User login
Follow-Up for Pediatric Depression Doubles With New Quality Initiative
TORONTO — An ambitious effort at a busy pediatrics clinic to improve follow-up in children and adolescents with a positive depression screen improved this quality metric, and it produced a fundamental change in approach.
“It was a big culture shift,” reported Landon B. Krantz, MD, a clinical fellow in the Division of General and Community Pediatrics at Cincinnati Children’s Hospital in Ohio. From a baseline position of screening, risk identification, and then referral, “we are now taking ownership of the process.”
Based on the substantial risk posed by significant levels of depression, guidelines recommend follow-up for any patient 12 years or older who has a positive screen, according to Dr. Krantz. At his center, they found only 19% had a documented follow-up within 30 days, even though timely intervention is important.
“Nearly half of suicide events in adolescents occur within 30 days after a positive PHQ-9 [9-question Patient Health Questionnaire] is completed,” said Dr. Krantz when presenting his data at the Pediatric Academic Societies annual meeting.
The issue has gained more urgency because of the substantial increase over the past several years in children presenting with depression and suicidal thoughts, according to Dr. Krantz. He said many are characterizing the upsurge as a mental health crisis in the pediatric age group.
Improving Follow-Up
. The goal at the outset was to increase the proportion to 35%.
“We know that a lot of children would receive follow-up at centers outside of our system,” said Dr. Krantz, explaining why the goal was relatively modest. Based on the likelihood that many follow-up visits would not be captured, he expected the final data would represent an underestimate.
Depression at baseline was defined as a score of 10 or higher on the PHQ-9 or any positive answer to item 9 on this screening tool, which asks specifically about thoughts of self-harm.
To be counted, follow-up had to be a documented encounter, whether by phone call, in-person visit, or telehealth visit.
“We needed patients to be checked. We did not count a prescription refill as a true follow-up,” Dr. Krantz specified.
There were numerous strategies implemented to improve follow-up, not least of which was an educational program to reinforce the importance and value of follow-up that was disseminated to clinicians in all of the participating clinics. Medical assistants were instructed to schedule a follow-up appointment for all patients who tested positive before they left the office. A target of 3 weeks was a strategy of overcorrection when so many patients were missing the initial 30-day window by just a few days.
The approach also involved an enhanced collaboration with psychologists to which patients were referred. Asking for expedited appointments when appropriate ensured that those at highest risk were prioritized, although Dr. Krantz said that this step was planned carefully to avoid overwhelming the mental health team.
“We monitored this and made sure it was not increasing the burden for psychologists from a capacity standpoint,” he said.
Other steps, like a depression action plan, which Dr. Krantz compared to an asthma action plan, were also implemented to reduce the risk of losing symptomatic patients before the chance for an effective treatment.
When compared with the 19% 30-day follow-up rate in the preintervention sample of 589 children, the 43.8% 30-day follow-up rate achieved in the 764 patients identified after implementation beat the original goal.
The improvement in follow-up was relatively consistent across all six clinics, which Dr. Krantz believes reflected a broad and shared change in a sense of responsibility for confirming that symptoms of depression were being addressed. Patients were still referred for psychological help, but referral was no longer considered enough.
“Children with mental health issues are still our patients in primary care,” said Dr. Krantz, who considers this an important change in orientation.
While the goal was to schedule patients for a follow-up at the time of a positive depression screen, Dr. Krantz described one important accommodation.
“The screen for depression was being performed in most cases during well visits, so patients and their families were not expecting to be discussing this issue,” he said. The diagnosis might be a particular surprise to parents who were not aware of any symptoms. In this case, Dr. Krantz said patients and families were given time to process the information and were contacted after a week to discuss further workup.
It is also notable that about one third of patients met the criteria for depression by answering positively to the PHQ-9 item on self-harm when they did not meet the 10 or more threshold depression score overall. In other words, these patients would have been missed without this criterion.
In the participating Cincinnati pediatric clinics, about 12%-13% of adolescents met the criteria for depression, which Dr. Krantz said is consistent with reports in the literature. He said the range is about 6%-24%.
Although outcomes were not tracked, there is evidence that early intervention for depression yields better outcomes than delayed intervention, according to Dr. Krantz. Based on approximately 600 positive screens for depression per year at his pediatric clinics, he estimated that his data predict at least 25% more patients will receive timely follow-up.
Seeking Solutions to a Growing Problem
There are several studies documenting the growing problem of adolescent depression and suicide and, for this reason, the topic is attracting a lot of attention, according to Corinna Rea, MD, MPH, a pediatrician working in the primary care center at Boston Children’s Hospital in Massachusetts.
Dr. Rea was not involved with the study, but when asked to comment, she said: “The results of this study were encouraging because we know that getting patients to care quickly is probably important.” She also agreed that referring patients with depression for care might not be enough, noting that a lot of patients do not follow up on recommendations to pursue a consultation or treatment.
“I am now involved in a project with the American Academy of Pediatrics to address this issue,” Dr. Rae said. She thinks that more work in this area is needed and agreed with Dr. Krantz that pediatricians should verify that children with depression are getting help even when other specialists are providing the treatment.
Dr. Krantz and Dr. Rae report no potential conflicts of interest.
TORONTO — An ambitious effort at a busy pediatrics clinic to improve follow-up in children and adolescents with a positive depression screen improved this quality metric, and it produced a fundamental change in approach.
“It was a big culture shift,” reported Landon B. Krantz, MD, a clinical fellow in the Division of General and Community Pediatrics at Cincinnati Children’s Hospital in Ohio. From a baseline position of screening, risk identification, and then referral, “we are now taking ownership of the process.”
Based on the substantial risk posed by significant levels of depression, guidelines recommend follow-up for any patient 12 years or older who has a positive screen, according to Dr. Krantz. At his center, they found only 19% had a documented follow-up within 30 days, even though timely intervention is important.
“Nearly half of suicide events in adolescents occur within 30 days after a positive PHQ-9 [9-question Patient Health Questionnaire] is completed,” said Dr. Krantz when presenting his data at the Pediatric Academic Societies annual meeting.
The issue has gained more urgency because of the substantial increase over the past several years in children presenting with depression and suicidal thoughts, according to Dr. Krantz. He said many are characterizing the upsurge as a mental health crisis in the pediatric age group.
Improving Follow-Up
. The goal at the outset was to increase the proportion to 35%.
“We know that a lot of children would receive follow-up at centers outside of our system,” said Dr. Krantz, explaining why the goal was relatively modest. Based on the likelihood that many follow-up visits would not be captured, he expected the final data would represent an underestimate.
Depression at baseline was defined as a score of 10 or higher on the PHQ-9 or any positive answer to item 9 on this screening tool, which asks specifically about thoughts of self-harm.
To be counted, follow-up had to be a documented encounter, whether by phone call, in-person visit, or telehealth visit.
“We needed patients to be checked. We did not count a prescription refill as a true follow-up,” Dr. Krantz specified.
There were numerous strategies implemented to improve follow-up, not least of which was an educational program to reinforce the importance and value of follow-up that was disseminated to clinicians in all of the participating clinics. Medical assistants were instructed to schedule a follow-up appointment for all patients who tested positive before they left the office. A target of 3 weeks was a strategy of overcorrection when so many patients were missing the initial 30-day window by just a few days.
The approach also involved an enhanced collaboration with psychologists to which patients were referred. Asking for expedited appointments when appropriate ensured that those at highest risk were prioritized, although Dr. Krantz said that this step was planned carefully to avoid overwhelming the mental health team.
“We monitored this and made sure it was not increasing the burden for psychologists from a capacity standpoint,” he said.
Other steps, like a depression action plan, which Dr. Krantz compared to an asthma action plan, were also implemented to reduce the risk of losing symptomatic patients before the chance for an effective treatment.
When compared with the 19% 30-day follow-up rate in the preintervention sample of 589 children, the 43.8% 30-day follow-up rate achieved in the 764 patients identified after implementation beat the original goal.
The improvement in follow-up was relatively consistent across all six clinics, which Dr. Krantz believes reflected a broad and shared change in a sense of responsibility for confirming that symptoms of depression were being addressed. Patients were still referred for psychological help, but referral was no longer considered enough.
“Children with mental health issues are still our patients in primary care,” said Dr. Krantz, who considers this an important change in orientation.
While the goal was to schedule patients for a follow-up at the time of a positive depression screen, Dr. Krantz described one important accommodation.
“The screen for depression was being performed in most cases during well visits, so patients and their families were not expecting to be discussing this issue,” he said. The diagnosis might be a particular surprise to parents who were not aware of any symptoms. In this case, Dr. Krantz said patients and families were given time to process the information and were contacted after a week to discuss further workup.
It is also notable that about one third of patients met the criteria for depression by answering positively to the PHQ-9 item on self-harm when they did not meet the 10 or more threshold depression score overall. In other words, these patients would have been missed without this criterion.
In the participating Cincinnati pediatric clinics, about 12%-13% of adolescents met the criteria for depression, which Dr. Krantz said is consistent with reports in the literature. He said the range is about 6%-24%.
Although outcomes were not tracked, there is evidence that early intervention for depression yields better outcomes than delayed intervention, according to Dr. Krantz. Based on approximately 600 positive screens for depression per year at his pediatric clinics, he estimated that his data predict at least 25% more patients will receive timely follow-up.
Seeking Solutions to a Growing Problem
There are several studies documenting the growing problem of adolescent depression and suicide and, for this reason, the topic is attracting a lot of attention, according to Corinna Rea, MD, MPH, a pediatrician working in the primary care center at Boston Children’s Hospital in Massachusetts.
Dr. Rea was not involved with the study, but when asked to comment, she said: “The results of this study were encouraging because we know that getting patients to care quickly is probably important.” She also agreed that referring patients with depression for care might not be enough, noting that a lot of patients do not follow up on recommendations to pursue a consultation or treatment.
“I am now involved in a project with the American Academy of Pediatrics to address this issue,” Dr. Rae said. She thinks that more work in this area is needed and agreed with Dr. Krantz that pediatricians should verify that children with depression are getting help even when other specialists are providing the treatment.
Dr. Krantz and Dr. Rae report no potential conflicts of interest.
TORONTO — An ambitious effort at a busy pediatrics clinic to improve follow-up in children and adolescents with a positive depression screen improved this quality metric, and it produced a fundamental change in approach.
“It was a big culture shift,” reported Landon B. Krantz, MD, a clinical fellow in the Division of General and Community Pediatrics at Cincinnati Children’s Hospital in Ohio. From a baseline position of screening, risk identification, and then referral, “we are now taking ownership of the process.”
Based on the substantial risk posed by significant levels of depression, guidelines recommend follow-up for any patient 12 years or older who has a positive screen, according to Dr. Krantz. At his center, they found only 19% had a documented follow-up within 30 days, even though timely intervention is important.
“Nearly half of suicide events in adolescents occur within 30 days after a positive PHQ-9 [9-question Patient Health Questionnaire] is completed,” said Dr. Krantz when presenting his data at the Pediatric Academic Societies annual meeting.
The issue has gained more urgency because of the substantial increase over the past several years in children presenting with depression and suicidal thoughts, according to Dr. Krantz. He said many are characterizing the upsurge as a mental health crisis in the pediatric age group.
Improving Follow-Up
. The goal at the outset was to increase the proportion to 35%.
“We know that a lot of children would receive follow-up at centers outside of our system,” said Dr. Krantz, explaining why the goal was relatively modest. Based on the likelihood that many follow-up visits would not be captured, he expected the final data would represent an underestimate.
Depression at baseline was defined as a score of 10 or higher on the PHQ-9 or any positive answer to item 9 on this screening tool, which asks specifically about thoughts of self-harm.
To be counted, follow-up had to be a documented encounter, whether by phone call, in-person visit, or telehealth visit.
“We needed patients to be checked. We did not count a prescription refill as a true follow-up,” Dr. Krantz specified.
There were numerous strategies implemented to improve follow-up, not least of which was an educational program to reinforce the importance and value of follow-up that was disseminated to clinicians in all of the participating clinics. Medical assistants were instructed to schedule a follow-up appointment for all patients who tested positive before they left the office. A target of 3 weeks was a strategy of overcorrection when so many patients were missing the initial 30-day window by just a few days.
The approach also involved an enhanced collaboration with psychologists to which patients were referred. Asking for expedited appointments when appropriate ensured that those at highest risk were prioritized, although Dr. Krantz said that this step was planned carefully to avoid overwhelming the mental health team.
“We monitored this and made sure it was not increasing the burden for psychologists from a capacity standpoint,” he said.
Other steps, like a depression action plan, which Dr. Krantz compared to an asthma action plan, were also implemented to reduce the risk of losing symptomatic patients before the chance for an effective treatment.
When compared with the 19% 30-day follow-up rate in the preintervention sample of 589 children, the 43.8% 30-day follow-up rate achieved in the 764 patients identified after implementation beat the original goal.
The improvement in follow-up was relatively consistent across all six clinics, which Dr. Krantz believes reflected a broad and shared change in a sense of responsibility for confirming that symptoms of depression were being addressed. Patients were still referred for psychological help, but referral was no longer considered enough.
“Children with mental health issues are still our patients in primary care,” said Dr. Krantz, who considers this an important change in orientation.
While the goal was to schedule patients for a follow-up at the time of a positive depression screen, Dr. Krantz described one important accommodation.
“The screen for depression was being performed in most cases during well visits, so patients and their families were not expecting to be discussing this issue,” he said. The diagnosis might be a particular surprise to parents who were not aware of any symptoms. In this case, Dr. Krantz said patients and families were given time to process the information and were contacted after a week to discuss further workup.
It is also notable that about one third of patients met the criteria for depression by answering positively to the PHQ-9 item on self-harm when they did not meet the 10 or more threshold depression score overall. In other words, these patients would have been missed without this criterion.
In the participating Cincinnati pediatric clinics, about 12%-13% of adolescents met the criteria for depression, which Dr. Krantz said is consistent with reports in the literature. He said the range is about 6%-24%.
Although outcomes were not tracked, there is evidence that early intervention for depression yields better outcomes than delayed intervention, according to Dr. Krantz. Based on approximately 600 positive screens for depression per year at his pediatric clinics, he estimated that his data predict at least 25% more patients will receive timely follow-up.
Seeking Solutions to a Growing Problem
There are several studies documenting the growing problem of adolescent depression and suicide and, for this reason, the topic is attracting a lot of attention, according to Corinna Rea, MD, MPH, a pediatrician working in the primary care center at Boston Children’s Hospital in Massachusetts.
Dr. Rea was not involved with the study, but when asked to comment, she said: “The results of this study were encouraging because we know that getting patients to care quickly is probably important.” She also agreed that referring patients with depression for care might not be enough, noting that a lot of patients do not follow up on recommendations to pursue a consultation or treatment.
“I am now involved in a project with the American Academy of Pediatrics to address this issue,” Dr. Rae said. She thinks that more work in this area is needed and agreed with Dr. Krantz that pediatricians should verify that children with depression are getting help even when other specialists are providing the treatment.
Dr. Krantz and Dr. Rae report no potential conflicts of interest.
FROM PAS 2024
Highly Pathogenic Avian Influenza (HPAI)
Imagine this: A 15-year-old male presents to an urgent care center with a one-day history of fever, cough, and shortness of breath. He is mildly tachypneic with bilateral scattered crackles on lung exam. A rapid test for COVID-19 and influenza is positive for influenza A — a surprising result in June.
An oxygen saturation of 90% prompts transfer to the emergency department at the local children’s hospital. The emergency medicine fellow is skeptical of the presumptive diagnosis. Influenza in the summer in a boy who had not traveled outside his small hometown in the southeastern United States? A respiratory viral panel also detected influenza A, but the specimen did not type as influenza A H1 or H3. This result prompted the laboratory technician to place a call to the ordering physician. “Does this patient have risk factors for avian flu?” the tech asked.
Highly pathogenic avian influenza (HPAI) A(H5N1) is not a new virus. It was discovered in waterfowl in China in 1996 and has since evolved into multiple clades and subclades, spreading to every continent on the globe except Oceania. It is called highly pathogenic because it kills a large number of the birds that it infects. In 2021, Clade 2.3.4.4b HPAI A(H5N1) viruses emerged in North America, causing large outbreaks in wild birds and farmed poultry populations, including backyard flocks. Sporadic infections have been identified in a diverse group of mammals, including foxes, raccoons, baby goats, bears, and harbor seals. In March of this year, HPAI A(H5N1) was detected for the first time in United States dairy cattle. As we go to press, the United States Department of Agriculture has detected HPAI A(H5N1) in dairy cattle on 36 farms in 9 states.
Human infections are rare, but often severe. Following a 1997 outbreak of HPAI A(H5N1) in Hong Kong, 18 people were infected and 6 died. Since then, more than 900 cases have been reported in humans and approximately half of these have been fatal. The spectrum of disease includes asymptomatic infection and mild disease, as occurred recently in Texas. A dairy farm worker who was exposed to dairy cattle presumed to be infected with HPAI A(H5N1) developed conjunctivitis and no other symptoms. An individual infected in Colorado in 2022 had no symptoms other than fatigue and recovered.
Human-to-human transmission was not identified with either of these cases, although very limited, non-sustained transmission has been observed in the past, usually in family members of infected people after prolonged close exposure.
Right now, most people in the United States are not at risk for HPAI A(H5N1) infection.
Careful history taking with our illustrative and hypothetical case revealed exposure to farm animals but in a state without known cases of HPAI A(H5N1) in dairy cattle. State health department officials nevertheless agreed with further testing of the patient. Some influenza diagnostic tests cleared by the US Food and Drug Administration (FDA) can detect some novel influenza A viruses such as HPAI A(H5N1) but cannot distinguish between infection with seasonal influenza A or novel influenza A viruses. Molecular assays may give an “influenza A untypeable” result, as in our case. The CDC urges further testing on these untypeable specimens at local or state public health laboratories. When HPAI A(H5N1) is suspected, a negative result on a commercially available test is not considered sufficient to exclude the possibility of infection.
Our patient was admitted to the hospital and droplet, contact, and airborne precautions were instituted along with antiviral treatment with oseltamivir. Preliminary analysis of HPAI A(H5N1) viruses predicts susceptibility to currently available antivirals. The admitting physician confirmed that the boy had received influenza vaccine in the preceding season but, unfortunately, seasonal vaccines do not protect against HPAI A(H5N1) infection.
Advice for Clinicians
Given the recent media attention and public health focus on HPAI A(H5N1), frontline clinicians may start receiving questions from patients and families and perhaps requests for testing. At this point, testing is generally recommended only for individuals with risk factors or known exposures. Healthcare providers with questions about testing are encouraged to reach out to their local or state health departments.
Public health authorities have provided recommendations for protection from HPAI. These include avoiding unprotected exposures to sick or dead wild birds, poultry, other domesticated birds, and wild or domesticated animals (including cattle). People should avoid unprotected contact with animals with suspected or confirmed HPAI A(H5N1)-virus infection or products from these animals, including raw or unpasteurized milk and raw milk products.
We can, however, reassure families that the commercial milk supply is safe. In late April, the FDA reported that HPAI viral fragments were found in one of five retail milk samples by polymerase chain reaction testing. Additional testing did not detect any live, infectious virus, indicating the effectiveness of pasteurization at inactivating the virus. Of importance to pediatricians and others pediatric clinicians, limited sampling of retail powdered infant formula and powdered milk products marketed as toddler formula revealed no viral fragments or viable virus.
The million-dollar question is whether HPAI A(H5N1) could start a new pandemic. To date, the virus has not acquired the mutations that would make it easily transmissible from person to person. If that changes and the virus does start spreading more widely, candidate vaccines that could protect against HPAI A(H5N1) have been developed and are part of the national stockpile. Let’s hope we don’t need them.
Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville (Ky.) and Norton Children’s Hospital, also in Louisville. She is a member of the American Academy of Pediatrics’ Committee on Infectious Diseases and the physician lead for Red Book Online. The opinions expressed in this article are her own. Dr. Bryant discloses that she has served as an investigator on clinical trials funded by Pfizer, Enanta and Gilead. Email her at [email protected]. (Also [email protected].)
Imagine this: A 15-year-old male presents to an urgent care center with a one-day history of fever, cough, and shortness of breath. He is mildly tachypneic with bilateral scattered crackles on lung exam. A rapid test for COVID-19 and influenza is positive for influenza A — a surprising result in June.
An oxygen saturation of 90% prompts transfer to the emergency department at the local children’s hospital. The emergency medicine fellow is skeptical of the presumptive diagnosis. Influenza in the summer in a boy who had not traveled outside his small hometown in the southeastern United States? A respiratory viral panel also detected influenza A, but the specimen did not type as influenza A H1 or H3. This result prompted the laboratory technician to place a call to the ordering physician. “Does this patient have risk factors for avian flu?” the tech asked.
Highly pathogenic avian influenza (HPAI) A(H5N1) is not a new virus. It was discovered in waterfowl in China in 1996 and has since evolved into multiple clades and subclades, spreading to every continent on the globe except Oceania. It is called highly pathogenic because it kills a large number of the birds that it infects. In 2021, Clade 2.3.4.4b HPAI A(H5N1) viruses emerged in North America, causing large outbreaks in wild birds and farmed poultry populations, including backyard flocks. Sporadic infections have been identified in a diverse group of mammals, including foxes, raccoons, baby goats, bears, and harbor seals. In March of this year, HPAI A(H5N1) was detected for the first time in United States dairy cattle. As we go to press, the United States Department of Agriculture has detected HPAI A(H5N1) in dairy cattle on 36 farms in 9 states.
Human infections are rare, but often severe. Following a 1997 outbreak of HPAI A(H5N1) in Hong Kong, 18 people were infected and 6 died. Since then, more than 900 cases have been reported in humans and approximately half of these have been fatal. The spectrum of disease includes asymptomatic infection and mild disease, as occurred recently in Texas. A dairy farm worker who was exposed to dairy cattle presumed to be infected with HPAI A(H5N1) developed conjunctivitis and no other symptoms. An individual infected in Colorado in 2022 had no symptoms other than fatigue and recovered.
Human-to-human transmission was not identified with either of these cases, although very limited, non-sustained transmission has been observed in the past, usually in family members of infected people after prolonged close exposure.
Right now, most people in the United States are not at risk for HPAI A(H5N1) infection.
Careful history taking with our illustrative and hypothetical case revealed exposure to farm animals but in a state without known cases of HPAI A(H5N1) in dairy cattle. State health department officials nevertheless agreed with further testing of the patient. Some influenza diagnostic tests cleared by the US Food and Drug Administration (FDA) can detect some novel influenza A viruses such as HPAI A(H5N1) but cannot distinguish between infection with seasonal influenza A or novel influenza A viruses. Molecular assays may give an “influenza A untypeable” result, as in our case. The CDC urges further testing on these untypeable specimens at local or state public health laboratories. When HPAI A(H5N1) is suspected, a negative result on a commercially available test is not considered sufficient to exclude the possibility of infection.
Our patient was admitted to the hospital and droplet, contact, and airborne precautions were instituted along with antiviral treatment with oseltamivir. Preliminary analysis of HPAI A(H5N1) viruses predicts susceptibility to currently available antivirals. The admitting physician confirmed that the boy had received influenza vaccine in the preceding season but, unfortunately, seasonal vaccines do not protect against HPAI A(H5N1) infection.
Advice for Clinicians
Given the recent media attention and public health focus on HPAI A(H5N1), frontline clinicians may start receiving questions from patients and families and perhaps requests for testing. At this point, testing is generally recommended only for individuals with risk factors or known exposures. Healthcare providers with questions about testing are encouraged to reach out to their local or state health departments.
Public health authorities have provided recommendations for protection from HPAI. These include avoiding unprotected exposures to sick or dead wild birds, poultry, other domesticated birds, and wild or domesticated animals (including cattle). People should avoid unprotected contact with animals with suspected or confirmed HPAI A(H5N1)-virus infection or products from these animals, including raw or unpasteurized milk and raw milk products.
We can, however, reassure families that the commercial milk supply is safe. In late April, the FDA reported that HPAI viral fragments were found in one of five retail milk samples by polymerase chain reaction testing. Additional testing did not detect any live, infectious virus, indicating the effectiveness of pasteurization at inactivating the virus. Of importance to pediatricians and others pediatric clinicians, limited sampling of retail powdered infant formula and powdered milk products marketed as toddler formula revealed no viral fragments or viable virus.
The million-dollar question is whether HPAI A(H5N1) could start a new pandemic. To date, the virus has not acquired the mutations that would make it easily transmissible from person to person. If that changes and the virus does start spreading more widely, candidate vaccines that could protect against HPAI A(H5N1) have been developed and are part of the national stockpile. Let’s hope we don’t need them.
Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville (Ky.) and Norton Children’s Hospital, also in Louisville. She is a member of the American Academy of Pediatrics’ Committee on Infectious Diseases and the physician lead for Red Book Online. The opinions expressed in this article are her own. Dr. Bryant discloses that she has served as an investigator on clinical trials funded by Pfizer, Enanta and Gilead. Email her at [email protected]. (Also [email protected].)
Imagine this: A 15-year-old male presents to an urgent care center with a one-day history of fever, cough, and shortness of breath. He is mildly tachypneic with bilateral scattered crackles on lung exam. A rapid test for COVID-19 and influenza is positive for influenza A — a surprising result in June.
An oxygen saturation of 90% prompts transfer to the emergency department at the local children’s hospital. The emergency medicine fellow is skeptical of the presumptive diagnosis. Influenza in the summer in a boy who had not traveled outside his small hometown in the southeastern United States? A respiratory viral panel also detected influenza A, but the specimen did not type as influenza A H1 or H3. This result prompted the laboratory technician to place a call to the ordering physician. “Does this patient have risk factors for avian flu?” the tech asked.
Highly pathogenic avian influenza (HPAI) A(H5N1) is not a new virus. It was discovered in waterfowl in China in 1996 and has since evolved into multiple clades and subclades, spreading to every continent on the globe except Oceania. It is called highly pathogenic because it kills a large number of the birds that it infects. In 2021, Clade 2.3.4.4b HPAI A(H5N1) viruses emerged in North America, causing large outbreaks in wild birds and farmed poultry populations, including backyard flocks. Sporadic infections have been identified in a diverse group of mammals, including foxes, raccoons, baby goats, bears, and harbor seals. In March of this year, HPAI A(H5N1) was detected for the first time in United States dairy cattle. As we go to press, the United States Department of Agriculture has detected HPAI A(H5N1) in dairy cattle on 36 farms in 9 states.
Human infections are rare, but often severe. Following a 1997 outbreak of HPAI A(H5N1) in Hong Kong, 18 people were infected and 6 died. Since then, more than 900 cases have been reported in humans and approximately half of these have been fatal. The spectrum of disease includes asymptomatic infection and mild disease, as occurred recently in Texas. A dairy farm worker who was exposed to dairy cattle presumed to be infected with HPAI A(H5N1) developed conjunctivitis and no other symptoms. An individual infected in Colorado in 2022 had no symptoms other than fatigue and recovered.
Human-to-human transmission was not identified with either of these cases, although very limited, non-sustained transmission has been observed in the past, usually in family members of infected people after prolonged close exposure.
Right now, most people in the United States are not at risk for HPAI A(H5N1) infection.
Careful history taking with our illustrative and hypothetical case revealed exposure to farm animals but in a state without known cases of HPAI A(H5N1) in dairy cattle. State health department officials nevertheless agreed with further testing of the patient. Some influenza diagnostic tests cleared by the US Food and Drug Administration (FDA) can detect some novel influenza A viruses such as HPAI A(H5N1) but cannot distinguish between infection with seasonal influenza A or novel influenza A viruses. Molecular assays may give an “influenza A untypeable” result, as in our case. The CDC urges further testing on these untypeable specimens at local or state public health laboratories. When HPAI A(H5N1) is suspected, a negative result on a commercially available test is not considered sufficient to exclude the possibility of infection.
Our patient was admitted to the hospital and droplet, contact, and airborne precautions were instituted along with antiviral treatment with oseltamivir. Preliminary analysis of HPAI A(H5N1) viruses predicts susceptibility to currently available antivirals. The admitting physician confirmed that the boy had received influenza vaccine in the preceding season but, unfortunately, seasonal vaccines do not protect against HPAI A(H5N1) infection.
Advice for Clinicians
Given the recent media attention and public health focus on HPAI A(H5N1), frontline clinicians may start receiving questions from patients and families and perhaps requests for testing. At this point, testing is generally recommended only for individuals with risk factors or known exposures. Healthcare providers with questions about testing are encouraged to reach out to their local or state health departments.
Public health authorities have provided recommendations for protection from HPAI. These include avoiding unprotected exposures to sick or dead wild birds, poultry, other domesticated birds, and wild or domesticated animals (including cattle). People should avoid unprotected contact with animals with suspected or confirmed HPAI A(H5N1)-virus infection or products from these animals, including raw or unpasteurized milk and raw milk products.
We can, however, reassure families that the commercial milk supply is safe. In late April, the FDA reported that HPAI viral fragments were found in one of five retail milk samples by polymerase chain reaction testing. Additional testing did not detect any live, infectious virus, indicating the effectiveness of pasteurization at inactivating the virus. Of importance to pediatricians and others pediatric clinicians, limited sampling of retail powdered infant formula and powdered milk products marketed as toddler formula revealed no viral fragments or viable virus.
The million-dollar question is whether HPAI A(H5N1) could start a new pandemic. To date, the virus has not acquired the mutations that would make it easily transmissible from person to person. If that changes and the virus does start spreading more widely, candidate vaccines that could protect against HPAI A(H5N1) have been developed and are part of the national stockpile. Let’s hope we don’t need them.
Dr. Bryant is a pediatrician specializing in infectious diseases at the University of Louisville (Ky.) and Norton Children’s Hospital, also in Louisville. She is a member of the American Academy of Pediatrics’ Committee on Infectious Diseases and the physician lead for Red Book Online. The opinions expressed in this article are her own. Dr. Bryant discloses that she has served as an investigator on clinical trials funded by Pfizer, Enanta and Gilead. Email her at [email protected]. (Also [email protected].)
Survey Spotlights Identification of Dermatologic Adverse Events From Cancer Therapies
“New cancer therapies have brought a diversity of treatment-related dermatologic adverse events (dAEs) beyond those experienced with conventional chemotherapy, which has demanded an evolving assessment of toxicities,” researchers led by Nicole R. LeBoeuf, MD, MPH, of the Department of Dermatology at Brigham and Women’s Hospital and the Center for Cutaneous Oncology at the Dana-Farber Brigham Cancer Center, Boston, wrote in a poster presented at the American Academy of Dermatology annual meeting.
The authors noted that “Version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE v5.0)” serves as the current, broadly accepted criteria for classification and grading during routine medical care and clinical trials. But despite extensive utilization of CTCAE, there is little data regarding its application.”
To evaluate how CTCAE is being used in clinical practice, they sent a four-case survey of dAEs to 81 dermatologists and 182 medical oncologists at six US-based academic institutions. For three of the cases, respondents were asked to classify and grade morbilliform, psoriasiform, and papulopustular rashes based on a review of photographs and text descriptions. For the fourth case, respondents were asked to grade a dAE using only a clinic note text description. The researchers used chi-square tests in R software to compare survey responses.
Compared with medical oncologists, dermatologists were significantly more likely to provide correct responses in characterizing morbilliform and psoriasiform eruptions. “As low as 12%” of medical oncologists were correct, and “as low as 87%” of dermatologists were correct (P < .001). Similarly, dermatologists were significantly more likely to grade the psoriasiform, papulopustular, and written cases correctly compared with medical oncologists (P < .001 for all associations).
“These cases demonstrated poor concordance of classification and grading between specialties and across medical oncology,” the authors concluded in their poster, noting that 87% of medical oncologists were interested in additional educational tools on dAEs. “With correct classification as low as 12%, medical oncologists may have more difficulty delivering appropriate, toxicity-specific therapy and may consider banal eruptions dangerous.”
Poor concordance of grading among the two groups of clinicians “raises the question of whether CTCAE v5.0 is an appropriate determinant for patient continuation on therapy or in trials,” they added. “As anticancer therapy becomes more complex — with new toxicities from novel agents and combinations — we must ensure we have a grading system that is valid across investigators and does not harm patients by instituting unnecessary treatment stops.”
Future studies, they said, “can explore what interventions beyond involvement of dermatologists improve classification and grading in practice.”
Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study, noted that with the continued expansion and introduction of new targeted and immunotherapies in the oncology space, “you can be sure we will continue to appreciate the importance and value of the field of supportive oncodermatology, as hair, skin, and nails are almost guaranteed collateral damage in this story.
“Ensuring early identification and consistent grading severity is not only important for the plethora of patients who are currently developing the litany of cutaneous adverse events but to evaluate potential mitigation strategies and even push along countermeasures down the FDA approval pathway,” Dr. Friedman said. In this study, the investigators demonstrated that work “is sorely needed, not just in dermatology but even more so for our colleagues across the aisle. A central tenet of supportive oncodermatology must also be education for all stakeholders, and the good news is our oncology partners will welcome it.”
Dr. LeBoeuf disclosed that she is a consultant to and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the submitted work. No other authors reported having financial disclosures. Dr. Friedman directs the supportive oncodermatology program at GW that received independent funding from La Roche-Posay.
A version of this article first appeared on Medscape.com.
“New cancer therapies have brought a diversity of treatment-related dermatologic adverse events (dAEs) beyond those experienced with conventional chemotherapy, which has demanded an evolving assessment of toxicities,” researchers led by Nicole R. LeBoeuf, MD, MPH, of the Department of Dermatology at Brigham and Women’s Hospital and the Center for Cutaneous Oncology at the Dana-Farber Brigham Cancer Center, Boston, wrote in a poster presented at the American Academy of Dermatology annual meeting.
The authors noted that “Version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE v5.0)” serves as the current, broadly accepted criteria for classification and grading during routine medical care and clinical trials. But despite extensive utilization of CTCAE, there is little data regarding its application.”
To evaluate how CTCAE is being used in clinical practice, they sent a four-case survey of dAEs to 81 dermatologists and 182 medical oncologists at six US-based academic institutions. For three of the cases, respondents were asked to classify and grade morbilliform, psoriasiform, and papulopustular rashes based on a review of photographs and text descriptions. For the fourth case, respondents were asked to grade a dAE using only a clinic note text description. The researchers used chi-square tests in R software to compare survey responses.
Compared with medical oncologists, dermatologists were significantly more likely to provide correct responses in characterizing morbilliform and psoriasiform eruptions. “As low as 12%” of medical oncologists were correct, and “as low as 87%” of dermatologists were correct (P < .001). Similarly, dermatologists were significantly more likely to grade the psoriasiform, papulopustular, and written cases correctly compared with medical oncologists (P < .001 for all associations).
“These cases demonstrated poor concordance of classification and grading between specialties and across medical oncology,” the authors concluded in their poster, noting that 87% of medical oncologists were interested in additional educational tools on dAEs. “With correct classification as low as 12%, medical oncologists may have more difficulty delivering appropriate, toxicity-specific therapy and may consider banal eruptions dangerous.”
Poor concordance of grading among the two groups of clinicians “raises the question of whether CTCAE v5.0 is an appropriate determinant for patient continuation on therapy or in trials,” they added. “As anticancer therapy becomes more complex — with new toxicities from novel agents and combinations — we must ensure we have a grading system that is valid across investigators and does not harm patients by instituting unnecessary treatment stops.”
Future studies, they said, “can explore what interventions beyond involvement of dermatologists improve classification and grading in practice.”
Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study, noted that with the continued expansion and introduction of new targeted and immunotherapies in the oncology space, “you can be sure we will continue to appreciate the importance and value of the field of supportive oncodermatology, as hair, skin, and nails are almost guaranteed collateral damage in this story.
“Ensuring early identification and consistent grading severity is not only important for the plethora of patients who are currently developing the litany of cutaneous adverse events but to evaluate potential mitigation strategies and even push along countermeasures down the FDA approval pathway,” Dr. Friedman said. In this study, the investigators demonstrated that work “is sorely needed, not just in dermatology but even more so for our colleagues across the aisle. A central tenet of supportive oncodermatology must also be education for all stakeholders, and the good news is our oncology partners will welcome it.”
Dr. LeBoeuf disclosed that she is a consultant to and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the submitted work. No other authors reported having financial disclosures. Dr. Friedman directs the supportive oncodermatology program at GW that received independent funding from La Roche-Posay.
A version of this article first appeared on Medscape.com.
“New cancer therapies have brought a diversity of treatment-related dermatologic adverse events (dAEs) beyond those experienced with conventional chemotherapy, which has demanded an evolving assessment of toxicities,” researchers led by Nicole R. LeBoeuf, MD, MPH, of the Department of Dermatology at Brigham and Women’s Hospital and the Center for Cutaneous Oncology at the Dana-Farber Brigham Cancer Center, Boston, wrote in a poster presented at the American Academy of Dermatology annual meeting.
The authors noted that “Version 5.0 of the Common Terminology Criteria for Adverse Events (CTCAE v5.0)” serves as the current, broadly accepted criteria for classification and grading during routine medical care and clinical trials. But despite extensive utilization of CTCAE, there is little data regarding its application.”
To evaluate how CTCAE is being used in clinical practice, they sent a four-case survey of dAEs to 81 dermatologists and 182 medical oncologists at six US-based academic institutions. For three of the cases, respondents were asked to classify and grade morbilliform, psoriasiform, and papulopustular rashes based on a review of photographs and text descriptions. For the fourth case, respondents were asked to grade a dAE using only a clinic note text description. The researchers used chi-square tests in R software to compare survey responses.
Compared with medical oncologists, dermatologists were significantly more likely to provide correct responses in characterizing morbilliform and psoriasiform eruptions. “As low as 12%” of medical oncologists were correct, and “as low as 87%” of dermatologists were correct (P < .001). Similarly, dermatologists were significantly more likely to grade the psoriasiform, papulopustular, and written cases correctly compared with medical oncologists (P < .001 for all associations).
“These cases demonstrated poor concordance of classification and grading between specialties and across medical oncology,” the authors concluded in their poster, noting that 87% of medical oncologists were interested in additional educational tools on dAEs. “With correct classification as low as 12%, medical oncologists may have more difficulty delivering appropriate, toxicity-specific therapy and may consider banal eruptions dangerous.”
Poor concordance of grading among the two groups of clinicians “raises the question of whether CTCAE v5.0 is an appropriate determinant for patient continuation on therapy or in trials,” they added. “As anticancer therapy becomes more complex — with new toxicities from novel agents and combinations — we must ensure we have a grading system that is valid across investigators and does not harm patients by instituting unnecessary treatment stops.”
Future studies, they said, “can explore what interventions beyond involvement of dermatologists improve classification and grading in practice.”
Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, who was asked to comment on the study, noted that with the continued expansion and introduction of new targeted and immunotherapies in the oncology space, “you can be sure we will continue to appreciate the importance and value of the field of supportive oncodermatology, as hair, skin, and nails are almost guaranteed collateral damage in this story.
“Ensuring early identification and consistent grading severity is not only important for the plethora of patients who are currently developing the litany of cutaneous adverse events but to evaluate potential mitigation strategies and even push along countermeasures down the FDA approval pathway,” Dr. Friedman said. In this study, the investigators demonstrated that work “is sorely needed, not just in dermatology but even more so for our colleagues across the aisle. A central tenet of supportive oncodermatology must also be education for all stakeholders, and the good news is our oncology partners will welcome it.”
Dr. LeBoeuf disclosed that she is a consultant to and has received honoraria from Bayer, Seattle Genetics, Sanofi, Silverback, Fortress Biotech, and Synox Therapeutics outside the submitted work. No other authors reported having financial disclosures. Dr. Friedman directs the supportive oncodermatology program at GW that received independent funding from La Roche-Posay.
A version of this article first appeared on Medscape.com.
FROM AAD 2024
Kids and Anti-Obesity Medications: Real-World Challenges
DENVER — The ability to provide adolescents with highly effective anti-obesity medications that now carry approvals from the US Food and Drug Administration (FDA) and support in guidelines offers reassurance of their use; however, a reality check often awaits for clinicians in terms of challenges ranging from accessing and affording the medications to managing real and rumored side effects.
Weighing in on the issues, experts at Obesity Medicine (OMA) 2024 offered some key strategies and practice hacks for overcoming those hurdles.
The incentive to provide treatment with popular glucagon-like peptide 1 (GLP-1) drugs such as semaglutide or the dual glucose-dependent insulinotropic peptide (GIP) GLP-1 tirzepatide lies in the evidence that their high efficacy in promoting weight loss, and hence preventing metabolic syndrome, has benefits that far outweigh the potential side effects, said Alaina Vidmar, MD, in presenting at the meeting.
“We can look at all the evidence and without question acknowledge that the GLP-1s/GIP agonists are the most effective agents that we currently have, with the least heterogeneity in response, and the most high responders compared with other agents,” said Dr. Vidmar, an assistant professor of clinical pediatrics at the Keck School of Medicine of University of Southern California and director of obesity medicine and bariatric surgery at Children’s Hospital Los Angeles.
The strength of the evidence is reflected in the landmark American Academy of Pediatrics (AAP) Clinical Practice Guideline for the Evaluation and Treatment of Children and Adolescents With Obesity, which recommends that “pediatricians and other primary healthcare providers should offer adolescents 12 years and older with obesity weight loss pharmacotherapy, according to medication indications, risks and may offer adolescents 8 years old with obesity weight loss pharmacotherapy, according to medication indications, risks.”
The AAP guidance echoes the recommendations of the drug makers and FDA that “a combination of specific behavioral techniques within the context of family-based behavioral treatment and the use of pharmacotherapy may be necessary to prevent life-limiting complications over time.”
However, in real-world practice, with the various challenges in providing that intensive, comprehensive care, clinicians should be prepared to get creative: “We sometimes have to do the best we can with what we have because the watchful waiting approach is not effective and leads to more harm than good,” Dr. Vidmar said.
Facilitating Access
The ongoing reported shortages in the highly popular anti-obesity medications, as well as insurance denials and high costs, are among the leading obstacles, for adolescents and adults alike.
Dr. Vidmar noted that key strategies at her center, Children’s Hospital Los Angeles, have been essential, however, in helping at least facilitate the authorization process.
The center’s approach began with contacting all the payers the center has contracts with to determine which of their policies cover these medications for adults and pediatrics and which agents are covered.
“This took work on the front end, but it was worth it because it helped us understand the framework for what we were going to go up against every time that we prescribed these medications,” she said.
Furthermore, the center’s specialty pharmacy set up contracts to be able to provide the drugs within the institution.
While the strategy can’t entirely mitigate the ongoing distribution concerns, “our pharmacy is now able to share with our weight management program what GLP-1s are available so that we can be more efficient in our work,” Dr. Vidmar said.
The center also created a list of contacts to provide to patients and their families, detailing local pharmacies that were most likely to have the medications.
Another strategy Dr. Vidmar’s center has utilized to allow the timely implementation of a GLP-1 treatment plan while awaiting a drug to become available is to create an alternative protocol, for instance, using liraglutide when awaiting semaglutide.
“If we are unable to get the lower doses of a weekly agent for titration, we have a standard protocol to bridge instead with liraglutide, and our patients, pharmacies, and even our authorizations are aware of the protocol,” Dr. Vidmar said.
“We often do not have a lot of control or agency over the distribution concerns; however, we can be thoughtful within our programs about how we titrate patients up to their full doses,” Dr. Vidmar said.
Mitigating Side Effects
When the medications are available, the common gastrointestinal (GI) side effects of nausea, vomiting, and diarrhea of the once-weekly injections are well-known, and these side effects can affect quality of life and daily function, Dr. Vidmar noted.
“We have to acknowledge that the seminal trials of these agents showed that nausea and vomiting occur in more than half of young people who take these agents during the initial titration period, and while the side effects are tolerated by many, they can be disruptive to daily life,” she said.
Encouragingly, “we also do know that for the majority of patients, those effects improve over time, and for many, they can be mitigated with nutrition changes.”
Dr. Vidmar shared a handout her center issues with key recommendations for mitigating GI effects in youth. These include:
- Eat smaller meals and eat slower
- Eat about half of what you usually eat
- Take about 15-20 minutes to eat your meal
- Aim for 60 g of protein per day
- Add fruits, vegetables, whole grains, and lean proteins to meals
- Limit foods that are spicy, greasy, or fried
- Drink water instead of sweet drinks
Consider Zofran as needed during the titration period for GI symptoms. “We’ve started using this at our institution and are teaching patients how to use it; it can really help mitigate any ER visits when there is any vomiting by educating patients and families and providing appropriate expectations, and that has been very helpful,” Dr. Vidmar said.
Regarding the GI effects, Dr. Vidmar noted she has observed that tirzepatide use (though still off-label) in youths “tends to have milder GI side effects among younger people.”
Mood Concerns?
Another concern that has emerged in public discussion regarding side effects is that of possible mood and suicidal ideation, raising concerns for adults and adolescents alike.
Upon investigating the reports, the FDA, in a statement, offered cautious reassurance that their review, including reports and clinical trials, “did not find an association between use of GLP-1 RAs and the occurrence of suicidal thoughts or actions.”
Noting that the agency is continuing to look into the issue, however, the FDA recommends that “healthcare professionals should monitor for and advise patients using GLP-1 RAs to report new or worsening depression, suicidal thoughts, or any unusual changes in mood or behavior.”
Concurrent Psychiatric Pharmacotherapy
Meanwhile, with weight gain a known and often challenging side effect of various psychiatric drugs, particularly in younger patients, obesity treatment of adolescents may commonly involve patients who are also being treated with those therapies.
Key culprits include certain antidepressants and antipsychotic medications, such as tricyclic antidepressants, and second-generation antipsychotics, such as olanzapine.
In terms of the use of GLP-1 medications for those patients, research includes a recent study of semaglutide in patients who were also being treated with antidepressants.
The study, a post hoc analysis of the STEP trials, showed “clinically meaningful weight loss regardless of baseline antidepressant use, with an adverse event profile consistent with previous studies.”
First author Robert F. Kushner, MD, said the study offers “reassurance that individuals who are taking antidepressant medications have a similar weight loss response and side-effect profile compared to individuals who are not taking these medications.”
Dr. Kushner, a professor of medicine and medicine education at Northwestern University in Chicago, and his team have not evaluated the safety profile for concomitant use with antipsychotic drugs. However, he noted that “there are studies showing that the daily GLP-1 drug liraglutide has been shown to be useful in combating antipsychotic-induced weight gain.”
“Similar studies will need to be conducted for the more effective agents, semaglutide and tirzepatide,” he said.
To counter the weight gain effects of antispychotics, metformin has long been a standard recommendation, and Dr. Vidmar noted that “I have historically always used metformin in this setting and found it very effective.”
However, the newer anti-obesity medications could prove to be important in those cases, Dr. Vidmar added.
“I do think and predict that GLP-1 agonists will be as effective, if not more, in combating the weight gain-promoting effects of these agents and act as a nice adjuvant to this treatment paradigm for psychiatrists.”
Dr. Vidmar has participated in an advisory board for Rhythm Pharmaceuticals. Dr. Kushner is on the advisory boards for Novo Nordisk, Weight Watchers, Lilly, Boehringer Ingelheim, and Altimmune.
A version of this article appeared on Medscape.com.
DENVER — The ability to provide adolescents with highly effective anti-obesity medications that now carry approvals from the US Food and Drug Administration (FDA) and support in guidelines offers reassurance of their use; however, a reality check often awaits for clinicians in terms of challenges ranging from accessing and affording the medications to managing real and rumored side effects.
Weighing in on the issues, experts at Obesity Medicine (OMA) 2024 offered some key strategies and practice hacks for overcoming those hurdles.
The incentive to provide treatment with popular glucagon-like peptide 1 (GLP-1) drugs such as semaglutide or the dual glucose-dependent insulinotropic peptide (GIP) GLP-1 tirzepatide lies in the evidence that their high efficacy in promoting weight loss, and hence preventing metabolic syndrome, has benefits that far outweigh the potential side effects, said Alaina Vidmar, MD, in presenting at the meeting.
“We can look at all the evidence and without question acknowledge that the GLP-1s/GIP agonists are the most effective agents that we currently have, with the least heterogeneity in response, and the most high responders compared with other agents,” said Dr. Vidmar, an assistant professor of clinical pediatrics at the Keck School of Medicine of University of Southern California and director of obesity medicine and bariatric surgery at Children’s Hospital Los Angeles.
The strength of the evidence is reflected in the landmark American Academy of Pediatrics (AAP) Clinical Practice Guideline for the Evaluation and Treatment of Children and Adolescents With Obesity, which recommends that “pediatricians and other primary healthcare providers should offer adolescents 12 years and older with obesity weight loss pharmacotherapy, according to medication indications, risks and may offer adolescents 8 years old with obesity weight loss pharmacotherapy, according to medication indications, risks.”
The AAP guidance echoes the recommendations of the drug makers and FDA that “a combination of specific behavioral techniques within the context of family-based behavioral treatment and the use of pharmacotherapy may be necessary to prevent life-limiting complications over time.”
However, in real-world practice, with the various challenges in providing that intensive, comprehensive care, clinicians should be prepared to get creative: “We sometimes have to do the best we can with what we have because the watchful waiting approach is not effective and leads to more harm than good,” Dr. Vidmar said.
Facilitating Access
The ongoing reported shortages in the highly popular anti-obesity medications, as well as insurance denials and high costs, are among the leading obstacles, for adolescents and adults alike.
Dr. Vidmar noted that key strategies at her center, Children’s Hospital Los Angeles, have been essential, however, in helping at least facilitate the authorization process.
The center’s approach began with contacting all the payers the center has contracts with to determine which of their policies cover these medications for adults and pediatrics and which agents are covered.
“This took work on the front end, but it was worth it because it helped us understand the framework for what we were going to go up against every time that we prescribed these medications,” she said.
Furthermore, the center’s specialty pharmacy set up contracts to be able to provide the drugs within the institution.
While the strategy can’t entirely mitigate the ongoing distribution concerns, “our pharmacy is now able to share with our weight management program what GLP-1s are available so that we can be more efficient in our work,” Dr. Vidmar said.
The center also created a list of contacts to provide to patients and their families, detailing local pharmacies that were most likely to have the medications.
Another strategy Dr. Vidmar’s center has utilized to allow the timely implementation of a GLP-1 treatment plan while awaiting a drug to become available is to create an alternative protocol, for instance, using liraglutide when awaiting semaglutide.
“If we are unable to get the lower doses of a weekly agent for titration, we have a standard protocol to bridge instead with liraglutide, and our patients, pharmacies, and even our authorizations are aware of the protocol,” Dr. Vidmar said.
“We often do not have a lot of control or agency over the distribution concerns; however, we can be thoughtful within our programs about how we titrate patients up to their full doses,” Dr. Vidmar said.
Mitigating Side Effects
When the medications are available, the common gastrointestinal (GI) side effects of nausea, vomiting, and diarrhea of the once-weekly injections are well-known, and these side effects can affect quality of life and daily function, Dr. Vidmar noted.
“We have to acknowledge that the seminal trials of these agents showed that nausea and vomiting occur in more than half of young people who take these agents during the initial titration period, and while the side effects are tolerated by many, they can be disruptive to daily life,” she said.
Encouragingly, “we also do know that for the majority of patients, those effects improve over time, and for many, they can be mitigated with nutrition changes.”
Dr. Vidmar shared a handout her center issues with key recommendations for mitigating GI effects in youth. These include:
- Eat smaller meals and eat slower
- Eat about half of what you usually eat
- Take about 15-20 minutes to eat your meal
- Aim for 60 g of protein per day
- Add fruits, vegetables, whole grains, and lean proteins to meals
- Limit foods that are spicy, greasy, or fried
- Drink water instead of sweet drinks
Consider Zofran as needed during the titration period for GI symptoms. “We’ve started using this at our institution and are teaching patients how to use it; it can really help mitigate any ER visits when there is any vomiting by educating patients and families and providing appropriate expectations, and that has been very helpful,” Dr. Vidmar said.
Regarding the GI effects, Dr. Vidmar noted she has observed that tirzepatide use (though still off-label) in youths “tends to have milder GI side effects among younger people.”
Mood Concerns?
Another concern that has emerged in public discussion regarding side effects is that of possible mood and suicidal ideation, raising concerns for adults and adolescents alike.
Upon investigating the reports, the FDA, in a statement, offered cautious reassurance that their review, including reports and clinical trials, “did not find an association between use of GLP-1 RAs and the occurrence of suicidal thoughts or actions.”
Noting that the agency is continuing to look into the issue, however, the FDA recommends that “healthcare professionals should monitor for and advise patients using GLP-1 RAs to report new or worsening depression, suicidal thoughts, or any unusual changes in mood or behavior.”
Concurrent Psychiatric Pharmacotherapy
Meanwhile, with weight gain a known and often challenging side effect of various psychiatric drugs, particularly in younger patients, obesity treatment of adolescents may commonly involve patients who are also being treated with those therapies.
Key culprits include certain antidepressants and antipsychotic medications, such as tricyclic antidepressants, and second-generation antipsychotics, such as olanzapine.
In terms of the use of GLP-1 medications for those patients, research includes a recent study of semaglutide in patients who were also being treated with antidepressants.
The study, a post hoc analysis of the STEP trials, showed “clinically meaningful weight loss regardless of baseline antidepressant use, with an adverse event profile consistent with previous studies.”
First author Robert F. Kushner, MD, said the study offers “reassurance that individuals who are taking antidepressant medications have a similar weight loss response and side-effect profile compared to individuals who are not taking these medications.”
Dr. Kushner, a professor of medicine and medicine education at Northwestern University in Chicago, and his team have not evaluated the safety profile for concomitant use with antipsychotic drugs. However, he noted that “there are studies showing that the daily GLP-1 drug liraglutide has been shown to be useful in combating antipsychotic-induced weight gain.”
“Similar studies will need to be conducted for the more effective agents, semaglutide and tirzepatide,” he said.
To counter the weight gain effects of antispychotics, metformin has long been a standard recommendation, and Dr. Vidmar noted that “I have historically always used metformin in this setting and found it very effective.”
However, the newer anti-obesity medications could prove to be important in those cases, Dr. Vidmar added.
“I do think and predict that GLP-1 agonists will be as effective, if not more, in combating the weight gain-promoting effects of these agents and act as a nice adjuvant to this treatment paradigm for psychiatrists.”
Dr. Vidmar has participated in an advisory board for Rhythm Pharmaceuticals. Dr. Kushner is on the advisory boards for Novo Nordisk, Weight Watchers, Lilly, Boehringer Ingelheim, and Altimmune.
A version of this article appeared on Medscape.com.
DENVER — The ability to provide adolescents with highly effective anti-obesity medications that now carry approvals from the US Food and Drug Administration (FDA) and support in guidelines offers reassurance of their use; however, a reality check often awaits for clinicians in terms of challenges ranging from accessing and affording the medications to managing real and rumored side effects.
Weighing in on the issues, experts at Obesity Medicine (OMA) 2024 offered some key strategies and practice hacks for overcoming those hurdles.
The incentive to provide treatment with popular glucagon-like peptide 1 (GLP-1) drugs such as semaglutide or the dual glucose-dependent insulinotropic peptide (GIP) GLP-1 tirzepatide lies in the evidence that their high efficacy in promoting weight loss, and hence preventing metabolic syndrome, has benefits that far outweigh the potential side effects, said Alaina Vidmar, MD, in presenting at the meeting.
“We can look at all the evidence and without question acknowledge that the GLP-1s/GIP agonists are the most effective agents that we currently have, with the least heterogeneity in response, and the most high responders compared with other agents,” said Dr. Vidmar, an assistant professor of clinical pediatrics at the Keck School of Medicine of University of Southern California and director of obesity medicine and bariatric surgery at Children’s Hospital Los Angeles.
The strength of the evidence is reflected in the landmark American Academy of Pediatrics (AAP) Clinical Practice Guideline for the Evaluation and Treatment of Children and Adolescents With Obesity, which recommends that “pediatricians and other primary healthcare providers should offer adolescents 12 years and older with obesity weight loss pharmacotherapy, according to medication indications, risks and may offer adolescents 8 years old with obesity weight loss pharmacotherapy, according to medication indications, risks.”
The AAP guidance echoes the recommendations of the drug makers and FDA that “a combination of specific behavioral techniques within the context of family-based behavioral treatment and the use of pharmacotherapy may be necessary to prevent life-limiting complications over time.”
However, in real-world practice, with the various challenges in providing that intensive, comprehensive care, clinicians should be prepared to get creative: “We sometimes have to do the best we can with what we have because the watchful waiting approach is not effective and leads to more harm than good,” Dr. Vidmar said.
Facilitating Access
The ongoing reported shortages in the highly popular anti-obesity medications, as well as insurance denials and high costs, are among the leading obstacles, for adolescents and adults alike.
Dr. Vidmar noted that key strategies at her center, Children’s Hospital Los Angeles, have been essential, however, in helping at least facilitate the authorization process.
The center’s approach began with contacting all the payers the center has contracts with to determine which of their policies cover these medications for adults and pediatrics and which agents are covered.
“This took work on the front end, but it was worth it because it helped us understand the framework for what we were going to go up against every time that we prescribed these medications,” she said.
Furthermore, the center’s specialty pharmacy set up contracts to be able to provide the drugs within the institution.
While the strategy can’t entirely mitigate the ongoing distribution concerns, “our pharmacy is now able to share with our weight management program what GLP-1s are available so that we can be more efficient in our work,” Dr. Vidmar said.
The center also created a list of contacts to provide to patients and their families, detailing local pharmacies that were most likely to have the medications.
Another strategy Dr. Vidmar’s center has utilized to allow the timely implementation of a GLP-1 treatment plan while awaiting a drug to become available is to create an alternative protocol, for instance, using liraglutide when awaiting semaglutide.
“If we are unable to get the lower doses of a weekly agent for titration, we have a standard protocol to bridge instead with liraglutide, and our patients, pharmacies, and even our authorizations are aware of the protocol,” Dr. Vidmar said.
“We often do not have a lot of control or agency over the distribution concerns; however, we can be thoughtful within our programs about how we titrate patients up to their full doses,” Dr. Vidmar said.
Mitigating Side Effects
When the medications are available, the common gastrointestinal (GI) side effects of nausea, vomiting, and diarrhea of the once-weekly injections are well-known, and these side effects can affect quality of life and daily function, Dr. Vidmar noted.
“We have to acknowledge that the seminal trials of these agents showed that nausea and vomiting occur in more than half of young people who take these agents during the initial titration period, and while the side effects are tolerated by many, they can be disruptive to daily life,” she said.
Encouragingly, “we also do know that for the majority of patients, those effects improve over time, and for many, they can be mitigated with nutrition changes.”
Dr. Vidmar shared a handout her center issues with key recommendations for mitigating GI effects in youth. These include:
- Eat smaller meals and eat slower
- Eat about half of what you usually eat
- Take about 15-20 minutes to eat your meal
- Aim for 60 g of protein per day
- Add fruits, vegetables, whole grains, and lean proteins to meals
- Limit foods that are spicy, greasy, or fried
- Drink water instead of sweet drinks
Consider Zofran as needed during the titration period for GI symptoms. “We’ve started using this at our institution and are teaching patients how to use it; it can really help mitigate any ER visits when there is any vomiting by educating patients and families and providing appropriate expectations, and that has been very helpful,” Dr. Vidmar said.
Regarding the GI effects, Dr. Vidmar noted she has observed that tirzepatide use (though still off-label) in youths “tends to have milder GI side effects among younger people.”
Mood Concerns?
Another concern that has emerged in public discussion regarding side effects is that of possible mood and suicidal ideation, raising concerns for adults and adolescents alike.
Upon investigating the reports, the FDA, in a statement, offered cautious reassurance that their review, including reports and clinical trials, “did not find an association between use of GLP-1 RAs and the occurrence of suicidal thoughts or actions.”
Noting that the agency is continuing to look into the issue, however, the FDA recommends that “healthcare professionals should monitor for and advise patients using GLP-1 RAs to report new or worsening depression, suicidal thoughts, or any unusual changes in mood or behavior.”
Concurrent Psychiatric Pharmacotherapy
Meanwhile, with weight gain a known and often challenging side effect of various psychiatric drugs, particularly in younger patients, obesity treatment of adolescents may commonly involve patients who are also being treated with those therapies.
Key culprits include certain antidepressants and antipsychotic medications, such as tricyclic antidepressants, and second-generation antipsychotics, such as olanzapine.
In terms of the use of GLP-1 medications for those patients, research includes a recent study of semaglutide in patients who were also being treated with antidepressants.
The study, a post hoc analysis of the STEP trials, showed “clinically meaningful weight loss regardless of baseline antidepressant use, with an adverse event profile consistent with previous studies.”
First author Robert F. Kushner, MD, said the study offers “reassurance that individuals who are taking antidepressant medications have a similar weight loss response and side-effect profile compared to individuals who are not taking these medications.”
Dr. Kushner, a professor of medicine and medicine education at Northwestern University in Chicago, and his team have not evaluated the safety profile for concomitant use with antipsychotic drugs. However, he noted that “there are studies showing that the daily GLP-1 drug liraglutide has been shown to be useful in combating antipsychotic-induced weight gain.”
“Similar studies will need to be conducted for the more effective agents, semaglutide and tirzepatide,” he said.
To counter the weight gain effects of antispychotics, metformin has long been a standard recommendation, and Dr. Vidmar noted that “I have historically always used metformin in this setting and found it very effective.”
However, the newer anti-obesity medications could prove to be important in those cases, Dr. Vidmar added.
“I do think and predict that GLP-1 agonists will be as effective, if not more, in combating the weight gain-promoting effects of these agents and act as a nice adjuvant to this treatment paradigm for psychiatrists.”
Dr. Vidmar has participated in an advisory board for Rhythm Pharmaceuticals. Dr. Kushner is on the advisory boards for Novo Nordisk, Weight Watchers, Lilly, Boehringer Ingelheim, and Altimmune.
A version of this article appeared on Medscape.com.
FROM OBESITY MEDICINE 2024
Customized Video Games Promising for ADHD, Depression, in Children
, results of a new review and meta-analysis suggested.
Although the video game–based or “gamified” digital mental health interventions (DMHIs) were associated with modest improvements in ADHD symptoms and depression, investigators found no significant benefit in the treatment of anxiety.
“The studies are showing these video games really do work, at least for ADHD and depression but maybe not for anxiety,” said Barry Bryant, MD, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore.
“The results may assist clinicians as they make recommendations to patients and parents regarding the efficacy of using these video games to treat mental health conditions.”
The findings were presented at the American Psychiatric Association (APA) 2024 Annual Meeting.
A Major Problem
Childhood mental illness is a “big problem,” with about 20% of children facing some mental health challenge such as ADHD, anxiety, or depression, said Dr. Bryant. Unfortunately, these youngsters typically have to wait a while to see a provider, he added.
DMHIs may be an option to consider in the meantime to help meet the increasing demand for treatment, he said.
Gamified DMHIs are like other video games, in that players advance in levels on digital platforms and are rewarded for progress. But they’re created specifically to target certain mental health conditions.
An ADHD game, for example, might involve users completing activities that require an increasing degree of attention. Games focused on depression might incorporate mindfulness and meditation practices or cognitive behavioral elements.
Experts in child psychiatry are involved in developing such games along with professionals in business and video game technology, said Dr. Bryant.
But the question is: Do these games really work?
Effective for ADHD, Depression
Investigators reviewed nearly 30 randomized controlled trials of gamified DMHIs as a treatment for anxiety, depression, and/or ADHD in people younger than 18 years that were published from January 1, 1990, to April 7, 2023.
The trials tested a wide variety of gamified DMHIs that fit the inclusion criteria: A control condition, a digital game intervention, sufficient data to calculate effect size, and available in English.
A meta-analysis was performed to examine the therapeutic effects of the gamified DMHIs for ADHD, depression, and anxiety. For all studies, the active treatment was compared with the control condition using Hedges’ g to measure effect size and 95% CIs.
Dr. Bryant noted there was significant heterogeneity of therapeutic effects between the studies and their corresponding gamified interventions.
The study found gamified DMHIs had a modest therapeutic effect for treating ADHD (pooled g = 0.280; P = .005) and depression (pooled g = 0.279; P = .005) in children and adolescents.
But games targeting anxiety didn’t seem to have the same positive impact (pooled g = 0.074; P = .197).
The results suggest the games “show potential and promise” for certain mental health conditions and could offer a “bridge” to accessing more traditional therapies, Dr. Bryant said.
“Maybe this is something that can help these children until they can get to see a psychiatrist, or it could be part of a comprehensive treatment plan,” he said.
The goal is to “make something that kids want to play and engage with” especially if they’re reluctant to sit in a therapist’s office.
The results provide clinicians with information they can actually use in their practices, said Dr. Bryant, adding that his team hopes to get their study published.
Gaining Traction
Commenting on the research, James Sherer, MD, medical director, Addiction Psychiatry, Overlook Medical Center, Atlantic Health System, said the study shows the literature supports video games, and these games “are gaining traction” in the field.
He noted the app for one such game, EndeavorRx, was one of the first to be approved by the US Food and Drug Administration (FDA) to treat ADHD in young people aged 8-17 years.
EndeavorRx challenges players to chase mystic creatures, race through different worlds, and use “boosts” to problem-solve while building their own universe, according to the company website.
By being incentivized to engage in certain activities, “there’s a level of executive functioning that’s being exercised and the idea is to do that repetitively,” said Dr. Sherer.
Users and their parents report improved ADHD symptoms after playing the game. One of the studies included in the review found 73% of children who played EndeavorRx reported improvement in their attention.
The company says there have been no serious adverse events seen in any clinical trial of EndeavorRx.
Dr. Sherer noted that many child psychiatrists play some sort of video game with their young patients who may be on the autism spectrum or have a learning disability.
“That may be one of the few ways to communicate with and effectively bond with the patient,” he said.
Despite their reputation of being violent and associated with “toxic subcultures,” video games can do a lot of good and be “restorative” for patients of all ages, Dr. Sherer added.
No relevant conflicts of interest were disclosed.
A version of this article appeared on Medscape.com.
, results of a new review and meta-analysis suggested.
Although the video game–based or “gamified” digital mental health interventions (DMHIs) were associated with modest improvements in ADHD symptoms and depression, investigators found no significant benefit in the treatment of anxiety.
“The studies are showing these video games really do work, at least for ADHD and depression but maybe not for anxiety,” said Barry Bryant, MD, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore.
“The results may assist clinicians as they make recommendations to patients and parents regarding the efficacy of using these video games to treat mental health conditions.”
The findings were presented at the American Psychiatric Association (APA) 2024 Annual Meeting.
A Major Problem
Childhood mental illness is a “big problem,” with about 20% of children facing some mental health challenge such as ADHD, anxiety, or depression, said Dr. Bryant. Unfortunately, these youngsters typically have to wait a while to see a provider, he added.
DMHIs may be an option to consider in the meantime to help meet the increasing demand for treatment, he said.
Gamified DMHIs are like other video games, in that players advance in levels on digital platforms and are rewarded for progress. But they’re created specifically to target certain mental health conditions.
An ADHD game, for example, might involve users completing activities that require an increasing degree of attention. Games focused on depression might incorporate mindfulness and meditation practices or cognitive behavioral elements.
Experts in child psychiatry are involved in developing such games along with professionals in business and video game technology, said Dr. Bryant.
But the question is: Do these games really work?
Effective for ADHD, Depression
Investigators reviewed nearly 30 randomized controlled trials of gamified DMHIs as a treatment for anxiety, depression, and/or ADHD in people younger than 18 years that were published from January 1, 1990, to April 7, 2023.
The trials tested a wide variety of gamified DMHIs that fit the inclusion criteria: A control condition, a digital game intervention, sufficient data to calculate effect size, and available in English.
A meta-analysis was performed to examine the therapeutic effects of the gamified DMHIs for ADHD, depression, and anxiety. For all studies, the active treatment was compared with the control condition using Hedges’ g to measure effect size and 95% CIs.
Dr. Bryant noted there was significant heterogeneity of therapeutic effects between the studies and their corresponding gamified interventions.
The study found gamified DMHIs had a modest therapeutic effect for treating ADHD (pooled g = 0.280; P = .005) and depression (pooled g = 0.279; P = .005) in children and adolescents.
But games targeting anxiety didn’t seem to have the same positive impact (pooled g = 0.074; P = .197).
The results suggest the games “show potential and promise” for certain mental health conditions and could offer a “bridge” to accessing more traditional therapies, Dr. Bryant said.
“Maybe this is something that can help these children until they can get to see a psychiatrist, or it could be part of a comprehensive treatment plan,” he said.
The goal is to “make something that kids want to play and engage with” especially if they’re reluctant to sit in a therapist’s office.
The results provide clinicians with information they can actually use in their practices, said Dr. Bryant, adding that his team hopes to get their study published.
Gaining Traction
Commenting on the research, James Sherer, MD, medical director, Addiction Psychiatry, Overlook Medical Center, Atlantic Health System, said the study shows the literature supports video games, and these games “are gaining traction” in the field.
He noted the app for one such game, EndeavorRx, was one of the first to be approved by the US Food and Drug Administration (FDA) to treat ADHD in young people aged 8-17 years.
EndeavorRx challenges players to chase mystic creatures, race through different worlds, and use “boosts” to problem-solve while building their own universe, according to the company website.
By being incentivized to engage in certain activities, “there’s a level of executive functioning that’s being exercised and the idea is to do that repetitively,” said Dr. Sherer.
Users and their parents report improved ADHD symptoms after playing the game. One of the studies included in the review found 73% of children who played EndeavorRx reported improvement in their attention.
The company says there have been no serious adverse events seen in any clinical trial of EndeavorRx.
Dr. Sherer noted that many child psychiatrists play some sort of video game with their young patients who may be on the autism spectrum or have a learning disability.
“That may be one of the few ways to communicate with and effectively bond with the patient,” he said.
Despite their reputation of being violent and associated with “toxic subcultures,” video games can do a lot of good and be “restorative” for patients of all ages, Dr. Sherer added.
No relevant conflicts of interest were disclosed.
A version of this article appeared on Medscape.com.
, results of a new review and meta-analysis suggested.
Although the video game–based or “gamified” digital mental health interventions (DMHIs) were associated with modest improvements in ADHD symptoms and depression, investigators found no significant benefit in the treatment of anxiety.
“The studies are showing these video games really do work, at least for ADHD and depression but maybe not for anxiety,” said Barry Bryant, MD, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore.
“The results may assist clinicians as they make recommendations to patients and parents regarding the efficacy of using these video games to treat mental health conditions.”
The findings were presented at the American Psychiatric Association (APA) 2024 Annual Meeting.
A Major Problem
Childhood mental illness is a “big problem,” with about 20% of children facing some mental health challenge such as ADHD, anxiety, or depression, said Dr. Bryant. Unfortunately, these youngsters typically have to wait a while to see a provider, he added.
DMHIs may be an option to consider in the meantime to help meet the increasing demand for treatment, he said.
Gamified DMHIs are like other video games, in that players advance in levels on digital platforms and are rewarded for progress. But they’re created specifically to target certain mental health conditions.
An ADHD game, for example, might involve users completing activities that require an increasing degree of attention. Games focused on depression might incorporate mindfulness and meditation practices or cognitive behavioral elements.
Experts in child psychiatry are involved in developing such games along with professionals in business and video game technology, said Dr. Bryant.
But the question is: Do these games really work?
Effective for ADHD, Depression
Investigators reviewed nearly 30 randomized controlled trials of gamified DMHIs as a treatment for anxiety, depression, and/or ADHD in people younger than 18 years that were published from January 1, 1990, to April 7, 2023.
The trials tested a wide variety of gamified DMHIs that fit the inclusion criteria: A control condition, a digital game intervention, sufficient data to calculate effect size, and available in English.
A meta-analysis was performed to examine the therapeutic effects of the gamified DMHIs for ADHD, depression, and anxiety. For all studies, the active treatment was compared with the control condition using Hedges’ g to measure effect size and 95% CIs.
Dr. Bryant noted there was significant heterogeneity of therapeutic effects between the studies and their corresponding gamified interventions.
The study found gamified DMHIs had a modest therapeutic effect for treating ADHD (pooled g = 0.280; P = .005) and depression (pooled g = 0.279; P = .005) in children and adolescents.
But games targeting anxiety didn’t seem to have the same positive impact (pooled g = 0.074; P = .197).
The results suggest the games “show potential and promise” for certain mental health conditions and could offer a “bridge” to accessing more traditional therapies, Dr. Bryant said.
“Maybe this is something that can help these children until they can get to see a psychiatrist, or it could be part of a comprehensive treatment plan,” he said.
The goal is to “make something that kids want to play and engage with” especially if they’re reluctant to sit in a therapist’s office.
The results provide clinicians with information they can actually use in their practices, said Dr. Bryant, adding that his team hopes to get their study published.
Gaining Traction
Commenting on the research, James Sherer, MD, medical director, Addiction Psychiatry, Overlook Medical Center, Atlantic Health System, said the study shows the literature supports video games, and these games “are gaining traction” in the field.
He noted the app for one such game, EndeavorRx, was one of the first to be approved by the US Food and Drug Administration (FDA) to treat ADHD in young people aged 8-17 years.
EndeavorRx challenges players to chase mystic creatures, race through different worlds, and use “boosts” to problem-solve while building their own universe, according to the company website.
By being incentivized to engage in certain activities, “there’s a level of executive functioning that’s being exercised and the idea is to do that repetitively,” said Dr. Sherer.
Users and their parents report improved ADHD symptoms after playing the game. One of the studies included in the review found 73% of children who played EndeavorRx reported improvement in their attention.
The company says there have been no serious adverse events seen in any clinical trial of EndeavorRx.
Dr. Sherer noted that many child psychiatrists play some sort of video game with their young patients who may be on the autism spectrum or have a learning disability.
“That may be one of the few ways to communicate with and effectively bond with the patient,” he said.
Despite their reputation of being violent and associated with “toxic subcultures,” video games can do a lot of good and be “restorative” for patients of all ages, Dr. Sherer added.
No relevant conflicts of interest were disclosed.
A version of this article appeared on Medscape.com.
FROM APA 2024
New mRNA Vaccines in Development for Cancer and Infections
Martina Prelog, MD, a pediatric and adolescent medicine specialist at the University Hospital of Würzburg in Germany, reported on the principles, research status, and perspectives for these vaccines at the 25th Travel and Health Forum of the Center for Travel Medicine in Berlin.
To understand the future, the immunologist first examined the past. “The induction of cellular and humoral immune responses by externally injected mRNA was discovered in the 1990s,” she said.
Instability Challenge
Significant hurdles in mRNA vaccinations included the instability of mRNA and the immune system’s ability to identify foreign mRNA as a threat and destroy mRNA fragments. “The breakthrough toward vaccination came through Dr. Katalin Karikó, who, along with Dr. Drew Weissman, both of the University of Pennsylvania School of Medicine, discovered in 2005 that modifications of mRNA (replacing the nucleoside uridine with pseudouridine) enable better stability of mRNA, reduced immunogenicity, and higher translational capacity at the ribosomes,” said Dr. Prelog.
With this discovery, the two researchers paved the way for the development of mRNA vaccines against COVID-19 and other diseases. They were awarded the Nobel Prize in medicine for their discovery last year.
Improved Scalability
“Since 2009, mRNA vaccines have been studied as a treatment option for cancer,” said Dr. Prelog. “Since 2012, they have been studied for the influenza virus and respiratory syncytial virus [RSV].” Consequently, several mRNA vaccines are currently in development or in approval studies. “The mRNA technology offers the advantage of quickly and flexibly responding to new variants of pathogens and the ability to scale up production when there is high demand for a particular vaccine.”
Different forms and designations of mRNA vaccines are used, depending on the application and desired effect, said Dr. Prelog.
In nucleoside-modified mRNA vaccines, modifications in the mRNA sequence enable the mRNA to remain in the body longer and to induce protein synthesis more effectively.
Lipid nanoparticle (LNP)–encapsulated mRNA vaccines protect the coding mRNA sequences against degradation by the body’s enzymes and facilitate the uptake of mRNA into cells, where it then triggers the production of the desired protein. In addition, LNPs are involved in cell stimulation and support the self-adjuvant effect of mRNA vaccines, thus eliminating the need for adjuvants.
Self-amplifying mRNA vaccines include a special mRNA that replicates itself in the cell and contains a sequence for RNA replicase, in addition to the coding sequence for the protein. This composition enables increased production of the target protein without the need for a high amount of external mRNA administration. Such vaccines could trigger a longer and stronger immune response because the immune system has more time to interact with the protein.
Cancer Immunotherapy
Dr. Prelog also discussed personalized vaccines for cancer immunotherapy. Personalized mRNA vaccines are tailored to the patient’s genetic characteristics and antigens. They could be used in cancer immunotherapy to activate the immune system selectively against tumor cells.
Multivalent mRNA vaccines contain mRNA that codes for multiple antigens rather than just one protein to generate an immune response. These vaccines could be particularly useful in fighting pathogens with variable or changing surface structures or in eliciting protection against multiple pathogens simultaneously.
The technology of mRNA-encoded antibodies involves introducing mRNA into the cell, which creates light and heavy chains of antibodies. This step leads to the formation of antibodies targeted against toxins (eg, diphtheria and tetanus), animal venoms, infectious agents, or tumor cells.
Genetic Engineering
Dr. Prelog also reviewed genetic engineering techniques. In regenerative therapy or protein replacement therapy, skin fibroblasts or other cells are transfected with mRNA to enable conversion into induced pluripotent stem cells. This approach avoids the risk for DNA integration into the genome and associated mutation risks.
Another approach is making post-transcriptional modifications through RNA interference. For example, RNA structures can be used to inhibit the translation of disease-causing proteins. This technique is currently being tested against HIV and tumors such as melanoma.
In addition, mRNA technologies can be combined with CRISPR/Cas9 technology (“gene scissors”) to influence the creation of gene products even more precisely. The advantage of this technique is that mRNA is only transiently expressed, thus preventing unwanted side effects. Furthermore, mRNA is translated directly in the cytoplasm, leading to a faster initiation of gene editing.
Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders, said Dr. Prelog.
Research in Infections
Research in the fields of infectious diseases and oncology is the most advanced: mRNA vaccines against influenza and RSV are already in advanced clinical trials, Dr. Prelog told this news organization.
“Conventional influenza vaccines contain immunogenic surface molecules against hemagglutinin and neuraminidase in various combinations of influenza strains A and B and are produced in egg or cell cultures,” she said. “This is a time-consuming manufacturing process that takes months and, particularly with the egg-based process, bears the risk of changing the vaccine strain.”
“Additionally, influenza viruses undergo antigenic shift and drift through recombination, thus requiring annual adjustments to the vaccines. Thus, these influenza vaccines often lose accuracy in targeting circulating seasonal influenza strains.”
Several mRNA vaccines being tested contain not only coding sequences against hemagglutinin and neuraminidase but also for structural proteins of influenza viruses. “These are more conserved and mutate less easily, meaning they could serve as the basis for universal pandemic influenza vaccines,” said Dr. Prelog.
An advantage of mRNA vaccines, she added, is the strong cellular immune response that they elicit. This response is intended to provide additional protection alongside specific antibodies. An mRNA vaccine with coding sequences for the pre-fusion protein of RSV is in phase 3 trials for approval for vaccination in patients aged 60 years and older. It shows high effectiveness even in older patients and those with comorbidities.
Elaborate Purification Process
Bacterial origin plasmid DNA is used to produce mRNA vaccines. The mRNA vaccines for COVID-19 raised concerns that production-related DNA residues could pose a safety risk and cause autoimmune diseases.
These vaccines “typically undergo a very elaborate purification process,” said Dr. Prelog. “This involves enzymatic digestion with DNase to fragment and deplete plasmid DNA, followed by purification using chromatography columns, so that no safety-relevant DNA fragments should remain afterward.”
Thus, the Paul-Ehrlich-Institut also pointed out the very small, fragmented plasmid DNA residues of bacterial origin in mRNA COVID-19 vaccines pose no risk, unlike residual DNA from animal cell culture might pose in other vaccines.
Prevention and Therapy
In addition to the numerous advantages of mRNA vaccines (such as rapid adaptability to new or mutated pathogens, scalability, rapid production capability, self-adjuvant effect, strong induction of cellular immune responses, and safety), there are also challenges in RNA technology as a preventive and therapeutic measure, according to Dr. Prelog.
“Stability and storability, as well as the costs of new vaccine developments, play a role, as do the long-term effects regarding the persistence of antibody and cellular responses,” she said. The COVID-19 mRNA vaccines, for example, showed a well-maintained cellular immune response despite a tendency toward a rapid decline in humoral immune response.
“The experience with COVID-19 mRNA vaccines and the new vaccine developments based on mRNA technology give hope for an efficient and safe preventive and therapeutic use, particularly in the fields of infectious diseases and oncology,” Dr. Prelog concluded.
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Martina Prelog, MD, a pediatric and adolescent medicine specialist at the University Hospital of Würzburg in Germany, reported on the principles, research status, and perspectives for these vaccines at the 25th Travel and Health Forum of the Center for Travel Medicine in Berlin.
To understand the future, the immunologist first examined the past. “The induction of cellular and humoral immune responses by externally injected mRNA was discovered in the 1990s,” she said.
Instability Challenge
Significant hurdles in mRNA vaccinations included the instability of mRNA and the immune system’s ability to identify foreign mRNA as a threat and destroy mRNA fragments. “The breakthrough toward vaccination came through Dr. Katalin Karikó, who, along with Dr. Drew Weissman, both of the University of Pennsylvania School of Medicine, discovered in 2005 that modifications of mRNA (replacing the nucleoside uridine with pseudouridine) enable better stability of mRNA, reduced immunogenicity, and higher translational capacity at the ribosomes,” said Dr. Prelog.
With this discovery, the two researchers paved the way for the development of mRNA vaccines against COVID-19 and other diseases. They were awarded the Nobel Prize in medicine for their discovery last year.
Improved Scalability
“Since 2009, mRNA vaccines have been studied as a treatment option for cancer,” said Dr. Prelog. “Since 2012, they have been studied for the influenza virus and respiratory syncytial virus [RSV].” Consequently, several mRNA vaccines are currently in development or in approval studies. “The mRNA technology offers the advantage of quickly and flexibly responding to new variants of pathogens and the ability to scale up production when there is high demand for a particular vaccine.”
Different forms and designations of mRNA vaccines are used, depending on the application and desired effect, said Dr. Prelog.
In nucleoside-modified mRNA vaccines, modifications in the mRNA sequence enable the mRNA to remain in the body longer and to induce protein synthesis more effectively.
Lipid nanoparticle (LNP)–encapsulated mRNA vaccines protect the coding mRNA sequences against degradation by the body’s enzymes and facilitate the uptake of mRNA into cells, where it then triggers the production of the desired protein. In addition, LNPs are involved in cell stimulation and support the self-adjuvant effect of mRNA vaccines, thus eliminating the need for adjuvants.
Self-amplifying mRNA vaccines include a special mRNA that replicates itself in the cell and contains a sequence for RNA replicase, in addition to the coding sequence for the protein. This composition enables increased production of the target protein without the need for a high amount of external mRNA administration. Such vaccines could trigger a longer and stronger immune response because the immune system has more time to interact with the protein.
Cancer Immunotherapy
Dr. Prelog also discussed personalized vaccines for cancer immunotherapy. Personalized mRNA vaccines are tailored to the patient’s genetic characteristics and antigens. They could be used in cancer immunotherapy to activate the immune system selectively against tumor cells.
Multivalent mRNA vaccines contain mRNA that codes for multiple antigens rather than just one protein to generate an immune response. These vaccines could be particularly useful in fighting pathogens with variable or changing surface structures or in eliciting protection against multiple pathogens simultaneously.
The technology of mRNA-encoded antibodies involves introducing mRNA into the cell, which creates light and heavy chains of antibodies. This step leads to the formation of antibodies targeted against toxins (eg, diphtheria and tetanus), animal venoms, infectious agents, or tumor cells.
Genetic Engineering
Dr. Prelog also reviewed genetic engineering techniques. In regenerative therapy or protein replacement therapy, skin fibroblasts or other cells are transfected with mRNA to enable conversion into induced pluripotent stem cells. This approach avoids the risk for DNA integration into the genome and associated mutation risks.
Another approach is making post-transcriptional modifications through RNA interference. For example, RNA structures can be used to inhibit the translation of disease-causing proteins. This technique is currently being tested against HIV and tumors such as melanoma.
In addition, mRNA technologies can be combined with CRISPR/Cas9 technology (“gene scissors”) to influence the creation of gene products even more precisely. The advantage of this technique is that mRNA is only transiently expressed, thus preventing unwanted side effects. Furthermore, mRNA is translated directly in the cytoplasm, leading to a faster initiation of gene editing.
Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders, said Dr. Prelog.
Research in Infections
Research in the fields of infectious diseases and oncology is the most advanced: mRNA vaccines against influenza and RSV are already in advanced clinical trials, Dr. Prelog told this news organization.
“Conventional influenza vaccines contain immunogenic surface molecules against hemagglutinin and neuraminidase in various combinations of influenza strains A and B and are produced in egg or cell cultures,” she said. “This is a time-consuming manufacturing process that takes months and, particularly with the egg-based process, bears the risk of changing the vaccine strain.”
“Additionally, influenza viruses undergo antigenic shift and drift through recombination, thus requiring annual adjustments to the vaccines. Thus, these influenza vaccines often lose accuracy in targeting circulating seasonal influenza strains.”
Several mRNA vaccines being tested contain not only coding sequences against hemagglutinin and neuraminidase but also for structural proteins of influenza viruses. “These are more conserved and mutate less easily, meaning they could serve as the basis for universal pandemic influenza vaccines,” said Dr. Prelog.
An advantage of mRNA vaccines, she added, is the strong cellular immune response that they elicit. This response is intended to provide additional protection alongside specific antibodies. An mRNA vaccine with coding sequences for the pre-fusion protein of RSV is in phase 3 trials for approval for vaccination in patients aged 60 years and older. It shows high effectiveness even in older patients and those with comorbidities.
Elaborate Purification Process
Bacterial origin plasmid DNA is used to produce mRNA vaccines. The mRNA vaccines for COVID-19 raised concerns that production-related DNA residues could pose a safety risk and cause autoimmune diseases.
These vaccines “typically undergo a very elaborate purification process,” said Dr. Prelog. “This involves enzymatic digestion with DNase to fragment and deplete plasmid DNA, followed by purification using chromatography columns, so that no safety-relevant DNA fragments should remain afterward.”
Thus, the Paul-Ehrlich-Institut also pointed out the very small, fragmented plasmid DNA residues of bacterial origin in mRNA COVID-19 vaccines pose no risk, unlike residual DNA from animal cell culture might pose in other vaccines.
Prevention and Therapy
In addition to the numerous advantages of mRNA vaccines (such as rapid adaptability to new or mutated pathogens, scalability, rapid production capability, self-adjuvant effect, strong induction of cellular immune responses, and safety), there are also challenges in RNA technology as a preventive and therapeutic measure, according to Dr. Prelog.
“Stability and storability, as well as the costs of new vaccine developments, play a role, as do the long-term effects regarding the persistence of antibody and cellular responses,” she said. The COVID-19 mRNA vaccines, for example, showed a well-maintained cellular immune response despite a tendency toward a rapid decline in humoral immune response.
“The experience with COVID-19 mRNA vaccines and the new vaccine developments based on mRNA technology give hope for an efficient and safe preventive and therapeutic use, particularly in the fields of infectious diseases and oncology,” Dr. Prelog concluded.
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Martina Prelog, MD, a pediatric and adolescent medicine specialist at the University Hospital of Würzburg in Germany, reported on the principles, research status, and perspectives for these vaccines at the 25th Travel and Health Forum of the Center for Travel Medicine in Berlin.
To understand the future, the immunologist first examined the past. “The induction of cellular and humoral immune responses by externally injected mRNA was discovered in the 1990s,” she said.
Instability Challenge
Significant hurdles in mRNA vaccinations included the instability of mRNA and the immune system’s ability to identify foreign mRNA as a threat and destroy mRNA fragments. “The breakthrough toward vaccination came through Dr. Katalin Karikó, who, along with Dr. Drew Weissman, both of the University of Pennsylvania School of Medicine, discovered in 2005 that modifications of mRNA (replacing the nucleoside uridine with pseudouridine) enable better stability of mRNA, reduced immunogenicity, and higher translational capacity at the ribosomes,” said Dr. Prelog.
With this discovery, the two researchers paved the way for the development of mRNA vaccines against COVID-19 and other diseases. They were awarded the Nobel Prize in medicine for their discovery last year.
Improved Scalability
“Since 2009, mRNA vaccines have been studied as a treatment option for cancer,” said Dr. Prelog. “Since 2012, they have been studied for the influenza virus and respiratory syncytial virus [RSV].” Consequently, several mRNA vaccines are currently in development or in approval studies. “The mRNA technology offers the advantage of quickly and flexibly responding to new variants of pathogens and the ability to scale up production when there is high demand for a particular vaccine.”
Different forms and designations of mRNA vaccines are used, depending on the application and desired effect, said Dr. Prelog.
In nucleoside-modified mRNA vaccines, modifications in the mRNA sequence enable the mRNA to remain in the body longer and to induce protein synthesis more effectively.
Lipid nanoparticle (LNP)–encapsulated mRNA vaccines protect the coding mRNA sequences against degradation by the body’s enzymes and facilitate the uptake of mRNA into cells, where it then triggers the production of the desired protein. In addition, LNPs are involved in cell stimulation and support the self-adjuvant effect of mRNA vaccines, thus eliminating the need for adjuvants.
Self-amplifying mRNA vaccines include a special mRNA that replicates itself in the cell and contains a sequence for RNA replicase, in addition to the coding sequence for the protein. This composition enables increased production of the target protein without the need for a high amount of external mRNA administration. Such vaccines could trigger a longer and stronger immune response because the immune system has more time to interact with the protein.
Cancer Immunotherapy
Dr. Prelog also discussed personalized vaccines for cancer immunotherapy. Personalized mRNA vaccines are tailored to the patient’s genetic characteristics and antigens. They could be used in cancer immunotherapy to activate the immune system selectively against tumor cells.
Multivalent mRNA vaccines contain mRNA that codes for multiple antigens rather than just one protein to generate an immune response. These vaccines could be particularly useful in fighting pathogens with variable or changing surface structures or in eliciting protection against multiple pathogens simultaneously.
The technology of mRNA-encoded antibodies involves introducing mRNA into the cell, which creates light and heavy chains of antibodies. This step leads to the formation of antibodies targeted against toxins (eg, diphtheria and tetanus), animal venoms, infectious agents, or tumor cells.
Genetic Engineering
Dr. Prelog also reviewed genetic engineering techniques. In regenerative therapy or protein replacement therapy, skin fibroblasts or other cells are transfected with mRNA to enable conversion into induced pluripotent stem cells. This approach avoids the risk for DNA integration into the genome and associated mutation risks.
Another approach is making post-transcriptional modifications through RNA interference. For example, RNA structures can be used to inhibit the translation of disease-causing proteins. This technique is currently being tested against HIV and tumors such as melanoma.
In addition, mRNA technologies can be combined with CRISPR/Cas9 technology (“gene scissors”) to influence the creation of gene products even more precisely. The advantage of this technique is that mRNA is only transiently expressed, thus preventing unwanted side effects. Furthermore, mRNA is translated directly in the cytoplasm, leading to a faster initiation of gene editing.
Of the numerous ongoing clinical mRNA vaccine studies, around 70% focus on infections, about 12% on cancer, and the rest on autoimmune diseases and neurodegenerative disorders, said Dr. Prelog.
Research in Infections
Research in the fields of infectious diseases and oncology is the most advanced: mRNA vaccines against influenza and RSV are already in advanced clinical trials, Dr. Prelog told this news organization.
“Conventional influenza vaccines contain immunogenic surface molecules against hemagglutinin and neuraminidase in various combinations of influenza strains A and B and are produced in egg or cell cultures,” she said. “This is a time-consuming manufacturing process that takes months and, particularly with the egg-based process, bears the risk of changing the vaccine strain.”
“Additionally, influenza viruses undergo antigenic shift and drift through recombination, thus requiring annual adjustments to the vaccines. Thus, these influenza vaccines often lose accuracy in targeting circulating seasonal influenza strains.”
Several mRNA vaccines being tested contain not only coding sequences against hemagglutinin and neuraminidase but also for structural proteins of influenza viruses. “These are more conserved and mutate less easily, meaning they could serve as the basis for universal pandemic influenza vaccines,” said Dr. Prelog.
An advantage of mRNA vaccines, she added, is the strong cellular immune response that they elicit. This response is intended to provide additional protection alongside specific antibodies. An mRNA vaccine with coding sequences for the pre-fusion protein of RSV is in phase 3 trials for approval for vaccination in patients aged 60 years and older. It shows high effectiveness even in older patients and those with comorbidities.
Elaborate Purification Process
Bacterial origin plasmid DNA is used to produce mRNA vaccines. The mRNA vaccines for COVID-19 raised concerns that production-related DNA residues could pose a safety risk and cause autoimmune diseases.
These vaccines “typically undergo a very elaborate purification process,” said Dr. Prelog. “This involves enzymatic digestion with DNase to fragment and deplete plasmid DNA, followed by purification using chromatography columns, so that no safety-relevant DNA fragments should remain afterward.”
Thus, the Paul-Ehrlich-Institut also pointed out the very small, fragmented plasmid DNA residues of bacterial origin in mRNA COVID-19 vaccines pose no risk, unlike residual DNA from animal cell culture might pose in other vaccines.
Prevention and Therapy
In addition to the numerous advantages of mRNA vaccines (such as rapid adaptability to new or mutated pathogens, scalability, rapid production capability, self-adjuvant effect, strong induction of cellular immune responses, and safety), there are also challenges in RNA technology as a preventive and therapeutic measure, according to Dr. Prelog.
“Stability and storability, as well as the costs of new vaccine developments, play a role, as do the long-term effects regarding the persistence of antibody and cellular responses,” she said. The COVID-19 mRNA vaccines, for example, showed a well-maintained cellular immune response despite a tendency toward a rapid decline in humoral immune response.
“The experience with COVID-19 mRNA vaccines and the new vaccine developments based on mRNA technology give hope for an efficient and safe preventive and therapeutic use, particularly in the fields of infectious diseases and oncology,” Dr. Prelog concluded.
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Can a Risk Score Predict Kidney Injury After Cisplatin?
Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.
Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.
A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.
Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.
However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.
Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.
“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
‘Herculean Effort’
“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.
“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.
The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.
The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.
Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.
Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.
Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.
The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.
Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
‘Definitive Work’
Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”
“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”
In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”
An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.
By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.
All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”
“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
‘Certainly Useful’
Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.
As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.
“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”
Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.
Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.
Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.
Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”
If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.
Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.
A version of this article appeared on Medscape.com.
Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.
Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.
A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.
Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.
However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.
Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.
“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
‘Herculean Effort’
“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.
“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.
The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.
The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.
Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.
Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.
Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.
The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.
Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
‘Definitive Work’
Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”
“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”
In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”
An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.
By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.
All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”
“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
‘Certainly Useful’
Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.
As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.
“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”
Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.
Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.
Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.
Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”
If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.
Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.
A version of this article appeared on Medscape.com.
Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.
Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.
A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.
Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.
However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.
Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.
“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
‘Herculean Effort’
“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.
“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.
The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.
The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.
Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.
Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.
Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.
The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.
Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
‘Definitive Work’
Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”
“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”
In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”
An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.
By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.
All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”
“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
‘Certainly Useful’
Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.
As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.
“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”
Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.
Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.
Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.
Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”
If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.
Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.
A version of this article appeared on Medscape.com.
FROM THE BMJ
Top Predictors of Substance Initiation in Youth Flagged
, new research suggests.
Aside from sociodemographic parameters, risk factors for substance use initiation include prenatal exposure to substances, peer use of alcohol and nicotine, and problematic school behavior, among other things, the study showed.
The results show certain modifiable risk factors may play a role in preventing youth from starting to use substances, said study author ReJoyce Green, PhD, research assistant professor, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston.
“If we’re designing, say, a prevention program or an early intervention program, these are things that could make a difference, so let’s make sure we’re bringing them into the conversation.”
The findings were presented at the annual meeting of the American Psychiatric Association American Psychiatric Association (APA) and published online in The American Journal of Psychiatry.
Critical Risk Factors
Use of alcohol, tobacco, and cannabis often begins during adolescence. One recent survey showed that 23% of 13-year-olds reported using alcohol, 17% reported vaping nicotine, and 8% reported vaping cannabis. Other research links younger age at substance use initiation to a more rapid transition to substance use disorders and higher rates of psychiatric disorders.
Previous studies examining predictors of substance use initiation in the Adolescent Brain Cognitive Development (ABCD) Study dataset focused primarily on self-reported measures, but the current study also looked at models that include hormones and neurocognitive factors as well as neuroimaging.
This study included 6829, 9- and 10-year-olds from the ABCD Study who had never tried substances and were followed for 3 years.
A sophisticated statistical approach was used to examine 420 variables as predictors of substance use initiation. Initiation was defined as trying any nonprescribed substance by age 12 years. “That’s including a single sip of alcohol or puff of a cigarette,” said Dr. Green.
In addition to alcohol, nicotine, and cannabis, researchers looked at initiation of synthetic cannabinoids, cocaine, methamphetamine, and ketamine, among other substances.
Self-reported measures included demographic characteristics, self and peer involvement with substance use, parenting behaviors, mental and physical health, and culture and environmental factors.
The analytical approach used machine-learning algorithms to compare the ability of domains to identify the most critical risk factors. Magnitudes of coefficients were used to assess variable importance, with positive coefficients indicating greater likelihood of substance initiation and negative coefficients indicating lower likelihood of initiation.
By age 12 years, 14.4% of the children studied reported substance initiation. Alcohol was the substance most commonly initiated (365 individuals), followed by nicotine (94 individuals) and cannabis (40 individuals), with few or no children initiating other substances.
Both those who did and did not initiate substances were similarly aged, and most participants identified as White and non-Hispanic. But the substance-use group had a lower percentage of girls and higher percentage of White participants compared with the no-substance-use group.
The model with only self-reported data had similar accuracy in predicting substance use initiation (area under the curve [AUC], 0.67) as models that added resource-intensive measures such as neurocognitive tests and hormones (AUC, 0.67) and neuroimaging (AUC, 0.66).
Religious Predictors
The strongest predictors of substance use initiation were related to religion: Youths whose parents reported a religious preference for Mormonism were less likely to initiate substance use (coefficient, -0.87), whereas youths whose parents reported a religious preference for Judaism were more likely to initiate substance use (coefficient, 0.32).
The third top predictor was race: Black youths were less likely to initiate substance use (coefficient, -0.32). This was followed by youths whose parents reported a religious preference for Islam who were also less likely to initiate substance use (coefficient, -0.25).
The research examined over 15 different religious categories, “so we really tried to be expansive,” noted Dr. Green.
It’s unclear why some religions appeared to have a protective impact when it comes to substance use initiation whereas others have the opposite effect. Future research could perhaps identify which components of religiosity affect substance use initiation. If so, these aspects could be developed and incorporated into prevention and intervention programs, said Dr. Green.
Next on the list of most important predictors was being a part of a household with an income of $12,000-$15,999; these youths were less likely to initiate substance use (coefficient, 0.22).
Within the culture and environment domain, a history of detention or suspension was a top predictor of substance use initiation (coefficient, 0.20). Prenatal exposure to substance use was also a robust predictor in the physical health category (coefficient, 0.15).
Other predictors included: parents with less than a high school degree or GED (coefficient, -0.14), substance use availability (coefficient, 0.12), and age at baseline (coefficient, 0.12).
The study also showed that better cognitive functioning in selected domains (eg, cognitive control, attention, and language ability) is associated with a greater likelihood of substance use initiation.
Shaping Future Prevention
Applying these findings in clinical settings could help tailor prevention and early intervention efforts, said the authors. It might be prudent to allocate resources to collecting data related to self-, peer-, and familial-related factors, “which were more informative in predicting substance use initiation during late childhood and early adolescence in the present study,” they wrote.
Researchers will continue to track these children through to a 10-year follow-up, said Dr. Green. “I’m really curious to see if the factors we found when they were 12 and 13, such as those related to peers and family, still hold when they’re ages 17 and 18, because there’s going to be a huge amount of brain development that’s happening throughout this phase.”
The group that initiated substance use and the group that didn’t initiate substance use were not totally balanced, and sample sizes for some religious categories were small. Another study limitation was that the analytic approach didn’t account for multilevel data within the context of site and families.
Commenting on the findings, Kathleen Brady, MD, PhD, distinguished university professor and director, South Carolina Clinical and Translational Research Institute, Medical University of South Carolina, said that the study is “critical and complex.” This, she said, is especially true as cannabis has become more accessible and potent, and as the federal government reportedly considers reclassifying it from a Schedule I drug (which includes highly dangerous, addictive substances with no medical use) to a Schedule III drug (which can be prescribed as a medication).
“The part that is the most frightening to me is the long-lasting effects that can happen when young people start using high-potency marijuana at an early age,” said Dr. Brady. “So, any information that we can give to parents, to teachers, to the public, and to doctors is important.”
She’s looking forward to getting more “incredibly important” information on substance use initiation as the study progresses and the teens get older.
The study received support from the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse.
A version of this article appeared on Medscape.com.
, new research suggests.
Aside from sociodemographic parameters, risk factors for substance use initiation include prenatal exposure to substances, peer use of alcohol and nicotine, and problematic school behavior, among other things, the study showed.
The results show certain modifiable risk factors may play a role in preventing youth from starting to use substances, said study author ReJoyce Green, PhD, research assistant professor, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston.
“If we’re designing, say, a prevention program or an early intervention program, these are things that could make a difference, so let’s make sure we’re bringing them into the conversation.”
The findings were presented at the annual meeting of the American Psychiatric Association American Psychiatric Association (APA) and published online in The American Journal of Psychiatry.
Critical Risk Factors
Use of alcohol, tobacco, and cannabis often begins during adolescence. One recent survey showed that 23% of 13-year-olds reported using alcohol, 17% reported vaping nicotine, and 8% reported vaping cannabis. Other research links younger age at substance use initiation to a more rapid transition to substance use disorders and higher rates of psychiatric disorders.
Previous studies examining predictors of substance use initiation in the Adolescent Brain Cognitive Development (ABCD) Study dataset focused primarily on self-reported measures, but the current study also looked at models that include hormones and neurocognitive factors as well as neuroimaging.
This study included 6829, 9- and 10-year-olds from the ABCD Study who had never tried substances and were followed for 3 years.
A sophisticated statistical approach was used to examine 420 variables as predictors of substance use initiation. Initiation was defined as trying any nonprescribed substance by age 12 years. “That’s including a single sip of alcohol or puff of a cigarette,” said Dr. Green.
In addition to alcohol, nicotine, and cannabis, researchers looked at initiation of synthetic cannabinoids, cocaine, methamphetamine, and ketamine, among other substances.
Self-reported measures included demographic characteristics, self and peer involvement with substance use, parenting behaviors, mental and physical health, and culture and environmental factors.
The analytical approach used machine-learning algorithms to compare the ability of domains to identify the most critical risk factors. Magnitudes of coefficients were used to assess variable importance, with positive coefficients indicating greater likelihood of substance initiation and negative coefficients indicating lower likelihood of initiation.
By age 12 years, 14.4% of the children studied reported substance initiation. Alcohol was the substance most commonly initiated (365 individuals), followed by nicotine (94 individuals) and cannabis (40 individuals), with few or no children initiating other substances.
Both those who did and did not initiate substances were similarly aged, and most participants identified as White and non-Hispanic. But the substance-use group had a lower percentage of girls and higher percentage of White participants compared with the no-substance-use group.
The model with only self-reported data had similar accuracy in predicting substance use initiation (area under the curve [AUC], 0.67) as models that added resource-intensive measures such as neurocognitive tests and hormones (AUC, 0.67) and neuroimaging (AUC, 0.66).
Religious Predictors
The strongest predictors of substance use initiation were related to religion: Youths whose parents reported a religious preference for Mormonism were less likely to initiate substance use (coefficient, -0.87), whereas youths whose parents reported a religious preference for Judaism were more likely to initiate substance use (coefficient, 0.32).
The third top predictor was race: Black youths were less likely to initiate substance use (coefficient, -0.32). This was followed by youths whose parents reported a religious preference for Islam who were also less likely to initiate substance use (coefficient, -0.25).
The research examined over 15 different religious categories, “so we really tried to be expansive,” noted Dr. Green.
It’s unclear why some religions appeared to have a protective impact when it comes to substance use initiation whereas others have the opposite effect. Future research could perhaps identify which components of religiosity affect substance use initiation. If so, these aspects could be developed and incorporated into prevention and intervention programs, said Dr. Green.
Next on the list of most important predictors was being a part of a household with an income of $12,000-$15,999; these youths were less likely to initiate substance use (coefficient, 0.22).
Within the culture and environment domain, a history of detention or suspension was a top predictor of substance use initiation (coefficient, 0.20). Prenatal exposure to substance use was also a robust predictor in the physical health category (coefficient, 0.15).
Other predictors included: parents with less than a high school degree or GED (coefficient, -0.14), substance use availability (coefficient, 0.12), and age at baseline (coefficient, 0.12).
The study also showed that better cognitive functioning in selected domains (eg, cognitive control, attention, and language ability) is associated with a greater likelihood of substance use initiation.
Shaping Future Prevention
Applying these findings in clinical settings could help tailor prevention and early intervention efforts, said the authors. It might be prudent to allocate resources to collecting data related to self-, peer-, and familial-related factors, “which were more informative in predicting substance use initiation during late childhood and early adolescence in the present study,” they wrote.
Researchers will continue to track these children through to a 10-year follow-up, said Dr. Green. “I’m really curious to see if the factors we found when they were 12 and 13, such as those related to peers and family, still hold when they’re ages 17 and 18, because there’s going to be a huge amount of brain development that’s happening throughout this phase.”
The group that initiated substance use and the group that didn’t initiate substance use were not totally balanced, and sample sizes for some religious categories were small. Another study limitation was that the analytic approach didn’t account for multilevel data within the context of site and families.
Commenting on the findings, Kathleen Brady, MD, PhD, distinguished university professor and director, South Carolina Clinical and Translational Research Institute, Medical University of South Carolina, said that the study is “critical and complex.” This, she said, is especially true as cannabis has become more accessible and potent, and as the federal government reportedly considers reclassifying it from a Schedule I drug (which includes highly dangerous, addictive substances with no medical use) to a Schedule III drug (which can be prescribed as a medication).
“The part that is the most frightening to me is the long-lasting effects that can happen when young people start using high-potency marijuana at an early age,” said Dr. Brady. “So, any information that we can give to parents, to teachers, to the public, and to doctors is important.”
She’s looking forward to getting more “incredibly important” information on substance use initiation as the study progresses and the teens get older.
The study received support from the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse.
A version of this article appeared on Medscape.com.
, new research suggests.
Aside from sociodemographic parameters, risk factors for substance use initiation include prenatal exposure to substances, peer use of alcohol and nicotine, and problematic school behavior, among other things, the study showed.
The results show certain modifiable risk factors may play a role in preventing youth from starting to use substances, said study author ReJoyce Green, PhD, research assistant professor, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston.
“If we’re designing, say, a prevention program or an early intervention program, these are things that could make a difference, so let’s make sure we’re bringing them into the conversation.”
The findings were presented at the annual meeting of the American Psychiatric Association American Psychiatric Association (APA) and published online in The American Journal of Psychiatry.
Critical Risk Factors
Use of alcohol, tobacco, and cannabis often begins during adolescence. One recent survey showed that 23% of 13-year-olds reported using alcohol, 17% reported vaping nicotine, and 8% reported vaping cannabis. Other research links younger age at substance use initiation to a more rapid transition to substance use disorders and higher rates of psychiatric disorders.
Previous studies examining predictors of substance use initiation in the Adolescent Brain Cognitive Development (ABCD) Study dataset focused primarily on self-reported measures, but the current study also looked at models that include hormones and neurocognitive factors as well as neuroimaging.
This study included 6829, 9- and 10-year-olds from the ABCD Study who had never tried substances and were followed for 3 years.
A sophisticated statistical approach was used to examine 420 variables as predictors of substance use initiation. Initiation was defined as trying any nonprescribed substance by age 12 years. “That’s including a single sip of alcohol or puff of a cigarette,” said Dr. Green.
In addition to alcohol, nicotine, and cannabis, researchers looked at initiation of synthetic cannabinoids, cocaine, methamphetamine, and ketamine, among other substances.
Self-reported measures included demographic characteristics, self and peer involvement with substance use, parenting behaviors, mental and physical health, and culture and environmental factors.
The analytical approach used machine-learning algorithms to compare the ability of domains to identify the most critical risk factors. Magnitudes of coefficients were used to assess variable importance, with positive coefficients indicating greater likelihood of substance initiation and negative coefficients indicating lower likelihood of initiation.
By age 12 years, 14.4% of the children studied reported substance initiation. Alcohol was the substance most commonly initiated (365 individuals), followed by nicotine (94 individuals) and cannabis (40 individuals), with few or no children initiating other substances.
Both those who did and did not initiate substances were similarly aged, and most participants identified as White and non-Hispanic. But the substance-use group had a lower percentage of girls and higher percentage of White participants compared with the no-substance-use group.
The model with only self-reported data had similar accuracy in predicting substance use initiation (area under the curve [AUC], 0.67) as models that added resource-intensive measures such as neurocognitive tests and hormones (AUC, 0.67) and neuroimaging (AUC, 0.66).
Religious Predictors
The strongest predictors of substance use initiation were related to religion: Youths whose parents reported a religious preference for Mormonism were less likely to initiate substance use (coefficient, -0.87), whereas youths whose parents reported a religious preference for Judaism were more likely to initiate substance use (coefficient, 0.32).
The third top predictor was race: Black youths were less likely to initiate substance use (coefficient, -0.32). This was followed by youths whose parents reported a religious preference for Islam who were also less likely to initiate substance use (coefficient, -0.25).
The research examined over 15 different religious categories, “so we really tried to be expansive,” noted Dr. Green.
It’s unclear why some religions appeared to have a protective impact when it comes to substance use initiation whereas others have the opposite effect. Future research could perhaps identify which components of religiosity affect substance use initiation. If so, these aspects could be developed and incorporated into prevention and intervention programs, said Dr. Green.
Next on the list of most important predictors was being a part of a household with an income of $12,000-$15,999; these youths were less likely to initiate substance use (coefficient, 0.22).
Within the culture and environment domain, a history of detention or suspension was a top predictor of substance use initiation (coefficient, 0.20). Prenatal exposure to substance use was also a robust predictor in the physical health category (coefficient, 0.15).
Other predictors included: parents with less than a high school degree or GED (coefficient, -0.14), substance use availability (coefficient, 0.12), and age at baseline (coefficient, 0.12).
The study also showed that better cognitive functioning in selected domains (eg, cognitive control, attention, and language ability) is associated with a greater likelihood of substance use initiation.
Shaping Future Prevention
Applying these findings in clinical settings could help tailor prevention and early intervention efforts, said the authors. It might be prudent to allocate resources to collecting data related to self-, peer-, and familial-related factors, “which were more informative in predicting substance use initiation during late childhood and early adolescence in the present study,” they wrote.
Researchers will continue to track these children through to a 10-year follow-up, said Dr. Green. “I’m really curious to see if the factors we found when they were 12 and 13, such as those related to peers and family, still hold when they’re ages 17 and 18, because there’s going to be a huge amount of brain development that’s happening throughout this phase.”
The group that initiated substance use and the group that didn’t initiate substance use were not totally balanced, and sample sizes for some religious categories were small. Another study limitation was that the analytic approach didn’t account for multilevel data within the context of site and families.
Commenting on the findings, Kathleen Brady, MD, PhD, distinguished university professor and director, South Carolina Clinical and Translational Research Institute, Medical University of South Carolina, said that the study is “critical and complex.” This, she said, is especially true as cannabis has become more accessible and potent, and as the federal government reportedly considers reclassifying it from a Schedule I drug (which includes highly dangerous, addictive substances with no medical use) to a Schedule III drug (which can be prescribed as a medication).
“The part that is the most frightening to me is the long-lasting effects that can happen when young people start using high-potency marijuana at an early age,” said Dr. Brady. “So, any information that we can give to parents, to teachers, to the public, and to doctors is important.”
She’s looking forward to getting more “incredibly important” information on substance use initiation as the study progresses and the teens get older.
The study received support from the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse.
A version of this article appeared on Medscape.com.
FROM APA 2024
A 6-Year-Old Female Presents With a Bruise-Like Lesion on the Lip, Tongue, and Chin Area Present Since Birth
Diagnosis: Venous Malformation
Although present at birth, they are not always clinically evident early in life. They also tend to grow with the child without spontaneous regression, causing potential cosmetic concerns or complications from impingement on surrounding tissue.
Venous malformations appear with a bluish color appearing beneath the skin and can vary significantly in size and severity. Venous malformations are compressible and characterized by low to stagnant blood flow, which can spontaneously thrombose. Clinically, this may cause pain, swelling, skin changes, tissue and limb overgrowth, or functional impairment depending on location and size.
Venous malformations result from disorganized angiogenesis secondary to sporadic mutations in somatic cells. The most common implicated gene is TEK, a receptor tyrosine kinase. PIK3CA has also been involved. Both genes are involved in the PI3K/AKT/mTOR pathway, which regulates cell growth, proliferation, and angiogenesis. In venous endothelial cells, abnormal angiogenesis and vessel maturation may lead to venous malformation formation. Dysplastic vessels frequently separate from normal veins but may be contiguous with the deep venous system.
Diagnosis involves clinical history and physical examination. Imaging with ultrasound and magnetic resonance imaging (MRI) may be utilized. While ultrasound may be preferred for superficial venous malformations, MRI or MRI with MR angiography (MRA) is the preferred method for venous malformation assessment. Genetic testing may be appropriate for complex malformations, as classification of lesions by underlying mutation may allow targeted therapy.
This patient’s past MRI and MRA findings were consistent with a venous malformation.
Treatment
Venous malformations rarely regress spontaneously. Treatment is required if venous malformations are symptomatic, which may include pain, swelling, deformity, thrombosis, or interference with daily activities of living. Treatment plans require consideration of patient goals of care. The main categories of therapy are embolization/sclerotherapy, surgical resection, and molecular targeted therapy.
Sclerotherapy is a well-tolerated and efficacious first-line therapy. It can be used as either nonsurgical curative therapy or preoperative adjunct therapy to minimize blood loss before surgical resection. While surgical resection may cause scarring, multimodal approaches with sclerotherapy or laser therapy can decrease complications. Molecular therapies aim to reduce vascular proliferation and symptoms. Referral to hematology/oncology for evaluation and consideration of chemotherapeutic agents may be required. Sirolimus has been shown in mice models to inhibit an endothelial cell tyrosine kinase receptor that plays a role in venous malformation growth. Multiple studies have proved its efficacy in managing complicated vascular anomalies, including venous malformations. Alpelisib is an inhibitor of PI3KCA, which is part of the pathway that contributes to venous malformation formation. Dactolisib, a dual inhibitor of the PI3KA and mTOR pathways, and rebastinib, a TEK inhibitor, are being investigated.
Differential Diagnoses
The differential diagnosis includes dermal melanocytosis, nevus of Ota, hemangioma of infancy, and ashy dermatosis. In addition, venous malformations can be part of more complex vascular malformations.
Dermal melanocytosis, also known as Mongolian spots, are blue-gray patches of discoloration on the skin that appear at birth or shortly after. They result from the arrest of dermal melanocytes in the dermis during fetal life and tissue modeling. They are commonly observed in those of Asian or African descent with darker skin types. Most often, they are located in the lumbar or sacral-gluteal region. Unlike venous malformations, they are benign and do not involve vascular abnormalities. They typically fade over time.
Nevus of Ota is a benign congenital condition that presents with blue-gray or brown patches of pigmentation on the skin around the eyes, cheeks, and forehead. They are dermal melanocytes with a speckled instead of uniform appearance. Nevus of Ota primarily affects individuals of Asian descent and typically presents in the trigeminal nerve distribution region. Treatment can be done to minimize deformity, generally with pigmented laser surgery.
Hemangiomas of infancy are common benign tumors of infancy caused by endothelial cell proliferation. They are characterized by rapid growth followed by spontaneous involution within the first year of life and for several years. Hemangiomas can be superficial, deep, or mixed with features of both superficial and deep. Superficial hemangiomas present as raised, lobulated, and bright red while deep hemangiomas present as a bluish-hued nodule, plaque, or tumor. They are diagnosed clinically but skin biopsies and imaging can confirm the suspected diagnosis. While hemangiomas may self-resolve, complicated hemangiomas can be treated with topical timolol, oral propranolol, topical and intralesional corticosteroids, pulsed-dye laser, and surgical resection.
Ashy dermatosis is a term for asymptomatic, gray-blue or ashy patches distributed symmetrically on the trunk, head, neck, and upper extremities. It primarily affects individuals with darker skin types (Fitzpatrick III-V), and is more common in patients with Hispanic, Asian, or African backgrounds. The direct cause of ashy dermatosis is unknown but it is thought to be linked to drug ingestion, genetics, infection, and immune-mediated mechanisms. The general treatment includes topical corticosteroids, clofazimine, topical calcineurin inhibitors, oral dapsone, phototherapy, topical retinoids, or isotretinoin to reduce inflammation and pigmentation.
Danny Lee and Samuel Le serve as research fellows and Jolina Bui as research associate in the Pediatric Dermatology Division of the Department of Dermatology at the University of California, San Diego, and Rady Children’s Hospital, San Diego. Dr. Eichenfield is Distinguished Professor of Dermatology and Pediatrics and Vice-Chair of the Department of Dermatology at the University of California, San Diego, and Rady Children’s Hospital, San Diego. The authors have no relevant financial disclosures.
Suggested Reading
Agarwal P, Patel BC. Nevus of Ota and Ito. [Updated 2023 Jul 10]. In: StatPearls [Internet]. StatPearls Publishing; 2024.
Dompmartin A et al. The VASCERN-VASCA Working Group Diagnostic and Management Pathways for Venous Malformations. J Vasc Anom (Phila). 2023 Mar 23;4(2):e064.
Dompmartin A et al. Venous malformation: Update on aetiopathogenesis, diagnosis and management. Phlebology. 2010 Oct;25(5):224-235.
Gupta D, Thappa DM. Mongolian spots. Indian J Dermatol Venereol Leprol. 2013 Jul-Aug;79(4):469-478.
Krowchuk DP et al. Clinical Practice Guideline for the Management of Infantile Hemangiomas. Pediatrics. 2019 Jan;143(1):e20183475.
Nguyen K, Khachemoune A. Ashy dermatosis: A review. Dermatol Online J. 2019 May 15;25(5):13030/qt44f462s8.
Patel ND, Chong AT et al. Venous Malformations. Semin Intervent Radiol. 2022 Dec 20;39(5):498-507.
Diagnosis: Venous Malformation
Although present at birth, they are not always clinically evident early in life. They also tend to grow with the child without spontaneous regression, causing potential cosmetic concerns or complications from impingement on surrounding tissue.
Venous malformations appear with a bluish color appearing beneath the skin and can vary significantly in size and severity. Venous malformations are compressible and characterized by low to stagnant blood flow, which can spontaneously thrombose. Clinically, this may cause pain, swelling, skin changes, tissue and limb overgrowth, or functional impairment depending on location and size.
Venous malformations result from disorganized angiogenesis secondary to sporadic mutations in somatic cells. The most common implicated gene is TEK, a receptor tyrosine kinase. PIK3CA has also been involved. Both genes are involved in the PI3K/AKT/mTOR pathway, which regulates cell growth, proliferation, and angiogenesis. In venous endothelial cells, abnormal angiogenesis and vessel maturation may lead to venous malformation formation. Dysplastic vessels frequently separate from normal veins but may be contiguous with the deep venous system.
Diagnosis involves clinical history and physical examination. Imaging with ultrasound and magnetic resonance imaging (MRI) may be utilized. While ultrasound may be preferred for superficial venous malformations, MRI or MRI with MR angiography (MRA) is the preferred method for venous malformation assessment. Genetic testing may be appropriate for complex malformations, as classification of lesions by underlying mutation may allow targeted therapy.
This patient’s past MRI and MRA findings were consistent with a venous malformation.
Treatment
Venous malformations rarely regress spontaneously. Treatment is required if venous malformations are symptomatic, which may include pain, swelling, deformity, thrombosis, or interference with daily activities of living. Treatment plans require consideration of patient goals of care. The main categories of therapy are embolization/sclerotherapy, surgical resection, and molecular targeted therapy.
Sclerotherapy is a well-tolerated and efficacious first-line therapy. It can be used as either nonsurgical curative therapy or preoperative adjunct therapy to minimize blood loss before surgical resection. While surgical resection may cause scarring, multimodal approaches with sclerotherapy or laser therapy can decrease complications. Molecular therapies aim to reduce vascular proliferation and symptoms. Referral to hematology/oncology for evaluation and consideration of chemotherapeutic agents may be required. Sirolimus has been shown in mice models to inhibit an endothelial cell tyrosine kinase receptor that plays a role in venous malformation growth. Multiple studies have proved its efficacy in managing complicated vascular anomalies, including venous malformations. Alpelisib is an inhibitor of PI3KCA, which is part of the pathway that contributes to venous malformation formation. Dactolisib, a dual inhibitor of the PI3KA and mTOR pathways, and rebastinib, a TEK inhibitor, are being investigated.
Differential Diagnoses
The differential diagnosis includes dermal melanocytosis, nevus of Ota, hemangioma of infancy, and ashy dermatosis. In addition, venous malformations can be part of more complex vascular malformations.
Dermal melanocytosis, also known as Mongolian spots, are blue-gray patches of discoloration on the skin that appear at birth or shortly after. They result from the arrest of dermal melanocytes in the dermis during fetal life and tissue modeling. They are commonly observed in those of Asian or African descent with darker skin types. Most often, they are located in the lumbar or sacral-gluteal region. Unlike venous malformations, they are benign and do not involve vascular abnormalities. They typically fade over time.
Nevus of Ota is a benign congenital condition that presents with blue-gray or brown patches of pigmentation on the skin around the eyes, cheeks, and forehead. They are dermal melanocytes with a speckled instead of uniform appearance. Nevus of Ota primarily affects individuals of Asian descent and typically presents in the trigeminal nerve distribution region. Treatment can be done to minimize deformity, generally with pigmented laser surgery.
Hemangiomas of infancy are common benign tumors of infancy caused by endothelial cell proliferation. They are characterized by rapid growth followed by spontaneous involution within the first year of life and for several years. Hemangiomas can be superficial, deep, or mixed with features of both superficial and deep. Superficial hemangiomas present as raised, lobulated, and bright red while deep hemangiomas present as a bluish-hued nodule, plaque, or tumor. They are diagnosed clinically but skin biopsies and imaging can confirm the suspected diagnosis. While hemangiomas may self-resolve, complicated hemangiomas can be treated with topical timolol, oral propranolol, topical and intralesional corticosteroids, pulsed-dye laser, and surgical resection.
Ashy dermatosis is a term for asymptomatic, gray-blue or ashy patches distributed symmetrically on the trunk, head, neck, and upper extremities. It primarily affects individuals with darker skin types (Fitzpatrick III-V), and is more common in patients with Hispanic, Asian, or African backgrounds. The direct cause of ashy dermatosis is unknown but it is thought to be linked to drug ingestion, genetics, infection, and immune-mediated mechanisms. The general treatment includes topical corticosteroids, clofazimine, topical calcineurin inhibitors, oral dapsone, phototherapy, topical retinoids, or isotretinoin to reduce inflammation and pigmentation.
Danny Lee and Samuel Le serve as research fellows and Jolina Bui as research associate in the Pediatric Dermatology Division of the Department of Dermatology at the University of California, San Diego, and Rady Children’s Hospital, San Diego. Dr. Eichenfield is Distinguished Professor of Dermatology and Pediatrics and Vice-Chair of the Department of Dermatology at the University of California, San Diego, and Rady Children’s Hospital, San Diego. The authors have no relevant financial disclosures.
Suggested Reading
Agarwal P, Patel BC. Nevus of Ota and Ito. [Updated 2023 Jul 10]. In: StatPearls [Internet]. StatPearls Publishing; 2024.
Dompmartin A et al. The VASCERN-VASCA Working Group Diagnostic and Management Pathways for Venous Malformations. J Vasc Anom (Phila). 2023 Mar 23;4(2):e064.
Dompmartin A et al. Venous malformation: Update on aetiopathogenesis, diagnosis and management. Phlebology. 2010 Oct;25(5):224-235.
Gupta D, Thappa DM. Mongolian spots. Indian J Dermatol Venereol Leprol. 2013 Jul-Aug;79(4):469-478.
Krowchuk DP et al. Clinical Practice Guideline for the Management of Infantile Hemangiomas. Pediatrics. 2019 Jan;143(1):e20183475.
Nguyen K, Khachemoune A. Ashy dermatosis: A review. Dermatol Online J. 2019 May 15;25(5):13030/qt44f462s8.
Patel ND, Chong AT et al. Venous Malformations. Semin Intervent Radiol. 2022 Dec 20;39(5):498-507.
Diagnosis: Venous Malformation
Although present at birth, they are not always clinically evident early in life. They also tend to grow with the child without spontaneous regression, causing potential cosmetic concerns or complications from impingement on surrounding tissue.
Venous malformations appear with a bluish color appearing beneath the skin and can vary significantly in size and severity. Venous malformations are compressible and characterized by low to stagnant blood flow, which can spontaneously thrombose. Clinically, this may cause pain, swelling, skin changes, tissue and limb overgrowth, or functional impairment depending on location and size.
Venous malformations result from disorganized angiogenesis secondary to sporadic mutations in somatic cells. The most common implicated gene is TEK, a receptor tyrosine kinase. PIK3CA has also been involved. Both genes are involved in the PI3K/AKT/mTOR pathway, which regulates cell growth, proliferation, and angiogenesis. In venous endothelial cells, abnormal angiogenesis and vessel maturation may lead to venous malformation formation. Dysplastic vessels frequently separate from normal veins but may be contiguous with the deep venous system.
Diagnosis involves clinical history and physical examination. Imaging with ultrasound and magnetic resonance imaging (MRI) may be utilized. While ultrasound may be preferred for superficial venous malformations, MRI or MRI with MR angiography (MRA) is the preferred method for venous malformation assessment. Genetic testing may be appropriate for complex malformations, as classification of lesions by underlying mutation may allow targeted therapy.
This patient’s past MRI and MRA findings were consistent with a venous malformation.
Treatment
Venous malformations rarely regress spontaneously. Treatment is required if venous malformations are symptomatic, which may include pain, swelling, deformity, thrombosis, or interference with daily activities of living. Treatment plans require consideration of patient goals of care. The main categories of therapy are embolization/sclerotherapy, surgical resection, and molecular targeted therapy.
Sclerotherapy is a well-tolerated and efficacious first-line therapy. It can be used as either nonsurgical curative therapy or preoperative adjunct therapy to minimize blood loss before surgical resection. While surgical resection may cause scarring, multimodal approaches with sclerotherapy or laser therapy can decrease complications. Molecular therapies aim to reduce vascular proliferation and symptoms. Referral to hematology/oncology for evaluation and consideration of chemotherapeutic agents may be required. Sirolimus has been shown in mice models to inhibit an endothelial cell tyrosine kinase receptor that plays a role in venous malformation growth. Multiple studies have proved its efficacy in managing complicated vascular anomalies, including venous malformations. Alpelisib is an inhibitor of PI3KCA, which is part of the pathway that contributes to venous malformation formation. Dactolisib, a dual inhibitor of the PI3KA and mTOR pathways, and rebastinib, a TEK inhibitor, are being investigated.
Differential Diagnoses
The differential diagnosis includes dermal melanocytosis, nevus of Ota, hemangioma of infancy, and ashy dermatosis. In addition, venous malformations can be part of more complex vascular malformations.
Dermal melanocytosis, also known as Mongolian spots, are blue-gray patches of discoloration on the skin that appear at birth or shortly after. They result from the arrest of dermal melanocytes in the dermis during fetal life and tissue modeling. They are commonly observed in those of Asian or African descent with darker skin types. Most often, they are located in the lumbar or sacral-gluteal region. Unlike venous malformations, they are benign and do not involve vascular abnormalities. They typically fade over time.
Nevus of Ota is a benign congenital condition that presents with blue-gray or brown patches of pigmentation on the skin around the eyes, cheeks, and forehead. They are dermal melanocytes with a speckled instead of uniform appearance. Nevus of Ota primarily affects individuals of Asian descent and typically presents in the trigeminal nerve distribution region. Treatment can be done to minimize deformity, generally with pigmented laser surgery.
Hemangiomas of infancy are common benign tumors of infancy caused by endothelial cell proliferation. They are characterized by rapid growth followed by spontaneous involution within the first year of life and for several years. Hemangiomas can be superficial, deep, or mixed with features of both superficial and deep. Superficial hemangiomas present as raised, lobulated, and bright red while deep hemangiomas present as a bluish-hued nodule, plaque, or tumor. They are diagnosed clinically but skin biopsies and imaging can confirm the suspected diagnosis. While hemangiomas may self-resolve, complicated hemangiomas can be treated with topical timolol, oral propranolol, topical and intralesional corticosteroids, pulsed-dye laser, and surgical resection.
Ashy dermatosis is a term for asymptomatic, gray-blue or ashy patches distributed symmetrically on the trunk, head, neck, and upper extremities. It primarily affects individuals with darker skin types (Fitzpatrick III-V), and is more common in patients with Hispanic, Asian, or African backgrounds. The direct cause of ashy dermatosis is unknown but it is thought to be linked to drug ingestion, genetics, infection, and immune-mediated mechanisms. The general treatment includes topical corticosteroids, clofazimine, topical calcineurin inhibitors, oral dapsone, phototherapy, topical retinoids, or isotretinoin to reduce inflammation and pigmentation.
Danny Lee and Samuel Le serve as research fellows and Jolina Bui as research associate in the Pediatric Dermatology Division of the Department of Dermatology at the University of California, San Diego, and Rady Children’s Hospital, San Diego. Dr. Eichenfield is Distinguished Professor of Dermatology and Pediatrics and Vice-Chair of the Department of Dermatology at the University of California, San Diego, and Rady Children’s Hospital, San Diego. The authors have no relevant financial disclosures.
Suggested Reading
Agarwal P, Patel BC. Nevus of Ota and Ito. [Updated 2023 Jul 10]. In: StatPearls [Internet]. StatPearls Publishing; 2024.
Dompmartin A et al. The VASCERN-VASCA Working Group Diagnostic and Management Pathways for Venous Malformations. J Vasc Anom (Phila). 2023 Mar 23;4(2):e064.
Dompmartin A et al. Venous malformation: Update on aetiopathogenesis, diagnosis and management. Phlebology. 2010 Oct;25(5):224-235.
Gupta D, Thappa DM. Mongolian spots. Indian J Dermatol Venereol Leprol. 2013 Jul-Aug;79(4):469-478.
Krowchuk DP et al. Clinical Practice Guideline for the Management of Infantile Hemangiomas. Pediatrics. 2019 Jan;143(1):e20183475.
Nguyen K, Khachemoune A. Ashy dermatosis: A review. Dermatol Online J. 2019 May 15;25(5):13030/qt44f462s8.
Patel ND, Chong AT et al. Venous Malformations. Semin Intervent Radiol. 2022 Dec 20;39(5):498-507.
A 6-year-old girl presents with a bruise-like lesion on the lip, tongue, and chin area present since birth. The family states that her tongue has been increasing in size and is painful. On physical exam, she presents with left lower mucosal lip fullness and an overlying violaceous hue extending into the oral mucosa and onto the left tongue. The left portion of the dorsal tongue displays an increased thickness and bluish discoloration and there is a pink, smooth papule on the left anterolateral tongue.
Pediatrician Credibility Remains Intact in Midst of Health Misinformation
TORONTO —
Despite acknowledging that health misinformation is on the rise, “nearly all the pediatricians we surveyed agreed or strongly agreed that their patients consider them a trusted information source,” reported Elizabeth A. Gottschlich, MA, a senior research associate with the American Academy of Pediatrics, Itasca, Illinois.
These data were generated by an ongoing cohort analysis called the Pediatricians Life and Career Experience Study (PLACES). Each year, two surveys are conducted with three groups of pediatricians in this cohort. They are defined by years in which they graduated from residency (2002-2004, 2009-2011, or 2016-2018).
While the longer survey of the two captures an array of issues regarding life and practice, the shorter “checkpoint” survey addresses a high-priority topic. In 2023, it was health misinformation. The data from this survey were presented at the Pediatric Academic Societies annual meeting.
About 40% of the 2706 pediatricians who completed this particular survey (just over 65% of the participants in PLACES) were general pediatricians, 50% were pediatric subspecialists, and 10% were hospitalists.
Almost all of the survey questions were answered on a five-point Likert scale.
A Matter of Trust
According to Ms. Gottschlich, approximately 80% of pediatricians agreed or strongly agreed that misinformation is a clinical issue for them. About one third of these strongly agreed, and only 6% disagreed.
There was also strong consensus that the problem has grown worse since the start of the COVID-19 epidemic. To this statement, 70% agreed or strongly agreed and 24% did not agree or disagree. Only 4% disagreed.
However, relatively few respondents appeared to be concerned about the ability of pediatricians to address the problem of misinformation, Ms. Gottschlich reported.
When asked to respond to the statement that the “community recognizes and uses pediatricians as trusted source for health information,” 87% agreed or strongly agreed. Of the remaining, 9% did not agree or disagree, leaving just 4% that disagreed or strongly disagreed.
For a similar but slightly different question, the consensus was even greater. To the statement “patients/families in your practice seek your input as a trusted source for health information,” 94% agreed or strongly agreed.
Encountering Misinformation
The survey went on to ask pediatricians about encounters with misinformation for seven specific issues. On the five-point Likert scale, the choices ranged from a few times per year to every day.
For reproductive health, gender-affirming care, and firearm injury prevention, about 80% of respondents answered at the very low end of the scale, meaning no more than about once per month. Encounters with misinformation was slightly greater with autism; nearly one third responded that they encountered misinformation once a week or more frequently.
For all three questions regarding vaccines, the proportions climbed substantially. Of these, the COVID-19 vaccine was the most common topic of misinformation, with more than half reporting that they addressed incorrect information once a week or more. Seven percent reported this occurs daily.
Nearly 40% of pediatricians responded that they dealt with misinformation about the HPV vaccine once per week or more, while 35% reported that they encountered misinformation this frequently about routine childhood vaccines. There was a small but not necessarily trivial proportion for each of these categories of vaccine who reported that they encountered misinformation on a daily basis.
When stratified by clinical focus, the encounters varied. For the COVID-19 vaccine, general pediatricians (67%) were far more likely to report addressing misinformation on a weekly or more frequent basis than hospitalists (39%) or subspecialists (46%). They were more than twice as likely to encounter misinformation about the HPV vaccine than hospitalists or pediatric subspecialists (46%, 17%, and 19%, respectively).
When stratified by urban, suburban, or rural practice areas, differences were relatively modest. Pediatricians in urban practices were less likely to face misinformation about HPV vaccine (29% vs 44% and 48% for suburban and rural areas, respectively), while pediatricians in rural practice were more likely to face misinformation about routine childhood vaccines (60% vs 33% and 35% for urban and suburban practices, respectively).
Differences were even narrower when misinformation encounters were compared among the West, Midwest, South, and Northeast. For the threshold of once per week or more commonly, misinformation about the COVID-19 vaccine was less common in the South (50% vs 55%-58% in the other areas), while misinformation about routine childhood vaccines was more commonly encountered in the West (41% vs 32%-35% in the other areas).
A Growing Problem
The confidence among pediatricians that their knowledge is valued is reassuring, according to Ms. Gottschlich, who noted that the U.S. Surgeon General declared health misinformation a serious threat to public health in 2021, but the problem of misinformation is growing, according to several sources.
One of these sources, at least in regard to adolescent health, appears to be social media, according to a recently published review article in JAMA Pediatrics. The lead author of that article, Monica L. Wang, DSc, has dual academic appointments at the Boston University School of Public Health and Harvard University’s T.H. Chan School of Public Health, Boston. Asked for a comment on this issue, she suggested that it might not be enough to just respond to misinformation but rather might be better to develop a dialogue that will reveal misconceptions.
“Just as they screen for preventive issues like seat belt use, sunscreen, and safe sex practices, [pediatricians should integrate] questions about health misinformation into visits, which can be a natural and effective way to encourage dialogue, proactively share accurate information, and promote well-being,” she said.
Agreeing with the premise that pediatricians are a credible source of information for parents and children, Dr. Wang very much endorses the principle that “pediatricians can play a critical role in addressing health misinformation.”
Ms. Gottschlich and Dr. Wang report no potential conflicts of interest.
TORONTO —
Despite acknowledging that health misinformation is on the rise, “nearly all the pediatricians we surveyed agreed or strongly agreed that their patients consider them a trusted information source,” reported Elizabeth A. Gottschlich, MA, a senior research associate with the American Academy of Pediatrics, Itasca, Illinois.
These data were generated by an ongoing cohort analysis called the Pediatricians Life and Career Experience Study (PLACES). Each year, two surveys are conducted with three groups of pediatricians in this cohort. They are defined by years in which they graduated from residency (2002-2004, 2009-2011, or 2016-2018).
While the longer survey of the two captures an array of issues regarding life and practice, the shorter “checkpoint” survey addresses a high-priority topic. In 2023, it was health misinformation. The data from this survey were presented at the Pediatric Academic Societies annual meeting.
About 40% of the 2706 pediatricians who completed this particular survey (just over 65% of the participants in PLACES) were general pediatricians, 50% were pediatric subspecialists, and 10% were hospitalists.
Almost all of the survey questions were answered on a five-point Likert scale.
A Matter of Trust
According to Ms. Gottschlich, approximately 80% of pediatricians agreed or strongly agreed that misinformation is a clinical issue for them. About one third of these strongly agreed, and only 6% disagreed.
There was also strong consensus that the problem has grown worse since the start of the COVID-19 epidemic. To this statement, 70% agreed or strongly agreed and 24% did not agree or disagree. Only 4% disagreed.
However, relatively few respondents appeared to be concerned about the ability of pediatricians to address the problem of misinformation, Ms. Gottschlich reported.
When asked to respond to the statement that the “community recognizes and uses pediatricians as trusted source for health information,” 87% agreed or strongly agreed. Of the remaining, 9% did not agree or disagree, leaving just 4% that disagreed or strongly disagreed.
For a similar but slightly different question, the consensus was even greater. To the statement “patients/families in your practice seek your input as a trusted source for health information,” 94% agreed or strongly agreed.
Encountering Misinformation
The survey went on to ask pediatricians about encounters with misinformation for seven specific issues. On the five-point Likert scale, the choices ranged from a few times per year to every day.
For reproductive health, gender-affirming care, and firearm injury prevention, about 80% of respondents answered at the very low end of the scale, meaning no more than about once per month. Encounters with misinformation was slightly greater with autism; nearly one third responded that they encountered misinformation once a week or more frequently.
For all three questions regarding vaccines, the proportions climbed substantially. Of these, the COVID-19 vaccine was the most common topic of misinformation, with more than half reporting that they addressed incorrect information once a week or more. Seven percent reported this occurs daily.
Nearly 40% of pediatricians responded that they dealt with misinformation about the HPV vaccine once per week or more, while 35% reported that they encountered misinformation this frequently about routine childhood vaccines. There was a small but not necessarily trivial proportion for each of these categories of vaccine who reported that they encountered misinformation on a daily basis.
When stratified by clinical focus, the encounters varied. For the COVID-19 vaccine, general pediatricians (67%) were far more likely to report addressing misinformation on a weekly or more frequent basis than hospitalists (39%) or subspecialists (46%). They were more than twice as likely to encounter misinformation about the HPV vaccine than hospitalists or pediatric subspecialists (46%, 17%, and 19%, respectively).
When stratified by urban, suburban, or rural practice areas, differences were relatively modest. Pediatricians in urban practices were less likely to face misinformation about HPV vaccine (29% vs 44% and 48% for suburban and rural areas, respectively), while pediatricians in rural practice were more likely to face misinformation about routine childhood vaccines (60% vs 33% and 35% for urban and suburban practices, respectively).
Differences were even narrower when misinformation encounters were compared among the West, Midwest, South, and Northeast. For the threshold of once per week or more commonly, misinformation about the COVID-19 vaccine was less common in the South (50% vs 55%-58% in the other areas), while misinformation about routine childhood vaccines was more commonly encountered in the West (41% vs 32%-35% in the other areas).
A Growing Problem
The confidence among pediatricians that their knowledge is valued is reassuring, according to Ms. Gottschlich, who noted that the U.S. Surgeon General declared health misinformation a serious threat to public health in 2021, but the problem of misinformation is growing, according to several sources.
One of these sources, at least in regard to adolescent health, appears to be social media, according to a recently published review article in JAMA Pediatrics. The lead author of that article, Monica L. Wang, DSc, has dual academic appointments at the Boston University School of Public Health and Harvard University’s T.H. Chan School of Public Health, Boston. Asked for a comment on this issue, she suggested that it might not be enough to just respond to misinformation but rather might be better to develop a dialogue that will reveal misconceptions.
“Just as they screen for preventive issues like seat belt use, sunscreen, and safe sex practices, [pediatricians should integrate] questions about health misinformation into visits, which can be a natural and effective way to encourage dialogue, proactively share accurate information, and promote well-being,” she said.
Agreeing with the premise that pediatricians are a credible source of information for parents and children, Dr. Wang very much endorses the principle that “pediatricians can play a critical role in addressing health misinformation.”
Ms. Gottschlich and Dr. Wang report no potential conflicts of interest.
TORONTO —
Despite acknowledging that health misinformation is on the rise, “nearly all the pediatricians we surveyed agreed or strongly agreed that their patients consider them a trusted information source,” reported Elizabeth A. Gottschlich, MA, a senior research associate with the American Academy of Pediatrics, Itasca, Illinois.
These data were generated by an ongoing cohort analysis called the Pediatricians Life and Career Experience Study (PLACES). Each year, two surveys are conducted with three groups of pediatricians in this cohort. They are defined by years in which they graduated from residency (2002-2004, 2009-2011, or 2016-2018).
While the longer survey of the two captures an array of issues regarding life and practice, the shorter “checkpoint” survey addresses a high-priority topic. In 2023, it was health misinformation. The data from this survey were presented at the Pediatric Academic Societies annual meeting.
About 40% of the 2706 pediatricians who completed this particular survey (just over 65% of the participants in PLACES) were general pediatricians, 50% were pediatric subspecialists, and 10% were hospitalists.
Almost all of the survey questions were answered on a five-point Likert scale.
A Matter of Trust
According to Ms. Gottschlich, approximately 80% of pediatricians agreed or strongly agreed that misinformation is a clinical issue for them. About one third of these strongly agreed, and only 6% disagreed.
There was also strong consensus that the problem has grown worse since the start of the COVID-19 epidemic. To this statement, 70% agreed or strongly agreed and 24% did not agree or disagree. Only 4% disagreed.
However, relatively few respondents appeared to be concerned about the ability of pediatricians to address the problem of misinformation, Ms. Gottschlich reported.
When asked to respond to the statement that the “community recognizes and uses pediatricians as trusted source for health information,” 87% agreed or strongly agreed. Of the remaining, 9% did not agree or disagree, leaving just 4% that disagreed or strongly disagreed.
For a similar but slightly different question, the consensus was even greater. To the statement “patients/families in your practice seek your input as a trusted source for health information,” 94% agreed or strongly agreed.
Encountering Misinformation
The survey went on to ask pediatricians about encounters with misinformation for seven specific issues. On the five-point Likert scale, the choices ranged from a few times per year to every day.
For reproductive health, gender-affirming care, and firearm injury prevention, about 80% of respondents answered at the very low end of the scale, meaning no more than about once per month. Encounters with misinformation was slightly greater with autism; nearly one third responded that they encountered misinformation once a week or more frequently.
For all three questions regarding vaccines, the proportions climbed substantially. Of these, the COVID-19 vaccine was the most common topic of misinformation, with more than half reporting that they addressed incorrect information once a week or more. Seven percent reported this occurs daily.
Nearly 40% of pediatricians responded that they dealt with misinformation about the HPV vaccine once per week or more, while 35% reported that they encountered misinformation this frequently about routine childhood vaccines. There was a small but not necessarily trivial proportion for each of these categories of vaccine who reported that they encountered misinformation on a daily basis.
When stratified by clinical focus, the encounters varied. For the COVID-19 vaccine, general pediatricians (67%) were far more likely to report addressing misinformation on a weekly or more frequent basis than hospitalists (39%) or subspecialists (46%). They were more than twice as likely to encounter misinformation about the HPV vaccine than hospitalists or pediatric subspecialists (46%, 17%, and 19%, respectively).
When stratified by urban, suburban, or rural practice areas, differences were relatively modest. Pediatricians in urban practices were less likely to face misinformation about HPV vaccine (29% vs 44% and 48% for suburban and rural areas, respectively), while pediatricians in rural practice were more likely to face misinformation about routine childhood vaccines (60% vs 33% and 35% for urban and suburban practices, respectively).
Differences were even narrower when misinformation encounters were compared among the West, Midwest, South, and Northeast. For the threshold of once per week or more commonly, misinformation about the COVID-19 vaccine was less common in the South (50% vs 55%-58% in the other areas), while misinformation about routine childhood vaccines was more commonly encountered in the West (41% vs 32%-35% in the other areas).
A Growing Problem
The confidence among pediatricians that their knowledge is valued is reassuring, according to Ms. Gottschlich, who noted that the U.S. Surgeon General declared health misinformation a serious threat to public health in 2021, but the problem of misinformation is growing, according to several sources.
One of these sources, at least in regard to adolescent health, appears to be social media, according to a recently published review article in JAMA Pediatrics. The lead author of that article, Monica L. Wang, DSc, has dual academic appointments at the Boston University School of Public Health and Harvard University’s T.H. Chan School of Public Health, Boston. Asked for a comment on this issue, she suggested that it might not be enough to just respond to misinformation but rather might be better to develop a dialogue that will reveal misconceptions.
“Just as they screen for preventive issues like seat belt use, sunscreen, and safe sex practices, [pediatricians should integrate] questions about health misinformation into visits, which can be a natural and effective way to encourage dialogue, proactively share accurate information, and promote well-being,” she said.
Agreeing with the premise that pediatricians are a credible source of information for parents and children, Dr. Wang very much endorses the principle that “pediatricians can play a critical role in addressing health misinformation.”
Ms. Gottschlich and Dr. Wang report no potential conflicts of interest.
FROM PAS 2024