Pediatrics

Arkansas has become the first state to pass a law prohibiting doctors from giving gender-affirming medical treatments to transgender youths, CNN reported.

Gov. Asa Hutchinson had vetoed the bill on April 5, calling it a “product of the cultural war in America.” But on April 6, the state House and Senate voted to override the veto, making it state law, CNN reported.

At least 17 other states are considering similar legislation, but the Arkansas bill was the first to reach the governor’s desk, the Washington Post reported.

The bill bans doctors from prescribing puberty blockers, hormone therapies, or genital-altering surgeries for anybody under 18. Ever referring a youth for such treatment from another doctor is prohibited.

“It is of grave concern to the General Assembly that the medical community is allowing individuals who experience distress at identifying with their biological sex to be subjects of irreversible and drastic nongenital gender reassignment surgery and irreversible, permanently sterilizing genital gender reassignment surgery, despite the lack of studies showing that the benefits of such extreme interventions outweigh the risks,” the text of the bill said.

Gov. Hutchinson, a Republican, had called the measure a “vast government overreach” in announcing his veto.

“The bill is overbroad, extreme, and does not grandfather those young people who are currently under hormone treatment,” Gov. Hutchinson said. “The young people who are currently under a doctor’s care will be without treatment when this law goes into effect. That means they will be looking to the black market or go out of state ... to find the treatment that they want and need. This is not the right path to put them on.”

Many medical groups have come out against this kind of legislation. The American Academy of Child and Adolescent Psychiatry says it “strongly opposes any efforts – legal, legislative, and otherwise – to block access to these recognized interventions.”

Chase Strangio, the deputy director for transgender justice with the American Civil Liberty Union’s LGBTQ & HIV Project, complimented Gov. Hutchinson for his veto. On April 6, he said the ACLU is preparing to challenge the bill in court, CNN said.

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

Arkansas has become the first state to pass a law prohibiting doctors from giving gender-affirming medical treatments to transgender youths, CNN reported.

Gov. Asa Hutchinson had vetoed the bill on April 5, calling it a “product of the cultural war in America.” But on April 6, the state House and Senate voted to override the veto, making it state law, CNN reported.

At least 17 other states are considering similar legislation, but the Arkansas bill was the first to reach the governor’s desk, the Washington Post reported.

The bill bans doctors from prescribing puberty blockers, hormone therapies, or genital-altering surgeries for anybody under 18. Ever referring a youth for such treatment from another doctor is prohibited.

“It is of grave concern to the General Assembly that the medical community is allowing individuals who experience distress at identifying with their biological sex to be subjects of irreversible and drastic nongenital gender reassignment surgery and irreversible, permanently sterilizing genital gender reassignment surgery, despite the lack of studies showing that the benefits of such extreme interventions outweigh the risks,” the text of the bill said.

Gov. Hutchinson, a Republican, had called the measure a “vast government overreach” in announcing his veto.

“The bill is overbroad, extreme, and does not grandfather those young people who are currently under hormone treatment,” Gov. Hutchinson said. “The young people who are currently under a doctor’s care will be without treatment when this law goes into effect. That means they will be looking to the black market or go out of state ... to find the treatment that they want and need. This is not the right path to put them on.”

Many medical groups have come out against this kind of legislation. The American Academy of Child and Adolescent Psychiatry says it “strongly opposes any efforts – legal, legislative, and otherwise – to block access to these recognized interventions.”

Chase Strangio, the deputy director for transgender justice with the American Civil Liberty Union’s LGBTQ & HIV Project, complimented Gov. Hutchinson for his veto. On April 6, he said the ACLU is preparing to challenge the bill in court, CNN said.

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

Arkansas has become the first state to pass a law prohibiting doctors from giving gender-affirming medical treatments to transgender youths, CNN reported.

Gov. Asa Hutchinson had vetoed the bill on April 5, calling it a “product of the cultural war in America.” But on April 6, the state House and Senate voted to override the veto, making it state law, CNN reported.

At least 17 other states are considering similar legislation, but the Arkansas bill was the first to reach the governor’s desk, the Washington Post reported.

The bill bans doctors from prescribing puberty blockers, hormone therapies, or genital-altering surgeries for anybody under 18. Ever referring a youth for such treatment from another doctor is prohibited.

“It is of grave concern to the General Assembly that the medical community is allowing individuals who experience distress at identifying with their biological sex to be subjects of irreversible and drastic nongenital gender reassignment surgery and irreversible, permanently sterilizing genital gender reassignment surgery, despite the lack of studies showing that the benefits of such extreme interventions outweigh the risks,” the text of the bill said.

Gov. Hutchinson, a Republican, had called the measure a “vast government overreach” in announcing his veto.

“The bill is overbroad, extreme, and does not grandfather those young people who are currently under hormone treatment,” Gov. Hutchinson said. “The young people who are currently under a doctor’s care will be without treatment when this law goes into effect. That means they will be looking to the black market or go out of state ... to find the treatment that they want and need. This is not the right path to put them on.”

Many medical groups have come out against this kind of legislation. The American Academy of Child and Adolescent Psychiatry says it “strongly opposes any efforts – legal, legislative, and otherwise – to block access to these recognized interventions.”

Chase Strangio, the deputy director for transgender justice with the American Civil Liberty Union’s LGBTQ & HIV Project, complimented Gov. Hutchinson for his veto. On April 6, he said the ACLU is preparing to challenge the bill in court, CNN said.

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

The use of telehealth may have skyrocketed during the COVID-19 pandemic, but it also exposed a digital divide, speaker after speaker said during a panel discussion at the Society for Pediatric Dermatology (SPD) pre-AAD meeting.

“We have seen large numbers of children struggle with access to school and access to health care because of lack of access to devices, challenges of broadband Internet access, culture, language, and educational barriers – just having trouble being comfortable with this technology,” said Natalie Pageler, MD, a pediatric intensivist and chief medical information officer at Stanford Children’s Health, Palo Alto, Calif.

“There are also privacy concerns, especially in situations where there are multiple families within a household. Finally, it’s important to remember that policy and reimbursement issues may have a significant effect on some of the socioeconomic barriers,” she added. “For example, many of our families who don’t have access to audio and video may be able to do a telephone call, but it’s important that telephone calls be considered a form of telehealth and be reimbursed to help increase the access to health care by these families. It also makes it easier to facilitate coordination of care. All of this leads to decreased time and costs for patients, families, and providers.”

Within the first few weeks of the pandemic, Dr. Pageler and colleagues at Stanford Children’s Health observed an increase from about 20 telehealth visits per day to more than 700 per day, which has held stable. While the benefits of telehealth are clear, many perceived barriers exist. In a study conducted prior to the COVID-19 pandemic, researchers identified a wide variety of barriers to implementation of telehealth, led by reimbursement, followed by poor business model sustainability, lack of provider time, and provider interest.

“Some of the barriers, like patient preferences for inpatient care, lack of provider interest in telehealth, and lack of provider time were easily overcome during the COVID pandemic,” Dr. Pageler said. “We dedicated the time to train immediately, because the need was so great.”

In 2018, Patrick McMahon, MD, and colleagues at Children’s Hospital of Philadelphia, launched a teledermatology program that provided direct-to-patient “E-visits” and recently pivoted to using this service only for acne patients through a program called “Acne Express.” The out-of-pocket cost to patients is $50 per consult and nearly 1,500 cases have been completed since 2018, which has saved patients and their parents an estimated 65,000 miles driving to the clinic.

To optimize the teledermatology experience, he suggested four pillars: educate, optimize, reach out, and tailor. “I think we need to draw upon some of the digital education we already have, including a handout for patients [on the SPD website] that offers tips on taking a clear photograph on their smartphones,” he said. “We’re also trying to use some of the cases and learnings from our teledermatology experiences to teach the providers. We are setting up CME modules that are sort of a flashcard-based teaching mechanism.”

To optimize teledermatology experiences, he continued, tracking demographics, diagnoses, number of cases, and turnaround time is helpful. “We can then track who’s coming in to see us at follow-up after a new visit through telehealth,” Dr. McMahon said. “This helps us repurpose things, pivot as needed, and find any glitches. Surveying the families is also critical. Finally, we need clinical support to tee-up visits and to ensure photos are submitted and efficient, and to match diagnoses and family preference with the right modality.”

Another panelist, Justin M. Ko, MD, MBA, who chairs the American Academy of Dermatology’s Task Force on Augmented Intelligence, said that digitally enabled and artificial intelligence (AI)-augmented care delivery offers a “unique opportunity” for increasing access and increasing the value of care delivered to patients.

“The role that we play as clinicians is central, and I think we can make significant strides by doing two things,” said Dr. Ko, chief of medical dermatology for Stanford (Calif.) Health Care. “One: extending the reach of our expertise, and the second: scaling the impact of the care we deliver by clinician-driven, patient-centered, digitally-enabled, AI-augmented care delivery innovation. This opportunity for digital care transformation is more than just a transition from in-person visits to video visits. We have to look at this as an opportunity to leverage the unique aspects of digital capabilities and fundamentally reimagine how we deliver care.”

The AAD’s Position Statement on Augmented Intelligence was published in 2019.

Between March and June of 2021, Neil S. Prose, MD, conducted about 300 televisits with patients. “I had a few spectacular visits where, for example, a teenage patient who had been challenging showed me all of her artwork and we became instantly more connected,” said Dr. Prose, professor of dermatology, pediatrics, and global health at Duke University, Durham, N.C. “Then there’s the potential for a long-term improvement in health care for some patients.”

[email protected]

The use of telehealth may have skyrocketed during the COVID-19 pandemic, but it also exposed a digital divide, speaker after speaker said during a panel discussion at the Society for Pediatric Dermatology (SPD) pre-AAD meeting.

“We have seen large numbers of children struggle with access to school and access to health care because of lack of access to devices, challenges of broadband Internet access, culture, language, and educational barriers – just having trouble being comfortable with this technology,” said Natalie Pageler, MD, a pediatric intensivist and chief medical information officer at Stanford Children’s Health, Palo Alto, Calif.

“There are also privacy concerns, especially in situations where there are multiple families within a household. Finally, it’s important to remember that policy and reimbursement issues may have a significant effect on some of the socioeconomic barriers,” she added. “For example, many of our families who don’t have access to audio and video may be able to do a telephone call, but it’s important that telephone calls be considered a form of telehealth and be reimbursed to help increase the access to health care by these families. It also makes it easier to facilitate coordination of care. All of this leads to decreased time and costs for patients, families, and providers.”

Within the first few weeks of the pandemic, Dr. Pageler and colleagues at Stanford Children’s Health observed an increase from about 20 telehealth visits per day to more than 700 per day, which has held stable. While the benefits of telehealth are clear, many perceived barriers exist. In a study conducted prior to the COVID-19 pandemic, researchers identified a wide variety of barriers to implementation of telehealth, led by reimbursement, followed by poor business model sustainability, lack of provider time, and provider interest.

“Some of the barriers, like patient preferences for inpatient care, lack of provider interest in telehealth, and lack of provider time were easily overcome during the COVID pandemic,” Dr. Pageler said. “We dedicated the time to train immediately, because the need was so great.”

In 2018, Patrick McMahon, MD, and colleagues at Children’s Hospital of Philadelphia, launched a teledermatology program that provided direct-to-patient “E-visits” and recently pivoted to using this service only for acne patients through a program called “Acne Express.” The out-of-pocket cost to patients is $50 per consult and nearly 1,500 cases have been completed since 2018, which has saved patients and their parents an estimated 65,000 miles driving to the clinic.

To optimize the teledermatology experience, he suggested four pillars: educate, optimize, reach out, and tailor. “I think we need to draw upon some of the digital education we already have, including a handout for patients [on the SPD website] that offers tips on taking a clear photograph on their smartphones,” he said. “We’re also trying to use some of the cases and learnings from our teledermatology experiences to teach the providers. We are setting up CME modules that are sort of a flashcard-based teaching mechanism.”

To optimize teledermatology experiences, he continued, tracking demographics, diagnoses, number of cases, and turnaround time is helpful. “We can then track who’s coming in to see us at follow-up after a new visit through telehealth,” Dr. McMahon said. “This helps us repurpose things, pivot as needed, and find any glitches. Surveying the families is also critical. Finally, we need clinical support to tee-up visits and to ensure photos are submitted and efficient, and to match diagnoses and family preference with the right modality.”

Another panelist, Justin M. Ko, MD, MBA, who chairs the American Academy of Dermatology’s Task Force on Augmented Intelligence, said that digitally enabled and artificial intelligence (AI)-augmented care delivery offers a “unique opportunity” for increasing access and increasing the value of care delivered to patients.

“The role that we play as clinicians is central, and I think we can make significant strides by doing two things,” said Dr. Ko, chief of medical dermatology for Stanford (Calif.) Health Care. “One: extending the reach of our expertise, and the second: scaling the impact of the care we deliver by clinician-driven, patient-centered, digitally-enabled, AI-augmented care delivery innovation. This opportunity for digital care transformation is more than just a transition from in-person visits to video visits. We have to look at this as an opportunity to leverage the unique aspects of digital capabilities and fundamentally reimagine how we deliver care.”

The AAD’s Position Statement on Augmented Intelligence was published in 2019.

Between March and June of 2021, Neil S. Prose, MD, conducted about 300 televisits with patients. “I had a few spectacular visits where, for example, a teenage patient who had been challenging showed me all of her artwork and we became instantly more connected,” said Dr. Prose, professor of dermatology, pediatrics, and global health at Duke University, Durham, N.C. “Then there’s the potential for a long-term improvement in health care for some patients.”

[email protected]

The use of telehealth may have skyrocketed during the COVID-19 pandemic, but it also exposed a digital divide, speaker after speaker said during a panel discussion at the Society for Pediatric Dermatology (SPD) pre-AAD meeting.

“We have seen large numbers of children struggle with access to school and access to health care because of lack of access to devices, challenges of broadband Internet access, culture, language, and educational barriers – just having trouble being comfortable with this technology,” said Natalie Pageler, MD, a pediatric intensivist and chief medical information officer at Stanford Children’s Health, Palo Alto, Calif.

“There are also privacy concerns, especially in situations where there are multiple families within a household. Finally, it’s important to remember that policy and reimbursement issues may have a significant effect on some of the socioeconomic barriers,” she added. “For example, many of our families who don’t have access to audio and video may be able to do a telephone call, but it’s important that telephone calls be considered a form of telehealth and be reimbursed to help increase the access to health care by these families. It also makes it easier to facilitate coordination of care. All of this leads to decreased time and costs for patients, families, and providers.”

Within the first few weeks of the pandemic, Dr. Pageler and colleagues at Stanford Children’s Health observed an increase from about 20 telehealth visits per day to more than 700 per day, which has held stable. While the benefits of telehealth are clear, many perceived barriers exist. In a study conducted prior to the COVID-19 pandemic, researchers identified a wide variety of barriers to implementation of telehealth, led by reimbursement, followed by poor business model sustainability, lack of provider time, and provider interest.

“Some of the barriers, like patient preferences for inpatient care, lack of provider interest in telehealth, and lack of provider time were easily overcome during the COVID pandemic,” Dr. Pageler said. “We dedicated the time to train immediately, because the need was so great.”

In 2018, Patrick McMahon, MD, and colleagues at Children’s Hospital of Philadelphia, launched a teledermatology program that provided direct-to-patient “E-visits” and recently pivoted to using this service only for acne patients through a program called “Acne Express.” The out-of-pocket cost to patients is $50 per consult and nearly 1,500 cases have been completed since 2018, which has saved patients and their parents an estimated 65,000 miles driving to the clinic.

To optimize the teledermatology experience, he suggested four pillars: educate, optimize, reach out, and tailor. “I think we need to draw upon some of the digital education we already have, including a handout for patients [on the SPD website] that offers tips on taking a clear photograph on their smartphones,” he said. “We’re also trying to use some of the cases and learnings from our teledermatology experiences to teach the providers. We are setting up CME modules that are sort of a flashcard-based teaching mechanism.”

To optimize teledermatology experiences, he continued, tracking demographics, diagnoses, number of cases, and turnaround time is helpful. “We can then track who’s coming in to see us at follow-up after a new visit through telehealth,” Dr. McMahon said. “This helps us repurpose things, pivot as needed, and find any glitches. Surveying the families is also critical. Finally, we need clinical support to tee-up visits and to ensure photos are submitted and efficient, and to match diagnoses and family preference with the right modality.”

Another panelist, Justin M. Ko, MD, MBA, who chairs the American Academy of Dermatology’s Task Force on Augmented Intelligence, said that digitally enabled and artificial intelligence (AI)-augmented care delivery offers a “unique opportunity” for increasing access and increasing the value of care delivered to patients.

“The role that we play as clinicians is central, and I think we can make significant strides by doing two things,” said Dr. Ko, chief of medical dermatology for Stanford (Calif.) Health Care. “One: extending the reach of our expertise, and the second: scaling the impact of the care we deliver by clinician-driven, patient-centered, digitally-enabled, AI-augmented care delivery innovation. This opportunity for digital care transformation is more than just a transition from in-person visits to video visits. We have to look at this as an opportunity to leverage the unique aspects of digital capabilities and fundamentally reimagine how we deliver care.”

The AAD’s Position Statement on Augmented Intelligence was published in 2019.

Between March and June of 2021, Neil S. Prose, MD, conducted about 300 televisits with patients. “I had a few spectacular visits where, for example, a teenage patient who had been challenging showed me all of her artwork and we became instantly more connected,” said Dr. Prose, professor of dermatology, pediatrics, and global health at Duke University, Durham, N.C. “Then there’s the potential for a long-term improvement in health care for some patients.”

[email protected]

There is no question that none of us, not just pediatricians, is doing a very good job of dealing with the obesity problem this nation faces. We can agree that a more active lifestyle that includes spells of vigorous activity is important for weight management. We know that in general overweight people sleep less than do those whose basal metabolic rate is normal. And, of course, we know that a diet high in calorie-dense foods is associated with unhealthy weight gain.

Not surprisingly, overweight individuals are usually struggling with all three of these challenges. They are less active, get too little sleep, and are ingesting a diet that is too calorie dense. In other words, they would benefit from a total lifestyle reboot. But you know as well as I do a change of that magnitude is much easier said than done. Few families can afford nor would they have the appetite for sending their children to a “fat camp” for 6 months with no guarantee of success.

Instead of throwing up our hands in the face of this monumental task or attacking it at close range, maybe we should aim our efforts at the risk associations that will yield the best results for our efforts. A group of researchers at the University of South Australia has just published a study in Pediatrics in which they provide some data that may help us target our interventions with obese and overweight children. The researchers did not investigate diet, but used accelerometers to determine how much time each child spent sleeping and a variety of activity levels. They then determined what effect changes in the child’s allocation of activity had on their adiposity.

The investigators found on a minute-to-minute basis that an increase in a child’s moderate-to-vigorous physical activity (MVPA) was up to six times more effective at influencing adiposity than was a decrease in sedentary time or an increase in sleep duration. For example, 17 minutes of MVPA had the same beneficial effect as 52 minutes more sleep or 56 minutes less sedentary time. Interestingly and somewhat surprisingly, the researchers found that light activity was positively associated with adiposity.

For those of us in primary care, this study from Australia suggests that our time (and the parents’ time) would be best spent figuring out how to include more MVPA in the child’s day and not focus so much on sleep duration and sedentary intervals.

However, before one can make any recommendation one must first have a clear understanding of how the child and his family spend the day. This process can be done in the office by interviewing the family. I have found that this is not as time consuming as one might think and often yields some valuable additional insight into the family’s dynamics. Sending the family home with an hourly log to be filled in or asking them to use a smartphone to record information will also work.

I must admit that at first I found the results of this study ran counter to my intuition. I have always felt that sleep is the linchpin to the solution of a variety of health style related problems. In my construct, more sleep has always been the first and easy answer and decreasing screen time the second. But, it turns out that increasing MVPA may give us the biggest bang for the buck. Which is fine with me.

The problem facing us is how we can be creative in adding that 20 minutes of vigorous activity. In most communities, we have allowed the school system to drop the ball. We can hope that this study will be confirmed or at least widely publicized. It feels like it is time to guarantee that every child gets a robust gym class every school day.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

There is no question that none of us, not just pediatricians, is doing a very good job of dealing with the obesity problem this nation faces. We can agree that a more active lifestyle that includes spells of vigorous activity is important for weight management. We know that in general overweight people sleep less than do those whose basal metabolic rate is normal. And, of course, we know that a diet high in calorie-dense foods is associated with unhealthy weight gain.

Not surprisingly, overweight individuals are usually struggling with all three of these challenges. They are less active, get too little sleep, and are ingesting a diet that is too calorie dense. In other words, they would benefit from a total lifestyle reboot. But you know as well as I do a change of that magnitude is much easier said than done. Few families can afford nor would they have the appetite for sending their children to a “fat camp” for 6 months with no guarantee of success.

Instead of throwing up our hands in the face of this monumental task or attacking it at close range, maybe we should aim our efforts at the risk associations that will yield the best results for our efforts. A group of researchers at the University of South Australia has just published a study in Pediatrics in which they provide some data that may help us target our interventions with obese and overweight children. The researchers did not investigate diet, but used accelerometers to determine how much time each child spent sleeping and a variety of activity levels. They then determined what effect changes in the child’s allocation of activity had on their adiposity.

The investigators found on a minute-to-minute basis that an increase in a child’s moderate-to-vigorous physical activity (MVPA) was up to six times more effective at influencing adiposity than was a decrease in sedentary time or an increase in sleep duration. For example, 17 minutes of MVPA had the same beneficial effect as 52 minutes more sleep or 56 minutes less sedentary time. Interestingly and somewhat surprisingly, the researchers found that light activity was positively associated with adiposity.

For those of us in primary care, this study from Australia suggests that our time (and the parents’ time) would be best spent figuring out how to include more MVPA in the child’s day and not focus so much on sleep duration and sedentary intervals.

However, before one can make any recommendation one must first have a clear understanding of how the child and his family spend the day. This process can be done in the office by interviewing the family. I have found that this is not as time consuming as one might think and often yields some valuable additional insight into the family’s dynamics. Sending the family home with an hourly log to be filled in or asking them to use a smartphone to record information will also work.

I must admit that at first I found the results of this study ran counter to my intuition. I have always felt that sleep is the linchpin to the solution of a variety of health style related problems. In my construct, more sleep has always been the first and easy answer and decreasing screen time the second. But, it turns out that increasing MVPA may give us the biggest bang for the buck. Which is fine with me.

The problem facing us is how we can be creative in adding that 20 minutes of vigorous activity. In most communities, we have allowed the school system to drop the ball. We can hope that this study will be confirmed or at least widely publicized. It feels like it is time to guarantee that every child gets a robust gym class every school day.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

There is no question that none of us, not just pediatricians, is doing a very good job of dealing with the obesity problem this nation faces. We can agree that a more active lifestyle that includes spells of vigorous activity is important for weight management. We know that in general overweight people sleep less than do those whose basal metabolic rate is normal. And, of course, we know that a diet high in calorie-dense foods is associated with unhealthy weight gain.

Not surprisingly, overweight individuals are usually struggling with all three of these challenges. They are less active, get too little sleep, and are ingesting a diet that is too calorie dense. In other words, they would benefit from a total lifestyle reboot. But you know as well as I do a change of that magnitude is much easier said than done. Few families can afford nor would they have the appetite for sending their children to a “fat camp” for 6 months with no guarantee of success.

Instead of throwing up our hands in the face of this monumental task or attacking it at close range, maybe we should aim our efforts at the risk associations that will yield the best results for our efforts. A group of researchers at the University of South Australia has just published a study in Pediatrics in which they provide some data that may help us target our interventions with obese and overweight children. The researchers did not investigate diet, but used accelerometers to determine how much time each child spent sleeping and a variety of activity levels. They then determined what effect changes in the child’s allocation of activity had on their adiposity.

The investigators found on a minute-to-minute basis that an increase in a child’s moderate-to-vigorous physical activity (MVPA) was up to six times more effective at influencing adiposity than was a decrease in sedentary time or an increase in sleep duration. For example, 17 minutes of MVPA had the same beneficial effect as 52 minutes more sleep or 56 minutes less sedentary time. Interestingly and somewhat surprisingly, the researchers found that light activity was positively associated with adiposity.

For those of us in primary care, this study from Australia suggests that our time (and the parents’ time) would be best spent figuring out how to include more MVPA in the child’s day and not focus so much on sleep duration and sedentary intervals.

However, before one can make any recommendation one must first have a clear understanding of how the child and his family spend the day. This process can be done in the office by interviewing the family. I have found that this is not as time consuming as one might think and often yields some valuable additional insight into the family’s dynamics. Sending the family home with an hourly log to be filled in or asking them to use a smartphone to record information will also work.

I must admit that at first I found the results of this study ran counter to my intuition. I have always felt that sleep is the linchpin to the solution of a variety of health style related problems. In my construct, more sleep has always been the first and easy answer and decreasing screen time the second. But, it turns out that increasing MVPA may give us the biggest bang for the buck. Which is fine with me.

The problem facing us is how we can be creative in adding that 20 minutes of vigorous activity. In most communities, we have allowed the school system to drop the ball. We can hope that this study will be confirmed or at least widely publicized. It feels like it is time to guarantee that every child gets a robust gym class every school day.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Approximately 40,000 children in the United States have lost a parent to COVID-19, based on data from a combination of death counts and simulation models.

dtiberio/iStock/Getty Images

The scale of mortality from COVID-19 among adults in the United States merits efforts to monitor how many children have lost a parent as a result of the pandemic, wrote Rachel Kidman, PhD, of Stony Brook (N.Y.) University and colleagues.

In a study published in JAMA Pediatrics, the researchers used kinship networks of White and Black individuals in the United States to estimate parental bereavement. They combined deaths from COVID-19 as of February 2021 and combined them with excess deaths, and estimated future bereavement based on a herd immunity scenario.

Overall, the model suggested that each death from COVID-19 results in potential parental bereavement for 0.78 children aged 0-17 years, representing an increase of 17.5%-20.2% in parental bereavement. The model indicated that, as of February 2021, 37,337 children aged 0-17 years had lost a parent to COVID-19, including 11,366 children age 0-9 years and 31,661 children and teens aged 10-17 years. A total of 20,600 of these children were non-Hispanic White and 7,600 were Black. Black children accounted for 20% of the bereaved children, although they account for approximately 14% of children aged 0-17 years in the United States, the researchers noted.

Including the excess death estimate, which refers to the difference between observed and expected deaths for the remainder of the pandemic, raised the total bereaved children to 43,000. A future mortality scenario using a total of 1,500,000 deaths from COVID-19 based on a natural herd immunity strategy increased the total estimate of bereaved children to 116,922.

The study findings were limited by several factors including the lack of data on nonparental primary caregivers, and the use of demographic models rather than survey or administrative data, the researchers noted.

However, the huge number of children who have experienced the death of a parent because of COVID-19 emphasizes the need for reforms to address health, educational, and economic impacts of this mass bereavement on children and teens, they said.

“Parentally bereaved children will also need targeted support to help with grief, particularly during this period of heightened social isolation,” they emphasized.

Establishment of a national child bereavement cohort could identify children early in the bereavement process to help ensure that they are connected to local supportive care and monitored for health and behavior problems, the researchers said. In addition, such a cohort could be used as a basis for a longitudinal study of the impact of mass parental bereavement during a unique period of social isolation and economic uncertainty, they concluded.
 

Study spotlights gaps in mental health care

The study is an important reminder of how COVID-19 has disrupted children’s lives, said Herschel Lessin, MD, of Children’s Medical Group in Poughkeepsie, N.Y., in an interview. Losing a parent because of COVID-19 is one more tragedy on the list of social and emotional disasters the pandemic has wrought on children, he said.

“There has to be some sort of national response to help children through all of this, not just one item at a time,” Dr. Lessin said. However, the management of children’s mental health in the United States has been subpar for decades, he noted, with few clinicians trained to specialize in treating behavioral and mental health issues in children. Consequently, more general pediatricians will continue to be faced with the mental health issues of bereaved children who desperately need support, he said.

Money remains a key barrier, as it keeps qualified clinicians from entering the field of pediatric mental and behavioral health, and even where there are mental health providers, most do not take insurance and have long waiting lists, Dr. Lessin noted.

General pediatricians were seeing more patients with ADHD, anxiety, and depression before the advent of COVID-19, though most are not trained in managing these conditions, said Dr. Lessin. “Approximately 25%-30% of my visits now are mental health related, and the pandemic will make it geometrically worse,” he said.

The current study, with its dramatic estimates of the number of children who have lost a parent because of COVID-19, may bring attention to the fact that more training and money are needed to support mental health programs for children, he said.

Lead author Dr. Kidman had no financial conflicts to disclose. The study was supported by grants to corresponding author Ashton M. Verdery, PhD, from the National Institute on Aging and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Lessin had no financial conflicts but serves on the Pediatric News editorial advisory board.

SOURCE: Kidman R et al. JAMA Pediatr. .

Approximately 40,000 children in the United States have lost a parent to COVID-19, based on data from a combination of death counts and simulation models.

dtiberio/iStock/Getty Images

The scale of mortality from COVID-19 among adults in the United States merits efforts to monitor how many children have lost a parent as a result of the pandemic, wrote Rachel Kidman, PhD, of Stony Brook (N.Y.) University and colleagues.

In a study published in JAMA Pediatrics, the researchers used kinship networks of White and Black individuals in the United States to estimate parental bereavement. They combined deaths from COVID-19 as of February 2021 and combined them with excess deaths, and estimated future bereavement based on a herd immunity scenario.

Overall, the model suggested that each death from COVID-19 results in potential parental bereavement for 0.78 children aged 0-17 years, representing an increase of 17.5%-20.2% in parental bereavement. The model indicated that, as of February 2021, 37,337 children aged 0-17 years had lost a parent to COVID-19, including 11,366 children age 0-9 years and 31,661 children and teens aged 10-17 years. A total of 20,600 of these children were non-Hispanic White and 7,600 were Black. Black children accounted for 20% of the bereaved children, although they account for approximately 14% of children aged 0-17 years in the United States, the researchers noted.

Including the excess death estimate, which refers to the difference between observed and expected deaths for the remainder of the pandemic, raised the total bereaved children to 43,000. A future mortality scenario using a total of 1,500,000 deaths from COVID-19 based on a natural herd immunity strategy increased the total estimate of bereaved children to 116,922.

The study findings were limited by several factors including the lack of data on nonparental primary caregivers, and the use of demographic models rather than survey or administrative data, the researchers noted.

However, the huge number of children who have experienced the death of a parent because of COVID-19 emphasizes the need for reforms to address health, educational, and economic impacts of this mass bereavement on children and teens, they said.

“Parentally bereaved children will also need targeted support to help with grief, particularly during this period of heightened social isolation,” they emphasized.

Establishment of a national child bereavement cohort could identify children early in the bereavement process to help ensure that they are connected to local supportive care and monitored for health and behavior problems, the researchers said. In addition, such a cohort could be used as a basis for a longitudinal study of the impact of mass parental bereavement during a unique period of social isolation and economic uncertainty, they concluded.
 

Study spotlights gaps in mental health care

The study is an important reminder of how COVID-19 has disrupted children’s lives, said Herschel Lessin, MD, of Children’s Medical Group in Poughkeepsie, N.Y., in an interview. Losing a parent because of COVID-19 is one more tragedy on the list of social and emotional disasters the pandemic has wrought on children, he said.

“There has to be some sort of national response to help children through all of this, not just one item at a time,” Dr. Lessin said. However, the management of children’s mental health in the United States has been subpar for decades, he noted, with few clinicians trained to specialize in treating behavioral and mental health issues in children. Consequently, more general pediatricians will continue to be faced with the mental health issues of bereaved children who desperately need support, he said.

Money remains a key barrier, as it keeps qualified clinicians from entering the field of pediatric mental and behavioral health, and even where there are mental health providers, most do not take insurance and have long waiting lists, Dr. Lessin noted.

General pediatricians were seeing more patients with ADHD, anxiety, and depression before the advent of COVID-19, though most are not trained in managing these conditions, said Dr. Lessin. “Approximately 25%-30% of my visits now are mental health related, and the pandemic will make it geometrically worse,” he said.

The current study, with its dramatic estimates of the number of children who have lost a parent because of COVID-19, may bring attention to the fact that more training and money are needed to support mental health programs for children, he said.

Lead author Dr. Kidman had no financial conflicts to disclose. The study was supported by grants to corresponding author Ashton M. Verdery, PhD, from the National Institute on Aging and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Lessin had no financial conflicts but serves on the Pediatric News editorial advisory board.

SOURCE: Kidman R et al. JAMA Pediatr. .

Approximately 40,000 children in the United States have lost a parent to COVID-19, based on data from a combination of death counts and simulation models.

dtiberio/iStock/Getty Images

The scale of mortality from COVID-19 among adults in the United States merits efforts to monitor how many children have lost a parent as a result of the pandemic, wrote Rachel Kidman, PhD, of Stony Brook (N.Y.) University and colleagues.

In a study published in JAMA Pediatrics, the researchers used kinship networks of White and Black individuals in the United States to estimate parental bereavement. They combined deaths from COVID-19 as of February 2021 and combined them with excess deaths, and estimated future bereavement based on a herd immunity scenario.

Overall, the model suggested that each death from COVID-19 results in potential parental bereavement for 0.78 children aged 0-17 years, representing an increase of 17.5%-20.2% in parental bereavement. The model indicated that, as of February 2021, 37,337 children aged 0-17 years had lost a parent to COVID-19, including 11,366 children age 0-9 years and 31,661 children and teens aged 10-17 years. A total of 20,600 of these children were non-Hispanic White and 7,600 were Black. Black children accounted for 20% of the bereaved children, although they account for approximately 14% of children aged 0-17 years in the United States, the researchers noted.

Including the excess death estimate, which refers to the difference between observed and expected deaths for the remainder of the pandemic, raised the total bereaved children to 43,000. A future mortality scenario using a total of 1,500,000 deaths from COVID-19 based on a natural herd immunity strategy increased the total estimate of bereaved children to 116,922.

The study findings were limited by several factors including the lack of data on nonparental primary caregivers, and the use of demographic models rather than survey or administrative data, the researchers noted.

However, the huge number of children who have experienced the death of a parent because of COVID-19 emphasizes the need for reforms to address health, educational, and economic impacts of this mass bereavement on children and teens, they said.

“Parentally bereaved children will also need targeted support to help with grief, particularly during this period of heightened social isolation,” they emphasized.

Establishment of a national child bereavement cohort could identify children early in the bereavement process to help ensure that they are connected to local supportive care and monitored for health and behavior problems, the researchers said. In addition, such a cohort could be used as a basis for a longitudinal study of the impact of mass parental bereavement during a unique period of social isolation and economic uncertainty, they concluded.
 

Study spotlights gaps in mental health care

The study is an important reminder of how COVID-19 has disrupted children’s lives, said Herschel Lessin, MD, of Children’s Medical Group in Poughkeepsie, N.Y., in an interview. Losing a parent because of COVID-19 is one more tragedy on the list of social and emotional disasters the pandemic has wrought on children, he said.

“There has to be some sort of national response to help children through all of this, not just one item at a time,” Dr. Lessin said. However, the management of children’s mental health in the United States has been subpar for decades, he noted, with few clinicians trained to specialize in treating behavioral and mental health issues in children. Consequently, more general pediatricians will continue to be faced with the mental health issues of bereaved children who desperately need support, he said.

Money remains a key barrier, as it keeps qualified clinicians from entering the field of pediatric mental and behavioral health, and even where there are mental health providers, most do not take insurance and have long waiting lists, Dr. Lessin noted.

General pediatricians were seeing more patients with ADHD, anxiety, and depression before the advent of COVID-19, though most are not trained in managing these conditions, said Dr. Lessin. “Approximately 25%-30% of my visits now are mental health related, and the pandemic will make it geometrically worse,” he said.

The current study, with its dramatic estimates of the number of children who have lost a parent because of COVID-19, may bring attention to the fact that more training and money are needed to support mental health programs for children, he said.

Lead author Dr. Kidman had no financial conflicts to disclose. The study was supported by grants to corresponding author Ashton M. Verdery, PhD, from the National Institute on Aging and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Lessin had no financial conflicts but serves on the Pediatric News editorial advisory board.

SOURCE: Kidman R et al. JAMA Pediatr. .

Nonalcoholic fatty liver disease (NAFLD) in children is almost always caused by excess body weight, not other etiologies, based on a retrospective analysis of 900 patients.

Just 2% of children with overweight or obesity and suspected NAFLD had other causes of liver disease, and none tested positive for autoimmune hepatitis (AIH), reported lead author Toshifumi Yodoshi, MD, PhD, of Cincinnati Children’s Hospital Medical Center, and colleagues.

“Currently, recommended testing of patients with suspected NAFLD includes ruling out the following conditions: AIH, Wilson disease, hemochromatosis, alpha-1 antitrypsin [A1AT] deficiency, viral hepatitis, celiac disease, and thyroid dysfunction,” the investigators wrote in Pediatrics.

Yet evidence supporting this particular battery of tests is scant; just one previous pediatric study has estimated the prevalence of other liver diseases among children with suspected NAFLD. The study showed that the second-most common etiology, after NAFLD, was AIH, at a rate of 4%.

But “the generalizability of these findings is uncertain,” noted Dr. Yodoshi and colleagues, as the study was conducted at one tertiary center in the western United States, among a population that was predominantly Hispanic.

This uncertainty spurred the present study, which was conducted at two pediatric centers: Cincinnati Children’s Hospital Medical Center (2009-2017) and Yale New Haven (Conn.) Children’s Hospital (2012-2017).

The final analysis involved 900 patients aged 18 years or younger with suspected NAFLD based on hepatic steatosis detected via imaging and/or elevated serum aminotransferases. Demographically, a slight majority of the patients were boys (63%), and approximately one-quarter (26%) were Hispanic. Median BMI z score was 2.45, with three out of four patients (76%) exhibiting severe obesity. Out of 900 patients, 358 (40%) underwent liver biopsy, among whom 46% had confirmed nonalcoholic steatohepatitis.

All patients underwent testing to exclude the aforementioned conditions using various diagnostics, revealing that just 2% of the population had etiologies other than NAFLD. Specifically, 11 children had thyroid dysfunction (1.2%), 3 had celiac disease (0.4%), 3 had A1AT deficiency (0.4%), 1 had hemophagocytic lymphohistiocytosis, and 1 had Hodgkin’s lymphoma. None of the children had Wilson disease, hepatitis B or C, or AIH.

Dr. Yodoshi and colleagues highlighted the latter finding, noting that 13% of the patients had autoantibodies for AIH, but “none met composite criteria.” This contrasts with the previous study from 2013, which found an AIH rate of 4%.

“Nonetheless,” the investigators went on, “NAFLD remains a diagnosis of exclusion, and key conditions that require specific treatments must be ruled out in the workup of patients with suspected NAFLD. In the future, the cost-effectiveness of this approach will need to be investigated.”

Interpreting the findings, Francis E. Rushton, MD, of Beaufort (S.C.) Memorial Hospital emphasized the implications for preventive and interventional health care.

“This study showing an absence of etiologies other than obesity in overweight children with NAFLD provides further impetus for pediatricians to work on both preventive and treatment regimens for weight issues,” Dr. Rushton said. “Linking community-based initiatives focused on adequate nutritional support with pediatric clinical support services is critical in solving issues related to overweight in children. Tracking BMI over time and developing healthy habit goals for patients are key parts of clinical interventions.” 

The study was funded by the National Institutes of Health. The investigators reported no conflicts of interest.

Nonalcoholic fatty liver disease (NAFLD) in children is almost always caused by excess body weight, not other etiologies, based on a retrospective analysis of 900 patients.

Just 2% of children with overweight or obesity and suspected NAFLD had other causes of liver disease, and none tested positive for autoimmune hepatitis (AIH), reported lead author Toshifumi Yodoshi, MD, PhD, of Cincinnati Children’s Hospital Medical Center, and colleagues.

“Currently, recommended testing of patients with suspected NAFLD includes ruling out the following conditions: AIH, Wilson disease, hemochromatosis, alpha-1 antitrypsin [A1AT] deficiency, viral hepatitis, celiac disease, and thyroid dysfunction,” the investigators wrote in Pediatrics.

Yet evidence supporting this particular battery of tests is scant; just one previous pediatric study has estimated the prevalence of other liver diseases among children with suspected NAFLD. The study showed that the second-most common etiology, after NAFLD, was AIH, at a rate of 4%.

But “the generalizability of these findings is uncertain,” noted Dr. Yodoshi and colleagues, as the study was conducted at one tertiary center in the western United States, among a population that was predominantly Hispanic.

This uncertainty spurred the present study, which was conducted at two pediatric centers: Cincinnati Children’s Hospital Medical Center (2009-2017) and Yale New Haven (Conn.) Children’s Hospital (2012-2017).

The final analysis involved 900 patients aged 18 years or younger with suspected NAFLD based on hepatic steatosis detected via imaging and/or elevated serum aminotransferases. Demographically, a slight majority of the patients were boys (63%), and approximately one-quarter (26%) were Hispanic. Median BMI z score was 2.45, with three out of four patients (76%) exhibiting severe obesity. Out of 900 patients, 358 (40%) underwent liver biopsy, among whom 46% had confirmed nonalcoholic steatohepatitis.

All patients underwent testing to exclude the aforementioned conditions using various diagnostics, revealing that just 2% of the population had etiologies other than NAFLD. Specifically, 11 children had thyroid dysfunction (1.2%), 3 had celiac disease (0.4%), 3 had A1AT deficiency (0.4%), 1 had hemophagocytic lymphohistiocytosis, and 1 had Hodgkin’s lymphoma. None of the children had Wilson disease, hepatitis B or C, or AIH.

Dr. Yodoshi and colleagues highlighted the latter finding, noting that 13% of the patients had autoantibodies for AIH, but “none met composite criteria.” This contrasts with the previous study from 2013, which found an AIH rate of 4%.

“Nonetheless,” the investigators went on, “NAFLD remains a diagnosis of exclusion, and key conditions that require specific treatments must be ruled out in the workup of patients with suspected NAFLD. In the future, the cost-effectiveness of this approach will need to be investigated.”

Interpreting the findings, Francis E. Rushton, MD, of Beaufort (S.C.) Memorial Hospital emphasized the implications for preventive and interventional health care.

“This study showing an absence of etiologies other than obesity in overweight children with NAFLD provides further impetus for pediatricians to work on both preventive and treatment regimens for weight issues,” Dr. Rushton said. “Linking community-based initiatives focused on adequate nutritional support with pediatric clinical support services is critical in solving issues related to overweight in children. Tracking BMI over time and developing healthy habit goals for patients are key parts of clinical interventions.” 

The study was funded by the National Institutes of Health. The investigators reported no conflicts of interest.

Nonalcoholic fatty liver disease (NAFLD) in children is almost always caused by excess body weight, not other etiologies, based on a retrospective analysis of 900 patients.

Just 2% of children with overweight or obesity and suspected NAFLD had other causes of liver disease, and none tested positive for autoimmune hepatitis (AIH), reported lead author Toshifumi Yodoshi, MD, PhD, of Cincinnati Children’s Hospital Medical Center, and colleagues.

“Currently, recommended testing of patients with suspected NAFLD includes ruling out the following conditions: AIH, Wilson disease, hemochromatosis, alpha-1 antitrypsin [A1AT] deficiency, viral hepatitis, celiac disease, and thyroid dysfunction,” the investigators wrote in Pediatrics.

Yet evidence supporting this particular battery of tests is scant; just one previous pediatric study has estimated the prevalence of other liver diseases among children with suspected NAFLD. The study showed that the second-most common etiology, after NAFLD, was AIH, at a rate of 4%.

But “the generalizability of these findings is uncertain,” noted Dr. Yodoshi and colleagues, as the study was conducted at one tertiary center in the western United States, among a population that was predominantly Hispanic.

This uncertainty spurred the present study, which was conducted at two pediatric centers: Cincinnati Children’s Hospital Medical Center (2009-2017) and Yale New Haven (Conn.) Children’s Hospital (2012-2017).

The final analysis involved 900 patients aged 18 years or younger with suspected NAFLD based on hepatic steatosis detected via imaging and/or elevated serum aminotransferases. Demographically, a slight majority of the patients were boys (63%), and approximately one-quarter (26%) were Hispanic. Median BMI z score was 2.45, with three out of four patients (76%) exhibiting severe obesity. Out of 900 patients, 358 (40%) underwent liver biopsy, among whom 46% had confirmed nonalcoholic steatohepatitis.

All patients underwent testing to exclude the aforementioned conditions using various diagnostics, revealing that just 2% of the population had etiologies other than NAFLD. Specifically, 11 children had thyroid dysfunction (1.2%), 3 had celiac disease (0.4%), 3 had A1AT deficiency (0.4%), 1 had hemophagocytic lymphohistiocytosis, and 1 had Hodgkin’s lymphoma. None of the children had Wilson disease, hepatitis B or C, or AIH.

Dr. Yodoshi and colleagues highlighted the latter finding, noting that 13% of the patients had autoantibodies for AIH, but “none met composite criteria.” This contrasts with the previous study from 2013, which found an AIH rate of 4%.

“Nonetheless,” the investigators went on, “NAFLD remains a diagnosis of exclusion, and key conditions that require specific treatments must be ruled out in the workup of patients with suspected NAFLD. In the future, the cost-effectiveness of this approach will need to be investigated.”

Interpreting the findings, Francis E. Rushton, MD, of Beaufort (S.C.) Memorial Hospital emphasized the implications for preventive and interventional health care.

“This study showing an absence of etiologies other than obesity in overweight children with NAFLD provides further impetus for pediatricians to work on both preventive and treatment regimens for weight issues,” Dr. Rushton said. “Linking community-based initiatives focused on adequate nutritional support with pediatric clinical support services is critical in solving issues related to overweight in children. Tracking BMI over time and developing healthy habit goals for patients are key parts of clinical interventions.” 

The study was funded by the National Institutes of Health. The investigators reported no conflicts of interest.

Has anyone else noticed how slow it has been on your pediatric floors? Well, you are not alone.

The COVID pandemic has had a significant impact on health care volumes, with pediatric volumes decreasing across the nation. A Children’s Hospital Association CEO survey, currently unpublished, noted a 10%-20% decline in inpatient admissions and a 30%-50% decline in pediatric ED visits this past year. Even our usual respiratory surge has been disrupted. The rate of influenza tracked by the CDC is around 1%, compared with the usual seasonal flu baseline national rate of 2.6%. These COVID-related declines have occurred amidst the backdrop of already-decreasing inpatient admissions because of the great work of the pediatric hospital medicine (PHM) community in reducing unnecessary admissions and lengths of stay.

For many hospitals, several factors related to the pandemic have raised significant financial concerns. According to Becker Hospital Review, as of August 2020 over 500 hospitals had furloughed workers. While 26 of those hospitals had brought back workers by December 2020, many did not. Similar financial concerns were noted in a Kaufmann Hall report from January 2021, which showed a median drop of 55% in operating margins. The CARES Act helped reduce some of the detrimental impact on operating margins, but it did not diminish the added burden of personal protective equipment expenses, longer length of stay for COVID patients, and a reimbursement shift to more government payors and uninsured caused by pandemic-forced job losses.

COVID’s impact specific to pediatric hospital medicine has been substantial. A recent unpublished survey by the PHM Economics Research Collaborative (PERC) demonstrated how COVID has affected pediatric hospital medicine programs. Forty-five unique PHM programs from over 21 states responded, with 98% reporting a decrease in pediatric inpatient admissions as well as ED visits. About 11% reported temporary unit closures, while 51% of all programs reported staffing restrictions ranging from hiring freezes to downsizing the number of hospitalists in the group. Salaries decreased in 26% of reporting programs, and 20%-56% described reduced benefits, ranging from less CME/vacation time and stipends to retirement benefits. The three most frequent benefit losses included annual salary increases, educational stipends, and bonuses.

Community hospitals felt the palpable, financial strain of decreasing pediatric admissions well before the pandemic. Hospitals like MedStar Franklin Square Hospital in Baltimore and Harrington Hospital in Southbridge, Mass., had decided to close their pediatrics units before COVID hit. In a 2014 unpublished survey of 349 community PHM (CPHM) programs, 57% of respondents felt that finances and justification for a pediatric program were primary concerns.

Responding to financial stressors is not a novel challenge for CPHM programs. To keep these vital pediatric programs in place despite lower inpatient volumes, those of us in CPHM have learned many lessons over the years on how to adapt. Such adaptations have included diversification in procedures and multifloor coverage in the hospital. Voiding cystourethrogram catheterizations and circumcisions are now more commonly performed by CPHM providers, who may also cover multiple areas of the hospital, including the ED, NICU, and well-newborn nursery. Comanagement of subspecialty or surgical patients is yet another example of such diversification.

Furthermore, the PERC survey showed that some PHM programs temporarily covered pediatric ICUs and step-down units and began doing ED and urgent care coverage as primary providers Most programs reported no change in newborn visits while 16% reported an increase in newborn volume and 14% reported a decrease in newborn volume. My own health system was one of the groups that had an increase in newborn volume. This was caused by community pediatricians who had stopped coming in to see their own newborns. This coverage adjustment has yet to return to baseline and will likely become permanent.

There was a 11% increase from prepandemic baselines (from 9% to 20%) in programs doing telemedicine. Most respondents stated that they will continue to offer telemedicine with an additional 25% of programs considering starting. There was also a slight increase during the pandemic of coverage of mental health units (from 11% to 13%), which may have led 11% of respondents to consider the addition of this service. The survey also noted that about 28% of PHM programs performed circumcisions, frenectomies, and sedation prepandemic, and 14%-18% are considering adding these services.

Overall, the financial stressors are improving, but our need to adapt in PHM is more pressing than ever. The pandemic has given us the push for evolution and some opportunities that did not exist before. One is the use of telemedicine to expand our subspecialty support to community hospitals, as well as to children’s hospitals in areas where subspecialists are in short supply. These telemedicine consults are being reimbursed for the first time, which allows more access to these services.

With the pandemic, many hospitals are moving to single room occupancy models. Construction to add more beds is costly, and unnecessary if we can utilize community hospitals to keep appropriate patients in their home communities. The opportunity to partner with community hospital programs to provide telemedicine support should not be overlooked. This is also an opportunity for academic referral centers to have more open beds for critical care and highly specialized patients.

Another opportunity is to expand scope by changing age limits, as 18% of respondents to the PERC survey reported that they had started to care for adults since the pandemic. The Pediatric Overflow Planning Contingency Response Network (POPCoRN) has been a valuable resource for education on caring for adults, guidance on which patient populations are appropriate, and the resources needed to do this. While caring for older adults, even in their 90s, was a pandemic-related phenomenon, there is an opportunity to see if the age limit we care for should be raised to 21, or even 25, as some CPHM programs had been doing prepandemic.

Along with the expansion of age limits, there are many other areas of opportunity highlighted within the PERC survey. These include expanding coverage within pediatric ICUs, EDs, and urgent care areas, along with coverage of well newborns that were previously covered by community pediatricians. Also, the increase of mental health admissions is another area where PHM programs might expand their services.

While I hope the financial stressors improve, hope is not a plan and therefore we need to think and prepare for what the post-COVID future may look like. Some have predicted a rebound pediatric respiratory surge next year as the masks come off and children return to in-person learning and daycare. This may be true, but we would be foolish not to use lessons from the pandemic as well as the past to consider options in our toolkit to become more financially stable. POPCoRN, as well as the American Academy of Pediatrics’ listserv and subcommittees, have been a source of collaboration and shared knowledge during a time when we have needed to quickly respond to ever-changing information. These networks and information sharing should be leveraged once the dust settles for us to prepare for future challenges.

New innovations may arise as we look at how we address the growing need for mental health services and incorporate new procedures, like point of care ultrasound. As Charles Darwin said: “It is not the strongest of the species that survives nor the most intelligent that survives. It is the one that is most adaptable to change.” It is time for us to evolve.
 

Dr. Dias is a clinical associate professor of pediatrics at Yale University, New Haven, Conn., in the division of pediatric hospital medicine. She has practiced community pediatric hospital medicine for over 21 years in New Jersey, Pennsylvania, and Connecticut. She is the chair of the Education Working Group for the AAP’s section on hospital medicine’s subcommittee on community hospitalists as well as the cochair of the Community Hospital Operations Group of the POPCoRN network.

Has anyone else noticed how slow it has been on your pediatric floors? Well, you are not alone.

The COVID pandemic has had a significant impact on health care volumes, with pediatric volumes decreasing across the nation. A Children’s Hospital Association CEO survey, currently unpublished, noted a 10%-20% decline in inpatient admissions and a 30%-50% decline in pediatric ED visits this past year. Even our usual respiratory surge has been disrupted. The rate of influenza tracked by the CDC is around 1%, compared with the usual seasonal flu baseline national rate of 2.6%. These COVID-related declines have occurred amidst the backdrop of already-decreasing inpatient admissions because of the great work of the pediatric hospital medicine (PHM) community in reducing unnecessary admissions and lengths of stay.

For many hospitals, several factors related to the pandemic have raised significant financial concerns. According to Becker Hospital Review, as of August 2020 over 500 hospitals had furloughed workers. While 26 of those hospitals had brought back workers by December 2020, many did not. Similar financial concerns were noted in a Kaufmann Hall report from January 2021, which showed a median drop of 55% in operating margins. The CARES Act helped reduce some of the detrimental impact on operating margins, but it did not diminish the added burden of personal protective equipment expenses, longer length of stay for COVID patients, and a reimbursement shift to more government payors and uninsured caused by pandemic-forced job losses.

COVID’s impact specific to pediatric hospital medicine has been substantial. A recent unpublished survey by the PHM Economics Research Collaborative (PERC) demonstrated how COVID has affected pediatric hospital medicine programs. Forty-five unique PHM programs from over 21 states responded, with 98% reporting a decrease in pediatric inpatient admissions as well as ED visits. About 11% reported temporary unit closures, while 51% of all programs reported staffing restrictions ranging from hiring freezes to downsizing the number of hospitalists in the group. Salaries decreased in 26% of reporting programs, and 20%-56% described reduced benefits, ranging from less CME/vacation time and stipends to retirement benefits. The three most frequent benefit losses included annual salary increases, educational stipends, and bonuses.

Community hospitals felt the palpable, financial strain of decreasing pediatric admissions well before the pandemic. Hospitals like MedStar Franklin Square Hospital in Baltimore and Harrington Hospital in Southbridge, Mass., had decided to close their pediatrics units before COVID hit. In a 2014 unpublished survey of 349 community PHM (CPHM) programs, 57% of respondents felt that finances and justification for a pediatric program were primary concerns.

Responding to financial stressors is not a novel challenge for CPHM programs. To keep these vital pediatric programs in place despite lower inpatient volumes, those of us in CPHM have learned many lessons over the years on how to adapt. Such adaptations have included diversification in procedures and multifloor coverage in the hospital. Voiding cystourethrogram catheterizations and circumcisions are now more commonly performed by CPHM providers, who may also cover multiple areas of the hospital, including the ED, NICU, and well-newborn nursery. Comanagement of subspecialty or surgical patients is yet another example of such diversification.

Furthermore, the PERC survey showed that some PHM programs temporarily covered pediatric ICUs and step-down units and began doing ED and urgent care coverage as primary providers Most programs reported no change in newborn visits while 16% reported an increase in newborn volume and 14% reported a decrease in newborn volume. My own health system was one of the groups that had an increase in newborn volume. This was caused by community pediatricians who had stopped coming in to see their own newborns. This coverage adjustment has yet to return to baseline and will likely become permanent.

There was a 11% increase from prepandemic baselines (from 9% to 20%) in programs doing telemedicine. Most respondents stated that they will continue to offer telemedicine with an additional 25% of programs considering starting. There was also a slight increase during the pandemic of coverage of mental health units (from 11% to 13%), which may have led 11% of respondents to consider the addition of this service. The survey also noted that about 28% of PHM programs performed circumcisions, frenectomies, and sedation prepandemic, and 14%-18% are considering adding these services.

Overall, the financial stressors are improving, but our need to adapt in PHM is more pressing than ever. The pandemic has given us the push for evolution and some opportunities that did not exist before. One is the use of telemedicine to expand our subspecialty support to community hospitals, as well as to children’s hospitals in areas where subspecialists are in short supply. These telemedicine consults are being reimbursed for the first time, which allows more access to these services.

With the pandemic, many hospitals are moving to single room occupancy models. Construction to add more beds is costly, and unnecessary if we can utilize community hospitals to keep appropriate patients in their home communities. The opportunity to partner with community hospital programs to provide telemedicine support should not be overlooked. This is also an opportunity for academic referral centers to have more open beds for critical care and highly specialized patients.

Another opportunity is to expand scope by changing age limits, as 18% of respondents to the PERC survey reported that they had started to care for adults since the pandemic. The Pediatric Overflow Planning Contingency Response Network (POPCoRN) has been a valuable resource for education on caring for adults, guidance on which patient populations are appropriate, and the resources needed to do this. While caring for older adults, even in their 90s, was a pandemic-related phenomenon, there is an opportunity to see if the age limit we care for should be raised to 21, or even 25, as some CPHM programs had been doing prepandemic.

Along with the expansion of age limits, there are many other areas of opportunity highlighted within the PERC survey. These include expanding coverage within pediatric ICUs, EDs, and urgent care areas, along with coverage of well newborns that were previously covered by community pediatricians. Also, the increase of mental health admissions is another area where PHM programs might expand their services.

While I hope the financial stressors improve, hope is not a plan and therefore we need to think and prepare for what the post-COVID future may look like. Some have predicted a rebound pediatric respiratory surge next year as the masks come off and children return to in-person learning and daycare. This may be true, but we would be foolish not to use lessons from the pandemic as well as the past to consider options in our toolkit to become more financially stable. POPCoRN, as well as the American Academy of Pediatrics’ listserv and subcommittees, have been a source of collaboration and shared knowledge during a time when we have needed to quickly respond to ever-changing information. These networks and information sharing should be leveraged once the dust settles for us to prepare for future challenges.

New innovations may arise as we look at how we address the growing need for mental health services and incorporate new procedures, like point of care ultrasound. As Charles Darwin said: “It is not the strongest of the species that survives nor the most intelligent that survives. It is the one that is most adaptable to change.” It is time for us to evolve.
 

Dr. Dias is a clinical associate professor of pediatrics at Yale University, New Haven, Conn., in the division of pediatric hospital medicine. She has practiced community pediatric hospital medicine for over 21 years in New Jersey, Pennsylvania, and Connecticut. She is the chair of the Education Working Group for the AAP’s section on hospital medicine’s subcommittee on community hospitalists as well as the cochair of the Community Hospital Operations Group of the POPCoRN network.

Has anyone else noticed how slow it has been on your pediatric floors? Well, you are not alone.

The COVID pandemic has had a significant impact on health care volumes, with pediatric volumes decreasing across the nation. A Children’s Hospital Association CEO survey, currently unpublished, noted a 10%-20% decline in inpatient admissions and a 30%-50% decline in pediatric ED visits this past year. Even our usual respiratory surge has been disrupted. The rate of influenza tracked by the CDC is around 1%, compared with the usual seasonal flu baseline national rate of 2.6%. These COVID-related declines have occurred amidst the backdrop of already-decreasing inpatient admissions because of the great work of the pediatric hospital medicine (PHM) community in reducing unnecessary admissions and lengths of stay.

For many hospitals, several factors related to the pandemic have raised significant financial concerns. According to Becker Hospital Review, as of August 2020 over 500 hospitals had furloughed workers. While 26 of those hospitals had brought back workers by December 2020, many did not. Similar financial concerns were noted in a Kaufmann Hall report from January 2021, which showed a median drop of 55% in operating margins. The CARES Act helped reduce some of the detrimental impact on operating margins, but it did not diminish the added burden of personal protective equipment expenses, longer length of stay for COVID patients, and a reimbursement shift to more government payors and uninsured caused by pandemic-forced job losses.

COVID’s impact specific to pediatric hospital medicine has been substantial. A recent unpublished survey by the PHM Economics Research Collaborative (PERC) demonstrated how COVID has affected pediatric hospital medicine programs. Forty-five unique PHM programs from over 21 states responded, with 98% reporting a decrease in pediatric inpatient admissions as well as ED visits. About 11% reported temporary unit closures, while 51% of all programs reported staffing restrictions ranging from hiring freezes to downsizing the number of hospitalists in the group. Salaries decreased in 26% of reporting programs, and 20%-56% described reduced benefits, ranging from less CME/vacation time and stipends to retirement benefits. The three most frequent benefit losses included annual salary increases, educational stipends, and bonuses.

Community hospitals felt the palpable, financial strain of decreasing pediatric admissions well before the pandemic. Hospitals like MedStar Franklin Square Hospital in Baltimore and Harrington Hospital in Southbridge, Mass., had decided to close their pediatrics units before COVID hit. In a 2014 unpublished survey of 349 community PHM (CPHM) programs, 57% of respondents felt that finances and justification for a pediatric program were primary concerns.

Responding to financial stressors is not a novel challenge for CPHM programs. To keep these vital pediatric programs in place despite lower inpatient volumes, those of us in CPHM have learned many lessons over the years on how to adapt. Such adaptations have included diversification in procedures and multifloor coverage in the hospital. Voiding cystourethrogram catheterizations and circumcisions are now more commonly performed by CPHM providers, who may also cover multiple areas of the hospital, including the ED, NICU, and well-newborn nursery. Comanagement of subspecialty or surgical patients is yet another example of such diversification.

Furthermore, the PERC survey showed that some PHM programs temporarily covered pediatric ICUs and step-down units and began doing ED and urgent care coverage as primary providers Most programs reported no change in newborn visits while 16% reported an increase in newborn volume and 14% reported a decrease in newborn volume. My own health system was one of the groups that had an increase in newborn volume. This was caused by community pediatricians who had stopped coming in to see their own newborns. This coverage adjustment has yet to return to baseline and will likely become permanent.

There was a 11% increase from prepandemic baselines (from 9% to 20%) in programs doing telemedicine. Most respondents stated that they will continue to offer telemedicine with an additional 25% of programs considering starting. There was also a slight increase during the pandemic of coverage of mental health units (from 11% to 13%), which may have led 11% of respondents to consider the addition of this service. The survey also noted that about 28% of PHM programs performed circumcisions, frenectomies, and sedation prepandemic, and 14%-18% are considering adding these services.

Overall, the financial stressors are improving, but our need to adapt in PHM is more pressing than ever. The pandemic has given us the push for evolution and some opportunities that did not exist before. One is the use of telemedicine to expand our subspecialty support to community hospitals, as well as to children’s hospitals in areas where subspecialists are in short supply. These telemedicine consults are being reimbursed for the first time, which allows more access to these services.

With the pandemic, many hospitals are moving to single room occupancy models. Construction to add more beds is costly, and unnecessary if we can utilize community hospitals to keep appropriate patients in their home communities. The opportunity to partner with community hospital programs to provide telemedicine support should not be overlooked. This is also an opportunity for academic referral centers to have more open beds for critical care and highly specialized patients.

Another opportunity is to expand scope by changing age limits, as 18% of respondents to the PERC survey reported that they had started to care for adults since the pandemic. The Pediatric Overflow Planning Contingency Response Network (POPCoRN) has been a valuable resource for education on caring for adults, guidance on which patient populations are appropriate, and the resources needed to do this. While caring for older adults, even in their 90s, was a pandemic-related phenomenon, there is an opportunity to see if the age limit we care for should be raised to 21, or even 25, as some CPHM programs had been doing prepandemic.

Along with the expansion of age limits, there are many other areas of opportunity highlighted within the PERC survey. These include expanding coverage within pediatric ICUs, EDs, and urgent care areas, along with coverage of well newborns that were previously covered by community pediatricians. Also, the increase of mental health admissions is another area where PHM programs might expand their services.

While I hope the financial stressors improve, hope is not a plan and therefore we need to think and prepare for what the post-COVID future may look like. Some have predicted a rebound pediatric respiratory surge next year as the masks come off and children return to in-person learning and daycare. This may be true, but we would be foolish not to use lessons from the pandemic as well as the past to consider options in our toolkit to become more financially stable. POPCoRN, as well as the American Academy of Pediatrics’ listserv and subcommittees, have been a source of collaboration and shared knowledge during a time when we have needed to quickly respond to ever-changing information. These networks and information sharing should be leveraged once the dust settles for us to prepare for future challenges.

New innovations may arise as we look at how we address the growing need for mental health services and incorporate new procedures, like point of care ultrasound. As Charles Darwin said: “It is not the strongest of the species that survives nor the most intelligent that survives. It is the one that is most adaptable to change.” It is time for us to evolve.
 

Dr. Dias is a clinical associate professor of pediatrics at Yale University, New Haven, Conn., in the division of pediatric hospital medicine. She has practiced community pediatric hospital medicine for over 21 years in New Jersey, Pennsylvania, and Connecticut. She is the chair of the Education Working Group for the AAP’s section on hospital medicine’s subcommittee on community hospitalists as well as the cochair of the Community Hospital Operations Group of the POPCoRN network.

Cardiovascular and metabolic risk factors are increased among transgender youths, compared with youths who are not transgender. Elevations in lipid levels and body mass index (BMI) also occur in adult transgender patients, new research shows.

“This is the first study of its size in the United States of which we are aware that looks at the odds of youth with a diagnosis of gender dysphoria having medical diagnoses that relate to overall metabolic and cardiovascular health,” first author Anna Valentine, MD, of Children’s Hospital Colorado, Aurora, said in a press statement.

Although previous studies have shown that among transgender adults, BMI is higher and there is an increased risk for cardiovascular events, such as stroke or heart attack, compared with nontransgender people, research on adolescent transgender patients has been lacking.

With a recent survey showing that nearly 2% of adolescents identify as transgender, interest in health outcomes among younger patients is high.

To investigate, Dr. Valentine, and colleagues evaluated data from the PEDSnet pediatric database on 4,177 youths who had received a diagnosis of gender dysphoria. The participants had been enrolled at six sites from 2009 to 2019. The researchers compared these patients in a ratio of 1:4 with 16,664 control persons who had not been diagnosed with gender dysphoria. They reported their findings as a poster at the annual meeting of the Endocrine Society.

For the propensity-score analysis, participants were matched according to year of birth, age at last visit, site, race, ethnicity, insurance status, and duration in the database.

In both the transgender and control groups, about 66% were female at birth, 73% were White, and 9% Hispanic. For both groups, the average age was 16.2 years at the last visit. The average duration in the database was 7 years.
 

Study didn’t distinguish between those receiving and those not receiving gender-affirming hormones

In the retrospective study, among those who identified as transgender, the rates of diagnoses of dyslipidemia (odds ratio, 1.6; P < .0001) and metabolic syndrome (OR, 1.9; P = .0086) were significantly higher, compared with those without gender dysphoria.

Among the transgender male patients (born female) but not transgender female patients (born male), rates of diagnoses of overweight/obesity (OR, 1.7; P < .0001) and polycystic ovary syndrome were higher (OR, 1.9, P = .0006), compared with controls.

Gender-affirming hormone therapy, such as with testosterone or estradiol, is among the suspected culprits for the cardiovascular effects. However, importantly, this study did not differentiate between patients who had received estradiol or testosterone for gender affirmation and those who had not, Dr. Valentine said.

“We don’t know [whether gender-affirming hormone therapy is a cause], as we have not looked at this yet,” she said in an interview. “We are looking at that in our next analyses and will be including that in our future publication.

“We’ll also be looking at the relationship between having overweight/obesity and the other diagnoses that influence cardiovascular health (high blood pressure, liver dysfunction, and abnormal cholesterol), as that could certainly be playing a role as well,” she said.

For many transgender patients, gender-affirming hormone therapy is lifelong. One question that needs to be evaluated concerns whether the dose of such therapy has a role on cardiovascular effects and if so, whether adjustments could be made without compromising the therapeutic effect, Dr. Valentine noted.

“This is an important question, and future research is needed to evaluate whether doses [of gender-affirming hormones] are related to cardiometabolic outcomes,” she said.

Potential confounders in the study include the fact that rates of overweight and obesity are higher among youths with gender dysphoria. This can in itself can increase the risk for other disorders, Dr. Valentine noted.

Furthermore, rates of mental health comorbidities are higher among youths with gender dysphoria. One consequence of this may be that they engage in less physical activity, she said.
 

Hormone therapy, health care disparities, or both could explain risk

In commenting on the study, Joshua D. Safer, MD, executive director of the Center for Transgender Medicine and Surgery, the Mount Sinai Health System, New York, said that although similar cardiovascular effects are known to occur in transgender adults as well, they may or may not be hormone related. Other factors can increase the risk.

“With transgender adults, any differences in lipids or cardiac risk factors relative to cisgender people might be attributable either to hormone therapy or to health care disparities,” he said in an interview.

“The data are mixed. It may be that most differences relate to lack of access to care and to mistreatment by society,” he said. “Even studies that focus on hormones see a worsened situation for trans women versus trans men.”

Other recent research that shows potential cardiovascular effects among adult transgender men includes a study of more than 1,000 transgender men (born female) who received testosterone. That study, which was also presented at the ENDO meeting and was reported by this news organization, found an increased risk for high hematocrit levels, which could lead to a thrombotic event.

However, a study published in Pediatrics, which was also reported by this news organization, that included 611 transgender youths who had taken gender-affirming hormone therapy for more than a year found no increased risk for thrombosis, even in the presence of thrombosis risk factors, including obesity, tobacco use, and family history of thrombosis. However, the senior author of that study pointed out that the duration of follow-up in that study was relatively short, which may have been why they did not find an increased risk for thrombosis.

Dr. Safer noted that transgender youths and adults alike face a host of cultural factors that could play a role in increased cardiovascular risks.

“For adults, the major candidate explanations for worse BMI and cardiac risk factors are societal mistreatment, and for trans women specifically, progestins. For youth, the major candidate explanations are societal mistreatment and lack of access to athletics,” he said.

The authors and Dr. Safer disclosed no relevant financial relationships.

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

Cardiovascular and metabolic risk factors are increased among transgender youths, compared with youths who are not transgender. Elevations in lipid levels and body mass index (BMI) also occur in adult transgender patients, new research shows.

“This is the first study of its size in the United States of which we are aware that looks at the odds of youth with a diagnosis of gender dysphoria having medical diagnoses that relate to overall metabolic and cardiovascular health,” first author Anna Valentine, MD, of Children’s Hospital Colorado, Aurora, said in a press statement.

Although previous studies have shown that among transgender adults, BMI is higher and there is an increased risk for cardiovascular events, such as stroke or heart attack, compared with nontransgender people, research on adolescent transgender patients has been lacking.

With a recent survey showing that nearly 2% of adolescents identify as transgender, interest in health outcomes among younger patients is high.

To investigate, Dr. Valentine, and colleagues evaluated data from the PEDSnet pediatric database on 4,177 youths who had received a diagnosis of gender dysphoria. The participants had been enrolled at six sites from 2009 to 2019. The researchers compared these patients in a ratio of 1:4 with 16,664 control persons who had not been diagnosed with gender dysphoria. They reported their findings as a poster at the annual meeting of the Endocrine Society.

For the propensity-score analysis, participants were matched according to year of birth, age at last visit, site, race, ethnicity, insurance status, and duration in the database.

In both the transgender and control groups, about 66% were female at birth, 73% were White, and 9% Hispanic. For both groups, the average age was 16.2 years at the last visit. The average duration in the database was 7 years.
 

Study didn’t distinguish between those receiving and those not receiving gender-affirming hormones

In the retrospective study, among those who identified as transgender, the rates of diagnoses of dyslipidemia (odds ratio, 1.6; P < .0001) and metabolic syndrome (OR, 1.9; P = .0086) were significantly higher, compared with those without gender dysphoria.

Among the transgender male patients (born female) but not transgender female patients (born male), rates of diagnoses of overweight/obesity (OR, 1.7; P < .0001) and polycystic ovary syndrome were higher (OR, 1.9, P = .0006), compared with controls.

Gender-affirming hormone therapy, such as with testosterone or estradiol, is among the suspected culprits for the cardiovascular effects. However, importantly, this study did not differentiate between patients who had received estradiol or testosterone for gender affirmation and those who had not, Dr. Valentine said.

“We don’t know [whether gender-affirming hormone therapy is a cause], as we have not looked at this yet,” she said in an interview. “We are looking at that in our next analyses and will be including that in our future publication.

“We’ll also be looking at the relationship between having overweight/obesity and the other diagnoses that influence cardiovascular health (high blood pressure, liver dysfunction, and abnormal cholesterol), as that could certainly be playing a role as well,” she said.

For many transgender patients, gender-affirming hormone therapy is lifelong. One question that needs to be evaluated concerns whether the dose of such therapy has a role on cardiovascular effects and if so, whether adjustments could be made without compromising the therapeutic effect, Dr. Valentine noted.

“This is an important question, and future research is needed to evaluate whether doses [of gender-affirming hormones] are related to cardiometabolic outcomes,” she said.

Potential confounders in the study include the fact that rates of overweight and obesity are higher among youths with gender dysphoria. This can in itself can increase the risk for other disorders, Dr. Valentine noted.

Furthermore, rates of mental health comorbidities are higher among youths with gender dysphoria. One consequence of this may be that they engage in less physical activity, she said.
 

Hormone therapy, health care disparities, or both could explain risk

In commenting on the study, Joshua D. Safer, MD, executive director of the Center for Transgender Medicine and Surgery, the Mount Sinai Health System, New York, said that although similar cardiovascular effects are known to occur in transgender adults as well, they may or may not be hormone related. Other factors can increase the risk.

“With transgender adults, any differences in lipids or cardiac risk factors relative to cisgender people might be attributable either to hormone therapy or to health care disparities,” he said in an interview.

“The data are mixed. It may be that most differences relate to lack of access to care and to mistreatment by society,” he said. “Even studies that focus on hormones see a worsened situation for trans women versus trans men.”

Other recent research that shows potential cardiovascular effects among adult transgender men includes a study of more than 1,000 transgender men (born female) who received testosterone. That study, which was also presented at the ENDO meeting and was reported by this news organization, found an increased risk for high hematocrit levels, which could lead to a thrombotic event.

However, a study published in Pediatrics, which was also reported by this news organization, that included 611 transgender youths who had taken gender-affirming hormone therapy for more than a year found no increased risk for thrombosis, even in the presence of thrombosis risk factors, including obesity, tobacco use, and family history of thrombosis. However, the senior author of that study pointed out that the duration of follow-up in that study was relatively short, which may have been why they did not find an increased risk for thrombosis.

Dr. Safer noted that transgender youths and adults alike face a host of cultural factors that could play a role in increased cardiovascular risks.

“For adults, the major candidate explanations for worse BMI and cardiac risk factors are societal mistreatment, and for trans women specifically, progestins. For youth, the major candidate explanations are societal mistreatment and lack of access to athletics,” he said.

The authors and Dr. Safer disclosed no relevant financial relationships.

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

Cardiovascular and metabolic risk factors are increased among transgender youths, compared with youths who are not transgender. Elevations in lipid levels and body mass index (BMI) also occur in adult transgender patients, new research shows.

“This is the first study of its size in the United States of which we are aware that looks at the odds of youth with a diagnosis of gender dysphoria having medical diagnoses that relate to overall metabolic and cardiovascular health,” first author Anna Valentine, MD, of Children’s Hospital Colorado, Aurora, said in a press statement.

Although previous studies have shown that among transgender adults, BMI is higher and there is an increased risk for cardiovascular events, such as stroke or heart attack, compared with nontransgender people, research on adolescent transgender patients has been lacking.

With a recent survey showing that nearly 2% of adolescents identify as transgender, interest in health outcomes among younger patients is high.

To investigate, Dr. Valentine, and colleagues evaluated data from the PEDSnet pediatric database on 4,177 youths who had received a diagnosis of gender dysphoria. The participants had been enrolled at six sites from 2009 to 2019. The researchers compared these patients in a ratio of 1:4 with 16,664 control persons who had not been diagnosed with gender dysphoria. They reported their findings as a poster at the annual meeting of the Endocrine Society.

For the propensity-score analysis, participants were matched according to year of birth, age at last visit, site, race, ethnicity, insurance status, and duration in the database.

In both the transgender and control groups, about 66% were female at birth, 73% were White, and 9% Hispanic. For both groups, the average age was 16.2 years at the last visit. The average duration in the database was 7 years.
 

Study didn’t distinguish between those receiving and those not receiving gender-affirming hormones

In the retrospective study, among those who identified as transgender, the rates of diagnoses of dyslipidemia (odds ratio, 1.6; P < .0001) and metabolic syndrome (OR, 1.9; P = .0086) were significantly higher, compared with those without gender dysphoria.

Among the transgender male patients (born female) but not transgender female patients (born male), rates of diagnoses of overweight/obesity (OR, 1.7; P < .0001) and polycystic ovary syndrome were higher (OR, 1.9, P = .0006), compared with controls.

Gender-affirming hormone therapy, such as with testosterone or estradiol, is among the suspected culprits for the cardiovascular effects. However, importantly, this study did not differentiate between patients who had received estradiol or testosterone for gender affirmation and those who had not, Dr. Valentine said.

“We don’t know [whether gender-affirming hormone therapy is a cause], as we have not looked at this yet,” she said in an interview. “We are looking at that in our next analyses and will be including that in our future publication.

“We’ll also be looking at the relationship between having overweight/obesity and the other diagnoses that influence cardiovascular health (high blood pressure, liver dysfunction, and abnormal cholesterol), as that could certainly be playing a role as well,” she said.

For many transgender patients, gender-affirming hormone therapy is lifelong. One question that needs to be evaluated concerns whether the dose of such therapy has a role on cardiovascular effects and if so, whether adjustments could be made without compromising the therapeutic effect, Dr. Valentine noted.

“This is an important question, and future research is needed to evaluate whether doses [of gender-affirming hormones] are related to cardiometabolic outcomes,” she said.

Potential confounders in the study include the fact that rates of overweight and obesity are higher among youths with gender dysphoria. This can in itself can increase the risk for other disorders, Dr. Valentine noted.

Furthermore, rates of mental health comorbidities are higher among youths with gender dysphoria. One consequence of this may be that they engage in less physical activity, she said.
 

Hormone therapy, health care disparities, or both could explain risk

In commenting on the study, Joshua D. Safer, MD, executive director of the Center for Transgender Medicine and Surgery, the Mount Sinai Health System, New York, said that although similar cardiovascular effects are known to occur in transgender adults as well, they may or may not be hormone related. Other factors can increase the risk.

“With transgender adults, any differences in lipids or cardiac risk factors relative to cisgender people might be attributable either to hormone therapy or to health care disparities,” he said in an interview.

“The data are mixed. It may be that most differences relate to lack of access to care and to mistreatment by society,” he said. “Even studies that focus on hormones see a worsened situation for trans women versus trans men.”

Other recent research that shows potential cardiovascular effects among adult transgender men includes a study of more than 1,000 transgender men (born female) who received testosterone. That study, which was also presented at the ENDO meeting and was reported by this news organization, found an increased risk for high hematocrit levels, which could lead to a thrombotic event.

However, a study published in Pediatrics, which was also reported by this news organization, that included 611 transgender youths who had taken gender-affirming hormone therapy for more than a year found no increased risk for thrombosis, even in the presence of thrombosis risk factors, including obesity, tobacco use, and family history of thrombosis. However, the senior author of that study pointed out that the duration of follow-up in that study was relatively short, which may have been why they did not find an increased risk for thrombosis.

Dr. Safer noted that transgender youths and adults alike face a host of cultural factors that could play a role in increased cardiovascular risks.

“For adults, the major candidate explanations for worse BMI and cardiac risk factors are societal mistreatment, and for trans women specifically, progestins. For youth, the major candidate explanations are societal mistreatment and lack of access to athletics,” he said.

The authors and Dr. Safer disclosed no relevant financial relationships.

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

The Food and Drug Administration has approved the nonstimulant medication viloxazine extended-release capsules (Qelbree, Supernus Pharmaceuticals) for the treatment of attention deficit hyperactivity disorder (ADHD) in children aged 6-17 years, the company has announced.

Viloxazine (formerly SPN-812) is a selective norepinephrine reuptake inhibitor. Capsules may be swallowed whole or opened and the entire contents sprinkled onto applesauce, as needed.

The approval of viloxazine is supported by data from four phase 3 clinical trials involving more than 1,000 pediatric patients aged 6-17 years, the company said.

In one randomized, placebo-controlled phase 3 study that included more than 400 children, viloxazine reduced symptoms of ADHD as soon as 1 week after dosing and was well tolerated.

As reported by this news organization, the study was published last July in Clinical Therapeutics.

In addition to its fast onset of action, the fact that it was effective for both inattentive and hyperactive/impulsive clusters of symptoms is “impressive,” study investigator Andrew Cutler, MD, clinical associate professor of psychiatry, SUNY Upstate Medical University, Syracuse, N.Y., said in an interview.

Also noteworthy was the improvement in measures of quality of life and function, “especially function in the areas of school, home life, family relations, and peer relationships, which can be really disrupted with ADHD,” Dr. Cutler said.

The prescribing label for viloxazine includes a boxed warning regarding the potential for suicidal thoughts and behaviors in some children with ADHD treated with the drug, especially within the first few months of treatment or when the dose is changed. 

In clinical trials, higher rates of suicidal thoughts and behavior were reported in pediatric patients treated with viloxazine than in patients treated with placebo. Patients taking viloxazine should be closely monitored for any new or sudden changes in mood, behavior, thoughts, and feelings.

Viloxazine has shown promise in a phase 3 trial involving adults with ADHD.

The company plans to submit a supplemental new drug application to the FDA for viloxazine in adults later this year.

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

The Food and Drug Administration has approved the nonstimulant medication viloxazine extended-release capsules (Qelbree, Supernus Pharmaceuticals) for the treatment of attention deficit hyperactivity disorder (ADHD) in children aged 6-17 years, the company has announced.

Viloxazine (formerly SPN-812) is a selective norepinephrine reuptake inhibitor. Capsules may be swallowed whole or opened and the entire contents sprinkled onto applesauce, as needed.

The approval of viloxazine is supported by data from four phase 3 clinical trials involving more than 1,000 pediatric patients aged 6-17 years, the company said.

In one randomized, placebo-controlled phase 3 study that included more than 400 children, viloxazine reduced symptoms of ADHD as soon as 1 week after dosing and was well tolerated.

As reported by this news organization, the study was published last July in Clinical Therapeutics.

In addition to its fast onset of action, the fact that it was effective for both inattentive and hyperactive/impulsive clusters of symptoms is “impressive,” study investigator Andrew Cutler, MD, clinical associate professor of psychiatry, SUNY Upstate Medical University, Syracuse, N.Y., said in an interview.

Also noteworthy was the improvement in measures of quality of life and function, “especially function in the areas of school, home life, family relations, and peer relationships, which can be really disrupted with ADHD,” Dr. Cutler said.

The prescribing label for viloxazine includes a boxed warning regarding the potential for suicidal thoughts and behaviors in some children with ADHD treated with the drug, especially within the first few months of treatment or when the dose is changed. 

In clinical trials, higher rates of suicidal thoughts and behavior were reported in pediatric patients treated with viloxazine than in patients treated with placebo. Patients taking viloxazine should be closely monitored for any new or sudden changes in mood, behavior, thoughts, and feelings.

Viloxazine has shown promise in a phase 3 trial involving adults with ADHD.

The company plans to submit a supplemental new drug application to the FDA for viloxazine in adults later this year.

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

The Food and Drug Administration has approved the nonstimulant medication viloxazine extended-release capsules (Qelbree, Supernus Pharmaceuticals) for the treatment of attention deficit hyperactivity disorder (ADHD) in children aged 6-17 years, the company has announced.

Viloxazine (formerly SPN-812) is a selective norepinephrine reuptake inhibitor. Capsules may be swallowed whole or opened and the entire contents sprinkled onto applesauce, as needed.

The approval of viloxazine is supported by data from four phase 3 clinical trials involving more than 1,000 pediatric patients aged 6-17 years, the company said.

In one randomized, placebo-controlled phase 3 study that included more than 400 children, viloxazine reduced symptoms of ADHD as soon as 1 week after dosing and was well tolerated.

As reported by this news organization, the study was published last July in Clinical Therapeutics.

In addition to its fast onset of action, the fact that it was effective for both inattentive and hyperactive/impulsive clusters of symptoms is “impressive,” study investigator Andrew Cutler, MD, clinical associate professor of psychiatry, SUNY Upstate Medical University, Syracuse, N.Y., said in an interview.

Also noteworthy was the improvement in measures of quality of life and function, “especially function in the areas of school, home life, family relations, and peer relationships, which can be really disrupted with ADHD,” Dr. Cutler said.

The prescribing label for viloxazine includes a boxed warning regarding the potential for suicidal thoughts and behaviors in some children with ADHD treated with the drug, especially within the first few months of treatment or when the dose is changed. 

In clinical trials, higher rates of suicidal thoughts and behavior were reported in pediatric patients treated with viloxazine than in patients treated with placebo. Patients taking viloxazine should be closely monitored for any new or sudden changes in mood, behavior, thoughts, and feelings.

Viloxazine has shown promise in a phase 3 trial involving adults with ADHD.

The company plans to submit a supplemental new drug application to the FDA for viloxazine in adults later this year.

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

Patients being treated with infliximab had weakened immune responses to the first dose of the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) and BNT162b2 (Pfizer/BioNTech) vaccines, compared with patients on vedolizumab (Entyvio), although a very significant number of patients from both groups seroconverted after their second dose, according to a new U.K. study of patients with inflammatory bowel disease (IBD).

NoSystem images/Getty Images

“Antibody testing and adapted vaccine schedules should be considered to protect these at-risk patients,” Nicholas A. Kennedy, PhD, MBBS, of the University of Exeter (England) and colleagues wrote in a preprint published March 29 on MedRxiv.

Infliximab is an anti–tumor necrosis factor (anti-TNF) monoclonal antibody that’s approved to treat adult and pediatric Crohn’s disease and ulcerative colitis, as well as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, whereas vedolizumab, a gut selective anti-integrin alpha4beta7 monoclonal antibody that is not associated with impaired systemic immune responses, is approved to treat Crohn’s disease and ulcerative colitis in adults.

A previous study from Kennedy and colleagues revealed that IBD patients on infliximab showed a weakened COVID-19 antibody response compared with patients on vedolizumab. To determine if treatment with anti-TNF drugs impacted the efficacy of the first shot of these two-dose COVID-19 vaccines, the researchers used data from the CLARITY IBD study to assess 865 infliximab- and 428 vedolizumab-treated participants without evidence of prior SARS-CoV-2 infection who had received uninterrupted biologic therapy since being recruited between Sept. 22 and Dec. 23, 2020.

In the 3-10 weeks after initial vaccination, geometric mean concentrations for SARS-CoV-2 anti-spike protein receptor-binding protein antibodies were lower in patients on infliximab, compared with patients on vedolizumab for both the Pfizer (6.0 U/mL [5.9] versus 28.8 U/mL [5.4], P < .0001) and AstraZeneca (4.7 U/mL [4.9] versus 13.8 U/mL [5.9]; P < .0001) vaccines. The researchers’ multivariable models reinforced those findings, with antibody concentrations lower in infliximab-treated patients for both the Pfizer (fold change, 0.29; 95% confidence interval, 0.21-0.40; P < .0001) and AstraZeneca (FC, 0.39; 95% CI, 0.30-0.51; P < .0001) vaccines.

After second doses of the two-dose Pfizer vaccine, 85% of patients on infliximab and 86% of patients on vedolizumab seroconverted (P = .68); similarly high seroconversion rates were seen in patients who had been infected with SARS-CoV-2 prior to receiving either vaccine. Several patient characteristics were associated with lower antibody concentrations regardless of vaccine type: being 60 years or older, use of immunomodulators, having Crohn’s disease, and being a smoker. Alternatively, non-White ethnicity was associated with higher antibody concentrations.

Evidence has ‘unclear clinical significance’

“These data, which require peer review, do not change my opinion on the safety and efficacy of COVID-19 vaccines in patients taking TNF inhibitors such as infliximab as monotherapy for the treatment of psoriatic disease,” Joel M. Gelfand MD, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania, Philadelphia, said in an interview.

Courtesy Dr. Joel M. Gelfand

“First, two peer-reviewed studies found good antibody response in patients on TNF inhibitors receiving COVID-19 vaccines (doi: 10.1136/annrheumdis-2021-220289; 10.1136/annrheumdis-2021-220272). Second, antibody responses were robust in the small cohort that received the second dose of a COVID-19 vaccine. We already know that, for the two messenger RNA-based vaccines available under emergency use authorization in the U.S., a second dose is required for optimal efficacy. Thus, evidence of a reduced antibody response after just one dose is of unclear clinical significance. Third, antibody responses are only a surrogate marker, and a low antibody response doesn’t necessarily mean the patient will not be protected by the vaccine.”
 

Focus on the second dose of a two-dose regimen

“Tell me about the response in people who got both doses of a vaccine that you’re supposed to get both doses of,” Jeffrey Curtis, MD, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham, said in an interview. “The number of patients in that subset was small [n = 27] but in my opinion that’s the most clinically relevant analysis and the one that patients and clinicians want answered.”

Courtesy UAB Photo

He also emphasized the uncertainty around what ‘protection’ means in these early days of studying COVID-19 vaccine responses. “You can define seroprotection or seroconversion as some absolute level of an antibody response, but if you want to say ‘Mrs. Smith, your antibody level was X,’ on whatever arbitrary scale with whoever’s arbitrary lab test, nobody actually knows that Mrs. Smith is now protected from SARS-CoV-2, or how protected,” he said.

“What is not terribly controversial is: If you can’t detect antibodies, the vaccine didn’t ‘take,’ if you will. But if I tell you that the mean antibody level was X with one drug and then 2X with another drug, does that mean that you’re twice as protected? We don’t know that. I’m fearful that people are looking at these studies and thinking that more is better. It might be, but we don’t know that to be true.”
 

Debating the cause of weakened immune responses

“The biological plausibility of being on an anti-TNF affecting your immune reaction to a messenger RNA or even a replication-deficient viral vector vaccine doesn’t make sense,” David T. Rubin, MD, professor of medicine at the University of Chicago and chair of the National Scientific Advisory Committee of the Crohn’s and Colitis Foundation, said in an interview.

“I’m sure immunologists may differ with me on this, but given what we have come to appreciate about these vaccine mechanisms, this finding doesn’t make intuitive sense. So we need to make sure that, when this happens, we look to the next studies and try to understand, was there any other confounder that may have resulted in these findings that was not adequately adjusted for or addressed in some other way?

“When you have a study of this size, you argue, ‘Because it’s so large, any effect that was seen must be real,’ ” he added. “Alternatively, to have a study of this size, by its very nature you are limited in being able to control for certain other factors or differences between the groups.”

That said, he commended the authors for their study and acknowledged the potential questions it raises about the single-shot Johnson & Johnson vaccine. “If you only get one and you’re on infliximab, this study implies that maybe that’s not enough,” he said. “Despite the fact that Johnson & Johnson was approved as a single dose, it may be necessary to think about it as the first of two, or maybe it’s not the preferred vaccine in this group of patients.”

The study was supported by the Royal Devon and Exeter and Hull University Hospital Foundation NHS Trusts and unrestricted educational grants from Biogen (Switzerland), Celltrion Healthcare (South Korea), Galapagos NV (Belgium), and F. Hoffmann-La Roche (Switzerland). The authors acknowledged numerous potential conflicts of interest, including receiving grants, personal fees, and nonfinancial support from various pharmaceutical companies.

Patients being treated with infliximab had weakened immune responses to the first dose of the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) and BNT162b2 (Pfizer/BioNTech) vaccines, compared with patients on vedolizumab (Entyvio), although a very significant number of patients from both groups seroconverted after their second dose, according to a new U.K. study of patients with inflammatory bowel disease (IBD).

NoSystem images/Getty Images

“Antibody testing and adapted vaccine schedules should be considered to protect these at-risk patients,” Nicholas A. Kennedy, PhD, MBBS, of the University of Exeter (England) and colleagues wrote in a preprint published March 29 on MedRxiv.

Infliximab is an anti–tumor necrosis factor (anti-TNF) monoclonal antibody that’s approved to treat adult and pediatric Crohn’s disease and ulcerative colitis, as well as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, whereas vedolizumab, a gut selective anti-integrin alpha4beta7 monoclonal antibody that is not associated with impaired systemic immune responses, is approved to treat Crohn’s disease and ulcerative colitis in adults.

A previous study from Kennedy and colleagues revealed that IBD patients on infliximab showed a weakened COVID-19 antibody response compared with patients on vedolizumab. To determine if treatment with anti-TNF drugs impacted the efficacy of the first shot of these two-dose COVID-19 vaccines, the researchers used data from the CLARITY IBD study to assess 865 infliximab- and 428 vedolizumab-treated participants without evidence of prior SARS-CoV-2 infection who had received uninterrupted biologic therapy since being recruited between Sept. 22 and Dec. 23, 2020.

In the 3-10 weeks after initial vaccination, geometric mean concentrations for SARS-CoV-2 anti-spike protein receptor-binding protein antibodies were lower in patients on infliximab, compared with patients on vedolizumab for both the Pfizer (6.0 U/mL [5.9] versus 28.8 U/mL [5.4], P < .0001) and AstraZeneca (4.7 U/mL [4.9] versus 13.8 U/mL [5.9]; P < .0001) vaccines. The researchers’ multivariable models reinforced those findings, with antibody concentrations lower in infliximab-treated patients for both the Pfizer (fold change, 0.29; 95% confidence interval, 0.21-0.40; P < .0001) and AstraZeneca (FC, 0.39; 95% CI, 0.30-0.51; P < .0001) vaccines.

After second doses of the two-dose Pfizer vaccine, 85% of patients on infliximab and 86% of patients on vedolizumab seroconverted (P = .68); similarly high seroconversion rates were seen in patients who had been infected with SARS-CoV-2 prior to receiving either vaccine. Several patient characteristics were associated with lower antibody concentrations regardless of vaccine type: being 60 years or older, use of immunomodulators, having Crohn’s disease, and being a smoker. Alternatively, non-White ethnicity was associated with higher antibody concentrations.

Evidence has ‘unclear clinical significance’

“These data, which require peer review, do not change my opinion on the safety and efficacy of COVID-19 vaccines in patients taking TNF inhibitors such as infliximab as monotherapy for the treatment of psoriatic disease,” Joel M. Gelfand MD, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania, Philadelphia, said in an interview.

Courtesy Dr. Joel M. Gelfand

“First, two peer-reviewed studies found good antibody response in patients on TNF inhibitors receiving COVID-19 vaccines (doi: 10.1136/annrheumdis-2021-220289; 10.1136/annrheumdis-2021-220272). Second, antibody responses were robust in the small cohort that received the second dose of a COVID-19 vaccine. We already know that, for the two messenger RNA-based vaccines available under emergency use authorization in the U.S., a second dose is required for optimal efficacy. Thus, evidence of a reduced antibody response after just one dose is of unclear clinical significance. Third, antibody responses are only a surrogate marker, and a low antibody response doesn’t necessarily mean the patient will not be protected by the vaccine.”
 

Focus on the second dose of a two-dose regimen

“Tell me about the response in people who got both doses of a vaccine that you’re supposed to get both doses of,” Jeffrey Curtis, MD, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham, said in an interview. “The number of patients in that subset was small [n = 27] but in my opinion that’s the most clinically relevant analysis and the one that patients and clinicians want answered.”

Courtesy UAB Photo

He also emphasized the uncertainty around what ‘protection’ means in these early days of studying COVID-19 vaccine responses. “You can define seroprotection or seroconversion as some absolute level of an antibody response, but if you want to say ‘Mrs. Smith, your antibody level was X,’ on whatever arbitrary scale with whoever’s arbitrary lab test, nobody actually knows that Mrs. Smith is now protected from SARS-CoV-2, or how protected,” he said.

“What is not terribly controversial is: If you can’t detect antibodies, the vaccine didn’t ‘take,’ if you will. But if I tell you that the mean antibody level was X with one drug and then 2X with another drug, does that mean that you’re twice as protected? We don’t know that. I’m fearful that people are looking at these studies and thinking that more is better. It might be, but we don’t know that to be true.”
 

Debating the cause of weakened immune responses

“The biological plausibility of being on an anti-TNF affecting your immune reaction to a messenger RNA or even a replication-deficient viral vector vaccine doesn’t make sense,” David T. Rubin, MD, professor of medicine at the University of Chicago and chair of the National Scientific Advisory Committee of the Crohn’s and Colitis Foundation, said in an interview.

“I’m sure immunologists may differ with me on this, but given what we have come to appreciate about these vaccine mechanisms, this finding doesn’t make intuitive sense. So we need to make sure that, when this happens, we look to the next studies and try to understand, was there any other confounder that may have resulted in these findings that was not adequately adjusted for or addressed in some other way?

“When you have a study of this size, you argue, ‘Because it’s so large, any effect that was seen must be real,’ ” he added. “Alternatively, to have a study of this size, by its very nature you are limited in being able to control for certain other factors or differences between the groups.”

That said, he commended the authors for their study and acknowledged the potential questions it raises about the single-shot Johnson & Johnson vaccine. “If you only get one and you’re on infliximab, this study implies that maybe that’s not enough,” he said. “Despite the fact that Johnson & Johnson was approved as a single dose, it may be necessary to think about it as the first of two, or maybe it’s not the preferred vaccine in this group of patients.”

The study was supported by the Royal Devon and Exeter and Hull University Hospital Foundation NHS Trusts and unrestricted educational grants from Biogen (Switzerland), Celltrion Healthcare (South Korea), Galapagos NV (Belgium), and F. Hoffmann-La Roche (Switzerland). The authors acknowledged numerous potential conflicts of interest, including receiving grants, personal fees, and nonfinancial support from various pharmaceutical companies.

Patients being treated with infliximab had weakened immune responses to the first dose of the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) and BNT162b2 (Pfizer/BioNTech) vaccines, compared with patients on vedolizumab (Entyvio), although a very significant number of patients from both groups seroconverted after their second dose, according to a new U.K. study of patients with inflammatory bowel disease (IBD).

NoSystem images/Getty Images

“Antibody testing and adapted vaccine schedules should be considered to protect these at-risk patients,” Nicholas A. Kennedy, PhD, MBBS, of the University of Exeter (England) and colleagues wrote in a preprint published March 29 on MedRxiv.

Infliximab is an anti–tumor necrosis factor (anti-TNF) monoclonal antibody that’s approved to treat adult and pediatric Crohn’s disease and ulcerative colitis, as well as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, whereas vedolizumab, a gut selective anti-integrin alpha4beta7 monoclonal antibody that is not associated with impaired systemic immune responses, is approved to treat Crohn’s disease and ulcerative colitis in adults.

A previous study from Kennedy and colleagues revealed that IBD patients on infliximab showed a weakened COVID-19 antibody response compared with patients on vedolizumab. To determine if treatment with anti-TNF drugs impacted the efficacy of the first shot of these two-dose COVID-19 vaccines, the researchers used data from the CLARITY IBD study to assess 865 infliximab- and 428 vedolizumab-treated participants without evidence of prior SARS-CoV-2 infection who had received uninterrupted biologic therapy since being recruited between Sept. 22 and Dec. 23, 2020.

In the 3-10 weeks after initial vaccination, geometric mean concentrations for SARS-CoV-2 anti-spike protein receptor-binding protein antibodies were lower in patients on infliximab, compared with patients on vedolizumab for both the Pfizer (6.0 U/mL [5.9] versus 28.8 U/mL [5.4], P < .0001) and AstraZeneca (4.7 U/mL [4.9] versus 13.8 U/mL [5.9]; P < .0001) vaccines. The researchers’ multivariable models reinforced those findings, with antibody concentrations lower in infliximab-treated patients for both the Pfizer (fold change, 0.29; 95% confidence interval, 0.21-0.40; P < .0001) and AstraZeneca (FC, 0.39; 95% CI, 0.30-0.51; P < .0001) vaccines.

After second doses of the two-dose Pfizer vaccine, 85% of patients on infliximab and 86% of patients on vedolizumab seroconverted (P = .68); similarly high seroconversion rates were seen in patients who had been infected with SARS-CoV-2 prior to receiving either vaccine. Several patient characteristics were associated with lower antibody concentrations regardless of vaccine type: being 60 years or older, use of immunomodulators, having Crohn’s disease, and being a smoker. Alternatively, non-White ethnicity was associated with higher antibody concentrations.

Evidence has ‘unclear clinical significance’

“These data, which require peer review, do not change my opinion on the safety and efficacy of COVID-19 vaccines in patients taking TNF inhibitors such as infliximab as monotherapy for the treatment of psoriatic disease,” Joel M. Gelfand MD, director of the psoriasis and phototherapy treatment center at the University of Pennsylvania, Philadelphia, said in an interview.

Courtesy Dr. Joel M. Gelfand

“First, two peer-reviewed studies found good antibody response in patients on TNF inhibitors receiving COVID-19 vaccines (doi: 10.1136/annrheumdis-2021-220289; 10.1136/annrheumdis-2021-220272). Second, antibody responses were robust in the small cohort that received the second dose of a COVID-19 vaccine. We already know that, for the two messenger RNA-based vaccines available under emergency use authorization in the U.S., a second dose is required for optimal efficacy. Thus, evidence of a reduced antibody response after just one dose is of unclear clinical significance. Third, antibody responses are only a surrogate marker, and a low antibody response doesn’t necessarily mean the patient will not be protected by the vaccine.”
 

Focus on the second dose of a two-dose regimen

“Tell me about the response in people who got both doses of a vaccine that you’re supposed to get both doses of,” Jeffrey Curtis, MD, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham, said in an interview. “The number of patients in that subset was small [n = 27] but in my opinion that’s the most clinically relevant analysis and the one that patients and clinicians want answered.”

Courtesy UAB Photo

He also emphasized the uncertainty around what ‘protection’ means in these early days of studying COVID-19 vaccine responses. “You can define seroprotection or seroconversion as some absolute level of an antibody response, but if you want to say ‘Mrs. Smith, your antibody level was X,’ on whatever arbitrary scale with whoever’s arbitrary lab test, nobody actually knows that Mrs. Smith is now protected from SARS-CoV-2, or how protected,” he said.

“What is not terribly controversial is: If you can’t detect antibodies, the vaccine didn’t ‘take,’ if you will. But if I tell you that the mean antibody level was X with one drug and then 2X with another drug, does that mean that you’re twice as protected? We don’t know that. I’m fearful that people are looking at these studies and thinking that more is better. It might be, but we don’t know that to be true.”
 

Debating the cause of weakened immune responses

“The biological plausibility of being on an anti-TNF affecting your immune reaction to a messenger RNA or even a replication-deficient viral vector vaccine doesn’t make sense,” David T. Rubin, MD, professor of medicine at the University of Chicago and chair of the National Scientific Advisory Committee of the Crohn’s and Colitis Foundation, said in an interview.

“I’m sure immunologists may differ with me on this, but given what we have come to appreciate about these vaccine mechanisms, this finding doesn’t make intuitive sense. So we need to make sure that, when this happens, we look to the next studies and try to understand, was there any other confounder that may have resulted in these findings that was not adequately adjusted for or addressed in some other way?

“When you have a study of this size, you argue, ‘Because it’s so large, any effect that was seen must be real,’ ” he added. “Alternatively, to have a study of this size, by its very nature you are limited in being able to control for certain other factors or differences between the groups.”

That said, he commended the authors for their study and acknowledged the potential questions it raises about the single-shot Johnson & Johnson vaccine. “If you only get one and you’re on infliximab, this study implies that maybe that’s not enough,” he said. “Despite the fact that Johnson & Johnson was approved as a single dose, it may be necessary to think about it as the first of two, or maybe it’s not the preferred vaccine in this group of patients.”

The study was supported by the Royal Devon and Exeter and Hull University Hospital Foundation NHS Trusts and unrestricted educational grants from Biogen (Switzerland), Celltrion Healthcare (South Korea), Galapagos NV (Belgium), and F. Hoffmann-La Roche (Switzerland). The authors acknowledged numerous potential conflicts of interest, including receiving grants, personal fees, and nonfinancial support from various pharmaceutical companies.

Children and adolescents with Prader-Willi syndrome (PWS) who received three daily, intranasal doses of carbetocin, an investigational, long-acting oxytocin analogue, had significant improvement in hyperphagia and anxiety during 8 weeks on treatment, compared with placebo in a multicenter, phase 3 trial with 119 patients.

The treatment also appeared safe during up to 56 additional weeks on active treatment, with no serious adverse effects nor “unexpected” events, and once completing the study about 95% of enrolled patients opted to remain on active treatment, Cheri L. Deal, MD, PhD, said at the annual meeting of the Endocrine Society.

Based on “the significant results for the placebo-controlled period, as well as for those finishing the 56-week extension, we may well have a new armament for helping these kids and their families deal with the unrelenting hunger of patients with PWS as well as some of the behavioral symptoms,” Dr. Deal, chief of endocrinology and diabetes at the Sainte-Justine Mother-Child University of Montreal Hospital, said in an interview. No treatment currently has labeling for addressing the hyperphagia or anxiety that is characteristic and often problematic for children and adolescents with PWS, an autosomal dominant genetic disease with an incidence of about 1 in 15,000 births and an estimated U.S. prevalence of about 9,000 cases, or about 1 case for every 37,000 people.
 

‘Gorgeous’ safety

“The results looked pretty positive, and we’re encouraged by what appears to be a good safety profile, so overall I think the PWS community is very excited by the results and is very interested in getting access to this drug,” commented Theresa V. Strong, PhD, director of research programs for the Foundation for Prader-Willi Research in Walnut, Calif., a group not involved with the study. Currently, “we have no effective treatments for these difficult behaviors” of hyperphagia and anxiety. Surveys and studies run by the foundation have documented that hyperphagia and anxiety “were the two most important symptoms that families would like to see treated,” Dr. Strong added in an interview.

PWS “is complex and affects almost every aspect of the lives of affected people and their families. Any treatment that can chip away at some of the problems these patients have can be a huge benefit to the patients and their families,” said Jennifer L. Miller, MD, a professor of pediatric endocrinology at the University of Florida, Gainesville, and a coinvestigator on the study.

But the finding that carbetocin appeared to address, at least in part, this unmet need while compiling a safety record that Dr. Miller called “gorgeous” and “remarkable,” also came with a few limitations.
 

Fewer patients than planned, and muddled outcomes

The CARE-PWS trial aimed to enroll 175 patients, but fell short once the COVID-19 pandemic hit. Plus the trial had two prespecified primary endpoints – improvements in a measure of hyperphagia, and in a measure of obsessive and compulsive behaviors – specifically in the 40 patients who received the higher of the two dosages studied, 9.6 mg t.i.d. intranasally. Neither endpoint showed significant improvement among the patients on this dosage, compared with the 40 patients who received placebo, although both outcomes trended in the right direction in the actively treated patients.

The study’s positive results came in a secondary treatment group, 39 patients who received 3.2 mg t.i.d., also intranasally. This subgroup had significant benefit, compared with placebo, for reducing hyperphagia symptoms as measured on the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score. After the first 8 weeks on treatment, patients on the lower carbetocin dosage had an average reduction in their HQ-CT score of greater than 5 points, more than double the reduction seen among control patients who received placebo.

Those on the 3.2-mg t.i.d. dosage also showed significant improvements, compared with placebo, for anxiety, measured by the PWS Anxiety and Distress Questionnaire Total Score, as well as on measures of clinical global impression of severity, and of clinical global impression of change. Like the higher-dosage patients the lower-dosage subgroup did not show a significant difference compared with placebo for the other primary endpoint, change in obsessive and compulsive behaviors as measured by the Children’s Yale-Brown Obsessive-Compulsive Scale Total Score, although also like the higher dosage the effect from the lower dosage trended toward benefit.

A further limitation was that, at the time of her report, presented in abstract OR16-3 at the meeting, Dr. Deal could only present complete 64-week follow-up for 72 patients, although this reassuringly showed that, as time on the 9.6-mg t.i.d. dosage continued beyond 8 weeks, patients gradually improved their HQ-CT response so that by 64 weeks on treatment their hyperphagia score had improved as much as in the patients who received the lower dosage.

In short, documented benefits occurred on the lower dosage, especially for clinically meaningful symptoms like hyperphagia and anxiety, but the study’s overall results were not fully consistent by statistical criteria.

Benefiting an unmet need?

“While it is regrettable that we did not get to 175 patients because of COVID-19, the dataset is significant enough for me to feel that the FDA [Food and Drug Administration] needs to take a very serious look and consider approval,” Dr. Deal said in an interview. “Once safety is assured, which I think it is, I can only hope that regulatory officials understand their unmet needs of this rare disease community and will allow the drug to move to the next stage.”

“This is a very rare disease, and having families participate in trials is really challenging,” especially while the COVID-19 pandemic continues, Dr. Strong said. For the pediatric and adolescent patients targeted in this study “it will take a while for COVID to go away and for families to feel safe again being in a trial, so a real concern is that a need for more clinical trials is not terribly feasible now. Given that the safety profile looked good and one dose seemed to have good efficacy, as long as the long-term data continue to look good we’d love for the FDA to look at the existing data and see whether there is a path forward.”

Dr. Miller highlighted the limitations of what the CARE-PWS findings show.

“Given that it was only an 8-week trial of drug against placebo, and the fact that the primary outcomes weren’t met for the higher dose, my thought is that potentially we need to study more patients for a longer period at the 3.2-mg dose,” she said. She acknowledged that the metric used in the study to assess obsessive and compulsive behaviors is “very difficult” to apply to patients with PWS because of uncertainties in scoring obsessions in patients “who are not very good at telling you what they’re thinking.” Plus, “it’s absolutely not a problem that we did not see an effect on obsession and compulsions if the treatment potentially improves anxiety and hyperphagia, which are very common.” A treatment that reliably reduces these symptoms “would be amazing,” Dr. Miller added.

“PWS is very rare, so it’s very hard to do trials. Maybe the FDA will approve carbetocin because it was safe and gave a signal of efficacy at the lower dose. But my thought is that additional treatment trials are needed with only the lower dose and with longer duration,” she said.

CARE-PWS enrolled patients with nutritional phase 3 PWS who were aged 7-18 years at any of 24 sites in the United States, Canada, or Australia during 2018-2020. They averaged about 12 years of age, and 56% were girls.

The most common adverse effect from carbetocin was flushing, occurring in 14% of those on the lower dose and 21% on the higher dose, but not in any placebo patient. Other adverse effects more common on the lower dose than in the placebo group included headache in 16%, and diarrhea in 9%.

Carbetocin is not only long-lasting in circulation, it also has better affinity for oxytocin receptors than for vasopressin receptors, reducing the potential for causing hyponatremia. The idea to use it in patients with PWS followed prior studies with oxytocin, which had shown dopamine interactions that reduced anxiety and influenced food ingestion behavior. Brain autopsy studies had shown that patients with Prader-Willi syndrome have substantially fewer neurons than usual producing oxytocin. Treatment with intranasal carbetocin had shown efficacy for improving hyperphagia and behavior in a controlled phase 2 study with 37 patients.

Carbetocin is approved for use in reducing excessive bleeding after childbirth, particularly cesarean, in more than 20 countries outside the United States.

CARE-PWS was sponsored by Levo Therapeutics, the company developing carbetocin. Dr. Deal has been an adviser to Levo Therapeutics. Dr. Strong is an employee of the Foundation for Prader-Willi Research, which has received support from Levo Therapeutics as well as from other drug companies, but which receives most of its funding from individuals. Dr. Miller has received research funding from Levo Therapeutics and also from Harmony Biosciences, Rhythm Pharmaceuticals, and Soleno Therapeutics.

[email protected]

Children and adolescents with Prader-Willi syndrome (PWS) who received three daily, intranasal doses of carbetocin, an investigational, long-acting oxytocin analogue, had significant improvement in hyperphagia and anxiety during 8 weeks on treatment, compared with placebo in a multicenter, phase 3 trial with 119 patients.

The treatment also appeared safe during up to 56 additional weeks on active treatment, with no serious adverse effects nor “unexpected” events, and once completing the study about 95% of enrolled patients opted to remain on active treatment, Cheri L. Deal, MD, PhD, said at the annual meeting of the Endocrine Society.

Based on “the significant results for the placebo-controlled period, as well as for those finishing the 56-week extension, we may well have a new armament for helping these kids and their families deal with the unrelenting hunger of patients with PWS as well as some of the behavioral symptoms,” Dr. Deal, chief of endocrinology and diabetes at the Sainte-Justine Mother-Child University of Montreal Hospital, said in an interview. No treatment currently has labeling for addressing the hyperphagia or anxiety that is characteristic and often problematic for children and adolescents with PWS, an autosomal dominant genetic disease with an incidence of about 1 in 15,000 births and an estimated U.S. prevalence of about 9,000 cases, or about 1 case for every 37,000 people.
 

‘Gorgeous’ safety

“The results looked pretty positive, and we’re encouraged by what appears to be a good safety profile, so overall I think the PWS community is very excited by the results and is very interested in getting access to this drug,” commented Theresa V. Strong, PhD, director of research programs for the Foundation for Prader-Willi Research in Walnut, Calif., a group not involved with the study. Currently, “we have no effective treatments for these difficult behaviors” of hyperphagia and anxiety. Surveys and studies run by the foundation have documented that hyperphagia and anxiety “were the two most important symptoms that families would like to see treated,” Dr. Strong added in an interview.

PWS “is complex and affects almost every aspect of the lives of affected people and their families. Any treatment that can chip away at some of the problems these patients have can be a huge benefit to the patients and their families,” said Jennifer L. Miller, MD, a professor of pediatric endocrinology at the University of Florida, Gainesville, and a coinvestigator on the study.

But the finding that carbetocin appeared to address, at least in part, this unmet need while compiling a safety record that Dr. Miller called “gorgeous” and “remarkable,” also came with a few limitations.
 

Fewer patients than planned, and muddled outcomes

The CARE-PWS trial aimed to enroll 175 patients, but fell short once the COVID-19 pandemic hit. Plus the trial had two prespecified primary endpoints – improvements in a measure of hyperphagia, and in a measure of obsessive and compulsive behaviors – specifically in the 40 patients who received the higher of the two dosages studied, 9.6 mg t.i.d. intranasally. Neither endpoint showed significant improvement among the patients on this dosage, compared with the 40 patients who received placebo, although both outcomes trended in the right direction in the actively treated patients.

The study’s positive results came in a secondary treatment group, 39 patients who received 3.2 mg t.i.d., also intranasally. This subgroup had significant benefit, compared with placebo, for reducing hyperphagia symptoms as measured on the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score. After the first 8 weeks on treatment, patients on the lower carbetocin dosage had an average reduction in their HQ-CT score of greater than 5 points, more than double the reduction seen among control patients who received placebo.

Those on the 3.2-mg t.i.d. dosage also showed significant improvements, compared with placebo, for anxiety, measured by the PWS Anxiety and Distress Questionnaire Total Score, as well as on measures of clinical global impression of severity, and of clinical global impression of change. Like the higher-dosage patients the lower-dosage subgroup did not show a significant difference compared with placebo for the other primary endpoint, change in obsessive and compulsive behaviors as measured by the Children’s Yale-Brown Obsessive-Compulsive Scale Total Score, although also like the higher dosage the effect from the lower dosage trended toward benefit.

A further limitation was that, at the time of her report, presented in abstract OR16-3 at the meeting, Dr. Deal could only present complete 64-week follow-up for 72 patients, although this reassuringly showed that, as time on the 9.6-mg t.i.d. dosage continued beyond 8 weeks, patients gradually improved their HQ-CT response so that by 64 weeks on treatment their hyperphagia score had improved as much as in the patients who received the lower dosage.

In short, documented benefits occurred on the lower dosage, especially for clinically meaningful symptoms like hyperphagia and anxiety, but the study’s overall results were not fully consistent by statistical criteria.

Benefiting an unmet need?

“While it is regrettable that we did not get to 175 patients because of COVID-19, the dataset is significant enough for me to feel that the FDA [Food and Drug Administration] needs to take a very serious look and consider approval,” Dr. Deal said in an interview. “Once safety is assured, which I think it is, I can only hope that regulatory officials understand their unmet needs of this rare disease community and will allow the drug to move to the next stage.”

“This is a very rare disease, and having families participate in trials is really challenging,” especially while the COVID-19 pandemic continues, Dr. Strong said. For the pediatric and adolescent patients targeted in this study “it will take a while for COVID to go away and for families to feel safe again being in a trial, so a real concern is that a need for more clinical trials is not terribly feasible now. Given that the safety profile looked good and one dose seemed to have good efficacy, as long as the long-term data continue to look good we’d love for the FDA to look at the existing data and see whether there is a path forward.”

Dr. Miller highlighted the limitations of what the CARE-PWS findings show.

“Given that it was only an 8-week trial of drug against placebo, and the fact that the primary outcomes weren’t met for the higher dose, my thought is that potentially we need to study more patients for a longer period at the 3.2-mg dose,” she said. She acknowledged that the metric used in the study to assess obsessive and compulsive behaviors is “very difficult” to apply to patients with PWS because of uncertainties in scoring obsessions in patients “who are not very good at telling you what they’re thinking.” Plus, “it’s absolutely not a problem that we did not see an effect on obsession and compulsions if the treatment potentially improves anxiety and hyperphagia, which are very common.” A treatment that reliably reduces these symptoms “would be amazing,” Dr. Miller added.

“PWS is very rare, so it’s very hard to do trials. Maybe the FDA will approve carbetocin because it was safe and gave a signal of efficacy at the lower dose. But my thought is that additional treatment trials are needed with only the lower dose and with longer duration,” she said.

CARE-PWS enrolled patients with nutritional phase 3 PWS who were aged 7-18 years at any of 24 sites in the United States, Canada, or Australia during 2018-2020. They averaged about 12 years of age, and 56% were girls.

The most common adverse effect from carbetocin was flushing, occurring in 14% of those on the lower dose and 21% on the higher dose, but not in any placebo patient. Other adverse effects more common on the lower dose than in the placebo group included headache in 16%, and diarrhea in 9%.

Carbetocin is not only long-lasting in circulation, it also has better affinity for oxytocin receptors than for vasopressin receptors, reducing the potential for causing hyponatremia. The idea to use it in patients with PWS followed prior studies with oxytocin, which had shown dopamine interactions that reduced anxiety and influenced food ingestion behavior. Brain autopsy studies had shown that patients with Prader-Willi syndrome have substantially fewer neurons than usual producing oxytocin. Treatment with intranasal carbetocin had shown efficacy for improving hyperphagia and behavior in a controlled phase 2 study with 37 patients.

Carbetocin is approved for use in reducing excessive bleeding after childbirth, particularly cesarean, in more than 20 countries outside the United States.

CARE-PWS was sponsored by Levo Therapeutics, the company developing carbetocin. Dr. Deal has been an adviser to Levo Therapeutics. Dr. Strong is an employee of the Foundation for Prader-Willi Research, which has received support from Levo Therapeutics as well as from other drug companies, but which receives most of its funding from individuals. Dr. Miller has received research funding from Levo Therapeutics and also from Harmony Biosciences, Rhythm Pharmaceuticals, and Soleno Therapeutics.

[email protected]

Children and adolescents with Prader-Willi syndrome (PWS) who received three daily, intranasal doses of carbetocin, an investigational, long-acting oxytocin analogue, had significant improvement in hyperphagia and anxiety during 8 weeks on treatment, compared with placebo in a multicenter, phase 3 trial with 119 patients.

The treatment also appeared safe during up to 56 additional weeks on active treatment, with no serious adverse effects nor “unexpected” events, and once completing the study about 95% of enrolled patients opted to remain on active treatment, Cheri L. Deal, MD, PhD, said at the annual meeting of the Endocrine Society.

Based on “the significant results for the placebo-controlled period, as well as for those finishing the 56-week extension, we may well have a new armament for helping these kids and their families deal with the unrelenting hunger of patients with PWS as well as some of the behavioral symptoms,” Dr. Deal, chief of endocrinology and diabetes at the Sainte-Justine Mother-Child University of Montreal Hospital, said in an interview. No treatment currently has labeling for addressing the hyperphagia or anxiety that is characteristic and often problematic for children and adolescents with PWS, an autosomal dominant genetic disease with an incidence of about 1 in 15,000 births and an estimated U.S. prevalence of about 9,000 cases, or about 1 case for every 37,000 people.
 

‘Gorgeous’ safety

“The results looked pretty positive, and we’re encouraged by what appears to be a good safety profile, so overall I think the PWS community is very excited by the results and is very interested in getting access to this drug,” commented Theresa V. Strong, PhD, director of research programs for the Foundation for Prader-Willi Research in Walnut, Calif., a group not involved with the study. Currently, “we have no effective treatments for these difficult behaviors” of hyperphagia and anxiety. Surveys and studies run by the foundation have documented that hyperphagia and anxiety “were the two most important symptoms that families would like to see treated,” Dr. Strong added in an interview.

PWS “is complex and affects almost every aspect of the lives of affected people and their families. Any treatment that can chip away at some of the problems these patients have can be a huge benefit to the patients and their families,” said Jennifer L. Miller, MD, a professor of pediatric endocrinology at the University of Florida, Gainesville, and a coinvestigator on the study.

But the finding that carbetocin appeared to address, at least in part, this unmet need while compiling a safety record that Dr. Miller called “gorgeous” and “remarkable,” also came with a few limitations.
 

Fewer patients than planned, and muddled outcomes

The CARE-PWS trial aimed to enroll 175 patients, but fell short once the COVID-19 pandemic hit. Plus the trial had two prespecified primary endpoints – improvements in a measure of hyperphagia, and in a measure of obsessive and compulsive behaviors – specifically in the 40 patients who received the higher of the two dosages studied, 9.6 mg t.i.d. intranasally. Neither endpoint showed significant improvement among the patients on this dosage, compared with the 40 patients who received placebo, although both outcomes trended in the right direction in the actively treated patients.

The study’s positive results came in a secondary treatment group, 39 patients who received 3.2 mg t.i.d., also intranasally. This subgroup had significant benefit, compared with placebo, for reducing hyperphagia symptoms as measured on the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score. After the first 8 weeks on treatment, patients on the lower carbetocin dosage had an average reduction in their HQ-CT score of greater than 5 points, more than double the reduction seen among control patients who received placebo.

Those on the 3.2-mg t.i.d. dosage also showed significant improvements, compared with placebo, for anxiety, measured by the PWS Anxiety and Distress Questionnaire Total Score, as well as on measures of clinical global impression of severity, and of clinical global impression of change. Like the higher-dosage patients the lower-dosage subgroup did not show a significant difference compared with placebo for the other primary endpoint, change in obsessive and compulsive behaviors as measured by the Children’s Yale-Brown Obsessive-Compulsive Scale Total Score, although also like the higher dosage the effect from the lower dosage trended toward benefit.

A further limitation was that, at the time of her report, presented in abstract OR16-3 at the meeting, Dr. Deal could only present complete 64-week follow-up for 72 patients, although this reassuringly showed that, as time on the 9.6-mg t.i.d. dosage continued beyond 8 weeks, patients gradually improved their HQ-CT response so that by 64 weeks on treatment their hyperphagia score had improved as much as in the patients who received the lower dosage.

In short, documented benefits occurred on the lower dosage, especially for clinically meaningful symptoms like hyperphagia and anxiety, but the study’s overall results were not fully consistent by statistical criteria.

Benefiting an unmet need?

“While it is regrettable that we did not get to 175 patients because of COVID-19, the dataset is significant enough for me to feel that the FDA [Food and Drug Administration] needs to take a very serious look and consider approval,” Dr. Deal said in an interview. “Once safety is assured, which I think it is, I can only hope that regulatory officials understand their unmet needs of this rare disease community and will allow the drug to move to the next stage.”

“This is a very rare disease, and having families participate in trials is really challenging,” especially while the COVID-19 pandemic continues, Dr. Strong said. For the pediatric and adolescent patients targeted in this study “it will take a while for COVID to go away and for families to feel safe again being in a trial, so a real concern is that a need for more clinical trials is not terribly feasible now. Given that the safety profile looked good and one dose seemed to have good efficacy, as long as the long-term data continue to look good we’d love for the FDA to look at the existing data and see whether there is a path forward.”

Dr. Miller highlighted the limitations of what the CARE-PWS findings show.

“Given that it was only an 8-week trial of drug against placebo, and the fact that the primary outcomes weren’t met for the higher dose, my thought is that potentially we need to study more patients for a longer period at the 3.2-mg dose,” she said. She acknowledged that the metric used in the study to assess obsessive and compulsive behaviors is “very difficult” to apply to patients with PWS because of uncertainties in scoring obsessions in patients “who are not very good at telling you what they’re thinking.” Plus, “it’s absolutely not a problem that we did not see an effect on obsession and compulsions if the treatment potentially improves anxiety and hyperphagia, which are very common.” A treatment that reliably reduces these symptoms “would be amazing,” Dr. Miller added.

“PWS is very rare, so it’s very hard to do trials. Maybe the FDA will approve carbetocin because it was safe and gave a signal of efficacy at the lower dose. But my thought is that additional treatment trials are needed with only the lower dose and with longer duration,” she said.

CARE-PWS enrolled patients with nutritional phase 3 PWS who were aged 7-18 years at any of 24 sites in the United States, Canada, or Australia during 2018-2020. They averaged about 12 years of age, and 56% were girls.

The most common adverse effect from carbetocin was flushing, occurring in 14% of those on the lower dose and 21% on the higher dose, but not in any placebo patient. Other adverse effects more common on the lower dose than in the placebo group included headache in 16%, and diarrhea in 9%.

Carbetocin is not only long-lasting in circulation, it also has better affinity for oxytocin receptors than for vasopressin receptors, reducing the potential for causing hyponatremia. The idea to use it in patients with PWS followed prior studies with oxytocin, which had shown dopamine interactions that reduced anxiety and influenced food ingestion behavior. Brain autopsy studies had shown that patients with Prader-Willi syndrome have substantially fewer neurons than usual producing oxytocin. Treatment with intranasal carbetocin had shown efficacy for improving hyperphagia and behavior in a controlled phase 2 study with 37 patients.

Carbetocin is approved for use in reducing excessive bleeding after childbirth, particularly cesarean, in more than 20 countries outside the United States.

CARE-PWS was sponsored by Levo Therapeutics, the company developing carbetocin. Dr. Deal has been an adviser to Levo Therapeutics. Dr. Strong is an employee of the Foundation for Prader-Willi Research, which has received support from Levo Therapeutics as well as from other drug companies, but which receives most of its funding from individuals. Dr. Miller has received research funding from Levo Therapeutics and also from Harmony Biosciences, Rhythm Pharmaceuticals, and Soleno Therapeutics.

[email protected]