves in the mirror each day, but rarely notice the changes. Watching patients grow older, seeing the minimum birth year for them advance, even being surprised when a drug I thought had just come out is now generic – those are the reminders of time’s passage that get my attention at work.

Not that it’s a bad thing. Time will go on, whether we want it to or not. After 20 years I still enjoy this job, and it allows me to support my family. I can’t ask for much more than that.

But each morning I scan through the names and birthdays on my schedule, and am amazed when I think about how clearly I remember my first day of medical school, college, and even high school like it had just happened.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I don’t see anyone under 18. After all, I’m not a child neurologist.

People will occasionally argue with this policy, claiming that it’s too rigid. Why not 17½? I know that some adult neurologists do see teenagers.

But not me. It’s easier to just have a solid line and stick by it.

So, by habit, I often note someone’s birthday on the schedule to make sure they’re old enough to see me. And, over the years, this has made me realize the passage of time more than a lot of things.

Not much changes in my office. I’ve been in the same building since 2013, had the same furniture for longer, and the same staff since 2004. So it’s easy to lose track of how long I’ve been doing this.

But when I started out I didn’t see anyone born after 1979. Today that’s crept up to 2003. How the hell did that happen?

With that came the even more sobering realization that my kids are now all old enough to be my patients.

Time flies by in this world. You do the same thing day in and day out, and suddenly you’re 20 years older and starting to think about retirement.

We all see ourselves in the mirror each day, but rarely notice the changes. Watching patients grow older, seeing the minimum birth year for them advance, even being surprised when a drug I thought had just come out is now generic – those are the reminders of time’s passage that get my attention at work.

Not that it’s a bad thing. Time will go on, whether we want it to or not. After 20 years I still enjoy this job, and it allows me to support my family. I can’t ask for much more than that.

But each morning I scan through the names and birthdays on my schedule, and am amazed when I think about how clearly I remember my first day of medical school, college, and even high school like it had just happened.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I don’t see anyone under 18. After all, I’m not a child neurologist.

People will occasionally argue with this policy, claiming that it’s too rigid. Why not 17½? I know that some adult neurologists do see teenagers.

But not me. It’s easier to just have a solid line and stick by it.

So, by habit, I often note someone’s birthday on the schedule to make sure they’re old enough to see me. And, over the years, this has made me realize the passage of time more than a lot of things.

Not much changes in my office. I’ve been in the same building since 2013, had the same furniture for longer, and the same staff since 2004. So it’s easy to lose track of how long I’ve been doing this.

But when I started out I didn’t see anyone born after 1979. Today that’s crept up to 2003. How the hell did that happen?

With that came the even more sobering realization that my kids are now all old enough to be my patients.

Time flies by in this world. You do the same thing day in and day out, and suddenly you’re 20 years older and starting to think about retirement.

We all see ourselves in the mirror each day, but rarely notice the changes. Watching patients grow older, seeing the minimum birth year for them advance, even being surprised when a drug I thought had just come out is now generic – those are the reminders of time’s passage that get my attention at work.

Not that it’s a bad thing. Time will go on, whether we want it to or not. After 20 years I still enjoy this job, and it allows me to support my family. I can’t ask for much more than that.

But each morning I scan through the names and birthdays on my schedule, and am amazed when I think about how clearly I remember my first day of medical school, college, and even high school like it had just happened.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.