Clinical Endocrinology News

Youth identifying as lesbian, gay, or bisexual were significantly less likely than were their peers to communicate with a physician or utilize health care in the past 12 months, according to data from a cohort study of approximately 4,000 adolescents.

Disparities in physical and mental health outcomes for individuals who identify as lesbian, gay, or bisexual (LGB) persist in the United States, and emerge in adolescents and young adults, wrote Sari L. Reisner, ScD, of Boston Children’s Hospital, and colleagues.

“LGB adult research indicates substantial unmet medical needs, including needed care and preventive care,” for reasons including “reluctance to disclose sexual identity to clinicians, lower health insurance rates, lack of culturally appropriate preventive services, and lack of clinician LGB care competence,” they said.

However, health use trends by adolescents who identify as LGB have not been well studied, they noted.

In a study published in JAMA Network Open, the researchers analyzed data from 4,256 participants in the third wave (10th grade) of adolescents in Healthy Passages, a longitudinal, observational cohort study of diverse public school students in Birmingham, Ala.; Houston; and Los Angeles County. Data were collected in grades 5, 7, and 10.

The study population included 640 youth who identified as LGB, and 3,616 non-LGB youth. Sexual status was based on responses to questions in the grade 10 youth survey. Health care use was based on the responses to questions about routine care, such as a regular checkup, and other care, such as a sick visit. Data on delayed care were collected from parents and youth. At baseline, the average age of the study participants in fifth grade was 11 years, 48.9% were female, 44.5% were Hispanic or Latino, and 28.9% were Black.

Overall, more LGB youth reported not receiving needed medical care when they thought they needed it within the past 12 months compared with non-LGB youth (42.4% of LGB vs. 30.2% of non-LGB youth; adjusted odds ratio 1.68). The most common conditions for which LGB youth did not seek care were sexually transmitted infections, contraception, and substance use.

Overall, the main reason given for not seeking medical care was that they thought the problem would go away (approximately 26% for LGB and non-LGB). Approximately twice as many LGB youth as non-LGB youth said they avoided medical care because they did not want their parents to know (14.5% vs. 9.4%).

Significantly more LGB youth than non-LGB youth reported difficulty communicating with their physicians in the past 12 months (15.3% vs. 9.4%; aOR 1.71). The main reasons for not communicating with a clinician about a topic of concern were that the adolescent did not want parents to know (40.7% of LGB and 30.2% of non-LGB) and that they were too embarrassed to talk about the topic (37.5% of LGB and 25.9% of non-LGB).

The researchers were not surprised that “LGB youth self-reported greater difficulty communicating with a clinician about topics they wanted to discuss,” but they found no significant differences in reasons for communication difficulty based on sexual orientation.

Approximately two-thirds (65.8%) of LGB youth reported feeling “a little or not at all comfortable” talking to a health care clinician about their sexual attractions, compared with approximately one-third (37.8%) of non-LGB youth.

Only 12.5% of the LGB youth said that their clinicians knew their sexual orientation, the researchers noted. However, clinicians need to know youths’ sexual orientation to provide appropriate and comprehensive care, they said, especially in light of the known negative health consequences of LGB internalized stigma, as well as the pertinence of certain sexual behaviors to preventive care and screening.

The study findings were limited by several factors including the cross-sectional design and inability to show causality, and by the incongruence of different dimensions of sexual orientation, the researchers noted. Other limitations included the use only of English and Spanish language, and a lack of complete information on disclosure of sexual orientation to parents, the researchers noted.

The results were strengthened by the diverse demographics, although they may not be generalizable to a wider population, they added.

However, the data show that responsive health care is needed to reduce disparities for LGB youth, they emphasized. “Care should be sensitive and respectful to sexual orientation for all youth, with clinicians taking time to ask adolescents about their sexual identity, attractions, and behaviors, particularly in sexual and reproductive health,” they concluded.
 

Adolescents suffer barriers similar to those of adults

“We know that significant health disparities exist for LGBTQ adults and adolescents,” Kelly Curran, MD, of the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview. “LGBTQ adults often have had poor experiences during health care encounters – ranging from poor interactions with inadequately trained clinicians to frank discrimination,” she said. “These experiences can prevent individuals from seeking health care in the future or disclosing important information during a medical visit, both of which can contribute to worsened health outcomes,” she emphasized.

Prior to this study, data to confirm similar patterns of decreased health care utilization in LGB youth were limited, Dr. Curran said. “Identifying and understanding barriers to health care for LGBTQ youth are essential to help address the disparities in this population,” she said.

Dr. Curran said she was not surprised by the study findings for adolescents, which reflect patterns seen in LGBTQ adults.

Overcoming barriers to encourage LGB youth to seek regular medical care involves “training health care professionals about LGBTQ health, teaching the skill of taking a nonjudgmental, inclusive history, and making health care facilities welcoming and inclusive, such as displaying a pride flag in clinic, and using forms asking for pronouns,” Dr. Curran said.

Dr. Curran said she thinks the trends in decreased health care use are similar for transgender youth. “I suspect, if anything, that transgender youth will have even further decreased health care utilization when compared to cisgender heterosexual peers and LGB peers,” she noted.

Going forward, it will be important to understand the reasons behind decreased health care use among LGB youth, such as poor experiences, discrimination, or fears about confidentiality, said Dr. Curran. “Additionally, it would be important to understand if this decreased health utilization also occurs with transgender youth,” she said.

The Healthy Passages Study was funded by the Centers for Disease Control and Prevention. One of the study coauthors disclosed funding from the Agency for Healthcare Research and Quality as part of the Harvard-wide Pediatric Health Services Research Fellowship Program. The researchers had no financial conflicts to disclose. Dr. Curran had no financial conflicts to disclose, but serves on the editorial advisory board of Pediatric News.

Youth identifying as lesbian, gay, or bisexual were significantly less likely than were their peers to communicate with a physician or utilize health care in the past 12 months, according to data from a cohort study of approximately 4,000 adolescents.

Disparities in physical and mental health outcomes for individuals who identify as lesbian, gay, or bisexual (LGB) persist in the United States, and emerge in adolescents and young adults, wrote Sari L. Reisner, ScD, of Boston Children’s Hospital, and colleagues.

“LGB adult research indicates substantial unmet medical needs, including needed care and preventive care,” for reasons including “reluctance to disclose sexual identity to clinicians, lower health insurance rates, lack of culturally appropriate preventive services, and lack of clinician LGB care competence,” they said.

However, health use trends by adolescents who identify as LGB have not been well studied, they noted.

In a study published in JAMA Network Open, the researchers analyzed data from 4,256 participants in the third wave (10th grade) of adolescents in Healthy Passages, a longitudinal, observational cohort study of diverse public school students in Birmingham, Ala.; Houston; and Los Angeles County. Data were collected in grades 5, 7, and 10.

The study population included 640 youth who identified as LGB, and 3,616 non-LGB youth. Sexual status was based on responses to questions in the grade 10 youth survey. Health care use was based on the responses to questions about routine care, such as a regular checkup, and other care, such as a sick visit. Data on delayed care were collected from parents and youth. At baseline, the average age of the study participants in fifth grade was 11 years, 48.9% were female, 44.5% were Hispanic or Latino, and 28.9% were Black.

Overall, more LGB youth reported not receiving needed medical care when they thought they needed it within the past 12 months compared with non-LGB youth (42.4% of LGB vs. 30.2% of non-LGB youth; adjusted odds ratio 1.68). The most common conditions for which LGB youth did not seek care were sexually transmitted infections, contraception, and substance use.

Overall, the main reason given for not seeking medical care was that they thought the problem would go away (approximately 26% for LGB and non-LGB). Approximately twice as many LGB youth as non-LGB youth said they avoided medical care because they did not want their parents to know (14.5% vs. 9.4%).

Significantly more LGB youth than non-LGB youth reported difficulty communicating with their physicians in the past 12 months (15.3% vs. 9.4%; aOR 1.71). The main reasons for not communicating with a clinician about a topic of concern were that the adolescent did not want parents to know (40.7% of LGB and 30.2% of non-LGB) and that they were too embarrassed to talk about the topic (37.5% of LGB and 25.9% of non-LGB).

The researchers were not surprised that “LGB youth self-reported greater difficulty communicating with a clinician about topics they wanted to discuss,” but they found no significant differences in reasons for communication difficulty based on sexual orientation.

Approximately two-thirds (65.8%) of LGB youth reported feeling “a little or not at all comfortable” talking to a health care clinician about their sexual attractions, compared with approximately one-third (37.8%) of non-LGB youth.

Only 12.5% of the LGB youth said that their clinicians knew their sexual orientation, the researchers noted. However, clinicians need to know youths’ sexual orientation to provide appropriate and comprehensive care, they said, especially in light of the known negative health consequences of LGB internalized stigma, as well as the pertinence of certain sexual behaviors to preventive care and screening.

The study findings were limited by several factors including the cross-sectional design and inability to show causality, and by the incongruence of different dimensions of sexual orientation, the researchers noted. Other limitations included the use only of English and Spanish language, and a lack of complete information on disclosure of sexual orientation to parents, the researchers noted.

The results were strengthened by the diverse demographics, although they may not be generalizable to a wider population, they added.

However, the data show that responsive health care is needed to reduce disparities for LGB youth, they emphasized. “Care should be sensitive and respectful to sexual orientation for all youth, with clinicians taking time to ask adolescents about their sexual identity, attractions, and behaviors, particularly in sexual and reproductive health,” they concluded.
 

Adolescents suffer barriers similar to those of adults

“We know that significant health disparities exist for LGBTQ adults and adolescents,” Kelly Curran, MD, of the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview. “LGBTQ adults often have had poor experiences during health care encounters – ranging from poor interactions with inadequately trained clinicians to frank discrimination,” she said. “These experiences can prevent individuals from seeking health care in the future or disclosing important information during a medical visit, both of which can contribute to worsened health outcomes,” she emphasized.

Prior to this study, data to confirm similar patterns of decreased health care utilization in LGB youth were limited, Dr. Curran said. “Identifying and understanding barriers to health care for LGBTQ youth are essential to help address the disparities in this population,” she said.

Dr. Curran said she was not surprised by the study findings for adolescents, which reflect patterns seen in LGBTQ adults.

Overcoming barriers to encourage LGB youth to seek regular medical care involves “training health care professionals about LGBTQ health, teaching the skill of taking a nonjudgmental, inclusive history, and making health care facilities welcoming and inclusive, such as displaying a pride flag in clinic, and using forms asking for pronouns,” Dr. Curran said.

Dr. Curran said she thinks the trends in decreased health care use are similar for transgender youth. “I suspect, if anything, that transgender youth will have even further decreased health care utilization when compared to cisgender heterosexual peers and LGB peers,” she noted.

Going forward, it will be important to understand the reasons behind decreased health care use among LGB youth, such as poor experiences, discrimination, or fears about confidentiality, said Dr. Curran. “Additionally, it would be important to understand if this decreased health utilization also occurs with transgender youth,” she said.

The Healthy Passages Study was funded by the Centers for Disease Control and Prevention. One of the study coauthors disclosed funding from the Agency for Healthcare Research and Quality as part of the Harvard-wide Pediatric Health Services Research Fellowship Program. The researchers had no financial conflicts to disclose. Dr. Curran had no financial conflicts to disclose, but serves on the editorial advisory board of Pediatric News.

Youth identifying as lesbian, gay, or bisexual were significantly less likely than were their peers to communicate with a physician or utilize health care in the past 12 months, according to data from a cohort study of approximately 4,000 adolescents.

Disparities in physical and mental health outcomes for individuals who identify as lesbian, gay, or bisexual (LGB) persist in the United States, and emerge in adolescents and young adults, wrote Sari L. Reisner, ScD, of Boston Children’s Hospital, and colleagues.

“LGB adult research indicates substantial unmet medical needs, including needed care and preventive care,” for reasons including “reluctance to disclose sexual identity to clinicians, lower health insurance rates, lack of culturally appropriate preventive services, and lack of clinician LGB care competence,” they said.

However, health use trends by adolescents who identify as LGB have not been well studied, they noted.

In a study published in JAMA Network Open, the researchers analyzed data from 4,256 participants in the third wave (10th grade) of adolescents in Healthy Passages, a longitudinal, observational cohort study of diverse public school students in Birmingham, Ala.; Houston; and Los Angeles County. Data were collected in grades 5, 7, and 10.

The study population included 640 youth who identified as LGB, and 3,616 non-LGB youth. Sexual status was based on responses to questions in the grade 10 youth survey. Health care use was based on the responses to questions about routine care, such as a regular checkup, and other care, such as a sick visit. Data on delayed care were collected from parents and youth. At baseline, the average age of the study participants in fifth grade was 11 years, 48.9% were female, 44.5% were Hispanic or Latino, and 28.9% were Black.

Overall, more LGB youth reported not receiving needed medical care when they thought they needed it within the past 12 months compared with non-LGB youth (42.4% of LGB vs. 30.2% of non-LGB youth; adjusted odds ratio 1.68). The most common conditions for which LGB youth did not seek care were sexually transmitted infections, contraception, and substance use.

Overall, the main reason given for not seeking medical care was that they thought the problem would go away (approximately 26% for LGB and non-LGB). Approximately twice as many LGB youth as non-LGB youth said they avoided medical care because they did not want their parents to know (14.5% vs. 9.4%).

Significantly more LGB youth than non-LGB youth reported difficulty communicating with their physicians in the past 12 months (15.3% vs. 9.4%; aOR 1.71). The main reasons for not communicating with a clinician about a topic of concern were that the adolescent did not want parents to know (40.7% of LGB and 30.2% of non-LGB) and that they were too embarrassed to talk about the topic (37.5% of LGB and 25.9% of non-LGB).

The researchers were not surprised that “LGB youth self-reported greater difficulty communicating with a clinician about topics they wanted to discuss,” but they found no significant differences in reasons for communication difficulty based on sexual orientation.

Approximately two-thirds (65.8%) of LGB youth reported feeling “a little or not at all comfortable” talking to a health care clinician about their sexual attractions, compared with approximately one-third (37.8%) of non-LGB youth.

Only 12.5% of the LGB youth said that their clinicians knew their sexual orientation, the researchers noted. However, clinicians need to know youths’ sexual orientation to provide appropriate and comprehensive care, they said, especially in light of the known negative health consequences of LGB internalized stigma, as well as the pertinence of certain sexual behaviors to preventive care and screening.

The study findings were limited by several factors including the cross-sectional design and inability to show causality, and by the incongruence of different dimensions of sexual orientation, the researchers noted. Other limitations included the use only of English and Spanish language, and a lack of complete information on disclosure of sexual orientation to parents, the researchers noted.

The results were strengthened by the diverse demographics, although they may not be generalizable to a wider population, they added.

However, the data show that responsive health care is needed to reduce disparities for LGB youth, they emphasized. “Care should be sensitive and respectful to sexual orientation for all youth, with clinicians taking time to ask adolescents about their sexual identity, attractions, and behaviors, particularly in sexual and reproductive health,” they concluded.
 

Adolescents suffer barriers similar to those of adults

“We know that significant health disparities exist for LGBTQ adults and adolescents,” Kelly Curran, MD, of the University of Oklahoma Health Sciences Center, Oklahoma City, said in an interview. “LGBTQ adults often have had poor experiences during health care encounters – ranging from poor interactions with inadequately trained clinicians to frank discrimination,” she said. “These experiences can prevent individuals from seeking health care in the future or disclosing important information during a medical visit, both of which can contribute to worsened health outcomes,” she emphasized.

Prior to this study, data to confirm similar patterns of decreased health care utilization in LGB youth were limited, Dr. Curran said. “Identifying and understanding barriers to health care for LGBTQ youth are essential to help address the disparities in this population,” she said.

Dr. Curran said she was not surprised by the study findings for adolescents, which reflect patterns seen in LGBTQ adults.

Overcoming barriers to encourage LGB youth to seek regular medical care involves “training health care professionals about LGBTQ health, teaching the skill of taking a nonjudgmental, inclusive history, and making health care facilities welcoming and inclusive, such as displaying a pride flag in clinic, and using forms asking for pronouns,” Dr. Curran said.

Dr. Curran said she thinks the trends in decreased health care use are similar for transgender youth. “I suspect, if anything, that transgender youth will have even further decreased health care utilization when compared to cisgender heterosexual peers and LGB peers,” she noted.

Going forward, it will be important to understand the reasons behind decreased health care use among LGB youth, such as poor experiences, discrimination, or fears about confidentiality, said Dr. Curran. “Additionally, it would be important to understand if this decreased health utilization also occurs with transgender youth,” she said.

The Healthy Passages Study was funded by the Centers for Disease Control and Prevention. One of the study coauthors disclosed funding from the Agency for Healthcare Research and Quality as part of the Harvard-wide Pediatric Health Services Research Fellowship Program. The researchers had no financial conflicts to disclose. Dr. Curran had no financial conflicts to disclose, but serves on the editorial advisory board of Pediatric News.

Inside the emergency department at Sparrow Hospital in Lansing, Mich., staff members are struggling to care for patients showing up much sicker than they’ve ever seen.

Tiffani Dusang, the ER’s nursing director, practically vibrates with pent-up anxiety, looking at patients lying on a long line of stretchers pushed up against the beige walls of the hospital hallways. “It’s hard to watch,” she said in a warm Texas twang.

But there’s nothing she can do. The ER’s 72 rooms are already filled.

“I always feel very, very bad when I walk down the hallway and see that people are in pain, or needing to sleep, or needing quiet. But they have to be in the hallway with, as you can see, 10 or 15 people walking by every minute,” Ms. Dusang said.

The scene is a stark contrast to where this emergency department — and thousands of others — were at the start of the pandemic. Except for initial hot spots like New York City, in spring 2020 many ERs across the country were often eerily empty. Terrified of contracting COVID-19, people who were sick with other things did their best to stay away from hospitals. Visits to emergency rooms dropped to half their typical levels, according to the Epic Health Research Network, and didn’t fully rebound until this summer.

But now, they’re too full. Even in parts of the country where covid isn’t overwhelming the health system, patients are showing up to the ER sicker than before the pandemic, their diseases more advanced and in need of more complicated care.

Months of treatment delays have exacerbated chronic conditions and worsened symptoms. Doctors and nurses say the severity of illness ranges widely and includes abdominal pain, respiratory problems, blood clots, heart conditions and suicide attempts, among other conditions.

But they can hardly be accommodated. Emergency departments, ideally, are meant to be brief ports in a storm, with patients staying just long enough to be sent home with instructions to follow up with primary care physicians, or sufficiently stabilized to be transferred “upstairs” to inpatient or intensive care units.

Except now those long-term care floors are full too, with a mix of covid and non-covid patients. People coming to the ER get warehoused for hours, even days, forcing ER staffers to perform long-term care roles they weren’t trained to do.

At Sparrow, space is a valuable commodity in the ER: A separate section of the hospital was turned into an overflow unit. Stretchers stack up in halls. A row of brown reclining chairs lines a wall, intended for patients who aren’t sick enough for a stretcher but are too sick to stay in the main waiting room.

Forget privacy, Alejos Perrientoz learned when he arrived. He came to the ER because his arm had been tingling and painful for over a week. He couldn’t hold a cup of coffee. A nurse gave him a full physical exam in a brown recliner, which made him self-conscious about having his shirt lifted in front of strangers. “I felt a little uncomfortable,” he whispered. “But I have no choice, you know? I’m in the hallway. There’s no rooms.

“We could have done the physical in the parking lot,” he added, managing a laugh.

Even patients who arrive by ambulance are not guaranteed a room: One nurse runs triage, screening those who absolutely need a bed, and those who can be put in the waiting area.

“I hate that we even have to make that determination,” MS. Dusang said. Lately, staff members have been pulling out some patients already in the ER’s rooms when others arrive who are more critically ill. “No one likes to take someone out of the privacy of their room and say, ‘We’re going to put you in a hallway because we need to get care to someone else.’”

ER patients have grown sicker

“We are hearing from members in every part of the country,” said Dr. Lisa Moreno, president of the American Academy of Emergency Medicine. “The Midwest, the South, the Northeast, the West … they are seeing this exact same phenomenon.”

Although the number of ER visits returned to pre-COVID levels this summer, admission rates, from the ER to the hospital’s inpatient floors, are still almost 20% higher. That’s according to the most recent analysis by the Epic Health Research Network, which pulls data from more than 120 million patients across the country.

“It’s an early indicator that what’s happening in the ED is that we’re seeing more acute cases than we were pre-pandemic,” said Caleb Cox, a data scientist at Epic.

Less acute cases, such as people with health issues like rashes or conjunctivitis, still aren’t going to the ER as much as they used to. Instead, they may be opting for an urgent care center or their primary care doctor, Mr. Cox explained. Meanwhile, there has been an increase in people coming to the ER with more serious conditions, like strokes and heart attacks.

So, even though the total number of patients coming to ERs is about the same as before the pandemic, “that’s absolutely going to feel like [if I’m an ER doctor or nurse] I’m seeing more patients and I’m seeing more acute patients,” Mr. Cox said.

Dr. Moreno, the AAEM president, works at an emergency department in New Orleans. She said the level of illness, and the inability to admit patients quickly and move them to beds upstairs, has created a level of chaos she described as “not even humane.”

At the beginning of a recent shift, she heard a patient crying nearby and went to investigate. It was a paraplegic man who’d recently had surgery for colon cancer. His large post-operative wound was sealed with a device called a wound vac, which pulls fluid from the wound into a drainage tube attached to a portable vacuum pump.

But the wound vac had malfunctioned, which is why he had come to the ER. Staffers were so busy, however, that by the time Dr. Moreno came in, the fluid from his wound was leaking everywhere.

“When I went in, the bed was covered,” she recalled. “I mean, he was lying in a puddle of secretions from this wound. And he was crying, because he said to me, ‘I’m paralyzed. I can’t move to get away from all these secretions, and I know I’m going to end up getting an infection. I know I’m going to end up getting an ulcer. I’ve been laying in this for, like, eight or nine hours.’”

The nurse in charge of his care told Dr. Moreno she simply hadn’t had time to help this patient yet. “She said, ‘I’ve had so many patients to take care of, and so many critical patients. I started [an IV] drip on this person. This person is on a cardiac monitor. I just didn’t have time to get in there.’”

“This is not humane care,” Dr. Moreno said. “This is horrible care.”

But it’s what can happen when emergency department staffers don’t have the resources they need to deal with the onslaught of competing demands.

“All the nurses and doctors had the highest level of intent to do the right thing for the person,” Dr. Moreno said. “But because of the high acuity of … a large number of patients, the staffing ratio of nurse to patient, even the staffing ratio of doctor to patient, this guy did not get the care that he deserved to get, just as a human being.”

The instance of unintended neglect that Dr. Moreno saw is extreme, and not the experience of most patients who arrive at ERs these days. But the problem is not new: Even before the pandemic, ER overcrowding had been a “widespread problem and a source of patient harm, according to a recent commentary in NEJM Catalyst Innovations in Care Delivery.

“ED crowding is not an issue of inconvenience,” the authors wrote. “There is incontrovertible evidence that ED crowding leads to significant patient harm, including morbidity and mortality related to consequential delays of treatment for both high- and low-acuity patients.”

And already-overwhelmed staffers are burning out.

Burnout feeds staffing shortages, and vice versa

Every morning, Tiffani Dusang wakes up and checks her Sparrow email with one singular hope: that she will not see yet another nurse resignation letter in her inbox.

“I cannot tell you how many of them [the nurses] tell me they went home crying” after their shifts, she said.

Despite Ms. Dusang’s best efforts to support her staffers, they’re leaving too fast to be replaced, either to take higher-paying gigs as a travel nurse, to try a less-stressful type of nursing, or simply walking away from the profession entirely.

Kelly Spitz has been an emergency department nurse at Sparrow for 10 years. But, lately, she has also fantasized about leaving. “It has crossed my mind several times,” she said, and yet she continues to come back. “Because I have a team here. And I love what I do.” But then she started to cry. The issue is not the hard work, or even the stress. She struggles with not being able to give her patients the kind of care and attention she wants to give them, and that they need and deserve, she said.

She often thinks about a patient whose test results revealed terminal cancer, she said. Ms. Spitz spent all day working the phones, hustling case managers, trying to get hospice care set up in the man’s home. He was going to die, and she just didn’t want him to have to die in the hospital, where only one visitor was allowed. She wanted to get him home, and back with his family.

Finally, after many hours, they found an ambulance to take him home.

Three days later, the man’s family members called Ms. Spitz: He had died surrounded by family. They were calling to thank her.

“I felt like I did my job there, because I got him home,” she said. But that’s a rare feeling these days. “I just hope it gets better. I hope it gets better soon.”

Around 4 p.m. at Sparrow Hospital as one shift approached its end, Ms. Dusang faced a new crisis: The overnight shift was more short-staffed than usual.

“Can we get two inpatient nurses?” she asked, hoping to borrow two nurses from one of the hospital floors upstairs.

“Already tried,” replied nurse Troy Latunski.

Without more staff, it’s going to be hard to care for new patients who come in overnight — from car crashes to seizures or other emergencies.

But Mr. Latunski had a plan: He would go home, snatch a few hours of sleep and return at 11 p.m. to work the overnight shift in the ER’s overflow unit. That meant he would be largely caring for eight patients, alone. On just a few short hours of sleep. But lately that seemed to be their only, and best, option.

Ms. Dusang considered for a moment, took a deep breath and nodded. “OK,” she said.

“Go home. Get some sleep. Thank you,” she added, shooting Mr. Latunski a grateful smile. And then she pivoted, because another nurse was approaching with an urgent question. On to the next crisis.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation. This story is part of a partnership that includes Michigan Radio, NPR and KHN.

Inside the emergency department at Sparrow Hospital in Lansing, Mich., staff members are struggling to care for patients showing up much sicker than they’ve ever seen.

Tiffani Dusang, the ER’s nursing director, practically vibrates with pent-up anxiety, looking at patients lying on a long line of stretchers pushed up against the beige walls of the hospital hallways. “It’s hard to watch,” she said in a warm Texas twang.

But there’s nothing she can do. The ER’s 72 rooms are already filled.

“I always feel very, very bad when I walk down the hallway and see that people are in pain, or needing to sleep, or needing quiet. But they have to be in the hallway with, as you can see, 10 or 15 people walking by every minute,” Ms. Dusang said.

The scene is a stark contrast to where this emergency department — and thousands of others — were at the start of the pandemic. Except for initial hot spots like New York City, in spring 2020 many ERs across the country were often eerily empty. Terrified of contracting COVID-19, people who were sick with other things did their best to stay away from hospitals. Visits to emergency rooms dropped to half their typical levels, according to the Epic Health Research Network, and didn’t fully rebound until this summer.

But now, they’re too full. Even in parts of the country where covid isn’t overwhelming the health system, patients are showing up to the ER sicker than before the pandemic, their diseases more advanced and in need of more complicated care.

Months of treatment delays have exacerbated chronic conditions and worsened symptoms. Doctors and nurses say the severity of illness ranges widely and includes abdominal pain, respiratory problems, blood clots, heart conditions and suicide attempts, among other conditions.

But they can hardly be accommodated. Emergency departments, ideally, are meant to be brief ports in a storm, with patients staying just long enough to be sent home with instructions to follow up with primary care physicians, or sufficiently stabilized to be transferred “upstairs” to inpatient or intensive care units.

Except now those long-term care floors are full too, with a mix of covid and non-covid patients. People coming to the ER get warehoused for hours, even days, forcing ER staffers to perform long-term care roles they weren’t trained to do.

At Sparrow, space is a valuable commodity in the ER: A separate section of the hospital was turned into an overflow unit. Stretchers stack up in halls. A row of brown reclining chairs lines a wall, intended for patients who aren’t sick enough for a stretcher but are too sick to stay in the main waiting room.

Forget privacy, Alejos Perrientoz learned when he arrived. He came to the ER because his arm had been tingling and painful for over a week. He couldn’t hold a cup of coffee. A nurse gave him a full physical exam in a brown recliner, which made him self-conscious about having his shirt lifted in front of strangers. “I felt a little uncomfortable,” he whispered. “But I have no choice, you know? I’m in the hallway. There’s no rooms.

“We could have done the physical in the parking lot,” he added, managing a laugh.

Even patients who arrive by ambulance are not guaranteed a room: One nurse runs triage, screening those who absolutely need a bed, and those who can be put in the waiting area.

“I hate that we even have to make that determination,” MS. Dusang said. Lately, staff members have been pulling out some patients already in the ER’s rooms when others arrive who are more critically ill. “No one likes to take someone out of the privacy of their room and say, ‘We’re going to put you in a hallway because we need to get care to someone else.’”

ER patients have grown sicker

“We are hearing from members in every part of the country,” said Dr. Lisa Moreno, president of the American Academy of Emergency Medicine. “The Midwest, the South, the Northeast, the West … they are seeing this exact same phenomenon.”

Although the number of ER visits returned to pre-COVID levels this summer, admission rates, from the ER to the hospital’s inpatient floors, are still almost 20% higher. That’s according to the most recent analysis by the Epic Health Research Network, which pulls data from more than 120 million patients across the country.

“It’s an early indicator that what’s happening in the ED is that we’re seeing more acute cases than we were pre-pandemic,” said Caleb Cox, a data scientist at Epic.

Less acute cases, such as people with health issues like rashes or conjunctivitis, still aren’t going to the ER as much as they used to. Instead, they may be opting for an urgent care center or their primary care doctor, Mr. Cox explained. Meanwhile, there has been an increase in people coming to the ER with more serious conditions, like strokes and heart attacks.

So, even though the total number of patients coming to ERs is about the same as before the pandemic, “that’s absolutely going to feel like [if I’m an ER doctor or nurse] I’m seeing more patients and I’m seeing more acute patients,” Mr. Cox said.

Dr. Moreno, the AAEM president, works at an emergency department in New Orleans. She said the level of illness, and the inability to admit patients quickly and move them to beds upstairs, has created a level of chaos she described as “not even humane.”

At the beginning of a recent shift, she heard a patient crying nearby and went to investigate. It was a paraplegic man who’d recently had surgery for colon cancer. His large post-operative wound was sealed with a device called a wound vac, which pulls fluid from the wound into a drainage tube attached to a portable vacuum pump.

But the wound vac had malfunctioned, which is why he had come to the ER. Staffers were so busy, however, that by the time Dr. Moreno came in, the fluid from his wound was leaking everywhere.

“When I went in, the bed was covered,” she recalled. “I mean, he was lying in a puddle of secretions from this wound. And he was crying, because he said to me, ‘I’m paralyzed. I can’t move to get away from all these secretions, and I know I’m going to end up getting an infection. I know I’m going to end up getting an ulcer. I’ve been laying in this for, like, eight or nine hours.’”

The nurse in charge of his care told Dr. Moreno she simply hadn’t had time to help this patient yet. “She said, ‘I’ve had so many patients to take care of, and so many critical patients. I started [an IV] drip on this person. This person is on a cardiac monitor. I just didn’t have time to get in there.’”

“This is not humane care,” Dr. Moreno said. “This is horrible care.”

But it’s what can happen when emergency department staffers don’t have the resources they need to deal with the onslaught of competing demands.

“All the nurses and doctors had the highest level of intent to do the right thing for the person,” Dr. Moreno said. “But because of the high acuity of … a large number of patients, the staffing ratio of nurse to patient, even the staffing ratio of doctor to patient, this guy did not get the care that he deserved to get, just as a human being.”

The instance of unintended neglect that Dr. Moreno saw is extreme, and not the experience of most patients who arrive at ERs these days. But the problem is not new: Even before the pandemic, ER overcrowding had been a “widespread problem and a source of patient harm, according to a recent commentary in NEJM Catalyst Innovations in Care Delivery.

“ED crowding is not an issue of inconvenience,” the authors wrote. “There is incontrovertible evidence that ED crowding leads to significant patient harm, including morbidity and mortality related to consequential delays of treatment for both high- and low-acuity patients.”

And already-overwhelmed staffers are burning out.

Burnout feeds staffing shortages, and vice versa

Every morning, Tiffani Dusang wakes up and checks her Sparrow email with one singular hope: that she will not see yet another nurse resignation letter in her inbox.

“I cannot tell you how many of them [the nurses] tell me they went home crying” after their shifts, she said.

Despite Ms. Dusang’s best efforts to support her staffers, they’re leaving too fast to be replaced, either to take higher-paying gigs as a travel nurse, to try a less-stressful type of nursing, or simply walking away from the profession entirely.

Kelly Spitz has been an emergency department nurse at Sparrow for 10 years. But, lately, she has also fantasized about leaving. “It has crossed my mind several times,” she said, and yet she continues to come back. “Because I have a team here. And I love what I do.” But then she started to cry. The issue is not the hard work, or even the stress. She struggles with not being able to give her patients the kind of care and attention she wants to give them, and that they need and deserve, she said.

She often thinks about a patient whose test results revealed terminal cancer, she said. Ms. Spitz spent all day working the phones, hustling case managers, trying to get hospice care set up in the man’s home. He was going to die, and she just didn’t want him to have to die in the hospital, where only one visitor was allowed. She wanted to get him home, and back with his family.

Finally, after many hours, they found an ambulance to take him home.

Three days later, the man’s family members called Ms. Spitz: He had died surrounded by family. They were calling to thank her.

“I felt like I did my job there, because I got him home,” she said. But that’s a rare feeling these days. “I just hope it gets better. I hope it gets better soon.”

Around 4 p.m. at Sparrow Hospital as one shift approached its end, Ms. Dusang faced a new crisis: The overnight shift was more short-staffed than usual.

“Can we get two inpatient nurses?” she asked, hoping to borrow two nurses from one of the hospital floors upstairs.

“Already tried,” replied nurse Troy Latunski.

Without more staff, it’s going to be hard to care for new patients who come in overnight — from car crashes to seizures or other emergencies.

But Mr. Latunski had a plan: He would go home, snatch a few hours of sleep and return at 11 p.m. to work the overnight shift in the ER’s overflow unit. That meant he would be largely caring for eight patients, alone. On just a few short hours of sleep. But lately that seemed to be their only, and best, option.

Ms. Dusang considered for a moment, took a deep breath and nodded. “OK,” she said.

“Go home. Get some sleep. Thank you,” she added, shooting Mr. Latunski a grateful smile. And then she pivoted, because another nurse was approaching with an urgent question. On to the next crisis.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation. This story is part of a partnership that includes Michigan Radio, NPR and KHN.

Inside the emergency department at Sparrow Hospital in Lansing, Mich., staff members are struggling to care for patients showing up much sicker than they’ve ever seen.

Tiffani Dusang, the ER’s nursing director, practically vibrates with pent-up anxiety, looking at patients lying on a long line of stretchers pushed up against the beige walls of the hospital hallways. “It’s hard to watch,” she said in a warm Texas twang.

But there’s nothing she can do. The ER’s 72 rooms are already filled.

“I always feel very, very bad when I walk down the hallway and see that people are in pain, or needing to sleep, or needing quiet. But they have to be in the hallway with, as you can see, 10 or 15 people walking by every minute,” Ms. Dusang said.

The scene is a stark contrast to where this emergency department — and thousands of others — were at the start of the pandemic. Except for initial hot spots like New York City, in spring 2020 many ERs across the country were often eerily empty. Terrified of contracting COVID-19, people who were sick with other things did their best to stay away from hospitals. Visits to emergency rooms dropped to half their typical levels, according to the Epic Health Research Network, and didn’t fully rebound until this summer.

But now, they’re too full. Even in parts of the country where covid isn’t overwhelming the health system, patients are showing up to the ER sicker than before the pandemic, their diseases more advanced and in need of more complicated care.

Months of treatment delays have exacerbated chronic conditions and worsened symptoms. Doctors and nurses say the severity of illness ranges widely and includes abdominal pain, respiratory problems, blood clots, heart conditions and suicide attempts, among other conditions.

But they can hardly be accommodated. Emergency departments, ideally, are meant to be brief ports in a storm, with patients staying just long enough to be sent home with instructions to follow up with primary care physicians, or sufficiently stabilized to be transferred “upstairs” to inpatient or intensive care units.

Except now those long-term care floors are full too, with a mix of covid and non-covid patients. People coming to the ER get warehoused for hours, even days, forcing ER staffers to perform long-term care roles they weren’t trained to do.

At Sparrow, space is a valuable commodity in the ER: A separate section of the hospital was turned into an overflow unit. Stretchers stack up in halls. A row of brown reclining chairs lines a wall, intended for patients who aren’t sick enough for a stretcher but are too sick to stay in the main waiting room.

Forget privacy, Alejos Perrientoz learned when he arrived. He came to the ER because his arm had been tingling and painful for over a week. He couldn’t hold a cup of coffee. A nurse gave him a full physical exam in a brown recliner, which made him self-conscious about having his shirt lifted in front of strangers. “I felt a little uncomfortable,” he whispered. “But I have no choice, you know? I’m in the hallway. There’s no rooms.

“We could have done the physical in the parking lot,” he added, managing a laugh.

Even patients who arrive by ambulance are not guaranteed a room: One nurse runs triage, screening those who absolutely need a bed, and those who can be put in the waiting area.

“I hate that we even have to make that determination,” MS. Dusang said. Lately, staff members have been pulling out some patients already in the ER’s rooms when others arrive who are more critically ill. “No one likes to take someone out of the privacy of their room and say, ‘We’re going to put you in a hallway because we need to get care to someone else.’”

ER patients have grown sicker

“We are hearing from members in every part of the country,” said Dr. Lisa Moreno, president of the American Academy of Emergency Medicine. “The Midwest, the South, the Northeast, the West … they are seeing this exact same phenomenon.”

Although the number of ER visits returned to pre-COVID levels this summer, admission rates, from the ER to the hospital’s inpatient floors, are still almost 20% higher. That’s according to the most recent analysis by the Epic Health Research Network, which pulls data from more than 120 million patients across the country.

“It’s an early indicator that what’s happening in the ED is that we’re seeing more acute cases than we were pre-pandemic,” said Caleb Cox, a data scientist at Epic.

Less acute cases, such as people with health issues like rashes or conjunctivitis, still aren’t going to the ER as much as they used to. Instead, they may be opting for an urgent care center or their primary care doctor, Mr. Cox explained. Meanwhile, there has been an increase in people coming to the ER with more serious conditions, like strokes and heart attacks.

So, even though the total number of patients coming to ERs is about the same as before the pandemic, “that’s absolutely going to feel like [if I’m an ER doctor or nurse] I’m seeing more patients and I’m seeing more acute patients,” Mr. Cox said.

Dr. Moreno, the AAEM president, works at an emergency department in New Orleans. She said the level of illness, and the inability to admit patients quickly and move them to beds upstairs, has created a level of chaos she described as “not even humane.”

At the beginning of a recent shift, she heard a patient crying nearby and went to investigate. It was a paraplegic man who’d recently had surgery for colon cancer. His large post-operative wound was sealed with a device called a wound vac, which pulls fluid from the wound into a drainage tube attached to a portable vacuum pump.

But the wound vac had malfunctioned, which is why he had come to the ER. Staffers were so busy, however, that by the time Dr. Moreno came in, the fluid from his wound was leaking everywhere.

“When I went in, the bed was covered,” she recalled. “I mean, he was lying in a puddle of secretions from this wound. And he was crying, because he said to me, ‘I’m paralyzed. I can’t move to get away from all these secretions, and I know I’m going to end up getting an infection. I know I’m going to end up getting an ulcer. I’ve been laying in this for, like, eight or nine hours.’”

The nurse in charge of his care told Dr. Moreno she simply hadn’t had time to help this patient yet. “She said, ‘I’ve had so many patients to take care of, and so many critical patients. I started [an IV] drip on this person. This person is on a cardiac monitor. I just didn’t have time to get in there.’”

“This is not humane care,” Dr. Moreno said. “This is horrible care.”

But it’s what can happen when emergency department staffers don’t have the resources they need to deal with the onslaught of competing demands.

“All the nurses and doctors had the highest level of intent to do the right thing for the person,” Dr. Moreno said. “But because of the high acuity of … a large number of patients, the staffing ratio of nurse to patient, even the staffing ratio of doctor to patient, this guy did not get the care that he deserved to get, just as a human being.”

The instance of unintended neglect that Dr. Moreno saw is extreme, and not the experience of most patients who arrive at ERs these days. But the problem is not new: Even before the pandemic, ER overcrowding had been a “widespread problem and a source of patient harm, according to a recent commentary in NEJM Catalyst Innovations in Care Delivery.

“ED crowding is not an issue of inconvenience,” the authors wrote. “There is incontrovertible evidence that ED crowding leads to significant patient harm, including morbidity and mortality related to consequential delays of treatment for both high- and low-acuity patients.”

And already-overwhelmed staffers are burning out.

Burnout feeds staffing shortages, and vice versa

Every morning, Tiffani Dusang wakes up and checks her Sparrow email with one singular hope: that she will not see yet another nurse resignation letter in her inbox.

“I cannot tell you how many of them [the nurses] tell me they went home crying” after their shifts, she said.

Despite Ms. Dusang’s best efforts to support her staffers, they’re leaving too fast to be replaced, either to take higher-paying gigs as a travel nurse, to try a less-stressful type of nursing, or simply walking away from the profession entirely.

Kelly Spitz has been an emergency department nurse at Sparrow for 10 years. But, lately, she has also fantasized about leaving. “It has crossed my mind several times,” she said, and yet she continues to come back. “Because I have a team here. And I love what I do.” But then she started to cry. The issue is not the hard work, or even the stress. She struggles with not being able to give her patients the kind of care and attention she wants to give them, and that they need and deserve, she said.

She often thinks about a patient whose test results revealed terminal cancer, she said. Ms. Spitz spent all day working the phones, hustling case managers, trying to get hospice care set up in the man’s home. He was going to die, and she just didn’t want him to have to die in the hospital, where only one visitor was allowed. She wanted to get him home, and back with his family.

Finally, after many hours, they found an ambulance to take him home.

Three days later, the man’s family members called Ms. Spitz: He had died surrounded by family. They were calling to thank her.

“I felt like I did my job there, because I got him home,” she said. But that’s a rare feeling these days. “I just hope it gets better. I hope it gets better soon.”

Around 4 p.m. at Sparrow Hospital as one shift approached its end, Ms. Dusang faced a new crisis: The overnight shift was more short-staffed than usual.

“Can we get two inpatient nurses?” she asked, hoping to borrow two nurses from one of the hospital floors upstairs.

“Already tried,” replied nurse Troy Latunski.

Without more staff, it’s going to be hard to care for new patients who come in overnight — from car crashes to seizures or other emergencies.

But Mr. Latunski had a plan: He would go home, snatch a few hours of sleep and return at 11 p.m. to work the overnight shift in the ER’s overflow unit. That meant he would be largely caring for eight patients, alone. On just a few short hours of sleep. But lately that seemed to be their only, and best, option.

Ms. Dusang considered for a moment, took a deep breath and nodded. “OK,” she said.

“Go home. Get some sleep. Thank you,” she added, shooting Mr. Latunski a grateful smile. And then she pivoted, because another nurse was approaching with an urgent question. On to the next crisis.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation. This story is part of a partnership that includes Michigan Radio, NPR and KHN.

The more fast food restaurants a person lives near in the United States, the more likely they are to develop type 2 diabetes, new research indicates.  

The national study of more than 4 million U.S. veterans also found the opposite association with supermarkets in suburban and rural communities but not others.

“Neighborhood food environment was associated with type 2 diabetes risk among U.S. veterans in multiple community types, suggesting potential avenues for action to address the burden of type 2 diabetes,” say Rania Kanchi, MPH, of the department of population health, New York University Langone Health, and colleagues.

Restriction of fast food establishments could benefit all types of communities, while interventions to increase supermarket availability could help minimize diabetes risk in suburban and rural communities, they stress.

“These actions, combined with increasing awareness of the risk of type 2 diabetes and the importance of healthy diet intake, might be associated with a decrease in the burden of type 2 diabetes among adults in the U.S.,” the researchers add.

The data were published online Oct. 29 in JAMA Network Open.

“The more we learn about the relationship between the food environment and chronic diseases like type 2 diabetes, the more policymakers can act by improving the mix of healthy food options sold in restaurants and food outlets, or by creating better zoning laws that promote optimal food options for residents,” commented Lorna Thorpe, PhD, MPH, professor in the department of population health at NYU Langone and senior author of the study in a press release.

In an accompanying editorial, Elham Hatef, MD, MPH, of the Center for Population Health IT at Johns Hopkins Bloomberg School of Public Health, Baltimore, calls the study “a great example of the capabilities of [health information technology] to provide a comprehensive assessment of a person’s health, which goes beyond just documenting clinical diseases and medical interventions.”
 

Research has large geographic breadth

The study is notable for its large geographic breadth, say the researchers.

“Most studies that examine the built food environment and its relationship to chronic diseases have been much smaller or conducted in localized areas,” Ms. Kanchi said in the press statement.

“Our study design is national in scope and allowed us to identify the types of communities that people are living in, characterize their food environment, and observe what happens to them over time. The size of our cohort allows for geographic generalizability in a way that other studies do not,” Ms. Kanchi continued.

The research included data for 4,100,650 individuals from the Veterans Affairs electronic health records (EHRs) who didn’t have type 2 diabetes at baseline, between 2008 and 2016. After a median follow-up of 5.5 person-years, 13.2% developed type 2 diabetes. Cumulative incidence was greater among those who were older, those who were non-Hispanic Black compared with other races, and those with disabilities and lower incomes.

The proportion of adults with type 2 diabetes was highest among those living in high-density urban communities (14.3%), followed by low-density urban (13.1%), rural (13.2%), and suburban (12.6%) communities.

Overall, a 10% increase in the number of fast food restaurants compared with other food establishments in a given neighborhood was associated with a 1% increased risk for incident type 2 diabetes in high-density urban, low-density urban, and rural communities and a 2% increased risk in suburban communities.

In contrast, a 10% increase in supermarket density compared with other food stores was associated with a lower risk for type 2 diabetes in suburban and rural communities, but the association wasn’t significant elsewhere.

“Taken together, our findings suggest that policies specific to fast food restaurants, such as [those] ... restricting the siting of fast food restaurants and healthy beverage default laws, may be effective in reducing type 2 diabetes risk in all community types,” say the authors.

“In urban areas where population and retail density are growing, it will be even more important to focus on these policies,” they emphasize.
 

Great example of capabilities of health information technology

In the editorial, Dr. Hatef notes that methodological advances, such as natural language processing and machine learning, have enabled health systems to use real-world data such as the free-text notes in the EHR to identify patient-level risk factors for diseases or disease complications.

Such methods could be further used to “evaluate the associations between social needs and place-based [social determinants of health] and type 2 diabetes incidence and management,” Dr. Hatef adds.

And linkage of data from the EHR to such community-level data “would help to comprehensively assess and identify patients likely to experience type 2 diabetes and its complications as a result of their risk factors or characteristics of the neighborhoods where they reside.”

“This approach could foster collaborations between the health systems and at-risk communities they serve and help to reallocate health system resources to those in most need in the community to reduce the burden of type 2 diabetes and other chronic conditions among racial minority groups and socioeconomically disadvantaged patients and to advance population health.”

The study was supported by the Centers for Disease Control and Prevention, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Aging, the Commonwealth Universal Research Enhancement program funded by the Pennsylvania Department of Health, the Urban Health Collaborative at Drexel University, and the Built Environment and Health Research Group at Columbia University. Ms. Kanchi and Dr. Hatef have reported no relevant financial relationships.

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

The more fast food restaurants a person lives near in the United States, the more likely they are to develop type 2 diabetes, new research indicates.  

The national study of more than 4 million U.S. veterans also found the opposite association with supermarkets in suburban and rural communities but not others.

“Neighborhood food environment was associated with type 2 diabetes risk among U.S. veterans in multiple community types, suggesting potential avenues for action to address the burden of type 2 diabetes,” say Rania Kanchi, MPH, of the department of population health, New York University Langone Health, and colleagues.

Restriction of fast food establishments could benefit all types of communities, while interventions to increase supermarket availability could help minimize diabetes risk in suburban and rural communities, they stress.

“These actions, combined with increasing awareness of the risk of type 2 diabetes and the importance of healthy diet intake, might be associated with a decrease in the burden of type 2 diabetes among adults in the U.S.,” the researchers add.

The data were published online Oct. 29 in JAMA Network Open.

“The more we learn about the relationship between the food environment and chronic diseases like type 2 diabetes, the more policymakers can act by improving the mix of healthy food options sold in restaurants and food outlets, or by creating better zoning laws that promote optimal food options for residents,” commented Lorna Thorpe, PhD, MPH, professor in the department of population health at NYU Langone and senior author of the study in a press release.

In an accompanying editorial, Elham Hatef, MD, MPH, of the Center for Population Health IT at Johns Hopkins Bloomberg School of Public Health, Baltimore, calls the study “a great example of the capabilities of [health information technology] to provide a comprehensive assessment of a person’s health, which goes beyond just documenting clinical diseases and medical interventions.”
 

Research has large geographic breadth

The study is notable for its large geographic breadth, say the researchers.

“Most studies that examine the built food environment and its relationship to chronic diseases have been much smaller or conducted in localized areas,” Ms. Kanchi said in the press statement.

“Our study design is national in scope and allowed us to identify the types of communities that people are living in, characterize their food environment, and observe what happens to them over time. The size of our cohort allows for geographic generalizability in a way that other studies do not,” Ms. Kanchi continued.

The research included data for 4,100,650 individuals from the Veterans Affairs electronic health records (EHRs) who didn’t have type 2 diabetes at baseline, between 2008 and 2016. After a median follow-up of 5.5 person-years, 13.2% developed type 2 diabetes. Cumulative incidence was greater among those who were older, those who were non-Hispanic Black compared with other races, and those with disabilities and lower incomes.

The proportion of adults with type 2 diabetes was highest among those living in high-density urban communities (14.3%), followed by low-density urban (13.1%), rural (13.2%), and suburban (12.6%) communities.

Overall, a 10% increase in the number of fast food restaurants compared with other food establishments in a given neighborhood was associated with a 1% increased risk for incident type 2 diabetes in high-density urban, low-density urban, and rural communities and a 2% increased risk in suburban communities.

In contrast, a 10% increase in supermarket density compared with other food stores was associated with a lower risk for type 2 diabetes in suburban and rural communities, but the association wasn’t significant elsewhere.

“Taken together, our findings suggest that policies specific to fast food restaurants, such as [those] ... restricting the siting of fast food restaurants and healthy beverage default laws, may be effective in reducing type 2 diabetes risk in all community types,” say the authors.

“In urban areas where population and retail density are growing, it will be even more important to focus on these policies,” they emphasize.
 

Great example of capabilities of health information technology

In the editorial, Dr. Hatef notes that methodological advances, such as natural language processing and machine learning, have enabled health systems to use real-world data such as the free-text notes in the EHR to identify patient-level risk factors for diseases or disease complications.

Such methods could be further used to “evaluate the associations between social needs and place-based [social determinants of health] and type 2 diabetes incidence and management,” Dr. Hatef adds.

And linkage of data from the EHR to such community-level data “would help to comprehensively assess and identify patients likely to experience type 2 diabetes and its complications as a result of their risk factors or characteristics of the neighborhoods where they reside.”

“This approach could foster collaborations between the health systems and at-risk communities they serve and help to reallocate health system resources to those in most need in the community to reduce the burden of type 2 diabetes and other chronic conditions among racial minority groups and socioeconomically disadvantaged patients and to advance population health.”

The study was supported by the Centers for Disease Control and Prevention, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Aging, the Commonwealth Universal Research Enhancement program funded by the Pennsylvania Department of Health, the Urban Health Collaborative at Drexel University, and the Built Environment and Health Research Group at Columbia University. Ms. Kanchi and Dr. Hatef have reported no relevant financial relationships.

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

The more fast food restaurants a person lives near in the United States, the more likely they are to develop type 2 diabetes, new research indicates.  

The national study of more than 4 million U.S. veterans also found the opposite association with supermarkets in suburban and rural communities but not others.

“Neighborhood food environment was associated with type 2 diabetes risk among U.S. veterans in multiple community types, suggesting potential avenues for action to address the burden of type 2 diabetes,” say Rania Kanchi, MPH, of the department of population health, New York University Langone Health, and colleagues.

Restriction of fast food establishments could benefit all types of communities, while interventions to increase supermarket availability could help minimize diabetes risk in suburban and rural communities, they stress.

“These actions, combined with increasing awareness of the risk of type 2 diabetes and the importance of healthy diet intake, might be associated with a decrease in the burden of type 2 diabetes among adults in the U.S.,” the researchers add.

The data were published online Oct. 29 in JAMA Network Open.

“The more we learn about the relationship between the food environment and chronic diseases like type 2 diabetes, the more policymakers can act by improving the mix of healthy food options sold in restaurants and food outlets, or by creating better zoning laws that promote optimal food options for residents,” commented Lorna Thorpe, PhD, MPH, professor in the department of population health at NYU Langone and senior author of the study in a press release.

In an accompanying editorial, Elham Hatef, MD, MPH, of the Center for Population Health IT at Johns Hopkins Bloomberg School of Public Health, Baltimore, calls the study “a great example of the capabilities of [health information technology] to provide a comprehensive assessment of a person’s health, which goes beyond just documenting clinical diseases and medical interventions.”
 

Research has large geographic breadth

The study is notable for its large geographic breadth, say the researchers.

“Most studies that examine the built food environment and its relationship to chronic diseases have been much smaller or conducted in localized areas,” Ms. Kanchi said in the press statement.

“Our study design is national in scope and allowed us to identify the types of communities that people are living in, characterize their food environment, and observe what happens to them over time. The size of our cohort allows for geographic generalizability in a way that other studies do not,” Ms. Kanchi continued.

The research included data for 4,100,650 individuals from the Veterans Affairs electronic health records (EHRs) who didn’t have type 2 diabetes at baseline, between 2008 and 2016. After a median follow-up of 5.5 person-years, 13.2% developed type 2 diabetes. Cumulative incidence was greater among those who were older, those who were non-Hispanic Black compared with other races, and those with disabilities and lower incomes.

The proportion of adults with type 2 diabetes was highest among those living in high-density urban communities (14.3%), followed by low-density urban (13.1%), rural (13.2%), and suburban (12.6%) communities.

Overall, a 10% increase in the number of fast food restaurants compared with other food establishments in a given neighborhood was associated with a 1% increased risk for incident type 2 diabetes in high-density urban, low-density urban, and rural communities and a 2% increased risk in suburban communities.

In contrast, a 10% increase in supermarket density compared with other food stores was associated with a lower risk for type 2 diabetes in suburban and rural communities, but the association wasn’t significant elsewhere.

“Taken together, our findings suggest that policies specific to fast food restaurants, such as [those] ... restricting the siting of fast food restaurants and healthy beverage default laws, may be effective in reducing type 2 diabetes risk in all community types,” say the authors.

“In urban areas where population and retail density are growing, it will be even more important to focus on these policies,” they emphasize.
 

Great example of capabilities of health information technology

In the editorial, Dr. Hatef notes that methodological advances, such as natural language processing and machine learning, have enabled health systems to use real-world data such as the free-text notes in the EHR to identify patient-level risk factors for diseases or disease complications.

Such methods could be further used to “evaluate the associations between social needs and place-based [social determinants of health] and type 2 diabetes incidence and management,” Dr. Hatef adds.

And linkage of data from the EHR to such community-level data “would help to comprehensively assess and identify patients likely to experience type 2 diabetes and its complications as a result of their risk factors or characteristics of the neighborhoods where they reside.”

“This approach could foster collaborations between the health systems and at-risk communities they serve and help to reallocate health system resources to those in most need in the community to reduce the burden of type 2 diabetes and other chronic conditions among racial minority groups and socioeconomically disadvantaged patients and to advance population health.”

The study was supported by the Centers for Disease Control and Prevention, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Aging, the Commonwealth Universal Research Enhancement program funded by the Pennsylvania Department of Health, the Urban Health Collaborative at Drexel University, and the Built Environment and Health Research Group at Columbia University. Ms. Kanchi and Dr. Hatef have reported no relevant financial relationships.

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

Almost all physicians write prescriptions, and each prescription requires a physician to assess the risks and benefits of the drug. If an adverse drug reaction occurs, physicians may be called on to defend their risk-benefit assessment in court.

The assessment of risk is complicated when there is a boxed warning that describes potentially serious and life-threatening adverse reactions associated with a drug. Some of our most commonly prescribed drugs have boxed warnings, and drugs that were initially approved by the Food and Drug Administration without boxed warnings may have them added years later.

One serious problem with boxed warnings is that there are no reliable mechanisms for making sure that physicians are aware of them. The warnings are typically not seen by physicians as printed product labels, just as physicians often don’t see the pills and capsules that they prescribe. Pharmacists who receive packaged drugs from manufacturers may be the only ones to see an actual printed boxed warning, but even those pharmacists have little reason to read each label and note changes when handling many bulk packages.

This problem is aggravated by misperceptions that many physicians have about boxed warnings and the increasingly intense scrutiny given to them by mass media and the courts. Lawyers can use boxed warnings to make a drug look dangerous, even when it’s not, and to make physicians look reckless when prescribing it. Therefore, it is important for physicians to understand what boxed warnings are, what they are not, the problems they cause, and how to minimize these problems.
 

What is a ‘boxed warning’?

The marketing and sale of drugs in the United States requires approval by the FDA. Approval requires manufacturers to prepare a document containing “Full Prescribing Information” for the drug and to include a printed copy in every package of the drug that is sold. This document is commonly called a “package insert,” but the FDA designates this document as the manufacturer’s product “label.”

In 1979, the FDA began requiring some labels to appear within thick, black rectangular borders; these have come to be known as boxed warnings. Boxed warnings are usually placed at the beginning of a label. They may be added to the label of a previously approved drug already on the market or included in the product label when first approved and marketed.

The requirement for a boxed warning most often arises when a signal appears during review of postmarketing surveillance data suggesting a possible and plausible association between a drug and an adverse reaction. Warnings may also be initiated in response to petitions from public interest groups, or upon the discovery of serious toxicity in animals. Regardless of their origin, the intent of a boxed warning is to highlight information that may have important therapeutic consequences and warrants heightened awareness among physicians.
 

What a boxed warning is not

A boxed warning is not “issued” by the FDA; it is merely required by the FDA. Specific wording or a template may be suggested by the FDA, but product labels and boxed warnings are written and issued by the manufacturer. This distinction may seem minor, but extensive litigation has occurred over whether manufacturers have met their duty to warn consumers about possible risks when using their products, and this duty cannot be shifted to the FDA.

A boxed warning may not be added to a product label at the option of a manufacturer. The FDA allows a boxed warning only if it requires the warning, to preserve its impact. It should be noted that some medical information sources (e.g., PDR.net) may include a “BOXED WARNING” in their drug monographs, but monographs not written by a manufacturer are not regulated by the FDA, and the text of their boxed warnings do not always correspond to the boxed warning that was approved by the FDA.

A boxed warning is not an indication that revocation of FDA approval is being considered or that it is likely to be revoked. FDA approval is subject to ongoing review and may be revoked at any time, without a prior boxed warning.

A boxed warning is not the highest level of warning. The FDA may require a manufacturer to send out a “Dear Health Care Provider” (DHCP) letter when an even higher or more urgent level of warning is deemed necessary. DHCP letters are usually accompanied by revisions of the product label, but most label revisions – and even most boxed warnings – are not accompanied by DHCP letters.

A boxed warning is not a statement about causation. Most warnings describe an “association” between a drug and an adverse effect, or “increased risk,” or instances of a particular adverse effect that “have been reported” in persons taking a drug. The words in a boxed warning are carefully chosen and require careful reading; in most cases they refrain from stating that a drug actually causes an adverse effect. The postmarketing surveillance data on which most warnings are based generally cannot provide the kind of evidence required to establish causation, and an association may be nothing more than an uncommon manifestation of the disorder for which the drug has been prescribed.

A boxed warning is not a statement about the probability of an adverse reaction occurring. The requirement for a boxed warning correlates better to the new recognition of a possible association than to the probability of an association. For example, penicillin has long been known to cause fatal anaphylaxis in 1/100,000 first-time administrations, but it does not have a boxed warning. The adverse consequences described in boxed warnings are often far less frequent – so much so that most physicians will never see them.

A boxed warning does not define the standard of care. The warning is a requirement imposed on the manufacturer, not on the practice of medicine. For legal purposes, the “standard of care” for the practice of medicine is defined state by state and is typically cast in terms such as “what most physicians would do in similar circumstances.” Physicians often prescribe drugs in spite of boxed warnings, just as they often prescribe drugs for “off label” indications, always balancing risk versus benefit.

A boxed warning does not constitute a contraindication to the use of a medication. Some warnings state that a drug is contraindicated in some situations, but product labels have another mandated section for listing contraindications, and most boxed warnings have no corresponding entry in that section.

A boxed warning does not necessarily constitute current information, nor is it always updated when new or contrary information becomes available. Revisions to boxed warnings, and to product labels in general, are made only after detailed review at the FDA, and the process of deciding whether an existing boxed warning continues to be appropriate may divert limited regulatory resources from more urgent priorities. Consequently, revisions to a boxed warning may lag behind the data that justify a revision by months or years. Revisions may never occur if softening or eliminating a boxed warning is deemed to be not worth the cost by a manufacturer.
 

Boxed warning problems for physicians

There is no reliable mechanism for manufacturers or the FDA to communicate boxed warnings directly to physicians, so it’s not clear how physicians are expected to stay informed about the issuance or revision of boxed warnings. They may first learn about new or revised warnings in the mass media, which is paying ever-increasing attention to press releases from the FDA. However, it can be difficult for the media to accurately convey the subtle and complex nature of a boxed warning in nontechnical terms.

Many physicians subscribe to various medical news alerts and attend continuing medical education (CME) programs, which often do an excellent job of highlighting new warnings, while hospitals, clinics, and pharmacies may broadcast news about boxed warnings in newsletters or other notices. But these notifications are ephemeral and may be missed by physicians who are overwhelmed by email, notices, newsletters, and CME programs.

The warnings that pop up in electronic medical records systems are often so numerous that physicians become trained to ignore them. Printed advertisements in professional journals must include mandated boxed warnings, but their visibility is waning as physicians increasingly read journals online.

Another conundrum is how to inform the public about boxed warnings.

Manufacturers are prohibited from direct-to-consumer advertising of drugs with boxed warnings, although the warnings are easily found on the Internet. Some patients expect and welcome detailed information from their physicians, so it’s a good policy to always and repeatedly review this information with them, especially if they are members of an identified risk group. However, that policy may be counterproductive if it dissuades anxious patients from needed therapy despite risk-benefit considerations that strongly favor it. Boxed warnings are well known to have “spillover effects” in which the aspersions cast by a boxed warning for a relatively small subgroup of patients causes use of a drug to decline among all patients.

Compounding this conundrum is that physicians rarely have sufficient information to gauge the magnitude of a risk, given that boxed warnings are often based on information from surveillance systems that cannot accurately quantify the risk or even establish a causal relationship. The text of a boxed warning generally does not provide the information needed for evidence-based clinical practice such as a quantitative estimate of effect, information about source and trustworthiness of the evidence, and guidance on implementation. For these and other reasons, FDA policies about various boxed warnings have been the target of significant criticism.

Medication guides are one mechanism to address the challenge of informing patients about the risks of drugs they are taking. FDA-approved medication guides are available for most drugs dispensed as outpatient prescriptions, they’re written in plain language for the consumer, and they include paraphrased versions of any boxed warning. Ideally, patients review these guides with their physicians or pharmacists, but the guides may be lengthy and raise questions that may not be answerable (e.g., about incidence rates). Patients may decline to review this information when a drug is prescribed or dispensed, and they may discard printed copies given to them without reading.
 

What can physicians do to minimize boxed warning problems?

Physicians should periodically review the product labels for drugs they commonly prescribe, including drugs they’ve prescribed for a long time. Prescription renewal requests can be used as a prompt to check for changes in a patient’s condition or other medications that might place a patient in the target population of a boxed warning. Physicians can subscribe to newsletters that announce and discuss significant product label changes, including alerts directly from the FDA. Physicians may also enlist their office staff to find and review boxed warnings for drugs being prescribed, noting which ones should require a conversation with any patient who has been or will be receiving this drug. They may want to make explicit mention in their encounter record that a boxed warning, medication guide, or overall risk-benefit assessment has been discussed.

Summary

The nature of boxed warnings, the means by which they are disseminated, and their role in clinical practice are all in great need of improvement. Until that occurs, boxed warnings offer some, but only very limited, help to patients and physicians who struggle to understand the risks of medications.

Dr. Axelsen is professor in the departments of pharmacology, biochemistry, and biophysics, and of medicine, infectious diseases section, University of Pennsylvania, Philadelphia. He disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

Almost all physicians write prescriptions, and each prescription requires a physician to assess the risks and benefits of the drug. If an adverse drug reaction occurs, physicians may be called on to defend their risk-benefit assessment in court.

The assessment of risk is complicated when there is a boxed warning that describes potentially serious and life-threatening adverse reactions associated with a drug. Some of our most commonly prescribed drugs have boxed warnings, and drugs that were initially approved by the Food and Drug Administration without boxed warnings may have them added years later.

One serious problem with boxed warnings is that there are no reliable mechanisms for making sure that physicians are aware of them. The warnings are typically not seen by physicians as printed product labels, just as physicians often don’t see the pills and capsules that they prescribe. Pharmacists who receive packaged drugs from manufacturers may be the only ones to see an actual printed boxed warning, but even those pharmacists have little reason to read each label and note changes when handling many bulk packages.

This problem is aggravated by misperceptions that many physicians have about boxed warnings and the increasingly intense scrutiny given to them by mass media and the courts. Lawyers can use boxed warnings to make a drug look dangerous, even when it’s not, and to make physicians look reckless when prescribing it. Therefore, it is important for physicians to understand what boxed warnings are, what they are not, the problems they cause, and how to minimize these problems.
 

What is a ‘boxed warning’?

The marketing and sale of drugs in the United States requires approval by the FDA. Approval requires manufacturers to prepare a document containing “Full Prescribing Information” for the drug and to include a printed copy in every package of the drug that is sold. This document is commonly called a “package insert,” but the FDA designates this document as the manufacturer’s product “label.”

In 1979, the FDA began requiring some labels to appear within thick, black rectangular borders; these have come to be known as boxed warnings. Boxed warnings are usually placed at the beginning of a label. They may be added to the label of a previously approved drug already on the market or included in the product label when first approved and marketed.

The requirement for a boxed warning most often arises when a signal appears during review of postmarketing surveillance data suggesting a possible and plausible association between a drug and an adverse reaction. Warnings may also be initiated in response to petitions from public interest groups, or upon the discovery of serious toxicity in animals. Regardless of their origin, the intent of a boxed warning is to highlight information that may have important therapeutic consequences and warrants heightened awareness among physicians.
 

What a boxed warning is not

A boxed warning is not “issued” by the FDA; it is merely required by the FDA. Specific wording or a template may be suggested by the FDA, but product labels and boxed warnings are written and issued by the manufacturer. This distinction may seem minor, but extensive litigation has occurred over whether manufacturers have met their duty to warn consumers about possible risks when using their products, and this duty cannot be shifted to the FDA.

A boxed warning may not be added to a product label at the option of a manufacturer. The FDA allows a boxed warning only if it requires the warning, to preserve its impact. It should be noted that some medical information sources (e.g., PDR.net) may include a “BOXED WARNING” in their drug monographs, but monographs not written by a manufacturer are not regulated by the FDA, and the text of their boxed warnings do not always correspond to the boxed warning that was approved by the FDA.

A boxed warning is not an indication that revocation of FDA approval is being considered or that it is likely to be revoked. FDA approval is subject to ongoing review and may be revoked at any time, without a prior boxed warning.

A boxed warning is not the highest level of warning. The FDA may require a manufacturer to send out a “Dear Health Care Provider” (DHCP) letter when an even higher or more urgent level of warning is deemed necessary. DHCP letters are usually accompanied by revisions of the product label, but most label revisions – and even most boxed warnings – are not accompanied by DHCP letters.

A boxed warning is not a statement about causation. Most warnings describe an “association” between a drug and an adverse effect, or “increased risk,” or instances of a particular adverse effect that “have been reported” in persons taking a drug. The words in a boxed warning are carefully chosen and require careful reading; in most cases they refrain from stating that a drug actually causes an adverse effect. The postmarketing surveillance data on which most warnings are based generally cannot provide the kind of evidence required to establish causation, and an association may be nothing more than an uncommon manifestation of the disorder for which the drug has been prescribed.

A boxed warning is not a statement about the probability of an adverse reaction occurring. The requirement for a boxed warning correlates better to the new recognition of a possible association than to the probability of an association. For example, penicillin has long been known to cause fatal anaphylaxis in 1/100,000 first-time administrations, but it does not have a boxed warning. The adverse consequences described in boxed warnings are often far less frequent – so much so that most physicians will never see them.

A boxed warning does not define the standard of care. The warning is a requirement imposed on the manufacturer, not on the practice of medicine. For legal purposes, the “standard of care” for the practice of medicine is defined state by state and is typically cast in terms such as “what most physicians would do in similar circumstances.” Physicians often prescribe drugs in spite of boxed warnings, just as they often prescribe drugs for “off label” indications, always balancing risk versus benefit.

A boxed warning does not constitute a contraindication to the use of a medication. Some warnings state that a drug is contraindicated in some situations, but product labels have another mandated section for listing contraindications, and most boxed warnings have no corresponding entry in that section.

A boxed warning does not necessarily constitute current information, nor is it always updated when new or contrary information becomes available. Revisions to boxed warnings, and to product labels in general, are made only after detailed review at the FDA, and the process of deciding whether an existing boxed warning continues to be appropriate may divert limited regulatory resources from more urgent priorities. Consequently, revisions to a boxed warning may lag behind the data that justify a revision by months or years. Revisions may never occur if softening or eliminating a boxed warning is deemed to be not worth the cost by a manufacturer.
 

Boxed warning problems for physicians

There is no reliable mechanism for manufacturers or the FDA to communicate boxed warnings directly to physicians, so it’s not clear how physicians are expected to stay informed about the issuance or revision of boxed warnings. They may first learn about new or revised warnings in the mass media, which is paying ever-increasing attention to press releases from the FDA. However, it can be difficult for the media to accurately convey the subtle and complex nature of a boxed warning in nontechnical terms.

Many physicians subscribe to various medical news alerts and attend continuing medical education (CME) programs, which often do an excellent job of highlighting new warnings, while hospitals, clinics, and pharmacies may broadcast news about boxed warnings in newsletters or other notices. But these notifications are ephemeral and may be missed by physicians who are overwhelmed by email, notices, newsletters, and CME programs.

The warnings that pop up in electronic medical records systems are often so numerous that physicians become trained to ignore them. Printed advertisements in professional journals must include mandated boxed warnings, but their visibility is waning as physicians increasingly read journals online.

Another conundrum is how to inform the public about boxed warnings.

Manufacturers are prohibited from direct-to-consumer advertising of drugs with boxed warnings, although the warnings are easily found on the Internet. Some patients expect and welcome detailed information from their physicians, so it’s a good policy to always and repeatedly review this information with them, especially if they are members of an identified risk group. However, that policy may be counterproductive if it dissuades anxious patients from needed therapy despite risk-benefit considerations that strongly favor it. Boxed warnings are well known to have “spillover effects” in which the aspersions cast by a boxed warning for a relatively small subgroup of patients causes use of a drug to decline among all patients.

Compounding this conundrum is that physicians rarely have sufficient information to gauge the magnitude of a risk, given that boxed warnings are often based on information from surveillance systems that cannot accurately quantify the risk or even establish a causal relationship. The text of a boxed warning generally does not provide the information needed for evidence-based clinical practice such as a quantitative estimate of effect, information about source and trustworthiness of the evidence, and guidance on implementation. For these and other reasons, FDA policies about various boxed warnings have been the target of significant criticism.

Medication guides are one mechanism to address the challenge of informing patients about the risks of drugs they are taking. FDA-approved medication guides are available for most drugs dispensed as outpatient prescriptions, they’re written in plain language for the consumer, and they include paraphrased versions of any boxed warning. Ideally, patients review these guides with their physicians or pharmacists, but the guides may be lengthy and raise questions that may not be answerable (e.g., about incidence rates). Patients may decline to review this information when a drug is prescribed or dispensed, and they may discard printed copies given to them without reading.
 

What can physicians do to minimize boxed warning problems?

Physicians should periodically review the product labels for drugs they commonly prescribe, including drugs they’ve prescribed for a long time. Prescription renewal requests can be used as a prompt to check for changes in a patient’s condition or other medications that might place a patient in the target population of a boxed warning. Physicians can subscribe to newsletters that announce and discuss significant product label changes, including alerts directly from the FDA. Physicians may also enlist their office staff to find and review boxed warnings for drugs being prescribed, noting which ones should require a conversation with any patient who has been or will be receiving this drug. They may want to make explicit mention in their encounter record that a boxed warning, medication guide, or overall risk-benefit assessment has been discussed.

Summary

The nature of boxed warnings, the means by which they are disseminated, and their role in clinical practice are all in great need of improvement. Until that occurs, boxed warnings offer some, but only very limited, help to patients and physicians who struggle to understand the risks of medications.

Dr. Axelsen is professor in the departments of pharmacology, biochemistry, and biophysics, and of medicine, infectious diseases section, University of Pennsylvania, Philadelphia. He disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

Almost all physicians write prescriptions, and each prescription requires a physician to assess the risks and benefits of the drug. If an adverse drug reaction occurs, physicians may be called on to defend their risk-benefit assessment in court.

The assessment of risk is complicated when there is a boxed warning that describes potentially serious and life-threatening adverse reactions associated with a drug. Some of our most commonly prescribed drugs have boxed warnings, and drugs that were initially approved by the Food and Drug Administration without boxed warnings may have them added years later.

One serious problem with boxed warnings is that there are no reliable mechanisms for making sure that physicians are aware of them. The warnings are typically not seen by physicians as printed product labels, just as physicians often don’t see the pills and capsules that they prescribe. Pharmacists who receive packaged drugs from manufacturers may be the only ones to see an actual printed boxed warning, but even those pharmacists have little reason to read each label and note changes when handling many bulk packages.

This problem is aggravated by misperceptions that many physicians have about boxed warnings and the increasingly intense scrutiny given to them by mass media and the courts. Lawyers can use boxed warnings to make a drug look dangerous, even when it’s not, and to make physicians look reckless when prescribing it. Therefore, it is important for physicians to understand what boxed warnings are, what they are not, the problems they cause, and how to minimize these problems.
 

What is a ‘boxed warning’?

The marketing and sale of drugs in the United States requires approval by the FDA. Approval requires manufacturers to prepare a document containing “Full Prescribing Information” for the drug and to include a printed copy in every package of the drug that is sold. This document is commonly called a “package insert,” but the FDA designates this document as the manufacturer’s product “label.”

In 1979, the FDA began requiring some labels to appear within thick, black rectangular borders; these have come to be known as boxed warnings. Boxed warnings are usually placed at the beginning of a label. They may be added to the label of a previously approved drug already on the market or included in the product label when first approved and marketed.

The requirement for a boxed warning most often arises when a signal appears during review of postmarketing surveillance data suggesting a possible and plausible association between a drug and an adverse reaction. Warnings may also be initiated in response to petitions from public interest groups, or upon the discovery of serious toxicity in animals. Regardless of their origin, the intent of a boxed warning is to highlight information that may have important therapeutic consequences and warrants heightened awareness among physicians.
 

What a boxed warning is not

A boxed warning is not “issued” by the FDA; it is merely required by the FDA. Specific wording or a template may be suggested by the FDA, but product labels and boxed warnings are written and issued by the manufacturer. This distinction may seem minor, but extensive litigation has occurred over whether manufacturers have met their duty to warn consumers about possible risks when using their products, and this duty cannot be shifted to the FDA.

A boxed warning may not be added to a product label at the option of a manufacturer. The FDA allows a boxed warning only if it requires the warning, to preserve its impact. It should be noted that some medical information sources (e.g., PDR.net) may include a “BOXED WARNING” in their drug monographs, but monographs not written by a manufacturer are not regulated by the FDA, and the text of their boxed warnings do not always correspond to the boxed warning that was approved by the FDA.

A boxed warning is not an indication that revocation of FDA approval is being considered or that it is likely to be revoked. FDA approval is subject to ongoing review and may be revoked at any time, without a prior boxed warning.

A boxed warning is not the highest level of warning. The FDA may require a manufacturer to send out a “Dear Health Care Provider” (DHCP) letter when an even higher or more urgent level of warning is deemed necessary. DHCP letters are usually accompanied by revisions of the product label, but most label revisions – and even most boxed warnings – are not accompanied by DHCP letters.

A boxed warning is not a statement about causation. Most warnings describe an “association” between a drug and an adverse effect, or “increased risk,” or instances of a particular adverse effect that “have been reported” in persons taking a drug. The words in a boxed warning are carefully chosen and require careful reading; in most cases they refrain from stating that a drug actually causes an adverse effect. The postmarketing surveillance data on which most warnings are based generally cannot provide the kind of evidence required to establish causation, and an association may be nothing more than an uncommon manifestation of the disorder for which the drug has been prescribed.

A boxed warning is not a statement about the probability of an adverse reaction occurring. The requirement for a boxed warning correlates better to the new recognition of a possible association than to the probability of an association. For example, penicillin has long been known to cause fatal anaphylaxis in 1/100,000 first-time administrations, but it does not have a boxed warning. The adverse consequences described in boxed warnings are often far less frequent – so much so that most physicians will never see them.

A boxed warning does not define the standard of care. The warning is a requirement imposed on the manufacturer, not on the practice of medicine. For legal purposes, the “standard of care” for the practice of medicine is defined state by state and is typically cast in terms such as “what most physicians would do in similar circumstances.” Physicians often prescribe drugs in spite of boxed warnings, just as they often prescribe drugs for “off label” indications, always balancing risk versus benefit.

A boxed warning does not constitute a contraindication to the use of a medication. Some warnings state that a drug is contraindicated in some situations, but product labels have another mandated section for listing contraindications, and most boxed warnings have no corresponding entry in that section.

A boxed warning does not necessarily constitute current information, nor is it always updated when new or contrary information becomes available. Revisions to boxed warnings, and to product labels in general, are made only after detailed review at the FDA, and the process of deciding whether an existing boxed warning continues to be appropriate may divert limited regulatory resources from more urgent priorities. Consequently, revisions to a boxed warning may lag behind the data that justify a revision by months or years. Revisions may never occur if softening or eliminating a boxed warning is deemed to be not worth the cost by a manufacturer.
 

Boxed warning problems for physicians

There is no reliable mechanism for manufacturers or the FDA to communicate boxed warnings directly to physicians, so it’s not clear how physicians are expected to stay informed about the issuance or revision of boxed warnings. They may first learn about new or revised warnings in the mass media, which is paying ever-increasing attention to press releases from the FDA. However, it can be difficult for the media to accurately convey the subtle and complex nature of a boxed warning in nontechnical terms.

Many physicians subscribe to various medical news alerts and attend continuing medical education (CME) programs, which often do an excellent job of highlighting new warnings, while hospitals, clinics, and pharmacies may broadcast news about boxed warnings in newsletters or other notices. But these notifications are ephemeral and may be missed by physicians who are overwhelmed by email, notices, newsletters, and CME programs.

The warnings that pop up in electronic medical records systems are often so numerous that physicians become trained to ignore them. Printed advertisements in professional journals must include mandated boxed warnings, but their visibility is waning as physicians increasingly read journals online.

Another conundrum is how to inform the public about boxed warnings.

Manufacturers are prohibited from direct-to-consumer advertising of drugs with boxed warnings, although the warnings are easily found on the Internet. Some patients expect and welcome detailed information from their physicians, so it’s a good policy to always and repeatedly review this information with them, especially if they are members of an identified risk group. However, that policy may be counterproductive if it dissuades anxious patients from needed therapy despite risk-benefit considerations that strongly favor it. Boxed warnings are well known to have “spillover effects” in which the aspersions cast by a boxed warning for a relatively small subgroup of patients causes use of a drug to decline among all patients.

Compounding this conundrum is that physicians rarely have sufficient information to gauge the magnitude of a risk, given that boxed warnings are often based on information from surveillance systems that cannot accurately quantify the risk or even establish a causal relationship. The text of a boxed warning generally does not provide the information needed for evidence-based clinical practice such as a quantitative estimate of effect, information about source and trustworthiness of the evidence, and guidance on implementation. For these and other reasons, FDA policies about various boxed warnings have been the target of significant criticism.

Medication guides are one mechanism to address the challenge of informing patients about the risks of drugs they are taking. FDA-approved medication guides are available for most drugs dispensed as outpatient prescriptions, they’re written in plain language for the consumer, and they include paraphrased versions of any boxed warning. Ideally, patients review these guides with their physicians or pharmacists, but the guides may be lengthy and raise questions that may not be answerable (e.g., about incidence rates). Patients may decline to review this information when a drug is prescribed or dispensed, and they may discard printed copies given to them without reading.
 

What can physicians do to minimize boxed warning problems?

Physicians should periodically review the product labels for drugs they commonly prescribe, including drugs they’ve prescribed for a long time. Prescription renewal requests can be used as a prompt to check for changes in a patient’s condition or other medications that might place a patient in the target population of a boxed warning. Physicians can subscribe to newsletters that announce and discuss significant product label changes, including alerts directly from the FDA. Physicians may also enlist their office staff to find and review boxed warnings for drugs being prescribed, noting which ones should require a conversation with any patient who has been or will be receiving this drug. They may want to make explicit mention in their encounter record that a boxed warning, medication guide, or overall risk-benefit assessment has been discussed.

Summary

The nature of boxed warnings, the means by which they are disseminated, and their role in clinical practice are all in great need of improvement. Until that occurs, boxed warnings offer some, but only very limited, help to patients and physicians who struggle to understand the risks of medications.

Dr. Axelsen is professor in the departments of pharmacology, biochemistry, and biophysics, and of medicine, infectious diseases section, University of Pennsylvania, Philadelphia. He disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

A novel investigational allogeneic stem cell–derived treatment resulted in near reversal of type 1 diabetes in a patient who had lived with the condition for about 40 years.

CIPhotos/Getty Images

The patient was the first in Vertex Pharmaceuticals’ phase 1/2 multicenter, single-arm, open-label clinical trial of the insulin-producing islet cell therapy VX-880 for patients with type 1 diabetes who have impaired hypoglycemic awareness and severe hypoglycemia.

The cells are delivered by infusion into the hepatic portal vein. As of now, chronic immunosuppression is required to prevent rejection, but several approaches are being studied to overcome the limitation.

“There’s hope that this is a real advance. It’s been long awaited, and it looks really encouraging,” James Markmann, MD, PhD, the surgeon who performed the procedure, told this news organization.

The use of insulin-producing pancreatic beta cells derived from human pluripotent stem cells, first reported in 2014 by a team at the Harvard Stem Cell Institute, Boston, is seen as a major advance over use of cadaveric donor islet cells because stem cell–derived islets are available in unlimited and uncontaminated supplies.

Cadaveric donor islets are being used in products such as donislecel (CellTrans), which was endorsed by a Food and Drug Administration advisory committee in the summer for the treatment of type 1 diabetes that can’t be managed with current therapies.

The patient in the Vertex trial isn’t the first reported stem cell–derived islet recipient with type 1 diabetes, but these cells are the first to be transplanted into the liver.

“This Vertex patient stood out because the reduction in insulin requirement ... was so striking,” noted Dr. Markmann, chief of the division of transplant surgery at Massachusetts General Hospital, Boston, who has been transplanting islet cells from cadaveric donors into humans via the hepatic portal vein for over 20 years.

“Nobody knew what to expect, as it hadn’t been done before, but certainly the results in this patient are better than what I would have expected from a deceased donor islet transplant,” he added.

Asked to comment, A.M. James Shapiro, MD, agreed. “I think the most important finding is that a stem cell–derived islet is now transplanted into the liver of a patient safely, so far,” he said in an interview.

Dr. Shapiro is clinical director of the living donor and islet cell transplantation programs at the University of Alberta, Edmonton. He pioneered cadaveric donor islet cell transplantation more than 20 years ago with the watershed Edmonton Protocol.

‘Impressive finding ... bodes well for ongoing efforts’

Vertex announced the result by press release. The company plans to transplant another 16 patients, staggering them over time at multiple centers.

The first patient was treated with a single infusion of VX-880 at half the target dose (per protocol for the first two study subjects), along with standard immunosuppressive therapy. At 90 days, the patient’s C-peptide, a measure of endogenous insulin secretion, rose from undetectable to 280 pmol/L fasting and 560 pmol/L post mixed-meal tolerance testing.

Over the same period, the patient’s hemoglobin A1c dropped from 8.6% at baseline to 7.2%. And within 7 days, the individual’s daily exogenous insulin requirement dropped from an average of 34 units to just 2.9 units, a 91% decrease.

The patient had experienced five severe hypoglycemic episodes in the year prior to transplant. They experienced some mild hypoglycemia soon after the procedure while insulin doses were being adjusted, but none thereafter. 

Dr. Shapiro said in an interview: “I was absolutely thrilled to see the first patient results with high C-peptide and a 91% reduction in insulin. That’s a pretty impressive finding for half dosing in the very first patient in a trial. I think it bodes really well for ongoing efforts in this area by Vertex and by others that have similar kinds of cells. It’s very exciting.”

However, he cautioned, “we do need some longer-term data to be sure there’s no off-target growth or other concerns. But based on the purity of this product, that risk is likely to be low.”

And he noted, “I think we still have to address the challenges of setting this process up. A huge amount of work has gone into manufacturing the cell product for a single patient. I think it remains to be seen whether the same technology can be delivered at a larger scale ... i.e., being able to treat hundreds or thousands of patients.”

A blog post on the website of diabetes charity JDRF called the result “outstanding.” “It’s a big deal,” they added. However, they also cautioned: “There are a few things to keep in mind while assessing the data. One is that these are only results from a single person. Data are needed from many more to fully evaluate the potential of this therapy. The second is that this person only received half the target dose of cells.”

Dr. Shapiro is working with another company, ViaCyte, which has also developed stem cell–derived islets. In contrast to the Vertex product, which is fully differentiated and delivered to the liver, ViaCyte’s PEC-Direct product is comprised of stem cell-derived pancreatic islet progenitor cells that are implanted subcutaneously in a pouch, allowing for vascularization.

In a late-breaking poster at the annual scientific sessions of the American Diabetes Association in June 2021, ViaCyte reported on a patient given PEC-Direct. In that patient, stimulated C-peptide increased from 0.1 ng/mL at baseline to 0.8 ng/mL at week 39, and there was a drop in A1c from 7.4% to 6.6%, with no adverse events.

Immunosuppression: Which approach will come closer to cure?

Thus far, the requirement for lifelong immunosuppression has meant that any islet cell replacement approach, including with stem cell–derived islets, has been limited to use in people with type 1 diabetes who have hypoglycemic unawareness or severely unpredictable blood glucose levels.

Two broad approaches are simultaneously being explored to overcome the rejection problem: Encapsulation of the cells to protect them from the immune system, and genetic modification of the cells so that they don’t provoke the immune system in the first place.

In 2022, Vertex plans to file an investigational new drug application for an encapsulated islet cell program with the FDA.

Dr. Markmann believes the genetic modification approach is more promising. “I’m not a believer in encapsulation. I think the foreign body response is hard to overcome. I think the answer will ultimately be genetically modifying the [cell] lines. ... The cell could express something that would potentially turn off the lymphocytes or interfere with the lymphocytes trying to attack them.”

Moreover, he said, “you don’t have to get rid of immunosuppression completely. It’s all [a] risk-benefit [equation]. Even if you could get it down to a single less-toxic [immunosuppressive] agent that would be a huge step.”

Dr. Shapiro commented: “All efforts and eyes are laser-focused on developing cells or approaches that will allow transplantation of this kind of stem cell without any immunosuppression or with low-dose immunosuppression that could be regarded as being exceedingly low risk.”

“Then, and only then, I think we could offer this kind of treatment to children who are just diagnosed with diabetes or to [a bigger proportion of] patients with type 1 or type 2 diabetes. ... The science has to be done in a step-wise fashion,” he added.

Microencapsulation, Dr. Shapiro noted, “is a big challenge because the process of capturing the cells and putting them into a device is really injurious to their survival. ... That may or may not work.”

Dr. Shapiro and his Edmonton team are now embarking on a new trial with ViaCyte and CRISPR Therapeutics using gene-edited cells that contain two knock-in genes and two knock-out genes shown to be less immunogenic and anti-inflammatory in rodent models.

“They look to be promising. We’re going to start a first-in-human trial in the next few months with those cells to see if they really are able to withstand a transplant without the need for immunosuppression. That will be a very exciting trial in itself,” Dr. Shapiro said, noting that they expect to enroll the first patients in the next few months.

However, he cautioned, “first we have to make sure that the gene-edited product continues to function in patients in the way that the original product did, that the cells survive, and that the gene modifications are actually effective. ... Maybe other iterations will be needed.”

“I think, as we move forward, we will ultimately have a gene-edited stem cell–derived product that is immune evasive and will survive. So, I’m ... optimistic that this is not as long term as you might think, and it’s ... happening much more rapidly – at least in first-in-human trials to test safety and preliminary efficacy.”

Dr. Shapiro is a consultant for ViaCyte.

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

A novel investigational allogeneic stem cell–derived treatment resulted in near reversal of type 1 diabetes in a patient who had lived with the condition for about 40 years.

CIPhotos/Getty Images

The patient was the first in Vertex Pharmaceuticals’ phase 1/2 multicenter, single-arm, open-label clinical trial of the insulin-producing islet cell therapy VX-880 for patients with type 1 diabetes who have impaired hypoglycemic awareness and severe hypoglycemia.

The cells are delivered by infusion into the hepatic portal vein. As of now, chronic immunosuppression is required to prevent rejection, but several approaches are being studied to overcome the limitation.

“There’s hope that this is a real advance. It’s been long awaited, and it looks really encouraging,” James Markmann, MD, PhD, the surgeon who performed the procedure, told this news organization.

The use of insulin-producing pancreatic beta cells derived from human pluripotent stem cells, first reported in 2014 by a team at the Harvard Stem Cell Institute, Boston, is seen as a major advance over use of cadaveric donor islet cells because stem cell–derived islets are available in unlimited and uncontaminated supplies.

Cadaveric donor islets are being used in products such as donislecel (CellTrans), which was endorsed by a Food and Drug Administration advisory committee in the summer for the treatment of type 1 diabetes that can’t be managed with current therapies.

The patient in the Vertex trial isn’t the first reported stem cell–derived islet recipient with type 1 diabetes, but these cells are the first to be transplanted into the liver.

“This Vertex patient stood out because the reduction in insulin requirement ... was so striking,” noted Dr. Markmann, chief of the division of transplant surgery at Massachusetts General Hospital, Boston, who has been transplanting islet cells from cadaveric donors into humans via the hepatic portal vein for over 20 years.

“Nobody knew what to expect, as it hadn’t been done before, but certainly the results in this patient are better than what I would have expected from a deceased donor islet transplant,” he added.

Asked to comment, A.M. James Shapiro, MD, agreed. “I think the most important finding is that a stem cell–derived islet is now transplanted into the liver of a patient safely, so far,” he said in an interview.

Dr. Shapiro is clinical director of the living donor and islet cell transplantation programs at the University of Alberta, Edmonton. He pioneered cadaveric donor islet cell transplantation more than 20 years ago with the watershed Edmonton Protocol.

‘Impressive finding ... bodes well for ongoing efforts’

Vertex announced the result by press release. The company plans to transplant another 16 patients, staggering them over time at multiple centers.

The first patient was treated with a single infusion of VX-880 at half the target dose (per protocol for the first two study subjects), along with standard immunosuppressive therapy. At 90 days, the patient’s C-peptide, a measure of endogenous insulin secretion, rose from undetectable to 280 pmol/L fasting and 560 pmol/L post mixed-meal tolerance testing.

Over the same period, the patient’s hemoglobin A1c dropped from 8.6% at baseline to 7.2%. And within 7 days, the individual’s daily exogenous insulin requirement dropped from an average of 34 units to just 2.9 units, a 91% decrease.

The patient had experienced five severe hypoglycemic episodes in the year prior to transplant. They experienced some mild hypoglycemia soon after the procedure while insulin doses were being adjusted, but none thereafter. 

Dr. Shapiro said in an interview: “I was absolutely thrilled to see the first patient results with high C-peptide and a 91% reduction in insulin. That’s a pretty impressive finding for half dosing in the very first patient in a trial. I think it bodes really well for ongoing efforts in this area by Vertex and by others that have similar kinds of cells. It’s very exciting.”

However, he cautioned, “we do need some longer-term data to be sure there’s no off-target growth or other concerns. But based on the purity of this product, that risk is likely to be low.”

And he noted, “I think we still have to address the challenges of setting this process up. A huge amount of work has gone into manufacturing the cell product for a single patient. I think it remains to be seen whether the same technology can be delivered at a larger scale ... i.e., being able to treat hundreds or thousands of patients.”

A blog post on the website of diabetes charity JDRF called the result “outstanding.” “It’s a big deal,” they added. However, they also cautioned: “There are a few things to keep in mind while assessing the data. One is that these are only results from a single person. Data are needed from many more to fully evaluate the potential of this therapy. The second is that this person only received half the target dose of cells.”

Dr. Shapiro is working with another company, ViaCyte, which has also developed stem cell–derived islets. In contrast to the Vertex product, which is fully differentiated and delivered to the liver, ViaCyte’s PEC-Direct product is comprised of stem cell-derived pancreatic islet progenitor cells that are implanted subcutaneously in a pouch, allowing for vascularization.

In a late-breaking poster at the annual scientific sessions of the American Diabetes Association in June 2021, ViaCyte reported on a patient given PEC-Direct. In that patient, stimulated C-peptide increased from 0.1 ng/mL at baseline to 0.8 ng/mL at week 39, and there was a drop in A1c from 7.4% to 6.6%, with no adverse events.

Immunosuppression: Which approach will come closer to cure?

Thus far, the requirement for lifelong immunosuppression has meant that any islet cell replacement approach, including with stem cell–derived islets, has been limited to use in people with type 1 diabetes who have hypoglycemic unawareness or severely unpredictable blood glucose levels.

Two broad approaches are simultaneously being explored to overcome the rejection problem: Encapsulation of the cells to protect them from the immune system, and genetic modification of the cells so that they don’t provoke the immune system in the first place.

In 2022, Vertex plans to file an investigational new drug application for an encapsulated islet cell program with the FDA.

Dr. Markmann believes the genetic modification approach is more promising. “I’m not a believer in encapsulation. I think the foreign body response is hard to overcome. I think the answer will ultimately be genetically modifying the [cell] lines. ... The cell could express something that would potentially turn off the lymphocytes or interfere with the lymphocytes trying to attack them.”

Moreover, he said, “you don’t have to get rid of immunosuppression completely. It’s all [a] risk-benefit [equation]. Even if you could get it down to a single less-toxic [immunosuppressive] agent that would be a huge step.”

Dr. Shapiro commented: “All efforts and eyes are laser-focused on developing cells or approaches that will allow transplantation of this kind of stem cell without any immunosuppression or with low-dose immunosuppression that could be regarded as being exceedingly low risk.”

“Then, and only then, I think we could offer this kind of treatment to children who are just diagnosed with diabetes or to [a bigger proportion of] patients with type 1 or type 2 diabetes. ... The science has to be done in a step-wise fashion,” he added.

Microencapsulation, Dr. Shapiro noted, “is a big challenge because the process of capturing the cells and putting them into a device is really injurious to their survival. ... That may or may not work.”

Dr. Shapiro and his Edmonton team are now embarking on a new trial with ViaCyte and CRISPR Therapeutics using gene-edited cells that contain two knock-in genes and two knock-out genes shown to be less immunogenic and anti-inflammatory in rodent models.

“They look to be promising. We’re going to start a first-in-human trial in the next few months with those cells to see if they really are able to withstand a transplant without the need for immunosuppression. That will be a very exciting trial in itself,” Dr. Shapiro said, noting that they expect to enroll the first patients in the next few months.

However, he cautioned, “first we have to make sure that the gene-edited product continues to function in patients in the way that the original product did, that the cells survive, and that the gene modifications are actually effective. ... Maybe other iterations will be needed.”

“I think, as we move forward, we will ultimately have a gene-edited stem cell–derived product that is immune evasive and will survive. So, I’m ... optimistic that this is not as long term as you might think, and it’s ... happening much more rapidly – at least in first-in-human trials to test safety and preliminary efficacy.”

Dr. Shapiro is a consultant for ViaCyte.

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

A novel investigational allogeneic stem cell–derived treatment resulted in near reversal of type 1 diabetes in a patient who had lived with the condition for about 40 years.

CIPhotos/Getty Images

The patient was the first in Vertex Pharmaceuticals’ phase 1/2 multicenter, single-arm, open-label clinical trial of the insulin-producing islet cell therapy VX-880 for patients with type 1 diabetes who have impaired hypoglycemic awareness and severe hypoglycemia.

The cells are delivered by infusion into the hepatic portal vein. As of now, chronic immunosuppression is required to prevent rejection, but several approaches are being studied to overcome the limitation.

“There’s hope that this is a real advance. It’s been long awaited, and it looks really encouraging,” James Markmann, MD, PhD, the surgeon who performed the procedure, told this news organization.

The use of insulin-producing pancreatic beta cells derived from human pluripotent stem cells, first reported in 2014 by a team at the Harvard Stem Cell Institute, Boston, is seen as a major advance over use of cadaveric donor islet cells because stem cell–derived islets are available in unlimited and uncontaminated supplies.

Cadaveric donor islets are being used in products such as donislecel (CellTrans), which was endorsed by a Food and Drug Administration advisory committee in the summer for the treatment of type 1 diabetes that can’t be managed with current therapies.

The patient in the Vertex trial isn’t the first reported stem cell–derived islet recipient with type 1 diabetes, but these cells are the first to be transplanted into the liver.

“This Vertex patient stood out because the reduction in insulin requirement ... was so striking,” noted Dr. Markmann, chief of the division of transplant surgery at Massachusetts General Hospital, Boston, who has been transplanting islet cells from cadaveric donors into humans via the hepatic portal vein for over 20 years.

“Nobody knew what to expect, as it hadn’t been done before, but certainly the results in this patient are better than what I would have expected from a deceased donor islet transplant,” he added.

Asked to comment, A.M. James Shapiro, MD, agreed. “I think the most important finding is that a stem cell–derived islet is now transplanted into the liver of a patient safely, so far,” he said in an interview.

Dr. Shapiro is clinical director of the living donor and islet cell transplantation programs at the University of Alberta, Edmonton. He pioneered cadaveric donor islet cell transplantation more than 20 years ago with the watershed Edmonton Protocol.

‘Impressive finding ... bodes well for ongoing efforts’

Vertex announced the result by press release. The company plans to transplant another 16 patients, staggering them over time at multiple centers.

The first patient was treated with a single infusion of VX-880 at half the target dose (per protocol for the first two study subjects), along with standard immunosuppressive therapy. At 90 days, the patient’s C-peptide, a measure of endogenous insulin secretion, rose from undetectable to 280 pmol/L fasting and 560 pmol/L post mixed-meal tolerance testing.

Over the same period, the patient’s hemoglobin A1c dropped from 8.6% at baseline to 7.2%. And within 7 days, the individual’s daily exogenous insulin requirement dropped from an average of 34 units to just 2.9 units, a 91% decrease.

The patient had experienced five severe hypoglycemic episodes in the year prior to transplant. They experienced some mild hypoglycemia soon after the procedure while insulin doses were being adjusted, but none thereafter. 

Dr. Shapiro said in an interview: “I was absolutely thrilled to see the first patient results with high C-peptide and a 91% reduction in insulin. That’s a pretty impressive finding for half dosing in the very first patient in a trial. I think it bodes really well for ongoing efforts in this area by Vertex and by others that have similar kinds of cells. It’s very exciting.”

However, he cautioned, “we do need some longer-term data to be sure there’s no off-target growth or other concerns. But based on the purity of this product, that risk is likely to be low.”

And he noted, “I think we still have to address the challenges of setting this process up. A huge amount of work has gone into manufacturing the cell product for a single patient. I think it remains to be seen whether the same technology can be delivered at a larger scale ... i.e., being able to treat hundreds or thousands of patients.”

A blog post on the website of diabetes charity JDRF called the result “outstanding.” “It’s a big deal,” they added. However, they also cautioned: “There are a few things to keep in mind while assessing the data. One is that these are only results from a single person. Data are needed from many more to fully evaluate the potential of this therapy. The second is that this person only received half the target dose of cells.”

Dr. Shapiro is working with another company, ViaCyte, which has also developed stem cell–derived islets. In contrast to the Vertex product, which is fully differentiated and delivered to the liver, ViaCyte’s PEC-Direct product is comprised of stem cell-derived pancreatic islet progenitor cells that are implanted subcutaneously in a pouch, allowing for vascularization.

In a late-breaking poster at the annual scientific sessions of the American Diabetes Association in June 2021, ViaCyte reported on a patient given PEC-Direct. In that patient, stimulated C-peptide increased from 0.1 ng/mL at baseline to 0.8 ng/mL at week 39, and there was a drop in A1c from 7.4% to 6.6%, with no adverse events.

Immunosuppression: Which approach will come closer to cure?

Thus far, the requirement for lifelong immunosuppression has meant that any islet cell replacement approach, including with stem cell–derived islets, has been limited to use in people with type 1 diabetes who have hypoglycemic unawareness or severely unpredictable blood glucose levels.

Two broad approaches are simultaneously being explored to overcome the rejection problem: Encapsulation of the cells to protect them from the immune system, and genetic modification of the cells so that they don’t provoke the immune system in the first place.

In 2022, Vertex plans to file an investigational new drug application for an encapsulated islet cell program with the FDA.

Dr. Markmann believes the genetic modification approach is more promising. “I’m not a believer in encapsulation. I think the foreign body response is hard to overcome. I think the answer will ultimately be genetically modifying the [cell] lines. ... The cell could express something that would potentially turn off the lymphocytes or interfere with the lymphocytes trying to attack them.”

Moreover, he said, “you don’t have to get rid of immunosuppression completely. It’s all [a] risk-benefit [equation]. Even if you could get it down to a single less-toxic [immunosuppressive] agent that would be a huge step.”

Dr. Shapiro commented: “All efforts and eyes are laser-focused on developing cells or approaches that will allow transplantation of this kind of stem cell without any immunosuppression or with low-dose immunosuppression that could be regarded as being exceedingly low risk.”

“Then, and only then, I think we could offer this kind of treatment to children who are just diagnosed with diabetes or to [a bigger proportion of] patients with type 1 or type 2 diabetes. ... The science has to be done in a step-wise fashion,” he added.

Microencapsulation, Dr. Shapiro noted, “is a big challenge because the process of capturing the cells and putting them into a device is really injurious to their survival. ... That may or may not work.”

Dr. Shapiro and his Edmonton team are now embarking on a new trial with ViaCyte and CRISPR Therapeutics using gene-edited cells that contain two knock-in genes and two knock-out genes shown to be less immunogenic and anti-inflammatory in rodent models.

“They look to be promising. We’re going to start a first-in-human trial in the next few months with those cells to see if they really are able to withstand a transplant without the need for immunosuppression. That will be a very exciting trial in itself,” Dr. Shapiro said, noting that they expect to enroll the first patients in the next few months.

However, he cautioned, “first we have to make sure that the gene-edited product continues to function in patients in the way that the original product did, that the cells survive, and that the gene modifications are actually effective. ... Maybe other iterations will be needed.”

“I think, as we move forward, we will ultimately have a gene-edited stem cell–derived product that is immune evasive and will survive. So, I’m ... optimistic that this is not as long term as you might think, and it’s ... happening much more rapidly – at least in first-in-human trials to test safety and preliminary efficacy.”

Dr. Shapiro is a consultant for ViaCyte.

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

Nearly two-thirds of Americans are not confident that they understood their doctor’s recommendations and the health information they discussed with their doctor after a visit, according to a new survey.

Confusion over health information and doctor advice is even higher among people who care for patients than among those who don’t provide care to their loved ones, the nationally representative survey from the AHIMA Foundation found.

The survey also shows that 80% of Americans – and an even higher portion of caregivers – are likely to research medical recommendations online after a doctor’s visit. But 1 in 4 people don’t know how to access their own medical records or find it difficult to do so.

The findings reflect the same low level of health literacy in the U.S. population that earlier surveys did. The results also indicate that little has changed since the Department of Health and Human Services released a National Action Plan to Improve Health Literacy in 2010.

That plan emphasized the need to develop and share accurate health information that helps people make decisions; to promote changes in the health care system that improve health information, communication, informed decision-making, and access to health services; and to increase the sharing and use of evidence-based health literacy practices.

According to the AHIMA Foundation report, 62% of Americans are not sure they understand their doctor’s advice and the health information discussed during a visit. Twenty-four percent say they don’t comprehend any of it, and 31% can’t remember what was said during the visit. Fifteen percent of those surveyed said they were more confused about their health than they were before the encounter with their doctor.
 

Caregivers have special issues

Forty-three percent of Americans are caregivers, the report notes, and 91% of those play an active role in managing someone else’s health. Millennials (65%) and Gen Xers (50%) are significantly more likely than Gen Zers (39%) and Boomers (20%) to be a caregiver.

Most caregivers have concerns about their loved ones’ ability to manage their own health. Most of them believe that doctors provide enough information, but 38% don’t believe a doctor can communicate effectively with the patient if the caregiver is not present.

Forty-three percent of caretakers don’t think their loved ones can understand medical information on their own. On the other hand, caregivers are more likely than people who don’t provide care to say the doctor confused them and to research the doctor’s advice after an appointment.

For many patients and caregivers, communications break down when they are with their health care provider. Twenty-two percent of Americans say they do not feel comfortable asking their doctor certain health questions. This inability to have a satisfactory dialogue with their doctor means that many patients leave their appointments without getting clear answers to their questions (24%) or without having an opportunity to ask any questions at all (17%).

This is not surprising, considering that a 2018 study found that doctors spend only 11 seconds, on average, listening to patients before interrupting them.
 

Depending on the internet

Overall, the AHIMA survey found, 42% of Americans research their doctor’s recommendations after an appointment. A higher percentage of caregivers than noncaregiver peers do so (47% vs. 38%). Eighty percent of respondents say they are “likely” to research their doctor’s advice online after a visit.

When they have a medical problem or a question about their condition, just as many Americans (59%) turn to the internet for an answer as contact their doctor directly, the survey found. Twenty-nine percent of the respondents consult friends, family, or colleagues; 23% look up medical records if they’re easily accessible; 19% ask pharmacists for advice; and 6% call an unspecified 800 number.

Americans feel secure in the health information they find on the internet. Among those who go online to look up information, 86% are confident that it is credible. And 42% report feeling relieved that they can find a lot of information about their health concerns. Respondents also say that the information they gather allows them to feel more confident in their doctor’s recommendations (35%) and that they feel better after having learned more on the internet than their doctor had told them (39%). Men are more likely than women to say that their confidence in their doctor’s recommendations increased after doing online research (40% vs. 30%).
 

Access to health records

Access to medical records would help people better understand their condition or diagnosis. But nearly half of Americans (48%) admit they don’t usually review their medical records until long after an appointment, and 52% say they rarely access their records at all.

One in four Americans say that they don’t know where to go to access their health information or that they didn’t find the process easy. More than half of those who have never had to find their records think the process would be difficult if they had to try.

Eighty-one percent of Americans use an online platform or portal to access their medical records or health information. Two-thirds of Americans who use an online portal trust that their medical information is kept safe and not shared with other people or organizations.

Four in five respondents agree that if they had access to all of their health information, including medical records, recommendations, conditions, and test results, they’d see an improvement in their health management. Fifty-nine percent of them believe they’d also be more confident about understanding their health, and 47% say they’d have greater trust in their doctor’s recommendations. Higher percentages of caregivers than noncaregivers say the same.

Younger people, those with a high school degree or less, and those who earn less than $50,000 are less likely than older, better educated, and more affluent people to understand their doctor’s health information and to ask questions of their providers.

People of color struggle with their relationships with doctors, are less satisfied than white people with the information they receive during visits, and are more likely than white peers to feel that if they had access to all their health information, they’d manage their health better and be more confident in their doctors’ recommendations, the survey found.

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

Nearly two-thirds of Americans are not confident that they understood their doctor’s recommendations and the health information they discussed with their doctor after a visit, according to a new survey.

Confusion over health information and doctor advice is even higher among people who care for patients than among those who don’t provide care to their loved ones, the nationally representative survey from the AHIMA Foundation found.

The survey also shows that 80% of Americans – and an even higher portion of caregivers – are likely to research medical recommendations online after a doctor’s visit. But 1 in 4 people don’t know how to access their own medical records or find it difficult to do so.

The findings reflect the same low level of health literacy in the U.S. population that earlier surveys did. The results also indicate that little has changed since the Department of Health and Human Services released a National Action Plan to Improve Health Literacy in 2010.

That plan emphasized the need to develop and share accurate health information that helps people make decisions; to promote changes in the health care system that improve health information, communication, informed decision-making, and access to health services; and to increase the sharing and use of evidence-based health literacy practices.

According to the AHIMA Foundation report, 62% of Americans are not sure they understand their doctor’s advice and the health information discussed during a visit. Twenty-four percent say they don’t comprehend any of it, and 31% can’t remember what was said during the visit. Fifteen percent of those surveyed said they were more confused about their health than they were before the encounter with their doctor.
 

Caregivers have special issues

Forty-three percent of Americans are caregivers, the report notes, and 91% of those play an active role in managing someone else’s health. Millennials (65%) and Gen Xers (50%) are significantly more likely than Gen Zers (39%) and Boomers (20%) to be a caregiver.

Most caregivers have concerns about their loved ones’ ability to manage their own health. Most of them believe that doctors provide enough information, but 38% don’t believe a doctor can communicate effectively with the patient if the caregiver is not present.

Forty-three percent of caretakers don’t think their loved ones can understand medical information on their own. On the other hand, caregivers are more likely than people who don’t provide care to say the doctor confused them and to research the doctor’s advice after an appointment.

For many patients and caregivers, communications break down when they are with their health care provider. Twenty-two percent of Americans say they do not feel comfortable asking their doctor certain health questions. This inability to have a satisfactory dialogue with their doctor means that many patients leave their appointments without getting clear answers to their questions (24%) or without having an opportunity to ask any questions at all (17%).

This is not surprising, considering that a 2018 study found that doctors spend only 11 seconds, on average, listening to patients before interrupting them.
 

Depending on the internet

Overall, the AHIMA survey found, 42% of Americans research their doctor’s recommendations after an appointment. A higher percentage of caregivers than noncaregiver peers do so (47% vs. 38%). Eighty percent of respondents say they are “likely” to research their doctor’s advice online after a visit.

When they have a medical problem or a question about their condition, just as many Americans (59%) turn to the internet for an answer as contact their doctor directly, the survey found. Twenty-nine percent of the respondents consult friends, family, or colleagues; 23% look up medical records if they’re easily accessible; 19% ask pharmacists for advice; and 6% call an unspecified 800 number.

Americans feel secure in the health information they find on the internet. Among those who go online to look up information, 86% are confident that it is credible. And 42% report feeling relieved that they can find a lot of information about their health concerns. Respondents also say that the information they gather allows them to feel more confident in their doctor’s recommendations (35%) and that they feel better after having learned more on the internet than their doctor had told them (39%). Men are more likely than women to say that their confidence in their doctor’s recommendations increased after doing online research (40% vs. 30%).
 

Access to health records

Access to medical records would help people better understand their condition or diagnosis. But nearly half of Americans (48%) admit they don’t usually review their medical records until long after an appointment, and 52% say they rarely access their records at all.

One in four Americans say that they don’t know where to go to access their health information or that they didn’t find the process easy. More than half of those who have never had to find their records think the process would be difficult if they had to try.

Eighty-one percent of Americans use an online platform or portal to access their medical records or health information. Two-thirds of Americans who use an online portal trust that their medical information is kept safe and not shared with other people or organizations.

Four in five respondents agree that if they had access to all of their health information, including medical records, recommendations, conditions, and test results, they’d see an improvement in their health management. Fifty-nine percent of them believe they’d also be more confident about understanding their health, and 47% say they’d have greater trust in their doctor’s recommendations. Higher percentages of caregivers than noncaregivers say the same.

Younger people, those with a high school degree or less, and those who earn less than $50,000 are less likely than older, better educated, and more affluent people to understand their doctor’s health information and to ask questions of their providers.

People of color struggle with their relationships with doctors, are less satisfied than white people with the information they receive during visits, and are more likely than white peers to feel that if they had access to all their health information, they’d manage their health better and be more confident in their doctors’ recommendations, the survey found.

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

Nearly two-thirds of Americans are not confident that they understood their doctor’s recommendations and the health information they discussed with their doctor after a visit, according to a new survey.

Confusion over health information and doctor advice is even higher among people who care for patients than among those who don’t provide care to their loved ones, the nationally representative survey from the AHIMA Foundation found.

The survey also shows that 80% of Americans – and an even higher portion of caregivers – are likely to research medical recommendations online after a doctor’s visit. But 1 in 4 people don’t know how to access their own medical records or find it difficult to do so.

The findings reflect the same low level of health literacy in the U.S. population that earlier surveys did. The results also indicate that little has changed since the Department of Health and Human Services released a National Action Plan to Improve Health Literacy in 2010.

That plan emphasized the need to develop and share accurate health information that helps people make decisions; to promote changes in the health care system that improve health information, communication, informed decision-making, and access to health services; and to increase the sharing and use of evidence-based health literacy practices.

According to the AHIMA Foundation report, 62% of Americans are not sure they understand their doctor’s advice and the health information discussed during a visit. Twenty-four percent say they don’t comprehend any of it, and 31% can’t remember what was said during the visit. Fifteen percent of those surveyed said they were more confused about their health than they were before the encounter with their doctor.
 

Caregivers have special issues

Forty-three percent of Americans are caregivers, the report notes, and 91% of those play an active role in managing someone else’s health. Millennials (65%) and Gen Xers (50%) are significantly more likely than Gen Zers (39%) and Boomers (20%) to be a caregiver.

Most caregivers have concerns about their loved ones’ ability to manage their own health. Most of them believe that doctors provide enough information, but 38% don’t believe a doctor can communicate effectively with the patient if the caregiver is not present.

Forty-three percent of caretakers don’t think their loved ones can understand medical information on their own. On the other hand, caregivers are more likely than people who don’t provide care to say the doctor confused them and to research the doctor’s advice after an appointment.

For many patients and caregivers, communications break down when they are with their health care provider. Twenty-two percent of Americans say they do not feel comfortable asking their doctor certain health questions. This inability to have a satisfactory dialogue with their doctor means that many patients leave their appointments without getting clear answers to their questions (24%) or without having an opportunity to ask any questions at all (17%).

This is not surprising, considering that a 2018 study found that doctors spend only 11 seconds, on average, listening to patients before interrupting them.
 

Depending on the internet

Overall, the AHIMA survey found, 42% of Americans research their doctor’s recommendations after an appointment. A higher percentage of caregivers than noncaregiver peers do so (47% vs. 38%). Eighty percent of respondents say they are “likely” to research their doctor’s advice online after a visit.

When they have a medical problem or a question about their condition, just as many Americans (59%) turn to the internet for an answer as contact their doctor directly, the survey found. Twenty-nine percent of the respondents consult friends, family, or colleagues; 23% look up medical records if they’re easily accessible; 19% ask pharmacists for advice; and 6% call an unspecified 800 number.

Americans feel secure in the health information they find on the internet. Among those who go online to look up information, 86% are confident that it is credible. And 42% report feeling relieved that they can find a lot of information about their health concerns. Respondents also say that the information they gather allows them to feel more confident in their doctor’s recommendations (35%) and that they feel better after having learned more on the internet than their doctor had told them (39%). Men are more likely than women to say that their confidence in their doctor’s recommendations increased after doing online research (40% vs. 30%).
 

Access to health records

Access to medical records would help people better understand their condition or diagnosis. But nearly half of Americans (48%) admit they don’t usually review their medical records until long after an appointment, and 52% say they rarely access their records at all.

One in four Americans say that they don’t know where to go to access their health information or that they didn’t find the process easy. More than half of those who have never had to find their records think the process would be difficult if they had to try.

Eighty-one percent of Americans use an online platform or portal to access their medical records or health information. Two-thirds of Americans who use an online portal trust that their medical information is kept safe and not shared with other people or organizations.

Four in five respondents agree that if they had access to all of their health information, including medical records, recommendations, conditions, and test results, they’d see an improvement in their health management. Fifty-nine percent of them believe they’d also be more confident about understanding their health, and 47% say they’d have greater trust in their doctor’s recommendations. Higher percentages of caregivers than noncaregivers say the same.

Younger people, those with a high school degree or less, and those who earn less than $50,000 are less likely than older, better educated, and more affluent people to understand their doctor’s health information and to ask questions of their providers.

People of color struggle with their relationships with doctors, are less satisfied than white people with the information they receive during visits, and are more likely than white peers to feel that if they had access to all their health information, they’d manage their health better and be more confident in their doctors’ recommendations, the survey found.

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

The Food and Drug Administration has authorized Pfizer’s COVID-19 vaccine for children ages 5 to 11, which means vaccines could be available to school-aged children starting next week.

The move brings families with young children a step closer to resuming their normal activities, and it should help further slow transmission of the coronavirus virus in the United States.

States have already placed their orders for initial doses of the vaccines. The Oct. 29 FDA authorization triggers the shipment of millions of doses to pediatricians, family practice doctors, children’s hospitals, community health centers, and pharmacies.

Next, a panel of experts known as the Advisory Committee on Immunization Practices, or ACIP, will meet Nov. 2 to vote on recommendations for use of the vaccine.

As soon as the Centers for Disease Control and Prevention’s director signs off on those recommendations, children can get the shots, perhaps as early as Nov. 3.

Pfizer’s vaccine for children is 10 micrograms, or one-third of the dose given to teens and adults. Kids get two doses of the vaccine 3 weeks apart. In clinical trials, the most common side effects were pain at the injection site, fatigue, and headache. These side effects were mild and disappeared quickly. There were no serious adverse events detected in the studies, which included about 3,100 children. In one study, the vaccine was 90% effective at preventing COVID-19 infections with symptoms in younger children.

There are about 28 million children in the United States between the ages of 5 and 12.

“As a mother and a physician, I know that parents, caregivers, school staff, and children have been waiting for today’s authorization. Vaccinating younger children against COVID-19 will bring us closer to returning to a sense of normalcy,” Acting FDA Commissioner Janet Woodcock, MD, said in an FDA news release.

“Our comprehensive and rigorous evaluation of the data pertaining to the vaccine’s safety and effectiveness should help assure parents and guardians that this vaccine meets our high standards,” she said.

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

The Food and Drug Administration has authorized Pfizer’s COVID-19 vaccine for children ages 5 to 11, which means vaccines could be available to school-aged children starting next week.

The move brings families with young children a step closer to resuming their normal activities, and it should help further slow transmission of the coronavirus virus in the United States.

States have already placed their orders for initial doses of the vaccines. The Oct. 29 FDA authorization triggers the shipment of millions of doses to pediatricians, family practice doctors, children’s hospitals, community health centers, and pharmacies.

Next, a panel of experts known as the Advisory Committee on Immunization Practices, or ACIP, will meet Nov. 2 to vote on recommendations for use of the vaccine.

As soon as the Centers for Disease Control and Prevention’s director signs off on those recommendations, children can get the shots, perhaps as early as Nov. 3.

Pfizer’s vaccine for children is 10 micrograms, or one-third of the dose given to teens and adults. Kids get two doses of the vaccine 3 weeks apart. In clinical trials, the most common side effects were pain at the injection site, fatigue, and headache. These side effects were mild and disappeared quickly. There were no serious adverse events detected in the studies, which included about 3,100 children. In one study, the vaccine was 90% effective at preventing COVID-19 infections with symptoms in younger children.

There are about 28 million children in the United States between the ages of 5 and 12.

“As a mother and a physician, I know that parents, caregivers, school staff, and children have been waiting for today’s authorization. Vaccinating younger children against COVID-19 will bring us closer to returning to a sense of normalcy,” Acting FDA Commissioner Janet Woodcock, MD, said in an FDA news release.

“Our comprehensive and rigorous evaluation of the data pertaining to the vaccine’s safety and effectiveness should help assure parents and guardians that this vaccine meets our high standards,” she said.

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

The Food and Drug Administration has authorized Pfizer’s COVID-19 vaccine for children ages 5 to 11, which means vaccines could be available to school-aged children starting next week.

The move brings families with young children a step closer to resuming their normal activities, and it should help further slow transmission of the coronavirus virus in the United States.

States have already placed their orders for initial doses of the vaccines. The Oct. 29 FDA authorization triggers the shipment of millions of doses to pediatricians, family practice doctors, children’s hospitals, community health centers, and pharmacies.

Next, a panel of experts known as the Advisory Committee on Immunization Practices, or ACIP, will meet Nov. 2 to vote on recommendations for use of the vaccine.

As soon as the Centers for Disease Control and Prevention’s director signs off on those recommendations, children can get the shots, perhaps as early as Nov. 3.

Pfizer’s vaccine for children is 10 micrograms, or one-third of the dose given to teens and adults. Kids get two doses of the vaccine 3 weeks apart. In clinical trials, the most common side effects were pain at the injection site, fatigue, and headache. These side effects were mild and disappeared quickly. There were no serious adverse events detected in the studies, which included about 3,100 children. In one study, the vaccine was 90% effective at preventing COVID-19 infections with symptoms in younger children.

There are about 28 million children in the United States between the ages of 5 and 12.

“As a mother and a physician, I know that parents, caregivers, school staff, and children have been waiting for today’s authorization. Vaccinating younger children against COVID-19 will bring us closer to returning to a sense of normalcy,” Acting FDA Commissioner Janet Woodcock, MD, said in an FDA news release.

“Our comprehensive and rigorous evaluation of the data pertaining to the vaccine’s safety and effectiveness should help assure parents and guardians that this vaccine meets our high standards,” she said.

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

Using sunscreen and following other sun-protective behaviors such as wearing long sleeves or staying in the shade do not decrease bone mineral density overall or increase the risk of osteoporotic fracture, according to a new study that included more than 3,000 men and women.

Aja Koska/Getty Images

“We have objective data for the first time, and in a large-scale representative population of the U.S. adults, to indicate sun protection is not associated with negative bone-related outcomes,” said study lead author Mohsen Afarideh, MD, MPH, a postdoctoral research fellow at the autoimmune skin diseases unit at the University of Pennsylvania, Philadelphia.

The study, published online in JAMA Dermatology, goes a step further than previous research by others that has found sunscreen use does not compromise vitamin D synthesis and has little effect on circulating 25-hydroxyvitamin D levels.

In the new study, researchers looked at three sun-protective behaviors – sunscreen use, staying in the shade, wearing long sleeves – and their effects on bone mineral density and the risk of fractures.

While the effects of sun-protective habits on blood levels of vitamin D and BMD scores are important, ‘’what we are more interested to know is if the sun-protective behaviors actually cause or increase the risk of fracture,” Dr. Afarideh said in an interview. “The answer to that is a firm ‘No.’ These data are very reassuring and will help clinicians to keep recommending sun protection to the public.”

Study details

Dr. Afarideh and his colleagues from the Mayo Clinic in Rochester, Minn., looked at data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2018, obtaining final information on 3,403 men and women, ages 20-59, who completed a dermatology questionnaire The men and women reported on the three sun-protective habits, and noted whether they followed these practices always or most of the time, sometimes, or never or rarely.

The frequency of the three behaviors was not widespread. Frequent staying in the shade was reported by 31.6% of the sample, wearing long sleeves by 11.8%, and sunscreen use by 26.1%.

The researchers also had data on the participants’ bone mineral density (BMD) scores along with dietary information such as milk consumption, vitamin D supplement use, taking steroid drugs, and exercise activity.

“Moderate sunscreen use was linked with a slightly lower lumbar BMD score,” Dr. Afarideh said, which was “the only significant association that could be interpreted as concerning.” And this was more likely to be seen in older respondents, he said.

However, otherwise they found the practice of the three behaviors was not associated with lower total or site-specific BMD z scores, nor was it linked with an increased risk of osteoporotic fractures. (The BMD z score compares an individual’s bone density to the average bone density of someone their same age and gender.)

The focus on fracture risk is the more important outcome, Dr. Afarideh said. And they found no increased risk overall of osteoporotic fractures in those who practiced sun-protective behaviors.

Moderate to frequent staying in the shade was actually linked with a reduced prevalence of spine fractures in the multivariate model (odds ratio, 0.19; 95% confidence interval, 0.04-0.86, P = .02). The researchers say that may be attributable to these respondents also being careful in other areas of life, such as avoiding falls and not participating in high-risk activities that would increase the chance of fractures. “However, this is just an assumption,” Dr. Afarideh said.

Expert perspectives

Other dermatologists not involved in the new research said the study results provide some “real-world” information that’s valuable for clinicians to share with patients.

“I think this is an important study on multiple levels,” said Henry W. Lim, MD, a former president of the American Academy of Dermatology who is a member of the department of dermatology and senior vice president of academic affairs at Henry Ford Health System, Detroit. “It is a well-done study, involving a large number. It is a real-life situation, asking people their photo protective behaviors and then looking at their bone mineral density.” The bottom line, he said: “Bone health is not affected by photo protection habits in real life.”

The findings are important but not surprising, said Antony R. Young, PhD, emeritus professor of experimental photobiology at St. John’s Institute of Dermatology, King’s College, London, who has researched sunscreens and vitamin D status. “My study showed that correct sunscreen use, albeit with a relatively low SPF of 15, did prevent sunburn in a high UVR [ultraviolet radiation] environment but did allow very good vitamin D synthesis. I think this is because the necessary dose of UVB is very low.”

Michele Green, MD, a New York dermatologist and clinical staff member at Lenox Hill Hospital there, said she often hears concerns about bone health from patients. “Every week, patients ask, ‘Why would I wear sunblock? Don’t I need sun for bone health? Don’t I need it for vitamin D?’’’

Now, she said, ‘’Dermatologists can point to the study and say ‘Don’t worry.’ It clarifies that using sunscreen won’t cause you to have osteoporosis.’’

Dr. Afarideh, who was a postdoctoral research fellow at the Mayo Clinic, and his coauthors, Megha M. Tollefson, MD, and Julio C. Sartori-Valinotti, of the Mayo Clinic, and Dr. Green had no disclosures. Dr. Lim and Dr. Young consult for the sunscreen industry.

Using sunscreen and following other sun-protective behaviors such as wearing long sleeves or staying in the shade do not decrease bone mineral density overall or increase the risk of osteoporotic fracture, according to a new study that included more than 3,000 men and women.

Aja Koska/Getty Images

“We have objective data for the first time, and in a large-scale representative population of the U.S. adults, to indicate sun protection is not associated with negative bone-related outcomes,” said study lead author Mohsen Afarideh, MD, MPH, a postdoctoral research fellow at the autoimmune skin diseases unit at the University of Pennsylvania, Philadelphia.

The study, published online in JAMA Dermatology, goes a step further than previous research by others that has found sunscreen use does not compromise vitamin D synthesis and has little effect on circulating 25-hydroxyvitamin D levels.

In the new study, researchers looked at three sun-protective behaviors – sunscreen use, staying in the shade, wearing long sleeves – and their effects on bone mineral density and the risk of fractures.

While the effects of sun-protective habits on blood levels of vitamin D and BMD scores are important, ‘’what we are more interested to know is if the sun-protective behaviors actually cause or increase the risk of fracture,” Dr. Afarideh said in an interview. “The answer to that is a firm ‘No.’ These data are very reassuring and will help clinicians to keep recommending sun protection to the public.”

Study details

Dr. Afarideh and his colleagues from the Mayo Clinic in Rochester, Minn., looked at data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2018, obtaining final information on 3,403 men and women, ages 20-59, who completed a dermatology questionnaire The men and women reported on the three sun-protective habits, and noted whether they followed these practices always or most of the time, sometimes, or never or rarely.

The frequency of the three behaviors was not widespread. Frequent staying in the shade was reported by 31.6% of the sample, wearing long sleeves by 11.8%, and sunscreen use by 26.1%.

The researchers also had data on the participants’ bone mineral density (BMD) scores along with dietary information such as milk consumption, vitamin D supplement use, taking steroid drugs, and exercise activity.

“Moderate sunscreen use was linked with a slightly lower lumbar BMD score,” Dr. Afarideh said, which was “the only significant association that could be interpreted as concerning.” And this was more likely to be seen in older respondents, he said.

However, otherwise they found the practice of the three behaviors was not associated with lower total or site-specific BMD z scores, nor was it linked with an increased risk of osteoporotic fractures. (The BMD z score compares an individual’s bone density to the average bone density of someone their same age and gender.)

The focus on fracture risk is the more important outcome, Dr. Afarideh said. And they found no increased risk overall of osteoporotic fractures in those who practiced sun-protective behaviors.

Moderate to frequent staying in the shade was actually linked with a reduced prevalence of spine fractures in the multivariate model (odds ratio, 0.19; 95% confidence interval, 0.04-0.86, P = .02). The researchers say that may be attributable to these respondents also being careful in other areas of life, such as avoiding falls and not participating in high-risk activities that would increase the chance of fractures. “However, this is just an assumption,” Dr. Afarideh said.

Expert perspectives

Other dermatologists not involved in the new research said the study results provide some “real-world” information that’s valuable for clinicians to share with patients.

“I think this is an important study on multiple levels,” said Henry W. Lim, MD, a former president of the American Academy of Dermatology who is a member of the department of dermatology and senior vice president of academic affairs at Henry Ford Health System, Detroit. “It is a well-done study, involving a large number. It is a real-life situation, asking people their photo protective behaviors and then looking at their bone mineral density.” The bottom line, he said: “Bone health is not affected by photo protection habits in real life.”

The findings are important but not surprising, said Antony R. Young, PhD, emeritus professor of experimental photobiology at St. John’s Institute of Dermatology, King’s College, London, who has researched sunscreens and vitamin D status. “My study showed that correct sunscreen use, albeit with a relatively low SPF of 15, did prevent sunburn in a high UVR [ultraviolet radiation] environment but did allow very good vitamin D synthesis. I think this is because the necessary dose of UVB is very low.”

Michele Green, MD, a New York dermatologist and clinical staff member at Lenox Hill Hospital there, said she often hears concerns about bone health from patients. “Every week, patients ask, ‘Why would I wear sunblock? Don’t I need sun for bone health? Don’t I need it for vitamin D?’’’

Now, she said, ‘’Dermatologists can point to the study and say ‘Don’t worry.’ It clarifies that using sunscreen won’t cause you to have osteoporosis.’’

Dr. Afarideh, who was a postdoctoral research fellow at the Mayo Clinic, and his coauthors, Megha M. Tollefson, MD, and Julio C. Sartori-Valinotti, of the Mayo Clinic, and Dr. Green had no disclosures. Dr. Lim and Dr. Young consult for the sunscreen industry.

Using sunscreen and following other sun-protective behaviors such as wearing long sleeves or staying in the shade do not decrease bone mineral density overall or increase the risk of osteoporotic fracture, according to a new study that included more than 3,000 men and women.

Aja Koska/Getty Images

“We have objective data for the first time, and in a large-scale representative population of the U.S. adults, to indicate sun protection is not associated with negative bone-related outcomes,” said study lead author Mohsen Afarideh, MD, MPH, a postdoctoral research fellow at the autoimmune skin diseases unit at the University of Pennsylvania, Philadelphia.

The study, published online in JAMA Dermatology, goes a step further than previous research by others that has found sunscreen use does not compromise vitamin D synthesis and has little effect on circulating 25-hydroxyvitamin D levels.

In the new study, researchers looked at three sun-protective behaviors – sunscreen use, staying in the shade, wearing long sleeves – and their effects on bone mineral density and the risk of fractures.

While the effects of sun-protective habits on blood levels of vitamin D and BMD scores are important, ‘’what we are more interested to know is if the sun-protective behaviors actually cause or increase the risk of fracture,” Dr. Afarideh said in an interview. “The answer to that is a firm ‘No.’ These data are very reassuring and will help clinicians to keep recommending sun protection to the public.”

Study details

Dr. Afarideh and his colleagues from the Mayo Clinic in Rochester, Minn., looked at data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2018, obtaining final information on 3,403 men and women, ages 20-59, who completed a dermatology questionnaire The men and women reported on the three sun-protective habits, and noted whether they followed these practices always or most of the time, sometimes, or never or rarely.

The frequency of the three behaviors was not widespread. Frequent staying in the shade was reported by 31.6% of the sample, wearing long sleeves by 11.8%, and sunscreen use by 26.1%.

The researchers also had data on the participants’ bone mineral density (BMD) scores along with dietary information such as milk consumption, vitamin D supplement use, taking steroid drugs, and exercise activity.

“Moderate sunscreen use was linked with a slightly lower lumbar BMD score,” Dr. Afarideh said, which was “the only significant association that could be interpreted as concerning.” And this was more likely to be seen in older respondents, he said.

However, otherwise they found the practice of the three behaviors was not associated with lower total or site-specific BMD z scores, nor was it linked with an increased risk of osteoporotic fractures. (The BMD z score compares an individual’s bone density to the average bone density of someone their same age and gender.)

The focus on fracture risk is the more important outcome, Dr. Afarideh said. And they found no increased risk overall of osteoporotic fractures in those who practiced sun-protective behaviors.

Moderate to frequent staying in the shade was actually linked with a reduced prevalence of spine fractures in the multivariate model (odds ratio, 0.19; 95% confidence interval, 0.04-0.86, P = .02). The researchers say that may be attributable to these respondents also being careful in other areas of life, such as avoiding falls and not participating in high-risk activities that would increase the chance of fractures. “However, this is just an assumption,” Dr. Afarideh said.

Expert perspectives

Other dermatologists not involved in the new research said the study results provide some “real-world” information that’s valuable for clinicians to share with patients.

“I think this is an important study on multiple levels,” said Henry W. Lim, MD, a former president of the American Academy of Dermatology who is a member of the department of dermatology and senior vice president of academic affairs at Henry Ford Health System, Detroit. “It is a well-done study, involving a large number. It is a real-life situation, asking people their photo protective behaviors and then looking at their bone mineral density.” The bottom line, he said: “Bone health is not affected by photo protection habits in real life.”

The findings are important but not surprising, said Antony R. Young, PhD, emeritus professor of experimental photobiology at St. John’s Institute of Dermatology, King’s College, London, who has researched sunscreens and vitamin D status. “My study showed that correct sunscreen use, albeit with a relatively low SPF of 15, did prevent sunburn in a high UVR [ultraviolet radiation] environment but did allow very good vitamin D synthesis. I think this is because the necessary dose of UVB is very low.”

Michele Green, MD, a New York dermatologist and clinical staff member at Lenox Hill Hospital there, said she often hears concerns about bone health from patients. “Every week, patients ask, ‘Why would I wear sunblock? Don’t I need sun for bone health? Don’t I need it for vitamin D?’’’

Now, she said, ‘’Dermatologists can point to the study and say ‘Don’t worry.’ It clarifies that using sunscreen won’t cause you to have osteoporosis.’’

Dr. Afarideh, who was a postdoctoral research fellow at the Mayo Clinic, and his coauthors, Megha M. Tollefson, MD, and Julio C. Sartori-Valinotti, of the Mayo Clinic, and Dr. Green had no disclosures. Dr. Lim and Dr. Young consult for the sunscreen industry.

A “green” adaptation to the traditional Mediterranean diet could help improve insulin sensitivity and reduce visceral fat by increasing levels of ghrelin, the “hunger hormone,” new research suggests.

The current study is a new analysis of data from the randomized DIRECT-PLUS trial, which showed that the addition of green tea and substitution of red meat for a plant-based (Mankai) protein shake at dinner – dubbed the “green Mediterranean diet” – resulted in further improved cardiometabolic benefits compared with the traditional Mediterranean diet among people with baseline abdominal obesity and/or dyslipidemia, according to the researchers.

They specifically looked at ghrelin, nicknamed the “hunger hormone,” a neuropeptide mainly secreted by the gastric epithelium. It acts on the pituitary gland to release growth hormone. Ghrelin concentrations increase during fasting and decrease after eating. Lower levels are associated with insulin resistance and obesity.

Fasting ghrelin levels were elevated with weight loss, but those increases were associated with improved insulin sensitivity and regression of visceral adipose tissue even beyond weight loss.

Although the caloric restriction and weight loss were comparable with the two Mediterranean diets, the green Mediterranean diet group had double the increase in fasting ghrelin as the traditional Mediterranean diet group, the researchers point out in their report .
 

‘Hypothesis-generating’ study pushes many hot topic buttons

“This specific study is the first to show that ghrelin levels play an important role in metabolic adaptation to a dietary or lifestyle intervention and that ghrelin is an important player in the axis of adiposity, insulin resistance, and metabolic health,” lead researcher Gal Tsaban, MD, told this news organization.

The data partially explain some of the prior beneficial effects seen with the Green Mediterranean diet, even after adjustment for weight loss, he explained, noting that the revised version of the diet “could be considered as an alternative lifestyle intervention with possible metabolic benefits even beyond the Mediterranean diet, which is what we currently recommend for patients.”

Asked for comment, Christopher Gardner, PhD, was not as enthusiastic.

He took issue with the fact that ghrelin wasn’t a primary or even a prespecified secondary outcome of the DIRECT-PLUS trial and because the specific plant-based ingredients of the green Mediterranean diet used in the study may not be widely available or desirable and therefore limit the study’s generalizability.

Dr. Gardner, who is director of nutrition studies at the Stanford Prevention Research Center, California, also said: “They’re tying lots of interesting things together. The Mediterranean diet is a cool thing, ghrelin is a cool thing, and insulin resistance is hugely important in this day and age, even though we don’t all agree on how to measure it.”

“But it gets tough as you try to link them all together for an exploratory outcome. ... To me it’s an interesting hypothesis-generating study that pushes a lot of interesting buttons that are hot topics in the field.”
 

Green Mediterranean diet led to higher ghrelin, metabolic benefits

In DIRECT-PLUS, a total of 294 adults (88% men) older than 30 years of age with abdominal obesity (waist circumference >102 cm for men or >88 cm for women), or dyslipidemia (triglycerides >150 mg/dL and HDL-cholesterol ≤40 mg/dL for men or ≤50 mg/dL for women) were included. Half had prediabetes or type 2 diabetes.

They were randomized to one of three diets: a diet based on standard healthy dietary guidelines; a traditional Mediterranean diet low in simple carbohydrates, rich in vegetables, with poultry and fish replacing beef and lamb and 28 g/day of walnuts; or the Green-Mediterranean diet, including 3-4 cups/day of green tea and 100 g/day of a green shake made from the Mankai strain of Wolffia globosa (also known as duckweed) replacing dinner, and 28 g/day of walnuts.

The Green Mediterranean diet included 800 mg more polyphenols than the traditional Mediterranean diet. Both were equally calorie-restricted, at about 1,500-1,800 kcal/day for men and 1,200-1,400 kcal/day for women. All three groups were instructed to engage in regular physical activity and were given free gym memberships.

The retention rate was 98.3% after 6 months and 89.8% after 18 months.

Weight loss was similar between the two Mediterranean diet groups (2.9% and 3.9% for the traditional and green versions, respectively) compared with the standard healthy diet (0.6%) (P < .05 for both Mediterranean diet groups vs. control).

After 6 months, fasting ghrelin increased in the traditional (8.0%; P = .015) and green (10.5%; P = 0.031) Mediterranean groups versus baseline, with no significant change in the control group.

By 18 months, fasting ghrelin was significantly greater compared with baseline only in the green Mediterranean group (P = .012).

Because the differences in fasting ghrelin trajectories were only significant in men – likely due to the small sample size of women – a subsequent 18-month analysis was limited to the men. In a multivariate model adjusted for age, intervention group, baseline biomarker values, and 18-month weight changes, the 18-month change in fasting ghrelin remained a significant predictor for changes in A1c and homeostatic model of insulin resistance (HOMA-IR; P = .022).

Because weight loss remained the most significant predictor of improved insulin resistance, a further analysis examined the association between changes in fasting ghrelin levels with changes in the fraction of insulin resistance marker that were not attributed to weight loss, per se. With the other adjustments, fasting ghrelin was associated with residual reductions in A1c (P = .003), HOMA-IR (P = .021), increased HDL-cholesterol (P = .024), and relative visceral adipose tissue loss (P = .003).  
 

No specific product needed to push Mediterranean diet towards vegan

Dr. Tsaban, a nutritional researcher and cardiologist at Ben-Gurion University and Soroka University Medical Center, Be’er-Sheva, Israel, said the Mankai shake is commonly consumed in Israel but is also available worldwide. The study participants, all employees at an isolated nuclear research facility in the Negev, were particularly motivated. “They didn’t have a satiety problem with the drink. It made them very full,” he said. The manufacturer supplied the shakes but didn’t fund the study, he added.

However, Dr. Tsaban said that the “green Mediterranean diet” doesn’t depend on specific products.

Rather, “the concept is to push the Mediterranean diet a bit further and to replace the animal-based protein with vegetable-based protein, to shift your dietary habits towards a more vegan lifestyle. It’s not completely vegan, but it’s trending there. ... Our main goal was to increase the polyphenol intake, the antioxidant intake from vegetables. ... I think it can be replicated.”

Dr. Gardner said, “At the end of the day, it’s an exploratory study. ... It raises some interesting points that give the rest of us room to follow-up on.”

The study was funded by grants from the German Research Foundation, the Israel Ministry of Health, the Israel Ministry of Science and Technology, and the California Walnut Commission. Dr. Tsaban has reported no further relevant financial relationships. Dr. Gardner has reported receiving study funding from Beyond Meat.

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

A “green” adaptation to the traditional Mediterranean diet could help improve insulin sensitivity and reduce visceral fat by increasing levels of ghrelin, the “hunger hormone,” new research suggests.

The current study is a new analysis of data from the randomized DIRECT-PLUS trial, which showed that the addition of green tea and substitution of red meat for a plant-based (Mankai) protein shake at dinner – dubbed the “green Mediterranean diet” – resulted in further improved cardiometabolic benefits compared with the traditional Mediterranean diet among people with baseline abdominal obesity and/or dyslipidemia, according to the researchers.

They specifically looked at ghrelin, nicknamed the “hunger hormone,” a neuropeptide mainly secreted by the gastric epithelium. It acts on the pituitary gland to release growth hormone. Ghrelin concentrations increase during fasting and decrease after eating. Lower levels are associated with insulin resistance and obesity.

Fasting ghrelin levels were elevated with weight loss, but those increases were associated with improved insulin sensitivity and regression of visceral adipose tissue even beyond weight loss.

Although the caloric restriction and weight loss were comparable with the two Mediterranean diets, the green Mediterranean diet group had double the increase in fasting ghrelin as the traditional Mediterranean diet group, the researchers point out in their report .
 

‘Hypothesis-generating’ study pushes many hot topic buttons

“This specific study is the first to show that ghrelin levels play an important role in metabolic adaptation to a dietary or lifestyle intervention and that ghrelin is an important player in the axis of adiposity, insulin resistance, and metabolic health,” lead researcher Gal Tsaban, MD, told this news organization.

The data partially explain some of the prior beneficial effects seen with the Green Mediterranean diet, even after adjustment for weight loss, he explained, noting that the revised version of the diet “could be considered as an alternative lifestyle intervention with possible metabolic benefits even beyond the Mediterranean diet, which is what we currently recommend for patients.”

Asked for comment, Christopher Gardner, PhD, was not as enthusiastic.

He took issue with the fact that ghrelin wasn’t a primary or even a prespecified secondary outcome of the DIRECT-PLUS trial and because the specific plant-based ingredients of the green Mediterranean diet used in the study may not be widely available or desirable and therefore limit the study’s generalizability.

Dr. Gardner, who is director of nutrition studies at the Stanford Prevention Research Center, California, also said: “They’re tying lots of interesting things together. The Mediterranean diet is a cool thing, ghrelin is a cool thing, and insulin resistance is hugely important in this day and age, even though we don’t all agree on how to measure it.”

“But it gets tough as you try to link them all together for an exploratory outcome. ... To me it’s an interesting hypothesis-generating study that pushes a lot of interesting buttons that are hot topics in the field.”
 

Green Mediterranean diet led to higher ghrelin, metabolic benefits

In DIRECT-PLUS, a total of 294 adults (88% men) older than 30 years of age with abdominal obesity (waist circumference >102 cm for men or >88 cm for women), or dyslipidemia (triglycerides >150 mg/dL and HDL-cholesterol ≤40 mg/dL for men or ≤50 mg/dL for women) were included. Half had prediabetes or type 2 diabetes.

They were randomized to one of three diets: a diet based on standard healthy dietary guidelines; a traditional Mediterranean diet low in simple carbohydrates, rich in vegetables, with poultry and fish replacing beef and lamb and 28 g/day of walnuts; or the Green-Mediterranean diet, including 3-4 cups/day of green tea and 100 g/day of a green shake made from the Mankai strain of Wolffia globosa (also known as duckweed) replacing dinner, and 28 g/day of walnuts.

The Green Mediterranean diet included 800 mg more polyphenols than the traditional Mediterranean diet. Both were equally calorie-restricted, at about 1,500-1,800 kcal/day for men and 1,200-1,400 kcal/day for women. All three groups were instructed to engage in regular physical activity and were given free gym memberships.

The retention rate was 98.3% after 6 months and 89.8% after 18 months.

Weight loss was similar between the two Mediterranean diet groups (2.9% and 3.9% for the traditional and green versions, respectively) compared with the standard healthy diet (0.6%) (P < .05 for both Mediterranean diet groups vs. control).

After 6 months, fasting ghrelin increased in the traditional (8.0%; P = .015) and green (10.5%; P = 0.031) Mediterranean groups versus baseline, with no significant change in the control group.

By 18 months, fasting ghrelin was significantly greater compared with baseline only in the green Mediterranean group (P = .012).

Because the differences in fasting ghrelin trajectories were only significant in men – likely due to the small sample size of women – a subsequent 18-month analysis was limited to the men. In a multivariate model adjusted for age, intervention group, baseline biomarker values, and 18-month weight changes, the 18-month change in fasting ghrelin remained a significant predictor for changes in A1c and homeostatic model of insulin resistance (HOMA-IR; P = .022).

Because weight loss remained the most significant predictor of improved insulin resistance, a further analysis examined the association between changes in fasting ghrelin levels with changes in the fraction of insulin resistance marker that were not attributed to weight loss, per se. With the other adjustments, fasting ghrelin was associated with residual reductions in A1c (P = .003), HOMA-IR (P = .021), increased HDL-cholesterol (P = .024), and relative visceral adipose tissue loss (P = .003).  
 

No specific product needed to push Mediterranean diet towards vegan

Dr. Tsaban, a nutritional researcher and cardiologist at Ben-Gurion University and Soroka University Medical Center, Be’er-Sheva, Israel, said the Mankai shake is commonly consumed in Israel but is also available worldwide. The study participants, all employees at an isolated nuclear research facility in the Negev, were particularly motivated. “They didn’t have a satiety problem with the drink. It made them very full,” he said. The manufacturer supplied the shakes but didn’t fund the study, he added.

However, Dr. Tsaban said that the “green Mediterranean diet” doesn’t depend on specific products.

Rather, “the concept is to push the Mediterranean diet a bit further and to replace the animal-based protein with vegetable-based protein, to shift your dietary habits towards a more vegan lifestyle. It’s not completely vegan, but it’s trending there. ... Our main goal was to increase the polyphenol intake, the antioxidant intake from vegetables. ... I think it can be replicated.”

Dr. Gardner said, “At the end of the day, it’s an exploratory study. ... It raises some interesting points that give the rest of us room to follow-up on.”

The study was funded by grants from the German Research Foundation, the Israel Ministry of Health, the Israel Ministry of Science and Technology, and the California Walnut Commission. Dr. Tsaban has reported no further relevant financial relationships. Dr. Gardner has reported receiving study funding from Beyond Meat.

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

A “green” adaptation to the traditional Mediterranean diet could help improve insulin sensitivity and reduce visceral fat by increasing levels of ghrelin, the “hunger hormone,” new research suggests.

The current study is a new analysis of data from the randomized DIRECT-PLUS trial, which showed that the addition of green tea and substitution of red meat for a plant-based (Mankai) protein shake at dinner – dubbed the “green Mediterranean diet” – resulted in further improved cardiometabolic benefits compared with the traditional Mediterranean diet among people with baseline abdominal obesity and/or dyslipidemia, according to the researchers.

They specifically looked at ghrelin, nicknamed the “hunger hormone,” a neuropeptide mainly secreted by the gastric epithelium. It acts on the pituitary gland to release growth hormone. Ghrelin concentrations increase during fasting and decrease after eating. Lower levels are associated with insulin resistance and obesity.

Fasting ghrelin levels were elevated with weight loss, but those increases were associated with improved insulin sensitivity and regression of visceral adipose tissue even beyond weight loss.

Although the caloric restriction and weight loss were comparable with the two Mediterranean diets, the green Mediterranean diet group had double the increase in fasting ghrelin as the traditional Mediterranean diet group, the researchers point out in their report .
 

‘Hypothesis-generating’ study pushes many hot topic buttons

“This specific study is the first to show that ghrelin levels play an important role in metabolic adaptation to a dietary or lifestyle intervention and that ghrelin is an important player in the axis of adiposity, insulin resistance, and metabolic health,” lead researcher Gal Tsaban, MD, told this news organization.

The data partially explain some of the prior beneficial effects seen with the Green Mediterranean diet, even after adjustment for weight loss, he explained, noting that the revised version of the diet “could be considered as an alternative lifestyle intervention with possible metabolic benefits even beyond the Mediterranean diet, which is what we currently recommend for patients.”

Asked for comment, Christopher Gardner, PhD, was not as enthusiastic.

He took issue with the fact that ghrelin wasn’t a primary or even a prespecified secondary outcome of the DIRECT-PLUS trial and because the specific plant-based ingredients of the green Mediterranean diet used in the study may not be widely available or desirable and therefore limit the study’s generalizability.

Dr. Gardner, who is director of nutrition studies at the Stanford Prevention Research Center, California, also said: “They’re tying lots of interesting things together. The Mediterranean diet is a cool thing, ghrelin is a cool thing, and insulin resistance is hugely important in this day and age, even though we don’t all agree on how to measure it.”

“But it gets tough as you try to link them all together for an exploratory outcome. ... To me it’s an interesting hypothesis-generating study that pushes a lot of interesting buttons that are hot topics in the field.”
 

Green Mediterranean diet led to higher ghrelin, metabolic benefits

In DIRECT-PLUS, a total of 294 adults (88% men) older than 30 years of age with abdominal obesity (waist circumference >102 cm for men or >88 cm for women), or dyslipidemia (triglycerides >150 mg/dL and HDL-cholesterol ≤40 mg/dL for men or ≤50 mg/dL for women) were included. Half had prediabetes or type 2 diabetes.

They were randomized to one of three diets: a diet based on standard healthy dietary guidelines; a traditional Mediterranean diet low in simple carbohydrates, rich in vegetables, with poultry and fish replacing beef and lamb and 28 g/day of walnuts; or the Green-Mediterranean diet, including 3-4 cups/day of green tea and 100 g/day of a green shake made from the Mankai strain of Wolffia globosa (also known as duckweed) replacing dinner, and 28 g/day of walnuts.

The Green Mediterranean diet included 800 mg more polyphenols than the traditional Mediterranean diet. Both were equally calorie-restricted, at about 1,500-1,800 kcal/day for men and 1,200-1,400 kcal/day for women. All three groups were instructed to engage in regular physical activity and were given free gym memberships.

The retention rate was 98.3% after 6 months and 89.8% after 18 months.

Weight loss was similar between the two Mediterranean diet groups (2.9% and 3.9% for the traditional and green versions, respectively) compared with the standard healthy diet (0.6%) (P < .05 for both Mediterranean diet groups vs. control).

After 6 months, fasting ghrelin increased in the traditional (8.0%; P = .015) and green (10.5%; P = 0.031) Mediterranean groups versus baseline, with no significant change in the control group.

By 18 months, fasting ghrelin was significantly greater compared with baseline only in the green Mediterranean group (P = .012).

Because the differences in fasting ghrelin trajectories were only significant in men – likely due to the small sample size of women – a subsequent 18-month analysis was limited to the men. In a multivariate model adjusted for age, intervention group, baseline biomarker values, and 18-month weight changes, the 18-month change in fasting ghrelin remained a significant predictor for changes in A1c and homeostatic model of insulin resistance (HOMA-IR; P = .022).

Because weight loss remained the most significant predictor of improved insulin resistance, a further analysis examined the association between changes in fasting ghrelin levels with changes in the fraction of insulin resistance marker that were not attributed to weight loss, per se. With the other adjustments, fasting ghrelin was associated with residual reductions in A1c (P = .003), HOMA-IR (P = .021), increased HDL-cholesterol (P = .024), and relative visceral adipose tissue loss (P = .003).  
 

No specific product needed to push Mediterranean diet towards vegan

Dr. Tsaban, a nutritional researcher and cardiologist at Ben-Gurion University and Soroka University Medical Center, Be’er-Sheva, Israel, said the Mankai shake is commonly consumed in Israel but is also available worldwide. The study participants, all employees at an isolated nuclear research facility in the Negev, were particularly motivated. “They didn’t have a satiety problem with the drink. It made them very full,” he said. The manufacturer supplied the shakes but didn’t fund the study, he added.

However, Dr. Tsaban said that the “green Mediterranean diet” doesn’t depend on specific products.

Rather, “the concept is to push the Mediterranean diet a bit further and to replace the animal-based protein with vegetable-based protein, to shift your dietary habits towards a more vegan lifestyle. It’s not completely vegan, but it’s trending there. ... Our main goal was to increase the polyphenol intake, the antioxidant intake from vegetables. ... I think it can be replicated.”

Dr. Gardner said, “At the end of the day, it’s an exploratory study. ... It raises some interesting points that give the rest of us room to follow-up on.”

The study was funded by grants from the German Research Foundation, the Israel Ministry of Health, the Israel Ministry of Science and Technology, and the California Walnut Commission. Dr. Tsaban has reported no further relevant financial relationships. Dr. Gardner has reported receiving study funding from Beyond Meat.

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

A human chorionic gonadotropin (hCG) test is commonly ordered by gynecologists prior to surgical procedures, in the workup of bleeding abnormalities, and in the follow-up of ectopic and molar pregnancies, to name a few indications. In doing so, occasionally clinicians will find themselves in the diagnostic dilemma of discovering an inexplicable low-level elevation in hCG, such as in a postmenopausal patient. This clinical picture can be confusing and can be concerning for conditions such as postmolar gestational trophoblastic neoplasia (GTN). However, there can be benign causes of this phenomenon.¹ To prevent unnecessary worry, investigation of treatments is important. In fact, misdiagnosis and inappropriate treatment of benign, low-level hCG levels with unnecessary chemotherapy is problematic mismanagement of gestational trophoblastic disease (GTD), and a major cause of litigation.

Human chorionic gonadotropin is a glycoprotein hormone with two subunits (alpha and beta). It can come from multiple sources, including trophoblastic cells, malignant trophoblastic cells, the pituitary gland, and exogenous sources.¹ Its alpha-subunit is identical to that of follicle stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH). Its beta-subunit is unique, though very similar to that of LH. The free hCG beta subunit can be produced by nontrophoblastic neoplasms. The gene for the beta subunit of hCG is in close proximity to the beta subunit of LH and increases in gonadotropin-releasing hormone (GnRH) in menopause can result in the stimulation of both genes. Understanding the sources of hCG-like glycoproteins and mechanisms for testing is important when considering possible causes for falsely elevated hCG.

Most commercially available serum hCG assays detect normal intact hCG and free beta subunits. They are typically sandwich assays utilizing antibody binding sites in which a solid-phase anti-hCG antibody to a specific hCG target is then mixed with the patient’s serum, trapping or binding the hCG, which is then treated with an indicator antibody. After being washed with the indicator or “capture” antibody, its relative (quantitative) levels can be measured.¹

Urine hCG testing (such as urine pregnancy tests) work through capillary action, drawing the patient’s urine across absorbent pads before reaching a pad which contains anti-hCG antibodies (the detection zone) in the test line. These tests are less sensitive than serum tests, but many can detect hCG levels <15-20 mIU/mL.¹

When ob.gyns. are asked to consult on or evaluate persistently low-level elevations of hCG in nonpregnant patients they should consider both malignant and nonmalignant etiologies. Malignant causes include GTN or quiescent GTD (e.g., after treatment of a molar pregnancy or GTN), choriocarcinoma (e.g., ovarian germ cell tumors), and nonchoriocarcinoma malignancies (such as cervical, pancreatic, breast, renal). Nonmalignant causes of hCG elevations in nonpregnant patients include pituitary hCG (in postmenopausal patients), exogenous hCG, and phantom hCG.

The first step in diagnostic workup is to perform a urine pregnancy test. Provided that the serum hCG level is > 20 mIU/mL, the urine HCG should be positive unless the cause of elevated levels is “phantom hCG” from heterophilic antibodies. When patients are exposed to animal antigens (such as in vaccines) they can develop antibodies such as human anti-mouse antibody. These antibodies have affinity to the binding antibodies used in many hCG sandwich assays and form a linkage between the solid phase antibody and the detection antibody creating a false-positive result. This false-positive test is only present in serum testing but not urine tests because the patient’s heterophilic antibodies are not excreted by the kidney and thus not available to create a false-positive result. An alternative method to make the diagnosis of phantom hCG is to request that the hCG testing be run at a different lab with a different assay (which may not react with the same affinity to the patient’s anti-animal heterophile antibodies), or to request that the lab perform serial dilutions. If phantom hCG from heterophile antibodies is at play, serial dilutions will result in a nonlinear dilution response.

If the patient’s urine hCG test is positive, then pregnancy should be ruled out with a transvaginal ultrasound. If negative, an ectopic pregnancy should still be considered (unless not medically plausible, such as in postmenopausal women or women who have undergone hysterectomy). In the absence of an intrauterine or ectopic pregnancy, a positive serum and urine pregnancy test could be from exogenous hCG, from malignancy or pituitary hCG. Use of exogenous hCG can be ruled out by taking a thorough history, with particular focus on asking about weight loss medications and muscle building therapies.

If pregnancy and exogenous hCG are ruled out, clinicians should assess for an occult hCG-secreting malignancy. The lab should be asked to measure the proportion of the free beta subunit of hCG, as this is typically what is secreted by malignancies. CT imaging of the chest, abdomen, and pelvis to search for an occult primary tumor should take place. If the patient has been recently treated for molar pregnancy or GTN, and serum hCG levels reside between 100 and 300 mIU/mL, quiescent GTD should be considered the diagnosis. Determination of the proportion of hyperglycosylated hCG to total hCG can help differentiate active choriocarcinoma from quiescent GTD. After restaging imaging has been done to confirm no measurable metastatic foci, observation can follow with monthly hCG measurements. The majority of these cases will eventually resolve without intervention within a year. Quiescent GTD and persistent low-level HCG in the absence of measurable GTN on imaging or symptoms does not require treatment with chemotherapy or hysterectomy, particularly in women who desire future fertility.²

Once occult malignancy has been ruled out, the remaining potential source of hCG is the pituitary gland. As mentioned earlier, hCG shares its morphology with TSH, LH, and FSH. This can result in cross reactivity and false positives. In the menopausal state, GnRH levels increase and thus so do pituitary LH and hCG levels. To confirm that the pituitary is the source of the low-level hCG levels, the provider should prescribe a course of hormonal treatment such as an oral contraceptive pill for a 2- to 3-month period. This should result in suppression of pituitary hCG, and serum hCG levels, as part of a negative feedback loop. Pituitary source of hCG is a benign condition, and, like quiescent GTD, phantom hCG or exogenous hCG does not require intervention.

Getting to the bottom of persistent low-level hCG elevations can be challenging. By following the step-wise algorithm listed here, clinicians can sequentially test for urine hCG, heterophilic antibodies, elevated free beta-subunit, occult malignancy, and pituitary hCG.
 

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest. Email her at obnews@mdedge.com.
 

References

1. Oyatogun O et al. Ther Adv Reprod Health 2021 Jun 13. doi: 10.1177/2F26334941211016412.

2. Soper JT. Obstet Gynecol. 2021 Feb 1;137(2):355-70.

A human chorionic gonadotropin (hCG) test is commonly ordered by gynecologists prior to surgical procedures, in the workup of bleeding abnormalities, and in the follow-up of ectopic and molar pregnancies, to name a few indications. In doing so, occasionally clinicians will find themselves in the diagnostic dilemma of discovering an inexplicable low-level elevation in hCG, such as in a postmenopausal patient. This clinical picture can be confusing and can be concerning for conditions such as postmolar gestational trophoblastic neoplasia (GTN). However, there can be benign causes of this phenomenon.¹ To prevent unnecessary worry, investigation of treatments is important. In fact, misdiagnosis and inappropriate treatment of benign, low-level hCG levels with unnecessary chemotherapy is problematic mismanagement of gestational trophoblastic disease (GTD), and a major cause of litigation.

Human chorionic gonadotropin is a glycoprotein hormone with two subunits (alpha and beta). It can come from multiple sources, including trophoblastic cells, malignant trophoblastic cells, the pituitary gland, and exogenous sources.¹ Its alpha-subunit is identical to that of follicle stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH). Its beta-subunit is unique, though very similar to that of LH. The free hCG beta subunit can be produced by nontrophoblastic neoplasms. The gene for the beta subunit of hCG is in close proximity to the beta subunit of LH and increases in gonadotropin-releasing hormone (GnRH) in menopause can result in the stimulation of both genes. Understanding the sources of hCG-like glycoproteins and mechanisms for testing is important when considering possible causes for falsely elevated hCG.

Most commercially available serum hCG assays detect normal intact hCG and free beta subunits. They are typically sandwich assays utilizing antibody binding sites in which a solid-phase anti-hCG antibody to a specific hCG target is then mixed with the patient’s serum, trapping or binding the hCG, which is then treated with an indicator antibody. After being washed with the indicator or “capture” antibody, its relative (quantitative) levels can be measured.¹

Urine hCG testing (such as urine pregnancy tests) work through capillary action, drawing the patient’s urine across absorbent pads before reaching a pad which contains anti-hCG antibodies (the detection zone) in the test line. These tests are less sensitive than serum tests, but many can detect hCG levels <15-20 mIU/mL.¹

When ob.gyns. are asked to consult on or evaluate persistently low-level elevations of hCG in nonpregnant patients they should consider both malignant and nonmalignant etiologies. Malignant causes include GTN or quiescent GTD (e.g., after treatment of a molar pregnancy or GTN), choriocarcinoma (e.g., ovarian germ cell tumors), and nonchoriocarcinoma malignancies (such as cervical, pancreatic, breast, renal). Nonmalignant causes of hCG elevations in nonpregnant patients include pituitary hCG (in postmenopausal patients), exogenous hCG, and phantom hCG.

The first step in diagnostic workup is to perform a urine pregnancy test. Provided that the serum hCG level is > 20 mIU/mL, the urine HCG should be positive unless the cause of elevated levels is “phantom hCG” from heterophilic antibodies. When patients are exposed to animal antigens (such as in vaccines) they can develop antibodies such as human anti-mouse antibody. These antibodies have affinity to the binding antibodies used in many hCG sandwich assays and form a linkage between the solid phase antibody and the detection antibody creating a false-positive result. This false-positive test is only present in serum testing but not urine tests because the patient’s heterophilic antibodies are not excreted by the kidney and thus not available to create a false-positive result. An alternative method to make the diagnosis of phantom hCG is to request that the hCG testing be run at a different lab with a different assay (which may not react with the same affinity to the patient’s anti-animal heterophile antibodies), or to request that the lab perform serial dilutions. If phantom hCG from heterophile antibodies is at play, serial dilutions will result in a nonlinear dilution response.

If the patient’s urine hCG test is positive, then pregnancy should be ruled out with a transvaginal ultrasound. If negative, an ectopic pregnancy should still be considered (unless not medically plausible, such as in postmenopausal women or women who have undergone hysterectomy). In the absence of an intrauterine or ectopic pregnancy, a positive serum and urine pregnancy test could be from exogenous hCG, from malignancy or pituitary hCG. Use of exogenous hCG can be ruled out by taking a thorough history, with particular focus on asking about weight loss medications and muscle building therapies.

If pregnancy and exogenous hCG are ruled out, clinicians should assess for an occult hCG-secreting malignancy. The lab should be asked to measure the proportion of the free beta subunit of hCG, as this is typically what is secreted by malignancies. CT imaging of the chest, abdomen, and pelvis to search for an occult primary tumor should take place. If the patient has been recently treated for molar pregnancy or GTN, and serum hCG levels reside between 100 and 300 mIU/mL, quiescent GTD should be considered the diagnosis. Determination of the proportion of hyperglycosylated hCG to total hCG can help differentiate active choriocarcinoma from quiescent GTD. After restaging imaging has been done to confirm no measurable metastatic foci, observation can follow with monthly hCG measurements. The majority of these cases will eventually resolve without intervention within a year. Quiescent GTD and persistent low-level HCG in the absence of measurable GTN on imaging or symptoms does not require treatment with chemotherapy or hysterectomy, particularly in women who desire future fertility.²

Once occult malignancy has been ruled out, the remaining potential source of hCG is the pituitary gland. As mentioned earlier, hCG shares its morphology with TSH, LH, and FSH. This can result in cross reactivity and false positives. In the menopausal state, GnRH levels increase and thus so do pituitary LH and hCG levels. To confirm that the pituitary is the source of the low-level hCG levels, the provider should prescribe a course of hormonal treatment such as an oral contraceptive pill for a 2- to 3-month period. This should result in suppression of pituitary hCG, and serum hCG levels, as part of a negative feedback loop. Pituitary source of hCG is a benign condition, and, like quiescent GTD, phantom hCG or exogenous hCG does not require intervention.

Getting to the bottom of persistent low-level hCG elevations can be challenging. By following the step-wise algorithm listed here, clinicians can sequentially test for urine hCG, heterophilic antibodies, elevated free beta-subunit, occult malignancy, and pituitary hCG.
 

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest. Email her at obnews@mdedge.com.
 

References

1. Oyatogun O et al. Ther Adv Reprod Health 2021 Jun 13. doi: 10.1177/2F26334941211016412.

2. Soper JT. Obstet Gynecol. 2021 Feb 1;137(2):355-70.

A human chorionic gonadotropin (hCG) test is commonly ordered by gynecologists prior to surgical procedures, in the workup of bleeding abnormalities, and in the follow-up of ectopic and molar pregnancies, to name a few indications. In doing so, occasionally clinicians will find themselves in the diagnostic dilemma of discovering an inexplicable low-level elevation in hCG, such as in a postmenopausal patient. This clinical picture can be confusing and can be concerning for conditions such as postmolar gestational trophoblastic neoplasia (GTN). However, there can be benign causes of this phenomenon.¹ To prevent unnecessary worry, investigation of treatments is important. In fact, misdiagnosis and inappropriate treatment of benign, low-level hCG levels with unnecessary chemotherapy is problematic mismanagement of gestational trophoblastic disease (GTD), and a major cause of litigation.

Human chorionic gonadotropin is a glycoprotein hormone with two subunits (alpha and beta). It can come from multiple sources, including trophoblastic cells, malignant trophoblastic cells, the pituitary gland, and exogenous sources.¹ Its alpha-subunit is identical to that of follicle stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH). Its beta-subunit is unique, though very similar to that of LH. The free hCG beta subunit can be produced by nontrophoblastic neoplasms. The gene for the beta subunit of hCG is in close proximity to the beta subunit of LH and increases in gonadotropin-releasing hormone (GnRH) in menopause can result in the stimulation of both genes. Understanding the sources of hCG-like glycoproteins and mechanisms for testing is important when considering possible causes for falsely elevated hCG.

Most commercially available serum hCG assays detect normal intact hCG and free beta subunits. They are typically sandwich assays utilizing antibody binding sites in which a solid-phase anti-hCG antibody to a specific hCG target is then mixed with the patient’s serum, trapping or binding the hCG, which is then treated with an indicator antibody. After being washed with the indicator or “capture” antibody, its relative (quantitative) levels can be measured.¹

Urine hCG testing (such as urine pregnancy tests) work through capillary action, drawing the patient’s urine across absorbent pads before reaching a pad which contains anti-hCG antibodies (the detection zone) in the test line. These tests are less sensitive than serum tests, but many can detect hCG levels <15-20 mIU/mL.¹

When ob.gyns. are asked to consult on or evaluate persistently low-level elevations of hCG in nonpregnant patients they should consider both malignant and nonmalignant etiologies. Malignant causes include GTN or quiescent GTD (e.g., after treatment of a molar pregnancy or GTN), choriocarcinoma (e.g., ovarian germ cell tumors), and nonchoriocarcinoma malignancies (such as cervical, pancreatic, breast, renal). Nonmalignant causes of hCG elevations in nonpregnant patients include pituitary hCG (in postmenopausal patients), exogenous hCG, and phantom hCG.

The first step in diagnostic workup is to perform a urine pregnancy test. Provided that the serum hCG level is > 20 mIU/mL, the urine HCG should be positive unless the cause of elevated levels is “phantom hCG” from heterophilic antibodies. When patients are exposed to animal antigens (such as in vaccines) they can develop antibodies such as human anti-mouse antibody. These antibodies have affinity to the binding antibodies used in many hCG sandwich assays and form a linkage between the solid phase antibody and the detection antibody creating a false-positive result. This false-positive test is only present in serum testing but not urine tests because the patient’s heterophilic antibodies are not excreted by the kidney and thus not available to create a false-positive result. An alternative method to make the diagnosis of phantom hCG is to request that the hCG testing be run at a different lab with a different assay (which may not react with the same affinity to the patient’s anti-animal heterophile antibodies), or to request that the lab perform serial dilutions. If phantom hCG from heterophile antibodies is at play, serial dilutions will result in a nonlinear dilution response.

If the patient’s urine hCG test is positive, then pregnancy should be ruled out with a transvaginal ultrasound. If negative, an ectopic pregnancy should still be considered (unless not medically plausible, such as in postmenopausal women or women who have undergone hysterectomy). In the absence of an intrauterine or ectopic pregnancy, a positive serum and urine pregnancy test could be from exogenous hCG, from malignancy or pituitary hCG. Use of exogenous hCG can be ruled out by taking a thorough history, with particular focus on asking about weight loss medications and muscle building therapies.

If pregnancy and exogenous hCG are ruled out, clinicians should assess for an occult hCG-secreting malignancy. The lab should be asked to measure the proportion of the free beta subunit of hCG, as this is typically what is secreted by malignancies. CT imaging of the chest, abdomen, and pelvis to search for an occult primary tumor should take place. If the patient has been recently treated for molar pregnancy or GTN, and serum hCG levels reside between 100 and 300 mIU/mL, quiescent GTD should be considered the diagnosis. Determination of the proportion of hyperglycosylated hCG to total hCG can help differentiate active choriocarcinoma from quiescent GTD. After restaging imaging has been done to confirm no measurable metastatic foci, observation can follow with monthly hCG measurements. The majority of these cases will eventually resolve without intervention within a year. Quiescent GTD and persistent low-level HCG in the absence of measurable GTN on imaging or symptoms does not require treatment with chemotherapy or hysterectomy, particularly in women who desire future fertility.²

Once occult malignancy has been ruled out, the remaining potential source of hCG is the pituitary gland. As mentioned earlier, hCG shares its morphology with TSH, LH, and FSH. This can result in cross reactivity and false positives. In the menopausal state, GnRH levels increase and thus so do pituitary LH and hCG levels. To confirm that the pituitary is the source of the low-level hCG levels, the provider should prescribe a course of hormonal treatment such as an oral contraceptive pill for a 2- to 3-month period. This should result in suppression of pituitary hCG, and serum hCG levels, as part of a negative feedback loop. Pituitary source of hCG is a benign condition, and, like quiescent GTD, phantom hCG or exogenous hCG does not require intervention.

Getting to the bottom of persistent low-level hCG elevations can be challenging. By following the step-wise algorithm listed here, clinicians can sequentially test for urine hCG, heterophilic antibodies, elevated free beta-subunit, occult malignancy, and pituitary hCG.
 

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest. Email her at obnews@mdedge.com.
 

References

1. Oyatogun O et al. Ther Adv Reprod Health 2021 Jun 13. doi: 10.1177/2F26334941211016412.

2. Soper JT. Obstet Gynecol. 2021 Feb 1;137(2):355-70.