A variety of treatments, most already commercially available, are under investigation for treating the constellation of overlapping symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), “long COVID,” and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, speakers presented data for a variety of approaches to ease symptoms common across postviral conditions, such as extreme fatigue, postexertional malaise (“crash”), cognitive dysfunction (“brain fog”), orthostatic intolerance including postural orthostatic tachycardia syndrome (POTS), and chronic pain. Most of the modalities are already commercially available for other indications, although some are costly and not covered by payers for these conditions.

“Both post–acute COVID-19 syndrome and ME/CFS are forms of postinfectious viral syndromes and they have overlapping symptoms. ... In the past, patients were told ‘you have chronic fatigue syndrome but there’s nothing we can do for it.’ That certainly is not the case. There aren’t cures, but there are many management techniques to improve symptoms,” Charles W. Lapp, MD, medical director of the Hunter-Hopkins Center, Charlotte, N.C., said in an interview.

A current mainstay of treatment for ME/CFS – including that triggered by COVID-19 – is activity pacing, in which patients learn to stay within their “energy envelopes” in order to avoid postexertional malaise, a worsening of all symptoms with exertion. The use of “graded exercise” is no longer recommended, per U.K. and U.S. guidelines.

Data for the following approaches were presented at the IACFS/ME conference:
 

Pyridostigmine (mestinon, others)

Pyridostigmine, an acetylcholinesterase inhibitor, is approved for the treatment of muscle weakness resulting from myasthenia gravis and is available in generic form. It has previously been shown to produce significant improvement in both symptom burden and heart rate response in POTS.

At the IACFS/ME conference, David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital Cardiopulmonary laboratory, both in Boston, summarized his group’s study in patients with ME/CFS using pyridostigmine as both a potential treatment for improving exercise capacity and a proof-of-concept that neurovascular dysregulation underlies exertional intolerance in the condition.

A total of 45 patients were randomized to 60 mg oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test, and a second test performed 50 minutes later. Peak VO₂ increased after pyridostigmine but decreased after placebo (+13.3 mL/min vs. –40.2 mL/min, P < .05). Cardiac output and right atrial pressure were also significantly improved with pyridostigmine and worse with placebo.

“We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. ... Pyridostigmine may be a useful repurposed off-label treatment [for] a subset of patients with exercise intolerance,” Dr. Systrom said.

Asked to comment, Dr. Lapp said: “We’ve used Mestinon for years because it helps with POTS and also with neurally mediated hypotension. Systrom is taking it to a new level because he’s shown that it increases preload to the heart.” However, he noted that it’s unclear whether the drug will help patients who don’t have POTS specifically. On the other hand, patients rarely experience side effects from the drug.

Since the generic tablets come only in 60-mg doses, and the starting dose is 30 mg three times a day, he advised cutting the tablets in half during titration up to 60 mg three times a day.
 

Oxaloacetate (benaGene)

David Lyons Kaufman, MD, of the Center for Complex Diseases, Mountain View, Calif., summarized data from his group’s recently published open-label, nonrandomized, “proof-of-concept” study on use of the commercially available nutritional supplement anhydrous enol-oxaloacetate for treating mental and physical fatigue in 76 patients with longstanding ME/CFS and 43 with long-COVID fatigue.

Oxaloacetate is a major step in the Krebs cycle within the mitochondria that are depleted in patients with ME/CFS. It is also an energy metabolite that has multiple effects in cells and mitochondria, Dr. Kaufman explained.

Doses ranging from 500 mg twice daily up to 1,000 mg three times a day were given for 6 weeks. Up to 33% of the patients with ME/CFS and up to 46.8% of the long-COVID group achieved clinical efficacy as measured by physical and mental fatigue scores, compared with just 5.9% of historical ME/CFS controls. All doses showed highly significant improvements.

The only adverse effects were occasional dyspepsia, which was avoided by taking the supplement with food, and insomnia, resolved by having them dose at breakfast and lunch, Dr. Kaufman said.

Following those preliminary data, there is now an ongoing 90-day, randomized, placebo-controlled clinical trial of 80 patients with ME/CFS using 2,000 mg anhydrous enol-oxaloacetate per day. Endpoints include multiple objective measures.

“We have a health care crisis with long COVID, and we’ve had this smoldering crisis with ME/CFS for decades that’s never been addressed. ME/CFS and long COVID, if not identical, are certainly overlapping. ... We have to pursue these translational medicine pilot studies as rapidly as possible,” Dr. Kaufman remarked.

Dr. Lapp told this news organization that it makes sense to use constituents of the Krebs cycle to improve mitochondrial function, but the problem with oxaloacetate is its cost. Dr. Kaufman mentioned that based on the preliminary trial, the therapeutic “sweet spot” appeared to be 1,000 mg twice daily. The manufacturer’s website lists the price for a single bottle of 30 250-mg capsules at $49, or $42 if purchased via a monthly subscription.

“It’s a benign drug, and it’s over the counter. I would give it to any patient who’s got a big wallet,” Dr. Lapp quipped, adding: “If they’ve got the money, they can order it tonight.”
 

Inspiritol

Inspiritol is an investigational “nebulized, inhaled, multimechanism medication designed to treat the major symptoms of respiratory distress with antioxidant, anti-inflammatory, and broad-spectrum antiviral and antibacterial properties. Inspiritol is composed of both endogenously produced and naturally occurring, well-tolerated biochemicals,” according to the company website.

The hypothesis, Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, said at the meeting, is that “ME/CFS and long COVID-19 result from an aberrant response to an immunological trigger like infection, which results in a permanently dysregulated immune system as a result of overactivation of CD8 T cells and subsequent exhaustion.”

Inspiritol, containing five antioxidants, acts as an immune modulator to reverse the CD8 T cell exhaustion and improve symptoms. Administration by inhaler delivers it directly to the brain from the lung. It was originally designed for use in chronic obstructive pulmonary disease and asthma and has shown efficacy for acute COVID-19, Dr. Selin said.

In a preliminary study, four patients with ME/CFS and five with long COVID have been treated with Inspiritol for 2-15 months, and all have self-reported improved symptoms. Cough has been the only reported side effect.

The company is pursuing an Investigational New Drug Application for the product with the Food and Drug Administration and has several patents pending. Dr. Lapp called Inspiritol “very interesting,” and said that reversal of CD8 “exhaustion” also would appear to be a promising approach. However, he noted, “the problem is that we don’t know what’s in it.”
 

Stellate ganglion block

Injection of local anesthetic near the stellate ganglion to block activity of the entire cervical sympathetic chain has been used for nearly a century to treat a variety of sympathetically mediated conditions, including complex regional pain syndrome (CRPS), shingles, and phantom-limb pain. More recently, it has been used in a variety of other conditions, including PTSD, Raynaud’s disease, menopausal hot flashes, and hyperhidrosis.

Insurance companies typically cover it for CRPS, neuropathic upper-extremity pain, hyperhidrosis, and Raynaud’s, said Luke Liu, MD, an anesthesiologist who is founder and chief executive officer of Alaska-based pain management company Neuroversion.

Deborah Duricka, PhD, also with Neuroversion, presented results from a now-published case series of 11 patients with long COVID who underwent stellate ganglion block by a board-certified anesthesiologist, first on one side at the level of C6, then on the contralateral side the following day.

Clinically meaningful benefits were seen in at least five of the patients in fatigue, memory problems, problems concentrating, rapid heartbeat, orthostatic intolerance, sleep problems, postexertional malaise, anxiety, and depression.

The hypothetical mechanism, she said, is that “sympathetic block prevents sympathetically driven vasoconstriction in carotid and vertebral arteries.”

Dr. Liu presented another case series of five patients with ME/CFS who underwent the procedure with ultrasound guidance, again on one side and the other side the next day. All had upper-limb autonomic issues such as Raynaud’s and/or neuropathic pain that had been refractory to more conventional treatments.

All five patients reported improvements in symptoms of ME/CFS, including energy level, cognition, pain, and postexertional malaise. One patient reported “feeling well for the first time in decades.” However, that patient relapsed after a mild viral illness 3.5 months after treatment. Some of the patients have required further treatments.

Dr. Lapp commented that, although the procedure is generally safe when performed by an experienced clinician, “Any time you do an injection like that, there’s a high risk that you could nick an artery or a vein or hit an essential nerve in the neck. That’s why it has to be done under fluoroscopy or ultrasound.”

He said he’s had a few patients undergo the procedure, mostly for CRPS, and they seem to have benefited from it. “It might increase cerebral blood flow and preload to the heart, so it might decrease ME/CFS symptoms and help with POTS as well.”

Nonetheless, Dr. Lapp said he wouldn’t consider stellate ganglion block as first-line treatment for ME/CFS or long COVID. “I think it would be for the treatment-resistant patient, when you’ve gone through all the treatments that we know and addressed all the comorbidities and they’re still not getting better.”

But, he added, it is a standard procedure. “Any pain clinic can do a stellate block.”
 

Transcutaneous auricular vagus nerve stimulation

Nicola Clague-Baker, PhD, a physiotherapist at the University of Liverpool (England), presented findings from an international survey of people with ME/CFS regarding their experience with transcutaneous auricular vagus nerve stimulation (taVNS) to manage their autonomic symptoms. The technique involves stimulation of the autonomic nervous system via the vagus nerve using electrodes applied to part of the ear. The theory is that the technique stimulates the parasympathetic nervous system and improves autonomic balance.

Two small previous trials showing benefit of vagus nerve stimulation for people with ME/CFS used more invasive and less comfortable methods of applying the stimulation rather than to the ear, Dr. Clague-Baker and colleagues noted in a poster. It has also been used successfully in treating POTS, another conference speaker noted.

A total of 131 people with ME/CFS (called simply “ME” in the United Kingdom) responded to a survey advertised on social media and websites. The majority (60%) were from the United Kingdom while the rest were from Europe, Australia, and North America. Most were female, and slightly more than half had lived with ME for 10 or more years.

The majority (72%) were still using taVNS, while 28% had stopped using it. Only 9% had used the modality for longer than a year. Respondents identified more than 30 benefits in symptoms and activities, with improvements in postexertional malaise (39%) and brain fog (37%) being the most common. One reported significant reduction in constipation.

However, respondents also mentioned more than 20 short- and long-term negatives, including headaches (15%) and long-term irritation at the site (9%). One participant reported a “big improvement in neuropathic pain, but not so much for muscles and joints.”

Overall, 80% reported that they would continue using taVNS and 67% said they would recommend it to others with ME, and 56% said that the system was mildly to very beneficial.

Dr. Lapp noted that several types of transcutaneous electrical nerve stimulation units with ear clips are sold online, and he’s seen them work well for migraine treatment. However, he cautioned that some patients have had side effects from the treatment, such as headaches and dizziness. “It’s putting an electrical current through your brain. In my mind, it’s another last-ditch measure.”

Dr. Lapp reported no financial disclosures.

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

A variety of treatments, most already commercially available, are under investigation for treating the constellation of overlapping symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), “long COVID,” and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, speakers presented data for a variety of approaches to ease symptoms common across postviral conditions, such as extreme fatigue, postexertional malaise (“crash”), cognitive dysfunction (“brain fog”), orthostatic intolerance including postural orthostatic tachycardia syndrome (POTS), and chronic pain. Most of the modalities are already commercially available for other indications, although some are costly and not covered by payers for these conditions.

“Both post–acute COVID-19 syndrome and ME/CFS are forms of postinfectious viral syndromes and they have overlapping symptoms. ... In the past, patients were told ‘you have chronic fatigue syndrome but there’s nothing we can do for it.’ That certainly is not the case. There aren’t cures, but there are many management techniques to improve symptoms,” Charles W. Lapp, MD, medical director of the Hunter-Hopkins Center, Charlotte, N.C., said in an interview.

A current mainstay of treatment for ME/CFS – including that triggered by COVID-19 – is activity pacing, in which patients learn to stay within their “energy envelopes” in order to avoid postexertional malaise, a worsening of all symptoms with exertion. The use of “graded exercise” is no longer recommended, per U.K. and U.S. guidelines.

Data for the following approaches were presented at the IACFS/ME conference:
 

Pyridostigmine (mestinon, others)

Pyridostigmine, an acetylcholinesterase inhibitor, is approved for the treatment of muscle weakness resulting from myasthenia gravis and is available in generic form. It has previously been shown to produce significant improvement in both symptom burden and heart rate response in POTS.

At the IACFS/ME conference, David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital Cardiopulmonary laboratory, both in Boston, summarized his group’s study in patients with ME/CFS using pyridostigmine as both a potential treatment for improving exercise capacity and a proof-of-concept that neurovascular dysregulation underlies exertional intolerance in the condition.

A total of 45 patients were randomized to 60 mg oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test, and a second test performed 50 minutes later. Peak VO₂ increased after pyridostigmine but decreased after placebo (+13.3 mL/min vs. –40.2 mL/min, P < .05). Cardiac output and right atrial pressure were also significantly improved with pyridostigmine and worse with placebo.

“We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. ... Pyridostigmine may be a useful repurposed off-label treatment [for] a subset of patients with exercise intolerance,” Dr. Systrom said.

Asked to comment, Dr. Lapp said: “We’ve used Mestinon for years because it helps with POTS and also with neurally mediated hypotension. Systrom is taking it to a new level because he’s shown that it increases preload to the heart.” However, he noted that it’s unclear whether the drug will help patients who don’t have POTS specifically. On the other hand, patients rarely experience side effects from the drug.

Since the generic tablets come only in 60-mg doses, and the starting dose is 30 mg three times a day, he advised cutting the tablets in half during titration up to 60 mg three times a day.
 

Oxaloacetate (benaGene)

David Lyons Kaufman, MD, of the Center for Complex Diseases, Mountain View, Calif., summarized data from his group’s recently published open-label, nonrandomized, “proof-of-concept” study on use of the commercially available nutritional supplement anhydrous enol-oxaloacetate for treating mental and physical fatigue in 76 patients with longstanding ME/CFS and 43 with long-COVID fatigue.

Oxaloacetate is a major step in the Krebs cycle within the mitochondria that are depleted in patients with ME/CFS. It is also an energy metabolite that has multiple effects in cells and mitochondria, Dr. Kaufman explained.

Doses ranging from 500 mg twice daily up to 1,000 mg three times a day were given for 6 weeks. Up to 33% of the patients with ME/CFS and up to 46.8% of the long-COVID group achieved clinical efficacy as measured by physical and mental fatigue scores, compared with just 5.9% of historical ME/CFS controls. All doses showed highly significant improvements.

The only adverse effects were occasional dyspepsia, which was avoided by taking the supplement with food, and insomnia, resolved by having them dose at breakfast and lunch, Dr. Kaufman said.

Following those preliminary data, there is now an ongoing 90-day, randomized, placebo-controlled clinical trial of 80 patients with ME/CFS using 2,000 mg anhydrous enol-oxaloacetate per day. Endpoints include multiple objective measures.

“We have a health care crisis with long COVID, and we’ve had this smoldering crisis with ME/CFS for decades that’s never been addressed. ME/CFS and long COVID, if not identical, are certainly overlapping. ... We have to pursue these translational medicine pilot studies as rapidly as possible,” Dr. Kaufman remarked.

Dr. Lapp told this news organization that it makes sense to use constituents of the Krebs cycle to improve mitochondrial function, but the problem with oxaloacetate is its cost. Dr. Kaufman mentioned that based on the preliminary trial, the therapeutic “sweet spot” appeared to be 1,000 mg twice daily. The manufacturer’s website lists the price for a single bottle of 30 250-mg capsules at $49, or $42 if purchased via a monthly subscription.

“It’s a benign drug, and it’s over the counter. I would give it to any patient who’s got a big wallet,” Dr. Lapp quipped, adding: “If they’ve got the money, they can order it tonight.”
 

Inspiritol

Inspiritol is an investigational “nebulized, inhaled, multimechanism medication designed to treat the major symptoms of respiratory distress with antioxidant, anti-inflammatory, and broad-spectrum antiviral and antibacterial properties. Inspiritol is composed of both endogenously produced and naturally occurring, well-tolerated biochemicals,” according to the company website.

The hypothesis, Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, said at the meeting, is that “ME/CFS and long COVID-19 result from an aberrant response to an immunological trigger like infection, which results in a permanently dysregulated immune system as a result of overactivation of CD8 T cells and subsequent exhaustion.”

Inspiritol, containing five antioxidants, acts as an immune modulator to reverse the CD8 T cell exhaustion and improve symptoms. Administration by inhaler delivers it directly to the brain from the lung. It was originally designed for use in chronic obstructive pulmonary disease and asthma and has shown efficacy for acute COVID-19, Dr. Selin said.

In a preliminary study, four patients with ME/CFS and five with long COVID have been treated with Inspiritol for 2-15 months, and all have self-reported improved symptoms. Cough has been the only reported side effect.

The company is pursuing an Investigational New Drug Application for the product with the Food and Drug Administration and has several patents pending. Dr. Lapp called Inspiritol “very interesting,” and said that reversal of CD8 “exhaustion” also would appear to be a promising approach. However, he noted, “the problem is that we don’t know what’s in it.”
 

Stellate ganglion block

Injection of local anesthetic near the stellate ganglion to block activity of the entire cervical sympathetic chain has been used for nearly a century to treat a variety of sympathetically mediated conditions, including complex regional pain syndrome (CRPS), shingles, and phantom-limb pain. More recently, it has been used in a variety of other conditions, including PTSD, Raynaud’s disease, menopausal hot flashes, and hyperhidrosis.

Insurance companies typically cover it for CRPS, neuropathic upper-extremity pain, hyperhidrosis, and Raynaud’s, said Luke Liu, MD, an anesthesiologist who is founder and chief executive officer of Alaska-based pain management company Neuroversion.

Deborah Duricka, PhD, also with Neuroversion, presented results from a now-published case series of 11 patients with long COVID who underwent stellate ganglion block by a board-certified anesthesiologist, first on one side at the level of C6, then on the contralateral side the following day.

Clinically meaningful benefits were seen in at least five of the patients in fatigue, memory problems, problems concentrating, rapid heartbeat, orthostatic intolerance, sleep problems, postexertional malaise, anxiety, and depression.

The hypothetical mechanism, she said, is that “sympathetic block prevents sympathetically driven vasoconstriction in carotid and vertebral arteries.”

Dr. Liu presented another case series of five patients with ME/CFS who underwent the procedure with ultrasound guidance, again on one side and the other side the next day. All had upper-limb autonomic issues such as Raynaud’s and/or neuropathic pain that had been refractory to more conventional treatments.

All five patients reported improvements in symptoms of ME/CFS, including energy level, cognition, pain, and postexertional malaise. One patient reported “feeling well for the first time in decades.” However, that patient relapsed after a mild viral illness 3.5 months after treatment. Some of the patients have required further treatments.

Dr. Lapp commented that, although the procedure is generally safe when performed by an experienced clinician, “Any time you do an injection like that, there’s a high risk that you could nick an artery or a vein or hit an essential nerve in the neck. That’s why it has to be done under fluoroscopy or ultrasound.”

He said he’s had a few patients undergo the procedure, mostly for CRPS, and they seem to have benefited from it. “It might increase cerebral blood flow and preload to the heart, so it might decrease ME/CFS symptoms and help with POTS as well.”

Nonetheless, Dr. Lapp said he wouldn’t consider stellate ganglion block as first-line treatment for ME/CFS or long COVID. “I think it would be for the treatment-resistant patient, when you’ve gone through all the treatments that we know and addressed all the comorbidities and they’re still not getting better.”

But, he added, it is a standard procedure. “Any pain clinic can do a stellate block.”
 

Transcutaneous auricular vagus nerve stimulation

Nicola Clague-Baker, PhD, a physiotherapist at the University of Liverpool (England), presented findings from an international survey of people with ME/CFS regarding their experience with transcutaneous auricular vagus nerve stimulation (taVNS) to manage their autonomic symptoms. The technique involves stimulation of the autonomic nervous system via the vagus nerve using electrodes applied to part of the ear. The theory is that the technique stimulates the parasympathetic nervous system and improves autonomic balance.

Two small previous trials showing benefit of vagus nerve stimulation for people with ME/CFS used more invasive and less comfortable methods of applying the stimulation rather than to the ear, Dr. Clague-Baker and colleagues noted in a poster. It has also been used successfully in treating POTS, another conference speaker noted.

A total of 131 people with ME/CFS (called simply “ME” in the United Kingdom) responded to a survey advertised on social media and websites. The majority (60%) were from the United Kingdom while the rest were from Europe, Australia, and North America. Most were female, and slightly more than half had lived with ME for 10 or more years.

The majority (72%) were still using taVNS, while 28% had stopped using it. Only 9% had used the modality for longer than a year. Respondents identified more than 30 benefits in symptoms and activities, with improvements in postexertional malaise (39%) and brain fog (37%) being the most common. One reported significant reduction in constipation.

However, respondents also mentioned more than 20 short- and long-term negatives, including headaches (15%) and long-term irritation at the site (9%). One participant reported a “big improvement in neuropathic pain, but not so much for muscles and joints.”

Overall, 80% reported that they would continue using taVNS and 67% said they would recommend it to others with ME, and 56% said that the system was mildly to very beneficial.

Dr. Lapp noted that several types of transcutaneous electrical nerve stimulation units with ear clips are sold online, and he’s seen them work well for migraine treatment. However, he cautioned that some patients have had side effects from the treatment, such as headaches and dizziness. “It’s putting an electrical current through your brain. In my mind, it’s another last-ditch measure.”

Dr. Lapp reported no financial disclosures.

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

A variety of treatments, most already commercially available, are under investigation for treating the constellation of overlapping symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), “long COVID,” and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, speakers presented data for a variety of approaches to ease symptoms common across postviral conditions, such as extreme fatigue, postexertional malaise (“crash”), cognitive dysfunction (“brain fog”), orthostatic intolerance including postural orthostatic tachycardia syndrome (POTS), and chronic pain. Most of the modalities are already commercially available for other indications, although some are costly and not covered by payers for these conditions.

“Both post–acute COVID-19 syndrome and ME/CFS are forms of postinfectious viral syndromes and they have overlapping symptoms. ... In the past, patients were told ‘you have chronic fatigue syndrome but there’s nothing we can do for it.’ That certainly is not the case. There aren’t cures, but there are many management techniques to improve symptoms,” Charles W. Lapp, MD, medical director of the Hunter-Hopkins Center, Charlotte, N.C., said in an interview.

A current mainstay of treatment for ME/CFS – including that triggered by COVID-19 – is activity pacing, in which patients learn to stay within their “energy envelopes” in order to avoid postexertional malaise, a worsening of all symptoms with exertion. The use of “graded exercise” is no longer recommended, per U.K. and U.S. guidelines.

Data for the following approaches were presented at the IACFS/ME conference:
 

Pyridostigmine (mestinon, others)

Pyridostigmine, an acetylcholinesterase inhibitor, is approved for the treatment of muscle weakness resulting from myasthenia gravis and is available in generic form. It has previously been shown to produce significant improvement in both symptom burden and heart rate response in POTS.

At the IACFS/ME conference, David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital Cardiopulmonary laboratory, both in Boston, summarized his group’s study in patients with ME/CFS using pyridostigmine as both a potential treatment for improving exercise capacity and a proof-of-concept that neurovascular dysregulation underlies exertional intolerance in the condition.

A total of 45 patients were randomized to 60 mg oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test, and a second test performed 50 minutes later. Peak VO₂ increased after pyridostigmine but decreased after placebo (+13.3 mL/min vs. –40.2 mL/min, P < .05). Cardiac output and right atrial pressure were also significantly improved with pyridostigmine and worse with placebo.

“We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. ... Pyridostigmine may be a useful repurposed off-label treatment [for] a subset of patients with exercise intolerance,” Dr. Systrom said.

Asked to comment, Dr. Lapp said: “We’ve used Mestinon for years because it helps with POTS and also with neurally mediated hypotension. Systrom is taking it to a new level because he’s shown that it increases preload to the heart.” However, he noted that it’s unclear whether the drug will help patients who don’t have POTS specifically. On the other hand, patients rarely experience side effects from the drug.

Since the generic tablets come only in 60-mg doses, and the starting dose is 30 mg three times a day, he advised cutting the tablets in half during titration up to 60 mg three times a day.
 

Oxaloacetate (benaGene)

David Lyons Kaufman, MD, of the Center for Complex Diseases, Mountain View, Calif., summarized data from his group’s recently published open-label, nonrandomized, “proof-of-concept” study on use of the commercially available nutritional supplement anhydrous enol-oxaloacetate for treating mental and physical fatigue in 76 patients with longstanding ME/CFS and 43 with long-COVID fatigue.

Oxaloacetate is a major step in the Krebs cycle within the mitochondria that are depleted in patients with ME/CFS. It is also an energy metabolite that has multiple effects in cells and mitochondria, Dr. Kaufman explained.

Doses ranging from 500 mg twice daily up to 1,000 mg three times a day were given for 6 weeks. Up to 33% of the patients with ME/CFS and up to 46.8% of the long-COVID group achieved clinical efficacy as measured by physical and mental fatigue scores, compared with just 5.9% of historical ME/CFS controls. All doses showed highly significant improvements.

The only adverse effects were occasional dyspepsia, which was avoided by taking the supplement with food, and insomnia, resolved by having them dose at breakfast and lunch, Dr. Kaufman said.

Following those preliminary data, there is now an ongoing 90-day, randomized, placebo-controlled clinical trial of 80 patients with ME/CFS using 2,000 mg anhydrous enol-oxaloacetate per day. Endpoints include multiple objective measures.

“We have a health care crisis with long COVID, and we’ve had this smoldering crisis with ME/CFS for decades that’s never been addressed. ME/CFS and long COVID, if not identical, are certainly overlapping. ... We have to pursue these translational medicine pilot studies as rapidly as possible,” Dr. Kaufman remarked.

Dr. Lapp told this news organization that it makes sense to use constituents of the Krebs cycle to improve mitochondrial function, but the problem with oxaloacetate is its cost. Dr. Kaufman mentioned that based on the preliminary trial, the therapeutic “sweet spot” appeared to be 1,000 mg twice daily. The manufacturer’s website lists the price for a single bottle of 30 250-mg capsules at $49, or $42 if purchased via a monthly subscription.

“It’s a benign drug, and it’s over the counter. I would give it to any patient who’s got a big wallet,” Dr. Lapp quipped, adding: “If they’ve got the money, they can order it tonight.”
 

Inspiritol

Inspiritol is an investigational “nebulized, inhaled, multimechanism medication designed to treat the major symptoms of respiratory distress with antioxidant, anti-inflammatory, and broad-spectrum antiviral and antibacterial properties. Inspiritol is composed of both endogenously produced and naturally occurring, well-tolerated biochemicals,” according to the company website.

The hypothesis, Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, said at the meeting, is that “ME/CFS and long COVID-19 result from an aberrant response to an immunological trigger like infection, which results in a permanently dysregulated immune system as a result of overactivation of CD8 T cells and subsequent exhaustion.”

Inspiritol, containing five antioxidants, acts as an immune modulator to reverse the CD8 T cell exhaustion and improve symptoms. Administration by inhaler delivers it directly to the brain from the lung. It was originally designed for use in chronic obstructive pulmonary disease and asthma and has shown efficacy for acute COVID-19, Dr. Selin said.

In a preliminary study, four patients with ME/CFS and five with long COVID have been treated with Inspiritol for 2-15 months, and all have self-reported improved symptoms. Cough has been the only reported side effect.

The company is pursuing an Investigational New Drug Application for the product with the Food and Drug Administration and has several patents pending. Dr. Lapp called Inspiritol “very interesting,” and said that reversal of CD8 “exhaustion” also would appear to be a promising approach. However, he noted, “the problem is that we don’t know what’s in it.”
 

Stellate ganglion block

Injection of local anesthetic near the stellate ganglion to block activity of the entire cervical sympathetic chain has been used for nearly a century to treat a variety of sympathetically mediated conditions, including complex regional pain syndrome (CRPS), shingles, and phantom-limb pain. More recently, it has been used in a variety of other conditions, including PTSD, Raynaud’s disease, menopausal hot flashes, and hyperhidrosis.

Insurance companies typically cover it for CRPS, neuropathic upper-extremity pain, hyperhidrosis, and Raynaud’s, said Luke Liu, MD, an anesthesiologist who is founder and chief executive officer of Alaska-based pain management company Neuroversion.

Deborah Duricka, PhD, also with Neuroversion, presented results from a now-published case series of 11 patients with long COVID who underwent stellate ganglion block by a board-certified anesthesiologist, first on one side at the level of C6, then on the contralateral side the following day.

Clinically meaningful benefits were seen in at least five of the patients in fatigue, memory problems, problems concentrating, rapid heartbeat, orthostatic intolerance, sleep problems, postexertional malaise, anxiety, and depression.

The hypothetical mechanism, she said, is that “sympathetic block prevents sympathetically driven vasoconstriction in carotid and vertebral arteries.”

Dr. Liu presented another case series of five patients with ME/CFS who underwent the procedure with ultrasound guidance, again on one side and the other side the next day. All had upper-limb autonomic issues such as Raynaud’s and/or neuropathic pain that had been refractory to more conventional treatments.

All five patients reported improvements in symptoms of ME/CFS, including energy level, cognition, pain, and postexertional malaise. One patient reported “feeling well for the first time in decades.” However, that patient relapsed after a mild viral illness 3.5 months after treatment. Some of the patients have required further treatments.

Dr. Lapp commented that, although the procedure is generally safe when performed by an experienced clinician, “Any time you do an injection like that, there’s a high risk that you could nick an artery or a vein or hit an essential nerve in the neck. That’s why it has to be done under fluoroscopy or ultrasound.”

He said he’s had a few patients undergo the procedure, mostly for CRPS, and they seem to have benefited from it. “It might increase cerebral blood flow and preload to the heart, so it might decrease ME/CFS symptoms and help with POTS as well.”

Nonetheless, Dr. Lapp said he wouldn’t consider stellate ganglion block as first-line treatment for ME/CFS or long COVID. “I think it would be for the treatment-resistant patient, when you’ve gone through all the treatments that we know and addressed all the comorbidities and they’re still not getting better.”

But, he added, it is a standard procedure. “Any pain clinic can do a stellate block.”
 

Transcutaneous auricular vagus nerve stimulation

Nicola Clague-Baker, PhD, a physiotherapist at the University of Liverpool (England), presented findings from an international survey of people with ME/CFS regarding their experience with transcutaneous auricular vagus nerve stimulation (taVNS) to manage their autonomic symptoms. The technique involves stimulation of the autonomic nervous system via the vagus nerve using electrodes applied to part of the ear. The theory is that the technique stimulates the parasympathetic nervous system and improves autonomic balance.

Two small previous trials showing benefit of vagus nerve stimulation for people with ME/CFS used more invasive and less comfortable methods of applying the stimulation rather than to the ear, Dr. Clague-Baker and colleagues noted in a poster. It has also been used successfully in treating POTS, another conference speaker noted.

A total of 131 people with ME/CFS (called simply “ME” in the United Kingdom) responded to a survey advertised on social media and websites. The majority (60%) were from the United Kingdom while the rest were from Europe, Australia, and North America. Most were female, and slightly more than half had lived with ME for 10 or more years.

The majority (72%) were still using taVNS, while 28% had stopped using it. Only 9% had used the modality for longer than a year. Respondents identified more than 30 benefits in symptoms and activities, with improvements in postexertional malaise (39%) and brain fog (37%) being the most common. One reported significant reduction in constipation.

However, respondents also mentioned more than 20 short- and long-term negatives, including headaches (15%) and long-term irritation at the site (9%). One participant reported a “big improvement in neuropathic pain, but not so much for muscles and joints.”

Overall, 80% reported that they would continue using taVNS and 67% said they would recommend it to others with ME, and 56% said that the system was mildly to very beneficial.

Dr. Lapp noted that several types of transcutaneous electrical nerve stimulation units with ear clips are sold online, and he’s seen them work well for migraine treatment. However, he cautioned that some patients have had side effects from the treatment, such as headaches and dizziness. “It’s putting an electrical current through your brain. In my mind, it’s another last-ditch measure.”

Dr. Lapp reported no financial disclosures.

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

Industry payments to U.S. gastroenterologists and hepatologists increased from 2014 to 2016 before beginning to steadily decrease after 2016, but they're largely concentrated among a small few, according to new research published in Gastroenterology.

South_agency/Getty Images

The study aimed to identify trends in these specialties in the years after the Sunshine Act, enacted in 2010, and the federal program Open Payments, established in 2013.

“Although Open Payments launched in September of 2014, all the joinpoints in our study occurred more than a year later in 2016, suggesting a delay in observable changes in behavior on industry physician relationships,” wrote Xiaohan Ying, MD, of Weill Cornell Medicine in New York, and colleagues. “Since 2016, we have seen a sustained reduction in general industry payments to physicians while research payments remained stable, which is likely the desired outcome of this program.”

That’s also the conclusion of Lawrence Kosinski, MD, MBA, a spokesperson for the American Gastroenterological Association, who was not involved in the study.

“Most all of us are aware of the Sunshine Act and have reacted accordingly, so I am not surprised that reimbursement per physician has declined over the time period,” Dr. Kosinski told this news organization. “Many physicians are very sensitive to their reporting and have decreased their exposures,” said Dr. Kosinski, founder of SonarMD and a member of the Health & Human Services Advisory Committee on Value-Based Payment. “What does surprise me is the marked disparity in payments with a very small number of physicians receiving tremendous reimbursement from speaking engagements and promotions.”

The researchers retrospectively analyzed industry payments to 26,981 practicing pediatric and adults gastroenterologists and hepatologists using the National Plan and Provider Enumeration System and data from Open Payments between January 2014 and December 2020. The researchers excluded education payments and focused on general payments, which “include charitable contribution, speaker fees, consulting fees, ownership and investments, education, entertainment, food and beverages, gift, honoraria, royalty and license, and travel and lodging,” they reported.
 

Who gets paid, and how much?

While $27.5 million was going to research and grants, most of the payments ($403.3 million) were general payments; out of the total payments to specialists, $30 million went to hepatology, and $400.8 million went to gastroenterology. Nearly all of the general payments ($398.1 million) were for noneducation purposes; 90.5% of general payments went to men and 9.5% went to women, at an average of $17,167 per person. Nearly half the payments (43.8%) were for speaker fees, totaling $174.3 million, followed by 18.4% going to consulting ($73.1 million) and 12.9% going to food and beverages ($51.5 million).

Most of the physicians accepting payments (86.6%) received less than $10,000, but this made up only 8.3% of all payments. Meanwhile, 74% of all the payments, $294.6 million, went to just 3.1% of the physicians, all of whom received more than $100,000.

That breakdown is what most caught Dr. Kosinki’s attention.

“It’s one thing for a speaker to declare that they are receiving funds from pharma, but they never let us know how much,” Dr. Kosinski said. “Some of these speakers are realizing a very significant payment, which could change the opinions of those listening to their presentations.”

The authors reported that a group of 50 top earners (0.2%) received more than $1 million between 2014 and 2020. Their payments totaled $94.8 million and accounted for nearly a quarter (23.8%) of all the payments. All but one of these physicians were men, and one physician has received more than $1 million every year since 2014.
 

Payments for guideline authors explored

The authors examined payments to practicing U.S. gastroenterologists and hepatologists who helped write clinical guidelines for the following organizations:

• American Gastroenterological Association (AGA).
• American College of Gastroenterology (ACG).
• American Association for the Study of Liver Disease (AASLD).
• North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN).
• American Society for Gastrointestinal Endoscopy (ASGE).

The 186 guidelines published between 2014 and 2020 had 632 physician authors, 415 of whom were practicing gastroenterologists and hepatologists in the United States. Most of these physicians (85.8%) received at least one industry payment, with payments to guideline authors totaling $43.6 million.

Similar to the lopsided breakdown for total payments across all physicians, the majority of the payments (87.4%, or $38.1 million) went to one-quarter of the authors, who each received more than $100,000 per person. Meanwhile, 38.2% of the guideline authors received less than $10,000.

“However, these numbers are likely to decrease in the future as professional societies, such as AASLD, require a majority of the guideline authors to be free of conflict of interest relevant to the subject matter,” the authors wrote. They added that members selected as part of the AGA’s guideline development group (GDG) must report all conflicts of interest, including indirect and intellectual ones, and are recused or excluded when appropriate. These guideline development group participants must also forgo speaking and consulting arrangements until one year after the guideline’s publication.
 

Trends have been shifting

Total industry payments initially grew at a rate of 11.4% a year between 2014 and 2016 before decreasing at a rate of 5.8% per year after 2016 (P = .03). Though a similar trend occurred at the individual level, it did not reach significance.

However, the trend differed slightly between men and women: Payments to men increased 10.4% annually until 2016 then decreased 6.8% per year thereafter, but women’s payments increased 11.3% per year until 2019. Between 2014 and 2019, the amount per person payment dropped 3.5% annually to physicians overall, but payments to women initially increased 35.4% a year between 2014 and 2016 before decreasing.

Although not statistically significant, trends for types of payments showed that speaker and food/beverage fees have been declining since 2016 while consulting fees have been declining since 2014.

“The reduction in industry payments could be due to the Hawthorne effect, where physicians alter their behavior after becoming aware that their payments were being monitored,” the authors wrote. “Although many physicians see themselves as less vulnerable to be biased by industry compensation, studies have shown that even small payments can affect behavior such as prescription pattern. Additionally, studies have found that patients are less likely to trust physicians who have received industry payments.”

The authors acknowledged the role of industry payments in funding clinical trials but noted that pharmaceutical companies themselves have been taking on more design and execution of trials in recent decades. Further, only 6% of all payments went to research and grant funding, a little more than half the payments for food and beverages.

“While industry research funding is undeniably crucial, it simply plays a very small role in total industry compensation for physicians,” the authors wrote. “While speaker events could be beneficial and educational for physicians and other audiences, these events could also be utilized as means to promote specific products. While it is beneficial to seek input from experienced gastroenterologists for novel therapies and devices, actions should be taken to place limitations on industry payments to physicians, especially for the top earners.”

One author reported speaker fees from W.L. Gore & Associates and Cook Medical. The other two others had no disclosures. No external funding was noted. Dr. Kosinski reported having no relevant disclosures.

This article was updated Aug. 9, 2022.

Industry payments to U.S. gastroenterologists and hepatologists increased from 2014 to 2016 before beginning to steadily decrease after 2016, but they're largely concentrated among a small few, according to new research published in Gastroenterology.

South_agency/Getty Images

The study aimed to identify trends in these specialties in the years after the Sunshine Act, enacted in 2010, and the federal program Open Payments, established in 2013.

“Although Open Payments launched in September of 2014, all the joinpoints in our study occurred more than a year later in 2016, suggesting a delay in observable changes in behavior on industry physician relationships,” wrote Xiaohan Ying, MD, of Weill Cornell Medicine in New York, and colleagues. “Since 2016, we have seen a sustained reduction in general industry payments to physicians while research payments remained stable, which is likely the desired outcome of this program.”

That’s also the conclusion of Lawrence Kosinski, MD, MBA, a spokesperson for the American Gastroenterological Association, who was not involved in the study.

“Most all of us are aware of the Sunshine Act and have reacted accordingly, so I am not surprised that reimbursement per physician has declined over the time period,” Dr. Kosinski told this news organization. “Many physicians are very sensitive to their reporting and have decreased their exposures,” said Dr. Kosinski, founder of SonarMD and a member of the Health & Human Services Advisory Committee on Value-Based Payment. “What does surprise me is the marked disparity in payments with a very small number of physicians receiving tremendous reimbursement from speaking engagements and promotions.”

The researchers retrospectively analyzed industry payments to 26,981 practicing pediatric and adults gastroenterologists and hepatologists using the National Plan and Provider Enumeration System and data from Open Payments between January 2014 and December 2020. The researchers excluded education payments and focused on general payments, which “include charitable contribution, speaker fees, consulting fees, ownership and investments, education, entertainment, food and beverages, gift, honoraria, royalty and license, and travel and lodging,” they reported.
 

Who gets paid, and how much?

While $27.5 million was going to research and grants, most of the payments ($403.3 million) were general payments; out of the total payments to specialists, $30 million went to hepatology, and $400.8 million went to gastroenterology. Nearly all of the general payments ($398.1 million) were for noneducation purposes; 90.5% of general payments went to men and 9.5% went to women, at an average of $17,167 per person. Nearly half the payments (43.8%) were for speaker fees, totaling $174.3 million, followed by 18.4% going to consulting ($73.1 million) and 12.9% going to food and beverages ($51.5 million).

Most of the physicians accepting payments (86.6%) received less than $10,000, but this made up only 8.3% of all payments. Meanwhile, 74% of all the payments, $294.6 million, went to just 3.1% of the physicians, all of whom received more than $100,000.

That breakdown is what most caught Dr. Kosinki’s attention.

“It’s one thing for a speaker to declare that they are receiving funds from pharma, but they never let us know how much,” Dr. Kosinski said. “Some of these speakers are realizing a very significant payment, which could change the opinions of those listening to their presentations.”

The authors reported that a group of 50 top earners (0.2%) received more than $1 million between 2014 and 2020. Their payments totaled $94.8 million and accounted for nearly a quarter (23.8%) of all the payments. All but one of these physicians were men, and one physician has received more than $1 million every year since 2014.
 

Payments for guideline authors explored

The authors examined payments to practicing U.S. gastroenterologists and hepatologists who helped write clinical guidelines for the following organizations:

• American Gastroenterological Association (AGA).
• American College of Gastroenterology (ACG).
• American Association for the Study of Liver Disease (AASLD).
• North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN).
• American Society for Gastrointestinal Endoscopy (ASGE).

The 186 guidelines published between 2014 and 2020 had 632 physician authors, 415 of whom were practicing gastroenterologists and hepatologists in the United States. Most of these physicians (85.8%) received at least one industry payment, with payments to guideline authors totaling $43.6 million.

Similar to the lopsided breakdown for total payments across all physicians, the majority of the payments (87.4%, or $38.1 million) went to one-quarter of the authors, who each received more than $100,000 per person. Meanwhile, 38.2% of the guideline authors received less than $10,000.

“However, these numbers are likely to decrease in the future as professional societies, such as AASLD, require a majority of the guideline authors to be free of conflict of interest relevant to the subject matter,” the authors wrote. They added that members selected as part of the AGA’s guideline development group (GDG) must report all conflicts of interest, including indirect and intellectual ones, and are recused or excluded when appropriate. These guideline development group participants must also forgo speaking and consulting arrangements until one year after the guideline’s publication.
 

Trends have been shifting

Total industry payments initially grew at a rate of 11.4% a year between 2014 and 2016 before decreasing at a rate of 5.8% per year after 2016 (P = .03). Though a similar trend occurred at the individual level, it did not reach significance.

However, the trend differed slightly between men and women: Payments to men increased 10.4% annually until 2016 then decreased 6.8% per year thereafter, but women’s payments increased 11.3% per year until 2019. Between 2014 and 2019, the amount per person payment dropped 3.5% annually to physicians overall, but payments to women initially increased 35.4% a year between 2014 and 2016 before decreasing.

Although not statistically significant, trends for types of payments showed that speaker and food/beverage fees have been declining since 2016 while consulting fees have been declining since 2014.

“The reduction in industry payments could be due to the Hawthorne effect, where physicians alter their behavior after becoming aware that their payments were being monitored,” the authors wrote. “Although many physicians see themselves as less vulnerable to be biased by industry compensation, studies have shown that even small payments can affect behavior such as prescription pattern. Additionally, studies have found that patients are less likely to trust physicians who have received industry payments.”

The authors acknowledged the role of industry payments in funding clinical trials but noted that pharmaceutical companies themselves have been taking on more design and execution of trials in recent decades. Further, only 6% of all payments went to research and grant funding, a little more than half the payments for food and beverages.

“While industry research funding is undeniably crucial, it simply plays a very small role in total industry compensation for physicians,” the authors wrote. “While speaker events could be beneficial and educational for physicians and other audiences, these events could also be utilized as means to promote specific products. While it is beneficial to seek input from experienced gastroenterologists for novel therapies and devices, actions should be taken to place limitations on industry payments to physicians, especially for the top earners.”

One author reported speaker fees from W.L. Gore & Associates and Cook Medical. The other two others had no disclosures. No external funding was noted. Dr. Kosinski reported having no relevant disclosures.

This article was updated Aug. 9, 2022.

Industry payments to U.S. gastroenterologists and hepatologists increased from 2014 to 2016 before beginning to steadily decrease after 2016, but they're largely concentrated among a small few, according to new research published in Gastroenterology.

South_agency/Getty Images

The study aimed to identify trends in these specialties in the years after the Sunshine Act, enacted in 2010, and the federal program Open Payments, established in 2013.

“Although Open Payments launched in September of 2014, all the joinpoints in our study occurred more than a year later in 2016, suggesting a delay in observable changes in behavior on industry physician relationships,” wrote Xiaohan Ying, MD, of Weill Cornell Medicine in New York, and colleagues. “Since 2016, we have seen a sustained reduction in general industry payments to physicians while research payments remained stable, which is likely the desired outcome of this program.”

That’s also the conclusion of Lawrence Kosinski, MD, MBA, a spokesperson for the American Gastroenterological Association, who was not involved in the study.

“Most all of us are aware of the Sunshine Act and have reacted accordingly, so I am not surprised that reimbursement per physician has declined over the time period,” Dr. Kosinski told this news organization. “Many physicians are very sensitive to their reporting and have decreased their exposures,” said Dr. Kosinski, founder of SonarMD and a member of the Health & Human Services Advisory Committee on Value-Based Payment. “What does surprise me is the marked disparity in payments with a very small number of physicians receiving tremendous reimbursement from speaking engagements and promotions.”

The researchers retrospectively analyzed industry payments to 26,981 practicing pediatric and adults gastroenterologists and hepatologists using the National Plan and Provider Enumeration System and data from Open Payments between January 2014 and December 2020. The researchers excluded education payments and focused on general payments, which “include charitable contribution, speaker fees, consulting fees, ownership and investments, education, entertainment, food and beverages, gift, honoraria, royalty and license, and travel and lodging,” they reported.
 

Who gets paid, and how much?

While $27.5 million was going to research and grants, most of the payments ($403.3 million) were general payments; out of the total payments to specialists, $30 million went to hepatology, and $400.8 million went to gastroenterology. Nearly all of the general payments ($398.1 million) were for noneducation purposes; 90.5% of general payments went to men and 9.5% went to women, at an average of $17,167 per person. Nearly half the payments (43.8%) were for speaker fees, totaling $174.3 million, followed by 18.4% going to consulting ($73.1 million) and 12.9% going to food and beverages ($51.5 million).

Most of the physicians accepting payments (86.6%) received less than $10,000, but this made up only 8.3% of all payments. Meanwhile, 74% of all the payments, $294.6 million, went to just 3.1% of the physicians, all of whom received more than $100,000.

That breakdown is what most caught Dr. Kosinki’s attention.

“It’s one thing for a speaker to declare that they are receiving funds from pharma, but they never let us know how much,” Dr. Kosinski said. “Some of these speakers are realizing a very significant payment, which could change the opinions of those listening to their presentations.”

The authors reported that a group of 50 top earners (0.2%) received more than $1 million between 2014 and 2020. Their payments totaled $94.8 million and accounted for nearly a quarter (23.8%) of all the payments. All but one of these physicians were men, and one physician has received more than $1 million every year since 2014.
 

Payments for guideline authors explored

The authors examined payments to practicing U.S. gastroenterologists and hepatologists who helped write clinical guidelines for the following organizations:

• American Gastroenterological Association (AGA).
• American College of Gastroenterology (ACG).
• American Association for the Study of Liver Disease (AASLD).
• North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN).
• American Society for Gastrointestinal Endoscopy (ASGE).

The 186 guidelines published between 2014 and 2020 had 632 physician authors, 415 of whom were practicing gastroenterologists and hepatologists in the United States. Most of these physicians (85.8%) received at least one industry payment, with payments to guideline authors totaling $43.6 million.

Similar to the lopsided breakdown for total payments across all physicians, the majority of the payments (87.4%, or $38.1 million) went to one-quarter of the authors, who each received more than $100,000 per person. Meanwhile, 38.2% of the guideline authors received less than $10,000.

“However, these numbers are likely to decrease in the future as professional societies, such as AASLD, require a majority of the guideline authors to be free of conflict of interest relevant to the subject matter,” the authors wrote. They added that members selected as part of the AGA’s guideline development group (GDG) must report all conflicts of interest, including indirect and intellectual ones, and are recused or excluded when appropriate. These guideline development group participants must also forgo speaking and consulting arrangements until one year after the guideline’s publication.
 

Trends have been shifting

Total industry payments initially grew at a rate of 11.4% a year between 2014 and 2016 before decreasing at a rate of 5.8% per year after 2016 (P = .03). Though a similar trend occurred at the individual level, it did not reach significance.

However, the trend differed slightly between men and women: Payments to men increased 10.4% annually until 2016 then decreased 6.8% per year thereafter, but women’s payments increased 11.3% per year until 2019. Between 2014 and 2019, the amount per person payment dropped 3.5% annually to physicians overall, but payments to women initially increased 35.4% a year between 2014 and 2016 before decreasing.

Although not statistically significant, trends for types of payments showed that speaker and food/beverage fees have been declining since 2016 while consulting fees have been declining since 2014.

“The reduction in industry payments could be due to the Hawthorne effect, where physicians alter their behavior after becoming aware that their payments were being monitored,” the authors wrote. “Although many physicians see themselves as less vulnerable to be biased by industry compensation, studies have shown that even small payments can affect behavior such as prescription pattern. Additionally, studies have found that patients are less likely to trust physicians who have received industry payments.”

The authors acknowledged the role of industry payments in funding clinical trials but noted that pharmaceutical companies themselves have been taking on more design and execution of trials in recent decades. Further, only 6% of all payments went to research and grant funding, a little more than half the payments for food and beverages.

“While industry research funding is undeniably crucial, it simply plays a very small role in total industry compensation for physicians,” the authors wrote. “While speaker events could be beneficial and educational for physicians and other audiences, these events could also be utilized as means to promote specific products. While it is beneficial to seek input from experienced gastroenterologists for novel therapies and devices, actions should be taken to place limitations on industry payments to physicians, especially for the top earners.”

One author reported speaker fees from W.L. Gore & Associates and Cook Medical. The other two others had no disclosures. No external funding was noted. Dr. Kosinski reported having no relevant disclosures.

This article was updated Aug. 9, 2022.

San Diego internist David B. Bittleman, MD, was finishing an appointment with a patient when the man’s caregiver slipped Dr. Bittleman a note as the patient walked out of the room.

“Call me tomorrow,” the mysterious message read.

Dr. Bittleman phoned the caregiver, who was the patient’s ex-wife, the next day. He assumed she wanted to discuss a routine issue, such as the patient’s treatment. But the reason she wanted to talk privately was far more ominous.

“He wants to kill you,” she said.

Dr. Bittleman was shocked. He knew the patient was angry about the fact that his opioid regimen had been tapered, but he didn’t think his fury would rise to possible homicide. The caregiver told Dr. Bittleman she believed her ex-husband was serious.

“The ex-wife and two adult sons were very alarmed by his erratic behavior,” Dr. Bittleman recalled. “She made it very clear that he said he planned to kill me. I feared for my life because I took his threat at face value.”
 

Patient sends alarming message, makes threats

When he went into medicine, Dr. Bittleman never imagined that he’d have to worry about being attacked or killed by a patient.

After spending 20 years in private practice, Dr. Bittleman was excited to accept a position at the Veterans Affairs San Diego health system. His extended family lived in the area, and he looked forward to helping veterans and to working with students, he said.

Dr. Bittleman had practiced primary care at the VA for about 5 years when he encountered the threatening patient, a veteran in his 60’s. The man was suffering from musculoskeletal pain and mental illness.

The patient had taken opioids on and off for many years. Dr. Bittleman felt that to continue the medication would not be safe, considering the man’s lifestyle.

“He had been maintained on oxycodone for chronic pain by previous providers, but I thought that was dangerous, given that he was mixing it with alcohol and marijuana,” he said. “I met with him and a substance use disorder physician for a conference call, and we explained we would need to taper the medication and eventually stop the opioids.”

Dr. Bittleman pleaded with the patient to enter drug rehab, and he offered him inpatient care for treatment of withdrawal. The man refused.

A few weeks later, Dr. Bittleman was checking the health center’s electronic messaging system. He found a disturbing message from the patient.

“You better learn jiu jitsu and hand-to-hand combat if you ever take my opioids away,” the message read. “You better learn how to defend yourself!”

Dr. Bittleman contacted the VA police and reported the message. The patient was interviewed by mental health professionals, but they did not believe he was dangerous, according to Dr. Bittleman.

“They are pretty limited to what they can do,” he said. “At a private practice, the patient might be fired or no longer allowed to come into the building, but the VA is a safety net institution. I’m not sure if he was even reprimanded.”

Two months later, the patient’s ex-wife shared the alarming news that the patient wanted to kill the doctor.

Dr. Bittleman went back to the police. They suggested he file a restraining order, which he sought that afternoon. By the end of the day, the judge had issued the restraining order, according to Dr. Bittleman and court records. The patient could not come within 100 yards of the physician, his clinic, car, or home.

But there was one frightening caveat. The order was temporary. It would last for only 2 weeks. To make the order permanent, Dr. Bittleman would have to go before the judge and argue why it was needed.

He wouldn’t be alone at the hearing. Someone else would be just paces away – the patient who wanted to murder him.
 

Doctor and patient face off before judge

As the hearing neared, Dr. Bittleman felt anxious, outraged, and fearful. He wondered whether the patient might make good on his threat.

Some colleagues suggested that Bittleman buy a gun, while others recommended he carry pepper spray. Dr. Bittleman had no interest in learning how to use a gun, he said. He took comfort in the fact that there were armed guards and metal detectors in his building, and there was a panic button under his desk.

“I was not sure I wanted to take care of patients anymore, especially chronic pain patients,” he said. “However, I went for some counseling with the Employee Assistance Program, and the therapist was helpful in normalizing my anxiety and acknowledging my fear.”

On the day of the hearing, Dr. Bittleman sat in the back of the courtroom. The patient, who sat near the front, glanced at Dr. Bittleman with a slight smile.

When his case was called, the judge explained that as the plaintiff, the burden was on Dr. Bittleman to prove the patient was a threat to his safety. He provided the judge a copy of the threatening message and a copy of the ex-wife’s note.

After reading the documents, the judge asked the patient to explain his side. The patient complained that the VA had denied him certain benefits and that he was forced to receive mental health treatment rehab that he “didn’t need.” The judge eventually interrupted the man to ask if he had threatened to kill Dr. Bittleman.

“Oh yes, your honor, I did say that, but I was only joking,” he told the judge.

The admission was enough. The judge issued a restraining order against the patient that would last 1 year. He could not have firearms, and if he violated the order, he would be arrested.

The terrifying saga was finally over.

“I never heard from the patient again,” Dr. Bittleman said. “His [care] location was changed, and police were required to come to all his visits with his new provider. I was relieved that if he ever came near me, he was going to jail.”

To raise awareness about such ordeals and the hassles that can follow, Dr. Bittleman wrote an article about his experience, which was published in the Annals of Family Medicine. He continues to treat patients at the VA, including those with chronic pain, but the memory of the menacing patient resurfaces from time to time.

“I do still think about it,” he said. “I know how to use my panic button, and I test it every 90 days. If there is a patient who concerns me, I will have the VA police wait nearby. I am very aware and upset by violence. When I hear about a doctor getting killed, I feel a clutch in my chest. How could I not relate? Here is a doctor who worked hard, who dedicated their life to help patients, and it comes to this? It’s so revolting. It makes me sick.”
 

Can you identify a violent patient?

Concern over threatening patients has grown across the country after recent violent attacks against physicians in Oklahoma and California. Two physicians were shot to death in June 2022 when a patient opened fire inside a Tulsa medical building. The primary target of the shooting was a surgeon who had performed surgery on the patient. Also in June, two nurses and an emergency physician were stabbed by a patient inside the Encino Hospital Medical Center. They survived.

The attacks raise questions about how to identify potentially violent patients and how to mitigate possible violence.

Threats and violence against health care professionals are nothing new, but they’re finally getting the attention they deserve, says Derek Schaller, MD, an emergency physician and assistant professor of emergency medicine at Central Michigan University in Mount Pleasant.

“Violence against personnel in medicine has been an issue for a long time; it’s just finally making headlines,” he said. “Way back when, it almost seemed like it was part of the job, part of the gig. But it shouldn’t be part of the gig. It’s not something we should be dealing with.”

It’s common for health care professionals and health centers to take a reactive approach to violent patients, but Dr. Schaller encourages a more proactive strategy. Central Michigan University Health, for example, recently studied its past violent encounters and analyzed the characteristics of violent patients. The analysis came after an increase in violent patient episodes at the health center in the past year, Dr. Schaller said.

The study yielded some interesting results, including that a large percentage of patients who became violent in the emergency department did so within the first hour they were in the hospital, he said.

“You would have thought it’s the patients who have been there and have been stuck in the emergency department for a while and who became disgruntled, but that was not the case,” Dr. Schaller said.

He recommends that physicians, medical practices, and hospitals carry out similar assessments of their patient populations and of past violent encounters to determine trends. His institution will be implementing a screening tool in triage to identify patients more likely to become violent so that health care professionals can intervene earlier, he said.

Such a screening tool is already demonstrating success in a variety of medical settings.

About 10 years ago, a research team led by Son Chae Kim, PhD, RN, found that the 10-item Aggressive Behavior Risk Assessment Tool (ABRAT) was able to identify potentially violent patients with reasonable sensitivity and specificity in hospital medical-surgical units.

Subsequently, the tool was modified for long-term care facilities, and again, researchers found that ABRAT was able to identify potentially violent residents with reasonable sensitivity and specificity, said Dr. Kim, ABRAT developer and a professor at Point Loma Nazarene University, San Diego.

In 2021, researchers embedded the checklist into an electronic health record (EHR) system and tested ABRAT in emergency departments.

“Currently, we are working with computer programmers to build an app that would make the ABRAT very easy to use in conjunction with EHR,” Dr. Kim said. “Instead of a nurse searching the EHR to find out if the patient has history of mental illness or aggressive behavior in the past, the app would automatically search the EHR and combine the nurse’s quick observation whether the patient is confused, agitated, staring, or threatening, to automatically calculate the violence risk.”

Dr. Kim and her team also developed a tool called VEST (Violent Event Severity Tool), a standardized objective workplace violence severity assessment. They are working with programmers to incorporate VEST into the app as well.

Dr. Kim’s hope is that the ABRAT tool can be modified for use in a range of health care settings.

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

San Diego internist David B. Bittleman, MD, was finishing an appointment with a patient when the man’s caregiver slipped Dr. Bittleman a note as the patient walked out of the room.

“Call me tomorrow,” the mysterious message read.

Dr. Bittleman phoned the caregiver, who was the patient’s ex-wife, the next day. He assumed she wanted to discuss a routine issue, such as the patient’s treatment. But the reason she wanted to talk privately was far more ominous.

“He wants to kill you,” she said.

Dr. Bittleman was shocked. He knew the patient was angry about the fact that his opioid regimen had been tapered, but he didn’t think his fury would rise to possible homicide. The caregiver told Dr. Bittleman she believed her ex-husband was serious.

“The ex-wife and two adult sons were very alarmed by his erratic behavior,” Dr. Bittleman recalled. “She made it very clear that he said he planned to kill me. I feared for my life because I took his threat at face value.”
 

Patient sends alarming message, makes threats

When he went into medicine, Dr. Bittleman never imagined that he’d have to worry about being attacked or killed by a patient.

After spending 20 years in private practice, Dr. Bittleman was excited to accept a position at the Veterans Affairs San Diego health system. His extended family lived in the area, and he looked forward to helping veterans and to working with students, he said.

Dr. Bittleman had practiced primary care at the VA for about 5 years when he encountered the threatening patient, a veteran in his 60’s. The man was suffering from musculoskeletal pain and mental illness.

The patient had taken opioids on and off for many years. Dr. Bittleman felt that to continue the medication would not be safe, considering the man’s lifestyle.

“He had been maintained on oxycodone for chronic pain by previous providers, but I thought that was dangerous, given that he was mixing it with alcohol and marijuana,” he said. “I met with him and a substance use disorder physician for a conference call, and we explained we would need to taper the medication and eventually stop the opioids.”

Dr. Bittleman pleaded with the patient to enter drug rehab, and he offered him inpatient care for treatment of withdrawal. The man refused.

A few weeks later, Dr. Bittleman was checking the health center’s electronic messaging system. He found a disturbing message from the patient.

“You better learn jiu jitsu and hand-to-hand combat if you ever take my opioids away,” the message read. “You better learn how to defend yourself!”

Dr. Bittleman contacted the VA police and reported the message. The patient was interviewed by mental health professionals, but they did not believe he was dangerous, according to Dr. Bittleman.

“They are pretty limited to what they can do,” he said. “At a private practice, the patient might be fired or no longer allowed to come into the building, but the VA is a safety net institution. I’m not sure if he was even reprimanded.”

Two months later, the patient’s ex-wife shared the alarming news that the patient wanted to kill the doctor.

Dr. Bittleman went back to the police. They suggested he file a restraining order, which he sought that afternoon. By the end of the day, the judge had issued the restraining order, according to Dr. Bittleman and court records. The patient could not come within 100 yards of the physician, his clinic, car, or home.

But there was one frightening caveat. The order was temporary. It would last for only 2 weeks. To make the order permanent, Dr. Bittleman would have to go before the judge and argue why it was needed.

He wouldn’t be alone at the hearing. Someone else would be just paces away – the patient who wanted to murder him.
 

Doctor and patient face off before judge

As the hearing neared, Dr. Bittleman felt anxious, outraged, and fearful. He wondered whether the patient might make good on his threat.

Some colleagues suggested that Bittleman buy a gun, while others recommended he carry pepper spray. Dr. Bittleman had no interest in learning how to use a gun, he said. He took comfort in the fact that there were armed guards and metal detectors in his building, and there was a panic button under his desk.

“I was not sure I wanted to take care of patients anymore, especially chronic pain patients,” he said. “However, I went for some counseling with the Employee Assistance Program, and the therapist was helpful in normalizing my anxiety and acknowledging my fear.”

On the day of the hearing, Dr. Bittleman sat in the back of the courtroom. The patient, who sat near the front, glanced at Dr. Bittleman with a slight smile.

When his case was called, the judge explained that as the plaintiff, the burden was on Dr. Bittleman to prove the patient was a threat to his safety. He provided the judge a copy of the threatening message and a copy of the ex-wife’s note.

After reading the documents, the judge asked the patient to explain his side. The patient complained that the VA had denied him certain benefits and that he was forced to receive mental health treatment rehab that he “didn’t need.” The judge eventually interrupted the man to ask if he had threatened to kill Dr. Bittleman.

“Oh yes, your honor, I did say that, but I was only joking,” he told the judge.

The admission was enough. The judge issued a restraining order against the patient that would last 1 year. He could not have firearms, and if he violated the order, he would be arrested.

The terrifying saga was finally over.

“I never heard from the patient again,” Dr. Bittleman said. “His [care] location was changed, and police were required to come to all his visits with his new provider. I was relieved that if he ever came near me, he was going to jail.”

To raise awareness about such ordeals and the hassles that can follow, Dr. Bittleman wrote an article about his experience, which was published in the Annals of Family Medicine. He continues to treat patients at the VA, including those with chronic pain, but the memory of the menacing patient resurfaces from time to time.

“I do still think about it,” he said. “I know how to use my panic button, and I test it every 90 days. If there is a patient who concerns me, I will have the VA police wait nearby. I am very aware and upset by violence. When I hear about a doctor getting killed, I feel a clutch in my chest. How could I not relate? Here is a doctor who worked hard, who dedicated their life to help patients, and it comes to this? It’s so revolting. It makes me sick.”
 

Can you identify a violent patient?

Concern over threatening patients has grown across the country after recent violent attacks against physicians in Oklahoma and California. Two physicians were shot to death in June 2022 when a patient opened fire inside a Tulsa medical building. The primary target of the shooting was a surgeon who had performed surgery on the patient. Also in June, two nurses and an emergency physician were stabbed by a patient inside the Encino Hospital Medical Center. They survived.

The attacks raise questions about how to identify potentially violent patients and how to mitigate possible violence.

Threats and violence against health care professionals are nothing new, but they’re finally getting the attention they deserve, says Derek Schaller, MD, an emergency physician and assistant professor of emergency medicine at Central Michigan University in Mount Pleasant.

“Violence against personnel in medicine has been an issue for a long time; it’s just finally making headlines,” he said. “Way back when, it almost seemed like it was part of the job, part of the gig. But it shouldn’t be part of the gig. It’s not something we should be dealing with.”

It’s common for health care professionals and health centers to take a reactive approach to violent patients, but Dr. Schaller encourages a more proactive strategy. Central Michigan University Health, for example, recently studied its past violent encounters and analyzed the characteristics of violent patients. The analysis came after an increase in violent patient episodes at the health center in the past year, Dr. Schaller said.

The study yielded some interesting results, including that a large percentage of patients who became violent in the emergency department did so within the first hour they were in the hospital, he said.

“You would have thought it’s the patients who have been there and have been stuck in the emergency department for a while and who became disgruntled, but that was not the case,” Dr. Schaller said.

He recommends that physicians, medical practices, and hospitals carry out similar assessments of their patient populations and of past violent encounters to determine trends. His institution will be implementing a screening tool in triage to identify patients more likely to become violent so that health care professionals can intervene earlier, he said.

Such a screening tool is already demonstrating success in a variety of medical settings.

About 10 years ago, a research team led by Son Chae Kim, PhD, RN, found that the 10-item Aggressive Behavior Risk Assessment Tool (ABRAT) was able to identify potentially violent patients with reasonable sensitivity and specificity in hospital medical-surgical units.

Subsequently, the tool was modified for long-term care facilities, and again, researchers found that ABRAT was able to identify potentially violent residents with reasonable sensitivity and specificity, said Dr. Kim, ABRAT developer and a professor at Point Loma Nazarene University, San Diego.

In 2021, researchers embedded the checklist into an electronic health record (EHR) system and tested ABRAT in emergency departments.

“Currently, we are working with computer programmers to build an app that would make the ABRAT very easy to use in conjunction with EHR,” Dr. Kim said. “Instead of a nurse searching the EHR to find out if the patient has history of mental illness or aggressive behavior in the past, the app would automatically search the EHR and combine the nurse’s quick observation whether the patient is confused, agitated, staring, or threatening, to automatically calculate the violence risk.”

Dr. Kim and her team also developed a tool called VEST (Violent Event Severity Tool), a standardized objective workplace violence severity assessment. They are working with programmers to incorporate VEST into the app as well.

Dr. Kim’s hope is that the ABRAT tool can be modified for use in a range of health care settings.

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

San Diego internist David B. Bittleman, MD, was finishing an appointment with a patient when the man’s caregiver slipped Dr. Bittleman a note as the patient walked out of the room.

“Call me tomorrow,” the mysterious message read.

Dr. Bittleman phoned the caregiver, who was the patient’s ex-wife, the next day. He assumed she wanted to discuss a routine issue, such as the patient’s treatment. But the reason she wanted to talk privately was far more ominous.

“He wants to kill you,” she said.

Dr. Bittleman was shocked. He knew the patient was angry about the fact that his opioid regimen had been tapered, but he didn’t think his fury would rise to possible homicide. The caregiver told Dr. Bittleman she believed her ex-husband was serious.

“The ex-wife and two adult sons were very alarmed by his erratic behavior,” Dr. Bittleman recalled. “She made it very clear that he said he planned to kill me. I feared for my life because I took his threat at face value.”
 

Patient sends alarming message, makes threats

When he went into medicine, Dr. Bittleman never imagined that he’d have to worry about being attacked or killed by a patient.

After spending 20 years in private practice, Dr. Bittleman was excited to accept a position at the Veterans Affairs San Diego health system. His extended family lived in the area, and he looked forward to helping veterans and to working with students, he said.

Dr. Bittleman had practiced primary care at the VA for about 5 years when he encountered the threatening patient, a veteran in his 60’s. The man was suffering from musculoskeletal pain and mental illness.

The patient had taken opioids on and off for many years. Dr. Bittleman felt that to continue the medication would not be safe, considering the man’s lifestyle.

“He had been maintained on oxycodone for chronic pain by previous providers, but I thought that was dangerous, given that he was mixing it with alcohol and marijuana,” he said. “I met with him and a substance use disorder physician for a conference call, and we explained we would need to taper the medication and eventually stop the opioids.”

Dr. Bittleman pleaded with the patient to enter drug rehab, and he offered him inpatient care for treatment of withdrawal. The man refused.

A few weeks later, Dr. Bittleman was checking the health center’s electronic messaging system. He found a disturbing message from the patient.

“You better learn jiu jitsu and hand-to-hand combat if you ever take my opioids away,” the message read. “You better learn how to defend yourself!”

Dr. Bittleman contacted the VA police and reported the message. The patient was interviewed by mental health professionals, but they did not believe he was dangerous, according to Dr. Bittleman.

“They are pretty limited to what they can do,” he said. “At a private practice, the patient might be fired or no longer allowed to come into the building, but the VA is a safety net institution. I’m not sure if he was even reprimanded.”

Two months later, the patient’s ex-wife shared the alarming news that the patient wanted to kill the doctor.

Dr. Bittleman went back to the police. They suggested he file a restraining order, which he sought that afternoon. By the end of the day, the judge had issued the restraining order, according to Dr. Bittleman and court records. The patient could not come within 100 yards of the physician, his clinic, car, or home.

But there was one frightening caveat. The order was temporary. It would last for only 2 weeks. To make the order permanent, Dr. Bittleman would have to go before the judge and argue why it was needed.

He wouldn’t be alone at the hearing. Someone else would be just paces away – the patient who wanted to murder him.
 

Doctor and patient face off before judge

As the hearing neared, Dr. Bittleman felt anxious, outraged, and fearful. He wondered whether the patient might make good on his threat.

Some colleagues suggested that Bittleman buy a gun, while others recommended he carry pepper spray. Dr. Bittleman had no interest in learning how to use a gun, he said. He took comfort in the fact that there were armed guards and metal detectors in his building, and there was a panic button under his desk.

“I was not sure I wanted to take care of patients anymore, especially chronic pain patients,” he said. “However, I went for some counseling with the Employee Assistance Program, and the therapist was helpful in normalizing my anxiety and acknowledging my fear.”

On the day of the hearing, Dr. Bittleman sat in the back of the courtroom. The patient, who sat near the front, glanced at Dr. Bittleman with a slight smile.

When his case was called, the judge explained that as the plaintiff, the burden was on Dr. Bittleman to prove the patient was a threat to his safety. He provided the judge a copy of the threatening message and a copy of the ex-wife’s note.

After reading the documents, the judge asked the patient to explain his side. The patient complained that the VA had denied him certain benefits and that he was forced to receive mental health treatment rehab that he “didn’t need.” The judge eventually interrupted the man to ask if he had threatened to kill Dr. Bittleman.

“Oh yes, your honor, I did say that, but I was only joking,” he told the judge.

The admission was enough. The judge issued a restraining order against the patient that would last 1 year. He could not have firearms, and if he violated the order, he would be arrested.

The terrifying saga was finally over.

“I never heard from the patient again,” Dr. Bittleman said. “His [care] location was changed, and police were required to come to all his visits with his new provider. I was relieved that if he ever came near me, he was going to jail.”

To raise awareness about such ordeals and the hassles that can follow, Dr. Bittleman wrote an article about his experience, which was published in the Annals of Family Medicine. He continues to treat patients at the VA, including those with chronic pain, but the memory of the menacing patient resurfaces from time to time.

“I do still think about it,” he said. “I know how to use my panic button, and I test it every 90 days. If there is a patient who concerns me, I will have the VA police wait nearby. I am very aware and upset by violence. When I hear about a doctor getting killed, I feel a clutch in my chest. How could I not relate? Here is a doctor who worked hard, who dedicated their life to help patients, and it comes to this? It’s so revolting. It makes me sick.”
 

Can you identify a violent patient?

Concern over threatening patients has grown across the country after recent violent attacks against physicians in Oklahoma and California. Two physicians were shot to death in June 2022 when a patient opened fire inside a Tulsa medical building. The primary target of the shooting was a surgeon who had performed surgery on the patient. Also in June, two nurses and an emergency physician were stabbed by a patient inside the Encino Hospital Medical Center. They survived.

The attacks raise questions about how to identify potentially violent patients and how to mitigate possible violence.

Threats and violence against health care professionals are nothing new, but they’re finally getting the attention they deserve, says Derek Schaller, MD, an emergency physician and assistant professor of emergency medicine at Central Michigan University in Mount Pleasant.

“Violence against personnel in medicine has been an issue for a long time; it’s just finally making headlines,” he said. “Way back when, it almost seemed like it was part of the job, part of the gig. But it shouldn’t be part of the gig. It’s not something we should be dealing with.”

It’s common for health care professionals and health centers to take a reactive approach to violent patients, but Dr. Schaller encourages a more proactive strategy. Central Michigan University Health, for example, recently studied its past violent encounters and analyzed the characteristics of violent patients. The analysis came after an increase in violent patient episodes at the health center in the past year, Dr. Schaller said.

The study yielded some interesting results, including that a large percentage of patients who became violent in the emergency department did so within the first hour they were in the hospital, he said.

“You would have thought it’s the patients who have been there and have been stuck in the emergency department for a while and who became disgruntled, but that was not the case,” Dr. Schaller said.

He recommends that physicians, medical practices, and hospitals carry out similar assessments of their patient populations and of past violent encounters to determine trends. His institution will be implementing a screening tool in triage to identify patients more likely to become violent so that health care professionals can intervene earlier, he said.

Such a screening tool is already demonstrating success in a variety of medical settings.

About 10 years ago, a research team led by Son Chae Kim, PhD, RN, found that the 10-item Aggressive Behavior Risk Assessment Tool (ABRAT) was able to identify potentially violent patients with reasonable sensitivity and specificity in hospital medical-surgical units.

Subsequently, the tool was modified for long-term care facilities, and again, researchers found that ABRAT was able to identify potentially violent residents with reasonable sensitivity and specificity, said Dr. Kim, ABRAT developer and a professor at Point Loma Nazarene University, San Diego.

In 2021, researchers embedded the checklist into an electronic health record (EHR) system and tested ABRAT in emergency departments.

“Currently, we are working with computer programmers to build an app that would make the ABRAT very easy to use in conjunction with EHR,” Dr. Kim said. “Instead of a nurse searching the EHR to find out if the patient has history of mental illness or aggressive behavior in the past, the app would automatically search the EHR and combine the nurse’s quick observation whether the patient is confused, agitated, staring, or threatening, to automatically calculate the violence risk.”

Dr. Kim and her team also developed a tool called VEST (Violent Event Severity Tool), a standardized objective workplace violence severity assessment. They are working with programmers to incorporate VEST into the app as well.

Dr. Kim’s hope is that the ABRAT tool can be modified for use in a range of health care settings.

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

The Food and Drug Administration has approved trastuzumab deruxtecan (Enhertu, Daiichi Sankyo/ AstraZeneca) for the treatment of patients with unresectable or metastatic HER2-low breast cancer.

This is the first therapy approved for HER2-low breast cancer, a newly defined subset of HER2-negative breast cancer in which there are some HER2 proteins on the cell surface, but not enough to warrant classification as HER2-positive cancer, the FDA said in a press release.

The indication is for patients who have received prior chemotherapy in the metastatic setting or for patients whose cancer has returned during adjuvant chemotherapy or within 6 months of completing it.

Approval was based on the DESTINY-Breast04 trial, which included 557 patients with unresectable or metastatic HER2-low breast cancer. The trial had two cohorts: 494 hormone receptor–positive (HR+) patients, and 63 hormone receptor–negative (HR–) patients.

Of these patients, 373 were randomly assigned to received trastuzumab deruxtecan every 3 weeks, and 184 were randomly assigned to receive physician’s choice of chemotherapy (eribulin, capecitabine, gemcitabine, nab paclitaxel, or paclitaxel).

Among patients who received trastuzumab deruxtecan, progression-free survival was longer (10.1 months vs. 5.4 months), as was overall survival (23.9 months vs. 17.5 months), compared with those in the chemotherapy group.

“Overall, these results establish HER2-low metastatic breast cancer as a targetable population of breast cancer with trastuzumab deruxtecan as a new standard of care in this setting,” Shanu Modi, MD, said in June at a press conference held during the annual meeting of the American Society of Clinical Oncology, where she presented the results.

The most common adverse reactions in the trial were nausea, fatigue, alopecia, vomiting, constipation, decreased appetite, musculoskeletal pain, and diarrhea. The agent carries a boxed warning regarding the risk of interstitial lung disease and embryo-fetal toxicity.

The targeted agent is not recommended for women who are pregnant.

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

The Food and Drug Administration has approved trastuzumab deruxtecan (Enhertu, Daiichi Sankyo/ AstraZeneca) for the treatment of patients with unresectable or metastatic HER2-low breast cancer.

This is the first therapy approved for HER2-low breast cancer, a newly defined subset of HER2-negative breast cancer in which there are some HER2 proteins on the cell surface, but not enough to warrant classification as HER2-positive cancer, the FDA said in a press release.

The indication is for patients who have received prior chemotherapy in the metastatic setting or for patients whose cancer has returned during adjuvant chemotherapy or within 6 months of completing it.

Approval was based on the DESTINY-Breast04 trial, which included 557 patients with unresectable or metastatic HER2-low breast cancer. The trial had two cohorts: 494 hormone receptor–positive (HR+) patients, and 63 hormone receptor–negative (HR–) patients.

Of these patients, 373 were randomly assigned to received trastuzumab deruxtecan every 3 weeks, and 184 were randomly assigned to receive physician’s choice of chemotherapy (eribulin, capecitabine, gemcitabine, nab paclitaxel, or paclitaxel).

Among patients who received trastuzumab deruxtecan, progression-free survival was longer (10.1 months vs. 5.4 months), as was overall survival (23.9 months vs. 17.5 months), compared with those in the chemotherapy group.

“Overall, these results establish HER2-low metastatic breast cancer as a targetable population of breast cancer with trastuzumab deruxtecan as a new standard of care in this setting,” Shanu Modi, MD, said in June at a press conference held during the annual meeting of the American Society of Clinical Oncology, where she presented the results.

The most common adverse reactions in the trial were nausea, fatigue, alopecia, vomiting, constipation, decreased appetite, musculoskeletal pain, and diarrhea. The agent carries a boxed warning regarding the risk of interstitial lung disease and embryo-fetal toxicity.

The targeted agent is not recommended for women who are pregnant.

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

The Food and Drug Administration has approved trastuzumab deruxtecan (Enhertu, Daiichi Sankyo/ AstraZeneca) for the treatment of patients with unresectable or metastatic HER2-low breast cancer.

This is the first therapy approved for HER2-low breast cancer, a newly defined subset of HER2-negative breast cancer in which there are some HER2 proteins on the cell surface, but not enough to warrant classification as HER2-positive cancer, the FDA said in a press release.

The indication is for patients who have received prior chemotherapy in the metastatic setting or for patients whose cancer has returned during adjuvant chemotherapy or within 6 months of completing it.

Approval was based on the DESTINY-Breast04 trial, which included 557 patients with unresectable or metastatic HER2-low breast cancer. The trial had two cohorts: 494 hormone receptor–positive (HR+) patients, and 63 hormone receptor–negative (HR–) patients.

Of these patients, 373 were randomly assigned to received trastuzumab deruxtecan every 3 weeks, and 184 were randomly assigned to receive physician’s choice of chemotherapy (eribulin, capecitabine, gemcitabine, nab paclitaxel, or paclitaxel).

Among patients who received trastuzumab deruxtecan, progression-free survival was longer (10.1 months vs. 5.4 months), as was overall survival (23.9 months vs. 17.5 months), compared with those in the chemotherapy group.

“Overall, these results establish HER2-low metastatic breast cancer as a targetable population of breast cancer with trastuzumab deruxtecan as a new standard of care in this setting,” Shanu Modi, MD, said in June at a press conference held during the annual meeting of the American Society of Clinical Oncology, where she presented the results.

The most common adverse reactions in the trial were nausea, fatigue, alopecia, vomiting, constipation, decreased appetite, musculoskeletal pain, and diarrhea. The agent carries a boxed warning regarding the risk of interstitial lung disease and embryo-fetal toxicity.

The targeted agent is not recommended for women who are pregnant.

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

Are you among the hundreds of millions of people worldwide with low back pain? If so, you may be familiar with standard treatments like surgery, shots, medications, and spinal manipulations. But new research suggests the solution for the world’s leading cause of disability may lie in fixing how the brain and the body communicate.

Setting out to challenge traditional treatments for chronic back pain, scientists across Australia, Europe, and the United States came together to test the effectiveness of altering how neural networks recognize pain for new research published this week in JAMA.

The randomized clinical trial recruited two groups of 138 participants with chronic low back pain, testing one group with a novel method called graded sensorimotor retraining intervention (RESOLVE) and the other with things like mock laser therapy and noninvasive brain stimulation.

The researchers found the RESOLVE 12-week training course resulted in a statistically significant improvement in pain intensity at 18 weeks.

“What we observed in our trial was a clinically meaningful effect on pain intensity and a clinically meaningful effect on disability. People were happier, they reported their backs felt better, and their quality of life was better,” the study’s lead author, James McAuley, PhD, said in a statement. “This is the first new treatment of its kind for back pain.”
 

Brainy talk

Communication between your brain and back changes over time when you have chronic lower back pain, leading the brain to interpret signals from the back differently and change how you move. It is thought that these neural changes make recovery from pain slower and more complicated , according to Neuroscience Research Australia (NeuRA), a nonprofit research institute in Sydney.

“Over time, the back becomes less fit, and the way the back and brain communicate is disrupted in ways that seem to reinforce the notion that the back is vulnerable and needs protecting,” said Dr. McAuley, a professor at the University of New South Wales, Sydney, and a NeuRA senior research scientist. “The treatment we devised aims to break this self-sustaining cycle.”

RESOLVE treatment focuses on improving this transformed brain-back communication by slowly retraining the body and the brain without the use of opioids or surgery. People in the study have reported improved quality of life 1 year later, according to Dr. McAuley.

The researchers said the pain improvement was “modest,” and the method will need to be tested on other patients and conditions. They hope to introduce this new treatment to doctors and physiotherapists within the next 6-9 months and have already enlisted partner organizations to start this process, according to NeuRA.

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

Are you among the hundreds of millions of people worldwide with low back pain? If so, you may be familiar with standard treatments like surgery, shots, medications, and spinal manipulations. But new research suggests the solution for the world’s leading cause of disability may lie in fixing how the brain and the body communicate.

Setting out to challenge traditional treatments for chronic back pain, scientists across Australia, Europe, and the United States came together to test the effectiveness of altering how neural networks recognize pain for new research published this week in JAMA.

The randomized clinical trial recruited two groups of 138 participants with chronic low back pain, testing one group with a novel method called graded sensorimotor retraining intervention (RESOLVE) and the other with things like mock laser therapy and noninvasive brain stimulation.

The researchers found the RESOLVE 12-week training course resulted in a statistically significant improvement in pain intensity at 18 weeks.

“What we observed in our trial was a clinically meaningful effect on pain intensity and a clinically meaningful effect on disability. People were happier, they reported their backs felt better, and their quality of life was better,” the study’s lead author, James McAuley, PhD, said in a statement. “This is the first new treatment of its kind for back pain.”
 

Brainy talk

Communication between your brain and back changes over time when you have chronic lower back pain, leading the brain to interpret signals from the back differently and change how you move. It is thought that these neural changes make recovery from pain slower and more complicated , according to Neuroscience Research Australia (NeuRA), a nonprofit research institute in Sydney.

“Over time, the back becomes less fit, and the way the back and brain communicate is disrupted in ways that seem to reinforce the notion that the back is vulnerable and needs protecting,” said Dr. McAuley, a professor at the University of New South Wales, Sydney, and a NeuRA senior research scientist. “The treatment we devised aims to break this self-sustaining cycle.”

RESOLVE treatment focuses on improving this transformed brain-back communication by slowly retraining the body and the brain without the use of opioids or surgery. People in the study have reported improved quality of life 1 year later, according to Dr. McAuley.

The researchers said the pain improvement was “modest,” and the method will need to be tested on other patients and conditions. They hope to introduce this new treatment to doctors and physiotherapists within the next 6-9 months and have already enlisted partner organizations to start this process, according to NeuRA.

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

Are you among the hundreds of millions of people worldwide with low back pain? If so, you may be familiar with standard treatments like surgery, shots, medications, and spinal manipulations. But new research suggests the solution for the world’s leading cause of disability may lie in fixing how the brain and the body communicate.

Setting out to challenge traditional treatments for chronic back pain, scientists across Australia, Europe, and the United States came together to test the effectiveness of altering how neural networks recognize pain for new research published this week in JAMA.

The randomized clinical trial recruited two groups of 138 participants with chronic low back pain, testing one group with a novel method called graded sensorimotor retraining intervention (RESOLVE) and the other with things like mock laser therapy and noninvasive brain stimulation.

The researchers found the RESOLVE 12-week training course resulted in a statistically significant improvement in pain intensity at 18 weeks.

“What we observed in our trial was a clinically meaningful effect on pain intensity and a clinically meaningful effect on disability. People were happier, they reported their backs felt better, and their quality of life was better,” the study’s lead author, James McAuley, PhD, said in a statement. “This is the first new treatment of its kind for back pain.”
 

Brainy talk

Communication between your brain and back changes over time when you have chronic lower back pain, leading the brain to interpret signals from the back differently and change how you move. It is thought that these neural changes make recovery from pain slower and more complicated , according to Neuroscience Research Australia (NeuRA), a nonprofit research institute in Sydney.

“Over time, the back becomes less fit, and the way the back and brain communicate is disrupted in ways that seem to reinforce the notion that the back is vulnerable and needs protecting,” said Dr. McAuley, a professor at the University of New South Wales, Sydney, and a NeuRA senior research scientist. “The treatment we devised aims to break this self-sustaining cycle.”

RESOLVE treatment focuses on improving this transformed brain-back communication by slowly retraining the body and the brain without the use of opioids or surgery. People in the study have reported improved quality of life 1 year later, according to Dr. McAuley.

The researchers said the pain improvement was “modest,” and the method will need to be tested on other patients and conditions. They hope to introduce this new treatment to doctors and physiotherapists within the next 6-9 months and have already enlisted partner organizations to start this process, according to NeuRA.

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

A simple blood test that looks for a combination of specific RNA snippets may become a novel way to screen for early-onset colorectal cancer, suggests a new study published online in Gastroenterology.

Researchers identified four microRNAs that together comprise a signature biomarker that can be used to detect and diagnose the presence of colorectal cancer from a liquid biopsy in a younger population.

MicroRNAs, or miRNAs, are small RNA molecules that do not encode proteins but are used instead to regulate gene expression. The study authors developed and validated a panel that detects four miRNAs occurring at higher levels in plasma samples from patients with early-onset colorectal cancer, with high sensitivity and specificity.

“The point would be to use this test as a routine part of annual healthcare, or for people in high-risk families every 6 months,” study senior author Ajay Goel, PhD, MS, chair of the department of molecular diagnostics and experimental therapeutics at the City of Hope Comprehensive Cancer Center, Duarte, Calif., said in an interview.

“It’s affordable, it can be done easily from a small tube of blood, and as long as that test stays negative, you’re good,” Dr. Goel said, because even if patients miss a test, the next one, whether it’s 6 months or a year later, will catch any potential cancer.

“Colon cancer is not going to kill somebody overnight, so this should be used as a precursor to colonoscopy. As long as that test is negative, you can postpone a colonoscopy,” he said.

Andrew T. Chan, MD, MPH, a professor of medicine at Harvard Medical School and vice chair of gastroenterology at Massachusetts General Hospital, both in Boston, who was not involved in the research, said in an interview that the findings are exciting.

“It would be really value-added to have a blood-based screening test,” Dr. Chan said, adding that researchers have pursued multiple different avenues in pursuit of one. “It’s very nice to see that area progress and to actually have some evidence that microRNAs could be a potential biomarker for colorectal cancer.”
 

Screening now insufficient for early-onset disease

The U.S. Preventive Services Task Force recently lowered the recommended age to 45 years to begin screening for colorectal cancer. Part of the rationale for the change came from the rising rates of early-onset colorectal cancer, a distinct clinical and molecular entity that tends to have poorer survival than late-onset disease, the authors noted.

Early-onset disease, occurring primarily in people under 50 without a family or genetic history of colorectal cancer, now makes up about 10%-15% of all new cases and continues to rise, they write.

“Early-onset colorectal cancer patients are more likely to exhibit an advanced stage tumor at initial presentation, distal tumor localization, signet ring histology, and a disease presentation with concurrent metastasis,” the authors wrote. “This raises the logistical clinical concern that, since the tumors in early-onset colorectal cancer patients are often more aggressive than those with late-onset colorectal cancer, a delayed diagnosis could have a significant adverse impact and can lead to early death.”

Yet current screening strategies are insufficient for detecting enough early-onset cases, the authors assert.

Colonoscopies are invasive, carry a risk for complications, and are cost- and time-prohibitive for people at average risk. Meanwhile, existing fecal and blood tests “lack adequate diagnostic performance for the early detection of colorectal cancer, especially early-onset colorectal cancer, as these assays have yet to be explored or developed in this population,” they wrote.

The ideal “diagnostic modality should preferably be acceptable to healthy individuals, inexpensive, rapid, and preferably noninvasive,” they note.
 

Finding and validating miRNA

The researchers therefore turned to the concept of a liquid biopsy, focusing on identifying miRNAs associated with colorectal cancer, because their expression tends to be stable in tissues, blood, stool, and other body fluids.

They first analyzed an miRNA expression profiling dataset from 1,061 individuals to look for miRNAs whose expression was higher in colorectal cancer patients. The dataset included 42 patients with stage 1-2 early-onset colorectal cancer, 370 patients with stage 1-2 late-onset colorectal cancer, 62 patients younger than 50 years without cancer, and 587 patients aged 50 years or older without cancer.

The researchers found 28 miRNAs that were significantly unregulated in early-onset colorectal cancer tissue samples, compared with cancer-free samples and 11 miRNAs unregulated specifically in only the early-onset colorectal cancer samples. Four of these 11 miRNAs were adequately distinct from one another and were detectable in the plasma samples that the researchers would use to train and validate them as a combination biomarker.

The researchers used 117 plasma samples from Japan, including 72 from people with early-onset colorectal cancer and 45 from healthy donors, to develop and train an assay detecting the four miRNAs. They then validated the assay using 142 plasma samples from Spain, including 77 with early-onset colorectal cancer and 65 healthy donors.

In the Japan cohort, the four-miRNA assay had a sensitivity of 90% and a specificity of 80%, with a positive predictive value (PPV) of 88% and a negative predictive value (NPV) of 84%. In the Spain cohort used for validation, the assay performed with a sensitivity of 82%, a specificity of 86%, a PPV of 88%, and an NPV of 80%.

“Taken together, the genome-wide transcriptomic profiling approach was indeed robust, as it identified the biomarkers that were successfully trained and validated in plasma specimens from independent cohorts of patients with early-onset colorectal cancer, hence highlighting their translational potential in the clinic for the detection of this malignancy in early stages,” the authors wrote.

By disease stage, the four-miRNA panel identified both early-stage (stage 1-2; sensitivity, 92%; specificity, 80%) and late-stage (stage 3-4; sensitivity, 79%; specificity, 86%) early-onset colorectal cancer in the validation cohort.
 

Clinical benefit of blood test

The researchers also assessed the benefit-harm trade-off of this liquid biopsy assay compared with other screening modalities, taking into consideration the risk for false positives and false negatives.

A decision curve analysis “revealed that the miRNA panel achieved a higher net benefit regardless of threshold probability in comparison to intervention for all patients or none of the patients,” the researchers reported. “These findings suggest that this miRNA panel might offer more clinical benefit with regards to the avoidance of physical harm and misdiagnosis.”

They also found that expression levels of these four miRNAs significantly decreased after surgical removal of the colorectal cancer, strongly suggesting that the miRNAs do originate with the tumor.

“To have a relatively inexpensive and noninvasive means of screening a younger population is a very important unmet need,” said Dr. Chan.

It’s not feasible to recommend colonoscopies in people younger than 45 years because of resource constraints, he said, so “this is a wonderful new development to actually have the possibility of a blood-based screening test for younger individuals, especially given that rising incidence of young-onset colorectal cancer.”

Dr. Goel pointed out that only half of those recommended to get screened for colorectal cancer actually undergo screening, and a large reason for that is the desire to avoid colonoscopy, a concern echoed in the findings of a recent study by Christopher V. Almario, MD, MSHPM, and colleagues.

Dr. Goel expects that this strategy would increase compliance with screening because it’s less invasive and more affordable, particularly for younger patients. He estimates that a commercial assay using this panel, if approved by the Food and Drug Administration, should cost less than $100.

Dr. Almario, an assistant professor of medicine at the Cedars-Sinai Karsh Division of Gastroenterology and Hepatology in Los Angeles, agreed that an FDA-approved blood-based screening test would be a “game-changer,” as long as it’s accurate and effective.

Though Dr. Almario did not review the data in Goel’s study, he said in an interview that a blood test for colorectal cancer screening would be “the holy grail, so to speak, in terms of really moving the needle on screening uptake.”
 

Next steps

Dr. Chan noted that one caveat to consider with this study is that it was done in a relatively small population of individuals, even though the test was validated in a second set of plasma samples.

“Additional validation needs to be done in larger numbers of patients to really understand the performance characteristics because it is possible that some of these signatures may, when they’re using a broader group of individuals, not perform as well,” Dr. Chan said.

Dr. Goel said he is working with several companies right now to develop and further test a commercial product. He anticipates it may be shelf-ready in 2-5 years.

“The take-home message is that clinicians need to be more cognizant of the fact that incidence of this disease is rising, and we need to do something about it,” Dr. Goel said, particularly for those younger than 45 years who currently don’t have a screening option.

“Now we have at least a sliver of hope for those who might be suffering from this disease, for those for whom we have zero screening or diagnostic tests,” he said.

The research was funded by the National Cancer Institute and Fundación MAPFRE Guanarteme. Dr. Goel, Dr. Chan, and Dr. Almario reported no conflicts of interest.

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

A simple blood test that looks for a combination of specific RNA snippets may become a novel way to screen for early-onset colorectal cancer, suggests a new study published online in Gastroenterology.

Researchers identified four microRNAs that together comprise a signature biomarker that can be used to detect and diagnose the presence of colorectal cancer from a liquid biopsy in a younger population.

MicroRNAs, or miRNAs, are small RNA molecules that do not encode proteins but are used instead to regulate gene expression. The study authors developed and validated a panel that detects four miRNAs occurring at higher levels in plasma samples from patients with early-onset colorectal cancer, with high sensitivity and specificity.

“The point would be to use this test as a routine part of annual healthcare, or for people in high-risk families every 6 months,” study senior author Ajay Goel, PhD, MS, chair of the department of molecular diagnostics and experimental therapeutics at the City of Hope Comprehensive Cancer Center, Duarte, Calif., said in an interview.

“It’s affordable, it can be done easily from a small tube of blood, and as long as that test stays negative, you’re good,” Dr. Goel said, because even if patients miss a test, the next one, whether it’s 6 months or a year later, will catch any potential cancer.

“Colon cancer is not going to kill somebody overnight, so this should be used as a precursor to colonoscopy. As long as that test is negative, you can postpone a colonoscopy,” he said.

Andrew T. Chan, MD, MPH, a professor of medicine at Harvard Medical School and vice chair of gastroenterology at Massachusetts General Hospital, both in Boston, who was not involved in the research, said in an interview that the findings are exciting.

“It would be really value-added to have a blood-based screening test,” Dr. Chan said, adding that researchers have pursued multiple different avenues in pursuit of one. “It’s very nice to see that area progress and to actually have some evidence that microRNAs could be a potential biomarker for colorectal cancer.”
 

Screening now insufficient for early-onset disease

The U.S. Preventive Services Task Force recently lowered the recommended age to 45 years to begin screening for colorectal cancer. Part of the rationale for the change came from the rising rates of early-onset colorectal cancer, a distinct clinical and molecular entity that tends to have poorer survival than late-onset disease, the authors noted.

Early-onset disease, occurring primarily in people under 50 without a family or genetic history of colorectal cancer, now makes up about 10%-15% of all new cases and continues to rise, they write.

“Early-onset colorectal cancer patients are more likely to exhibit an advanced stage tumor at initial presentation, distal tumor localization, signet ring histology, and a disease presentation with concurrent metastasis,” the authors wrote. “This raises the logistical clinical concern that, since the tumors in early-onset colorectal cancer patients are often more aggressive than those with late-onset colorectal cancer, a delayed diagnosis could have a significant adverse impact and can lead to early death.”

Yet current screening strategies are insufficient for detecting enough early-onset cases, the authors assert.

Colonoscopies are invasive, carry a risk for complications, and are cost- and time-prohibitive for people at average risk. Meanwhile, existing fecal and blood tests “lack adequate diagnostic performance for the early detection of colorectal cancer, especially early-onset colorectal cancer, as these assays have yet to be explored or developed in this population,” they wrote.

The ideal “diagnostic modality should preferably be acceptable to healthy individuals, inexpensive, rapid, and preferably noninvasive,” they note.
 

Finding and validating miRNA

The researchers therefore turned to the concept of a liquid biopsy, focusing on identifying miRNAs associated with colorectal cancer, because their expression tends to be stable in tissues, blood, stool, and other body fluids.

They first analyzed an miRNA expression profiling dataset from 1,061 individuals to look for miRNAs whose expression was higher in colorectal cancer patients. The dataset included 42 patients with stage 1-2 early-onset colorectal cancer, 370 patients with stage 1-2 late-onset colorectal cancer, 62 patients younger than 50 years without cancer, and 587 patients aged 50 years or older without cancer.

The researchers found 28 miRNAs that were significantly unregulated in early-onset colorectal cancer tissue samples, compared with cancer-free samples and 11 miRNAs unregulated specifically in only the early-onset colorectal cancer samples. Four of these 11 miRNAs were adequately distinct from one another and were detectable in the plasma samples that the researchers would use to train and validate them as a combination biomarker.

The researchers used 117 plasma samples from Japan, including 72 from people with early-onset colorectal cancer and 45 from healthy donors, to develop and train an assay detecting the four miRNAs. They then validated the assay using 142 plasma samples from Spain, including 77 with early-onset colorectal cancer and 65 healthy donors.

In the Japan cohort, the four-miRNA assay had a sensitivity of 90% and a specificity of 80%, with a positive predictive value (PPV) of 88% and a negative predictive value (NPV) of 84%. In the Spain cohort used for validation, the assay performed with a sensitivity of 82%, a specificity of 86%, a PPV of 88%, and an NPV of 80%.

“Taken together, the genome-wide transcriptomic profiling approach was indeed robust, as it identified the biomarkers that were successfully trained and validated in plasma specimens from independent cohorts of patients with early-onset colorectal cancer, hence highlighting their translational potential in the clinic for the detection of this malignancy in early stages,” the authors wrote.

By disease stage, the four-miRNA panel identified both early-stage (stage 1-2; sensitivity, 92%; specificity, 80%) and late-stage (stage 3-4; sensitivity, 79%; specificity, 86%) early-onset colorectal cancer in the validation cohort.
 

Clinical benefit of blood test

The researchers also assessed the benefit-harm trade-off of this liquid biopsy assay compared with other screening modalities, taking into consideration the risk for false positives and false negatives.

A decision curve analysis “revealed that the miRNA panel achieved a higher net benefit regardless of threshold probability in comparison to intervention for all patients or none of the patients,” the researchers reported. “These findings suggest that this miRNA panel might offer more clinical benefit with regards to the avoidance of physical harm and misdiagnosis.”

They also found that expression levels of these four miRNAs significantly decreased after surgical removal of the colorectal cancer, strongly suggesting that the miRNAs do originate with the tumor.

“To have a relatively inexpensive and noninvasive means of screening a younger population is a very important unmet need,” said Dr. Chan.

It’s not feasible to recommend colonoscopies in people younger than 45 years because of resource constraints, he said, so “this is a wonderful new development to actually have the possibility of a blood-based screening test for younger individuals, especially given that rising incidence of young-onset colorectal cancer.”

Dr. Goel pointed out that only half of those recommended to get screened for colorectal cancer actually undergo screening, and a large reason for that is the desire to avoid colonoscopy, a concern echoed in the findings of a recent study by Christopher V. Almario, MD, MSHPM, and colleagues.

Dr. Goel expects that this strategy would increase compliance with screening because it’s less invasive and more affordable, particularly for younger patients. He estimates that a commercial assay using this panel, if approved by the Food and Drug Administration, should cost less than $100.

Dr. Almario, an assistant professor of medicine at the Cedars-Sinai Karsh Division of Gastroenterology and Hepatology in Los Angeles, agreed that an FDA-approved blood-based screening test would be a “game-changer,” as long as it’s accurate and effective.

Though Dr. Almario did not review the data in Goel’s study, he said in an interview that a blood test for colorectal cancer screening would be “the holy grail, so to speak, in terms of really moving the needle on screening uptake.”
 

Next steps

Dr. Chan noted that one caveat to consider with this study is that it was done in a relatively small population of individuals, even though the test was validated in a second set of plasma samples.

“Additional validation needs to be done in larger numbers of patients to really understand the performance characteristics because it is possible that some of these signatures may, when they’re using a broader group of individuals, not perform as well,” Dr. Chan said.

Dr. Goel said he is working with several companies right now to develop and further test a commercial product. He anticipates it may be shelf-ready in 2-5 years.

“The take-home message is that clinicians need to be more cognizant of the fact that incidence of this disease is rising, and we need to do something about it,” Dr. Goel said, particularly for those younger than 45 years who currently don’t have a screening option.

“Now we have at least a sliver of hope for those who might be suffering from this disease, for those for whom we have zero screening or diagnostic tests,” he said.

The research was funded by the National Cancer Institute and Fundación MAPFRE Guanarteme. Dr. Goel, Dr. Chan, and Dr. Almario reported no conflicts of interest.

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

A simple blood test that looks for a combination of specific RNA snippets may become a novel way to screen for early-onset colorectal cancer, suggests a new study published online in Gastroenterology.

Researchers identified four microRNAs that together comprise a signature biomarker that can be used to detect and diagnose the presence of colorectal cancer from a liquid biopsy in a younger population.

MicroRNAs, or miRNAs, are small RNA molecules that do not encode proteins but are used instead to regulate gene expression. The study authors developed and validated a panel that detects four miRNAs occurring at higher levels in plasma samples from patients with early-onset colorectal cancer, with high sensitivity and specificity.

“The point would be to use this test as a routine part of annual healthcare, or for people in high-risk families every 6 months,” study senior author Ajay Goel, PhD, MS, chair of the department of molecular diagnostics and experimental therapeutics at the City of Hope Comprehensive Cancer Center, Duarte, Calif., said in an interview.

“It’s affordable, it can be done easily from a small tube of blood, and as long as that test stays negative, you’re good,” Dr. Goel said, because even if patients miss a test, the next one, whether it’s 6 months or a year later, will catch any potential cancer.

“Colon cancer is not going to kill somebody overnight, so this should be used as a precursor to colonoscopy. As long as that test is negative, you can postpone a colonoscopy,” he said.

Andrew T. Chan, MD, MPH, a professor of medicine at Harvard Medical School and vice chair of gastroenterology at Massachusetts General Hospital, both in Boston, who was not involved in the research, said in an interview that the findings are exciting.

“It would be really value-added to have a blood-based screening test,” Dr. Chan said, adding that researchers have pursued multiple different avenues in pursuit of one. “It’s very nice to see that area progress and to actually have some evidence that microRNAs could be a potential biomarker for colorectal cancer.”
 

Screening now insufficient for early-onset disease

The U.S. Preventive Services Task Force recently lowered the recommended age to 45 years to begin screening for colorectal cancer. Part of the rationale for the change came from the rising rates of early-onset colorectal cancer, a distinct clinical and molecular entity that tends to have poorer survival than late-onset disease, the authors noted.

Early-onset disease, occurring primarily in people under 50 without a family or genetic history of colorectal cancer, now makes up about 10%-15% of all new cases and continues to rise, they write.

“Early-onset colorectal cancer patients are more likely to exhibit an advanced stage tumor at initial presentation, distal tumor localization, signet ring histology, and a disease presentation with concurrent metastasis,” the authors wrote. “This raises the logistical clinical concern that, since the tumors in early-onset colorectal cancer patients are often more aggressive than those with late-onset colorectal cancer, a delayed diagnosis could have a significant adverse impact and can lead to early death.”

Yet current screening strategies are insufficient for detecting enough early-onset cases, the authors assert.

Colonoscopies are invasive, carry a risk for complications, and are cost- and time-prohibitive for people at average risk. Meanwhile, existing fecal and blood tests “lack adequate diagnostic performance for the early detection of colorectal cancer, especially early-onset colorectal cancer, as these assays have yet to be explored or developed in this population,” they wrote.

The ideal “diagnostic modality should preferably be acceptable to healthy individuals, inexpensive, rapid, and preferably noninvasive,” they note.
 

Finding and validating miRNA

The researchers therefore turned to the concept of a liquid biopsy, focusing on identifying miRNAs associated with colorectal cancer, because their expression tends to be stable in tissues, blood, stool, and other body fluids.

They first analyzed an miRNA expression profiling dataset from 1,061 individuals to look for miRNAs whose expression was higher in colorectal cancer patients. The dataset included 42 patients with stage 1-2 early-onset colorectal cancer, 370 patients with stage 1-2 late-onset colorectal cancer, 62 patients younger than 50 years without cancer, and 587 patients aged 50 years or older without cancer.

The researchers found 28 miRNAs that were significantly unregulated in early-onset colorectal cancer tissue samples, compared with cancer-free samples and 11 miRNAs unregulated specifically in only the early-onset colorectal cancer samples. Four of these 11 miRNAs were adequately distinct from one another and were detectable in the plasma samples that the researchers would use to train and validate them as a combination biomarker.

The researchers used 117 plasma samples from Japan, including 72 from people with early-onset colorectal cancer and 45 from healthy donors, to develop and train an assay detecting the four miRNAs. They then validated the assay using 142 plasma samples from Spain, including 77 with early-onset colorectal cancer and 65 healthy donors.

In the Japan cohort, the four-miRNA assay had a sensitivity of 90% and a specificity of 80%, with a positive predictive value (PPV) of 88% and a negative predictive value (NPV) of 84%. In the Spain cohort used for validation, the assay performed with a sensitivity of 82%, a specificity of 86%, a PPV of 88%, and an NPV of 80%.

“Taken together, the genome-wide transcriptomic profiling approach was indeed robust, as it identified the biomarkers that were successfully trained and validated in plasma specimens from independent cohorts of patients with early-onset colorectal cancer, hence highlighting their translational potential in the clinic for the detection of this malignancy in early stages,” the authors wrote.

By disease stage, the four-miRNA panel identified both early-stage (stage 1-2; sensitivity, 92%; specificity, 80%) and late-stage (stage 3-4; sensitivity, 79%; specificity, 86%) early-onset colorectal cancer in the validation cohort.
 

Clinical benefit of blood test

The researchers also assessed the benefit-harm trade-off of this liquid biopsy assay compared with other screening modalities, taking into consideration the risk for false positives and false negatives.

A decision curve analysis “revealed that the miRNA panel achieved a higher net benefit regardless of threshold probability in comparison to intervention for all patients or none of the patients,” the researchers reported. “These findings suggest that this miRNA panel might offer more clinical benefit with regards to the avoidance of physical harm and misdiagnosis.”

They also found that expression levels of these four miRNAs significantly decreased after surgical removal of the colorectal cancer, strongly suggesting that the miRNAs do originate with the tumor.

“To have a relatively inexpensive and noninvasive means of screening a younger population is a very important unmet need,” said Dr. Chan.

It’s not feasible to recommend colonoscopies in people younger than 45 years because of resource constraints, he said, so “this is a wonderful new development to actually have the possibility of a blood-based screening test for younger individuals, especially given that rising incidence of young-onset colorectal cancer.”

Dr. Goel pointed out that only half of those recommended to get screened for colorectal cancer actually undergo screening, and a large reason for that is the desire to avoid colonoscopy, a concern echoed in the findings of a recent study by Christopher V. Almario, MD, MSHPM, and colleagues.

Dr. Goel expects that this strategy would increase compliance with screening because it’s less invasive and more affordable, particularly for younger patients. He estimates that a commercial assay using this panel, if approved by the Food and Drug Administration, should cost less than $100.

Dr. Almario, an assistant professor of medicine at the Cedars-Sinai Karsh Division of Gastroenterology and Hepatology in Los Angeles, agreed that an FDA-approved blood-based screening test would be a “game-changer,” as long as it’s accurate and effective.

Though Dr. Almario did not review the data in Goel’s study, he said in an interview that a blood test for colorectal cancer screening would be “the holy grail, so to speak, in terms of really moving the needle on screening uptake.”
 

Next steps

Dr. Chan noted that one caveat to consider with this study is that it was done in a relatively small population of individuals, even though the test was validated in a second set of plasma samples.

“Additional validation needs to be done in larger numbers of patients to really understand the performance characteristics because it is possible that some of these signatures may, when they’re using a broader group of individuals, not perform as well,” Dr. Chan said.

Dr. Goel said he is working with several companies right now to develop and further test a commercial product. He anticipates it may be shelf-ready in 2-5 years.

“The take-home message is that clinicians need to be more cognizant of the fact that incidence of this disease is rising, and we need to do something about it,” Dr. Goel said, particularly for those younger than 45 years who currently don’t have a screening option.

“Now we have at least a sliver of hope for those who might be suffering from this disease, for those for whom we have zero screening or diagnostic tests,” he said.

The research was funded by the National Cancer Institute and Fundación MAPFRE Guanarteme. Dr. Goel, Dr. Chan, and Dr. Almario reported no conflicts of interest.

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

Among biologic agents, vedolizumab (Entyvio) and ustekinumab (Stelara) are associated with lower rates of infection-related hospitalizations than anti-tumor necrosis factor (TNF) agents in older patients with inflammatory bowel disease (IBD), but only if older patients also have comorbidities, U.S. researchers have found.

The researchers examined U.S. health insurance claims for three cohorts – patients with IBD who were treated with anti-TNF agents, vedolizumab, and ustekinumab – and found no overall difference in infection rates or infection-related hospitalizations between the groups.

But in patients with a greater burden of comorbidity, the monoclonal antibodies vedolizumab and ustekinumab were associated with lower rates of infection-related hospitalizations, compared with anti-TNF agents, with 22% less for vedolizumab and 34% less for ustekinumab.

In the “first pharmacoepidemiologic study comparing all approved classes of biologic agents to treat IBD focused on older adults,” the authors say they “demonstrate that comorbidity is a mediator of infections requiring hospitalizations.”

“These data can help counsel older adults who are about to initiate a biologic agent in clinical practice,” they write.

The research was published online in The American Journal of Gastroenterology.

Co-lead author Bharati Kochar, MD, MS, a gastroenterologist at Massachusetts General Hospital, Boston, said that the real question, when we’re seeing an older patient, is which medications are safer.

“Not surprisingly, we found that there was no overall difference in the three classes of medications,” she said, adding that “if you take your healthy older adults without any serious comorbidities, anti-TNF agents are not different in terms of a safety profile.”

With the more selective biologics like vedolizumab and ustekinumab seeming to confer a lower risk for serious infections in patients with comorbidities, Dr. Kochar said the hope is that their study will help doctors feel more confident in prescribing and encourage thinking about the patient in a broader manner beyond chronological age.
 

Real-world study on older adults with IBD

The authors note that the number of older adults with IBD is rising rapidly. It is estimated that almost 1 million individuals aged 60 years and older in the United States are living with the disease.

They add that there has been a rapid proliferation of treatment options for both Crohn’s disease and ulcerative colitis, but the likelihood of achieving remission may vary by mechanism of immunosuppression.

Older adults have a higher baseline risk for infections than younger adults, regardless of treatment type, the authors underline; yet, older adults with IBD are disproportionately under-represented in clinical trials of IBD therapies.

Recognizing the need for real-world studies focused on older adults, Dr. Kochar and her colleagues gathered claims data from a commercial U.S. health insurance plan totaling nearly 86 million individuals between 2008 and 2019.

They identified patients with IBD aged 60 years or older (average age, 67 years) who had at least one claim for vedolizumab, ustekinumab, or anti-TNF agents, including adalimumab, infliximab, golimumab, or certolizumab pegol.

The cohorts included 2,369 patients treated with anti-TNF agents, 972 who were started on vedolizumab and 352 who were given ustekinumab.

Patients were excluded if they received vedolizumab or ustekinumab during the first 6 months of treatment and were then switched to anti-TNF therapy.

The on-treatment period was defined as starting with the index treatment date and ending with the date of treatment discontinuation. Treatment was required to last more than 90 days.

The overall incidence rates for any infection were similar across the three treatment groups, at 3,606 per 1,000 person-years in the anti-TNF group, 3,748 per 1,000 person-years in patients given vedolizumab, and 3,139 per 1,000 person-years in those treated with ustekinumab.

There were also no significant differences in the rate of infection-related hospitalizations, at a hazard ratio for vedolizumab versus anti-TNF agents of 0.94, and for ustekinumab, again versus anti-TNF agents, of 0.92.

However, the authors found that there was a “significant interaction” between comorbidities and treatment in terms of infection-related hospitalizations.

Among IBD patients older than 60 with a Charlson Comorbidity Index (CCI) score of greater than 1, treatment with vedolizumab and ustekinumab was associated with a significantly lower rate of infection-related hospitalizations versus anti-TNF agents, at hazard ratios of 0.78 and 0.66, respectively.

In contrast, the rates of hospitalization were similar between the treatment groups among patients without significant comorbidity.

Interestingly, patients with ulcerative colitis treated with vedolizumab also had a lower rate of infection versus those given anti-TNF agents, at a hazard ratio of 0.96, while no such difference was seen in patients with Crohn’s disease.
 

Results will help refine clinical practice

Approached for comment, Dana J. Lukin, MD, PhD, clinical director of translational research at the Jill Roberts Center for Inflammatory Bowel Disease, New York, said the study is limited by the lack of granular data on disease activity.

Moreover, he told this news organization that since it is not a randomized controlled trial, the selection of medications in the claims database may have factored in some of the intangible contraindications to anti-TNF agents.

“It makes sense that comorbidity confers the biggest risk for hospitalization from infections,” Dr. Lukin said, adding that “what is interesting is that there is no difference overall in infection rates between any of the medication classes.”

He said the study therefore “rebuffs the traditional thinking” that, among older adults, anti-TNF agents will be associated with a higher risk of infections per se, “because really it’s specifically among those patients who have more comorbidities.”

Most importantly, Dr. Lukin said that the findings will help to refine clinical practice, as clinicians are specifically tasked with treating the inflammatory bowel disease but are not necessarily focused on comorbidities, which patients accrue more and more as they age.

Dr. Lukin continued that, for patients with comorbid conditions, “we should carefully consider using a non–anti-TNF agent.”

“We should also not be afraid to continue to use anti-TNF agents” in those without comorbidities, he added, as they are “very effective in patients who might need them for their disease-related characteristics.”

The study was supported in part by grants from the National Institutes of Health, the Crohn’s and Colitis Foundation, and the Chleck Family Foundation.

Dr. Lukin declares relationships with Takeda, Abbvie, and Janssen. No other relevant financial relationships were declared.

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

Among biologic agents, vedolizumab (Entyvio) and ustekinumab (Stelara) are associated with lower rates of infection-related hospitalizations than anti-tumor necrosis factor (TNF) agents in older patients with inflammatory bowel disease (IBD), but only if older patients also have comorbidities, U.S. researchers have found.

The researchers examined U.S. health insurance claims for three cohorts – patients with IBD who were treated with anti-TNF agents, vedolizumab, and ustekinumab – and found no overall difference in infection rates or infection-related hospitalizations between the groups.

But in patients with a greater burden of comorbidity, the monoclonal antibodies vedolizumab and ustekinumab were associated with lower rates of infection-related hospitalizations, compared with anti-TNF agents, with 22% less for vedolizumab and 34% less for ustekinumab.

In the “first pharmacoepidemiologic study comparing all approved classes of biologic agents to treat IBD focused on older adults,” the authors say they “demonstrate that comorbidity is a mediator of infections requiring hospitalizations.”

“These data can help counsel older adults who are about to initiate a biologic agent in clinical practice,” they write.

The research was published online in The American Journal of Gastroenterology.

Co-lead author Bharati Kochar, MD, MS, a gastroenterologist at Massachusetts General Hospital, Boston, said that the real question, when we’re seeing an older patient, is which medications are safer.

“Not surprisingly, we found that there was no overall difference in the three classes of medications,” she said, adding that “if you take your healthy older adults without any serious comorbidities, anti-TNF agents are not different in terms of a safety profile.”

With the more selective biologics like vedolizumab and ustekinumab seeming to confer a lower risk for serious infections in patients with comorbidities, Dr. Kochar said the hope is that their study will help doctors feel more confident in prescribing and encourage thinking about the patient in a broader manner beyond chronological age.
 

Real-world study on older adults with IBD

The authors note that the number of older adults with IBD is rising rapidly. It is estimated that almost 1 million individuals aged 60 years and older in the United States are living with the disease.

They add that there has been a rapid proliferation of treatment options for both Crohn’s disease and ulcerative colitis, but the likelihood of achieving remission may vary by mechanism of immunosuppression.

Older adults have a higher baseline risk for infections than younger adults, regardless of treatment type, the authors underline; yet, older adults with IBD are disproportionately under-represented in clinical trials of IBD therapies.

Recognizing the need for real-world studies focused on older adults, Dr. Kochar and her colleagues gathered claims data from a commercial U.S. health insurance plan totaling nearly 86 million individuals between 2008 and 2019.

They identified patients with IBD aged 60 years or older (average age, 67 years) who had at least one claim for vedolizumab, ustekinumab, or anti-TNF agents, including adalimumab, infliximab, golimumab, or certolizumab pegol.

The cohorts included 2,369 patients treated with anti-TNF agents, 972 who were started on vedolizumab and 352 who were given ustekinumab.

Patients were excluded if they received vedolizumab or ustekinumab during the first 6 months of treatment and were then switched to anti-TNF therapy.

The on-treatment period was defined as starting with the index treatment date and ending with the date of treatment discontinuation. Treatment was required to last more than 90 days.

The overall incidence rates for any infection were similar across the three treatment groups, at 3,606 per 1,000 person-years in the anti-TNF group, 3,748 per 1,000 person-years in patients given vedolizumab, and 3,139 per 1,000 person-years in those treated with ustekinumab.

There were also no significant differences in the rate of infection-related hospitalizations, at a hazard ratio for vedolizumab versus anti-TNF agents of 0.94, and for ustekinumab, again versus anti-TNF agents, of 0.92.

However, the authors found that there was a “significant interaction” between comorbidities and treatment in terms of infection-related hospitalizations.

Among IBD patients older than 60 with a Charlson Comorbidity Index (CCI) score of greater than 1, treatment with vedolizumab and ustekinumab was associated with a significantly lower rate of infection-related hospitalizations versus anti-TNF agents, at hazard ratios of 0.78 and 0.66, respectively.

In contrast, the rates of hospitalization were similar between the treatment groups among patients without significant comorbidity.

Interestingly, patients with ulcerative colitis treated with vedolizumab also had a lower rate of infection versus those given anti-TNF agents, at a hazard ratio of 0.96, while no such difference was seen in patients with Crohn’s disease.
 

Results will help refine clinical practice

Approached for comment, Dana J. Lukin, MD, PhD, clinical director of translational research at the Jill Roberts Center for Inflammatory Bowel Disease, New York, said the study is limited by the lack of granular data on disease activity.

Moreover, he told this news organization that since it is not a randomized controlled trial, the selection of medications in the claims database may have factored in some of the intangible contraindications to anti-TNF agents.

“It makes sense that comorbidity confers the biggest risk for hospitalization from infections,” Dr. Lukin said, adding that “what is interesting is that there is no difference overall in infection rates between any of the medication classes.”

He said the study therefore “rebuffs the traditional thinking” that, among older adults, anti-TNF agents will be associated with a higher risk of infections per se, “because really it’s specifically among those patients who have more comorbidities.”

Most importantly, Dr. Lukin said that the findings will help to refine clinical practice, as clinicians are specifically tasked with treating the inflammatory bowel disease but are not necessarily focused on comorbidities, which patients accrue more and more as they age.

Dr. Lukin continued that, for patients with comorbid conditions, “we should carefully consider using a non–anti-TNF agent.”

“We should also not be afraid to continue to use anti-TNF agents” in those without comorbidities, he added, as they are “very effective in patients who might need them for their disease-related characteristics.”

The study was supported in part by grants from the National Institutes of Health, the Crohn’s and Colitis Foundation, and the Chleck Family Foundation.

Dr. Lukin declares relationships with Takeda, Abbvie, and Janssen. No other relevant financial relationships were declared.

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

Among biologic agents, vedolizumab (Entyvio) and ustekinumab (Stelara) are associated with lower rates of infection-related hospitalizations than anti-tumor necrosis factor (TNF) agents in older patients with inflammatory bowel disease (IBD), but only if older patients also have comorbidities, U.S. researchers have found.

The researchers examined U.S. health insurance claims for three cohorts – patients with IBD who were treated with anti-TNF agents, vedolizumab, and ustekinumab – and found no overall difference in infection rates or infection-related hospitalizations between the groups.

But in patients with a greater burden of comorbidity, the monoclonal antibodies vedolizumab and ustekinumab were associated with lower rates of infection-related hospitalizations, compared with anti-TNF agents, with 22% less for vedolizumab and 34% less for ustekinumab.

In the “first pharmacoepidemiologic study comparing all approved classes of biologic agents to treat IBD focused on older adults,” the authors say they “demonstrate that comorbidity is a mediator of infections requiring hospitalizations.”

“These data can help counsel older adults who are about to initiate a biologic agent in clinical practice,” they write.

The research was published online in The American Journal of Gastroenterology.

Co-lead author Bharati Kochar, MD, MS, a gastroenterologist at Massachusetts General Hospital, Boston, said that the real question, when we’re seeing an older patient, is which medications are safer.

“Not surprisingly, we found that there was no overall difference in the three classes of medications,” she said, adding that “if you take your healthy older adults without any serious comorbidities, anti-TNF agents are not different in terms of a safety profile.”

With the more selective biologics like vedolizumab and ustekinumab seeming to confer a lower risk for serious infections in patients with comorbidities, Dr. Kochar said the hope is that their study will help doctors feel more confident in prescribing and encourage thinking about the patient in a broader manner beyond chronological age.
 

Real-world study on older adults with IBD

The authors note that the number of older adults with IBD is rising rapidly. It is estimated that almost 1 million individuals aged 60 years and older in the United States are living with the disease.

They add that there has been a rapid proliferation of treatment options for both Crohn’s disease and ulcerative colitis, but the likelihood of achieving remission may vary by mechanism of immunosuppression.

Older adults have a higher baseline risk for infections than younger adults, regardless of treatment type, the authors underline; yet, older adults with IBD are disproportionately under-represented in clinical trials of IBD therapies.

Recognizing the need for real-world studies focused on older adults, Dr. Kochar and her colleagues gathered claims data from a commercial U.S. health insurance plan totaling nearly 86 million individuals between 2008 and 2019.

They identified patients with IBD aged 60 years or older (average age, 67 years) who had at least one claim for vedolizumab, ustekinumab, or anti-TNF agents, including adalimumab, infliximab, golimumab, or certolizumab pegol.

The cohorts included 2,369 patients treated with anti-TNF agents, 972 who were started on vedolizumab and 352 who were given ustekinumab.

Patients were excluded if they received vedolizumab or ustekinumab during the first 6 months of treatment and were then switched to anti-TNF therapy.

The on-treatment period was defined as starting with the index treatment date and ending with the date of treatment discontinuation. Treatment was required to last more than 90 days.

The overall incidence rates for any infection were similar across the three treatment groups, at 3,606 per 1,000 person-years in the anti-TNF group, 3,748 per 1,000 person-years in patients given vedolizumab, and 3,139 per 1,000 person-years in those treated with ustekinumab.

There were also no significant differences in the rate of infection-related hospitalizations, at a hazard ratio for vedolizumab versus anti-TNF agents of 0.94, and for ustekinumab, again versus anti-TNF agents, of 0.92.

However, the authors found that there was a “significant interaction” between comorbidities and treatment in terms of infection-related hospitalizations.

Among IBD patients older than 60 with a Charlson Comorbidity Index (CCI) score of greater than 1, treatment with vedolizumab and ustekinumab was associated with a significantly lower rate of infection-related hospitalizations versus anti-TNF agents, at hazard ratios of 0.78 and 0.66, respectively.

In contrast, the rates of hospitalization were similar between the treatment groups among patients without significant comorbidity.

Interestingly, patients with ulcerative colitis treated with vedolizumab also had a lower rate of infection versus those given anti-TNF agents, at a hazard ratio of 0.96, while no such difference was seen in patients with Crohn’s disease.
 

Results will help refine clinical practice

Approached for comment, Dana J. Lukin, MD, PhD, clinical director of translational research at the Jill Roberts Center for Inflammatory Bowel Disease, New York, said the study is limited by the lack of granular data on disease activity.

Moreover, he told this news organization that since it is not a randomized controlled trial, the selection of medications in the claims database may have factored in some of the intangible contraindications to anti-TNF agents.

“It makes sense that comorbidity confers the biggest risk for hospitalization from infections,” Dr. Lukin said, adding that “what is interesting is that there is no difference overall in infection rates between any of the medication classes.”

He said the study therefore “rebuffs the traditional thinking” that, among older adults, anti-TNF agents will be associated with a higher risk of infections per se, “because really it’s specifically among those patients who have more comorbidities.”

Most importantly, Dr. Lukin said that the findings will help to refine clinical practice, as clinicians are specifically tasked with treating the inflammatory bowel disease but are not necessarily focused on comorbidities, which patients accrue more and more as they age.

Dr. Lukin continued that, for patients with comorbid conditions, “we should carefully consider using a non–anti-TNF agent.”

“We should also not be afraid to continue to use anti-TNF agents” in those without comorbidities, he added, as they are “very effective in patients who might need them for their disease-related characteristics.”

The study was supported in part by grants from the National Institutes of Health, the Crohn’s and Colitis Foundation, and the Chleck Family Foundation.

Dr. Lukin declares relationships with Takeda, Abbvie, and Janssen. No other relevant financial relationships were declared.

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

People who are socially isolated or lonely have an increased risk for myocardial infarction, stroke, and death, independent of other factors, the American Heart Association concludes in a new scientific statement.

More than 4 decades of research have “clearly demonstrated that social isolation and loneliness are both associated with adverse health outcomes,” writing group chair Crystal Wiley Cené, MD, University of California San Diego Health, said in a news release.

“Given the prevalence of social disconnectedness across the United States, the public health impact is quite significant,” Dr. Cené added.

The writing group says more research is needed to develop, implement, and test interventions to improve cardiovascular (CV) and brain health in people who are socially isolated or lonely.

The scientific statement was published online in the Journal of the American Heart Association.
 

Common and potentially deadly

Social isolation is defined as having infrequent in-person contact with people and loneliness is when a person feels he or she is alone or has less connection with others than desired.

It’s estimated that one-quarter of community-dwelling Americans 65 years and older are socially isolated, with even more experiencing loneliness.

The problem is not limited to older adults, however. Research suggests that younger adults also experience social isolation and loneliness, which might be attributed to more social media use and less frequent in-person activities.

Dr. Cené and colleagues reviewed observational and intervention research on social isolation published through July 2021 to examine the impact of social isolation and loneliness on CV and brain health.

The evidence is most consistent for a direct association between social isolation, loneliness, and death from coronary heart disease (CHD) and stroke, they reported.

For example, one meta-analysis of 19 studies showed that social isolation and loneliness increase the risk for CHD by 29%; most of these studies focused on acute MI and/or CHD death as the measure of CHD.

A meta-analysis of eight longitudinal observational studies showed social isolation and loneliness were associated with a 32% increased risk for stroke, after adjustment for age, sex, and socioeconomic status.

The literature also suggests social isolation and loneliness are associated with worse prognoses in adults with existing CHD or history of stroke.

One systematic review showed that socially isolated people with CHD had a two- to threefold increase in illness and death over 6 years, independent of cardiac risk factors.

Other research suggests that socially isolated adults with three or fewer social contacts per month have a 40% increased risk for recurrent stroke or MI.

There are fewer and less robust data on the association between social isolation and loneliness with heart failure (HF), dementia, and cognitive impairment, the writing group noted.

It’s also unclear whether actually being isolated (social isolation) or feeling isolated (loneliness) matters most for cardiovascular and brain health, because only a few studies have examined both in the same sample, they pointed out.

However, a study published in Neurology in June showed that older adults who reported feeling socially isolated had worse cognitive function at baseline than did those who did not report social isolation, and were 26% more likely to have dementia at follow-up, as reported by this news organization.
 

Urgent need for interventions

“There is an urgent need to develop, implement, and evaluate programs and strategies to reduce the negative effects of social isolation and loneliness on cardiovascular and brain health, particularly for at-risk populations,” Dr. Cené said in the news release. 

She encourages clinicians to ask patients about their social life and whether they are satisfied with their level of interactions with friends and family, and to be prepared to refer patients who are socially isolated or lonely, especially those with a history of CHD or stroke, to community resources to help them connect with others.

Fitness programs and recreational activities at senior centers, as well as interventions that address negative thoughts of self-worth and other negative thinking, have shown promise in reducing isolation and loneliness, the writing group said.

This scientific statement was prepared by the volunteer writing group on behalf of the AHA Social Determinants of Health Committee of the Council on Epidemiology and Prevention and the Council on Quality of Care and Outcomes Research; the Prevention Science Committee of the Council on Epidemiology and Prevention and the Council on Quality of Care and Outcomes Research; the Prevention Science Committee of the Council on Epidemiology and Prevention and the Council on Cardiovascular and Stroke Nursing; the Council on Arteriosclerosis, Thrombosis, and Vascular Biology; and the Stroke Council.

This research had no commercial funding. Members of the writing group have disclosed no relevant conflicts of interest.

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

People who are socially isolated or lonely have an increased risk for myocardial infarction, stroke, and death, independent of other factors, the American Heart Association concludes in a new scientific statement.

More than 4 decades of research have “clearly demonstrated that social isolation and loneliness are both associated with adverse health outcomes,” writing group chair Crystal Wiley Cené, MD, University of California San Diego Health, said in a news release.

“Given the prevalence of social disconnectedness across the United States, the public health impact is quite significant,” Dr. Cené added.

The writing group says more research is needed to develop, implement, and test interventions to improve cardiovascular (CV) and brain health in people who are socially isolated or lonely.

The scientific statement was published online in the Journal of the American Heart Association.
 

Common and potentially deadly

Social isolation is defined as having infrequent in-person contact with people and loneliness is when a person feels he or she is alone or has less connection with others than desired.

It’s estimated that one-quarter of community-dwelling Americans 65 years and older are socially isolated, with even more experiencing loneliness.

The problem is not limited to older adults, however. Research suggests that younger adults also experience social isolation and loneliness, which might be attributed to more social media use and less frequent in-person activities.

Dr. Cené and colleagues reviewed observational and intervention research on social isolation published through July 2021 to examine the impact of social isolation and loneliness on CV and brain health.

The evidence is most consistent for a direct association between social isolation, loneliness, and death from coronary heart disease (CHD) and stroke, they reported.

For example, one meta-analysis of 19 studies showed that social isolation and loneliness increase the risk for CHD by 29%; most of these studies focused on acute MI and/or CHD death as the measure of CHD.

A meta-analysis of eight longitudinal observational studies showed social isolation and loneliness were associated with a 32% increased risk for stroke, after adjustment for age, sex, and socioeconomic status.

The literature also suggests social isolation and loneliness are associated with worse prognoses in adults with existing CHD or history of stroke.

One systematic review showed that socially isolated people with CHD had a two- to threefold increase in illness and death over 6 years, independent of cardiac risk factors.

Other research suggests that socially isolated adults with three or fewer social contacts per month have a 40% increased risk for recurrent stroke or MI.

There are fewer and less robust data on the association between social isolation and loneliness with heart failure (HF), dementia, and cognitive impairment, the writing group noted.

It’s also unclear whether actually being isolated (social isolation) or feeling isolated (loneliness) matters most for cardiovascular and brain health, because only a few studies have examined both in the same sample, they pointed out.

However, a study published in Neurology in June showed that older adults who reported feeling socially isolated had worse cognitive function at baseline than did those who did not report social isolation, and were 26% more likely to have dementia at follow-up, as reported by this news organization.
 

Urgent need for interventions

“There is an urgent need to develop, implement, and evaluate programs and strategies to reduce the negative effects of social isolation and loneliness on cardiovascular and brain health, particularly for at-risk populations,” Dr. Cené said in the news release. 

She encourages clinicians to ask patients about their social life and whether they are satisfied with their level of interactions with friends and family, and to be prepared to refer patients who are socially isolated or lonely, especially those with a history of CHD or stroke, to community resources to help them connect with others.

Fitness programs and recreational activities at senior centers, as well as interventions that address negative thoughts of self-worth and other negative thinking, have shown promise in reducing isolation and loneliness, the writing group said.

This scientific statement was prepared by the volunteer writing group on behalf of the AHA Social Determinants of Health Committee of the Council on Epidemiology and Prevention and the Council on Quality of Care and Outcomes Research; the Prevention Science Committee of the Council on Epidemiology and Prevention and the Council on Quality of Care and Outcomes Research; the Prevention Science Committee of the Council on Epidemiology and Prevention and the Council on Cardiovascular and Stroke Nursing; the Council on Arteriosclerosis, Thrombosis, and Vascular Biology; and the Stroke Council.

This research had no commercial funding. Members of the writing group have disclosed no relevant conflicts of interest.

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

People who are socially isolated or lonely have an increased risk for myocardial infarction, stroke, and death, independent of other factors, the American Heart Association concludes in a new scientific statement.

More than 4 decades of research have “clearly demonstrated that social isolation and loneliness are both associated with adverse health outcomes,” writing group chair Crystal Wiley Cené, MD, University of California San Diego Health, said in a news release.

“Given the prevalence of social disconnectedness across the United States, the public health impact is quite significant,” Dr. Cené added.

The writing group says more research is needed to develop, implement, and test interventions to improve cardiovascular (CV) and brain health in people who are socially isolated or lonely.

The scientific statement was published online in the Journal of the American Heart Association.
 

Common and potentially deadly

Social isolation is defined as having infrequent in-person contact with people and loneliness is when a person feels he or she is alone or has less connection with others than desired.

It’s estimated that one-quarter of community-dwelling Americans 65 years and older are socially isolated, with even more experiencing loneliness.

The problem is not limited to older adults, however. Research suggests that younger adults also experience social isolation and loneliness, which might be attributed to more social media use and less frequent in-person activities.

Dr. Cené and colleagues reviewed observational and intervention research on social isolation published through July 2021 to examine the impact of social isolation and loneliness on CV and brain health.

The evidence is most consistent for a direct association between social isolation, loneliness, and death from coronary heart disease (CHD) and stroke, they reported.

For example, one meta-analysis of 19 studies showed that social isolation and loneliness increase the risk for CHD by 29%; most of these studies focused on acute MI and/or CHD death as the measure of CHD.

A meta-analysis of eight longitudinal observational studies showed social isolation and loneliness were associated with a 32% increased risk for stroke, after adjustment for age, sex, and socioeconomic status.

The literature also suggests social isolation and loneliness are associated with worse prognoses in adults with existing CHD or history of stroke.

One systematic review showed that socially isolated people with CHD had a two- to threefold increase in illness and death over 6 years, independent of cardiac risk factors.

Other research suggests that socially isolated adults with three or fewer social contacts per month have a 40% increased risk for recurrent stroke or MI.

There are fewer and less robust data on the association between social isolation and loneliness with heart failure (HF), dementia, and cognitive impairment, the writing group noted.

It’s also unclear whether actually being isolated (social isolation) or feeling isolated (loneliness) matters most for cardiovascular and brain health, because only a few studies have examined both in the same sample, they pointed out.

However, a study published in Neurology in June showed that older adults who reported feeling socially isolated had worse cognitive function at baseline than did those who did not report social isolation, and were 26% more likely to have dementia at follow-up, as reported by this news organization.
 

Urgent need for interventions

“There is an urgent need to develop, implement, and evaluate programs and strategies to reduce the negative effects of social isolation and loneliness on cardiovascular and brain health, particularly for at-risk populations,” Dr. Cené said in the news release. 

She encourages clinicians to ask patients about their social life and whether they are satisfied with their level of interactions with friends and family, and to be prepared to refer patients who are socially isolated or lonely, especially those with a history of CHD or stroke, to community resources to help them connect with others.

Fitness programs and recreational activities at senior centers, as well as interventions that address negative thoughts of self-worth and other negative thinking, have shown promise in reducing isolation and loneliness, the writing group said.

This scientific statement was prepared by the volunteer writing group on behalf of the AHA Social Determinants of Health Committee of the Council on Epidemiology and Prevention and the Council on Quality of Care and Outcomes Research; the Prevention Science Committee of the Council on Epidemiology and Prevention and the Council on Quality of Care and Outcomes Research; the Prevention Science Committee of the Council on Epidemiology and Prevention and the Council on Cardiovascular and Stroke Nursing; the Council on Arteriosclerosis, Thrombosis, and Vascular Biology; and the Stroke Council.

This research had no commercial funding. Members of the writing group have disclosed no relevant conflicts of interest.

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

Patients who take beta-blockers or antiplatelet agents are lowering their risk for cardiovascular events, but the protection may fall short for those who spend time outdoors on hot summer days, hints a limited analysis published as a letter in Nature Cardiovascular Research.

Patients taking either a beta-blocker or antiplatelet, or both medications together, appeared at elevated risk for nonfatal acute MI specifically on days when the weather turned hot, suggests the registry cohort study that covered 14 years of clinical and meteorologic data.

rottadana/Thinkstock

“The take-away message is not that patients should stop using these two medications, by no means. We’re raising cautions for patients taking them, to watch out for themselves during high-heat days,” lead author Kai Chen, PhD, Yale University, New Haven, Conn., said in an interview.

“We’re not giving the message that these drugs have harmful effects” because the nature of the links between the medications and MI in the study, with its potential for confounding, remain unknown, said Dr. Chen, from the department of environmental health sciences and Yale Center on Climate Change and Health.

For example, patients who take beta-blockers or antiplatelets tend to be sicker than patients not on the drugs, which could make heat-related MI more likely, and the drugs wrongly appear to be culprits, he observed. The analysis contained signals that could support either scenario.

The study is based on cases of nonfatal MI in Augsburg, Germany, that are part of the MONICA-KORA MI registry. The odds of a heat-related nonfatal MI, it suggests, were increased 63% among patients taking antiplatelets and by 65% among those on beta-blockers, compared with those not on these drugs. The odds went up by 75% among those on both drug classes, but the risks weren’t raised in patients not taking them.
 

Rising heat-related MI

Chen said analysis was inspired by a 2019 report – also based on MONICA-KORA, from many of the same authors and using similar methods to track events by daily air temperature – that showed a rising trend for heat-related MI and declining rate for MI related to cold weather from 1987 to 2014. A next step, he figured, would be to determine whether the MI risk trends were associated with any cardiovascular medications.

The current study’s signal of risk related to antiplatelets and beta-blockers did not emerge for ACE inhibitors, calcium-channel blockers, or diuretics. Statins showed a link to increased nonfatal MI risk, but solely among participants aged younger than 60 years, who were also far less likely to have pre-existing coronary heart disease (CHD). He and his colleagues chose not to highlight that finding, Dr. Chen said, because the age subgroup analysis was grossly underpowered.

The overall analysis involved 2,494 cases of nonfatal MI that occurred during the warmer months – May to September – from 2001 to 2014. It was limited to nonfatal cases – those with at least a month of survival after hospital admission – because of insufficient data on medication use associated with fatal MIs, the report states.

Nonfatal MIs were defined as heat-related if they struck on days reaching the 95th percentile for temperature across the 14 years, in this case 24.2 °C (about 75.6 °F), relative to the average temperature of lowest nonfatal MI risk across the cohort, 7.5 °C (about 45.5 °F).

Patients served as both cases and their own controls, in that air temperature exposures on the day of their MI (case day) were compared with the remaining same days of the week in the same calendar month (control days). That approach, the report stated, “automatically controls for long-term time trends, seasonality, day of the week, and time-invariant confounders (for example, pre-existing cardiovascular disease).”

The odds ratio for heat-related MI for patients on antiplatelets was 1.63 (95% confidence interval, 1.07-2.46), and for antiplatelet nonusers was 0.94 (95% CI, 0.68-1.29). The difference between the two ratios was significant (P = .04).

The corresponding OR for patients taking beta-blockers was 1.65 (95% CI, 1.11-2.45), and for nonusers of beta-blockers was 0.90 (95% CI, 0.64-1.26). Again, the OR difference was significant (P = .02).

The ORs for users of both medication classes and nonusers of either med class, respectively, were 1.75 (95% CI, 1.12-2.73) and 0.84 (95% CI, 0.59-1.19). The latter OR was significantly lower than former (P = .01).

In a sign that antiplatelet and beta-blocker use might have been just a marker for sicker patients who were more vulnerable to heat-related MI, Chen said, the nonfatal MI risk was significantly elevated (OR, 2.17; 95% CI, 1.40-3.38) among patients with pre-existing CHD, but not among those free of pre-existing CHD (OR, 0.88; 95% CI, 0.65-1.20); the odds difference was P < .01.

That signal of confounding by indication is somewhat countered, the report states, by variations in nonfatal MI risk by age group. The increased chances of an event seen overall in relation to beta-blockers and antiplatelets were more pronounced among the 39% of patients aged 25-59 years (P < .01). That’s in spite that group’s lower CHD prevalence. The risk elevation solely among the older patients was attenuated and rendered nonsignificant, even with their greater CHD burden, the report noted.

The report speculates on a potential mechanism by which beta-blockers, at least, might conceivably raise the risk for heat-related MI. “Beta-receptor blockers inhibit skin vasodilation, resulting in reduced heat dissipation through convection and, at the same time, could intensify the blood-pressure-lowering effect of other antihypertensive drugs, which then could lead to syncope.”

Beta-blockers, Dr. Chen said, “can mechanistically make people more vulnerable to heat. That’s one potential explanation. Or it could be that these people taking the medications are just sicker. Whatever the reasons, the phenomenon we observed is that these patients taking these two medications are at higher risk during high-temperature days.”

Dr. Chen and the other authors declare no competing interests.

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

Patients who take beta-blockers or antiplatelet agents are lowering their risk for cardiovascular events, but the protection may fall short for those who spend time outdoors on hot summer days, hints a limited analysis published as a letter in Nature Cardiovascular Research.

Patients taking either a beta-blocker or antiplatelet, or both medications together, appeared at elevated risk for nonfatal acute MI specifically on days when the weather turned hot, suggests the registry cohort study that covered 14 years of clinical and meteorologic data.

rottadana/Thinkstock

“The take-away message is not that patients should stop using these two medications, by no means. We’re raising cautions for patients taking them, to watch out for themselves during high-heat days,” lead author Kai Chen, PhD, Yale University, New Haven, Conn., said in an interview.

“We’re not giving the message that these drugs have harmful effects” because the nature of the links between the medications and MI in the study, with its potential for confounding, remain unknown, said Dr. Chen, from the department of environmental health sciences and Yale Center on Climate Change and Health.

For example, patients who take beta-blockers or antiplatelets tend to be sicker than patients not on the drugs, which could make heat-related MI more likely, and the drugs wrongly appear to be culprits, he observed. The analysis contained signals that could support either scenario.

The study is based on cases of nonfatal MI in Augsburg, Germany, that are part of the MONICA-KORA MI registry. The odds of a heat-related nonfatal MI, it suggests, were increased 63% among patients taking antiplatelets and by 65% among those on beta-blockers, compared with those not on these drugs. The odds went up by 75% among those on both drug classes, but the risks weren’t raised in patients not taking them.
 

Rising heat-related MI

Chen said analysis was inspired by a 2019 report – also based on MONICA-KORA, from many of the same authors and using similar methods to track events by daily air temperature – that showed a rising trend for heat-related MI and declining rate for MI related to cold weather from 1987 to 2014. A next step, he figured, would be to determine whether the MI risk trends were associated with any cardiovascular medications.

The current study’s signal of risk related to antiplatelets and beta-blockers did not emerge for ACE inhibitors, calcium-channel blockers, or diuretics. Statins showed a link to increased nonfatal MI risk, but solely among participants aged younger than 60 years, who were also far less likely to have pre-existing coronary heart disease (CHD). He and his colleagues chose not to highlight that finding, Dr. Chen said, because the age subgroup analysis was grossly underpowered.

The overall analysis involved 2,494 cases of nonfatal MI that occurred during the warmer months – May to September – from 2001 to 2014. It was limited to nonfatal cases – those with at least a month of survival after hospital admission – because of insufficient data on medication use associated with fatal MIs, the report states.

Nonfatal MIs were defined as heat-related if they struck on days reaching the 95th percentile for temperature across the 14 years, in this case 24.2 °C (about 75.6 °F), relative to the average temperature of lowest nonfatal MI risk across the cohort, 7.5 °C (about 45.5 °F).

Patients served as both cases and their own controls, in that air temperature exposures on the day of their MI (case day) were compared with the remaining same days of the week in the same calendar month (control days). That approach, the report stated, “automatically controls for long-term time trends, seasonality, day of the week, and time-invariant confounders (for example, pre-existing cardiovascular disease).”

The odds ratio for heat-related MI for patients on antiplatelets was 1.63 (95% confidence interval, 1.07-2.46), and for antiplatelet nonusers was 0.94 (95% CI, 0.68-1.29). The difference between the two ratios was significant (P = .04).

The corresponding OR for patients taking beta-blockers was 1.65 (95% CI, 1.11-2.45), and for nonusers of beta-blockers was 0.90 (95% CI, 0.64-1.26). Again, the OR difference was significant (P = .02).

The ORs for users of both medication classes and nonusers of either med class, respectively, were 1.75 (95% CI, 1.12-2.73) and 0.84 (95% CI, 0.59-1.19). The latter OR was significantly lower than former (P = .01).

In a sign that antiplatelet and beta-blocker use might have been just a marker for sicker patients who were more vulnerable to heat-related MI, Chen said, the nonfatal MI risk was significantly elevated (OR, 2.17; 95% CI, 1.40-3.38) among patients with pre-existing CHD, but not among those free of pre-existing CHD (OR, 0.88; 95% CI, 0.65-1.20); the odds difference was P < .01.

That signal of confounding by indication is somewhat countered, the report states, by variations in nonfatal MI risk by age group. The increased chances of an event seen overall in relation to beta-blockers and antiplatelets were more pronounced among the 39% of patients aged 25-59 years (P < .01). That’s in spite that group’s lower CHD prevalence. The risk elevation solely among the older patients was attenuated and rendered nonsignificant, even with their greater CHD burden, the report noted.

The report speculates on a potential mechanism by which beta-blockers, at least, might conceivably raise the risk for heat-related MI. “Beta-receptor blockers inhibit skin vasodilation, resulting in reduced heat dissipation through convection and, at the same time, could intensify the blood-pressure-lowering effect of other antihypertensive drugs, which then could lead to syncope.”

Beta-blockers, Dr. Chen said, “can mechanistically make people more vulnerable to heat. That’s one potential explanation. Or it could be that these people taking the medications are just sicker. Whatever the reasons, the phenomenon we observed is that these patients taking these two medications are at higher risk during high-temperature days.”

Dr. Chen and the other authors declare no competing interests.

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

Patients who take beta-blockers or antiplatelet agents are lowering their risk for cardiovascular events, but the protection may fall short for those who spend time outdoors on hot summer days, hints a limited analysis published as a letter in Nature Cardiovascular Research.

Patients taking either a beta-blocker or antiplatelet, or both medications together, appeared at elevated risk for nonfatal acute MI specifically on days when the weather turned hot, suggests the registry cohort study that covered 14 years of clinical and meteorologic data.

rottadana/Thinkstock

“The take-away message is not that patients should stop using these two medications, by no means. We’re raising cautions for patients taking them, to watch out for themselves during high-heat days,” lead author Kai Chen, PhD, Yale University, New Haven, Conn., said in an interview.

“We’re not giving the message that these drugs have harmful effects” because the nature of the links between the medications and MI in the study, with its potential for confounding, remain unknown, said Dr. Chen, from the department of environmental health sciences and Yale Center on Climate Change and Health.

For example, patients who take beta-blockers or antiplatelets tend to be sicker than patients not on the drugs, which could make heat-related MI more likely, and the drugs wrongly appear to be culprits, he observed. The analysis contained signals that could support either scenario.

The study is based on cases of nonfatal MI in Augsburg, Germany, that are part of the MONICA-KORA MI registry. The odds of a heat-related nonfatal MI, it suggests, were increased 63% among patients taking antiplatelets and by 65% among those on beta-blockers, compared with those not on these drugs. The odds went up by 75% among those on both drug classes, but the risks weren’t raised in patients not taking them.
 

Rising heat-related MI

Chen said analysis was inspired by a 2019 report – also based on MONICA-KORA, from many of the same authors and using similar methods to track events by daily air temperature – that showed a rising trend for heat-related MI and declining rate for MI related to cold weather from 1987 to 2014. A next step, he figured, would be to determine whether the MI risk trends were associated with any cardiovascular medications.

The current study’s signal of risk related to antiplatelets and beta-blockers did not emerge for ACE inhibitors, calcium-channel blockers, or diuretics. Statins showed a link to increased nonfatal MI risk, but solely among participants aged younger than 60 years, who were also far less likely to have pre-existing coronary heart disease (CHD). He and his colleagues chose not to highlight that finding, Dr. Chen said, because the age subgroup analysis was grossly underpowered.

The overall analysis involved 2,494 cases of nonfatal MI that occurred during the warmer months – May to September – from 2001 to 2014. It was limited to nonfatal cases – those with at least a month of survival after hospital admission – because of insufficient data on medication use associated with fatal MIs, the report states.

Nonfatal MIs were defined as heat-related if they struck on days reaching the 95th percentile for temperature across the 14 years, in this case 24.2 °C (about 75.6 °F), relative to the average temperature of lowest nonfatal MI risk across the cohort, 7.5 °C (about 45.5 °F).

Patients served as both cases and their own controls, in that air temperature exposures on the day of their MI (case day) were compared with the remaining same days of the week in the same calendar month (control days). That approach, the report stated, “automatically controls for long-term time trends, seasonality, day of the week, and time-invariant confounders (for example, pre-existing cardiovascular disease).”

The odds ratio for heat-related MI for patients on antiplatelets was 1.63 (95% confidence interval, 1.07-2.46), and for antiplatelet nonusers was 0.94 (95% CI, 0.68-1.29). The difference between the two ratios was significant (P = .04).

The corresponding OR for patients taking beta-blockers was 1.65 (95% CI, 1.11-2.45), and for nonusers of beta-blockers was 0.90 (95% CI, 0.64-1.26). Again, the OR difference was significant (P = .02).

The ORs for users of both medication classes and nonusers of either med class, respectively, were 1.75 (95% CI, 1.12-2.73) and 0.84 (95% CI, 0.59-1.19). The latter OR was significantly lower than former (P = .01).

In a sign that antiplatelet and beta-blocker use might have been just a marker for sicker patients who were more vulnerable to heat-related MI, Chen said, the nonfatal MI risk was significantly elevated (OR, 2.17; 95% CI, 1.40-3.38) among patients with pre-existing CHD, but not among those free of pre-existing CHD (OR, 0.88; 95% CI, 0.65-1.20); the odds difference was P < .01.

That signal of confounding by indication is somewhat countered, the report states, by variations in nonfatal MI risk by age group. The increased chances of an event seen overall in relation to beta-blockers and antiplatelets were more pronounced among the 39% of patients aged 25-59 years (P < .01). That’s in spite that group’s lower CHD prevalence. The risk elevation solely among the older patients was attenuated and rendered nonsignificant, even with their greater CHD burden, the report noted.

The report speculates on a potential mechanism by which beta-blockers, at least, might conceivably raise the risk for heat-related MI. “Beta-receptor blockers inhibit skin vasodilation, resulting in reduced heat dissipation through convection and, at the same time, could intensify the blood-pressure-lowering effect of other antihypertensive drugs, which then could lead to syncope.”

Beta-blockers, Dr. Chen said, “can mechanistically make people more vulnerable to heat. That’s one potential explanation. Or it could be that these people taking the medications are just sicker. Whatever the reasons, the phenomenon we observed is that these patients taking these two medications are at higher risk during high-temperature days.”

Dr. Chen and the other authors declare no competing interests.

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

A new study sheds light on the neurologic underpinnings of late-life depression (LLD) with apathy and its frequently poor response to treatment.

Investigators headed by Faith Gunning, PhD, of the Institute of Geriatric Psychiatry, Weill Cornell Medicine, New York, analyzed baseline and posttreatment brain MRIs and functional MRIs (fMRIs) of older adults with depression who participated in a 12-week open-label nonrandomized clinical trial of escitalopram. Participants had undergone clinical and cognitive assessments.

Disturbances were found in resting state functional connectivity (rsFC) between the salience network (SN) and other large-scale networks that support goal-directed behavior, especially in patients with depression who also had features of apathy.

Even after participants had completed escitalopram treatment, apathy-related variability in functional connectivity was associated with poor antidepressant response and persistent cognitive dysfunction.

“This study suggests that, among older adults with depression, distinct network abnormalities may be associated with apathy and poor response to first-line pharmacotherapy and may serve as promising targets for novel interventions,” the investigators write.

The study was published online in JAMA Network Open.
 

A leading cause of disability

LLD is a “leading cause of disability and medical morbidity in older adulthood,” with one-third to one-half of patients with LLD also suffering from apathy, the authors write.

Older adults with depression and comorbid apathy have poorer outcomes, including lower remission rates and poorer response to first-line antidepressants, compared with those with LLD but who do not have apathy.

Despite the high prevalence of apathy in people with depression, “little is known about its optimal treatment and, more broadly, about the brain-based mechanisms of apathy,” the authors note.

An “emerging hypothesis” points to the role of a compromised SN and its large-scale connections between apathy and poor treatment response in LLD.

The SN (which includes the insula and the dorsal anterior cingulate cortex) “attributes motivational value to a stimulus” and “dynamically coordinates the activity of other large-scale networks, including the executive control network and default mode network (DMN).”

Preliminary studies of apathy in patients with depression report reduced volume in structures of the SN and suggest disruption in functional connectivity among the SN, DMN, and the executive control network; but the mechanisms linking apathy to poor antidepressant response in LLD “are not well understood.”

“Connectometry” is a “novel approach to diffusion MRI analysis that quantifies the local connectome of white matter pathways.” It has been used along with resting-state imagery, but it had not been used in studying apathy.

The researchers investigated the functional connectivity of the SN, hypothesizing that alterations in connectivity among key nodes of the SN and other core circuits that modulate goal-directed behavior (DMN and the executive control network) were implicated in individuals with depression and apathy.

They applied connectometry to “identify pathway-level disruptions in structural connectivity,” hypothesizing that compromise of frontoparietal and frontolimbic pathways would be associated with apathy in patients with LLD.

They also wanted to know whether apathy-related network abnormalities were associated with antidepressant response after 12 weeks of pharmacotherapy with the selective serotonin reuptake inhibitor escitalopram.
 

Emerging model

The study included 40 older adults (65% women; mean [SD] age, 70.0 [6.6] years) with DSM-IV–diagnosis major depressive disorder (without psychotic features) who were from a single-group, open-label escitalopram treatment trial.

The Hamilton-Depression (HAM-D) scale was used to assess depression, while the Apathy Evaluation Scale was used to assess apathy. On the Apathy Evaluation Scale, a score of greater than 40.5 represents “clinically significant apathy.” Participants completed these tests at baseline and after 12 weeks of escitalopram treatment.

They also completed a battery of neuropsychological tests to assess cognition and underwent MRI imaging. fMRI was used to map group differences in rsFC of the SN, and diffusion connectometry was used to “evaluate pathway-level disruptions in structural connectivity.”

Of the participants, 20 had clinically significant apathy. There were no differences in age, sex, educational level, or the severity of depression at baseline between those who did and those who did not have apathy.

Compared with participants with depression but not apathy, those with depression and comorbid apathy had lower rsFC of salience network seeds (specifically, the dorsolateral prefrontal cortex [DLPFC], premotor cortex, midcingulate cortex, and paracentral lobule).

They also had greater rsFC in the lateral temporal cortex and temporal pole (z > 2.7; Bonferroni-corrected threshold of P < .0125).

Additionally, participants with apathy had lower structural connectivity in the splenium, cingulum, and fronto-occipital fasciculus, compared with those without apathy (t > 2.5; false discovery rate–corrected P = .02).

Of the 27 participants who completed escitalopram treatment; 16 (59%) achieved remission (defined as an HAM-D score <10). Participants with apathy had poorer response to escitalopram treatment.

Lower insula-DLPFC/midcingulate cortex rsFC was associated with less improvement in depressive symptoms (HAM-D percentage change, beta [df] = .588 [26]; P = .001) as well as a greater likelihood that the participant would not achieve remission after treatment (odds ratio, 1.041; 95% confidence interval, 1.003-1.081; P = .04).

In regression models, lower insula-DLPFC/midcingulate cortex rsFC was found to be a mediator of the association between baseline apathy and persistence of depression.

The SN findings were also relevant to cognition. Lower dorsal anterior cingulate-DLPFC/paracentral rsFC was found to be associated with residual cognitive difficulties on measures of attention and executive function (beta [df] = .445 [26] and beta [df] = .384 [26], respectively; for each, P = .04).

“These findings support an emerging model of apathy, which proposes that apathy may arise from dysfunctional interactions among core networks (that is, SN, DMN, and executive control) that support motivated behavior,” the investigators write.

“This may cause a failure of network integration, leading to difficulties with salience processing, action planning, and behavioral initiation that manifests clinically as apathy,” they conclude.

One limitation they note was the lack of longitudinal follow-up after acute treatment and a “relatively limited neuropsychological battery.” Therefore, they could not “establish the persistence of treatment differences nor the specificity of cognitive associations.”

The investigators add that “novel interventions that modulate interactions among affected circuits may help to improve clinical outcomes in this distinct subgroup of older adults with depression, for whom few effective treatments exist.”

Commenting on the study, Helen Lavretsy, MD, professor of psychiatry in residence and director of the Late-Life Mood, Stress, and Wellness Research Program and the Integrative Psychiatry Clinic, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, said, the findings “can be used in future studies targeting apathy and the underlying neural mechanisms of brain connectivity.” Dr. Lavretsy was not involved with the study.
The study was supported by grants from the National Institute of Mental Health. Dr. Gunning reported receiving grants from the National Institute of Mental Health during the conduct of the study and grants from Akili Interactive. The other authors’ disclosures are listed on the original article. Dr. Lavretsky reports no relevant financial relationships.

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

A new study sheds light on the neurologic underpinnings of late-life depression (LLD) with apathy and its frequently poor response to treatment.

Investigators headed by Faith Gunning, PhD, of the Institute of Geriatric Psychiatry, Weill Cornell Medicine, New York, analyzed baseline and posttreatment brain MRIs and functional MRIs (fMRIs) of older adults with depression who participated in a 12-week open-label nonrandomized clinical trial of escitalopram. Participants had undergone clinical and cognitive assessments.

Disturbances were found in resting state functional connectivity (rsFC) between the salience network (SN) and other large-scale networks that support goal-directed behavior, especially in patients with depression who also had features of apathy.

Even after participants had completed escitalopram treatment, apathy-related variability in functional connectivity was associated with poor antidepressant response and persistent cognitive dysfunction.

“This study suggests that, among older adults with depression, distinct network abnormalities may be associated with apathy and poor response to first-line pharmacotherapy and may serve as promising targets for novel interventions,” the investigators write.

The study was published online in JAMA Network Open.
 

A leading cause of disability

LLD is a “leading cause of disability and medical morbidity in older adulthood,” with one-third to one-half of patients with LLD also suffering from apathy, the authors write.

Older adults with depression and comorbid apathy have poorer outcomes, including lower remission rates and poorer response to first-line antidepressants, compared with those with LLD but who do not have apathy.

Despite the high prevalence of apathy in people with depression, “little is known about its optimal treatment and, more broadly, about the brain-based mechanisms of apathy,” the authors note.

An “emerging hypothesis” points to the role of a compromised SN and its large-scale connections between apathy and poor treatment response in LLD.

The SN (which includes the insula and the dorsal anterior cingulate cortex) “attributes motivational value to a stimulus” and “dynamically coordinates the activity of other large-scale networks, including the executive control network and default mode network (DMN).”

Preliminary studies of apathy in patients with depression report reduced volume in structures of the SN and suggest disruption in functional connectivity among the SN, DMN, and the executive control network; but the mechanisms linking apathy to poor antidepressant response in LLD “are not well understood.”

“Connectometry” is a “novel approach to diffusion MRI analysis that quantifies the local connectome of white matter pathways.” It has been used along with resting-state imagery, but it had not been used in studying apathy.

The researchers investigated the functional connectivity of the SN, hypothesizing that alterations in connectivity among key nodes of the SN and other core circuits that modulate goal-directed behavior (DMN and the executive control network) were implicated in individuals with depression and apathy.

They applied connectometry to “identify pathway-level disruptions in structural connectivity,” hypothesizing that compromise of frontoparietal and frontolimbic pathways would be associated with apathy in patients with LLD.

They also wanted to know whether apathy-related network abnormalities were associated with antidepressant response after 12 weeks of pharmacotherapy with the selective serotonin reuptake inhibitor escitalopram.
 

Emerging model

The study included 40 older adults (65% women; mean [SD] age, 70.0 [6.6] years) with DSM-IV–diagnosis major depressive disorder (without psychotic features) who were from a single-group, open-label escitalopram treatment trial.

The Hamilton-Depression (HAM-D) scale was used to assess depression, while the Apathy Evaluation Scale was used to assess apathy. On the Apathy Evaluation Scale, a score of greater than 40.5 represents “clinically significant apathy.” Participants completed these tests at baseline and after 12 weeks of escitalopram treatment.

They also completed a battery of neuropsychological tests to assess cognition and underwent MRI imaging. fMRI was used to map group differences in rsFC of the SN, and diffusion connectometry was used to “evaluate pathway-level disruptions in structural connectivity.”

Of the participants, 20 had clinically significant apathy. There were no differences in age, sex, educational level, or the severity of depression at baseline between those who did and those who did not have apathy.

Compared with participants with depression but not apathy, those with depression and comorbid apathy had lower rsFC of salience network seeds (specifically, the dorsolateral prefrontal cortex [DLPFC], premotor cortex, midcingulate cortex, and paracentral lobule).

They also had greater rsFC in the lateral temporal cortex and temporal pole (z > 2.7; Bonferroni-corrected threshold of P < .0125).

Additionally, participants with apathy had lower structural connectivity in the splenium, cingulum, and fronto-occipital fasciculus, compared with those without apathy (t > 2.5; false discovery rate–corrected P = .02).

Of the 27 participants who completed escitalopram treatment; 16 (59%) achieved remission (defined as an HAM-D score <10). Participants with apathy had poorer response to escitalopram treatment.

Lower insula-DLPFC/midcingulate cortex rsFC was associated with less improvement in depressive symptoms (HAM-D percentage change, beta [df] = .588 [26]; P = .001) as well as a greater likelihood that the participant would not achieve remission after treatment (odds ratio, 1.041; 95% confidence interval, 1.003-1.081; P = .04).

In regression models, lower insula-DLPFC/midcingulate cortex rsFC was found to be a mediator of the association between baseline apathy and persistence of depression.

The SN findings were also relevant to cognition. Lower dorsal anterior cingulate-DLPFC/paracentral rsFC was found to be associated with residual cognitive difficulties on measures of attention and executive function (beta [df] = .445 [26] and beta [df] = .384 [26], respectively; for each, P = .04).

“These findings support an emerging model of apathy, which proposes that apathy may arise from dysfunctional interactions among core networks (that is, SN, DMN, and executive control) that support motivated behavior,” the investigators write.

“This may cause a failure of network integration, leading to difficulties with salience processing, action planning, and behavioral initiation that manifests clinically as apathy,” they conclude.

One limitation they note was the lack of longitudinal follow-up after acute treatment and a “relatively limited neuropsychological battery.” Therefore, they could not “establish the persistence of treatment differences nor the specificity of cognitive associations.”

The investigators add that “novel interventions that modulate interactions among affected circuits may help to improve clinical outcomes in this distinct subgroup of older adults with depression, for whom few effective treatments exist.”

Commenting on the study, Helen Lavretsy, MD, professor of psychiatry in residence and director of the Late-Life Mood, Stress, and Wellness Research Program and the Integrative Psychiatry Clinic, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, said, the findings “can be used in future studies targeting apathy and the underlying neural mechanisms of brain connectivity.” Dr. Lavretsy was not involved with the study.
The study was supported by grants from the National Institute of Mental Health. Dr. Gunning reported receiving grants from the National Institute of Mental Health during the conduct of the study and grants from Akili Interactive. The other authors’ disclosures are listed on the original article. Dr. Lavretsky reports no relevant financial relationships.

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

A new study sheds light on the neurologic underpinnings of late-life depression (LLD) with apathy and its frequently poor response to treatment.

Investigators headed by Faith Gunning, PhD, of the Institute of Geriatric Psychiatry, Weill Cornell Medicine, New York, analyzed baseline and posttreatment brain MRIs and functional MRIs (fMRIs) of older adults with depression who participated in a 12-week open-label nonrandomized clinical trial of escitalopram. Participants had undergone clinical and cognitive assessments.

Disturbances were found in resting state functional connectivity (rsFC) between the salience network (SN) and other large-scale networks that support goal-directed behavior, especially in patients with depression who also had features of apathy.

Even after participants had completed escitalopram treatment, apathy-related variability in functional connectivity was associated with poor antidepressant response and persistent cognitive dysfunction.

“This study suggests that, among older adults with depression, distinct network abnormalities may be associated with apathy and poor response to first-line pharmacotherapy and may serve as promising targets for novel interventions,” the investigators write.

The study was published online in JAMA Network Open.
 

A leading cause of disability

LLD is a “leading cause of disability and medical morbidity in older adulthood,” with one-third to one-half of patients with LLD also suffering from apathy, the authors write.

Older adults with depression and comorbid apathy have poorer outcomes, including lower remission rates and poorer response to first-line antidepressants, compared with those with LLD but who do not have apathy.

Despite the high prevalence of apathy in people with depression, “little is known about its optimal treatment and, more broadly, about the brain-based mechanisms of apathy,” the authors note.

An “emerging hypothesis” points to the role of a compromised SN and its large-scale connections between apathy and poor treatment response in LLD.

The SN (which includes the insula and the dorsal anterior cingulate cortex) “attributes motivational value to a stimulus” and “dynamically coordinates the activity of other large-scale networks, including the executive control network and default mode network (DMN).”

Preliminary studies of apathy in patients with depression report reduced volume in structures of the SN and suggest disruption in functional connectivity among the SN, DMN, and the executive control network; but the mechanisms linking apathy to poor antidepressant response in LLD “are not well understood.”

“Connectometry” is a “novel approach to diffusion MRI analysis that quantifies the local connectome of white matter pathways.” It has been used along with resting-state imagery, but it had not been used in studying apathy.

The researchers investigated the functional connectivity of the SN, hypothesizing that alterations in connectivity among key nodes of the SN and other core circuits that modulate goal-directed behavior (DMN and the executive control network) were implicated in individuals with depression and apathy.

They applied connectometry to “identify pathway-level disruptions in structural connectivity,” hypothesizing that compromise of frontoparietal and frontolimbic pathways would be associated with apathy in patients with LLD.

They also wanted to know whether apathy-related network abnormalities were associated with antidepressant response after 12 weeks of pharmacotherapy with the selective serotonin reuptake inhibitor escitalopram.
 

Emerging model

The study included 40 older adults (65% women; mean [SD] age, 70.0 [6.6] years) with DSM-IV–diagnosis major depressive disorder (without psychotic features) who were from a single-group, open-label escitalopram treatment trial.

The Hamilton-Depression (HAM-D) scale was used to assess depression, while the Apathy Evaluation Scale was used to assess apathy. On the Apathy Evaluation Scale, a score of greater than 40.5 represents “clinically significant apathy.” Participants completed these tests at baseline and after 12 weeks of escitalopram treatment.

They also completed a battery of neuropsychological tests to assess cognition and underwent MRI imaging. fMRI was used to map group differences in rsFC of the SN, and diffusion connectometry was used to “evaluate pathway-level disruptions in structural connectivity.”

Of the participants, 20 had clinically significant apathy. There were no differences in age, sex, educational level, or the severity of depression at baseline between those who did and those who did not have apathy.

Compared with participants with depression but not apathy, those with depression and comorbid apathy had lower rsFC of salience network seeds (specifically, the dorsolateral prefrontal cortex [DLPFC], premotor cortex, midcingulate cortex, and paracentral lobule).

They also had greater rsFC in the lateral temporal cortex and temporal pole (z > 2.7; Bonferroni-corrected threshold of P < .0125).

Additionally, participants with apathy had lower structural connectivity in the splenium, cingulum, and fronto-occipital fasciculus, compared with those without apathy (t > 2.5; false discovery rate–corrected P = .02).

Of the 27 participants who completed escitalopram treatment; 16 (59%) achieved remission (defined as an HAM-D score <10). Participants with apathy had poorer response to escitalopram treatment.

Lower insula-DLPFC/midcingulate cortex rsFC was associated with less improvement in depressive symptoms (HAM-D percentage change, beta [df] = .588 [26]; P = .001) as well as a greater likelihood that the participant would not achieve remission after treatment (odds ratio, 1.041; 95% confidence interval, 1.003-1.081; P = .04).

In regression models, lower insula-DLPFC/midcingulate cortex rsFC was found to be a mediator of the association between baseline apathy and persistence of depression.

The SN findings were also relevant to cognition. Lower dorsal anterior cingulate-DLPFC/paracentral rsFC was found to be associated with residual cognitive difficulties on measures of attention and executive function (beta [df] = .445 [26] and beta [df] = .384 [26], respectively; for each, P = .04).

“These findings support an emerging model of apathy, which proposes that apathy may arise from dysfunctional interactions among core networks (that is, SN, DMN, and executive control) that support motivated behavior,” the investigators write.

“This may cause a failure of network integration, leading to difficulties with salience processing, action planning, and behavioral initiation that manifests clinically as apathy,” they conclude.

One limitation they note was the lack of longitudinal follow-up after acute treatment and a “relatively limited neuropsychological battery.” Therefore, they could not “establish the persistence of treatment differences nor the specificity of cognitive associations.”

The investigators add that “novel interventions that modulate interactions among affected circuits may help to improve clinical outcomes in this distinct subgroup of older adults with depression, for whom few effective treatments exist.”

Commenting on the study, Helen Lavretsy, MD, professor of psychiatry in residence and director of the Late-Life Mood, Stress, and Wellness Research Program and the Integrative Psychiatry Clinic, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, said, the findings “can be used in future studies targeting apathy and the underlying neural mechanisms of brain connectivity.” Dr. Lavretsy was not involved with the study.
The study was supported by grants from the National Institute of Mental Health. Dr. Gunning reported receiving grants from the National Institute of Mental Health during the conduct of the study and grants from Akili Interactive. The other authors’ disclosures are listed on the original article. Dr. Lavretsky reports no relevant financial relationships.

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