Literature Review

Bass-heavy rock music applied directly to the abdomen of diabetic mice implanted with music-sensitive insulin-releasing cells attenuates postprandial glycemic excursions and restores normoglycemia, reveals a series of experiments.

The research was published in The Lancet Diabetes & Endocrinology.

After developing a cell line in which music-sensitive calcium channels triggered the release of insulin-containing vesicles, the researchers conducted a series of studies identifying the optimal frequency, pitch, and volume of sounds for triggering release.

After settling on low-bass heavy popular music, they tested their system on mice with type 1 diabetes that had the insulin-releasing cells implanted in their abdomen. Applying the music directly at 60 dB led to near wild-type levels of insulin in the blood within 15 minutes.

“With only 4 hours required for a full refill, [the system] can provide several therapeutic doses a day,” says Martin Fussenegger, PhD, professor of biotechnology and bioengineering, Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland, and colleagues.

“This would match the typical needs of people with type 2 diabetes consuming three meals a day, and for whom administration of prandial insulin is an established treatment option, as they do not have capability for early postprandial insulin secretion from preformed insulin.”

As the system requires nothing more than portable battery-powered commercially available loudspeakers, the multiple daily dosing of biopharmaceuticals becomes “straightforward in the absence of medical infrastructure or staff, simply by having the patient listen to the prescribed music.”

It therefore “could be an interesting option for cell-based therapies, especially where the need for frequent dosing raises compliance issues.”

It is a “very exciting piece of work, no doubt,” said Anandwardhan A. Hardikar, PhD, group leader, Diabetes and Islet Biology Group, Translational Health Research Institute, Western Sydney University, Penrith NSW, Australia.

He pointed out that the concept of using music to drive gene expression “is something we’ve known for the last 20 years,” but bringing the different strands of research together to generate cells that can be implanted into mice is “an amazing idea.”

Dr. Hardikar, who was not involved in the study, said, however, the publication of the study as a correspondence “does not allow for a lot of the detail that I would have expected as an academic,” and consequently some questions remain.

The most important is whether the music itself is required to trigger the insulin release, as opposed simply to sounds in general.

Is Music or Sound the “Trigger?”

Music is “frequency, it’s the amplitude of the waveform, and it’s the duration for which those waveforms are present,” he noted, but the same profile can be achieved by cutting up and editing the melody so it becomes a jumble of sounds.

For Dr. Hardikar, the “best control” for the study would be to have no music as well as the edited song, with “bits of pieces” played randomly so “it sounds like it’s the same frequency and amplitude.”

Then it would be clear whether the effect is owing to the “noise, or we have to appreciate the melody.”

The other outstanding question is whether the results “can directly translate to larger animals,” such as humans, Dr. Hardikar said.

The authors point out that when translated into mechanical vibrations in the middle ear, the acoustic waves of music activate mechanosensitive ion channels, a form of trigger that is seen across the animal kingdom.

They go on to highlight that while gene switches have been developed for use in next-generation cell-based therapies for a range of conditions, small-molecular trigger compounds face a number of challenges and may cause adverse effects.

With “traceless triggers” such as light, ultrasound, magnetic fields, radio waves, electricity, and heat also facing issues, there is a “need for new switching modalities.”

The researchers therefore developed a music-inducible cellular control (MUSIC) system, which leverages the known intracellular calcium surge in response to music, via calcium-permeable mechanosensitive channels, to drive the release of biopharmaceuticals from vesicles.

They then generated MUSIC-controlled insulin-releasing cell lines, finding that, using a customized box containing off-the-shelf loudspeakers, they could induce channel activation and insulin release with 60 dB at 50 Hz, which is “within the safe range for the human ear.”

Further experiments revealed that insulin release was greatest at 50-100 Hz, and higher than that seen with potassium chloride, the “gold-standard” depolarization control for calcium channels.

The researchers then showed that with optimal stimulation at 50 Hz and 60 dB, channel activation and subsequent insulin release required at least 3 seconds of continuous music, “which might protect the cellular device from inadvertent activation during everyday activities.”

Next, they examined the impact of different musical genres on insulin release, finding that low-bass heavy popular music and movie soundtracks induced maximum release, while the responses were more diverse to classical and guitar-based music.

Specifically, “We Will Rock You,” by the British rock band Queen, induced the release of 70% of available insulin within 5 minutes and 100% within 15 minutes. This, the team notes, is “similar to the dynamics of glucose-triggered insulin release by human pancreatic islets.”

Exposing the cells to a second music session at different intervals revealed that full insulin refill was achieved within 4 hours, which “would be appropriate to attenuate glycemic excursions associated with typical dietary habits.”

Finally, the researchers tested the system in vivo, constructing a box with two off-the-shelf loudspeakers that focuses acoustic waves, via deflectors, onto the abdomens of mice with type 1 diabetes.

Exposing the mice, which had been implanted with microencapsulated MUSIC cells in the peritoneum, to low-bass acoustic waves at 60 dB (50 m/s2) for 15 minutes allowed them to achieve near wild-type levels of insulin in the blood and restored normoglycemia.

Moreover, “Queen’s song ‘We Will Rock You’ generated sufficient insulin to rapidly attenuate postprandial glycemic excursions during glucose tolerance tests,” the team says.

In contrast, animals without implants, or those that had implants but did not have music immersion, remained severely hyperglycemic, they add.

They also note that the effect was seen only when the sound waves “directly impinge on the skin just above the implantation site” for at least 15 minutes, with no increase in insulin release observed with commercially available headphones or ear plugs, such as Apple AirPods, or with loud environmental noises.

Consequently, “therapeutic MUSIC sessions would still be compatible with listening to other types of music or listening to all types of music via headphones,” the researchers write, and are “compatible with standard drug administration schemes.”

The study was supported by a European Research Council advanced grant and in part by the Swiss National Science Foundation NCCR Molecular Systems Engineering. One author acknowledges the support of the Chinese Scholarship Council.

No relevant financial relationships were declared.

A version of this article appeared on Medscape.com.

Bass-heavy rock music applied directly to the abdomen of diabetic mice implanted with music-sensitive insulin-releasing cells attenuates postprandial glycemic excursions and restores normoglycemia, reveals a series of experiments.

The research was published in The Lancet Diabetes & Endocrinology.

After developing a cell line in which music-sensitive calcium channels triggered the release of insulin-containing vesicles, the researchers conducted a series of studies identifying the optimal frequency, pitch, and volume of sounds for triggering release.

After settling on low-bass heavy popular music, they tested their system on mice with type 1 diabetes that had the insulin-releasing cells implanted in their abdomen. Applying the music directly at 60 dB led to near wild-type levels of insulin in the blood within 15 minutes.

“With only 4 hours required for a full refill, [the system] can provide several therapeutic doses a day,” says Martin Fussenegger, PhD, professor of biotechnology and bioengineering, Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland, and colleagues.

“This would match the typical needs of people with type 2 diabetes consuming three meals a day, and for whom administration of prandial insulin is an established treatment option, as they do not have capability for early postprandial insulin secretion from preformed insulin.”

As the system requires nothing more than portable battery-powered commercially available loudspeakers, the multiple daily dosing of biopharmaceuticals becomes “straightforward in the absence of medical infrastructure or staff, simply by having the patient listen to the prescribed music.”

It therefore “could be an interesting option for cell-based therapies, especially where the need for frequent dosing raises compliance issues.”

It is a “very exciting piece of work, no doubt,” said Anandwardhan A. Hardikar, PhD, group leader, Diabetes and Islet Biology Group, Translational Health Research Institute, Western Sydney University, Penrith NSW, Australia.

He pointed out that the concept of using music to drive gene expression “is something we’ve known for the last 20 years,” but bringing the different strands of research together to generate cells that can be implanted into mice is “an amazing idea.”

Dr. Hardikar, who was not involved in the study, said, however, the publication of the study as a correspondence “does not allow for a lot of the detail that I would have expected as an academic,” and consequently some questions remain.

The most important is whether the music itself is required to trigger the insulin release, as opposed simply to sounds in general.

Is Music or Sound the “Trigger?”

Music is “frequency, it’s the amplitude of the waveform, and it’s the duration for which those waveforms are present,” he noted, but the same profile can be achieved by cutting up and editing the melody so it becomes a jumble of sounds.

For Dr. Hardikar, the “best control” for the study would be to have no music as well as the edited song, with “bits of pieces” played randomly so “it sounds like it’s the same frequency and amplitude.”

Then it would be clear whether the effect is owing to the “noise, or we have to appreciate the melody.”

The other outstanding question is whether the results “can directly translate to larger animals,” such as humans, Dr. Hardikar said.

The authors point out that when translated into mechanical vibrations in the middle ear, the acoustic waves of music activate mechanosensitive ion channels, a form of trigger that is seen across the animal kingdom.

They go on to highlight that while gene switches have been developed for use in next-generation cell-based therapies for a range of conditions, small-molecular trigger compounds face a number of challenges and may cause adverse effects.

With “traceless triggers” such as light, ultrasound, magnetic fields, radio waves, electricity, and heat also facing issues, there is a “need for new switching modalities.”

The researchers therefore developed a music-inducible cellular control (MUSIC) system, which leverages the known intracellular calcium surge in response to music, via calcium-permeable mechanosensitive channels, to drive the release of biopharmaceuticals from vesicles.

They then generated MUSIC-controlled insulin-releasing cell lines, finding that, using a customized box containing off-the-shelf loudspeakers, they could induce channel activation and insulin release with 60 dB at 50 Hz, which is “within the safe range for the human ear.”

Further experiments revealed that insulin release was greatest at 50-100 Hz, and higher than that seen with potassium chloride, the “gold-standard” depolarization control for calcium channels.

The researchers then showed that with optimal stimulation at 50 Hz and 60 dB, channel activation and subsequent insulin release required at least 3 seconds of continuous music, “which might protect the cellular device from inadvertent activation during everyday activities.”

Next, they examined the impact of different musical genres on insulin release, finding that low-bass heavy popular music and movie soundtracks induced maximum release, while the responses were more diverse to classical and guitar-based music.

Specifically, “We Will Rock You,” by the British rock band Queen, induced the release of 70% of available insulin within 5 minutes and 100% within 15 minutes. This, the team notes, is “similar to the dynamics of glucose-triggered insulin release by human pancreatic islets.”

Exposing the cells to a second music session at different intervals revealed that full insulin refill was achieved within 4 hours, which “would be appropriate to attenuate glycemic excursions associated with typical dietary habits.”

Finally, the researchers tested the system in vivo, constructing a box with two off-the-shelf loudspeakers that focuses acoustic waves, via deflectors, onto the abdomens of mice with type 1 diabetes.

Exposing the mice, which had been implanted with microencapsulated MUSIC cells in the peritoneum, to low-bass acoustic waves at 60 dB (50 m/s2) for 15 minutes allowed them to achieve near wild-type levels of insulin in the blood and restored normoglycemia.

Moreover, “Queen’s song ‘We Will Rock You’ generated sufficient insulin to rapidly attenuate postprandial glycemic excursions during glucose tolerance tests,” the team says.

In contrast, animals without implants, or those that had implants but did not have music immersion, remained severely hyperglycemic, they add.

They also note that the effect was seen only when the sound waves “directly impinge on the skin just above the implantation site” for at least 15 minutes, with no increase in insulin release observed with commercially available headphones or ear plugs, such as Apple AirPods, or with loud environmental noises.

Consequently, “therapeutic MUSIC sessions would still be compatible with listening to other types of music or listening to all types of music via headphones,” the researchers write, and are “compatible with standard drug administration schemes.”

The study was supported by a European Research Council advanced grant and in part by the Swiss National Science Foundation NCCR Molecular Systems Engineering. One author acknowledges the support of the Chinese Scholarship Council.

No relevant financial relationships were declared.

A version of this article appeared on Medscape.com.

Bass-heavy rock music applied directly to the abdomen of diabetic mice implanted with music-sensitive insulin-releasing cells attenuates postprandial glycemic excursions and restores normoglycemia, reveals a series of experiments.

The research was published in The Lancet Diabetes & Endocrinology.

After developing a cell line in which music-sensitive calcium channels triggered the release of insulin-containing vesicles, the researchers conducted a series of studies identifying the optimal frequency, pitch, and volume of sounds for triggering release.

After settling on low-bass heavy popular music, they tested their system on mice with type 1 diabetes that had the insulin-releasing cells implanted in their abdomen. Applying the music directly at 60 dB led to near wild-type levels of insulin in the blood within 15 minutes.

“With only 4 hours required for a full refill, [the system] can provide several therapeutic doses a day,” says Martin Fussenegger, PhD, professor of biotechnology and bioengineering, Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland, and colleagues.

“This would match the typical needs of people with type 2 diabetes consuming three meals a day, and for whom administration of prandial insulin is an established treatment option, as they do not have capability for early postprandial insulin secretion from preformed insulin.”

As the system requires nothing more than portable battery-powered commercially available loudspeakers, the multiple daily dosing of biopharmaceuticals becomes “straightforward in the absence of medical infrastructure or staff, simply by having the patient listen to the prescribed music.”

It therefore “could be an interesting option for cell-based therapies, especially where the need for frequent dosing raises compliance issues.”

It is a “very exciting piece of work, no doubt,” said Anandwardhan A. Hardikar, PhD, group leader, Diabetes and Islet Biology Group, Translational Health Research Institute, Western Sydney University, Penrith NSW, Australia.

He pointed out that the concept of using music to drive gene expression “is something we’ve known for the last 20 years,” but bringing the different strands of research together to generate cells that can be implanted into mice is “an amazing idea.”

Dr. Hardikar, who was not involved in the study, said, however, the publication of the study as a correspondence “does not allow for a lot of the detail that I would have expected as an academic,” and consequently some questions remain.

The most important is whether the music itself is required to trigger the insulin release, as opposed simply to sounds in general.

Is Music or Sound the “Trigger?”

Music is “frequency, it’s the amplitude of the waveform, and it’s the duration for which those waveforms are present,” he noted, but the same profile can be achieved by cutting up and editing the melody so it becomes a jumble of sounds.

For Dr. Hardikar, the “best control” for the study would be to have no music as well as the edited song, with “bits of pieces” played randomly so “it sounds like it’s the same frequency and amplitude.”

Then it would be clear whether the effect is owing to the “noise, or we have to appreciate the melody.”

The other outstanding question is whether the results “can directly translate to larger animals,” such as humans, Dr. Hardikar said.

The authors point out that when translated into mechanical vibrations in the middle ear, the acoustic waves of music activate mechanosensitive ion channels, a form of trigger that is seen across the animal kingdom.

They go on to highlight that while gene switches have been developed for use in next-generation cell-based therapies for a range of conditions, small-molecular trigger compounds face a number of challenges and may cause adverse effects.

With “traceless triggers” such as light, ultrasound, magnetic fields, radio waves, electricity, and heat also facing issues, there is a “need for new switching modalities.”

The researchers therefore developed a music-inducible cellular control (MUSIC) system, which leverages the known intracellular calcium surge in response to music, via calcium-permeable mechanosensitive channels, to drive the release of biopharmaceuticals from vesicles.

They then generated MUSIC-controlled insulin-releasing cell lines, finding that, using a customized box containing off-the-shelf loudspeakers, they could induce channel activation and insulin release with 60 dB at 50 Hz, which is “within the safe range for the human ear.”

Further experiments revealed that insulin release was greatest at 50-100 Hz, and higher than that seen with potassium chloride, the “gold-standard” depolarization control for calcium channels.

The researchers then showed that with optimal stimulation at 50 Hz and 60 dB, channel activation and subsequent insulin release required at least 3 seconds of continuous music, “which might protect the cellular device from inadvertent activation during everyday activities.”

Next, they examined the impact of different musical genres on insulin release, finding that low-bass heavy popular music and movie soundtracks induced maximum release, while the responses were more diverse to classical and guitar-based music.

Specifically, “We Will Rock You,” by the British rock band Queen, induced the release of 70% of available insulin within 5 minutes and 100% within 15 minutes. This, the team notes, is “similar to the dynamics of glucose-triggered insulin release by human pancreatic islets.”

Exposing the cells to a second music session at different intervals revealed that full insulin refill was achieved within 4 hours, which “would be appropriate to attenuate glycemic excursions associated with typical dietary habits.”

Finally, the researchers tested the system in vivo, constructing a box with two off-the-shelf loudspeakers that focuses acoustic waves, via deflectors, onto the abdomens of mice with type 1 diabetes.

Exposing the mice, which had been implanted with microencapsulated MUSIC cells in the peritoneum, to low-bass acoustic waves at 60 dB (50 m/s2) for 15 minutes allowed them to achieve near wild-type levels of insulin in the blood and restored normoglycemia.

Moreover, “Queen’s song ‘We Will Rock You’ generated sufficient insulin to rapidly attenuate postprandial glycemic excursions during glucose tolerance tests,” the team says.

In contrast, animals without implants, or those that had implants but did not have music immersion, remained severely hyperglycemic, they add.

They also note that the effect was seen only when the sound waves “directly impinge on the skin just above the implantation site” for at least 15 minutes, with no increase in insulin release observed with commercially available headphones or ear plugs, such as Apple AirPods, or with loud environmental noises.

Consequently, “therapeutic MUSIC sessions would still be compatible with listening to other types of music or listening to all types of music via headphones,” the researchers write, and are “compatible with standard drug administration schemes.”

The study was supported by a European Research Council advanced grant and in part by the Swiss National Science Foundation NCCR Molecular Systems Engineering. One author acknowledges the support of the Chinese Scholarship Council.

No relevant financial relationships were declared.

A version of this article appeared on Medscape.com.

Depression, constipation, cystitis/urinary tract infections (UTIs), and sexual dysfunction may be early warning signs of multiple sclerosis (MS) 5 years prior to diagnosis, new research shows.

However, these prodromal symptoms are also more likely to occur in people with two other autoimmune diseases — lupus and Crohn’s disease — and therefore, will not help earlier diagnosis, study investigator, Céline Louapre, professor of neurology, Sorbonne University and Paris Brain Institute, Paris, France, said in an interview.

“On the other hand, in certain patients who may be at particular risk of developing MS, such as in certain familial forms or in patients with incidental inflammatory lesions discovered on MRI, the presence of these symptoms could suggest an already active process, prior to the first typical symptoms of the disease,” she noted.
 

Retracing MS Origins

The case-control study, published online in Neurology, included 20,174 people with newly diagnosed MS who were matched to 54,790 without MS, as well as 30,477 with Crohn’s disease and 7337 with lupus.

Using International Classification of Diseases, 10th revision (ICD-10) codes in electronic health records, the researchers assessed the associations between 113 diseases and symptoms in the 5 years before and after an MS diagnosis.

Twelve ICD-10 codes were significantly positively associated with the risk for MS compared with controls without MS.

After considering ICD-10 codes suggestive of neurologic symptoms as the first diagnosis of MS, the following five ICD-10 codes remained significantly associated with MS:

• Depression (odds ratio [OR], 1.22; 95% CI, 1.11-1.34)
• Sexual dysfunction (OR, 1.47; 95% CI, 1.11-1.95)
• Constipation (OR, 1.5; 95% CI, 1.27-1.78)
• Cystitis (OR, 1.21; 95% CI, 1.05-1.39)
• UTIs of unspecified site (OR, 1.38; 95% CI, 1.18-1.61)

However, none of these conditions was selectively associated with MS in comparison with both lupus and Crohn’s disease. All five ICD-10 codes identified were still associated with MS during the 5 years after diagnosis.

“The importance of investigating prodromal signs in MS is that it allows us to retrace the origins of the disease,” said Dr. Louapre.

“The main contribution of the data on prodromes in MS is to clarify that the disease and its mechanisms are frequently underway well before the first typical neurological symptoms, and that the causes of MS are probably present many years before diagnosis,” she added.

A limitation of the study was that data were not available for other factors that could influence people’s risk of developing MS, such as education level, ethnicity, body mass index, socioeconomic status, or genetic information.

It also remains unclear whether the conditions linked to MS are risk factors for the disease or nonspecific early MS symptoms.
 

Preventing Disease Evolution

In a linked editorial, Ruth Ann Marrie, MD, PhD, with the University of Manitoba, Manitoba, Canada, and Raffaele Palladino, MD, PhD, with the University of Naples Federico II, Naples, Italy, note these findings highlight the challenges of accurately identifying the prodromal stage of a specific disease.

“Commonalities of prodromal features are recognized across neurodegenerative diseases; this is also true for immune-mediated diseases, and it is not surprising, given shared etiologic factors and pathobiological mechanisms,” they point out.

“This suggests that we should be trying to link prodromal features to specific underlying pathobiological changes rather than specific diseases. This approach would require use of different study designs, including broad, deeply phenotyped cohorts, but would allow us to develop and test interventions targeted at those mechanisms, and could ultimately achieve the goal of preventing disease evolution,” they add.

The study was supported by the French National Research Agency. Dr. Louapre has received consulting or travel fees from Biogen, Novartis, Roche, Sanofi, Teva, and Merck Serono, unrelated to this study. Dr. Marrie is a coinvestigator on studies receiving funding from Biogen Idec and Roche Canada; receives research funding from CIHR, Research Manitoba, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Crohn’s and Colitis Canada, National Multiple Sclerosis Society, CMSC, the Arthritis Society and the US Department of Defense; and serves on the editorial board of Neurology. Dr. Palladino has taken part in advisory boards/consultancy for MSD and Sanofi and has received support from the UK MS Society.

A version of this article appeared on Medscape.com.

Depression, constipation, cystitis/urinary tract infections (UTIs), and sexual dysfunction may be early warning signs of multiple sclerosis (MS) 5 years prior to diagnosis, new research shows.

However, these prodromal symptoms are also more likely to occur in people with two other autoimmune diseases — lupus and Crohn’s disease — and therefore, will not help earlier diagnosis, study investigator, Céline Louapre, professor of neurology, Sorbonne University and Paris Brain Institute, Paris, France, said in an interview.

“On the other hand, in certain patients who may be at particular risk of developing MS, such as in certain familial forms or in patients with incidental inflammatory lesions discovered on MRI, the presence of these symptoms could suggest an already active process, prior to the first typical symptoms of the disease,” she noted.
 

Retracing MS Origins

The case-control study, published online in Neurology, included 20,174 people with newly diagnosed MS who were matched to 54,790 without MS, as well as 30,477 with Crohn’s disease and 7337 with lupus.

Using International Classification of Diseases, 10th revision (ICD-10) codes in electronic health records, the researchers assessed the associations between 113 diseases and symptoms in the 5 years before and after an MS diagnosis.

Twelve ICD-10 codes were significantly positively associated with the risk for MS compared with controls without MS.

After considering ICD-10 codes suggestive of neurologic symptoms as the first diagnosis of MS, the following five ICD-10 codes remained significantly associated with MS:

• Depression (odds ratio [OR], 1.22; 95% CI, 1.11-1.34)
• Sexual dysfunction (OR, 1.47; 95% CI, 1.11-1.95)
• Constipation (OR, 1.5; 95% CI, 1.27-1.78)
• Cystitis (OR, 1.21; 95% CI, 1.05-1.39)
• UTIs of unspecified site (OR, 1.38; 95% CI, 1.18-1.61)

However, none of these conditions was selectively associated with MS in comparison with both lupus and Crohn’s disease. All five ICD-10 codes identified were still associated with MS during the 5 years after diagnosis.

“The importance of investigating prodromal signs in MS is that it allows us to retrace the origins of the disease,” said Dr. Louapre.

“The main contribution of the data on prodromes in MS is to clarify that the disease and its mechanisms are frequently underway well before the first typical neurological symptoms, and that the causes of MS are probably present many years before diagnosis,” she added.

A limitation of the study was that data were not available for other factors that could influence people’s risk of developing MS, such as education level, ethnicity, body mass index, socioeconomic status, or genetic information.

It also remains unclear whether the conditions linked to MS are risk factors for the disease or nonspecific early MS symptoms.
 

Preventing Disease Evolution

In a linked editorial, Ruth Ann Marrie, MD, PhD, with the University of Manitoba, Manitoba, Canada, and Raffaele Palladino, MD, PhD, with the University of Naples Federico II, Naples, Italy, note these findings highlight the challenges of accurately identifying the prodromal stage of a specific disease.

“Commonalities of prodromal features are recognized across neurodegenerative diseases; this is also true for immune-mediated diseases, and it is not surprising, given shared etiologic factors and pathobiological mechanisms,” they point out.

“This suggests that we should be trying to link prodromal features to specific underlying pathobiological changes rather than specific diseases. This approach would require use of different study designs, including broad, deeply phenotyped cohorts, but would allow us to develop and test interventions targeted at those mechanisms, and could ultimately achieve the goal of preventing disease evolution,” they add.

The study was supported by the French National Research Agency. Dr. Louapre has received consulting or travel fees from Biogen, Novartis, Roche, Sanofi, Teva, and Merck Serono, unrelated to this study. Dr. Marrie is a coinvestigator on studies receiving funding from Biogen Idec and Roche Canada; receives research funding from CIHR, Research Manitoba, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Crohn’s and Colitis Canada, National Multiple Sclerosis Society, CMSC, the Arthritis Society and the US Department of Defense; and serves on the editorial board of Neurology. Dr. Palladino has taken part in advisory boards/consultancy for MSD and Sanofi and has received support from the UK MS Society.

A version of this article appeared on Medscape.com.

Depression, constipation, cystitis/urinary tract infections (UTIs), and sexual dysfunction may be early warning signs of multiple sclerosis (MS) 5 years prior to diagnosis, new research shows.

However, these prodromal symptoms are also more likely to occur in people with two other autoimmune diseases — lupus and Crohn’s disease — and therefore, will not help earlier diagnosis, study investigator, Céline Louapre, professor of neurology, Sorbonne University and Paris Brain Institute, Paris, France, said in an interview.

“On the other hand, in certain patients who may be at particular risk of developing MS, such as in certain familial forms or in patients with incidental inflammatory lesions discovered on MRI, the presence of these symptoms could suggest an already active process, prior to the first typical symptoms of the disease,” she noted.
 

Retracing MS Origins

The case-control study, published online in Neurology, included 20,174 people with newly diagnosed MS who were matched to 54,790 without MS, as well as 30,477 with Crohn’s disease and 7337 with lupus.

Using International Classification of Diseases, 10th revision (ICD-10) codes in electronic health records, the researchers assessed the associations between 113 diseases and symptoms in the 5 years before and after an MS diagnosis.

Twelve ICD-10 codes were significantly positively associated with the risk for MS compared with controls without MS.

After considering ICD-10 codes suggestive of neurologic symptoms as the first diagnosis of MS, the following five ICD-10 codes remained significantly associated with MS:

• Depression (odds ratio [OR], 1.22; 95% CI, 1.11-1.34)
• Sexual dysfunction (OR, 1.47; 95% CI, 1.11-1.95)
• Constipation (OR, 1.5; 95% CI, 1.27-1.78)
• Cystitis (OR, 1.21; 95% CI, 1.05-1.39)
• UTIs of unspecified site (OR, 1.38; 95% CI, 1.18-1.61)

However, none of these conditions was selectively associated with MS in comparison with both lupus and Crohn’s disease. All five ICD-10 codes identified were still associated with MS during the 5 years after diagnosis.

“The importance of investigating prodromal signs in MS is that it allows us to retrace the origins of the disease,” said Dr. Louapre.

“The main contribution of the data on prodromes in MS is to clarify that the disease and its mechanisms are frequently underway well before the first typical neurological symptoms, and that the causes of MS are probably present many years before diagnosis,” she added.

A limitation of the study was that data were not available for other factors that could influence people’s risk of developing MS, such as education level, ethnicity, body mass index, socioeconomic status, or genetic information.

It also remains unclear whether the conditions linked to MS are risk factors for the disease or nonspecific early MS symptoms.
 

Preventing Disease Evolution

In a linked editorial, Ruth Ann Marrie, MD, PhD, with the University of Manitoba, Manitoba, Canada, and Raffaele Palladino, MD, PhD, with the University of Naples Federico II, Naples, Italy, note these findings highlight the challenges of accurately identifying the prodromal stage of a specific disease.

“Commonalities of prodromal features are recognized across neurodegenerative diseases; this is also true for immune-mediated diseases, and it is not surprising, given shared etiologic factors and pathobiological mechanisms,” they point out.

“This suggests that we should be trying to link prodromal features to specific underlying pathobiological changes rather than specific diseases. This approach would require use of different study designs, including broad, deeply phenotyped cohorts, but would allow us to develop and test interventions targeted at those mechanisms, and could ultimately achieve the goal of preventing disease evolution,” they add.

The study was supported by the French National Research Agency. Dr. Louapre has received consulting or travel fees from Biogen, Novartis, Roche, Sanofi, Teva, and Merck Serono, unrelated to this study. Dr. Marrie is a coinvestigator on studies receiving funding from Biogen Idec and Roche Canada; receives research funding from CIHR, Research Manitoba, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Crohn’s and Colitis Canada, National Multiple Sclerosis Society, CMSC, the Arthritis Society and the US Department of Defense; and serves on the editorial board of Neurology. Dr. Palladino has taken part in advisory boards/consultancy for MSD and Sanofi and has received support from the UK MS Society.

A version of this article appeared on Medscape.com.

As revolutionary as glucagon-like peptide 1 (GLP-1) drugs are, they still last for only so long in the body. Patients with diabetes typically must be injected once or twice a day (liraglutide) or once a week (semaglutide). This could hinder proper diabetes management, as adherence tends to go down the more frequent the dose. 

But what if a single GLP-1 injection could last for 4 months?

Stanford engineers have developed an injectable hydrogel depot that releases GLP-1 slowly as the hydrogel gradually “melts away like a sugar cube dissolving in water, molecule by molecule,” said Eric Appel, PhD, the project’s principal investigator and an associate professor of materials science and engineering at Stanford (Calif.) University.

So far, the team has tested the new drug delivery system in rats, and they say human clinical trials could start within 2 years.

Mathematical modeling indicated that one shot of liraglutide could maintain exposure in humans for 120 days, or about 4 months, according to their study in Cell Reports Medicine.

“Patient adherence is of critical importance to diabetes care,” said Alex Abramson, PhD, assistant professor in the chemical and biomolecular engineering department at Georgia Tech, who was not involved in the study. “It’s very exciting to have a potential new system that can last 4 months on a single injection.”

Long-Acting Injectables Have Come a Long Way

The first long-acting injectable — Lupron Depot, a monthly treatment for advanced prostate cancer — was approved in 1989. Since then, long-acting injectable depots have revolutionized the treatment and management of conditions ranging from osteoarthritis knee pain to schizophrenia to opioid use disorder. In 2021, the US Food and Drug Administration approved Apretude — an injectable treatment for HIV pre-exposure prevention that needs to be given every 2 months, compared with daily for the pill equivalent. Other new and innovative developments are underway: Researchers at the University of Connecticut are working on a transdermal microneedle patch — with many tiny vaccine-loaded needles — that could provide multiple doses of a vaccine over time, no boosters needed.

At Stanford, Appel’s lab has spent years developing gels for drug delivery. His team uses a class of hydrogel called polymer-nanoparticle (PNP), which features weakly bound polymers and nanoparticles that can dissipate slowly over time.

The goal is to address a longstanding challenge with long-acting formulations: Achieving steady release. Because the hydrogel is “self-healing” — able to repair damages and restore its shape — it’s less likely to burst and release its drug cargo too early. 

“Our PNP hydrogels possess a number of really unique characteristics,” Dr. Appel said. They have “excellent” biocompatibility, based on animal studies, and could work with a wide range of drugs. In proof-of-concept mouse studies, Dr. Appel and his team have shown that these hydrogels could also be used to make vaccines last longer, ferry cancer immunotherapies directly to tumors, and deliver antibodies for the prevention of infectious diseases like SARS-CoV-2.

Though the recent study on GLP-1s focused on treating type 2 diabetes, the same formulation could also be used to treat obesity, said Dr. Appel.

The researchers tested the tech using two GLP-1 receptor agonists — semaglutide and liraglutide. In rats, one shot maintained therapeutic serum concentrations of semaglutide or liraglutide over 42 days. With semaglutide, a significant portion was released quickly, followed by controlled release. Liraglutide, on the other hand, was released gradually as the hydrogel dissolved. This suggests the liraglutide hydrogel may be better tolerated, as a sudden peak in drug serum concentration is associated with adverse effects.

The researchers used pharmacokinetic modeling to predict how liraglutide would behave in humans with a larger injection volume, finding that a single dose could maintain therapeutic levels for about 4 months.

“Moving forward, it will be important to determine whether a burst release from the formulation causes any side effects,” Dr. Abramson noted. “Furthermore, it will be important to minimize the injection volumes in humans.”

But first, more studies in larger animals are needed. Next, Dr. Appel and his team plan to test the technology in pigs, whose skin and endocrine systems are most like humans’. If those trials go well, Dr. Appel said, human clinical trials could start within 2 years.
 

A version of this article appeared on Medscape.com.

As revolutionary as glucagon-like peptide 1 (GLP-1) drugs are, they still last for only so long in the body. Patients with diabetes typically must be injected once or twice a day (liraglutide) or once a week (semaglutide). This could hinder proper diabetes management, as adherence tends to go down the more frequent the dose. 

But what if a single GLP-1 injection could last for 4 months?

Stanford engineers have developed an injectable hydrogel depot that releases GLP-1 slowly as the hydrogel gradually “melts away like a sugar cube dissolving in water, molecule by molecule,” said Eric Appel, PhD, the project’s principal investigator and an associate professor of materials science and engineering at Stanford (Calif.) University.

So far, the team has tested the new drug delivery system in rats, and they say human clinical trials could start within 2 years.

Mathematical modeling indicated that one shot of liraglutide could maintain exposure in humans for 120 days, or about 4 months, according to their study in Cell Reports Medicine.

“Patient adherence is of critical importance to diabetes care,” said Alex Abramson, PhD, assistant professor in the chemical and biomolecular engineering department at Georgia Tech, who was not involved in the study. “It’s very exciting to have a potential new system that can last 4 months on a single injection.”

Long-Acting Injectables Have Come a Long Way

The first long-acting injectable — Lupron Depot, a monthly treatment for advanced prostate cancer — was approved in 1989. Since then, long-acting injectable depots have revolutionized the treatment and management of conditions ranging from osteoarthritis knee pain to schizophrenia to opioid use disorder. In 2021, the US Food and Drug Administration approved Apretude — an injectable treatment for HIV pre-exposure prevention that needs to be given every 2 months, compared with daily for the pill equivalent. Other new and innovative developments are underway: Researchers at the University of Connecticut are working on a transdermal microneedle patch — with many tiny vaccine-loaded needles — that could provide multiple doses of a vaccine over time, no boosters needed.

At Stanford, Appel’s lab has spent years developing gels for drug delivery. His team uses a class of hydrogel called polymer-nanoparticle (PNP), which features weakly bound polymers and nanoparticles that can dissipate slowly over time.

The goal is to address a longstanding challenge with long-acting formulations: Achieving steady release. Because the hydrogel is “self-healing” — able to repair damages and restore its shape — it’s less likely to burst and release its drug cargo too early. 

“Our PNP hydrogels possess a number of really unique characteristics,” Dr. Appel said. They have “excellent” biocompatibility, based on animal studies, and could work with a wide range of drugs. In proof-of-concept mouse studies, Dr. Appel and his team have shown that these hydrogels could also be used to make vaccines last longer, ferry cancer immunotherapies directly to tumors, and deliver antibodies for the prevention of infectious diseases like SARS-CoV-2.

Though the recent study on GLP-1s focused on treating type 2 diabetes, the same formulation could also be used to treat obesity, said Dr. Appel.

The researchers tested the tech using two GLP-1 receptor agonists — semaglutide and liraglutide. In rats, one shot maintained therapeutic serum concentrations of semaglutide or liraglutide over 42 days. With semaglutide, a significant portion was released quickly, followed by controlled release. Liraglutide, on the other hand, was released gradually as the hydrogel dissolved. This suggests the liraglutide hydrogel may be better tolerated, as a sudden peak in drug serum concentration is associated with adverse effects.

The researchers used pharmacokinetic modeling to predict how liraglutide would behave in humans with a larger injection volume, finding that a single dose could maintain therapeutic levels for about 4 months.

“Moving forward, it will be important to determine whether a burst release from the formulation causes any side effects,” Dr. Abramson noted. “Furthermore, it will be important to minimize the injection volumes in humans.”

But first, more studies in larger animals are needed. Next, Dr. Appel and his team plan to test the technology in pigs, whose skin and endocrine systems are most like humans’. If those trials go well, Dr. Appel said, human clinical trials could start within 2 years.
 

A version of this article appeared on Medscape.com.

As revolutionary as glucagon-like peptide 1 (GLP-1) drugs are, they still last for only so long in the body. Patients with diabetes typically must be injected once or twice a day (liraglutide) or once a week (semaglutide). This could hinder proper diabetes management, as adherence tends to go down the more frequent the dose. 

But what if a single GLP-1 injection could last for 4 months?

Stanford engineers have developed an injectable hydrogel depot that releases GLP-1 slowly as the hydrogel gradually “melts away like a sugar cube dissolving in water, molecule by molecule,” said Eric Appel, PhD, the project’s principal investigator and an associate professor of materials science and engineering at Stanford (Calif.) University.

So far, the team has tested the new drug delivery system in rats, and they say human clinical trials could start within 2 years.

Mathematical modeling indicated that one shot of liraglutide could maintain exposure in humans for 120 days, or about 4 months, according to their study in Cell Reports Medicine.

“Patient adherence is of critical importance to diabetes care,” said Alex Abramson, PhD, assistant professor in the chemical and biomolecular engineering department at Georgia Tech, who was not involved in the study. “It’s very exciting to have a potential new system that can last 4 months on a single injection.”

Long-Acting Injectables Have Come a Long Way

The first long-acting injectable — Lupron Depot, a monthly treatment for advanced prostate cancer — was approved in 1989. Since then, long-acting injectable depots have revolutionized the treatment and management of conditions ranging from osteoarthritis knee pain to schizophrenia to opioid use disorder. In 2021, the US Food and Drug Administration approved Apretude — an injectable treatment for HIV pre-exposure prevention that needs to be given every 2 months, compared with daily for the pill equivalent. Other new and innovative developments are underway: Researchers at the University of Connecticut are working on a transdermal microneedle patch — with many tiny vaccine-loaded needles — that could provide multiple doses of a vaccine over time, no boosters needed.

At Stanford, Appel’s lab has spent years developing gels for drug delivery. His team uses a class of hydrogel called polymer-nanoparticle (PNP), which features weakly bound polymers and nanoparticles that can dissipate slowly over time.

The goal is to address a longstanding challenge with long-acting formulations: Achieving steady release. Because the hydrogel is “self-healing” — able to repair damages and restore its shape — it’s less likely to burst and release its drug cargo too early. 

“Our PNP hydrogels possess a number of really unique characteristics,” Dr. Appel said. They have “excellent” biocompatibility, based on animal studies, and could work with a wide range of drugs. In proof-of-concept mouse studies, Dr. Appel and his team have shown that these hydrogels could also be used to make vaccines last longer, ferry cancer immunotherapies directly to tumors, and deliver antibodies for the prevention of infectious diseases like SARS-CoV-2.

Though the recent study on GLP-1s focused on treating type 2 diabetes, the same formulation could also be used to treat obesity, said Dr. Appel.

The researchers tested the tech using two GLP-1 receptor agonists — semaglutide and liraglutide. In rats, one shot maintained therapeutic serum concentrations of semaglutide or liraglutide over 42 days. With semaglutide, a significant portion was released quickly, followed by controlled release. Liraglutide, on the other hand, was released gradually as the hydrogel dissolved. This suggests the liraglutide hydrogel may be better tolerated, as a sudden peak in drug serum concentration is associated with adverse effects.

The researchers used pharmacokinetic modeling to predict how liraglutide would behave in humans with a larger injection volume, finding that a single dose could maintain therapeutic levels for about 4 months.

“Moving forward, it will be important to determine whether a burst release from the formulation causes any side effects,” Dr. Abramson noted. “Furthermore, it will be important to minimize the injection volumes in humans.”

But first, more studies in larger animals are needed. Next, Dr. Appel and his team plan to test the technology in pigs, whose skin and endocrine systems are most like humans’. If those trials go well, Dr. Appel said, human clinical trials could start within 2 years.
 

A version of this article appeared on Medscape.com.

TOPLINE:

People who are extroverted and conscientious and have a positive outlook may be at lower dementia risk, whereas those who score highly for neuroticism and have a negative outlook may be at increased risk, new research suggests. 

METHODOLOGY: 

• Researchers examined the link between the “big five” personality traits (conscientiousness, extraversion, openness to experience, neuroticism, and agreeableness) and subjective well-being (positive and negative affect and life satisfaction) and clinical symptoms of dementia (cognitive test performance) and neuropathology at autopsy. 
• Data for the meta-analysis came from eight longitudinal studies with 44,531 adults (aged 49-81 years at baseline; 26%-61% women) followed for up to 21 years, during which 1703 incident cases of dementia occurred. 
• Bayesian multilevel models tested whether personality traits and subjective well-being differentially predicted neuropsychological and neuropathologic characteristics of dementia. 

TAKEAWAY:

• High neuroticism, negative affect, and low conscientiousness were risk factors for dementia, whereas conscientiousness, extraversion, and positive affect were protective.
• Across all analyses, there was directional consistency in estimates across samples, which is noteworthy given between-study differences in sociodemographic and design characteristics. 
• No consistent associations were found between psychological factors and neuropathology. 
• However, individuals higher in conscientiousness who did not receive a clinical diagnosis tended to have a lower Braak stage at autopsy, suggesting the possibility that conscientiousness is related to cognitive resilience. 

IN PRACTICE:

“These results replicate and extend evidence that personality traits may assist in early identification and dementia-care planning strategies, as well as risk stratification for dementia diagnosis. Moreover, our findings provide further support for recommendations to incorporate psychological trait measures into clinical screening or diagnosis criteria,” the authors write. SOURCE:

The study, with first author Emorie Beck, PhD, Department of Psychology, University of California, Davis, was published online on November 29, 2023, in Alzheimer’s & Dementia.

 LIMITATIONS:

Access to autopsy data was limited. The findings may not generalize across racial groups. The analysis did not examine dynamic associations between changing personality and cognition and neuropathology over time.

DISCLOSURES:

The study was supported by grants from the National Institute on Aging. The authors have declared no conflicts of interest.

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

TOPLINE:

People who are extroverted and conscientious and have a positive outlook may be at lower dementia risk, whereas those who score highly for neuroticism and have a negative outlook may be at increased risk, new research suggests. 

METHODOLOGY: 

• Researchers examined the link between the “big five” personality traits (conscientiousness, extraversion, openness to experience, neuroticism, and agreeableness) and subjective well-being (positive and negative affect and life satisfaction) and clinical symptoms of dementia (cognitive test performance) and neuropathology at autopsy. 
• Data for the meta-analysis came from eight longitudinal studies with 44,531 adults (aged 49-81 years at baseline; 26%-61% women) followed for up to 21 years, during which 1703 incident cases of dementia occurred. 
• Bayesian multilevel models tested whether personality traits and subjective well-being differentially predicted neuropsychological and neuropathologic characteristics of dementia. 

TAKEAWAY:

• High neuroticism, negative affect, and low conscientiousness were risk factors for dementia, whereas conscientiousness, extraversion, and positive affect were protective.
• Across all analyses, there was directional consistency in estimates across samples, which is noteworthy given between-study differences in sociodemographic and design characteristics. 
• No consistent associations were found between psychological factors and neuropathology. 
• However, individuals higher in conscientiousness who did not receive a clinical diagnosis tended to have a lower Braak stage at autopsy, suggesting the possibility that conscientiousness is related to cognitive resilience. 

IN PRACTICE:

“These results replicate and extend evidence that personality traits may assist in early identification and dementia-care planning strategies, as well as risk stratification for dementia diagnosis. Moreover, our findings provide further support for recommendations to incorporate psychological trait measures into clinical screening or diagnosis criteria,” the authors write. SOURCE:

The study, with first author Emorie Beck, PhD, Department of Psychology, University of California, Davis, was published online on November 29, 2023, in Alzheimer’s & Dementia.

 LIMITATIONS:

Access to autopsy data was limited. The findings may not generalize across racial groups. The analysis did not examine dynamic associations between changing personality and cognition and neuropathology over time.

DISCLOSURES:

The study was supported by grants from the National Institute on Aging. The authors have declared no conflicts of interest.

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

TOPLINE:

People who are extroverted and conscientious and have a positive outlook may be at lower dementia risk, whereas those who score highly for neuroticism and have a negative outlook may be at increased risk, new research suggests. 

METHODOLOGY: 

• Researchers examined the link between the “big five” personality traits (conscientiousness, extraversion, openness to experience, neuroticism, and agreeableness) and subjective well-being (positive and negative affect and life satisfaction) and clinical symptoms of dementia (cognitive test performance) and neuropathology at autopsy. 
• Data for the meta-analysis came from eight longitudinal studies with 44,531 adults (aged 49-81 years at baseline; 26%-61% women) followed for up to 21 years, during which 1703 incident cases of dementia occurred. 
• Bayesian multilevel models tested whether personality traits and subjective well-being differentially predicted neuropsychological and neuropathologic characteristics of dementia. 

TAKEAWAY:

• High neuroticism, negative affect, and low conscientiousness were risk factors for dementia, whereas conscientiousness, extraversion, and positive affect were protective.
• Across all analyses, there was directional consistency in estimates across samples, which is noteworthy given between-study differences in sociodemographic and design characteristics. 
• No consistent associations were found between psychological factors and neuropathology. 
• However, individuals higher in conscientiousness who did not receive a clinical diagnosis tended to have a lower Braak stage at autopsy, suggesting the possibility that conscientiousness is related to cognitive resilience. 

IN PRACTICE:

“These results replicate and extend evidence that personality traits may assist in early identification and dementia-care planning strategies, as well as risk stratification for dementia diagnosis. Moreover, our findings provide further support for recommendations to incorporate psychological trait measures into clinical screening or diagnosis criteria,” the authors write. SOURCE:

The study, with first author Emorie Beck, PhD, Department of Psychology, University of California, Davis, was published online on November 29, 2023, in Alzheimer’s & Dementia.

 LIMITATIONS:

Access to autopsy data was limited. The findings may not generalize across racial groups. The analysis did not examine dynamic associations between changing personality and cognition and neuropathology over time.

DISCLOSURES:

The study was supported by grants from the National Institute on Aging. The authors have declared no conflicts of interest.

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

TOPLINE:

Adults diagnosed with coronary heart disease (CHD) are at an increased risk for dementia, including all-cause dementia, Alzheimer›s disease (AD), and vascular dementia (VD), with the risk highest — at 36% — if onset is before age 45, results of a large observational study show.

METHODOLOGY:

• The study included 432,667 of the more than 500,000 participants in the UK Biobank, with a mean age of 56.9 years, 50,685 (11.7%) of whom had CHD and 50,445 had data on age at CHD onset.
• Researchers divided participants into three groups according to age at CHD onset (below 45 years, 45-59 years, and 60 years and older), and carried out a propensity score matching analysis.
• Outcomes included all-cause dementia, AD, and VD.
• Covariates included age, sex, race, educational level, body mass index, low-density lipoprotein cholesterol, smoking status, alcohol intake, exercise, depressed mood, hypertension, diabetes, statin use, and apolipoprotein E4 status.

TAKEAWAY:

• During a median follow-up of 12.8 years, researchers identified 5876 cases of all-cause dementia, 2540 cases of AD, and 1220 cases of VD.
• Fully adjusted models showed participants with CHD had significantly higher risks than those without CHD of developing all-cause dementia (hazard ratio [HR], 1.36; 95% CI, 1.28-1.45; P < .001), AD (HR, 1.13; 95% CI, 1.02-1.24; P = .019), and VD (HR, 1.78; 95% CI, 1.56-2.02; P < .001). The higher risk for VD suggests CHD has a more profound influence on neuropathologic changes involved in this dementia type, said the authors.
• Those with CHD diagnosed at a younger age had higher risks of developing dementia (HR per 10-year decrease in age, 1.25; 95% CI, 1.20-1.30 for all-cause dementia, 1.29; 95% CI, 1.20-1.38 for AD, and 1.22; 95% CI, 1.13-1.31 for VD; P for all < .001).
• Propensity score matching analysis showed patients with CHD had significantly higher risks for dementia compared with matched controls, with the highest risk seen in patients diagnosed before age 45 (HR, 2.40; 95% CI, 1.79-3.20; P < .001), followed by those diagnosed between 45 and 59 years (HR, 1.46; 95% CI, 1.32-1.62; P < .001) and at or above 60 years (HR, 1.11; 95% CI, 1.03-1.19; P = .005), with similar results for AD and VD.

IN PRACTICE:

The findings suggest “additional attention should be paid to the cognitive status of patients with CHD, especially the ones diagnosed with CHD at a young age,” the authors conclude, noting that “timely intervention, such as cognitive training, could be implemented once signs of cognitive deteriorations are detected.”

SOURCE:

The study was conducted by Jie Liang, BS, School of Nursing, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, and colleagues. It was published online on November 29, 2023, in the Journal of the American Heart Association.

LIMITATIONS:

As this is an observational study, it can’t conclude a causal relationship. Although the authors adjusted for many potential confounders, unknown risk factors that also contribute to CHD can’t be ruled out. As the study excluded 69,744 participants, selection bias is possible. The study included a mostly White population.

DISCLOSURES:

The study was supported by the National Natural Science Foundation of China, the Non-Profit Central Research Institute Fund of the Chinese Academy of Medical Sciences, and the China Medical Board. The authors have no relevant conflicts of interest.

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

TOPLINE:

Adults diagnosed with coronary heart disease (CHD) are at an increased risk for dementia, including all-cause dementia, Alzheimer›s disease (AD), and vascular dementia (VD), with the risk highest — at 36% — if onset is before age 45, results of a large observational study show.

METHODOLOGY:

• The study included 432,667 of the more than 500,000 participants in the UK Biobank, with a mean age of 56.9 years, 50,685 (11.7%) of whom had CHD and 50,445 had data on age at CHD onset.
• Researchers divided participants into three groups according to age at CHD onset (below 45 years, 45-59 years, and 60 years and older), and carried out a propensity score matching analysis.
• Outcomes included all-cause dementia, AD, and VD.
• Covariates included age, sex, race, educational level, body mass index, low-density lipoprotein cholesterol, smoking status, alcohol intake, exercise, depressed mood, hypertension, diabetes, statin use, and apolipoprotein E4 status.

TAKEAWAY:

• During a median follow-up of 12.8 years, researchers identified 5876 cases of all-cause dementia, 2540 cases of AD, and 1220 cases of VD.
• Fully adjusted models showed participants with CHD had significantly higher risks than those without CHD of developing all-cause dementia (hazard ratio [HR], 1.36; 95% CI, 1.28-1.45; P < .001), AD (HR, 1.13; 95% CI, 1.02-1.24; P = .019), and VD (HR, 1.78; 95% CI, 1.56-2.02; P < .001). The higher risk for VD suggests CHD has a more profound influence on neuropathologic changes involved in this dementia type, said the authors.
• Those with CHD diagnosed at a younger age had higher risks of developing dementia (HR per 10-year decrease in age, 1.25; 95% CI, 1.20-1.30 for all-cause dementia, 1.29; 95% CI, 1.20-1.38 for AD, and 1.22; 95% CI, 1.13-1.31 for VD; P for all < .001).
• Propensity score matching analysis showed patients with CHD had significantly higher risks for dementia compared with matched controls, with the highest risk seen in patients diagnosed before age 45 (HR, 2.40; 95% CI, 1.79-3.20; P < .001), followed by those diagnosed between 45 and 59 years (HR, 1.46; 95% CI, 1.32-1.62; P < .001) and at or above 60 years (HR, 1.11; 95% CI, 1.03-1.19; P = .005), with similar results for AD and VD.

IN PRACTICE:

The findings suggest “additional attention should be paid to the cognitive status of patients with CHD, especially the ones diagnosed with CHD at a young age,” the authors conclude, noting that “timely intervention, such as cognitive training, could be implemented once signs of cognitive deteriorations are detected.”

SOURCE:

The study was conducted by Jie Liang, BS, School of Nursing, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, and colleagues. It was published online on November 29, 2023, in the Journal of the American Heart Association.

LIMITATIONS:

As this is an observational study, it can’t conclude a causal relationship. Although the authors adjusted for many potential confounders, unknown risk factors that also contribute to CHD can’t be ruled out. As the study excluded 69,744 participants, selection bias is possible. The study included a mostly White population.

DISCLOSURES:

The study was supported by the National Natural Science Foundation of China, the Non-Profit Central Research Institute Fund of the Chinese Academy of Medical Sciences, and the China Medical Board. The authors have no relevant conflicts of interest.

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

TOPLINE:

Adults diagnosed with coronary heart disease (CHD) are at an increased risk for dementia, including all-cause dementia, Alzheimer›s disease (AD), and vascular dementia (VD), with the risk highest — at 36% — if onset is before age 45, results of a large observational study show.

METHODOLOGY:

• The study included 432,667 of the more than 500,000 participants in the UK Biobank, with a mean age of 56.9 years, 50,685 (11.7%) of whom had CHD and 50,445 had data on age at CHD onset.
• Researchers divided participants into three groups according to age at CHD onset (below 45 years, 45-59 years, and 60 years and older), and carried out a propensity score matching analysis.
• Outcomes included all-cause dementia, AD, and VD.
• Covariates included age, sex, race, educational level, body mass index, low-density lipoprotein cholesterol, smoking status, alcohol intake, exercise, depressed mood, hypertension, diabetes, statin use, and apolipoprotein E4 status.

TAKEAWAY:

• During a median follow-up of 12.8 years, researchers identified 5876 cases of all-cause dementia, 2540 cases of AD, and 1220 cases of VD.
• Fully adjusted models showed participants with CHD had significantly higher risks than those without CHD of developing all-cause dementia (hazard ratio [HR], 1.36; 95% CI, 1.28-1.45; P < .001), AD (HR, 1.13; 95% CI, 1.02-1.24; P = .019), and VD (HR, 1.78; 95% CI, 1.56-2.02; P < .001). The higher risk for VD suggests CHD has a more profound influence on neuropathologic changes involved in this dementia type, said the authors.
• Those with CHD diagnosed at a younger age had higher risks of developing dementia (HR per 10-year decrease in age, 1.25; 95% CI, 1.20-1.30 for all-cause dementia, 1.29; 95% CI, 1.20-1.38 for AD, and 1.22; 95% CI, 1.13-1.31 for VD; P for all < .001).
• Propensity score matching analysis showed patients with CHD had significantly higher risks for dementia compared with matched controls, with the highest risk seen in patients diagnosed before age 45 (HR, 2.40; 95% CI, 1.79-3.20; P < .001), followed by those diagnosed between 45 and 59 years (HR, 1.46; 95% CI, 1.32-1.62; P < .001) and at or above 60 years (HR, 1.11; 95% CI, 1.03-1.19; P = .005), with similar results for AD and VD.

IN PRACTICE:

The findings suggest “additional attention should be paid to the cognitive status of patients with CHD, especially the ones diagnosed with CHD at a young age,” the authors conclude, noting that “timely intervention, such as cognitive training, could be implemented once signs of cognitive deteriorations are detected.”

SOURCE:

The study was conducted by Jie Liang, BS, School of Nursing, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, and colleagues. It was published online on November 29, 2023, in the Journal of the American Heart Association.

LIMITATIONS:

As this is an observational study, it can’t conclude a causal relationship. Although the authors adjusted for many potential confounders, unknown risk factors that also contribute to CHD can’t be ruled out. As the study excluded 69,744 participants, selection bias is possible. The study included a mostly White population.

DISCLOSURES:

The study was supported by the National Natural Science Foundation of China, the Non-Profit Central Research Institute Fund of the Chinese Academy of Medical Sciences, and the China Medical Board. The authors have no relevant conflicts of interest.

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

TOPLINE:

For relief of acute migraine, triptans, ergots, and antiemetics are two to five times more effective than ibuprofen, and acetaminophen is the least effective medication, new results from large, real-world analysis of self-reported patient data show. 

METHODOLOGY: 

• Researchers analyzed nearly 11 million migraine attack records extracted from Migraine Buddy, an e-diary smartphone app, over a 6-year period. 
• They evaluated self-reported treatment effectiveness for 25 acute migraine medications among seven classes: acetaminophen, NSAIDs, triptans, combination analgesics, ergots, antiemetics, and opioids. 
• A two-level nested multivariate logistic regression model adjusted for within-subject dependency and for concomitant medications taken within each analyzed migraine attack. 
• The final analysis included nearly 5 million medication-outcome pairs from 3.1 million migraine attacks in 278,000 medication users. 

TAKEAWAY:

• Using ibuprofen as the reference, triptans, ergots, and antiemetics were the top three medication classes with the highest effectiveness (mean odds ratios [OR] 4.80, 3.02, and 2.67, respectively). 
• The next most effective medication classes were opioids (OR, 2.49), NSAIDs other than ibuprofen (OR, 1.94), combination analgesics acetaminophen/acetylsalicylic acid/caffeine (OR, 1.69), and others (OR, 1.49).
• Acetaminophen (OR, 0.83) was considered to be the least effective.
• The most effective individual medications were eletriptan (Relpax) (OR, 6.1); zolmitriptan (Zomig) (OR, 5.7); and sumatriptan (Imitrex) (OR, 5.2).

IN PRACTICE:

“Our findings that triptans, ergots, and antiemetics are the most effective classes of medications align with the guideline recommendations and offer generalizable insights to complement clinical practice,” the authors wrote. 

laflor/gettyimages

SOURCE:

The study, with first author Chia-Chun Chiang, MD, Department of Neurology, Mayo Clinic, Rochester, Minnesota, was published online November 29 in Neurology.

LIMITATIONS:

The findings are based on subjective user-reported ratings of effectiveness and information on side effects, dosages, and formulations were not available. The newer migraine medication classes, gepants and ditans, were not included due to the relatively lower number of treated attacks. The regression model did not include age, gender, pain intensity, and other migraine-associated symptoms, which could potentially affect treatment effectiveness. 

DISCLOSURES: 

Funding for the study was provided by the Kanagawa University of Human Service research fund. A full list of author disclosures can be found with the original article.

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

TOPLINE:

For relief of acute migraine, triptans, ergots, and antiemetics are two to five times more effective than ibuprofen, and acetaminophen is the least effective medication, new results from large, real-world analysis of self-reported patient data show. 

METHODOLOGY: 

• Researchers analyzed nearly 11 million migraine attack records extracted from Migraine Buddy, an e-diary smartphone app, over a 6-year period. 
• They evaluated self-reported treatment effectiveness for 25 acute migraine medications among seven classes: acetaminophen, NSAIDs, triptans, combination analgesics, ergots, antiemetics, and opioids. 
• A two-level nested multivariate logistic regression model adjusted for within-subject dependency and for concomitant medications taken within each analyzed migraine attack. 
• The final analysis included nearly 5 million medication-outcome pairs from 3.1 million migraine attacks in 278,000 medication users. 

TAKEAWAY:

• Using ibuprofen as the reference, triptans, ergots, and antiemetics were the top three medication classes with the highest effectiveness (mean odds ratios [OR] 4.80, 3.02, and 2.67, respectively). 
• The next most effective medication classes were opioids (OR, 2.49), NSAIDs other than ibuprofen (OR, 1.94), combination analgesics acetaminophen/acetylsalicylic acid/caffeine (OR, 1.69), and others (OR, 1.49).
• Acetaminophen (OR, 0.83) was considered to be the least effective.
• The most effective individual medications were eletriptan (Relpax) (OR, 6.1); zolmitriptan (Zomig) (OR, 5.7); and sumatriptan (Imitrex) (OR, 5.2).

IN PRACTICE:

“Our findings that triptans, ergots, and antiemetics are the most effective classes of medications align with the guideline recommendations and offer generalizable insights to complement clinical practice,” the authors wrote. 

laflor/gettyimages

SOURCE:

The study, with first author Chia-Chun Chiang, MD, Department of Neurology, Mayo Clinic, Rochester, Minnesota, was published online November 29 in Neurology.

LIMITATIONS:

The findings are based on subjective user-reported ratings of effectiveness and information on side effects, dosages, and formulations were not available. The newer migraine medication classes, gepants and ditans, were not included due to the relatively lower number of treated attacks. The regression model did not include age, gender, pain intensity, and other migraine-associated symptoms, which could potentially affect treatment effectiveness. 

DISCLOSURES: 

Funding for the study was provided by the Kanagawa University of Human Service research fund. A full list of author disclosures can be found with the original article.

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

TOPLINE:

For relief of acute migraine, triptans, ergots, and antiemetics are two to five times more effective than ibuprofen, and acetaminophen is the least effective medication, new results from large, real-world analysis of self-reported patient data show. 

METHODOLOGY: 

• Researchers analyzed nearly 11 million migraine attack records extracted from Migraine Buddy, an e-diary smartphone app, over a 6-year period. 
• They evaluated self-reported treatment effectiveness for 25 acute migraine medications among seven classes: acetaminophen, NSAIDs, triptans, combination analgesics, ergots, antiemetics, and opioids. 
• A two-level nested multivariate logistic regression model adjusted for within-subject dependency and for concomitant medications taken within each analyzed migraine attack. 
• The final analysis included nearly 5 million medication-outcome pairs from 3.1 million migraine attacks in 278,000 medication users. 

TAKEAWAY:

• Using ibuprofen as the reference, triptans, ergots, and antiemetics were the top three medication classes with the highest effectiveness (mean odds ratios [OR] 4.80, 3.02, and 2.67, respectively). 
• The next most effective medication classes were opioids (OR, 2.49), NSAIDs other than ibuprofen (OR, 1.94), combination analgesics acetaminophen/acetylsalicylic acid/caffeine (OR, 1.69), and others (OR, 1.49).
• Acetaminophen (OR, 0.83) was considered to be the least effective.
• The most effective individual medications were eletriptan (Relpax) (OR, 6.1); zolmitriptan (Zomig) (OR, 5.7); and sumatriptan (Imitrex) (OR, 5.2).

IN PRACTICE:

“Our findings that triptans, ergots, and antiemetics are the most effective classes of medications align with the guideline recommendations and offer generalizable insights to complement clinical practice,” the authors wrote. 

laflor/gettyimages

SOURCE:

The study, with first author Chia-Chun Chiang, MD, Department of Neurology, Mayo Clinic, Rochester, Minnesota, was published online November 29 in Neurology.

LIMITATIONS:

The findings are based on subjective user-reported ratings of effectiveness and information on side effects, dosages, and formulations were not available. The newer migraine medication classes, gepants and ditans, were not included due to the relatively lower number of treated attacks. The regression model did not include age, gender, pain intensity, and other migraine-associated symptoms, which could potentially affect treatment effectiveness. 

DISCLOSURES: 

Funding for the study was provided by the Kanagawa University of Human Service research fund. A full list of author disclosures can be found with the original article.

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

TOPLINE: 

Excessive television-watching is tied to an increased risk for dementia, Parkinson’s disease (PD), and depression, whereas a limited amount of daily computer use that is not work-related is linked to a lower risk for dementia.

METHODOLOGY:

• Investigators analyzed data on 473,184 people aged 39-72 years from the UK Biobank who were enrolled from 2006 to 2010 and followed until a diagnosis of dementia, PD, depression, death, or study end (2018 for Wales residents; 2021 for residents of England and Scotland).
• Participants reported on the number of hours they spent outside of work exercising, watching television, and using the computer.
• MRI was conducted to determine participants’ brain volume.

TAKEAWAY: 

• During the study, 6096 people developed dementia, 3000 developed PD, 23,600 developed depression, 1200 developed dementia and depression, and 486 developed PD and depression.
• Compared with those who watched TV for under 1 hour per day, those who reported watching 4 or more hours per day had a 28% higher risk for dementia (adjusted hazard ratio [aHR], 1.28; 95% CI, 1.17-1.39), a 35% higher risk for depression, (aHR, 1.35; 95% CI, 1.29-1.40) and a 16% greater risk for PD (aHR, 1.16; 95% CI, 1.03-1.29).
• However, moderate computer use outside of work seemed somewhat protective. Participants who used the computer for 30-60 minutes per day had lower risks for dementia (aHR, 0.68; 95% CI, 0.64-0.72), PD, (aHR, 0.86; 95% CI, 0.79-0.93), and depression (aHR, 0.85; 95% CI, 0.83-0.88) compared with those who reported the lowest levels of computer usage.
• Replacing 30 minutes per day of computer time with an equal amount of structured exercise was associated with decreased risk for dementia (aHR, 0.74; 95% CI, 0.85-0.95) and PD (aHR, 0.84; 95% CI, 0.78-0.90).

IN PRACTICE:

The association between extended periods of TV use and higher risk for PD and dementia could be explained by a lack of activity, the authors note. They add that sedentary behavior is, “associated with biomarkers of low-grade inflammation and changes in inflammation markers that could initiate and or worsen neuroinflammation and contribute to neurodegeneration.”

SOURCE:

Hanzhang Wu, PhD, of Tianjin University of Traditional Medicine in Tianjin, China, led the study, which was published online in the International Journal of Behavioral Nutrition and Physical Activity.

LIMITATIONS: 

Screen behaviors were assessed using self-report measures, which is subject to recall bias. Also, there may have been variables confounding the findings for which investigators did not account. 

DISCLOSURES:

The study was funded by the National Natural Science Foundation of China, the Tianjin Major Public Health Science and Technology Project, the National Health Commission of China, the Food Science and Technology Foundation of Chinese Institute of Food Science and Technology, the China Cohort Consortium, and the Chinese Nutrition Society Nutrition Research Foundation–DSM Research Fund, China. There were no disclosures reported.

Eve Bender has no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE: 

Excessive television-watching is tied to an increased risk for dementia, Parkinson’s disease (PD), and depression, whereas a limited amount of daily computer use that is not work-related is linked to a lower risk for dementia.

METHODOLOGY:

• Investigators analyzed data on 473,184 people aged 39-72 years from the UK Biobank who were enrolled from 2006 to 2010 and followed until a diagnosis of dementia, PD, depression, death, or study end (2018 for Wales residents; 2021 for residents of England and Scotland).
• Participants reported on the number of hours they spent outside of work exercising, watching television, and using the computer.
• MRI was conducted to determine participants’ brain volume.

TAKEAWAY: 

• During the study, 6096 people developed dementia, 3000 developed PD, 23,600 developed depression, 1200 developed dementia and depression, and 486 developed PD and depression.
• Compared with those who watched TV for under 1 hour per day, those who reported watching 4 or more hours per day had a 28% higher risk for dementia (adjusted hazard ratio [aHR], 1.28; 95% CI, 1.17-1.39), a 35% higher risk for depression, (aHR, 1.35; 95% CI, 1.29-1.40) and a 16% greater risk for PD (aHR, 1.16; 95% CI, 1.03-1.29).
• However, moderate computer use outside of work seemed somewhat protective. Participants who used the computer for 30-60 minutes per day had lower risks for dementia (aHR, 0.68; 95% CI, 0.64-0.72), PD, (aHR, 0.86; 95% CI, 0.79-0.93), and depression (aHR, 0.85; 95% CI, 0.83-0.88) compared with those who reported the lowest levels of computer usage.
• Replacing 30 minutes per day of computer time with an equal amount of structured exercise was associated with decreased risk for dementia (aHR, 0.74; 95% CI, 0.85-0.95) and PD (aHR, 0.84; 95% CI, 0.78-0.90).

IN PRACTICE:

The association between extended periods of TV use and higher risk for PD and dementia could be explained by a lack of activity, the authors note. They add that sedentary behavior is, “associated with biomarkers of low-grade inflammation and changes in inflammation markers that could initiate and or worsen neuroinflammation and contribute to neurodegeneration.”

SOURCE:

Hanzhang Wu, PhD, of Tianjin University of Traditional Medicine in Tianjin, China, led the study, which was published online in the International Journal of Behavioral Nutrition and Physical Activity.

LIMITATIONS: 

Screen behaviors were assessed using self-report measures, which is subject to recall bias. Also, there may have been variables confounding the findings for which investigators did not account. 

DISCLOSURES:

The study was funded by the National Natural Science Foundation of China, the Tianjin Major Public Health Science and Technology Project, the National Health Commission of China, the Food Science and Technology Foundation of Chinese Institute of Food Science and Technology, the China Cohort Consortium, and the Chinese Nutrition Society Nutrition Research Foundation–DSM Research Fund, China. There were no disclosures reported.

Eve Bender has no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE: 

Excessive television-watching is tied to an increased risk for dementia, Parkinson’s disease (PD), and depression, whereas a limited amount of daily computer use that is not work-related is linked to a lower risk for dementia.

METHODOLOGY:

• Investigators analyzed data on 473,184 people aged 39-72 years from the UK Biobank who were enrolled from 2006 to 2010 and followed until a diagnosis of dementia, PD, depression, death, or study end (2018 for Wales residents; 2021 for residents of England and Scotland).
• Participants reported on the number of hours they spent outside of work exercising, watching television, and using the computer.
• MRI was conducted to determine participants’ brain volume.

TAKEAWAY: 

• During the study, 6096 people developed dementia, 3000 developed PD, 23,600 developed depression, 1200 developed dementia and depression, and 486 developed PD and depression.
• Compared with those who watched TV for under 1 hour per day, those who reported watching 4 or more hours per day had a 28% higher risk for dementia (adjusted hazard ratio [aHR], 1.28; 95% CI, 1.17-1.39), a 35% higher risk for depression, (aHR, 1.35; 95% CI, 1.29-1.40) and a 16% greater risk for PD (aHR, 1.16; 95% CI, 1.03-1.29).
• However, moderate computer use outside of work seemed somewhat protective. Participants who used the computer for 30-60 minutes per day had lower risks for dementia (aHR, 0.68; 95% CI, 0.64-0.72), PD, (aHR, 0.86; 95% CI, 0.79-0.93), and depression (aHR, 0.85; 95% CI, 0.83-0.88) compared with those who reported the lowest levels of computer usage.
• Replacing 30 minutes per day of computer time with an equal amount of structured exercise was associated with decreased risk for dementia (aHR, 0.74; 95% CI, 0.85-0.95) and PD (aHR, 0.84; 95% CI, 0.78-0.90).

IN PRACTICE:

The association between extended periods of TV use and higher risk for PD and dementia could be explained by a lack of activity, the authors note. They add that sedentary behavior is, “associated with biomarkers of low-grade inflammation and changes in inflammation markers that could initiate and or worsen neuroinflammation and contribute to neurodegeneration.”

SOURCE:

Hanzhang Wu, PhD, of Tianjin University of Traditional Medicine in Tianjin, China, led the study, which was published online in the International Journal of Behavioral Nutrition and Physical Activity.

LIMITATIONS: 

Screen behaviors were assessed using self-report measures, which is subject to recall bias. Also, there may have been variables confounding the findings for which investigators did not account. 

DISCLOSURES:

The study was funded by the National Natural Science Foundation of China, the Tianjin Major Public Health Science and Technology Project, the National Health Commission of China, the Food Science and Technology Foundation of Chinese Institute of Food Science and Technology, the China Cohort Consortium, and the Chinese Nutrition Society Nutrition Research Foundation–DSM Research Fund, China. There were no disclosures reported.

Eve Bender has no relevant financial relationships.

A version of this article appeared on Medscape.com.

Primary care clinicians play a central role in maintaining the cardiovascular-kidney-metabolic (CKM) health of patients, according to a new advisory from the American Heart Association.

The advisory, published recently in Circulation introduces the concept of CKM health and reevaluates the relationships between obesity, diabetes, kidney disease, and cardiovascular disease (CVD).

“This approach not only raises awareness, it also empowers PCPs to diagnose and treat these conditions more holistically,” Salim Hayek, MD, associate professor of cardiovascular disease and internal medicine, and medical director of the Frankel Cardiovascular Center Clinics at the University of Michigan in Ann Arbor, said in an interview.

 

New CKM Staging, Testing, and Care Strategies

The advisory introduces a new scoring system that ranges from stage 0 (patients with no risk factors for CKM) through stage 4 (patients with clinical CVD in CKM syndrome). Each stage requires specific management strategies and may include screening starting at age 30 years for diabetes, hypertension, and heart failure.

“Stage 0 CKM is usually found in young people, and CKM risk factors and scores typically increase as people age,” said Sean M. Drake, MD, a primary care physician at Henry Ford Health in Sterling Heights, Michigan. 

Dr. Drake advised PCPs to encourage patients who are at stage 0 to maintain ideal cardiovascular health and to monitor those at risk of progressing through the stages.

While PCPs already perform many of the tests the advisory recommends, the conditions overlap and an abnormality in one system should prompt more testing for other conditions. Additional tests, such as urine albumin-creatinine ratio, and more frequent glomerular filtration rate and lipid profile are advised, according to Dr. Drake.

“There also appears to be a role for additional cardiac testing, including echocardiograms and coronary CT scans, and for liver fibrosis screening,” Dr. Drake said. “Medications such as SGLT2 inhibitors, GLP-1 receptor agonists, and ACE inhibitors, beyond current routine use, are emphasized.” 

To better characterize body composition and help diagnose metabolic syndrome, the advisory also recommends measuring waist circumference, which is not routine practice, noted Joshua J. Joseph, MD, MPH, an associate professor of endocrinology, diabetes, and metabolism at The Ohio State University Wexner Medical Center in Columbus, and a co-author of the advisory. 

Recognizing the interconnected nature of cardiac, kidney, and metabolic diseases encourages a shift in mindset for clinicians, according to Neha Pagidipati, MD, MPH, a cardiologist at Duke Health in Durham, North Carolina.

“We have often been trained to focus on the specific problem in front of us,” Dr. Pagidipati said. “We need to be hyper-aware that many patients we see are at risk for multiple CKM entities. We need to be proactive about screening for and treating these when appropriate.”

The advisory emphasizes the need for CKM coordinators to support teams of clinicians from primary care, cardiology, endocrinology, nephrology, nursing, and pharmacy, as well as social workers, care navigators, or community health workers, Dr. Joseph said. 

“The advisory repositions the PCP at the forefront of CKM care coordination, marking a departure from the traditional model where subspecialists primarily manage complications,” Dr. Hayek added.
 

Changes to Payment

The new recommendations are consistent with current management guidelines for obesity, hypertriglyceridemia, hypertension, type 2 diabetes, and chronic kidney disease. 

“The advisory provides integrated algorithms for cardiovascular prevention and management, with specific therapeutic guidance tied to CKM stages, bringing together the current evidence for best practices from the various guidelines and filling gaps in a unified approach,” Dr. Joseph said. 

In addition, the advisory draws attention to the care of younger patients, who may be at increased risk for cardiovascular disease due to lifestyle factors, according to Nishant Shah, MD, assistant professor of medicine at Duke. 

“It considers barriers to care that prevent people from optimizing their cardiovascular health,” Dr. Shah said. 

Although the advisory does not specify proposed payment changes to support the new care model, the move towards value-based care may require billing practices that accommodate integrated care as well as more frequent and more specialized testing, Dr. Hayek said. 

“The advisory is an empowering tool for PCPs, underscoring their critical role in healthcare,” Dr. Hayek said. “It encourages PCPs to advocate for integrated care within their practices and to consider workflow adjustments that enhance the identification and initiation of preventive care for at-risk patients.”

Funding information was not provided. 

Dr. Joseph reports no relevant financial involvements; several advisory co-authors report financial involvements with pharmaceutical companies. Dr. Pagidipati reports relevant financial involvement with pharmaceutical companies. Dr. Hayek, Dr. Drake, and Dr. Shah report no relevant financial involvements. Dr. Joseph is an author of the advisory. Dr. Pagidipati, Dr. Hayek, Dr. Drake, and Dr. Shah were not involved in the writing of the advisory.

A version of this article appeared on Medscape.com.

Primary care clinicians play a central role in maintaining the cardiovascular-kidney-metabolic (CKM) health of patients, according to a new advisory from the American Heart Association.

The advisory, published recently in Circulation introduces the concept of CKM health and reevaluates the relationships between obesity, diabetes, kidney disease, and cardiovascular disease (CVD).

“This approach not only raises awareness, it also empowers PCPs to diagnose and treat these conditions more holistically,” Salim Hayek, MD, associate professor of cardiovascular disease and internal medicine, and medical director of the Frankel Cardiovascular Center Clinics at the University of Michigan in Ann Arbor, said in an interview.

 

New CKM Staging, Testing, and Care Strategies

The advisory introduces a new scoring system that ranges from stage 0 (patients with no risk factors for CKM) through stage 4 (patients with clinical CVD in CKM syndrome). Each stage requires specific management strategies and may include screening starting at age 30 years for diabetes, hypertension, and heart failure.

“Stage 0 CKM is usually found in young people, and CKM risk factors and scores typically increase as people age,” said Sean M. Drake, MD, a primary care physician at Henry Ford Health in Sterling Heights, Michigan. 

Dr. Drake advised PCPs to encourage patients who are at stage 0 to maintain ideal cardiovascular health and to monitor those at risk of progressing through the stages.

While PCPs already perform many of the tests the advisory recommends, the conditions overlap and an abnormality in one system should prompt more testing for other conditions. Additional tests, such as urine albumin-creatinine ratio, and more frequent glomerular filtration rate and lipid profile are advised, according to Dr. Drake.

“There also appears to be a role for additional cardiac testing, including echocardiograms and coronary CT scans, and for liver fibrosis screening,” Dr. Drake said. “Medications such as SGLT2 inhibitors, GLP-1 receptor agonists, and ACE inhibitors, beyond current routine use, are emphasized.” 

To better characterize body composition and help diagnose metabolic syndrome, the advisory also recommends measuring waist circumference, which is not routine practice, noted Joshua J. Joseph, MD, MPH, an associate professor of endocrinology, diabetes, and metabolism at The Ohio State University Wexner Medical Center in Columbus, and a co-author of the advisory. 

Recognizing the interconnected nature of cardiac, kidney, and metabolic diseases encourages a shift in mindset for clinicians, according to Neha Pagidipati, MD, MPH, a cardiologist at Duke Health in Durham, North Carolina.

“We have often been trained to focus on the specific problem in front of us,” Dr. Pagidipati said. “We need to be hyper-aware that many patients we see are at risk for multiple CKM entities. We need to be proactive about screening for and treating these when appropriate.”

The advisory emphasizes the need for CKM coordinators to support teams of clinicians from primary care, cardiology, endocrinology, nephrology, nursing, and pharmacy, as well as social workers, care navigators, or community health workers, Dr. Joseph said. 

“The advisory repositions the PCP at the forefront of CKM care coordination, marking a departure from the traditional model where subspecialists primarily manage complications,” Dr. Hayek added.
 

Changes to Payment

The new recommendations are consistent with current management guidelines for obesity, hypertriglyceridemia, hypertension, type 2 diabetes, and chronic kidney disease. 

“The advisory provides integrated algorithms for cardiovascular prevention and management, with specific therapeutic guidance tied to CKM stages, bringing together the current evidence for best practices from the various guidelines and filling gaps in a unified approach,” Dr. Joseph said. 

In addition, the advisory draws attention to the care of younger patients, who may be at increased risk for cardiovascular disease due to lifestyle factors, according to Nishant Shah, MD, assistant professor of medicine at Duke. 

“It considers barriers to care that prevent people from optimizing their cardiovascular health,” Dr. Shah said. 

Although the advisory does not specify proposed payment changes to support the new care model, the move towards value-based care may require billing practices that accommodate integrated care as well as more frequent and more specialized testing, Dr. Hayek said. 

“The advisory is an empowering tool for PCPs, underscoring their critical role in healthcare,” Dr. Hayek said. “It encourages PCPs to advocate for integrated care within their practices and to consider workflow adjustments that enhance the identification and initiation of preventive care for at-risk patients.”

Funding information was not provided. 

Dr. Joseph reports no relevant financial involvements; several advisory co-authors report financial involvements with pharmaceutical companies. Dr. Pagidipati reports relevant financial involvement with pharmaceutical companies. Dr. Hayek, Dr. Drake, and Dr. Shah report no relevant financial involvements. Dr. Joseph is an author of the advisory. Dr. Pagidipati, Dr. Hayek, Dr. Drake, and Dr. Shah were not involved in the writing of the advisory.

A version of this article appeared on Medscape.com.

Primary care clinicians play a central role in maintaining the cardiovascular-kidney-metabolic (CKM) health of patients, according to a new advisory from the American Heart Association.

The advisory, published recently in Circulation introduces the concept of CKM health and reevaluates the relationships between obesity, diabetes, kidney disease, and cardiovascular disease (CVD).

“This approach not only raises awareness, it also empowers PCPs to diagnose and treat these conditions more holistically,” Salim Hayek, MD, associate professor of cardiovascular disease and internal medicine, and medical director of the Frankel Cardiovascular Center Clinics at the University of Michigan in Ann Arbor, said in an interview.

 

New CKM Staging, Testing, and Care Strategies

The advisory introduces a new scoring system that ranges from stage 0 (patients with no risk factors for CKM) through stage 4 (patients with clinical CVD in CKM syndrome). Each stage requires specific management strategies and may include screening starting at age 30 years for diabetes, hypertension, and heart failure.

“Stage 0 CKM is usually found in young people, and CKM risk factors and scores typically increase as people age,” said Sean M. Drake, MD, a primary care physician at Henry Ford Health in Sterling Heights, Michigan. 

Dr. Drake advised PCPs to encourage patients who are at stage 0 to maintain ideal cardiovascular health and to monitor those at risk of progressing through the stages.

While PCPs already perform many of the tests the advisory recommends, the conditions overlap and an abnormality in one system should prompt more testing for other conditions. Additional tests, such as urine albumin-creatinine ratio, and more frequent glomerular filtration rate and lipid profile are advised, according to Dr. Drake.

“There also appears to be a role for additional cardiac testing, including echocardiograms and coronary CT scans, and for liver fibrosis screening,” Dr. Drake said. “Medications such as SGLT2 inhibitors, GLP-1 receptor agonists, and ACE inhibitors, beyond current routine use, are emphasized.” 

To better characterize body composition and help diagnose metabolic syndrome, the advisory also recommends measuring waist circumference, which is not routine practice, noted Joshua J. Joseph, MD, MPH, an associate professor of endocrinology, diabetes, and metabolism at The Ohio State University Wexner Medical Center in Columbus, and a co-author of the advisory. 

Recognizing the interconnected nature of cardiac, kidney, and metabolic diseases encourages a shift in mindset for clinicians, according to Neha Pagidipati, MD, MPH, a cardiologist at Duke Health in Durham, North Carolina.

“We have often been trained to focus on the specific problem in front of us,” Dr. Pagidipati said. “We need to be hyper-aware that many patients we see are at risk for multiple CKM entities. We need to be proactive about screening for and treating these when appropriate.”

The advisory emphasizes the need for CKM coordinators to support teams of clinicians from primary care, cardiology, endocrinology, nephrology, nursing, and pharmacy, as well as social workers, care navigators, or community health workers, Dr. Joseph said. 

“The advisory repositions the PCP at the forefront of CKM care coordination, marking a departure from the traditional model where subspecialists primarily manage complications,” Dr. Hayek added.
 

Changes to Payment

The new recommendations are consistent with current management guidelines for obesity, hypertriglyceridemia, hypertension, type 2 diabetes, and chronic kidney disease. 

“The advisory provides integrated algorithms for cardiovascular prevention and management, with specific therapeutic guidance tied to CKM stages, bringing together the current evidence for best practices from the various guidelines and filling gaps in a unified approach,” Dr. Joseph said. 

In addition, the advisory draws attention to the care of younger patients, who may be at increased risk for cardiovascular disease due to lifestyle factors, according to Nishant Shah, MD, assistant professor of medicine at Duke. 

“It considers barriers to care that prevent people from optimizing their cardiovascular health,” Dr. Shah said. 

Although the advisory does not specify proposed payment changes to support the new care model, the move towards value-based care may require billing practices that accommodate integrated care as well as more frequent and more specialized testing, Dr. Hayek said. 

“The advisory is an empowering tool for PCPs, underscoring their critical role in healthcare,” Dr. Hayek said. “It encourages PCPs to advocate for integrated care within their practices and to consider workflow adjustments that enhance the identification and initiation of preventive care for at-risk patients.”

Funding information was not provided. 

Dr. Joseph reports no relevant financial involvements; several advisory co-authors report financial involvements with pharmaceutical companies. Dr. Pagidipati reports relevant financial involvement with pharmaceutical companies. Dr. Hayek, Dr. Drake, and Dr. Shah report no relevant financial involvements. Dr. Joseph is an author of the advisory. Dr. Pagidipati, Dr. Hayek, Dr. Drake, and Dr. Shah were not involved in the writing of the advisory.

A version of this article appeared on Medscape.com.

TOPLINE: 

Having a first menstrual period (menarche) at age 10 or younger was linked with a greater risk for type 2 diabetes and a greater risk of stroke in women with diabetes, a retrospective study of US women under age 65 found.

METHODOLOGY:

• Researchers analyzed data from 17,377 women who were aged 20-65 years when they participated in a National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 and reported their age at first menstruation, which was classified as ≤ 10, 11, 12, 13, 14, or ≥ 15 years of age.
• In total, 0.2% of the women (1773) had type 2 diabetes; of these, 11.5% (205) had cardiovascular disease (CVD), defined as coronary heart disease (CHD), myocardial infarction, or stroke.
• Compared with women who had their first menstrual period at age 13 (the mean age in this population), those who had their period at age ≤ 10 had a significantly greater risk of having type 2 diabetes, after adjustment for age, race/ethnicity, education, parity, menopause status, family history of diabetes, smoking status, physical activity, alcohol consumption, and body mass index (odds ratio, 1.32; 95% CI, 1.03-1.69; P trend = .03).
• Among the women with diabetes, compared with those who had their first menstrual period at age 13, those who had it at age ≤ 10 had a significantly greater risk of having stroke (OR, 2.66; 95% CI, 1.07-6.64; P trend = .02), but not CVD or CHD, after adjustment for these multiple variables.

TAKEAWAY:

• In a racially and ethnically diverse national sample of US women younger than 65, “extremely early” age at first menstrual period was associated with significantly increased risk for type 2 diabetes; among the women with type 2 diabetes, it was associated with significantly increased risk for stroke but not CVD or CHD, after adjustment for multiple variables.
• Early age at menarche may be an early indicator of the cardiometabolic disease trajectory in women.

IN PRACTICE:

“Women with early-life exposures such as early age at menarche need to be further examined for diabetes and prevention research and strategies for progression of diabetes complications,” the study authors write. 

SOURCE:

The authors, mainly from Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, and also from Harvard Medical School, Boston, Massachusetts, published their findings in BMJ Nutrition, Prevention & Health.

LIMITATIONS:

• The women who participated in NHANES may not be representative of all women in the United States (selection bias).
• The study only included women who reported the age when they had their first menstrual period (selection bias).
• This was a cross-sectional, observational study, so it cannot show causality.
• The women may have reported the wrong age at which they had their first period (recall bias and social desirability bias).
• The women may have inaccurately reported CVD and type 2 diabetes (recall bias and social desirability bias).

DISCLOSURES:

The researchers were supported by grants from the National Heart, Lung, and Blood Institute and from the National Institute of General Medical Sciences of the National Institutes of Health.

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

TOPLINE: 

Having a first menstrual period (menarche) at age 10 or younger was linked with a greater risk for type 2 diabetes and a greater risk of stroke in women with diabetes, a retrospective study of US women under age 65 found.

METHODOLOGY:

• Researchers analyzed data from 17,377 women who were aged 20-65 years when they participated in a National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 and reported their age at first menstruation, which was classified as ≤ 10, 11, 12, 13, 14, or ≥ 15 years of age.
• In total, 0.2% of the women (1773) had type 2 diabetes; of these, 11.5% (205) had cardiovascular disease (CVD), defined as coronary heart disease (CHD), myocardial infarction, or stroke.
• Compared with women who had their first menstrual period at age 13 (the mean age in this population), those who had their period at age ≤ 10 had a significantly greater risk of having type 2 diabetes, after adjustment for age, race/ethnicity, education, parity, menopause status, family history of diabetes, smoking status, physical activity, alcohol consumption, and body mass index (odds ratio, 1.32; 95% CI, 1.03-1.69; P trend = .03).
• Among the women with diabetes, compared with those who had their first menstrual period at age 13, those who had it at age ≤ 10 had a significantly greater risk of having stroke (OR, 2.66; 95% CI, 1.07-6.64; P trend = .02), but not CVD or CHD, after adjustment for these multiple variables.

TAKEAWAY:

• In a racially and ethnically diverse national sample of US women younger than 65, “extremely early” age at first menstrual period was associated with significantly increased risk for type 2 diabetes; among the women with type 2 diabetes, it was associated with significantly increased risk for stroke but not CVD or CHD, after adjustment for multiple variables.
• Early age at menarche may be an early indicator of the cardiometabolic disease trajectory in women.

IN PRACTICE:

“Women with early-life exposures such as early age at menarche need to be further examined for diabetes and prevention research and strategies for progression of diabetes complications,” the study authors write. 

SOURCE:

The authors, mainly from Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, and also from Harvard Medical School, Boston, Massachusetts, published their findings in BMJ Nutrition, Prevention & Health.

LIMITATIONS:

• The women who participated in NHANES may not be representative of all women in the United States (selection bias).
• The study only included women who reported the age when they had their first menstrual period (selection bias).
• This was a cross-sectional, observational study, so it cannot show causality.
• The women may have reported the wrong age at which they had their first period (recall bias and social desirability bias).
• The women may have inaccurately reported CVD and type 2 diabetes (recall bias and social desirability bias).

DISCLOSURES:

The researchers were supported by grants from the National Heart, Lung, and Blood Institute and from the National Institute of General Medical Sciences of the National Institutes of Health.

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

TOPLINE: 

Having a first menstrual period (menarche) at age 10 or younger was linked with a greater risk for type 2 diabetes and a greater risk of stroke in women with diabetes, a retrospective study of US women under age 65 found.

METHODOLOGY:

• Researchers analyzed data from 17,377 women who were aged 20-65 years when they participated in a National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 and reported their age at first menstruation, which was classified as ≤ 10, 11, 12, 13, 14, or ≥ 15 years of age.
• In total, 0.2% of the women (1773) had type 2 diabetes; of these, 11.5% (205) had cardiovascular disease (CVD), defined as coronary heart disease (CHD), myocardial infarction, or stroke.
• Compared with women who had their first menstrual period at age 13 (the mean age in this population), those who had their period at age ≤ 10 had a significantly greater risk of having type 2 diabetes, after adjustment for age, race/ethnicity, education, parity, menopause status, family history of diabetes, smoking status, physical activity, alcohol consumption, and body mass index (odds ratio, 1.32; 95% CI, 1.03-1.69; P trend = .03).
• Among the women with diabetes, compared with those who had their first menstrual period at age 13, those who had it at age ≤ 10 had a significantly greater risk of having stroke (OR, 2.66; 95% CI, 1.07-6.64; P trend = .02), but not CVD or CHD, after adjustment for these multiple variables.

TAKEAWAY:

• In a racially and ethnically diverse national sample of US women younger than 65, “extremely early” age at first menstrual period was associated with significantly increased risk for type 2 diabetes; among the women with type 2 diabetes, it was associated with significantly increased risk for stroke but not CVD or CHD, after adjustment for multiple variables.
• Early age at menarche may be an early indicator of the cardiometabolic disease trajectory in women.

IN PRACTICE:

“Women with early-life exposures such as early age at menarche need to be further examined for diabetes and prevention research and strategies for progression of diabetes complications,” the study authors write. 

SOURCE:

The authors, mainly from Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, and also from Harvard Medical School, Boston, Massachusetts, published their findings in BMJ Nutrition, Prevention & Health.

LIMITATIONS:

• The women who participated in NHANES may not be representative of all women in the United States (selection bias).
• The study only included women who reported the age when they had their first menstrual period (selection bias).
• This was a cross-sectional, observational study, so it cannot show causality.
• The women may have reported the wrong age at which they had their first period (recall bias and social desirability bias).
• The women may have inaccurately reported CVD and type 2 diabetes (recall bias and social desirability bias).

DISCLOSURES:

The researchers were supported by grants from the National Heart, Lung, and Blood Institute and from the National Institute of General Medical Sciences of the National Institutes of Health.

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

An experimental therapy that uses deep brain stimulation (DBS) to deliver precise electrical pulses to an area deep inside the brain restored executive function in patients with moderate to severe traumatic brain injury (msTBI) and chronic sequelae.

Participants in this first-in-humans trial experienced brain injuries between 3-18 years before the study that left them with persistent neuropsychological impairment and a range of functional disabilities.

This is the first time a DBS device has been implanted in the central thalamus in humans, an area of the brain measuring only a few millimeters wide that helps regulate consciousness.

Placing the electrodes required a novel surgical technique developed by the investigators that included virtual models of each participant’s brain, microelectrode recording, and neuroimaging to identify neuronal circuits affected by the TBI.

After 3 months of 12-hour daily DBS treatments, participants’ performance on cognitive tests improved by an average of 32% from baseline. Participants were able to read books, watch TV shows, play video games, complete schoolwork, and felt significantly less fatigued during the day.

Although the small trial only included five patients, the work is already being hailed by other experts as significant.“We were looking for partial restoration of executive attention and expected [the treatment] would have an effect, but I wouldn’t have anticipated the effect size we saw,” co-lead investigator Nicholas Schiff, MD, professor of neuroscience at Weill Cornell Medical College, New York City, said in an interview.

The findings were published online Dec. 4 in Nature Medicine.

“No Trivial Feat”

An estimated 5.3 million children and adults are living with a permanent TBI-related disability in the US today. There currently is no effective therapy for impaired attention, executive function, working memory or information-processing speed caused by the initial injury.

Previous research suggests that a loss of activity in key brain circuits in the thalamus may be associated with a loss of cognitive function.

The investigators recruited six adults (four men and two women) between the ages of 22 and 60 years with a history of msTBI and chronic neuropsychological impairment and functional disability. One participant was later withdrawn from the trial for protocol noncompliance.

Participants completed a range of questionnaires and tests to establish baseline cognitive, psychological, and quality-of-life status.

To restore lost executive functioning in the brain, investigators had to target not only the central lateral nucleus, but also the neuronal network connected to the region that reaches other parts of the brain.

“To do both of those things we had to develop a whole toolset in order to model both the target and trajectory, which had to be right to make it work properly,” co-lead investigator Jaimie Henderson, MD, professor of neurosurgery at Stanford University College of Medicine, Stanford, California, said in an interview. “That gave us a pretty narrow window in which to work and getting an electrode accurately to this target is not a trivial feat.”

“A Moving Target”

Each participant’s brain physiology was slightly different, meaning the path that worked for one individual might not work for another. The surgery was further complicated by shifting in the brain that occurred as individual electrodes were placed.

“It was a literal moving target,” Dr. Henderson said.

In the beginning, investigators used microelectrode recording to “listen” to individual neurons to see which ones weren’t firing correctly.

When that method failed to offer the precise information needed for electrode placement, the investigators switched to neuroimaging, which allowed them to complete the surgery more quickly and accurately.

Participants remained in the hospital 1-2 days after surgery. They returned for postoperative imaging 30 days after surgery and were randomly assigned to different schedules for a 14-day titration period to optimize DBS stimulation.

The primary outcome was a 10% improvement on part B of the trail-making test, a neuropsychological test that measures executive functioning.

After 90 days of 12-hour daily DBS treatments, participants’ scores increased 15%–52% (average 32%) from baseline. Participants also reported an average of 33% decline in fatigue, one of the most common side effects of msTBI, and an average 80% improvement in attention.

The main safety risk during the 3- to-4-hour procedure is bleeding, which didn’t affect any of the participants in this study. One participant developed a surgical site infection, but all other side effects were mild.

After the 90-day treatment period, the study plan called for patients to be randomly assigned to a blinded withdrawal of treatment, with the DBS turned off for 21 days. Two of the patients declined to be randomized. DBS was turned off in one participant while the other two continued as normal.

After 3 weeks, the patient whose DBS was turned off showed a 34% decline on cognitive tests. The device was reactivated after the study and that participant has since reported improvements.

The DBS devices continue to function in all participants. Although their performance is not being measured as part of the study, anecdotal reports indicate sustained improvement in executive functioning.

“The brain injury causes this global down-regulation of brain function and what we think that this is doing is turning that back up again,” Dr. Henderson said. “At a very simplistic level, what we’re trying to do is turn the lights back up after the dimmer switch is switched down from the injury.”

New Hope

TBI patients are usually treated aggressively during the first year, when significant improvements are most likely, but there are few therapeutic options beyond that time, said neurologist Javier Cardenas, MD, who commented on the findings for this article.

“Many providers throw their hands up after a year in terms of intervention and then we’re always looking at potential declines over time,” said Dr. Cardenas, director of the Concussion and Brain Injury Center at the Rockefeller Neuroscience Institution, West Virginia University, Morgantown. “Most people plateau and don’t decline but we’re always worried about a secondary decline in traumatic brain injury.”Surgery is usually only employed immediately following the brain injury. The notion of surgery as a therapeutic option years after the initial assault on the brain is novel, said Jimmy Yang, MD, assistant professor of neurologic surgery at Ohio State University College of Medicine, Columbus, who commented on the findings for this article.

“While deep brain stimulation surgery in clinical practice is specifically tailored to each patient we treat, this study goes a step further by integrating research tools that have not yet made it to the clinical realm,” Dr. Yang said. “As a result, while these methods are not commonly used in clinical care, the overall strategy highlights how research advances are linked to clinical advances.”

Investigators are working to secure funding for a larger phase 2 trial.

“With millions of people affected by traumatic brain injury but without effective therapies, this study brings hope that options are on the horizon to help these patients,” Dr. Yang said.

The study was supported by funding from the National Institute of Health BRAIN Initiative and a grant from the Translational Science Center at Weill Cornell Medical College. Surgical implants were provided by Medtronic. Dr. Henderson and Dr. Schiff are listed as inventors on several patent applications for the experimental DBS therapy described in the study. Dr. Cardenas and Dr. Yang report no relevant financial relationships.

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

An experimental therapy that uses deep brain stimulation (DBS) to deliver precise electrical pulses to an area deep inside the brain restored executive function in patients with moderate to severe traumatic brain injury (msTBI) and chronic sequelae.

Participants in this first-in-humans trial experienced brain injuries between 3-18 years before the study that left them with persistent neuropsychological impairment and a range of functional disabilities.

This is the first time a DBS device has been implanted in the central thalamus in humans, an area of the brain measuring only a few millimeters wide that helps regulate consciousness.

Placing the electrodes required a novel surgical technique developed by the investigators that included virtual models of each participant’s brain, microelectrode recording, and neuroimaging to identify neuronal circuits affected by the TBI.

After 3 months of 12-hour daily DBS treatments, participants’ performance on cognitive tests improved by an average of 32% from baseline. Participants were able to read books, watch TV shows, play video games, complete schoolwork, and felt significantly less fatigued during the day.

Although the small trial only included five patients, the work is already being hailed by other experts as significant.“We were looking for partial restoration of executive attention and expected [the treatment] would have an effect, but I wouldn’t have anticipated the effect size we saw,” co-lead investigator Nicholas Schiff, MD, professor of neuroscience at Weill Cornell Medical College, New York City, said in an interview.

The findings were published online Dec. 4 in Nature Medicine.

“No Trivial Feat”

An estimated 5.3 million children and adults are living with a permanent TBI-related disability in the US today. There currently is no effective therapy for impaired attention, executive function, working memory or information-processing speed caused by the initial injury.

Previous research suggests that a loss of activity in key brain circuits in the thalamus may be associated with a loss of cognitive function.

The investigators recruited six adults (four men and two women) between the ages of 22 and 60 years with a history of msTBI and chronic neuropsychological impairment and functional disability. One participant was later withdrawn from the trial for protocol noncompliance.

Participants completed a range of questionnaires and tests to establish baseline cognitive, psychological, and quality-of-life status.

To restore lost executive functioning in the brain, investigators had to target not only the central lateral nucleus, but also the neuronal network connected to the region that reaches other parts of the brain.

“To do both of those things we had to develop a whole toolset in order to model both the target and trajectory, which had to be right to make it work properly,” co-lead investigator Jaimie Henderson, MD, professor of neurosurgery at Stanford University College of Medicine, Stanford, California, said in an interview. “That gave us a pretty narrow window in which to work and getting an electrode accurately to this target is not a trivial feat.”

“A Moving Target”

Each participant’s brain physiology was slightly different, meaning the path that worked for one individual might not work for another. The surgery was further complicated by shifting in the brain that occurred as individual electrodes were placed.

“It was a literal moving target,” Dr. Henderson said.

In the beginning, investigators used microelectrode recording to “listen” to individual neurons to see which ones weren’t firing correctly.

When that method failed to offer the precise information needed for electrode placement, the investigators switched to neuroimaging, which allowed them to complete the surgery more quickly and accurately.

Participants remained in the hospital 1-2 days after surgery. They returned for postoperative imaging 30 days after surgery and were randomly assigned to different schedules for a 14-day titration period to optimize DBS stimulation.

The primary outcome was a 10% improvement on part B of the trail-making test, a neuropsychological test that measures executive functioning.

After 90 days of 12-hour daily DBS treatments, participants’ scores increased 15%–52% (average 32%) from baseline. Participants also reported an average of 33% decline in fatigue, one of the most common side effects of msTBI, and an average 80% improvement in attention.

The main safety risk during the 3- to-4-hour procedure is bleeding, which didn’t affect any of the participants in this study. One participant developed a surgical site infection, but all other side effects were mild.

After the 90-day treatment period, the study plan called for patients to be randomly assigned to a blinded withdrawal of treatment, with the DBS turned off for 21 days. Two of the patients declined to be randomized. DBS was turned off in one participant while the other two continued as normal.

After 3 weeks, the patient whose DBS was turned off showed a 34% decline on cognitive tests. The device was reactivated after the study and that participant has since reported improvements.

The DBS devices continue to function in all participants. Although their performance is not being measured as part of the study, anecdotal reports indicate sustained improvement in executive functioning.

“The brain injury causes this global down-regulation of brain function and what we think that this is doing is turning that back up again,” Dr. Henderson said. “At a very simplistic level, what we’re trying to do is turn the lights back up after the dimmer switch is switched down from the injury.”

New Hope

TBI patients are usually treated aggressively during the first year, when significant improvements are most likely, but there are few therapeutic options beyond that time, said neurologist Javier Cardenas, MD, who commented on the findings for this article.

“Many providers throw their hands up after a year in terms of intervention and then we’re always looking at potential declines over time,” said Dr. Cardenas, director of the Concussion and Brain Injury Center at the Rockefeller Neuroscience Institution, West Virginia University, Morgantown. “Most people plateau and don’t decline but we’re always worried about a secondary decline in traumatic brain injury.”Surgery is usually only employed immediately following the brain injury. The notion of surgery as a therapeutic option years after the initial assault on the brain is novel, said Jimmy Yang, MD, assistant professor of neurologic surgery at Ohio State University College of Medicine, Columbus, who commented on the findings for this article.

“While deep brain stimulation surgery in clinical practice is specifically tailored to each patient we treat, this study goes a step further by integrating research tools that have not yet made it to the clinical realm,” Dr. Yang said. “As a result, while these methods are not commonly used in clinical care, the overall strategy highlights how research advances are linked to clinical advances.”

Investigators are working to secure funding for a larger phase 2 trial.

“With millions of people affected by traumatic brain injury but without effective therapies, this study brings hope that options are on the horizon to help these patients,” Dr. Yang said.

The study was supported by funding from the National Institute of Health BRAIN Initiative and a grant from the Translational Science Center at Weill Cornell Medical College. Surgical implants were provided by Medtronic. Dr. Henderson and Dr. Schiff are listed as inventors on several patent applications for the experimental DBS therapy described in the study. Dr. Cardenas and Dr. Yang report no relevant financial relationships.

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

An experimental therapy that uses deep brain stimulation (DBS) to deliver precise electrical pulses to an area deep inside the brain restored executive function in patients with moderate to severe traumatic brain injury (msTBI) and chronic sequelae.

Participants in this first-in-humans trial experienced brain injuries between 3-18 years before the study that left them with persistent neuropsychological impairment and a range of functional disabilities.

This is the first time a DBS device has been implanted in the central thalamus in humans, an area of the brain measuring only a few millimeters wide that helps regulate consciousness.

Placing the electrodes required a novel surgical technique developed by the investigators that included virtual models of each participant’s brain, microelectrode recording, and neuroimaging to identify neuronal circuits affected by the TBI.

After 3 months of 12-hour daily DBS treatments, participants’ performance on cognitive tests improved by an average of 32% from baseline. Participants were able to read books, watch TV shows, play video games, complete schoolwork, and felt significantly less fatigued during the day.

Although the small trial only included five patients, the work is already being hailed by other experts as significant.“We were looking for partial restoration of executive attention and expected [the treatment] would have an effect, but I wouldn’t have anticipated the effect size we saw,” co-lead investigator Nicholas Schiff, MD, professor of neuroscience at Weill Cornell Medical College, New York City, said in an interview.

The findings were published online Dec. 4 in Nature Medicine.

“No Trivial Feat”

An estimated 5.3 million children and adults are living with a permanent TBI-related disability in the US today. There currently is no effective therapy for impaired attention, executive function, working memory or information-processing speed caused by the initial injury.

Previous research suggests that a loss of activity in key brain circuits in the thalamus may be associated with a loss of cognitive function.

The investigators recruited six adults (four men and two women) between the ages of 22 and 60 years with a history of msTBI and chronic neuropsychological impairment and functional disability. One participant was later withdrawn from the trial for protocol noncompliance.

Participants completed a range of questionnaires and tests to establish baseline cognitive, psychological, and quality-of-life status.

To restore lost executive functioning in the brain, investigators had to target not only the central lateral nucleus, but also the neuronal network connected to the region that reaches other parts of the brain.

“To do both of those things we had to develop a whole toolset in order to model both the target and trajectory, which had to be right to make it work properly,” co-lead investigator Jaimie Henderson, MD, professor of neurosurgery at Stanford University College of Medicine, Stanford, California, said in an interview. “That gave us a pretty narrow window in which to work and getting an electrode accurately to this target is not a trivial feat.”

“A Moving Target”

Each participant’s brain physiology was slightly different, meaning the path that worked for one individual might not work for another. The surgery was further complicated by shifting in the brain that occurred as individual electrodes were placed.

“It was a literal moving target,” Dr. Henderson said.

In the beginning, investigators used microelectrode recording to “listen” to individual neurons to see which ones weren’t firing correctly.

When that method failed to offer the precise information needed for electrode placement, the investigators switched to neuroimaging, which allowed them to complete the surgery more quickly and accurately.

Participants remained in the hospital 1-2 days after surgery. They returned for postoperative imaging 30 days after surgery and were randomly assigned to different schedules for a 14-day titration period to optimize DBS stimulation.

The primary outcome was a 10% improvement on part B of the trail-making test, a neuropsychological test that measures executive functioning.

After 90 days of 12-hour daily DBS treatments, participants’ scores increased 15%–52% (average 32%) from baseline. Participants also reported an average of 33% decline in fatigue, one of the most common side effects of msTBI, and an average 80% improvement in attention.

The main safety risk during the 3- to-4-hour procedure is bleeding, which didn’t affect any of the participants in this study. One participant developed a surgical site infection, but all other side effects were mild.

After the 90-day treatment period, the study plan called for patients to be randomly assigned to a blinded withdrawal of treatment, with the DBS turned off for 21 days. Two of the patients declined to be randomized. DBS was turned off in one participant while the other two continued as normal.

After 3 weeks, the patient whose DBS was turned off showed a 34% decline on cognitive tests. The device was reactivated after the study and that participant has since reported improvements.

The DBS devices continue to function in all participants. Although their performance is not being measured as part of the study, anecdotal reports indicate sustained improvement in executive functioning.

“The brain injury causes this global down-regulation of brain function and what we think that this is doing is turning that back up again,” Dr. Henderson said. “At a very simplistic level, what we’re trying to do is turn the lights back up after the dimmer switch is switched down from the injury.”

New Hope

TBI patients are usually treated aggressively during the first year, when significant improvements are most likely, but there are few therapeutic options beyond that time, said neurologist Javier Cardenas, MD, who commented on the findings for this article.

“Many providers throw their hands up after a year in terms of intervention and then we’re always looking at potential declines over time,” said Dr. Cardenas, director of the Concussion and Brain Injury Center at the Rockefeller Neuroscience Institution, West Virginia University, Morgantown. “Most people plateau and don’t decline but we’re always worried about a secondary decline in traumatic brain injury.”Surgery is usually only employed immediately following the brain injury. The notion of surgery as a therapeutic option years after the initial assault on the brain is novel, said Jimmy Yang, MD, assistant professor of neurologic surgery at Ohio State University College of Medicine, Columbus, who commented on the findings for this article.

“While deep brain stimulation surgery in clinical practice is specifically tailored to each patient we treat, this study goes a step further by integrating research tools that have not yet made it to the clinical realm,” Dr. Yang said. “As a result, while these methods are not commonly used in clinical care, the overall strategy highlights how research advances are linked to clinical advances.”

Investigators are working to secure funding for a larger phase 2 trial.

“With millions of people affected by traumatic brain injury but without effective therapies, this study brings hope that options are on the horizon to help these patients,” Dr. Yang said.

The study was supported by funding from the National Institute of Health BRAIN Initiative and a grant from the Translational Science Center at Weill Cornell Medical College. Surgical implants were provided by Medtronic. Dr. Henderson and Dr. Schiff are listed as inventors on several patent applications for the experimental DBS therapy described in the study. Dr. Cardenas and Dr. Yang report no relevant financial relationships.

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