Noninvasive brain stimulation may help restore a sense of smell in patients with chronic anosmia or hyposmia related to COVID-19, early research suggests.

Results of a small, double-blind, sham-controlled study showed anodal transcranial direct current stimulation (A-tDCS) combined with olfactory training (OT) provided notable and durable improvement in seven patients with persistent COVID-19–related hyposmia or anosmia.

“We are proud and very excited about these results. Although seven patients is a small sample, it is still notable,” lead investigator Fabio Bandini, MD, head of the department of neurology, ASL 3 Genovese, Genoa, Italy, said in an interview.

tDCS is cheap, safe, accessible, and very easy to administer. It has been used in rehabilitative treatment for 15 years, but this is the first time it has been used for this kind of problem, Dr. Bandini added.

The study was published online in the Journal of Neurology, Neurosurgery, and Psychiatry.
 

First study of its kind

Approximately 1% of patients with COVID will suffer from long-term smell loss, and given the widespread global impact of COVID, this represents a substantial number who have experienced or will potentially experience chronic smell loss because of the disease.

Loss of smell associated with COVID may last anywhere from 15 to 180 days after a SAR-CoV-2 infection, the researchers noted. Research suggests there is central nervous system involvement in COVID anosmia, mostly in the orbitofrontal cortex – the neural substrate for conscious olfactory perception.

“Smell loss has important consequences in everyday life for food, for hazards, for socialization. Usually, you recover from smell loss after 2 or 3 months, but after 6 months, that is considered permanent,” said Dr. Bandini.

Some research has pointed to the activation of the orbital frontal cortex for control of olfactory perception, so Dr. Bandini and colleagues wanted to explore whether stimulating this area could improve smell disturbances in post-COVID patients.

The study included seven consecutive patients with hyposmia or anosmia from COVID-19 lasting at least 6 months and who had a score of less than 12 on the Sniffin’ Sticks identification subtest. Exclusion criteria included severe mood disorder, rhinologic diseases, epilepsy, and sensitive scalp. No medications for alleviating olfactory symptoms were permitted.

Patients’ smell performances were assessed immediately prior to stimulation (t0) and rated on a scale of 0-10, with a score of 0 indicating a complete loss of smell and a score of 10 indicating a full sense of smell as the subjective measure. Sniffin’ Sticks, a validated test that assesses smell threshold, discrimination, and validation, was used as an objective measure.

In the 20-minute OT session, patients had to sniff 10 odors (rose, eucalyptus, lemon, star anise, rosemary, strawberry, coconut, vanilla, pine tree, and bergamot) in a random order for 10 seconds each then were asked to identify the smell and rate its intensity. The training was applied once in each session.

A-tDCS or sham-transcranial direct current stimulation (S-tDCS) was administered at the same time. In the active stimulation the anode was placed over the left prefrontal cortex because the orbitofrontal cortex is not directly accessible by A-tDCS.

The patients participated in olfactory training with S-tDCS for the first 2 weeks. In the second 2 weeks of the study, they received OT with A-tDCS.

The order of sham and A-tDCS stimulation was not counterbalanced to avoid potential carryover effects if A-tDCS had been applied first. The patients and assessors collecting the data were blinded.

The smell assessment was repeated immediately after S-tDCS (t1), A-tDCS (t2) and 3 months from the end of stimulation (t3), using the same odors and the same order of the first assessment.

The Wilcoxon test was used to compare each assessment (t1, t2, and t3) with baseline, indicating a two-sided alpha less than 0.05, which was considered statistically significant.

Both the subjective and objective measures showed a statistically significant improvement at t2 and t3, with average measurements doubled or even tripled, compared with t0 and t1. In addition, all patients demonstrated notable improvement in smell performance.

This study, said Dr. Bandini, is the first to use A-tDCS to treat patients with persistent smell loss due to COVID. Not only did the results show significant improvement in all study participants, compared with baseline but the beneficial effect lasted up to 3 months after treatment, demonstrating a durable effect.

Dr. Bandini noted that the study’s small sample size is a major limitation of the research so he hopes to enlarge it in future research testing A-tDCS for COVID-related smell loss and work toward providing this therapy on an outpatient basis.
 

Encouraging results offer new hope

Commenting on the research, Cheng-Ying Ho, MD, associate professor of pathology at the Johns Hopkins University, Baltimore, described the study as “interesting and encouraging.

“Even though there is a small percentage of patients that suffer persistent smell loss from COVID, it’s still a large number of people who have smell dysfunction and are unable to recover.”

“So far, there is no treatment for COVID-related or viral infection–related smell loss. The only thing that can be done is olfactory training, but the effect is very limited. There is no drug or other type of therapy for smell loss so far,” said Dr. Ho, whose areas of expertise include neuromuscular pathology, pediatric neuropathology, and neuropathology of infectious diseases.

“Even though it’s a small study with only seven patients, the results are very encouraging. After 2 weeks of stimulation, almost all had smell recovery that lasted several months. The weakness of the study is that they didn’t have a control group. The next step would be to expand the study to include more participants and have an adequate control group that received the sham stimuli to see if their results still stand when they have more participants.

“This very encouraging and relatively noninvasive treatment modality can give patients with smell loss some hope that this therapy can help them recover their sense of smell to some degree. The study seems to suggest that either the tDCS can stimulate nerve regrowth or that it actually can correct the rewiring of the brain,” added Dr. Ho.

The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors. No competing interests were declared.

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

Noninvasive brain stimulation may help restore a sense of smell in patients with chronic anosmia or hyposmia related to COVID-19, early research suggests.

Results of a small, double-blind, sham-controlled study showed anodal transcranial direct current stimulation (A-tDCS) combined with olfactory training (OT) provided notable and durable improvement in seven patients with persistent COVID-19–related hyposmia or anosmia.

“We are proud and very excited about these results. Although seven patients is a small sample, it is still notable,” lead investigator Fabio Bandini, MD, head of the department of neurology, ASL 3 Genovese, Genoa, Italy, said in an interview.

tDCS is cheap, safe, accessible, and very easy to administer. It has been used in rehabilitative treatment for 15 years, but this is the first time it has been used for this kind of problem, Dr. Bandini added.

The study was published online in the Journal of Neurology, Neurosurgery, and Psychiatry.
 

First study of its kind

Approximately 1% of patients with COVID will suffer from long-term smell loss, and given the widespread global impact of COVID, this represents a substantial number who have experienced or will potentially experience chronic smell loss because of the disease.

Loss of smell associated with COVID may last anywhere from 15 to 180 days after a SAR-CoV-2 infection, the researchers noted. Research suggests there is central nervous system involvement in COVID anosmia, mostly in the orbitofrontal cortex – the neural substrate for conscious olfactory perception.

“Smell loss has important consequences in everyday life for food, for hazards, for socialization. Usually, you recover from smell loss after 2 or 3 months, but after 6 months, that is considered permanent,” said Dr. Bandini.

Some research has pointed to the activation of the orbital frontal cortex for control of olfactory perception, so Dr. Bandini and colleagues wanted to explore whether stimulating this area could improve smell disturbances in post-COVID patients.

The study included seven consecutive patients with hyposmia or anosmia from COVID-19 lasting at least 6 months and who had a score of less than 12 on the Sniffin’ Sticks identification subtest. Exclusion criteria included severe mood disorder, rhinologic diseases, epilepsy, and sensitive scalp. No medications for alleviating olfactory symptoms were permitted.

Patients’ smell performances were assessed immediately prior to stimulation (t0) and rated on a scale of 0-10, with a score of 0 indicating a complete loss of smell and a score of 10 indicating a full sense of smell as the subjective measure. Sniffin’ Sticks, a validated test that assesses smell threshold, discrimination, and validation, was used as an objective measure.

In the 20-minute OT session, patients had to sniff 10 odors (rose, eucalyptus, lemon, star anise, rosemary, strawberry, coconut, vanilla, pine tree, and bergamot) in a random order for 10 seconds each then were asked to identify the smell and rate its intensity. The training was applied once in each session.

A-tDCS or sham-transcranial direct current stimulation (S-tDCS) was administered at the same time. In the active stimulation the anode was placed over the left prefrontal cortex because the orbitofrontal cortex is not directly accessible by A-tDCS.

The patients participated in olfactory training with S-tDCS for the first 2 weeks. In the second 2 weeks of the study, they received OT with A-tDCS.

The order of sham and A-tDCS stimulation was not counterbalanced to avoid potential carryover effects if A-tDCS had been applied first. The patients and assessors collecting the data were blinded.

The smell assessment was repeated immediately after S-tDCS (t1), A-tDCS (t2) and 3 months from the end of stimulation (t3), using the same odors and the same order of the first assessment.

The Wilcoxon test was used to compare each assessment (t1, t2, and t3) with baseline, indicating a two-sided alpha less than 0.05, which was considered statistically significant.

Both the subjective and objective measures showed a statistically significant improvement at t2 and t3, with average measurements doubled or even tripled, compared with t0 and t1. In addition, all patients demonstrated notable improvement in smell performance.

This study, said Dr. Bandini, is the first to use A-tDCS to treat patients with persistent smell loss due to COVID. Not only did the results show significant improvement in all study participants, compared with baseline but the beneficial effect lasted up to 3 months after treatment, demonstrating a durable effect.

Dr. Bandini noted that the study’s small sample size is a major limitation of the research so he hopes to enlarge it in future research testing A-tDCS for COVID-related smell loss and work toward providing this therapy on an outpatient basis.
 

Encouraging results offer new hope

Commenting on the research, Cheng-Ying Ho, MD, associate professor of pathology at the Johns Hopkins University, Baltimore, described the study as “interesting and encouraging.

“Even though there is a small percentage of patients that suffer persistent smell loss from COVID, it’s still a large number of people who have smell dysfunction and are unable to recover.”

“So far, there is no treatment for COVID-related or viral infection–related smell loss. The only thing that can be done is olfactory training, but the effect is very limited. There is no drug or other type of therapy for smell loss so far,” said Dr. Ho, whose areas of expertise include neuromuscular pathology, pediatric neuropathology, and neuropathology of infectious diseases.

“Even though it’s a small study with only seven patients, the results are very encouraging. After 2 weeks of stimulation, almost all had smell recovery that lasted several months. The weakness of the study is that they didn’t have a control group. The next step would be to expand the study to include more participants and have an adequate control group that received the sham stimuli to see if their results still stand when they have more participants.

“This very encouraging and relatively noninvasive treatment modality can give patients with smell loss some hope that this therapy can help them recover their sense of smell to some degree. The study seems to suggest that either the tDCS can stimulate nerve regrowth or that it actually can correct the rewiring of the brain,” added Dr. Ho.

The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors. No competing interests were declared.

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

Noninvasive brain stimulation may help restore a sense of smell in patients with chronic anosmia or hyposmia related to COVID-19, early research suggests.

Results of a small, double-blind, sham-controlled study showed anodal transcranial direct current stimulation (A-tDCS) combined with olfactory training (OT) provided notable and durable improvement in seven patients with persistent COVID-19–related hyposmia or anosmia.

“We are proud and very excited about these results. Although seven patients is a small sample, it is still notable,” lead investigator Fabio Bandini, MD, head of the department of neurology, ASL 3 Genovese, Genoa, Italy, said in an interview.

tDCS is cheap, safe, accessible, and very easy to administer. It has been used in rehabilitative treatment for 15 years, but this is the first time it has been used for this kind of problem, Dr. Bandini added.

The study was published online in the Journal of Neurology, Neurosurgery, and Psychiatry.
 

First study of its kind

Approximately 1% of patients with COVID will suffer from long-term smell loss, and given the widespread global impact of COVID, this represents a substantial number who have experienced or will potentially experience chronic smell loss because of the disease.

Loss of smell associated with COVID may last anywhere from 15 to 180 days after a SAR-CoV-2 infection, the researchers noted. Research suggests there is central nervous system involvement in COVID anosmia, mostly in the orbitofrontal cortex – the neural substrate for conscious olfactory perception.

“Smell loss has important consequences in everyday life for food, for hazards, for socialization. Usually, you recover from smell loss after 2 or 3 months, but after 6 months, that is considered permanent,” said Dr. Bandini.

Some research has pointed to the activation of the orbital frontal cortex for control of olfactory perception, so Dr. Bandini and colleagues wanted to explore whether stimulating this area could improve smell disturbances in post-COVID patients.

The study included seven consecutive patients with hyposmia or anosmia from COVID-19 lasting at least 6 months and who had a score of less than 12 on the Sniffin’ Sticks identification subtest. Exclusion criteria included severe mood disorder, rhinologic diseases, epilepsy, and sensitive scalp. No medications for alleviating olfactory symptoms were permitted.

Patients’ smell performances were assessed immediately prior to stimulation (t0) and rated on a scale of 0-10, with a score of 0 indicating a complete loss of smell and a score of 10 indicating a full sense of smell as the subjective measure. Sniffin’ Sticks, a validated test that assesses smell threshold, discrimination, and validation, was used as an objective measure.

In the 20-minute OT session, patients had to sniff 10 odors (rose, eucalyptus, lemon, star anise, rosemary, strawberry, coconut, vanilla, pine tree, and bergamot) in a random order for 10 seconds each then were asked to identify the smell and rate its intensity. The training was applied once in each session.

A-tDCS or sham-transcranial direct current stimulation (S-tDCS) was administered at the same time. In the active stimulation the anode was placed over the left prefrontal cortex because the orbitofrontal cortex is not directly accessible by A-tDCS.

The patients participated in olfactory training with S-tDCS for the first 2 weeks. In the second 2 weeks of the study, they received OT with A-tDCS.

The order of sham and A-tDCS stimulation was not counterbalanced to avoid potential carryover effects if A-tDCS had been applied first. The patients and assessors collecting the data were blinded.

The smell assessment was repeated immediately after S-tDCS (t1), A-tDCS (t2) and 3 months from the end of stimulation (t3), using the same odors and the same order of the first assessment.

The Wilcoxon test was used to compare each assessment (t1, t2, and t3) with baseline, indicating a two-sided alpha less than 0.05, which was considered statistically significant.

Both the subjective and objective measures showed a statistically significant improvement at t2 and t3, with average measurements doubled or even tripled, compared with t0 and t1. In addition, all patients demonstrated notable improvement in smell performance.

This study, said Dr. Bandini, is the first to use A-tDCS to treat patients with persistent smell loss due to COVID. Not only did the results show significant improvement in all study participants, compared with baseline but the beneficial effect lasted up to 3 months after treatment, demonstrating a durable effect.

Dr. Bandini noted that the study’s small sample size is a major limitation of the research so he hopes to enlarge it in future research testing A-tDCS for COVID-related smell loss and work toward providing this therapy on an outpatient basis.
 

Encouraging results offer new hope

Commenting on the research, Cheng-Ying Ho, MD, associate professor of pathology at the Johns Hopkins University, Baltimore, described the study as “interesting and encouraging.

“Even though there is a small percentage of patients that suffer persistent smell loss from COVID, it’s still a large number of people who have smell dysfunction and are unable to recover.”

“So far, there is no treatment for COVID-related or viral infection–related smell loss. The only thing that can be done is olfactory training, but the effect is very limited. There is no drug or other type of therapy for smell loss so far,” said Dr. Ho, whose areas of expertise include neuromuscular pathology, pediatric neuropathology, and neuropathology of infectious diseases.

“Even though it’s a small study with only seven patients, the results are very encouraging. After 2 weeks of stimulation, almost all had smell recovery that lasted several months. The weakness of the study is that they didn’t have a control group. The next step would be to expand the study to include more participants and have an adequate control group that received the sham stimuli to see if their results still stand when they have more participants.

“This very encouraging and relatively noninvasive treatment modality can give patients with smell loss some hope that this therapy can help them recover their sense of smell to some degree. The study seems to suggest that either the tDCS can stimulate nerve regrowth or that it actually can correct the rewiring of the brain,” added Dr. Ho.

The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors. No competing interests were declared.

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

Aiming for a disease activity target while reducing biologic therapy could be a winning approach for patients with psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), according to the results of a new study presented at the annual European Congress of Rheumatology.

The findings show that a treat-to-target (T2T) strategy with tapering using a tumor necrosis factor (TNF) inhibitor produces results that are noninferior to a T2T strategy that doesn’t include tapering in these patients.

“Our study has for the first time shown that a treat-to-target tapering strategy is just as good as full-dose continuation, while reducing medication use substantially,” first author Celia Michielsens, MD, a PhD student and researcher at Sint Maartenskliniek in Nijmegen, the Netherlands, said in an interview before her presentation of the study during an oral abstract session at the congress. “Stepwise tapering is also better than fixed-dose reduction or discontinuation, since it is much more individualized.”

The study is now published in Annals of the Rheumatic Diseases.

In the randomized, controlled, open-label, noninferiority study, researchers enrolled patients with PsA or axSpA who were using a TNF inhibitor such as etanercept, adalimumab, or infliximab, and had stable low disease activity for at least 6 months. Patients needed to have a Psoriatic Arthritis Disease Activity Score (PASDAS) of 3.2 or less, or an Ankylosing Spondylitis Disease Activity Score (ASDAS) of at 2.1 or less. In cases of flare, patients were treated with NSAIDs and/or glucorticoids, and if they still had not reached low disease activity after a month, their previous TNF inhibitor dose was reinstated to the last effective interval or dosage, which was maintained throughout the study period. When the patient was already using a full TNF-inhibitor dose or if dose adjustment did not suffice, patients were switched to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD).

Participants were randomized, from January 2019 to June 2021, to a tapering or a nontapering T2T strategy in a 2:1 fashion. Then researchers then followed them for 12 months and aimed to determine if the tapering strategy proved noninferior to not tapering within a predefined 20% margin for noninferiority, which Dr. Michielsens said was derived from other studies and what her group determined to be “an acceptable risk.”

Results show strategy is ‘feasible in daily clinical care’

A total of 81 patients – 42 with PsA and 39 with axSpA – were in the group with tapering, and 41 were in the group without tapering: 22 with PsA and 19 with axSpA.

At 12 months, researchers found that 69% of the patients in the group with tapering had low disease activity, measured via the PASDAS and ASDAS, compared with 73% in patients who did not taper. And those in the tapering group saw their medication use dramatically reduced. At the 12-month mark, they were taking just 53% of the defined daily dose for maintenance, compared with 91% of the defined daily dose for the group that didn’t taper.

The researchers were able to successfully taper 72% of the patients in the tapering group, with 28% of them discontinuing their TNF-inhibitor medication entirely. The incidence of flares was 85% in the tapering group and 78% in the nontapering group, a nonsignificant difference (P = .32).

The start of a new medication or an increase in use of an existing medication was more frequent in the tapering group, and significantly so for NSAIDs. An increase in NSAID use was seen in 54% of the tapering group and in just 24% of the nontapering group (P = .002).

Conventional synthetic DMARD use went up in the tapering group, compared with the nontapering group, but this was only among the PsA patients and the change in use was not statistically significant. There were also more frequent increases in glucocorticoid use in the tapering group, compared with the nontapering group, but this was not significant.

Dr. Michielsens said the findings show the value of an individualized approach in treating patients with PsA or axSpA.

“Our study – and those [studies] in rheumatoid arthritis earlier – deliver the highest quality of evidence that disease activity–guided dose personalization can, and in fact should, be used in clinical practice,” she said. “Our pragmatic treat-to-target tapering strategy is feasible in daily clinical care, although treat-to-target using PASDAS and ASDAS needs some implementation. In shared decision-making with patients, a 50% reduction in TNFi use is obtainable, while maintaining low disease activity.”

The increase in the use of NSAIDs is something to be aware of, but it is “not concerning,” Dr. Michielsens added. She pointed out that the NSAID use was typically temporary, used when flares arose, and that the drugs are effective, safe, and inexpensive. She also noted that the use of TNF blockers decreased more than the use of NSAIDs increased.

“This seems a perfectly acceptable trade-off that can be discussed with your patient,” she said.

The 12-month duration of the study is likely long enough to show that the tapering strategy works, Dr. Michielsens said. In rheumatoid arthritis studies, for example, differences in strategies didn’t change after 1 year.

“That said, we are doing an observational extension study to provide more insights in the long-term effects of this treat-to-target strategy,” she said. “At the end of this summer, all patients will have completed their extended follow-up period – a 12-month observational period – so hopefully we can present the results next year at EULAR.”

This study received funding from ReumaNederland. Dr. Michielsens did not have any financial interests to disclose. Two coauthors reported financial relationships with numerous pharmaceutical companies.

Aiming for a disease activity target while reducing biologic therapy could be a winning approach for patients with psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), according to the results of a new study presented at the annual European Congress of Rheumatology.

The findings show that a treat-to-target (T2T) strategy with tapering using a tumor necrosis factor (TNF) inhibitor produces results that are noninferior to a T2T strategy that doesn’t include tapering in these patients.

“Our study has for the first time shown that a treat-to-target tapering strategy is just as good as full-dose continuation, while reducing medication use substantially,” first author Celia Michielsens, MD, a PhD student and researcher at Sint Maartenskliniek in Nijmegen, the Netherlands, said in an interview before her presentation of the study during an oral abstract session at the congress. “Stepwise tapering is also better than fixed-dose reduction or discontinuation, since it is much more individualized.”

The study is now published in Annals of the Rheumatic Diseases.

In the randomized, controlled, open-label, noninferiority study, researchers enrolled patients with PsA or axSpA who were using a TNF inhibitor such as etanercept, adalimumab, or infliximab, and had stable low disease activity for at least 6 months. Patients needed to have a Psoriatic Arthritis Disease Activity Score (PASDAS) of 3.2 or less, or an Ankylosing Spondylitis Disease Activity Score (ASDAS) of at 2.1 or less. In cases of flare, patients were treated with NSAIDs and/or glucorticoids, and if they still had not reached low disease activity after a month, their previous TNF inhibitor dose was reinstated to the last effective interval or dosage, which was maintained throughout the study period. When the patient was already using a full TNF-inhibitor dose or if dose adjustment did not suffice, patients were switched to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD).

Participants were randomized, from January 2019 to June 2021, to a tapering or a nontapering T2T strategy in a 2:1 fashion. Then researchers then followed them for 12 months and aimed to determine if the tapering strategy proved noninferior to not tapering within a predefined 20% margin for noninferiority, which Dr. Michielsens said was derived from other studies and what her group determined to be “an acceptable risk.”

Results show strategy is ‘feasible in daily clinical care’

A total of 81 patients – 42 with PsA and 39 with axSpA – were in the group with tapering, and 41 were in the group without tapering: 22 with PsA and 19 with axSpA.

At 12 months, researchers found that 69% of the patients in the group with tapering had low disease activity, measured via the PASDAS and ASDAS, compared with 73% in patients who did not taper. And those in the tapering group saw their medication use dramatically reduced. At the 12-month mark, they were taking just 53% of the defined daily dose for maintenance, compared with 91% of the defined daily dose for the group that didn’t taper.

The researchers were able to successfully taper 72% of the patients in the tapering group, with 28% of them discontinuing their TNF-inhibitor medication entirely. The incidence of flares was 85% in the tapering group and 78% in the nontapering group, a nonsignificant difference (P = .32).

The start of a new medication or an increase in use of an existing medication was more frequent in the tapering group, and significantly so for NSAIDs. An increase in NSAID use was seen in 54% of the tapering group and in just 24% of the nontapering group (P = .002).

Conventional synthetic DMARD use went up in the tapering group, compared with the nontapering group, but this was only among the PsA patients and the change in use was not statistically significant. There were also more frequent increases in glucocorticoid use in the tapering group, compared with the nontapering group, but this was not significant.

Dr. Michielsens said the findings show the value of an individualized approach in treating patients with PsA or axSpA.

“Our study – and those [studies] in rheumatoid arthritis earlier – deliver the highest quality of evidence that disease activity–guided dose personalization can, and in fact should, be used in clinical practice,” she said. “Our pragmatic treat-to-target tapering strategy is feasible in daily clinical care, although treat-to-target using PASDAS and ASDAS needs some implementation. In shared decision-making with patients, a 50% reduction in TNFi use is obtainable, while maintaining low disease activity.”

The increase in the use of NSAIDs is something to be aware of, but it is “not concerning,” Dr. Michielsens added. She pointed out that the NSAID use was typically temporary, used when flares arose, and that the drugs are effective, safe, and inexpensive. She also noted that the use of TNF blockers decreased more than the use of NSAIDs increased.

“This seems a perfectly acceptable trade-off that can be discussed with your patient,” she said.

The 12-month duration of the study is likely long enough to show that the tapering strategy works, Dr. Michielsens said. In rheumatoid arthritis studies, for example, differences in strategies didn’t change after 1 year.

“That said, we are doing an observational extension study to provide more insights in the long-term effects of this treat-to-target strategy,” she said. “At the end of this summer, all patients will have completed their extended follow-up period – a 12-month observational period – so hopefully we can present the results next year at EULAR.”

This study received funding from ReumaNederland. Dr. Michielsens did not have any financial interests to disclose. Two coauthors reported financial relationships with numerous pharmaceutical companies.

Aiming for a disease activity target while reducing biologic therapy could be a winning approach for patients with psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), according to the results of a new study presented at the annual European Congress of Rheumatology.

The findings show that a treat-to-target (T2T) strategy with tapering using a tumor necrosis factor (TNF) inhibitor produces results that are noninferior to a T2T strategy that doesn’t include tapering in these patients.

“Our study has for the first time shown that a treat-to-target tapering strategy is just as good as full-dose continuation, while reducing medication use substantially,” first author Celia Michielsens, MD, a PhD student and researcher at Sint Maartenskliniek in Nijmegen, the Netherlands, said in an interview before her presentation of the study during an oral abstract session at the congress. “Stepwise tapering is also better than fixed-dose reduction or discontinuation, since it is much more individualized.”

The study is now published in Annals of the Rheumatic Diseases.

In the randomized, controlled, open-label, noninferiority study, researchers enrolled patients with PsA or axSpA who were using a TNF inhibitor such as etanercept, adalimumab, or infliximab, and had stable low disease activity for at least 6 months. Patients needed to have a Psoriatic Arthritis Disease Activity Score (PASDAS) of 3.2 or less, or an Ankylosing Spondylitis Disease Activity Score (ASDAS) of at 2.1 or less. In cases of flare, patients were treated with NSAIDs and/or glucorticoids, and if they still had not reached low disease activity after a month, their previous TNF inhibitor dose was reinstated to the last effective interval or dosage, which was maintained throughout the study period. When the patient was already using a full TNF-inhibitor dose or if dose adjustment did not suffice, patients were switched to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD).

Participants were randomized, from January 2019 to June 2021, to a tapering or a nontapering T2T strategy in a 2:1 fashion. Then researchers then followed them for 12 months and aimed to determine if the tapering strategy proved noninferior to not tapering within a predefined 20% margin for noninferiority, which Dr. Michielsens said was derived from other studies and what her group determined to be “an acceptable risk.”

Results show strategy is ‘feasible in daily clinical care’

A total of 81 patients – 42 with PsA and 39 with axSpA – were in the group with tapering, and 41 were in the group without tapering: 22 with PsA and 19 with axSpA.

At 12 months, researchers found that 69% of the patients in the group with tapering had low disease activity, measured via the PASDAS and ASDAS, compared with 73% in patients who did not taper. And those in the tapering group saw their medication use dramatically reduced. At the 12-month mark, they were taking just 53% of the defined daily dose for maintenance, compared with 91% of the defined daily dose for the group that didn’t taper.

The researchers were able to successfully taper 72% of the patients in the tapering group, with 28% of them discontinuing their TNF-inhibitor medication entirely. The incidence of flares was 85% in the tapering group and 78% in the nontapering group, a nonsignificant difference (P = .32).

The start of a new medication or an increase in use of an existing medication was more frequent in the tapering group, and significantly so for NSAIDs. An increase in NSAID use was seen in 54% of the tapering group and in just 24% of the nontapering group (P = .002).

Conventional synthetic DMARD use went up in the tapering group, compared with the nontapering group, but this was only among the PsA patients and the change in use was not statistically significant. There were also more frequent increases in glucocorticoid use in the tapering group, compared with the nontapering group, but this was not significant.

Dr. Michielsens said the findings show the value of an individualized approach in treating patients with PsA or axSpA.

“Our study – and those [studies] in rheumatoid arthritis earlier – deliver the highest quality of evidence that disease activity–guided dose personalization can, and in fact should, be used in clinical practice,” she said. “Our pragmatic treat-to-target tapering strategy is feasible in daily clinical care, although treat-to-target using PASDAS and ASDAS needs some implementation. In shared decision-making with patients, a 50% reduction in TNFi use is obtainable, while maintaining low disease activity.”

The increase in the use of NSAIDs is something to be aware of, but it is “not concerning,” Dr. Michielsens added. She pointed out that the NSAID use was typically temporary, used when flares arose, and that the drugs are effective, safe, and inexpensive. She also noted that the use of TNF blockers decreased more than the use of NSAIDs increased.

“This seems a perfectly acceptable trade-off that can be discussed with your patient,” she said.

The 12-month duration of the study is likely long enough to show that the tapering strategy works, Dr. Michielsens said. In rheumatoid arthritis studies, for example, differences in strategies didn’t change after 1 year.

“That said, we are doing an observational extension study to provide more insights in the long-term effects of this treat-to-target strategy,” she said. “At the end of this summer, all patients will have completed their extended follow-up period – a 12-month observational period – so hopefully we can present the results next year at EULAR.”

This study received funding from ReumaNederland. Dr. Michielsens did not have any financial interests to disclose. Two coauthors reported financial relationships with numerous pharmaceutical companies.

Acupuncture deep needling provides significant, long-term relief from chronic tension type headache (TTH), new research suggests. Result of a randomized trial showed that though the majority of participants reported some relief from TTH after 8 weeks of acupuncture treatment, those who received needling at a depth of 12.5-20.0 mm reported the greatest reduction in headache frequency and severity.

At this depth, acupuncture promotes deqi sensation, a feeling of numbness, soreness, heaviness, or irritating pain in the needling site that is considered key to successful acupuncture treatment in traditional Chinese acupuncture theory.

“Our study showed that deqi sensation could enhance the effect of acupuncture in the treatment of chronic TTH, and the effect of acupuncture lasted at least 6 months when the treatment was stopped,” said co-investigator Ying Li, MD, PhD, The Third Hospital/Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, China.

The findings were published online in Neurology.
 

Deqi sensation key

TTH is the most common type of headache, with a lifetime prevalence of up to 78% in some studies. The pain is often described as throbbing or a vice-like tightness on both sides of the head. TTH is considered chronic when it occurs at least 15 days a month.

Previous studies have suggested that acupuncture can offer relief from headache pain, but specific information on TTH, especially chronic TTH, has been lacking.

To address the issue, researchers designed a parallel-design, patient-and-assessor blinded randomized controlled trial with 218 individuals with a history of chronic TTH. All were untreated with prophylactic treatment in the previous 3 months.

The treatment group (n = 110) received 20 sessions of true acupuncture (TA) over 8 weeks. This included three sessions per week in the first 4 weeks and two sessions per week in the last 4 weeks. The depth of needling at each point ranged from 12.5 to 20 mm, which is needed to achieve deqi sensation.

The control group (n = 108) received superficial acupuncture (SA) on the same schedule as the TA group and at traditional acupuncture points. However, this was done at a maximum depth of 2 mm, which is not deep enough for deqi sensation.

At week 16, 68.2% of the participants receiving TA reported a greater than 50% reduction in monthly headache days, compared with 48.1% of those receiving SA (odds ratio, 2.65; P < .001).

Mean monthly headache days decreased from 20.38 days at baseline to 7.48 days at week 32 in the TA group versus 22.6 days at baseline to 11.94 days in the SA group.

Headache intensity and severity decreased in both groups, although those who achieved deqi sensation reported the most improvement.

Only four patients reported adverse effects, all of which were mild and none requiring treatment.

Patients in both groups reported some pain relief, suggesting that those who are not comfortable with deqi sensation may still benefit from superficial acupuncture, although to a lesser extent, Dr. Li said.

“We assume that the point-specific effect and placebo effect were combined to give the patients relief of headaches,” Dr. Li added. “Further, the effect of deqi sensation added more treatment effect. This might be explained by gate-control theory or other unknown mechanisms.”
 

Deeper understanding?

Commenting on the research, Jennifer Bickel, MD, a senior member of neurology at Moffit Cancer Center and professor of oncologic sciences at University of South Florida, Tampa, said that the study provides a deeper understanding of acupuncture’s efficacy for chronic TTH, which could aid clinicians who are unfamiliar with the therapy or when and how to refer treatment.

“This study provides a more descriptive outline for what type of acupuncture treatment and duration can be effective for patients so doctors can prep patients on what to expect and so doctors can better assess if patients received appropriate acupuncture for their headaches,” said Dr. Bickel, who was not involved with the research.

However, she noted that the acupuncture sites and techniques did not vary during the trial. Although that makes sense for a controlled study, it may not reflect real-world clinical practice, she added.

“The downside is that the study didn’t fully reflect that most acupuncturists in clinical practice would alter treatments during the 20 sessions based on the patient’s response and accompanying symptoms or comorbidities,” Dr. Bickel said.

The study also lacked information on medication overuse headache or patients’ prior history of TTH treatments.

“This could be helpful to understand which patients in clinical practice are most likely to benefit from treatment,” Dr. Bickel said.

Study authors received funding from the Department of Science and Technology of Sichuan Province and the National Natural Science Foundation of China. Dr. Li, Dr. Bickel, and Dr. Vickers report no relevant financial relationships.

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

Acupuncture deep needling provides significant, long-term relief from chronic tension type headache (TTH), new research suggests. Result of a randomized trial showed that though the majority of participants reported some relief from TTH after 8 weeks of acupuncture treatment, those who received needling at a depth of 12.5-20.0 mm reported the greatest reduction in headache frequency and severity.

At this depth, acupuncture promotes deqi sensation, a feeling of numbness, soreness, heaviness, or irritating pain in the needling site that is considered key to successful acupuncture treatment in traditional Chinese acupuncture theory.

“Our study showed that deqi sensation could enhance the effect of acupuncture in the treatment of chronic TTH, and the effect of acupuncture lasted at least 6 months when the treatment was stopped,” said co-investigator Ying Li, MD, PhD, The Third Hospital/Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, China.

The findings were published online in Neurology.
 

Deqi sensation key

TTH is the most common type of headache, with a lifetime prevalence of up to 78% in some studies. The pain is often described as throbbing or a vice-like tightness on both sides of the head. TTH is considered chronic when it occurs at least 15 days a month.

Previous studies have suggested that acupuncture can offer relief from headache pain, but specific information on TTH, especially chronic TTH, has been lacking.

To address the issue, researchers designed a parallel-design, patient-and-assessor blinded randomized controlled trial with 218 individuals with a history of chronic TTH. All were untreated with prophylactic treatment in the previous 3 months.

The treatment group (n = 110) received 20 sessions of true acupuncture (TA) over 8 weeks. This included three sessions per week in the first 4 weeks and two sessions per week in the last 4 weeks. The depth of needling at each point ranged from 12.5 to 20 mm, which is needed to achieve deqi sensation.

The control group (n = 108) received superficial acupuncture (SA) on the same schedule as the TA group and at traditional acupuncture points. However, this was done at a maximum depth of 2 mm, which is not deep enough for deqi sensation.

At week 16, 68.2% of the participants receiving TA reported a greater than 50% reduction in monthly headache days, compared with 48.1% of those receiving SA (odds ratio, 2.65; P < .001).

Mean monthly headache days decreased from 20.38 days at baseline to 7.48 days at week 32 in the TA group versus 22.6 days at baseline to 11.94 days in the SA group.

Headache intensity and severity decreased in both groups, although those who achieved deqi sensation reported the most improvement.

Only four patients reported adverse effects, all of which were mild and none requiring treatment.

Patients in both groups reported some pain relief, suggesting that those who are not comfortable with deqi sensation may still benefit from superficial acupuncture, although to a lesser extent, Dr. Li said.

“We assume that the point-specific effect and placebo effect were combined to give the patients relief of headaches,” Dr. Li added. “Further, the effect of deqi sensation added more treatment effect. This might be explained by gate-control theory or other unknown mechanisms.”
 

Deeper understanding?

Commenting on the research, Jennifer Bickel, MD, a senior member of neurology at Moffit Cancer Center and professor of oncologic sciences at University of South Florida, Tampa, said that the study provides a deeper understanding of acupuncture’s efficacy for chronic TTH, which could aid clinicians who are unfamiliar with the therapy or when and how to refer treatment.

“This study provides a more descriptive outline for what type of acupuncture treatment and duration can be effective for patients so doctors can prep patients on what to expect and so doctors can better assess if patients received appropriate acupuncture for their headaches,” said Dr. Bickel, who was not involved with the research.

However, she noted that the acupuncture sites and techniques did not vary during the trial. Although that makes sense for a controlled study, it may not reflect real-world clinical practice, she added.

“The downside is that the study didn’t fully reflect that most acupuncturists in clinical practice would alter treatments during the 20 sessions based on the patient’s response and accompanying symptoms or comorbidities,” Dr. Bickel said.

The study also lacked information on medication overuse headache or patients’ prior history of TTH treatments.

“This could be helpful to understand which patients in clinical practice are most likely to benefit from treatment,” Dr. Bickel said.

Study authors received funding from the Department of Science and Technology of Sichuan Province and the National Natural Science Foundation of China. Dr. Li, Dr. Bickel, and Dr. Vickers report no relevant financial relationships.

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

Acupuncture deep needling provides significant, long-term relief from chronic tension type headache (TTH), new research suggests. Result of a randomized trial showed that though the majority of participants reported some relief from TTH after 8 weeks of acupuncture treatment, those who received needling at a depth of 12.5-20.0 mm reported the greatest reduction in headache frequency and severity.

At this depth, acupuncture promotes deqi sensation, a feeling of numbness, soreness, heaviness, or irritating pain in the needling site that is considered key to successful acupuncture treatment in traditional Chinese acupuncture theory.

“Our study showed that deqi sensation could enhance the effect of acupuncture in the treatment of chronic TTH, and the effect of acupuncture lasted at least 6 months when the treatment was stopped,” said co-investigator Ying Li, MD, PhD, The Third Hospital/Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, China.

The findings were published online in Neurology.
 

Deqi sensation key

TTH is the most common type of headache, with a lifetime prevalence of up to 78% in some studies. The pain is often described as throbbing or a vice-like tightness on both sides of the head. TTH is considered chronic when it occurs at least 15 days a month.

Previous studies have suggested that acupuncture can offer relief from headache pain, but specific information on TTH, especially chronic TTH, has been lacking.

To address the issue, researchers designed a parallel-design, patient-and-assessor blinded randomized controlled trial with 218 individuals with a history of chronic TTH. All were untreated with prophylactic treatment in the previous 3 months.

The treatment group (n = 110) received 20 sessions of true acupuncture (TA) over 8 weeks. This included three sessions per week in the first 4 weeks and two sessions per week in the last 4 weeks. The depth of needling at each point ranged from 12.5 to 20 mm, which is needed to achieve deqi sensation.

The control group (n = 108) received superficial acupuncture (SA) on the same schedule as the TA group and at traditional acupuncture points. However, this was done at a maximum depth of 2 mm, which is not deep enough for deqi sensation.

At week 16, 68.2% of the participants receiving TA reported a greater than 50% reduction in monthly headache days, compared with 48.1% of those receiving SA (odds ratio, 2.65; P < .001).

Mean monthly headache days decreased from 20.38 days at baseline to 7.48 days at week 32 in the TA group versus 22.6 days at baseline to 11.94 days in the SA group.

Headache intensity and severity decreased in both groups, although those who achieved deqi sensation reported the most improvement.

Only four patients reported adverse effects, all of which were mild and none requiring treatment.

Patients in both groups reported some pain relief, suggesting that those who are not comfortable with deqi sensation may still benefit from superficial acupuncture, although to a lesser extent, Dr. Li said.

“We assume that the point-specific effect and placebo effect were combined to give the patients relief of headaches,” Dr. Li added. “Further, the effect of deqi sensation added more treatment effect. This might be explained by gate-control theory or other unknown mechanisms.”
 

Deeper understanding?

Commenting on the research, Jennifer Bickel, MD, a senior member of neurology at Moffit Cancer Center and professor of oncologic sciences at University of South Florida, Tampa, said that the study provides a deeper understanding of acupuncture’s efficacy for chronic TTH, which could aid clinicians who are unfamiliar with the therapy or when and how to refer treatment.

“This study provides a more descriptive outline for what type of acupuncture treatment and duration can be effective for patients so doctors can prep patients on what to expect and so doctors can better assess if patients received appropriate acupuncture for their headaches,” said Dr. Bickel, who was not involved with the research.

However, she noted that the acupuncture sites and techniques did not vary during the trial. Although that makes sense for a controlled study, it may not reflect real-world clinical practice, she added.

“The downside is that the study didn’t fully reflect that most acupuncturists in clinical practice would alter treatments during the 20 sessions based on the patient’s response and accompanying symptoms or comorbidities,” Dr. Bickel said.

The study also lacked information on medication overuse headache or patients’ prior history of TTH treatments.

“This could be helpful to understand which patients in clinical practice are most likely to benefit from treatment,” Dr. Bickel said.

Study authors received funding from the Department of Science and Technology of Sichuan Province and the National Natural Science Foundation of China. Dr. Li, Dr. Bickel, and Dr. Vickers report no relevant financial relationships.

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

Infertility, pregnancy loss, and stillbirth increased women’s later risk of both nonfatal and fatal stroke, based on data from more than 600,000 women.

“To date, multiple studies have generated an expanding body of evidence on the association between pregnancy complications (e.g., gestational diabetes and preeclampsia) and the long-term risk of stroke, but studies on associations with infertility, miscarriage, or stillbirth have produced mixed evidence,” Chen Liang, a PhD candidate at the University of Queensland, Brisbane, Australia, and colleagues wrote.

In a study published in the BMJ, the researchers reviewed data from eight observational cohort studies across seven countries (Australia, China, Japan, the Netherlands, Sweden, the United Kingdom, and the United States). The participants were part of the InterLACE (International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events) consortium established in 2021. Most observational studies included in the analysis began between 1990 and 2000.

The study population included 618,851 women aged 32-73 years at baseline for whom data on infertility, miscarriage, or stillbirth, were available. The primary outcome was the association of infertility, recurrent miscarriage, and stillbirth with risk of first fatal or nonfatal stroke, and the results were further stratified by subtype. Stroke was identified through self-reports, linked hospital data, national patient registers, or death registry data. Baseline was defined as the first incidence of infertility, miscarriage, or stillbirth. The exception was the National Survey of Health and Development, a British birth cohort started in 1946, that collected data retrospectively.

The median follow-up period was 13 years for nonfatal stroke and 9.4 years for fatal stroke.

Overall, 17.2%, 16.6%, and 4.6% of the women experienced infertility, miscarriage, and stillbirth, respectively.

Women with a history of infertility had a significantly higher nonfatal stroke risk, compared with those without infertility (hazard ratio, 1.14). Further analysis by stroke subtypes showed an increased association between miscarriage and ischemic stroke (HR, 1.15).

Those with a history of miscarriage also had an increased risk of nonfatal stroke, compared with those without miscarriages (HR, 1.11). In the miscarriage group, the risk of stroke increased with the number of miscarriages, with adjusted HRs of 1.07, 1.12, and 1.35 for women with one, two, and three or more miscarriages, respectively. When stratified by stroke subtype, women with three or more miscarriages were more likely than women with no miscarriages to experience ischemic and hemorrhagic nonfatal strokes.

Associations were similar between miscarriage history and fatal stroke risk. Women with one, two, and three or more miscarriages had increased risk of fatal stroke, compared with those with no miscarriages (aHR, 1.08, 1.26, and 1.82, respectively, and women with three or more miscarriages had a higher risk of ischemic and hemorrhagic stroke (aHR, 1.83 and 1.84, respectively).

Women with a history of stillbirth had an approximately 31% increased risk of nonfatal stroke, compared with those with no history of stillbirth, with aHRs similar for single and recurrent stillbirths (1.32 and 1.29, respectively). Ischemic nonfatal stroke risk was higher in women with any stillbirth, compared with those without stillbirth (aHR, 1.77). Fatal stroke risk also was higher in women with any stillbirth, compared with those without, and this risk increased with the number of stillbirths (HR, 0.97 and HR, 1.26 for those with one stillbirth and two or more, respectively).

“The increased risk of stroke associated with infertility or recurrent stillbirths was mainly driven by a single subtype of stroke (nonfatal ischemic stroke or fatal hemorrhagic stroke, respectively), whereas the risk of stroke associated with recurrent miscarriages was driven by both subtypes,” the researchers wrote.

The researchers cited endothelial dysfunction as a potential underlying mechanism for increased stroke risk associated with pregnancy complications. “Endothelial dysfunction might lead to pregnancy loss through placentation-related defects, persist after a complicated pregnancy, and contribute to the development of stroke through reduced vasodilation, proinflammatory status, and prothrombic properties,” and that history of recurrent pregnancy loss might be a female-specific risk factor for stroke.

To mitigate this risk, they advised early monitoring of women with a history of recurrent miscarriages and stillbirths for stroke risk factors such as high blood pressure, blood sugar levels, and lipid levels.

The study findings were limited by several factors including the use of questionnaires to collect information on infertility, miscarriage, and stillbirth, and the potential variation in definitions of infertility, miscarriage, and stillbirth across the included studies, and a lack of data on the effect of different causes or treatments based on reproductive histories, the researchers noted. Other limitations include incomplete data on stroke subtypes and inability to adjust for all covariates such as thyroid disorders and endometriosis. However, the results were strengthened by the large study size and geographically and racially diverse population, extend the current knowledge on associations between infertility, miscarriage, and stillbirth with stroke, and highlight the need for more research on underlying mechanisms.
 

Data support gender-specific stroke risk stratification

“Studies that seek to understand gender differences and disparities in adverse outcomes, such as stroke risk, are extremely important given that women historically were excluded from research studies,” Catherine M. Albright, MD, of the University of Washington, Seattle, said in an interview. “By doing these studies, we are able to better risk stratify people in order to better predict and modify risks,” added Dr. Albright, who was not involved in the current study.

“It is well known than adverse pregnancy outcomes such as hypertension in pregnancy, fetal growth restriction, and preterm birth, lead to increased risk of cardiovascular disease and stroke later in life, so the general findings of an association between other adverse reproductive and pregnancy outcomes leads to increased stroke risk are not surprising,” she said.

“The take-home message is that outcomes for pregnancy really do provide a window to future health,” said Dr. Albright. “For clinicians, especially non-ob.gyns., knowing a complete pregnancy history for any new patient is important and can help risk-stratify patients, especially as we continue to gain knowledge like what is shown in this study.”

However, “this study did not evaluate why individual patients may have had infertility, recurrent pregnancy loss, or stillbirth, so research to look further into this association to determine if there is an underlying medical condition that could be treated and therefore possibly reduce both pregnancy complications and future stroke risks would be important,” Dr. Albright noted.

The study was supported by the Australian National Health and Medical Research Council Centres of Research Excellence; one corresponding author was supported by an Australian National Health and Medical Research Council Investigator grant. The researchers had no financial conflicts to disclose. Dr. Albright had no financial conflicts to disclose.

Infertility, pregnancy loss, and stillbirth increased women’s later risk of both nonfatal and fatal stroke, based on data from more than 600,000 women.

“To date, multiple studies have generated an expanding body of evidence on the association between pregnancy complications (e.g., gestational diabetes and preeclampsia) and the long-term risk of stroke, but studies on associations with infertility, miscarriage, or stillbirth have produced mixed evidence,” Chen Liang, a PhD candidate at the University of Queensland, Brisbane, Australia, and colleagues wrote.

In a study published in the BMJ, the researchers reviewed data from eight observational cohort studies across seven countries (Australia, China, Japan, the Netherlands, Sweden, the United Kingdom, and the United States). The participants were part of the InterLACE (International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events) consortium established in 2021. Most observational studies included in the analysis began between 1990 and 2000.

The study population included 618,851 women aged 32-73 years at baseline for whom data on infertility, miscarriage, or stillbirth, were available. The primary outcome was the association of infertility, recurrent miscarriage, and stillbirth with risk of first fatal or nonfatal stroke, and the results were further stratified by subtype. Stroke was identified through self-reports, linked hospital data, national patient registers, or death registry data. Baseline was defined as the first incidence of infertility, miscarriage, or stillbirth. The exception was the National Survey of Health and Development, a British birth cohort started in 1946, that collected data retrospectively.

The median follow-up period was 13 years for nonfatal stroke and 9.4 years for fatal stroke.

Overall, 17.2%, 16.6%, and 4.6% of the women experienced infertility, miscarriage, and stillbirth, respectively.

Women with a history of infertility had a significantly higher nonfatal stroke risk, compared with those without infertility (hazard ratio, 1.14). Further analysis by stroke subtypes showed an increased association between miscarriage and ischemic stroke (HR, 1.15).

Those with a history of miscarriage also had an increased risk of nonfatal stroke, compared with those without miscarriages (HR, 1.11). In the miscarriage group, the risk of stroke increased with the number of miscarriages, with adjusted HRs of 1.07, 1.12, and 1.35 for women with one, two, and three or more miscarriages, respectively. When stratified by stroke subtype, women with three or more miscarriages were more likely than women with no miscarriages to experience ischemic and hemorrhagic nonfatal strokes.

Associations were similar between miscarriage history and fatal stroke risk. Women with one, two, and three or more miscarriages had increased risk of fatal stroke, compared with those with no miscarriages (aHR, 1.08, 1.26, and 1.82, respectively, and women with three or more miscarriages had a higher risk of ischemic and hemorrhagic stroke (aHR, 1.83 and 1.84, respectively).

Women with a history of stillbirth had an approximately 31% increased risk of nonfatal stroke, compared with those with no history of stillbirth, with aHRs similar for single and recurrent stillbirths (1.32 and 1.29, respectively). Ischemic nonfatal stroke risk was higher in women with any stillbirth, compared with those without stillbirth (aHR, 1.77). Fatal stroke risk also was higher in women with any stillbirth, compared with those without, and this risk increased with the number of stillbirths (HR, 0.97 and HR, 1.26 for those with one stillbirth and two or more, respectively).

“The increased risk of stroke associated with infertility or recurrent stillbirths was mainly driven by a single subtype of stroke (nonfatal ischemic stroke or fatal hemorrhagic stroke, respectively), whereas the risk of stroke associated with recurrent miscarriages was driven by both subtypes,” the researchers wrote.

The researchers cited endothelial dysfunction as a potential underlying mechanism for increased stroke risk associated with pregnancy complications. “Endothelial dysfunction might lead to pregnancy loss through placentation-related defects, persist after a complicated pregnancy, and contribute to the development of stroke through reduced vasodilation, proinflammatory status, and prothrombic properties,” and that history of recurrent pregnancy loss might be a female-specific risk factor for stroke.

To mitigate this risk, they advised early monitoring of women with a history of recurrent miscarriages and stillbirths for stroke risk factors such as high blood pressure, blood sugar levels, and lipid levels.

The study findings were limited by several factors including the use of questionnaires to collect information on infertility, miscarriage, and stillbirth, and the potential variation in definitions of infertility, miscarriage, and stillbirth across the included studies, and a lack of data on the effect of different causes or treatments based on reproductive histories, the researchers noted. Other limitations include incomplete data on stroke subtypes and inability to adjust for all covariates such as thyroid disorders and endometriosis. However, the results were strengthened by the large study size and geographically and racially diverse population, extend the current knowledge on associations between infertility, miscarriage, and stillbirth with stroke, and highlight the need for more research on underlying mechanisms.
 

Data support gender-specific stroke risk stratification

“Studies that seek to understand gender differences and disparities in adverse outcomes, such as stroke risk, are extremely important given that women historically were excluded from research studies,” Catherine M. Albright, MD, of the University of Washington, Seattle, said in an interview. “By doing these studies, we are able to better risk stratify people in order to better predict and modify risks,” added Dr. Albright, who was not involved in the current study.

“It is well known than adverse pregnancy outcomes such as hypertension in pregnancy, fetal growth restriction, and preterm birth, lead to increased risk of cardiovascular disease and stroke later in life, so the general findings of an association between other adverse reproductive and pregnancy outcomes leads to increased stroke risk are not surprising,” she said.

“The take-home message is that outcomes for pregnancy really do provide a window to future health,” said Dr. Albright. “For clinicians, especially non-ob.gyns., knowing a complete pregnancy history for any new patient is important and can help risk-stratify patients, especially as we continue to gain knowledge like what is shown in this study.”

However, “this study did not evaluate why individual patients may have had infertility, recurrent pregnancy loss, or stillbirth, so research to look further into this association to determine if there is an underlying medical condition that could be treated and therefore possibly reduce both pregnancy complications and future stroke risks would be important,” Dr. Albright noted.

The study was supported by the Australian National Health and Medical Research Council Centres of Research Excellence; one corresponding author was supported by an Australian National Health and Medical Research Council Investigator grant. The researchers had no financial conflicts to disclose. Dr. Albright had no financial conflicts to disclose.

Infertility, pregnancy loss, and stillbirth increased women’s later risk of both nonfatal and fatal stroke, based on data from more than 600,000 women.

“To date, multiple studies have generated an expanding body of evidence on the association between pregnancy complications (e.g., gestational diabetes and preeclampsia) and the long-term risk of stroke, but studies on associations with infertility, miscarriage, or stillbirth have produced mixed evidence,” Chen Liang, a PhD candidate at the University of Queensland, Brisbane, Australia, and colleagues wrote.

In a study published in the BMJ, the researchers reviewed data from eight observational cohort studies across seven countries (Australia, China, Japan, the Netherlands, Sweden, the United Kingdom, and the United States). The participants were part of the InterLACE (International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events) consortium established in 2021. Most observational studies included in the analysis began between 1990 and 2000.

The study population included 618,851 women aged 32-73 years at baseline for whom data on infertility, miscarriage, or stillbirth, were available. The primary outcome was the association of infertility, recurrent miscarriage, and stillbirth with risk of first fatal or nonfatal stroke, and the results were further stratified by subtype. Stroke was identified through self-reports, linked hospital data, national patient registers, or death registry data. Baseline was defined as the first incidence of infertility, miscarriage, or stillbirth. The exception was the National Survey of Health and Development, a British birth cohort started in 1946, that collected data retrospectively.

The median follow-up period was 13 years for nonfatal stroke and 9.4 years for fatal stroke.

Overall, 17.2%, 16.6%, and 4.6% of the women experienced infertility, miscarriage, and stillbirth, respectively.

Women with a history of infertility had a significantly higher nonfatal stroke risk, compared with those without infertility (hazard ratio, 1.14). Further analysis by stroke subtypes showed an increased association between miscarriage and ischemic stroke (HR, 1.15).

Those with a history of miscarriage also had an increased risk of nonfatal stroke, compared with those without miscarriages (HR, 1.11). In the miscarriage group, the risk of stroke increased with the number of miscarriages, with adjusted HRs of 1.07, 1.12, and 1.35 for women with one, two, and three or more miscarriages, respectively. When stratified by stroke subtype, women with three or more miscarriages were more likely than women with no miscarriages to experience ischemic and hemorrhagic nonfatal strokes.

Associations were similar between miscarriage history and fatal stroke risk. Women with one, two, and three or more miscarriages had increased risk of fatal stroke, compared with those with no miscarriages (aHR, 1.08, 1.26, and 1.82, respectively, and women with three or more miscarriages had a higher risk of ischemic and hemorrhagic stroke (aHR, 1.83 and 1.84, respectively).

Women with a history of stillbirth had an approximately 31% increased risk of nonfatal stroke, compared with those with no history of stillbirth, with aHRs similar for single and recurrent stillbirths (1.32 and 1.29, respectively). Ischemic nonfatal stroke risk was higher in women with any stillbirth, compared with those without stillbirth (aHR, 1.77). Fatal stroke risk also was higher in women with any stillbirth, compared with those without, and this risk increased with the number of stillbirths (HR, 0.97 and HR, 1.26 for those with one stillbirth and two or more, respectively).

“The increased risk of stroke associated with infertility or recurrent stillbirths was mainly driven by a single subtype of stroke (nonfatal ischemic stroke or fatal hemorrhagic stroke, respectively), whereas the risk of stroke associated with recurrent miscarriages was driven by both subtypes,” the researchers wrote.

The researchers cited endothelial dysfunction as a potential underlying mechanism for increased stroke risk associated with pregnancy complications. “Endothelial dysfunction might lead to pregnancy loss through placentation-related defects, persist after a complicated pregnancy, and contribute to the development of stroke through reduced vasodilation, proinflammatory status, and prothrombic properties,” and that history of recurrent pregnancy loss might be a female-specific risk factor for stroke.

To mitigate this risk, they advised early monitoring of women with a history of recurrent miscarriages and stillbirths for stroke risk factors such as high blood pressure, blood sugar levels, and lipid levels.

The study findings were limited by several factors including the use of questionnaires to collect information on infertility, miscarriage, and stillbirth, and the potential variation in definitions of infertility, miscarriage, and stillbirth across the included studies, and a lack of data on the effect of different causes or treatments based on reproductive histories, the researchers noted. Other limitations include incomplete data on stroke subtypes and inability to adjust for all covariates such as thyroid disorders and endometriosis. However, the results were strengthened by the large study size and geographically and racially diverse population, extend the current knowledge on associations between infertility, miscarriage, and stillbirth with stroke, and highlight the need for more research on underlying mechanisms.
 

Data support gender-specific stroke risk stratification

“Studies that seek to understand gender differences and disparities in adverse outcomes, such as stroke risk, are extremely important given that women historically were excluded from research studies,” Catherine M. Albright, MD, of the University of Washington, Seattle, said in an interview. “By doing these studies, we are able to better risk stratify people in order to better predict and modify risks,” added Dr. Albright, who was not involved in the current study.

“It is well known than adverse pregnancy outcomes such as hypertension in pregnancy, fetal growth restriction, and preterm birth, lead to increased risk of cardiovascular disease and stroke later in life, so the general findings of an association between other adverse reproductive and pregnancy outcomes leads to increased stroke risk are not surprising,” she said.

“The take-home message is that outcomes for pregnancy really do provide a window to future health,” said Dr. Albright. “For clinicians, especially non-ob.gyns., knowing a complete pregnancy history for any new patient is important and can help risk-stratify patients, especially as we continue to gain knowledge like what is shown in this study.”

However, “this study did not evaluate why individual patients may have had infertility, recurrent pregnancy loss, or stillbirth, so research to look further into this association to determine if there is an underlying medical condition that could be treated and therefore possibly reduce both pregnancy complications and future stroke risks would be important,” Dr. Albright noted.

The study was supported by the Australian National Health and Medical Research Council Centres of Research Excellence; one corresponding author was supported by an Australian National Health and Medical Research Council Investigator grant. The researchers had no financial conflicts to disclose. Dr. Albright had no financial conflicts to disclose.

A new artificial intelligence (AI) system can help expert endoscopists improve their colonoscopies, a new study indicates.

Endoscopists using the computer program SKOUT (Iterative Scopes) achieved a 27% better detection rate of adenomas per colonoscopy, compared with endoscopists working without computer assistance, said lead author Aasma Shaukat, MD, MPH, director of outcomes research in the division of gastroenterology and hepatology at New York University.

The study showed that AI colonoscopy systems can work in a routine population of U.S. patients, Dr. Shaukat said in an interview.

“As gastroenterologists, we are very excited,” she said.

The study was published online in Gastroenterology and was presented at the annual Digestive Disease^® Week.

Previous research has shown that experienced endoscopists miss many polyps. To improve their detection rate, multiple companies have used machine learning to develop algorithms to identify suspicious areas.

“Once the computer sees the polyp, it puts a bounding box around it,” said Dr. Shaukat. “It draws the attention of the endoscopist to it. It assists the endoscopist but doesn’t replace the endoscopist.”

The Food and Drug Administration has approved two such systems: EndoScreener (Wision AI) and GI Genius (Cosmo Pharmaceuticals).

The SKOUT algorithm was trained on 3,616 full-length colonoscopy procedure videos from multiple centers. In bench testing, it achieved a 93.5% polyp-level true positive rate and a 2.3% false positive rate.
 

Randomized trial pits AI against standard procedure

To see how well the system works in the clinic, Dr. Shaukat and colleagues recruited 22 U.S. board-certified gastroenterologists from five academic and community centers. The gastroenterologists all had a minimum adenoma detection rate of 25%, defined as the number of colonoscopies in which at least one adenoma is found, divided by the number of colonoscopies performed. All the gastroenterologists had performed a minimum of 1,000 colonoscopy procedures.

The researchers randomly assigned 682 patients to undergo colonoscopy with the SKOUT and 677 to undergo colonoscopy using the standard procedure. The patients were aged 40 years or older and were scheduled for either screening or surveillance.

The endoscopists who received computer assistance detected 1.05 adenomas per colonoscopy versus 0.83 for those who did not have computer assistance, a statistically significant difference.

The proportion of resections with clinically significant histology was 71.7% with standard colonoscopies versus 67.4% with computer-assisted colonoscopies. This fell within the 14% margin that the researchers had set to show noninferiority for the computer system.

“The important thing is not just detecting all polyps but the polyps we care about, which are adenomas, and doing so without increasing the false positive rate,” said Dr. Shaukat.

The adenoma detection rate was 43.9% for the standard procedure and 47.8% for the computer-assisted procedure. This difference was not statistically significant, but Dr. Shaukat argued that the adenoma detection rate is not the best measure of success, because endoscopists sometimes stop looking for polyps once they find one.

The overall sessile serrated lesion detection rate for the standard colonoscopies was 16.0% versus 12.6% for the computer-assisted colonoscopies, which also was not statistically significant.
 

Next steps

This study is important because it was a large, multicenter trial in the United States, said Omer Ahmad, BSc, MBBS, MRCP, a gastroenterologist and clinical researcher at University College London, who was not involved in the study. Most of the trials of AI have been in China or Europe. “It was very important just to see this replicated in the U.S. population.”

The average procedure time was 15.41 minutes for the standard colonoscopies versus 15.82 minutes for the computer-assisted colonoscopies, which was not statistically different.

“It is important to note that the studies so far suggest that false positives do not have a significant impact on workflow,” said Dr. Ahmad.

The next crucial step in evaluating AI colonoscopy will be to track the effects over the long term, said Dr. Shaukat.

“As these technologies get approved and we see them in practice, we need to see that it’s leading to some outcome, like reduced colon cancer,” she said.

That also may be necessary before payers in the United States are willing to pay the additional cost for this technology, she added.

In the meantime, Dr. Ahmad said computer assistance is improving his own colonoscopies.

“I have found the systems have spotted some polyps that I may have otherwise missed,” he said. “There is a false positive rate, but for me, it doesn’t distract from my workflow.”

He believes the systems will be particularly helpful in improving the performance of less-skilled endoscopists.

He is also looking forward to systems that can help complete the reports needed at the end of each colonoscopy. “Most of us dislike having to write a laborious report and having to code everything at the end of the procedure,” he said.

The study was funded by Iterative Scopes. Dr. Shaukat reported having received research funding to her institution for the current study from Iterative Scopes and consulting fees from Freenome and Medtronic. Dr. Ahmad reports receiving speaker fees from the Canadian Association of Gastroenterology/Medtronic.

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

A new artificial intelligence (AI) system can help expert endoscopists improve their colonoscopies, a new study indicates.

Endoscopists using the computer program SKOUT (Iterative Scopes) achieved a 27% better detection rate of adenomas per colonoscopy, compared with endoscopists working without computer assistance, said lead author Aasma Shaukat, MD, MPH, director of outcomes research in the division of gastroenterology and hepatology at New York University.

The study showed that AI colonoscopy systems can work in a routine population of U.S. patients, Dr. Shaukat said in an interview.

“As gastroenterologists, we are very excited,” she said.

The study was published online in Gastroenterology and was presented at the annual Digestive Disease^® Week.

Previous research has shown that experienced endoscopists miss many polyps. To improve their detection rate, multiple companies have used machine learning to develop algorithms to identify suspicious areas.

“Once the computer sees the polyp, it puts a bounding box around it,” said Dr. Shaukat. “It draws the attention of the endoscopist to it. It assists the endoscopist but doesn’t replace the endoscopist.”

The Food and Drug Administration has approved two such systems: EndoScreener (Wision AI) and GI Genius (Cosmo Pharmaceuticals).

The SKOUT algorithm was trained on 3,616 full-length colonoscopy procedure videos from multiple centers. In bench testing, it achieved a 93.5% polyp-level true positive rate and a 2.3% false positive rate.
 

Randomized trial pits AI against standard procedure

To see how well the system works in the clinic, Dr. Shaukat and colleagues recruited 22 U.S. board-certified gastroenterologists from five academic and community centers. The gastroenterologists all had a minimum adenoma detection rate of 25%, defined as the number of colonoscopies in which at least one adenoma is found, divided by the number of colonoscopies performed. All the gastroenterologists had performed a minimum of 1,000 colonoscopy procedures.

The researchers randomly assigned 682 patients to undergo colonoscopy with the SKOUT and 677 to undergo colonoscopy using the standard procedure. The patients were aged 40 years or older and were scheduled for either screening or surveillance.

The endoscopists who received computer assistance detected 1.05 adenomas per colonoscopy versus 0.83 for those who did not have computer assistance, a statistically significant difference.

The proportion of resections with clinically significant histology was 71.7% with standard colonoscopies versus 67.4% with computer-assisted colonoscopies. This fell within the 14% margin that the researchers had set to show noninferiority for the computer system.

“The important thing is not just detecting all polyps but the polyps we care about, which are adenomas, and doing so without increasing the false positive rate,” said Dr. Shaukat.

The adenoma detection rate was 43.9% for the standard procedure and 47.8% for the computer-assisted procedure. This difference was not statistically significant, but Dr. Shaukat argued that the adenoma detection rate is not the best measure of success, because endoscopists sometimes stop looking for polyps once they find one.

The overall sessile serrated lesion detection rate for the standard colonoscopies was 16.0% versus 12.6% for the computer-assisted colonoscopies, which also was not statistically significant.
 

Next steps

This study is important because it was a large, multicenter trial in the United States, said Omer Ahmad, BSc, MBBS, MRCP, a gastroenterologist and clinical researcher at University College London, who was not involved in the study. Most of the trials of AI have been in China or Europe. “It was very important just to see this replicated in the U.S. population.”

The average procedure time was 15.41 minutes for the standard colonoscopies versus 15.82 minutes for the computer-assisted colonoscopies, which was not statistically different.

“It is important to note that the studies so far suggest that false positives do not have a significant impact on workflow,” said Dr. Ahmad.

The next crucial step in evaluating AI colonoscopy will be to track the effects over the long term, said Dr. Shaukat.

“As these technologies get approved and we see them in practice, we need to see that it’s leading to some outcome, like reduced colon cancer,” she said.

That also may be necessary before payers in the United States are willing to pay the additional cost for this technology, she added.

In the meantime, Dr. Ahmad said computer assistance is improving his own colonoscopies.

“I have found the systems have spotted some polyps that I may have otherwise missed,” he said. “There is a false positive rate, but for me, it doesn’t distract from my workflow.”

He believes the systems will be particularly helpful in improving the performance of less-skilled endoscopists.

He is also looking forward to systems that can help complete the reports needed at the end of each colonoscopy. “Most of us dislike having to write a laborious report and having to code everything at the end of the procedure,” he said.

The study was funded by Iterative Scopes. Dr. Shaukat reported having received research funding to her institution for the current study from Iterative Scopes and consulting fees from Freenome and Medtronic. Dr. Ahmad reports receiving speaker fees from the Canadian Association of Gastroenterology/Medtronic.

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

A new artificial intelligence (AI) system can help expert endoscopists improve their colonoscopies, a new study indicates.

Endoscopists using the computer program SKOUT (Iterative Scopes) achieved a 27% better detection rate of adenomas per colonoscopy, compared with endoscopists working without computer assistance, said lead author Aasma Shaukat, MD, MPH, director of outcomes research in the division of gastroenterology and hepatology at New York University.

The study showed that AI colonoscopy systems can work in a routine population of U.S. patients, Dr. Shaukat said in an interview.

“As gastroenterologists, we are very excited,” she said.

The study was published online in Gastroenterology and was presented at the annual Digestive Disease^® Week.

Previous research has shown that experienced endoscopists miss many polyps. To improve their detection rate, multiple companies have used machine learning to develop algorithms to identify suspicious areas.

“Once the computer sees the polyp, it puts a bounding box around it,” said Dr. Shaukat. “It draws the attention of the endoscopist to it. It assists the endoscopist but doesn’t replace the endoscopist.”

The Food and Drug Administration has approved two such systems: EndoScreener (Wision AI) and GI Genius (Cosmo Pharmaceuticals).

The SKOUT algorithm was trained on 3,616 full-length colonoscopy procedure videos from multiple centers. In bench testing, it achieved a 93.5% polyp-level true positive rate and a 2.3% false positive rate.
 

Randomized trial pits AI against standard procedure

To see how well the system works in the clinic, Dr. Shaukat and colleagues recruited 22 U.S. board-certified gastroenterologists from five academic and community centers. The gastroenterologists all had a minimum adenoma detection rate of 25%, defined as the number of colonoscopies in which at least one adenoma is found, divided by the number of colonoscopies performed. All the gastroenterologists had performed a minimum of 1,000 colonoscopy procedures.

The researchers randomly assigned 682 patients to undergo colonoscopy with the SKOUT and 677 to undergo colonoscopy using the standard procedure. The patients were aged 40 years or older and were scheduled for either screening or surveillance.

The endoscopists who received computer assistance detected 1.05 adenomas per colonoscopy versus 0.83 for those who did not have computer assistance, a statistically significant difference.

The proportion of resections with clinically significant histology was 71.7% with standard colonoscopies versus 67.4% with computer-assisted colonoscopies. This fell within the 14% margin that the researchers had set to show noninferiority for the computer system.

“The important thing is not just detecting all polyps but the polyps we care about, which are adenomas, and doing so without increasing the false positive rate,” said Dr. Shaukat.

The adenoma detection rate was 43.9% for the standard procedure and 47.8% for the computer-assisted procedure. This difference was not statistically significant, but Dr. Shaukat argued that the adenoma detection rate is not the best measure of success, because endoscopists sometimes stop looking for polyps once they find one.

The overall sessile serrated lesion detection rate for the standard colonoscopies was 16.0% versus 12.6% for the computer-assisted colonoscopies, which also was not statistically significant.
 

Next steps

This study is important because it was a large, multicenter trial in the United States, said Omer Ahmad, BSc, MBBS, MRCP, a gastroenterologist and clinical researcher at University College London, who was not involved in the study. Most of the trials of AI have been in China or Europe. “It was very important just to see this replicated in the U.S. population.”

The average procedure time was 15.41 minutes for the standard colonoscopies versus 15.82 minutes for the computer-assisted colonoscopies, which was not statistically different.

“It is important to note that the studies so far suggest that false positives do not have a significant impact on workflow,” said Dr. Ahmad.

The next crucial step in evaluating AI colonoscopy will be to track the effects over the long term, said Dr. Shaukat.

“As these technologies get approved and we see them in practice, we need to see that it’s leading to some outcome, like reduced colon cancer,” she said.

That also may be necessary before payers in the United States are willing to pay the additional cost for this technology, she added.

In the meantime, Dr. Ahmad said computer assistance is improving his own colonoscopies.

“I have found the systems have spotted some polyps that I may have otherwise missed,” he said. “There is a false positive rate, but for me, it doesn’t distract from my workflow.”

He believes the systems will be particularly helpful in improving the performance of less-skilled endoscopists.

He is also looking forward to systems that can help complete the reports needed at the end of each colonoscopy. “Most of us dislike having to write a laborious report and having to code everything at the end of the procedure,” he said.

The study was funded by Iterative Scopes. Dr. Shaukat reported having received research funding to her institution for the current study from Iterative Scopes and consulting fees from Freenome and Medtronic. Dr. Ahmad reports receiving speaker fees from the Canadian Association of Gastroenterology/Medtronic.

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

HP-3070, an asenapine transdermal system, is superior to placebo in reducing schizophrenia-associated hostility, results of a phase 3 study show.

The results suggest that these effects are at least partially independent of general antipsychotic effects or effects on sedation or akathisia.

“It’s important not to assume that antipsychotics decrease hostility by having people feel more sedated and that the only way to treat someone hostile is by sedating them,” lead investigator Leslie Citrome, MD, MPH, clinical professor of psychiatry and behavioral sciences, New York Medical College, Valhalla, told this news organization.

“Our findings suggest that transdermal asenapine has a specific antihostility effect in patients with schizophrenia,” he added.

A complex disorder

“Patients with schizophrenia are known to potentially exhibit aggressive, hostile behavior, especially during the acute phase of the illness, thus making effective management critical,” the authors write.

Dr. Citrome said schizophrenia is a complex condition that consists of five different symptom domains. These include positive (hallucinations, delusions), negative (amotivation, apathy), disorganization (cognitive symptoms), depression/anxiety, and excitability/hostility symptoms.

“These five domains are more or less independent of each other, in terms of treatment effects,” he noted.

Dr. Citrome has long been interested in the activity of antipsychotics and their impact on these various symptoms – particularly hostility – and recently published a review focusing on the impact of an array of antipsychotics on this symptom domain.

“What struck me here is that this is a transdermal system, a patch,” Dr. Citrome said. “None of the sedation that would ordinarily be associated with a sublingual asenapine would be present here.”

Dr. Citrome wanted to investigate whether the transdermal system would have an impact on hostility because, if so, “it would support the notion that hostility is an independent treatment target in schizophrenia.”

To investigate, Dr. Citrome and co-authors analyzed data from the pivotal HP-3070 phase 3 randomized, double-blind, placebo-controlled study of adults with schizophrenia who were randomly selected to receive either HP-3070 7.6 mg/24h, HP-3070 3.8 mg/24h, or placebo for 6 weeks.

The trial found that once-daily applications of HP-3070 demonstrated significant improvement in Positive and Negative Syndrome Scale (PANSS) total scores after 2-3 weeks of treatment, with the improvements sustained through week 6.

The current study was a post hoc analysis focusing specifically on 442 patients with hostility and agitation (defined as PANSS hostility item score > 1).

The outcome was the least-squares mean (LSM) changes in the PANSS hostility item. They also analyzed PANSS–Excited Component (PANSS-EC) from baseline to week 6 in all study participants. Findings were adjusted for the presence of somnolence or akathisia.

Demographic and baseline disease characteristics were “balanced” between the HP-3070–6.6-mg and the HP-3070–3.8-mg groups (n = 151 and n = 147, respectively) and the placebo group (n = 144) in the intent-to-treat analysis, with a mean (standard deviation) age of between 41.5 and 42.3 (11.6-11.9) years. Roughly three-quarters of participants were White, and most participants had a mean duration of between 15 and 16 years since diagnosis.
 

Independent effect

At week 6, the LSM mean change from baseline (CFB) in the PANSS hostility score was superior in both treatment groups at 6 weeks, compared with placebo (7.6 mg/24 hr: CFB, –0.4; 95% confidence interval, –0.6 to –0.2; P  < .001; 3.8 mg/24 hr: CFB, –0.3; 95% CI, –0.6 to –0.1; P < .01).

The findings remained significant, even after the researchers adjusted for covariates.

For all patients, regardless of baseline PANSS hostility item score, PANSS-EC week 6 LSM CFB was greater in both treatment groups compared with placebo (7.6 mg/24 hr: CFB, –1.1; 95% CI, –1.9 to –0.4; P < .01; 3.8 mg/24 hr: CFB, –1.3; 95% CI, –2.0 to –0.6; P  < .001).

Patients with a PANSS hostility score > 1 at baseline in both treatment groups also showed significant improvement in PANSS-EC score, compared with the placebo, beginning at week 2 and continuing through week 6.

“These effects of HP-3070 treatment on the PANSS hostility item score remained, even after adjustment for confounding variables, suggesting that the effect of HP-3070 on reducing symptoms of hostility may at be at least partially independent of general antipsychotic effects on hallucinations or delusions or the presence or absence of relevant medication-induced adverse effects, such as sedation or akathisia,” the authors comment.

They note that a limitation of the study is that it was conducted post hoc. In addition, the mean baseline PANSS hostility score was “low,” even among those with a score > 1, “translating to a severity level of minimal to mild,” which “limits the generalizability” of the analysis.
 

Important treatment target

Commenting on the study, Rifaat El-Mallakh, MD, MS, director of the Mood Disorders Research Program, department of psychiatry and behavioral sciences, University of Louisville (Ky.) School of Medicine, said, “aggression and hostility may exhibit themselves as symptoms of a psychotic illness or independent of psychosis and are an important treatment target.”

Dr. El-Mallakh, who was not involved with the study, said the “most effective anti-aggression medicine is clozapine.” He believes that it is this effect that “gives clozapine its stellar reputation,” rather than its antipsychotic effect.

“Of importance, the anti-aggression effect of clozapine is independent of its antipsychotic effect, which is an important point because if the behavior is rooted in psychosis, then successful treatment of psychosis with any agent should reduce aggression.”

The researchers “demonstrated that the effect was independent of psychosis” but because the study only recruited people with schizophrenia, the researchers “could not examine to see if the effect is independent of diagnosis,” Dr. El-Mallakh said.

“It is important to consider aggression/hostility as an independent behavior in pharmacologic studies, because it probably has its own biochemistry and neuroanatomy,” he added.

This study was funded by Hisamitsu Pharmaceutical. Dr. Citrome has received nonfinancial support from Hisamitsu Pharmaceutical and personal fees from Noven Pharmaceuticals during the conduct of the study; personal fees from numerous companies and organizations; and one-off ad hoc consulting for medical education companies such as Medscape, NACCME, NEI, Vindico, and universities and professional organizations/societies outside the submitted work. He has stocks and received royalties from numerous companies and organizations. Dr. El-Mallakh is a speaker for Noven, as well as Indivior, Intracellular, Janssen, Lundbeck, Otsuka, Sunovion, and Teva.

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

HP-3070, an asenapine transdermal system, is superior to placebo in reducing schizophrenia-associated hostility, results of a phase 3 study show.

The results suggest that these effects are at least partially independent of general antipsychotic effects or effects on sedation or akathisia.

“It’s important not to assume that antipsychotics decrease hostility by having people feel more sedated and that the only way to treat someone hostile is by sedating them,” lead investigator Leslie Citrome, MD, MPH, clinical professor of psychiatry and behavioral sciences, New York Medical College, Valhalla, told this news organization.

“Our findings suggest that transdermal asenapine has a specific antihostility effect in patients with schizophrenia,” he added.

A complex disorder

“Patients with schizophrenia are known to potentially exhibit aggressive, hostile behavior, especially during the acute phase of the illness, thus making effective management critical,” the authors write.

Dr. Citrome said schizophrenia is a complex condition that consists of five different symptom domains. These include positive (hallucinations, delusions), negative (amotivation, apathy), disorganization (cognitive symptoms), depression/anxiety, and excitability/hostility symptoms.

“These five domains are more or less independent of each other, in terms of treatment effects,” he noted.

Dr. Citrome has long been interested in the activity of antipsychotics and their impact on these various symptoms – particularly hostility – and recently published a review focusing on the impact of an array of antipsychotics on this symptom domain.

“What struck me here is that this is a transdermal system, a patch,” Dr. Citrome said. “None of the sedation that would ordinarily be associated with a sublingual asenapine would be present here.”

Dr. Citrome wanted to investigate whether the transdermal system would have an impact on hostility because, if so, “it would support the notion that hostility is an independent treatment target in schizophrenia.”

To investigate, Dr. Citrome and co-authors analyzed data from the pivotal HP-3070 phase 3 randomized, double-blind, placebo-controlled study of adults with schizophrenia who were randomly selected to receive either HP-3070 7.6 mg/24h, HP-3070 3.8 mg/24h, or placebo for 6 weeks.

The trial found that once-daily applications of HP-3070 demonstrated significant improvement in Positive and Negative Syndrome Scale (PANSS) total scores after 2-3 weeks of treatment, with the improvements sustained through week 6.

The current study was a post hoc analysis focusing specifically on 442 patients with hostility and agitation (defined as PANSS hostility item score > 1).

The outcome was the least-squares mean (LSM) changes in the PANSS hostility item. They also analyzed PANSS–Excited Component (PANSS-EC) from baseline to week 6 in all study participants. Findings were adjusted for the presence of somnolence or akathisia.

Demographic and baseline disease characteristics were “balanced” between the HP-3070–6.6-mg and the HP-3070–3.8-mg groups (n = 151 and n = 147, respectively) and the placebo group (n = 144) in the intent-to-treat analysis, with a mean (standard deviation) age of between 41.5 and 42.3 (11.6-11.9) years. Roughly three-quarters of participants were White, and most participants had a mean duration of between 15 and 16 years since diagnosis.
 

Independent effect

At week 6, the LSM mean change from baseline (CFB) in the PANSS hostility score was superior in both treatment groups at 6 weeks, compared with placebo (7.6 mg/24 hr: CFB, –0.4; 95% confidence interval, –0.6 to –0.2; P  < .001; 3.8 mg/24 hr: CFB, –0.3; 95% CI, –0.6 to –0.1; P < .01).

The findings remained significant, even after the researchers adjusted for covariates.

For all patients, regardless of baseline PANSS hostility item score, PANSS-EC week 6 LSM CFB was greater in both treatment groups compared with placebo (7.6 mg/24 hr: CFB, –1.1; 95% CI, –1.9 to –0.4; P < .01; 3.8 mg/24 hr: CFB, –1.3; 95% CI, –2.0 to –0.6; P  < .001).

Patients with a PANSS hostility score > 1 at baseline in both treatment groups also showed significant improvement in PANSS-EC score, compared with the placebo, beginning at week 2 and continuing through week 6.

“These effects of HP-3070 treatment on the PANSS hostility item score remained, even after adjustment for confounding variables, suggesting that the effect of HP-3070 on reducing symptoms of hostility may at be at least partially independent of general antipsychotic effects on hallucinations or delusions or the presence or absence of relevant medication-induced adverse effects, such as sedation or akathisia,” the authors comment.

They note that a limitation of the study is that it was conducted post hoc. In addition, the mean baseline PANSS hostility score was “low,” even among those with a score > 1, “translating to a severity level of minimal to mild,” which “limits the generalizability” of the analysis.
 

Important treatment target

Commenting on the study, Rifaat El-Mallakh, MD, MS, director of the Mood Disorders Research Program, department of psychiatry and behavioral sciences, University of Louisville (Ky.) School of Medicine, said, “aggression and hostility may exhibit themselves as symptoms of a psychotic illness or independent of psychosis and are an important treatment target.”

Dr. El-Mallakh, who was not involved with the study, said the “most effective anti-aggression medicine is clozapine.” He believes that it is this effect that “gives clozapine its stellar reputation,” rather than its antipsychotic effect.

“Of importance, the anti-aggression effect of clozapine is independent of its antipsychotic effect, which is an important point because if the behavior is rooted in psychosis, then successful treatment of psychosis with any agent should reduce aggression.”

The researchers “demonstrated that the effect was independent of psychosis” but because the study only recruited people with schizophrenia, the researchers “could not examine to see if the effect is independent of diagnosis,” Dr. El-Mallakh said.

“It is important to consider aggression/hostility as an independent behavior in pharmacologic studies, because it probably has its own biochemistry and neuroanatomy,” he added.

This study was funded by Hisamitsu Pharmaceutical. Dr. Citrome has received nonfinancial support from Hisamitsu Pharmaceutical and personal fees from Noven Pharmaceuticals during the conduct of the study; personal fees from numerous companies and organizations; and one-off ad hoc consulting for medical education companies such as Medscape, NACCME, NEI, Vindico, and universities and professional organizations/societies outside the submitted work. He has stocks and received royalties from numerous companies and organizations. Dr. El-Mallakh is a speaker for Noven, as well as Indivior, Intracellular, Janssen, Lundbeck, Otsuka, Sunovion, and Teva.

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

HP-3070, an asenapine transdermal system, is superior to placebo in reducing schizophrenia-associated hostility, results of a phase 3 study show.

The results suggest that these effects are at least partially independent of general antipsychotic effects or effects on sedation or akathisia.

“It’s important not to assume that antipsychotics decrease hostility by having people feel more sedated and that the only way to treat someone hostile is by sedating them,” lead investigator Leslie Citrome, MD, MPH, clinical professor of psychiatry and behavioral sciences, New York Medical College, Valhalla, told this news organization.

“Our findings suggest that transdermal asenapine has a specific antihostility effect in patients with schizophrenia,” he added.

A complex disorder

“Patients with schizophrenia are known to potentially exhibit aggressive, hostile behavior, especially during the acute phase of the illness, thus making effective management critical,” the authors write.

Dr. Citrome said schizophrenia is a complex condition that consists of five different symptom domains. These include positive (hallucinations, delusions), negative (amotivation, apathy), disorganization (cognitive symptoms), depression/anxiety, and excitability/hostility symptoms.

“These five domains are more or less independent of each other, in terms of treatment effects,” he noted.

Dr. Citrome has long been interested in the activity of antipsychotics and their impact on these various symptoms – particularly hostility – and recently published a review focusing on the impact of an array of antipsychotics on this symptom domain.

“What struck me here is that this is a transdermal system, a patch,” Dr. Citrome said. “None of the sedation that would ordinarily be associated with a sublingual asenapine would be present here.”

Dr. Citrome wanted to investigate whether the transdermal system would have an impact on hostility because, if so, “it would support the notion that hostility is an independent treatment target in schizophrenia.”

To investigate, Dr. Citrome and co-authors analyzed data from the pivotal HP-3070 phase 3 randomized, double-blind, placebo-controlled study of adults with schizophrenia who were randomly selected to receive either HP-3070 7.6 mg/24h, HP-3070 3.8 mg/24h, or placebo for 6 weeks.

The trial found that once-daily applications of HP-3070 demonstrated significant improvement in Positive and Negative Syndrome Scale (PANSS) total scores after 2-3 weeks of treatment, with the improvements sustained through week 6.

The current study was a post hoc analysis focusing specifically on 442 patients with hostility and agitation (defined as PANSS hostility item score > 1).

The outcome was the least-squares mean (LSM) changes in the PANSS hostility item. They also analyzed PANSS–Excited Component (PANSS-EC) from baseline to week 6 in all study participants. Findings were adjusted for the presence of somnolence or akathisia.

Demographic and baseline disease characteristics were “balanced” between the HP-3070–6.6-mg and the HP-3070–3.8-mg groups (n = 151 and n = 147, respectively) and the placebo group (n = 144) in the intent-to-treat analysis, with a mean (standard deviation) age of between 41.5 and 42.3 (11.6-11.9) years. Roughly three-quarters of participants were White, and most participants had a mean duration of between 15 and 16 years since diagnosis.
 

Independent effect

At week 6, the LSM mean change from baseline (CFB) in the PANSS hostility score was superior in both treatment groups at 6 weeks, compared with placebo (7.6 mg/24 hr: CFB, –0.4; 95% confidence interval, –0.6 to –0.2; P  < .001; 3.8 mg/24 hr: CFB, –0.3; 95% CI, –0.6 to –0.1; P < .01).

The findings remained significant, even after the researchers adjusted for covariates.

For all patients, regardless of baseline PANSS hostility item score, PANSS-EC week 6 LSM CFB was greater in both treatment groups compared with placebo (7.6 mg/24 hr: CFB, –1.1; 95% CI, –1.9 to –0.4; P < .01; 3.8 mg/24 hr: CFB, –1.3; 95% CI, –2.0 to –0.6; P  < .001).

Patients with a PANSS hostility score > 1 at baseline in both treatment groups also showed significant improvement in PANSS-EC score, compared with the placebo, beginning at week 2 and continuing through week 6.

“These effects of HP-3070 treatment on the PANSS hostility item score remained, even after adjustment for confounding variables, suggesting that the effect of HP-3070 on reducing symptoms of hostility may at be at least partially independent of general antipsychotic effects on hallucinations or delusions or the presence or absence of relevant medication-induced adverse effects, such as sedation or akathisia,” the authors comment.

They note that a limitation of the study is that it was conducted post hoc. In addition, the mean baseline PANSS hostility score was “low,” even among those with a score > 1, “translating to a severity level of minimal to mild,” which “limits the generalizability” of the analysis.
 

Important treatment target

Commenting on the study, Rifaat El-Mallakh, MD, MS, director of the Mood Disorders Research Program, department of psychiatry and behavioral sciences, University of Louisville (Ky.) School of Medicine, said, “aggression and hostility may exhibit themselves as symptoms of a psychotic illness or independent of psychosis and are an important treatment target.”

Dr. El-Mallakh, who was not involved with the study, said the “most effective anti-aggression medicine is clozapine.” He believes that it is this effect that “gives clozapine its stellar reputation,” rather than its antipsychotic effect.

“Of importance, the anti-aggression effect of clozapine is independent of its antipsychotic effect, which is an important point because if the behavior is rooted in psychosis, then successful treatment of psychosis with any agent should reduce aggression.”

The researchers “demonstrated that the effect was independent of psychosis” but because the study only recruited people with schizophrenia, the researchers “could not examine to see if the effect is independent of diagnosis,” Dr. El-Mallakh said.

“It is important to consider aggression/hostility as an independent behavior in pharmacologic studies, because it probably has its own biochemistry and neuroanatomy,” he added.

This study was funded by Hisamitsu Pharmaceutical. Dr. Citrome has received nonfinancial support from Hisamitsu Pharmaceutical and personal fees from Noven Pharmaceuticals during the conduct of the study; personal fees from numerous companies and organizations; and one-off ad hoc consulting for medical education companies such as Medscape, NACCME, NEI, Vindico, and universities and professional organizations/societies outside the submitted work. He has stocks and received royalties from numerous companies and organizations. Dr. El-Mallakh is a speaker for Noven, as well as Indivior, Intracellular, Janssen, Lundbeck, Otsuka, Sunovion, and Teva.

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

Infants who were introduced to a low-protein diet – high in fruit, vegetables, and roots – ate more fruits and vegetables at 12 and 18 months of age, compared with those who ate a conventional diet, in a new study.

The “Nordic diet” has shown health benefits in children and adults, but has not been studied in infants, said Ulrica Johansson, MD, of Umeå (Sweden) University, in a presentation on the study at the annual meeting of the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition.

A healthy and sustainable diet early in life could have a significant impact on future health, Dr. Johansson said in an interview.

Dr. Johansson and colleagues aimed to investigate the effect of a Nordic diet in infants aged 4-18 months in the OTIS trial. All infants were breastfed or formula-fed at baseline.
 

Study methods and results

A total of 250 infants aged 4-6 months were randomized to consuming a Nordic diet or a conventional diet. Those in the Nordic group received exposures to Nordic foods and flavors, including Nordic fruit, berries, vegetables, and roots. Those in the conventional group received baby food products that followed the current Swedish dietary recommendations for infants. The researchers collected data on dietary intake, biomarkers, and growth from baseline up to 18 months of age.

Notably, acceptance of all the flavors in the Nordic diet was high, including those with sour or bitter taste, such as cranberry and white radish, Dr. Johansson said in her presentation. Food refusals were few, and did not differ among the Nordic food offerings.

At both 12- and 18-month follow-ups, infants in the Nordic group consumed 42%-45% more fruits and vegetables compared with those in the conventional group (P < .001). Plasma folate levels also were significantly higher in the Nordic group compared with in the conventional group, at both 12 months and 18 months (P < .001 and P < .003, respectively).

The daily mean protein intake ranged from 17% to 29% lower in the Nordic group compared with in the conventional group, at both 12 months and 18 months. The intake of protein in terms of g/kg of body weight was significantly lower in the Nordic group, at both time points. Lower protein intake was confirmed by blood urea nitrogen measurements.

The protein intake in the Nordic group still fell within the safe level recommended for healthy growth in young children by the World Health Organization, noted Dr. Johansson, and no significant differences were observed in growth between the groups. Total energy intake, iron status, and duration of breastfeeding also remained similar between the groups throughout the study period.

Parents received support from research nurses via social media and monthly clinic visits, which she believes contributed to the success of the intervention, she said.
 

Nordic diet offers feasible encouragement of healthy eating

The key message for clinicians, and for parents of young children, is that “the protein-reduced, Nordic diet is both feasible and safe for infants’ growth, nutritional requirements, and development during the complementary feeding period,” Dr. Johansson said in an interview. “Thus, it may serve as a healthy and environmentally sustainable diet alternative for infants and their parents in the future.”

“Nordic foods are feasible to use when exposing infants to a variety of flavors so that healthy food preferences can be established early in life; Nordic berries and some root vegetables are preferable when introducing bitter and sour tastes during the sensitive period,” she added.

“Multicomponent interventions with long-term follow-up are required to advance the field of child nutrition research,” Dr. Johansson emphasized. Home-based interventions are lacking, and “more studies are needed to bridge the gap in research between the transfer period from baby food to family food at 1-2 years of age.”

Large, randomized controlled studies of Nordic diet during infancy and later childhood are needed as well, said Dr. Johansson. “The long-term effects of the Nordic diet during this highly dynamic period of childhood need continued follow-up to school age to give indications of any lasting health effects,” and the researchers plan to follow the current study population at 7 years of age.

Findings reinforce need for better nutrition

Previous research documents concern for childhood obesity associated with higher intake of protein, fats and overall calories in infancy, said Cathy Haut, DNP, CPNP-AC, CPNP-PC, a pediatric nurse practitioner in Rehoboth Beach, Del., in an interview. “The inclusion of high-calorie, high-fat foods contributes to obesity in all children, so focusing on intake of fruits and vegetables is extremely important early in life,” she said.

A key barrier to the widespread use of a Nordic-type diet is that and vegetables tend to be more expensive than other foods and may not be readily available to all families, especially lower income families, Dr. Haut added.

However, for primary care clinicians, the current study reinforces the need to encourage the intake of fruits and vegetables at all ages, beginning in infancy, she said.

Looking ahead, “there is still limited information in the literature about the ideal recommended daily protein, except for increased amounts needed for preterm infants, early infancy, and during periods of healing,” Dr. Haut emphasized. “Some controls for this study were not included in the abstract, such as monitoring what foods were given to the infants in the conventional group. Parent and caregiver interpretation of recommendations can be highly variable,” she noted. Also, “The activity levels of late infancy and toddlers can vary in terms of energy usage, especially when crawling, walking, running and other exercise-related activities begin. These factors were not readily available in the abstract/study,” she said.  

The OTIS trial was sponsored by Semper. Dr. Johansson had no financial conflicts to disclose. Dr. Haut had no financial conflicts to disclose, but serves on the Editorial Advisory Board of Pediatric News.

Infants who were introduced to a low-protein diet – high in fruit, vegetables, and roots – ate more fruits and vegetables at 12 and 18 months of age, compared with those who ate a conventional diet, in a new study.

The “Nordic diet” has shown health benefits in children and adults, but has not been studied in infants, said Ulrica Johansson, MD, of Umeå (Sweden) University, in a presentation on the study at the annual meeting of the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition.

A healthy and sustainable diet early in life could have a significant impact on future health, Dr. Johansson said in an interview.

Dr. Johansson and colleagues aimed to investigate the effect of a Nordic diet in infants aged 4-18 months in the OTIS trial. All infants were breastfed or formula-fed at baseline.
 

Study methods and results

A total of 250 infants aged 4-6 months were randomized to consuming a Nordic diet or a conventional diet. Those in the Nordic group received exposures to Nordic foods and flavors, including Nordic fruit, berries, vegetables, and roots. Those in the conventional group received baby food products that followed the current Swedish dietary recommendations for infants. The researchers collected data on dietary intake, biomarkers, and growth from baseline up to 18 months of age.

Notably, acceptance of all the flavors in the Nordic diet was high, including those with sour or bitter taste, such as cranberry and white radish, Dr. Johansson said in her presentation. Food refusals were few, and did not differ among the Nordic food offerings.

At both 12- and 18-month follow-ups, infants in the Nordic group consumed 42%-45% more fruits and vegetables compared with those in the conventional group (P < .001). Plasma folate levels also were significantly higher in the Nordic group compared with in the conventional group, at both 12 months and 18 months (P < .001 and P < .003, respectively).

The daily mean protein intake ranged from 17% to 29% lower in the Nordic group compared with in the conventional group, at both 12 months and 18 months. The intake of protein in terms of g/kg of body weight was significantly lower in the Nordic group, at both time points. Lower protein intake was confirmed by blood urea nitrogen measurements.

The protein intake in the Nordic group still fell within the safe level recommended for healthy growth in young children by the World Health Organization, noted Dr. Johansson, and no significant differences were observed in growth between the groups. Total energy intake, iron status, and duration of breastfeeding also remained similar between the groups throughout the study period.

Parents received support from research nurses via social media and monthly clinic visits, which she believes contributed to the success of the intervention, she said.
 

Nordic diet offers feasible encouragement of healthy eating

The key message for clinicians, and for parents of young children, is that “the protein-reduced, Nordic diet is both feasible and safe for infants’ growth, nutritional requirements, and development during the complementary feeding period,” Dr. Johansson said in an interview. “Thus, it may serve as a healthy and environmentally sustainable diet alternative for infants and their parents in the future.”

“Nordic foods are feasible to use when exposing infants to a variety of flavors so that healthy food preferences can be established early in life; Nordic berries and some root vegetables are preferable when introducing bitter and sour tastes during the sensitive period,” she added.

“Multicomponent interventions with long-term follow-up are required to advance the field of child nutrition research,” Dr. Johansson emphasized. Home-based interventions are lacking, and “more studies are needed to bridge the gap in research between the transfer period from baby food to family food at 1-2 years of age.”

Large, randomized controlled studies of Nordic diet during infancy and later childhood are needed as well, said Dr. Johansson. “The long-term effects of the Nordic diet during this highly dynamic period of childhood need continued follow-up to school age to give indications of any lasting health effects,” and the researchers plan to follow the current study population at 7 years of age.

Findings reinforce need for better nutrition

Previous research documents concern for childhood obesity associated with higher intake of protein, fats and overall calories in infancy, said Cathy Haut, DNP, CPNP-AC, CPNP-PC, a pediatric nurse practitioner in Rehoboth Beach, Del., in an interview. “The inclusion of high-calorie, high-fat foods contributes to obesity in all children, so focusing on intake of fruits and vegetables is extremely important early in life,” she said.

A key barrier to the widespread use of a Nordic-type diet is that and vegetables tend to be more expensive than other foods and may not be readily available to all families, especially lower income families, Dr. Haut added.

However, for primary care clinicians, the current study reinforces the need to encourage the intake of fruits and vegetables at all ages, beginning in infancy, she said.

Looking ahead, “there is still limited information in the literature about the ideal recommended daily protein, except for increased amounts needed for preterm infants, early infancy, and during periods of healing,” Dr. Haut emphasized. “Some controls for this study were not included in the abstract, such as monitoring what foods were given to the infants in the conventional group. Parent and caregiver interpretation of recommendations can be highly variable,” she noted. Also, “The activity levels of late infancy and toddlers can vary in terms of energy usage, especially when crawling, walking, running and other exercise-related activities begin. These factors were not readily available in the abstract/study,” she said.  

The OTIS trial was sponsored by Semper. Dr. Johansson had no financial conflicts to disclose. Dr. Haut had no financial conflicts to disclose, but serves on the Editorial Advisory Board of Pediatric News.

Infants who were introduced to a low-protein diet – high in fruit, vegetables, and roots – ate more fruits and vegetables at 12 and 18 months of age, compared with those who ate a conventional diet, in a new study.

The “Nordic diet” has shown health benefits in children and adults, but has not been studied in infants, said Ulrica Johansson, MD, of Umeå (Sweden) University, in a presentation on the study at the annual meeting of the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition.

A healthy and sustainable diet early in life could have a significant impact on future health, Dr. Johansson said in an interview.

Dr. Johansson and colleagues aimed to investigate the effect of a Nordic diet in infants aged 4-18 months in the OTIS trial. All infants were breastfed or formula-fed at baseline.
 

Study methods and results

A total of 250 infants aged 4-6 months were randomized to consuming a Nordic diet or a conventional diet. Those in the Nordic group received exposures to Nordic foods and flavors, including Nordic fruit, berries, vegetables, and roots. Those in the conventional group received baby food products that followed the current Swedish dietary recommendations for infants. The researchers collected data on dietary intake, biomarkers, and growth from baseline up to 18 months of age.

Notably, acceptance of all the flavors in the Nordic diet was high, including those with sour or bitter taste, such as cranberry and white radish, Dr. Johansson said in her presentation. Food refusals were few, and did not differ among the Nordic food offerings.

At both 12- and 18-month follow-ups, infants in the Nordic group consumed 42%-45% more fruits and vegetables compared with those in the conventional group (P < .001). Plasma folate levels also were significantly higher in the Nordic group compared with in the conventional group, at both 12 months and 18 months (P < .001 and P < .003, respectively).

The daily mean protein intake ranged from 17% to 29% lower in the Nordic group compared with in the conventional group, at both 12 months and 18 months. The intake of protein in terms of g/kg of body weight was significantly lower in the Nordic group, at both time points. Lower protein intake was confirmed by blood urea nitrogen measurements.

The protein intake in the Nordic group still fell within the safe level recommended for healthy growth in young children by the World Health Organization, noted Dr. Johansson, and no significant differences were observed in growth between the groups. Total energy intake, iron status, and duration of breastfeeding also remained similar between the groups throughout the study period.

Parents received support from research nurses via social media and monthly clinic visits, which she believes contributed to the success of the intervention, she said.
 

Nordic diet offers feasible encouragement of healthy eating

The key message for clinicians, and for parents of young children, is that “the protein-reduced, Nordic diet is both feasible and safe for infants’ growth, nutritional requirements, and development during the complementary feeding period,” Dr. Johansson said in an interview. “Thus, it may serve as a healthy and environmentally sustainable diet alternative for infants and their parents in the future.”

“Nordic foods are feasible to use when exposing infants to a variety of flavors so that healthy food preferences can be established early in life; Nordic berries and some root vegetables are preferable when introducing bitter and sour tastes during the sensitive period,” she added.

“Multicomponent interventions with long-term follow-up are required to advance the field of child nutrition research,” Dr. Johansson emphasized. Home-based interventions are lacking, and “more studies are needed to bridge the gap in research between the transfer period from baby food to family food at 1-2 years of age.”

Large, randomized controlled studies of Nordic diet during infancy and later childhood are needed as well, said Dr. Johansson. “The long-term effects of the Nordic diet during this highly dynamic period of childhood need continued follow-up to school age to give indications of any lasting health effects,” and the researchers plan to follow the current study population at 7 years of age.

Findings reinforce need for better nutrition

Previous research documents concern for childhood obesity associated with higher intake of protein, fats and overall calories in infancy, said Cathy Haut, DNP, CPNP-AC, CPNP-PC, a pediatric nurse practitioner in Rehoboth Beach, Del., in an interview. “The inclusion of high-calorie, high-fat foods contributes to obesity in all children, so focusing on intake of fruits and vegetables is extremely important early in life,” she said.

A key barrier to the widespread use of a Nordic-type diet is that and vegetables tend to be more expensive than other foods and may not be readily available to all families, especially lower income families, Dr. Haut added.

However, for primary care clinicians, the current study reinforces the need to encourage the intake of fruits and vegetables at all ages, beginning in infancy, she said.

Looking ahead, “there is still limited information in the literature about the ideal recommended daily protein, except for increased amounts needed for preterm infants, early infancy, and during periods of healing,” Dr. Haut emphasized. “Some controls for this study were not included in the abstract, such as monitoring what foods were given to the infants in the conventional group. Parent and caregiver interpretation of recommendations can be highly variable,” she noted. Also, “The activity levels of late infancy and toddlers can vary in terms of energy usage, especially when crawling, walking, running and other exercise-related activities begin. These factors were not readily available in the abstract/study,” she said.  

The OTIS trial was sponsored by Semper. Dr. Johansson had no financial conflicts to disclose. Dr. Haut had no financial conflicts to disclose, but serves on the Editorial Advisory Board of Pediatric News.

Lisocabtagene maraleucel, also known as liso-cel (Breyanzi), has been approved by the Food and Drug Administration for the second-line treatment of adult patients with relapsed or refractory large B-cell lymphoma (r/r LBCL).

This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.

Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).

A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.

Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:

• Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
• Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.

Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.

In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.

The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.

The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.

Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.

The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.

Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.

Lisocabtagene maraleucel, also known as liso-cel (Breyanzi), has been approved by the Food and Drug Administration for the second-line treatment of adult patients with relapsed or refractory large B-cell lymphoma (r/r LBCL).

This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.

Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).

A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.

Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:

• Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
• Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.

Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.

In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.

The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.

The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.

Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.

The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.

Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.

Lisocabtagene maraleucel, also known as liso-cel (Breyanzi), has been approved by the Food and Drug Administration for the second-line treatment of adult patients with relapsed or refractory large B-cell lymphoma (r/r LBCL).

This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.

Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).

A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.

Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:

• Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
• Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.

Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.

In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.

The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.

The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.

Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.

The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.

Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.

Bacteria that cause typhoid fever are becoming increasingly resistant to common antibiotics worldwide, a new analysis indicates.

Resistant strains of Salmonella enterica serovar typhi – almost all originating in South Asia – have spread across borders nearly 200 times since 1990.

Until now, analysis has been limited by small samples. This genome analysis is the largest to date and included 3,489 newly sequenced isolates (collected between 2014 and 2019) from prospective surveillance studies in four of the countries with the highest typhoid burden: Bangladesh, Nepal, Pakistan, and India.

Findings of the study, led by Kesia Esther da Silva, PhD, with the division of infectious diseases and geographic medicine at Stanford (Calif.) University, were published online in The Lancet Microbe.
 

Global deaths: 100,000 annually

Typhoid fever remains a global public health threat, causing 11 million infections and more than 100,000 deaths each year. Most cases (70%) are in South Asia, but typhoid also has significant presence in sub-Saharan Africa, Southeast Asia, and Oceania.

The findings are further evidence of the need for a global response, the authors write.

Jason Andrews, MD, a coauthor and associate professor in the division of infectious diseases and geographic medicine at Stanford University, said in an interview that the research helps pinpoint where the highest burden is and where the biggest need is for the two highly effective typhoid vaccines.

“We’re seeing higher levels of resistance than we’ve ever seen before against our latest and greatest antibiotics,” he said.

He said so far, strategies for tackling typhoid have involved country-level decisions and local funding and that needs to be shifted to a global priority. “Given contemporary travel migration patterns, what we see is that when antimicrobial resistance develops in one country, it quickly spreads to other countries.”

Dr. Andrews said the United States sees about 300-500 typhoid cases a year. “About 80% of those cases involve people traveling from South Asia,” he said.

Infections also come from people from the United States visiting high-burden countries, especially to see family. Often they don’t perceive the risk and skip vaccination, he said. U.S. clinicians can help with educating patients traveling to typhoid-endemic regions on pretravel vaccination.

Physician awareness is also important when patients have recently returned from such regions. Data from this study show a need to carefully consider which antibiotics will be effective with the growing resistance.
 

Only one oral option left in Pakistan

“We are running low on treatment options for typhoid,” Dr. Andrews said. The resistance pattern in Pakistan, for example, has left only one oral option, azithromycin, and resistance is building to that.

Without that option, “we’ll have to hospitalize patients and give intravenous antibiotics,” he said. “That’s concerning.”

Moreover, some resistant strains from Pakistan have been turning up in the United States.

“There are actually some cases that have not been tracked at all to travelers going to Pakistan and are thought to be from local transmission in the United States,” he said.

Valida Bajrovic, MD, assistant professor of medicine in infectious diseases at the Icahn School of Medicine at Mount Sinai, New York, said in an interview that, in addition to vaccinating travelers before they head to typhoid-endemic areas, physicians should educate patients on avoiding fecal transmission of typhoid with vigilant hand washing, drinking bottled water, and avoiding foods that may have been prepared in unsanitary conditions.

Dr. Bajrovic, who directs the antimicrobial stewardship efforts at the Mount Sinai Morningside and Mount Sinai West Hospitals, said stricter antimicrobial stewardship efforts are needed, particularly in Europe and South Asia, but also in the United States.

“Restriction of antibiotic use is the way to prevent antibiotic resistance,” she said, adding that such restrictions need to be part of a global effort.

Strains in the study were classified as multidrug resistant (MDR) if they contained genes resistant to ampicillin, chloramphenicol, and trimethoprim/sulfamethoxazole. The authors also traced the presence of genes demonstrating resistance to macrolides and quinolones.

At first, fluoroquinolones were effective against MDR S. typhi and in the 1990s became the primary therapy. By the 2010s, however, the majority of S. typhi in south Asia contained mutations in the quinolone resistance-determining regions.

The authors wrote: “We found evidence of frequent international (n = 138) and intercontinental transfers (n = 59) of antimicrobial-resistant S. typhi.”

According to the analysis, since 2000, MDR S. typhi has declined steadily in Bangladesh and India and remained at less than 5% of typhoid strains in Nepal, though it has increased slightly in Pakistan.

However, these are being replaced “with strains containing ceftriaxone resistance (extensively drug resistant), high-level fluoroquinolone resistance, or azithromycin resistance, which are reversing declines in the effective population size of S. typhi,” the authors wrote.

The analysis supports urgency for prevention measures, including use of typhoid conjugate vaccines in typhoid-endemic countries, the authors said.

But given the rise in international spread of increasingly resistant strains, they said, preventive measures should not be limited to those countries.

The study was funded by the Bill & Melinda Gates Foundation. Dr. Da Silva, Dr. Andrews, and Dr. Bajrovic have disclosed no relevant financial relationships.

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

Bacteria that cause typhoid fever are becoming increasingly resistant to common antibiotics worldwide, a new analysis indicates.

Resistant strains of Salmonella enterica serovar typhi – almost all originating in South Asia – have spread across borders nearly 200 times since 1990.

Until now, analysis has been limited by small samples. This genome analysis is the largest to date and included 3,489 newly sequenced isolates (collected between 2014 and 2019) from prospective surveillance studies in four of the countries with the highest typhoid burden: Bangladesh, Nepal, Pakistan, and India.

Findings of the study, led by Kesia Esther da Silva, PhD, with the division of infectious diseases and geographic medicine at Stanford (Calif.) University, were published online in The Lancet Microbe.
 

Global deaths: 100,000 annually

Typhoid fever remains a global public health threat, causing 11 million infections and more than 100,000 deaths each year. Most cases (70%) are in South Asia, but typhoid also has significant presence in sub-Saharan Africa, Southeast Asia, and Oceania.

The findings are further evidence of the need for a global response, the authors write.

Jason Andrews, MD, a coauthor and associate professor in the division of infectious diseases and geographic medicine at Stanford University, said in an interview that the research helps pinpoint where the highest burden is and where the biggest need is for the two highly effective typhoid vaccines.

“We’re seeing higher levels of resistance than we’ve ever seen before against our latest and greatest antibiotics,” he said.

He said so far, strategies for tackling typhoid have involved country-level decisions and local funding and that needs to be shifted to a global priority. “Given contemporary travel migration patterns, what we see is that when antimicrobial resistance develops in one country, it quickly spreads to other countries.”

Dr. Andrews said the United States sees about 300-500 typhoid cases a year. “About 80% of those cases involve people traveling from South Asia,” he said.

Infections also come from people from the United States visiting high-burden countries, especially to see family. Often they don’t perceive the risk and skip vaccination, he said. U.S. clinicians can help with educating patients traveling to typhoid-endemic regions on pretravel vaccination.

Physician awareness is also important when patients have recently returned from such regions. Data from this study show a need to carefully consider which antibiotics will be effective with the growing resistance.
 

Only one oral option left in Pakistan

“We are running low on treatment options for typhoid,” Dr. Andrews said. The resistance pattern in Pakistan, for example, has left only one oral option, azithromycin, and resistance is building to that.

Without that option, “we’ll have to hospitalize patients and give intravenous antibiotics,” he said. “That’s concerning.”

Moreover, some resistant strains from Pakistan have been turning up in the United States.

“There are actually some cases that have not been tracked at all to travelers going to Pakistan and are thought to be from local transmission in the United States,” he said.

Valida Bajrovic, MD, assistant professor of medicine in infectious diseases at the Icahn School of Medicine at Mount Sinai, New York, said in an interview that, in addition to vaccinating travelers before they head to typhoid-endemic areas, physicians should educate patients on avoiding fecal transmission of typhoid with vigilant hand washing, drinking bottled water, and avoiding foods that may have been prepared in unsanitary conditions.

Dr. Bajrovic, who directs the antimicrobial stewardship efforts at the Mount Sinai Morningside and Mount Sinai West Hospitals, said stricter antimicrobial stewardship efforts are needed, particularly in Europe and South Asia, but also in the United States.

“Restriction of antibiotic use is the way to prevent antibiotic resistance,” she said, adding that such restrictions need to be part of a global effort.

Strains in the study were classified as multidrug resistant (MDR) if they contained genes resistant to ampicillin, chloramphenicol, and trimethoprim/sulfamethoxazole. The authors also traced the presence of genes demonstrating resistance to macrolides and quinolones.

At first, fluoroquinolones were effective against MDR S. typhi and in the 1990s became the primary therapy. By the 2010s, however, the majority of S. typhi in south Asia contained mutations in the quinolone resistance-determining regions.

The authors wrote: “We found evidence of frequent international (n = 138) and intercontinental transfers (n = 59) of antimicrobial-resistant S. typhi.”

According to the analysis, since 2000, MDR S. typhi has declined steadily in Bangladesh and India and remained at less than 5% of typhoid strains in Nepal, though it has increased slightly in Pakistan.

However, these are being replaced “with strains containing ceftriaxone resistance (extensively drug resistant), high-level fluoroquinolone resistance, or azithromycin resistance, which are reversing declines in the effective population size of S. typhi,” the authors wrote.

The analysis supports urgency for prevention measures, including use of typhoid conjugate vaccines in typhoid-endemic countries, the authors said.

But given the rise in international spread of increasingly resistant strains, they said, preventive measures should not be limited to those countries.

The study was funded by the Bill & Melinda Gates Foundation. Dr. Da Silva, Dr. Andrews, and Dr. Bajrovic have disclosed no relevant financial relationships.

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

Bacteria that cause typhoid fever are becoming increasingly resistant to common antibiotics worldwide, a new analysis indicates.

Resistant strains of Salmonella enterica serovar typhi – almost all originating in South Asia – have spread across borders nearly 200 times since 1990.

Until now, analysis has been limited by small samples. This genome analysis is the largest to date and included 3,489 newly sequenced isolates (collected between 2014 and 2019) from prospective surveillance studies in four of the countries with the highest typhoid burden: Bangladesh, Nepal, Pakistan, and India.

Findings of the study, led by Kesia Esther da Silva, PhD, with the division of infectious diseases and geographic medicine at Stanford (Calif.) University, were published online in The Lancet Microbe.
 

Global deaths: 100,000 annually

Typhoid fever remains a global public health threat, causing 11 million infections and more than 100,000 deaths each year. Most cases (70%) are in South Asia, but typhoid also has significant presence in sub-Saharan Africa, Southeast Asia, and Oceania.

The findings are further evidence of the need for a global response, the authors write.

Jason Andrews, MD, a coauthor and associate professor in the division of infectious diseases and geographic medicine at Stanford University, said in an interview that the research helps pinpoint where the highest burden is and where the biggest need is for the two highly effective typhoid vaccines.

“We’re seeing higher levels of resistance than we’ve ever seen before against our latest and greatest antibiotics,” he said.

He said so far, strategies for tackling typhoid have involved country-level decisions and local funding and that needs to be shifted to a global priority. “Given contemporary travel migration patterns, what we see is that when antimicrobial resistance develops in one country, it quickly spreads to other countries.”

Dr. Andrews said the United States sees about 300-500 typhoid cases a year. “About 80% of those cases involve people traveling from South Asia,” he said.

Infections also come from people from the United States visiting high-burden countries, especially to see family. Often they don’t perceive the risk and skip vaccination, he said. U.S. clinicians can help with educating patients traveling to typhoid-endemic regions on pretravel vaccination.

Physician awareness is also important when patients have recently returned from such regions. Data from this study show a need to carefully consider which antibiotics will be effective with the growing resistance.
 

Only one oral option left in Pakistan

“We are running low on treatment options for typhoid,” Dr. Andrews said. The resistance pattern in Pakistan, for example, has left only one oral option, azithromycin, and resistance is building to that.

Without that option, “we’ll have to hospitalize patients and give intravenous antibiotics,” he said. “That’s concerning.”

Moreover, some resistant strains from Pakistan have been turning up in the United States.

“There are actually some cases that have not been tracked at all to travelers going to Pakistan and are thought to be from local transmission in the United States,” he said.

Valida Bajrovic, MD, assistant professor of medicine in infectious diseases at the Icahn School of Medicine at Mount Sinai, New York, said in an interview that, in addition to vaccinating travelers before they head to typhoid-endemic areas, physicians should educate patients on avoiding fecal transmission of typhoid with vigilant hand washing, drinking bottled water, and avoiding foods that may have been prepared in unsanitary conditions.

Dr. Bajrovic, who directs the antimicrobial stewardship efforts at the Mount Sinai Morningside and Mount Sinai West Hospitals, said stricter antimicrobial stewardship efforts are needed, particularly in Europe and South Asia, but also in the United States.

“Restriction of antibiotic use is the way to prevent antibiotic resistance,” she said, adding that such restrictions need to be part of a global effort.

Strains in the study were classified as multidrug resistant (MDR) if they contained genes resistant to ampicillin, chloramphenicol, and trimethoprim/sulfamethoxazole. The authors also traced the presence of genes demonstrating resistance to macrolides and quinolones.

At first, fluoroquinolones were effective against MDR S. typhi and in the 1990s became the primary therapy. By the 2010s, however, the majority of S. typhi in south Asia contained mutations in the quinolone resistance-determining regions.

The authors wrote: “We found evidence of frequent international (n = 138) and intercontinental transfers (n = 59) of antimicrobial-resistant S. typhi.”

According to the analysis, since 2000, MDR S. typhi has declined steadily in Bangladesh and India and remained at less than 5% of typhoid strains in Nepal, though it has increased slightly in Pakistan.

However, these are being replaced “with strains containing ceftriaxone resistance (extensively drug resistant), high-level fluoroquinolone resistance, or azithromycin resistance, which are reversing declines in the effective population size of S. typhi,” the authors wrote.

The analysis supports urgency for prevention measures, including use of typhoid conjugate vaccines in typhoid-endemic countries, the authors said.

But given the rise in international spread of increasingly resistant strains, they said, preventive measures should not be limited to those countries.

The study was funded by the Bill & Melinda Gates Foundation. Dr. Da Silva, Dr. Andrews, and Dr. Bajrovic have disclosed no relevant financial relationships.

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

It took Michael Golden, MD, 5 years to decide to switch to a concierge practice, in which patients pay a monthly or annual fee for more personalized care. Dr. Golden, an internist in Beverly, Mass., changed course in 2021, during the COVID-19 pandemic.

“I’m not sure why I hesitated for so long,” said Dr. Golden.

Once they take the plunge into concierge practice or direct primary care (DPC) – a related form of retainer-based practice – many doctors are delighted with the change. But taking the plunge is a big step that they sometimes put off for years.

“The main factors for waiting are fear, uncertainty, and doubt,” said Leigh “Jack” Forbush, DO, a family physician who runs a DPC practice in Hampden, Maine, and mentors doctors contemplating the switch.

According to Dr. Forbush, the critical questions doctors ask themselves are, “Will I be able to find enough paying patients?” and – in the case of DPC practices, which cancel insurance – “Can I live without the money I get from insurers?”

Terry Bauer, CEO of Specialdocs Consultants in Highland Park, Ill., which helps doctors move to a concierge practice, said many of his clients put off the decision for as long as 15 years.

“Clients became progressively worn out – or even burnt out – by the demands of fee-for-service medicine,” said Dr. Bauer. “For women, the tipping point can be when their kids ask, ‘Mom, do you like your job better than me?’ For men, it may be more about feeling tired and unsatisfied with their work.”

But once these doctors make the switch, it’s with all their heart. “A client recently told me that if he couldn’t open a concierge practice, he might have to quit medicine,” Dr. Bauer said. “And he’s only 51.”
 

Few doctors regret switching

A 2020 survey of DPC physicians for the Society of Actuaries found that 99% reported having better or much better overall personal and professional satisfaction.

Retainer-based physicians report feeling much more relaxed after they start a concierge practice. On many workdays, Dr. Golden takes a walk on a trail in the woods behind his office. “That’s something I couldn’t do before,” he said. “And I go to my kids’ soccer games. I’m able to be present in their lives now.”

Since retainer-based doctors have markedly fewer patients, they can form personal relationships with each one. When Dr. Golden switched, he “went from having a couple of thousand patients to a few hundred,” he said.

“I know each patient now,” said Dorothy Cohen Serna, MD, an internist in Cypress, Tex., who moved to concierge in 2017. “I don’t need to look at their chart to know who they are.”

Dr. Serna said patients’ close relationship with her helped them get through the worst months of the pandemic. “They were scared, depressed, and concerned, and they needed a lot of individual attention,” she said.

Because they see fewer patients, concierge doctors can lengthen appointment times to about 30 minutes – or longer, if necessary. They no longer have a problem answering patients’ “doorknob questions” – wholly new concerns brought up at the end of the visit.

“The appointment might be for a sprained ankle, and then the patient might mention they haven’t been sleeping well,” Dr. Golden said. “I have time to talk about that without worrying that my schedule is getting backed up.”
 

Why patients sign up

Retainer-based practices are still an exotic concept in many areas, but patients are beginning to understand the value, said Shalini Kaneriya, MD, an internist in Herndon, Va,, who switched her practice to concierge in 2018.

Several hundred patients followed her into her new practice because “people realized their care would be better if they had a concierge doctor,” she said. Two years ago, partly because of growing demand, she recruited another physician as an associate.

“People want a relationship with their doctor,” Dr. Serna added. “It’s hard to provide that in a regular practice.”

Todd Granger, MD, an internist who opened a DPC practice in Chapel Hill, N.C., in 2016, said new patients often mention feeling rushed through appointments with their previous doctors. Also, “it’s hard to get to see a doctor around here.”

Scott Bernstein, MD, an internist who runs a DPC practice in Scottsdale, Ariz., said he can arrange to have patients see specialists much faster than if they try to make appointments on their own. “I personally call specialists and then prep my patients on how to deal with the appointment,” he said.

Retainer-based practices tend to have a greater number of older and chronically ill patients, but they also attract patients who need less care. “The healthier patients find value in our proactive approach to prevention and wellness,” Dr. Serna said.

Some concierge physicians charge higher fees to patients who need more care, but many decide this is too complicated and charge everyone the same fee. Dr. Granger said he initially had a variable fee schedule, but when some lower-paying patients began to need more visits, he had to consider charging them extra. “Now I basically have just one fee,” he said.
 

Not a good fit for many physicians

Dr. Bauer said a lot of physicians are interested in retainer-based practice, but many of them might not make the income they had hoped for. Specialdocs interviews physicians who inquire about the model and ultimately doesn’t contract with 80% of them, Dr. Bauer said.

To be able to sign up and retain enough patients, the doctor’s attitude is important. “You have to be driven by the desire to go deep with patients -- to work hard with them and deal with their issues,” said Erika Bliss, MD, who runs a DPC practice in Seattle.

Dr. Bernstein said retainer-based physicians have to be interested in lifestyle issues, such as diet, exercise, and sleep. “I spend a lot of time dealing with issues like how to incorporate physical activity into daily routines,” he said. “Some doctors wouldn’t enjoy doing that.”

Also, concierge physicians have to be available all the time. “Patients have my cell phone number,” Dr. Granger said. “They could call in the middle of the night, but they usually don’t.”

To ensure that they get some time off, many concierge physicians have partners. Dr. Bernstein and another DPC doctor maintain separate practices but cover for each other. Each takes every other weekend off plus 6 weeks every year.
 

Can you attract enough patients?

A key challenge is finding enough patients to sustain a concierge practice. Planning the switch involves setting a target number of patients needed for the doctor to make a decent income after paying practice expenses. For example, a doctor charging $300 a month to 250 patients would gross $900,000 per year, and then pay practice expenses from that.

Attracting the target number of patients can take months or even years. After almost 6 years, Dr. Granger said, he has around 240 patients ― well below his target number of 440.

Partly because the practice model is not well known in North Carolina, Dr. Granger set his fee very low, at $60 a month, then raised it to $75. That means his practice has been grossing just $216,000 a year. But he is not about to give up. He plans to raise his fee in July and hopes that word of mouth will add more patients.

If physicians cannot earn enough in their concierge practice, Dr. Bauer said, they may moonlight at a local hospital or work for a telemedicine company. He hasn’t heard of physicians closing their concierge practice and returning to their previous practice model. “They didn’t like what they were doing before,” he said.
 

Opening up to lower-income patients

Dr. Granger’s $75 monthly fee is an example of how retainer-based medicine has transformed itself from a gold-plated service for rich people to a service that middle-class and even lower-income people can afford. DPC practices like Dr. Granger’s have dramatically lowered expenses by cutting out the need to bill insurance companies. Some DPC practices further reduce expenses by not having any staff and by renting out office space.

Dr. Forbush’s Pine Tree State patients are mostly blue-collar workers – electricians, plumbers, people who work in small businesses. He charges them $150 a month, which most patients who don’t have health insurance can afford. He said three-quarters of his patients lack health insurance, although some have back-up finances, such as health savings accounts.

Since his patients have to pay out of pocket for tests and specialists, Dr. Forbush keeps referrals in check by handling many problems himself. “Since I have more time to spend with the patient, I can often work out issues that other doctors might ask specialists to deal with,” he said.

He has learned some dermatologic procedures. “There are plenty of things I can handle on my own,” he said.

Dr. Granger adds that by examining patients during longer appointments, expensive diagnostic exams are not always necessary.
 

The challenges for this model

Many experts warn that retainer-based practices won’t work for doctors who want to leave employment or for doctors fresh out of residency. Not having your own patients to bring into the new practice is a big minus, because this is the best way to start the new practice.

Still, there are other ways to find patients. Dr. Bauer said physicians can advertise online, make themselves known by giving speeches in the community, or contract with small employers to treat their workers.

Dr. Bauer said some of his clients were employed physicians, and he thinks they will become a bigger factor now that fewer doctors remain in private practice. The chief barrier for employed physicians is the restrictive covenant that prevents them from setting up a practice nearby. But Dr. Bauer said some employers are willing to waive restrictive covenants for retainer-based doctors.

New physicians are also adopting the concierge model. Dr. Forbush said physicians straight out of residency have set up DPC practices in Maine. They signed up patients for their new practices even before they graduated, he said.

Retainer-based medicine is still mainly limited to primary care physicians, but according to Dr. Bauer, it can also work for specialists who have long-term relationships with patients, such as cardiologists, ob.gyns., rheumatologists, neurologists, and endocrinologists.
 

No going back

Most doctors who make the switch to retainer-based practice understand that there’s likely no going back. When Dr. Bernstein switched, he announced the change to patients and canceled insurance contracts. “It was make or break,” he said. “I had no parachute.”

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

It took Michael Golden, MD, 5 years to decide to switch to a concierge practice, in which patients pay a monthly or annual fee for more personalized care. Dr. Golden, an internist in Beverly, Mass., changed course in 2021, during the COVID-19 pandemic.

“I’m not sure why I hesitated for so long,” said Dr. Golden.

Once they take the plunge into concierge practice or direct primary care (DPC) – a related form of retainer-based practice – many doctors are delighted with the change. But taking the plunge is a big step that they sometimes put off for years.

“The main factors for waiting are fear, uncertainty, and doubt,” said Leigh “Jack” Forbush, DO, a family physician who runs a DPC practice in Hampden, Maine, and mentors doctors contemplating the switch.

According to Dr. Forbush, the critical questions doctors ask themselves are, “Will I be able to find enough paying patients?” and – in the case of DPC practices, which cancel insurance – “Can I live without the money I get from insurers?”

Terry Bauer, CEO of Specialdocs Consultants in Highland Park, Ill., which helps doctors move to a concierge practice, said many of his clients put off the decision for as long as 15 years.

“Clients became progressively worn out – or even burnt out – by the demands of fee-for-service medicine,” said Dr. Bauer. “For women, the tipping point can be when their kids ask, ‘Mom, do you like your job better than me?’ For men, it may be more about feeling tired and unsatisfied with their work.”

But once these doctors make the switch, it’s with all their heart. “A client recently told me that if he couldn’t open a concierge practice, he might have to quit medicine,” Dr. Bauer said. “And he’s only 51.”
 

Few doctors regret switching

A 2020 survey of DPC physicians for the Society of Actuaries found that 99% reported having better or much better overall personal and professional satisfaction.

Retainer-based physicians report feeling much more relaxed after they start a concierge practice. On many workdays, Dr. Golden takes a walk on a trail in the woods behind his office. “That’s something I couldn’t do before,” he said. “And I go to my kids’ soccer games. I’m able to be present in their lives now.”

Since retainer-based doctors have markedly fewer patients, they can form personal relationships with each one. When Dr. Golden switched, he “went from having a couple of thousand patients to a few hundred,” he said.

“I know each patient now,” said Dorothy Cohen Serna, MD, an internist in Cypress, Tex., who moved to concierge in 2017. “I don’t need to look at their chart to know who they are.”

Dr. Serna said patients’ close relationship with her helped them get through the worst months of the pandemic. “They were scared, depressed, and concerned, and they needed a lot of individual attention,” she said.

Because they see fewer patients, concierge doctors can lengthen appointment times to about 30 minutes – or longer, if necessary. They no longer have a problem answering patients’ “doorknob questions” – wholly new concerns brought up at the end of the visit.

“The appointment might be for a sprained ankle, and then the patient might mention they haven’t been sleeping well,” Dr. Golden said. “I have time to talk about that without worrying that my schedule is getting backed up.”
 

Why patients sign up

Retainer-based practices are still an exotic concept in many areas, but patients are beginning to understand the value, said Shalini Kaneriya, MD, an internist in Herndon, Va,, who switched her practice to concierge in 2018.

Several hundred patients followed her into her new practice because “people realized their care would be better if they had a concierge doctor,” she said. Two years ago, partly because of growing demand, she recruited another physician as an associate.

“People want a relationship with their doctor,” Dr. Serna added. “It’s hard to provide that in a regular practice.”

Todd Granger, MD, an internist who opened a DPC practice in Chapel Hill, N.C., in 2016, said new patients often mention feeling rushed through appointments with their previous doctors. Also, “it’s hard to get to see a doctor around here.”

Scott Bernstein, MD, an internist who runs a DPC practice in Scottsdale, Ariz., said he can arrange to have patients see specialists much faster than if they try to make appointments on their own. “I personally call specialists and then prep my patients on how to deal with the appointment,” he said.

Retainer-based practices tend to have a greater number of older and chronically ill patients, but they also attract patients who need less care. “The healthier patients find value in our proactive approach to prevention and wellness,” Dr. Serna said.

Some concierge physicians charge higher fees to patients who need more care, but many decide this is too complicated and charge everyone the same fee. Dr. Granger said he initially had a variable fee schedule, but when some lower-paying patients began to need more visits, he had to consider charging them extra. “Now I basically have just one fee,” he said.
 

Not a good fit for many physicians

Dr. Bauer said a lot of physicians are interested in retainer-based practice, but many of them might not make the income they had hoped for. Specialdocs interviews physicians who inquire about the model and ultimately doesn’t contract with 80% of them, Dr. Bauer said.

To be able to sign up and retain enough patients, the doctor’s attitude is important. “You have to be driven by the desire to go deep with patients -- to work hard with them and deal with their issues,” said Erika Bliss, MD, who runs a DPC practice in Seattle.

Dr. Bernstein said retainer-based physicians have to be interested in lifestyle issues, such as diet, exercise, and sleep. “I spend a lot of time dealing with issues like how to incorporate physical activity into daily routines,” he said. “Some doctors wouldn’t enjoy doing that.”

Also, concierge physicians have to be available all the time. “Patients have my cell phone number,” Dr. Granger said. “They could call in the middle of the night, but they usually don’t.”

To ensure that they get some time off, many concierge physicians have partners. Dr. Bernstein and another DPC doctor maintain separate practices but cover for each other. Each takes every other weekend off plus 6 weeks every year.
 

Can you attract enough patients?

A key challenge is finding enough patients to sustain a concierge practice. Planning the switch involves setting a target number of patients needed for the doctor to make a decent income after paying practice expenses. For example, a doctor charging $300 a month to 250 patients would gross $900,000 per year, and then pay practice expenses from that.

Attracting the target number of patients can take months or even years. After almost 6 years, Dr. Granger said, he has around 240 patients ― well below his target number of 440.

Partly because the practice model is not well known in North Carolina, Dr. Granger set his fee very low, at $60 a month, then raised it to $75. That means his practice has been grossing just $216,000 a year. But he is not about to give up. He plans to raise his fee in July and hopes that word of mouth will add more patients.

If physicians cannot earn enough in their concierge practice, Dr. Bauer said, they may moonlight at a local hospital or work for a telemedicine company. He hasn’t heard of physicians closing their concierge practice and returning to their previous practice model. “They didn’t like what they were doing before,” he said.
 

Opening up to lower-income patients

Dr. Granger’s $75 monthly fee is an example of how retainer-based medicine has transformed itself from a gold-plated service for rich people to a service that middle-class and even lower-income people can afford. DPC practices like Dr. Granger’s have dramatically lowered expenses by cutting out the need to bill insurance companies. Some DPC practices further reduce expenses by not having any staff and by renting out office space.

Dr. Forbush’s Pine Tree State patients are mostly blue-collar workers – electricians, plumbers, people who work in small businesses. He charges them $150 a month, which most patients who don’t have health insurance can afford. He said three-quarters of his patients lack health insurance, although some have back-up finances, such as health savings accounts.

Since his patients have to pay out of pocket for tests and specialists, Dr. Forbush keeps referrals in check by handling many problems himself. “Since I have more time to spend with the patient, I can often work out issues that other doctors might ask specialists to deal with,” he said.

He has learned some dermatologic procedures. “There are plenty of things I can handle on my own,” he said.

Dr. Granger adds that by examining patients during longer appointments, expensive diagnostic exams are not always necessary.
 

The challenges for this model

Many experts warn that retainer-based practices won’t work for doctors who want to leave employment or for doctors fresh out of residency. Not having your own patients to bring into the new practice is a big minus, because this is the best way to start the new practice.

Still, there are other ways to find patients. Dr. Bauer said physicians can advertise online, make themselves known by giving speeches in the community, or contract with small employers to treat their workers.

Dr. Bauer said some of his clients were employed physicians, and he thinks they will become a bigger factor now that fewer doctors remain in private practice. The chief barrier for employed physicians is the restrictive covenant that prevents them from setting up a practice nearby. But Dr. Bauer said some employers are willing to waive restrictive covenants for retainer-based doctors.

New physicians are also adopting the concierge model. Dr. Forbush said physicians straight out of residency have set up DPC practices in Maine. They signed up patients for their new practices even before they graduated, he said.

Retainer-based medicine is still mainly limited to primary care physicians, but according to Dr. Bauer, it can also work for specialists who have long-term relationships with patients, such as cardiologists, ob.gyns., rheumatologists, neurologists, and endocrinologists.
 

No going back

Most doctors who make the switch to retainer-based practice understand that there’s likely no going back. When Dr. Bernstein switched, he announced the change to patients and canceled insurance contracts. “It was make or break,” he said. “I had no parachute.”

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

It took Michael Golden, MD, 5 years to decide to switch to a concierge practice, in which patients pay a monthly or annual fee for more personalized care. Dr. Golden, an internist in Beverly, Mass., changed course in 2021, during the COVID-19 pandemic.

“I’m not sure why I hesitated for so long,” said Dr. Golden.

Once they take the plunge into concierge practice or direct primary care (DPC) – a related form of retainer-based practice – many doctors are delighted with the change. But taking the plunge is a big step that they sometimes put off for years.

“The main factors for waiting are fear, uncertainty, and doubt,” said Leigh “Jack” Forbush, DO, a family physician who runs a DPC practice in Hampden, Maine, and mentors doctors contemplating the switch.

According to Dr. Forbush, the critical questions doctors ask themselves are, “Will I be able to find enough paying patients?” and – in the case of DPC practices, which cancel insurance – “Can I live without the money I get from insurers?”

Terry Bauer, CEO of Specialdocs Consultants in Highland Park, Ill., which helps doctors move to a concierge practice, said many of his clients put off the decision for as long as 15 years.

“Clients became progressively worn out – or even burnt out – by the demands of fee-for-service medicine,” said Dr. Bauer. “For women, the tipping point can be when their kids ask, ‘Mom, do you like your job better than me?’ For men, it may be more about feeling tired and unsatisfied with their work.”

But once these doctors make the switch, it’s with all their heart. “A client recently told me that if he couldn’t open a concierge practice, he might have to quit medicine,” Dr. Bauer said. “And he’s only 51.”
 

Few doctors regret switching

A 2020 survey of DPC physicians for the Society of Actuaries found that 99% reported having better or much better overall personal and professional satisfaction.

Retainer-based physicians report feeling much more relaxed after they start a concierge practice. On many workdays, Dr. Golden takes a walk on a trail in the woods behind his office. “That’s something I couldn’t do before,” he said. “And I go to my kids’ soccer games. I’m able to be present in their lives now.”

Since retainer-based doctors have markedly fewer patients, they can form personal relationships with each one. When Dr. Golden switched, he “went from having a couple of thousand patients to a few hundred,” he said.

“I know each patient now,” said Dorothy Cohen Serna, MD, an internist in Cypress, Tex., who moved to concierge in 2017. “I don’t need to look at their chart to know who they are.”

Dr. Serna said patients’ close relationship with her helped them get through the worst months of the pandemic. “They were scared, depressed, and concerned, and they needed a lot of individual attention,” she said.

Because they see fewer patients, concierge doctors can lengthen appointment times to about 30 minutes – or longer, if necessary. They no longer have a problem answering patients’ “doorknob questions” – wholly new concerns brought up at the end of the visit.

“The appointment might be for a sprained ankle, and then the patient might mention they haven’t been sleeping well,” Dr. Golden said. “I have time to talk about that without worrying that my schedule is getting backed up.”
 

Why patients sign up

Retainer-based practices are still an exotic concept in many areas, but patients are beginning to understand the value, said Shalini Kaneriya, MD, an internist in Herndon, Va,, who switched her practice to concierge in 2018.

Several hundred patients followed her into her new practice because “people realized their care would be better if they had a concierge doctor,” she said. Two years ago, partly because of growing demand, she recruited another physician as an associate.

“People want a relationship with their doctor,” Dr. Serna added. “It’s hard to provide that in a regular practice.”

Todd Granger, MD, an internist who opened a DPC practice in Chapel Hill, N.C., in 2016, said new patients often mention feeling rushed through appointments with their previous doctors. Also, “it’s hard to get to see a doctor around here.”

Scott Bernstein, MD, an internist who runs a DPC practice in Scottsdale, Ariz., said he can arrange to have patients see specialists much faster than if they try to make appointments on their own. “I personally call specialists and then prep my patients on how to deal with the appointment,” he said.

Retainer-based practices tend to have a greater number of older and chronically ill patients, but they also attract patients who need less care. “The healthier patients find value in our proactive approach to prevention and wellness,” Dr. Serna said.

Some concierge physicians charge higher fees to patients who need more care, but many decide this is too complicated and charge everyone the same fee. Dr. Granger said he initially had a variable fee schedule, but when some lower-paying patients began to need more visits, he had to consider charging them extra. “Now I basically have just one fee,” he said.
 

Not a good fit for many physicians

Dr. Bauer said a lot of physicians are interested in retainer-based practice, but many of them might not make the income they had hoped for. Specialdocs interviews physicians who inquire about the model and ultimately doesn’t contract with 80% of them, Dr. Bauer said.

To be able to sign up and retain enough patients, the doctor’s attitude is important. “You have to be driven by the desire to go deep with patients -- to work hard with them and deal with their issues,” said Erika Bliss, MD, who runs a DPC practice in Seattle.

Dr. Bernstein said retainer-based physicians have to be interested in lifestyle issues, such as diet, exercise, and sleep. “I spend a lot of time dealing with issues like how to incorporate physical activity into daily routines,” he said. “Some doctors wouldn’t enjoy doing that.”

Also, concierge physicians have to be available all the time. “Patients have my cell phone number,” Dr. Granger said. “They could call in the middle of the night, but they usually don’t.”

To ensure that they get some time off, many concierge physicians have partners. Dr. Bernstein and another DPC doctor maintain separate practices but cover for each other. Each takes every other weekend off plus 6 weeks every year.
 

Can you attract enough patients?

A key challenge is finding enough patients to sustain a concierge practice. Planning the switch involves setting a target number of patients needed for the doctor to make a decent income after paying practice expenses. For example, a doctor charging $300 a month to 250 patients would gross $900,000 per year, and then pay practice expenses from that.

Attracting the target number of patients can take months or even years. After almost 6 years, Dr. Granger said, he has around 240 patients ― well below his target number of 440.

Partly because the practice model is not well known in North Carolina, Dr. Granger set his fee very low, at $60 a month, then raised it to $75. That means his practice has been grossing just $216,000 a year. But he is not about to give up. He plans to raise his fee in July and hopes that word of mouth will add more patients.

If physicians cannot earn enough in their concierge practice, Dr. Bauer said, they may moonlight at a local hospital or work for a telemedicine company. He hasn’t heard of physicians closing their concierge practice and returning to their previous practice model. “They didn’t like what they were doing before,” he said.
 

Opening up to lower-income patients

Dr. Granger’s $75 monthly fee is an example of how retainer-based medicine has transformed itself from a gold-plated service for rich people to a service that middle-class and even lower-income people can afford. DPC practices like Dr. Granger’s have dramatically lowered expenses by cutting out the need to bill insurance companies. Some DPC practices further reduce expenses by not having any staff and by renting out office space.

Dr. Forbush’s Pine Tree State patients are mostly blue-collar workers – electricians, plumbers, people who work in small businesses. He charges them $150 a month, which most patients who don’t have health insurance can afford. He said three-quarters of his patients lack health insurance, although some have back-up finances, such as health savings accounts.

Since his patients have to pay out of pocket for tests and specialists, Dr. Forbush keeps referrals in check by handling many problems himself. “Since I have more time to spend with the patient, I can often work out issues that other doctors might ask specialists to deal with,” he said.

He has learned some dermatologic procedures. “There are plenty of things I can handle on my own,” he said.

Dr. Granger adds that by examining patients during longer appointments, expensive diagnostic exams are not always necessary.
 

The challenges for this model

Many experts warn that retainer-based practices won’t work for doctors who want to leave employment or for doctors fresh out of residency. Not having your own patients to bring into the new practice is a big minus, because this is the best way to start the new practice.

Still, there are other ways to find patients. Dr. Bauer said physicians can advertise online, make themselves known by giving speeches in the community, or contract with small employers to treat their workers.

Dr. Bauer said some of his clients were employed physicians, and he thinks they will become a bigger factor now that fewer doctors remain in private practice. The chief barrier for employed physicians is the restrictive covenant that prevents them from setting up a practice nearby. But Dr. Bauer said some employers are willing to waive restrictive covenants for retainer-based doctors.

New physicians are also adopting the concierge model. Dr. Forbush said physicians straight out of residency have set up DPC practices in Maine. They signed up patients for their new practices even before they graduated, he said.

Retainer-based medicine is still mainly limited to primary care physicians, but according to Dr. Bauer, it can also work for specialists who have long-term relationships with patients, such as cardiologists, ob.gyns., rheumatologists, neurologists, and endocrinologists.
 

No going back

Most doctors who make the switch to retainer-based practice understand that there’s likely no going back. When Dr. Bernstein switched, he announced the change to patients and canceled insurance contracts. “It was make or break,” he said. “I had no parachute.”

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