The number of state psychiatric hospital beds has hit a historic low with about 11 beds per 100,000 population, a new report showed.

More than half of those beds (52%) were occupied by forensic patients, individuals with serious mental illness (SMI) who were committed to the state hospital through the criminal legal system to help establish competency for trial.

“The shortage of psychiatric beds has real consequences for people with SMI — some will wait months in jail despite not yet being found guilty of a crime, others will be denied admission despite being critically ill, and others still will be discharged prematurely onto the streets to free up beds, where they may grow sicker and be at an elevated risk of mortality,” wrote report coauthors Shanti Silver of the Treatment Advocacy Center (TAC) in Arlington and Elizabeth Sinclair Hanq of the National Association of State Mental Health Program Directors in Alexandria, Virginia.

Published online on January 24, Prevention Over Punishment: Finding the Right Balance of Civil and Forensic State Psychiatric Hospital Beds recommends that state and local governments work together to open additional state psychiatric hospital beds for civil and forensic patients with SMI.

To obtain data about the availability of state psychiatric hospital beds, TAC surveyed state officials from April to August 2023. Official responses were provided by 41 states and the District of Columbia.

Information for the remaining states was gathered from state websites, media articles, preexisting reports, hospital admission staff, or personal contacts living in those states.

The median occupancy rate for state-run hospitals in the new report was 90%, well above the 85% level investigators say usually signals a bed shortage. Overall, 73% of states reported occupancy rates above that level, with 11 states operating at 95% capacity.

The proportion of state psychiatric beds occupied by forensic patients has increased by 12% since 2016, largely driven by the growing number of individuals awaiting a competency determination to stand trial. Before they occupy these beds, however, people with SMI can languish in jail for months or even years, waiting for a bed to open.

About 15% of all state hospital beds and 31% of forensic beds across 34 states were occupied by individuals who had been found not guilty of a crime by reasons of insanity.

“The prioritization of admission of forensic patients has effectively created a system where someone must be arrested to access a state hospital bed,” report coauthor Lisa Dailey, TAC executive director, told this news organization. “But there are not enough beds for forensic patients either; thousands of inmates are waiting in jail on any given day for a bed to open up.”

There are several factors contributing to the scarcity of beds, including an existing hospital staffing shortage made worse by the COVID-19 pandemic and a lack of appropriate discharge facilities.

Report authors offered a number of recommendations to federal, state, and local officials to increase the availability of state-run psychiatric hospital beds, including infrastructure changes involving recruiting and retaining staff for state hospitals and funding new discharge or step-down facilities so that patients have a place to recover when they leave the hospital.

Policy changes could also help, the report noted. Policymakers should consider “dismiss and transfer” procedures to address the backlog of nearly 6000 people with SMI waiting for a state hospital bed to achieve competency to stand trial. With “dismiss and transfer,” criminal charges are dismissed or suspended while an application for civil commitment is filed in the probate court. Once a civil commitment order has been issued, the individual is released to an outpatient commitment program for treatment.

“States must strive for prevention over punishment,” the report concluded.

There was no study funding reported, nor were disclosures available.
 

A version of this article appeared on Medscape.com.

The number of state psychiatric hospital beds has hit a historic low with about 11 beds per 100,000 population, a new report showed.

More than half of those beds (52%) were occupied by forensic patients, individuals with serious mental illness (SMI) who were committed to the state hospital through the criminal legal system to help establish competency for trial.

“The shortage of psychiatric beds has real consequences for people with SMI — some will wait months in jail despite not yet being found guilty of a crime, others will be denied admission despite being critically ill, and others still will be discharged prematurely onto the streets to free up beds, where they may grow sicker and be at an elevated risk of mortality,” wrote report coauthors Shanti Silver of the Treatment Advocacy Center (TAC) in Arlington and Elizabeth Sinclair Hanq of the National Association of State Mental Health Program Directors in Alexandria, Virginia.

Published online on January 24, Prevention Over Punishment: Finding the Right Balance of Civil and Forensic State Psychiatric Hospital Beds recommends that state and local governments work together to open additional state psychiatric hospital beds for civil and forensic patients with SMI.

To obtain data about the availability of state psychiatric hospital beds, TAC surveyed state officials from April to August 2023. Official responses were provided by 41 states and the District of Columbia.

Information for the remaining states was gathered from state websites, media articles, preexisting reports, hospital admission staff, or personal contacts living in those states.

The median occupancy rate for state-run hospitals in the new report was 90%, well above the 85% level investigators say usually signals a bed shortage. Overall, 73% of states reported occupancy rates above that level, with 11 states operating at 95% capacity.

The proportion of state psychiatric beds occupied by forensic patients has increased by 12% since 2016, largely driven by the growing number of individuals awaiting a competency determination to stand trial. Before they occupy these beds, however, people with SMI can languish in jail for months or even years, waiting for a bed to open.

About 15% of all state hospital beds and 31% of forensic beds across 34 states were occupied by individuals who had been found not guilty of a crime by reasons of insanity.

“The prioritization of admission of forensic patients has effectively created a system where someone must be arrested to access a state hospital bed,” report coauthor Lisa Dailey, TAC executive director, told this news organization. “But there are not enough beds for forensic patients either; thousands of inmates are waiting in jail on any given day for a bed to open up.”

There are several factors contributing to the scarcity of beds, including an existing hospital staffing shortage made worse by the COVID-19 pandemic and a lack of appropriate discharge facilities.

Report authors offered a number of recommendations to federal, state, and local officials to increase the availability of state-run psychiatric hospital beds, including infrastructure changes involving recruiting and retaining staff for state hospitals and funding new discharge or step-down facilities so that patients have a place to recover when they leave the hospital.

Policy changes could also help, the report noted. Policymakers should consider “dismiss and transfer” procedures to address the backlog of nearly 6000 people with SMI waiting for a state hospital bed to achieve competency to stand trial. With “dismiss and transfer,” criminal charges are dismissed or suspended while an application for civil commitment is filed in the probate court. Once a civil commitment order has been issued, the individual is released to an outpatient commitment program for treatment.

“States must strive for prevention over punishment,” the report concluded.

There was no study funding reported, nor were disclosures available.
 

A version of this article appeared on Medscape.com.

The number of state psychiatric hospital beds has hit a historic low with about 11 beds per 100,000 population, a new report showed.

More than half of those beds (52%) were occupied by forensic patients, individuals with serious mental illness (SMI) who were committed to the state hospital through the criminal legal system to help establish competency for trial.

“The shortage of psychiatric beds has real consequences for people with SMI — some will wait months in jail despite not yet being found guilty of a crime, others will be denied admission despite being critically ill, and others still will be discharged prematurely onto the streets to free up beds, where they may grow sicker and be at an elevated risk of mortality,” wrote report coauthors Shanti Silver of the Treatment Advocacy Center (TAC) in Arlington and Elizabeth Sinclair Hanq of the National Association of State Mental Health Program Directors in Alexandria, Virginia.

Published online on January 24, Prevention Over Punishment: Finding the Right Balance of Civil and Forensic State Psychiatric Hospital Beds recommends that state and local governments work together to open additional state psychiatric hospital beds for civil and forensic patients with SMI.

To obtain data about the availability of state psychiatric hospital beds, TAC surveyed state officials from April to August 2023. Official responses were provided by 41 states and the District of Columbia.

Information for the remaining states was gathered from state websites, media articles, preexisting reports, hospital admission staff, or personal contacts living in those states.

The median occupancy rate for state-run hospitals in the new report was 90%, well above the 85% level investigators say usually signals a bed shortage. Overall, 73% of states reported occupancy rates above that level, with 11 states operating at 95% capacity.

The proportion of state psychiatric beds occupied by forensic patients has increased by 12% since 2016, largely driven by the growing number of individuals awaiting a competency determination to stand trial. Before they occupy these beds, however, people with SMI can languish in jail for months or even years, waiting for a bed to open.

About 15% of all state hospital beds and 31% of forensic beds across 34 states were occupied by individuals who had been found not guilty of a crime by reasons of insanity.

“The prioritization of admission of forensic patients has effectively created a system where someone must be arrested to access a state hospital bed,” report coauthor Lisa Dailey, TAC executive director, told this news organization. “But there are not enough beds for forensic patients either; thousands of inmates are waiting in jail on any given day for a bed to open up.”

There are several factors contributing to the scarcity of beds, including an existing hospital staffing shortage made worse by the COVID-19 pandemic and a lack of appropriate discharge facilities.

Report authors offered a number of recommendations to federal, state, and local officials to increase the availability of state-run psychiatric hospital beds, including infrastructure changes involving recruiting and retaining staff for state hospitals and funding new discharge or step-down facilities so that patients have a place to recover when they leave the hospital.

Policy changes could also help, the report noted. Policymakers should consider “dismiss and transfer” procedures to address the backlog of nearly 6000 people with SMI waiting for a state hospital bed to achieve competency to stand trial. With “dismiss and transfer,” criminal charges are dismissed or suspended while an application for civil commitment is filed in the probate court. Once a civil commitment order has been issued, the individual is released to an outpatient commitment program for treatment.

“States must strive for prevention over punishment,” the report concluded.

There was no study funding reported, nor were disclosures available.
 

A version of this article appeared on Medscape.com.

Faced with a positive human papillomavirus (HPV) test, patients are quickly overwhelmed by anxiety-inducing questions. It is crucial to provide them with adequate responses to reassure them, emphasized Jean-Louis Mergui, MD, president of the International Federation for Colposcopy, during the press conference of the Congress of the French Society of Colposcopy and Cervico-Vaginal Pathology.

“Do I have cancer? When did I catch this papillomavirus? Is it dangerous for my partner? How do I get rid of it?” “Not everyone is equipped to answer these four questions. However, it is extremely important that healthcare professionals provide correct answers to patients so that they stop worrying,” Dr. Mergui explained.
 

Papillomavirus and Cancer

One of the first instincts of patients who receive a positive HPV test is to turn to the Internet. There, they read about “high-risk HPV, which is potentially oncogenic,” and become completely panicked, said Dr. Mergui.

However, among women, the probability of having a high-grade CIN3 lesion or higher on the cervix when the HPV test is positive is about 7%, according to the ATHENA study. “About 93% of patients do not have a severe lesion on the cervix. That’s why colposcopy is not performed on all patients. They need to be reassured,” said Dr. Mergui. When the papillomavirus persists, there is a risk for a cervical lesion. After 11 years, between 20% and 30% of patients develop a high-grade lesion on the cervix. However, on average, a high-risk HPV is spontaneously eliminated within 1-2 years. “After 14 months, 50% of women will test negative for their papillomavirus,” Dr. Mergui noted.

“High-risk HPV does not mean there is a lesion; it means there is a risk of developing a lesion on the cervix one day. That’s why these patients need to be monitored and explored,” he added.

In practice, when a patient aged between 30 and 65 years has a positive HPV test, cytology is performed to look for lesions. Only in the case of an abnormal smear, ASC-US, is colposcopy recommended. In the absence of a lesion, a control HPV test is conducted 1 year later to monitor virus persistence.

It should be noted that patients who have been treated for a cervical lesion have a five times higher risk of developing invasive cervical, vaginal, or vulvar cancer. Therefore, treated patients must be monitored once every 3 years for life.
 

Time of Infection

Many patients ask, “When did I catch this papillomavirus?” In response, Dr. Mergui first emphasized that HPV infection is common. “Between ages 15 and 30 years, most of us are infected with a high-risk HPV. When we look at the incidence between ages 15 and 25 years, every year, 20% of all young girls are infected with HPV, including 17% with high-risk HPV. The virus is usually caught within the first 5 years of sexual activity, and typically disappears after about a year,” he explained.

However, the most disturbing scenario for patients is when their last examination was negative, and there is no apparent reason for having caught the virus since then. Suspicion often falls on the partner. Once again, the gynecologist seeks to reassure.

It is possible that the last time screening was conducted, the virus was not sought (HPV test), but rather cervical lesions were sought by smear. However, a normal smear does not mean that the papillomavirus is not present. A negative cytology does not mean a negative HPV test. As we have seen, the virus is not always associated with the presence of a lesion, explained Dr. Mergui.

Also, having had a negative HPV test a few years earlier does not mean that one was not already infected. The HPV test determines the quantity of virus. Therefore, it is possible that the virus was present in small quantities that were without clinical significance (hence, a negative test). However, a few years later, the virus may have multiplied, and the HPV test became positive.

“Sometimes, the virus re-emerges 40, 50 years after infection due to age-related immune decline,” said Dr. Mergui. “So, just because the smear was negative or the HPV test was negative at the last examination does not mean that one was infected between the two.” Moreover, only 15% of couples have the same virus present on the penis or vagina, he pointed out.
 

Protecting One’s Partner

Once the diagnosis is made, it is often too late to protect the partner because they have already been infected. “It is certain that the partner will be infected or has already been infected because when the patient comes to you with a positive HPV test, she has already had sexual intercourse. It is worth noting that the virus can be transmitted through digital touching, and condoms are not very effective in preventing virus transmission,” said Dr. Mergui.

The speaker further clarified that the risk for men is much lower than that for women. “In women, about 40,000 lesions linked to high-risk HPV types, precancerous or cancerous, are observed every year. In men, this number is 1900. So, this represents 20 times fewer neoplastic lesions in men. The problem in men is oropharyngeal lesions, which are three times more common than in women. However, there is no screening for oropharyngeal cancer.”

So, when should the partner consult? Dr. Mergui advised consulting when there are clinically visible lesions (small warts, bumps, or ear, nose, and throat symptoms). “I do not recommend systematic examination of male or female partners,” he added.
 

Clearing the Virus

There are treatments for cervical lesions but not for papillomavirus infection.

“The only thing that can be suggested is quitting smoking, which increases viral clearance, thus reducing viral load. Also, the use of condoms helps improve viral clearance, but when women have a stable relationship, it seems unrealistic to think they will constantly use condoms. Finally, the prophylactic vaccine has been proposed, but it does not treat the infection. In fact, the real solution is to tell patients that they need to continue regular monitoring,” said Dr. Mergui.

“It should be noted that an ongoing study at the European level seems to show that when women who have undergone surgical treatment for a high-grade cervical lesion are vaccinated at the time of treatment or just after treatment, it reduces the risk of recurrence by 50%. So, the risk of recurrence is around 7%-8%. This strategy could be interesting, but for now, there is no official recommendation,” Dr. Mergui concluded.
 

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

Faced with a positive human papillomavirus (HPV) test, patients are quickly overwhelmed by anxiety-inducing questions. It is crucial to provide them with adequate responses to reassure them, emphasized Jean-Louis Mergui, MD, president of the International Federation for Colposcopy, during the press conference of the Congress of the French Society of Colposcopy and Cervico-Vaginal Pathology.

“Do I have cancer? When did I catch this papillomavirus? Is it dangerous for my partner? How do I get rid of it?” “Not everyone is equipped to answer these four questions. However, it is extremely important that healthcare professionals provide correct answers to patients so that they stop worrying,” Dr. Mergui explained.
 

Papillomavirus and Cancer

One of the first instincts of patients who receive a positive HPV test is to turn to the Internet. There, they read about “high-risk HPV, which is potentially oncogenic,” and become completely panicked, said Dr. Mergui.

However, among women, the probability of having a high-grade CIN3 lesion or higher on the cervix when the HPV test is positive is about 7%, according to the ATHENA study. “About 93% of patients do not have a severe lesion on the cervix. That’s why colposcopy is not performed on all patients. They need to be reassured,” said Dr. Mergui. When the papillomavirus persists, there is a risk for a cervical lesion. After 11 years, between 20% and 30% of patients develop a high-grade lesion on the cervix. However, on average, a high-risk HPV is spontaneously eliminated within 1-2 years. “After 14 months, 50% of women will test negative for their papillomavirus,” Dr. Mergui noted.

“High-risk HPV does not mean there is a lesion; it means there is a risk of developing a lesion on the cervix one day. That’s why these patients need to be monitored and explored,” he added.

In practice, when a patient aged between 30 and 65 years has a positive HPV test, cytology is performed to look for lesions. Only in the case of an abnormal smear, ASC-US, is colposcopy recommended. In the absence of a lesion, a control HPV test is conducted 1 year later to monitor virus persistence.

It should be noted that patients who have been treated for a cervical lesion have a five times higher risk of developing invasive cervical, vaginal, or vulvar cancer. Therefore, treated patients must be monitored once every 3 years for life.
 

Time of Infection

Many patients ask, “When did I catch this papillomavirus?” In response, Dr. Mergui first emphasized that HPV infection is common. “Between ages 15 and 30 years, most of us are infected with a high-risk HPV. When we look at the incidence between ages 15 and 25 years, every year, 20% of all young girls are infected with HPV, including 17% with high-risk HPV. The virus is usually caught within the first 5 years of sexual activity, and typically disappears after about a year,” he explained.

However, the most disturbing scenario for patients is when their last examination was negative, and there is no apparent reason for having caught the virus since then. Suspicion often falls on the partner. Once again, the gynecologist seeks to reassure.

It is possible that the last time screening was conducted, the virus was not sought (HPV test), but rather cervical lesions were sought by smear. However, a normal smear does not mean that the papillomavirus is not present. A negative cytology does not mean a negative HPV test. As we have seen, the virus is not always associated with the presence of a lesion, explained Dr. Mergui.

Also, having had a negative HPV test a few years earlier does not mean that one was not already infected. The HPV test determines the quantity of virus. Therefore, it is possible that the virus was present in small quantities that were without clinical significance (hence, a negative test). However, a few years later, the virus may have multiplied, and the HPV test became positive.

“Sometimes, the virus re-emerges 40, 50 years after infection due to age-related immune decline,” said Dr. Mergui. “So, just because the smear was negative or the HPV test was negative at the last examination does not mean that one was infected between the two.” Moreover, only 15% of couples have the same virus present on the penis or vagina, he pointed out.
 

Protecting One’s Partner

Once the diagnosis is made, it is often too late to protect the partner because they have already been infected. “It is certain that the partner will be infected or has already been infected because when the patient comes to you with a positive HPV test, she has already had sexual intercourse. It is worth noting that the virus can be transmitted through digital touching, and condoms are not very effective in preventing virus transmission,” said Dr. Mergui.

The speaker further clarified that the risk for men is much lower than that for women. “In women, about 40,000 lesions linked to high-risk HPV types, precancerous or cancerous, are observed every year. In men, this number is 1900. So, this represents 20 times fewer neoplastic lesions in men. The problem in men is oropharyngeal lesions, which are three times more common than in women. However, there is no screening for oropharyngeal cancer.”

So, when should the partner consult? Dr. Mergui advised consulting when there are clinically visible lesions (small warts, bumps, or ear, nose, and throat symptoms). “I do not recommend systematic examination of male or female partners,” he added.
 

Clearing the Virus

There are treatments for cervical lesions but not for papillomavirus infection.

“The only thing that can be suggested is quitting smoking, which increases viral clearance, thus reducing viral load. Also, the use of condoms helps improve viral clearance, but when women have a stable relationship, it seems unrealistic to think they will constantly use condoms. Finally, the prophylactic vaccine has been proposed, but it does not treat the infection. In fact, the real solution is to tell patients that they need to continue regular monitoring,” said Dr. Mergui.

“It should be noted that an ongoing study at the European level seems to show that when women who have undergone surgical treatment for a high-grade cervical lesion are vaccinated at the time of treatment or just after treatment, it reduces the risk of recurrence by 50%. So, the risk of recurrence is around 7%-8%. This strategy could be interesting, but for now, there is no official recommendation,” Dr. Mergui concluded.
 

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

Faced with a positive human papillomavirus (HPV) test, patients are quickly overwhelmed by anxiety-inducing questions. It is crucial to provide them with adequate responses to reassure them, emphasized Jean-Louis Mergui, MD, president of the International Federation for Colposcopy, during the press conference of the Congress of the French Society of Colposcopy and Cervico-Vaginal Pathology.

“Do I have cancer? When did I catch this papillomavirus? Is it dangerous for my partner? How do I get rid of it?” “Not everyone is equipped to answer these four questions. However, it is extremely important that healthcare professionals provide correct answers to patients so that they stop worrying,” Dr. Mergui explained.
 

Papillomavirus and Cancer

One of the first instincts of patients who receive a positive HPV test is to turn to the Internet. There, they read about “high-risk HPV, which is potentially oncogenic,” and become completely panicked, said Dr. Mergui.

However, among women, the probability of having a high-grade CIN3 lesion or higher on the cervix when the HPV test is positive is about 7%, according to the ATHENA study. “About 93% of patients do not have a severe lesion on the cervix. That’s why colposcopy is not performed on all patients. They need to be reassured,” said Dr. Mergui. When the papillomavirus persists, there is a risk for a cervical lesion. After 11 years, between 20% and 30% of patients develop a high-grade lesion on the cervix. However, on average, a high-risk HPV is spontaneously eliminated within 1-2 years. “After 14 months, 50% of women will test negative for their papillomavirus,” Dr. Mergui noted.

“High-risk HPV does not mean there is a lesion; it means there is a risk of developing a lesion on the cervix one day. That’s why these patients need to be monitored and explored,” he added.

In practice, when a patient aged between 30 and 65 years has a positive HPV test, cytology is performed to look for lesions. Only in the case of an abnormal smear, ASC-US, is colposcopy recommended. In the absence of a lesion, a control HPV test is conducted 1 year later to monitor virus persistence.

It should be noted that patients who have been treated for a cervical lesion have a five times higher risk of developing invasive cervical, vaginal, or vulvar cancer. Therefore, treated patients must be monitored once every 3 years for life.
 

Time of Infection

Many patients ask, “When did I catch this papillomavirus?” In response, Dr. Mergui first emphasized that HPV infection is common. “Between ages 15 and 30 years, most of us are infected with a high-risk HPV. When we look at the incidence between ages 15 and 25 years, every year, 20% of all young girls are infected with HPV, including 17% with high-risk HPV. The virus is usually caught within the first 5 years of sexual activity, and typically disappears after about a year,” he explained.

However, the most disturbing scenario for patients is when their last examination was negative, and there is no apparent reason for having caught the virus since then. Suspicion often falls on the partner. Once again, the gynecologist seeks to reassure.

It is possible that the last time screening was conducted, the virus was not sought (HPV test), but rather cervical lesions were sought by smear. However, a normal smear does not mean that the papillomavirus is not present. A negative cytology does not mean a negative HPV test. As we have seen, the virus is not always associated with the presence of a lesion, explained Dr. Mergui.

Also, having had a negative HPV test a few years earlier does not mean that one was not already infected. The HPV test determines the quantity of virus. Therefore, it is possible that the virus was present in small quantities that were without clinical significance (hence, a negative test). However, a few years later, the virus may have multiplied, and the HPV test became positive.

“Sometimes, the virus re-emerges 40, 50 years after infection due to age-related immune decline,” said Dr. Mergui. “So, just because the smear was negative or the HPV test was negative at the last examination does not mean that one was infected between the two.” Moreover, only 15% of couples have the same virus present on the penis or vagina, he pointed out.
 

Protecting One’s Partner

Once the diagnosis is made, it is often too late to protect the partner because they have already been infected. “It is certain that the partner will be infected or has already been infected because when the patient comes to you with a positive HPV test, she has already had sexual intercourse. It is worth noting that the virus can be transmitted through digital touching, and condoms are not very effective in preventing virus transmission,” said Dr. Mergui.

The speaker further clarified that the risk for men is much lower than that for women. “In women, about 40,000 lesions linked to high-risk HPV types, precancerous or cancerous, are observed every year. In men, this number is 1900. So, this represents 20 times fewer neoplastic lesions in men. The problem in men is oropharyngeal lesions, which are three times more common than in women. However, there is no screening for oropharyngeal cancer.”

So, when should the partner consult? Dr. Mergui advised consulting when there are clinically visible lesions (small warts, bumps, or ear, nose, and throat symptoms). “I do not recommend systematic examination of male or female partners,” he added.
 

Clearing the Virus

There are treatments for cervical lesions but not for papillomavirus infection.

“The only thing that can be suggested is quitting smoking, which increases viral clearance, thus reducing viral load. Also, the use of condoms helps improve viral clearance, but when women have a stable relationship, it seems unrealistic to think they will constantly use condoms. Finally, the prophylactic vaccine has been proposed, but it does not treat the infection. In fact, the real solution is to tell patients that they need to continue regular monitoring,” said Dr. Mergui.

“It should be noted that an ongoing study at the European level seems to show that when women who have undergone surgical treatment for a high-grade cervical lesion are vaccinated at the time of treatment or just after treatment, it reduces the risk of recurrence by 50%. So, the risk of recurrence is around 7%-8%. This strategy could be interesting, but for now, there is no official recommendation,” Dr. Mergui concluded.
 

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

WASHINGTON — Continuous glucose monitoring (CGM) is widely used during pregnancy for individuals with type 1 diabetes — with pregnancy-specific target metrics now chosen and benefits on perinatal outcomes demonstrated — but more research is needed to elucidate its role in the growing population of pregnant people with type 2 diabetes and gestational diabetes (GDM). And overall, there are still “many more questions unanswered about CGM use in pregnancy than what we have answered,” Celeste Durnwald, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

There’s much to learn about how to best interpret “the detailed and complex data that CGM provides,” and what targets in addition to time in range (TIR) are most important, said Dr. Durnwald, director of the perinatal diabetes program and associate professor of ob.gyn. at the Hospital of the University of Pennsylvania, Philadelphia, in a presentation on CGM.

Among other questions are whether fasting glucose is “as important in the era of CGM,” and whether there should be different glycemic targets for nocturnal versus daytime TIR, she said. Moreover, questions justifiably remain about whether the TIR targets for type 1 diabetes in pregnancy are indeed optimal, she said in a discussion period.

Ongoing research is looking at whether CGM can motivate and guide patients with GDM through diet and lifestyle changes such that “we can see changes in amounts of medication we use,” Dr. Durnwald noted in her presentation. “There’s a whole breadth of research looking at whether CGM can help predict diagnosis of GDM, large for gestational age, or preeclampsia, and what are the targets.”

Maternal hypoglycemia during pregnancy — a time when strict glycemic control is recommended to reduce the risk of congenital malformations and other fetal and neonatal morbidity — remains a concern in type 1 diabetes, even with widespread use of CGM in this population, said Barak Rosenn, MD, during a presentation on glycemic control in type 1 diabetes.

A pilot study of a newly designed pregnancy-specific closed-loop insulin delivery system, published last year (Diabetes Care. 2023;46:1425-31), has offered the first “really encouraging information about the ability to use our most up-to-date technology to help our type 1 patients maintain strict control and at the same time decrease their risk of severe hypoglycemia,” said Dr. Rosenn, a maternal-fetal medicine specialist at the Jersey City Medical Center, Jersey City, New Jersey.

Guidance for tight intrapartum glucose control, meanwhile, has been backed by little evidence, said Michal Fishel Bartal, MD, MS, and some recent studies and reviews have shown little to no effect of such tight control on neonatal hypoglycemia, which is the aim of the guidance.

“We need to reexamine current recommendations,” said Dr. Bartal, assistant professor in the division of maternal-fetal medicine at the University of Texas Health Science Center, Houston, during a presentation on intrapartum care. “There’s very limited evidence-based data for the way we manage people with diabetes [during labor and delivery].”

The Knowns And Unknowns of CGM in Pregnancy

The multicenter, international CONCEPTT trial (Continuous Glucose Monitoring in Pregnant Women With Type 1 Diabetes), published in 2017, was the first trial to demonstrate improvements in perinatal outcomes, and it “brought CGM to the forefront in terms of widespread use,” Dr. Durnwald said.

The trial randomized more than 300 patients with type 1 diabetes who were pregnant or planning pregnancy (both users of insulin pumps and users of multiple insulin injections) to continuous, real-time CGM in addition to finger-stick glucose monitoring, or standard finger-stick glucose tests alone. In addition to small improvements in A1c and 7% more TIR (without an increase in hypoglycemia), pregnant CGM users had reductions in large-for-gestational age (LGA) births (53% vs 69%, P = .0489), neonatal intensive care admissions lasting more than 24 hours, and severe neonatal hypoglycemia.

Numbers needed to treat to prevent adverse outcomes in the CONCEPTT trial were six for LGA, six for NICU admission, and eight for neonatal hypoglycemia.

Data from the CONCEPTT trial featured prominently in the development of consensus recommendations for CGM targets in pregnancy by an international expert panel endorsed by the American Diabetes Association. In its 2019 report, the group recommended a target range of 63-140 mg/dL for type 1 and type 2 diabetes during pregnancy (compared with 70-180 mg/dL outside of pregnancy), and a TIR > 70% for pregnant people with type 1 diabetes. (Targets for time below range and time above range are also defined for type 1.)

More data are needed, the group said, in order to recommend TIR targets for type 2 diabetes in pregnancy or GDM (Diabetes Care. 2019;42:1593-603). “Many argue,” Dr. Durnwald said, “that there could be more stringent targets for those at less risk for [maternal] hypoglycemia, especially our GDM population.”

There’s a question of whether even higher TIR would further improve perinatal outcomes, she said, “or will we reach a threshold where higher TIR doesn’t get us a [further] reduction in LGA or preeclampsia.”

And while TIR is “certainly our buzzword,” lower mean glucose levels have also been associated with a lower risk of LGA and other adverse neonatal outcomes. A 2019 retrospective study from Sweden, for instance, analyzed patterns of CGM data from 186 pregnant women with type 1 diabetes and found significant associations between elevated mean glucose levels (in the second and third trimesters) and both LGA and an adverse neonatal composite outcome (Diabetologia. 2019;62:1143-53).

Elevated TIR was also associated with LGA, but “mean glucose had the strongest association with the rate of LGA,” Dr. Durnwald said.

Similarly, a 2020 subanalysis of the CONCEPTT trial data found that a higher mean glucose at both 24 and 34 weeks of gestation was significantly associated with a greater risk of LGA (Diabetes Care. 2020;43:1178-84), and a smaller 2015 analysis of data from two randomized controlled trials of CGM in pregnant women with type 1 and type 2 diabetes found this association in trimesters 2 and 3 (Diabetes Care. 2015;38;1319-25).

The ADA’s Standards of Care in Diabetes (Diabetes Care. 2024;47:S282-S294) endorse CGM as an adjunctive tool in pregnancy — not as a replacement for all traditional blood glucose monitoring — and advise that the use of CGM-reported mean glucose is superior to the use of estimated A1c, glucose management indicator, and other calculations to estimate A1c. Changes occur in pregnancy, Dr. Durnwald pointed out. “Most experts will identify a [target] mean glucose < 120 mg/dL in those with type 1, but there’s potential to have a mean glucose closer to 100 in certainly our patients with GDM and some of our patients with type 2,” she said. To a lesser extent, researchers have also looked at the effect of CMG-reported glycemic variability on outcomes such as LGA, with at least two studies finding some association, and there has been some research on nocturnal glucose and LGA, Dr. Durnwald said. CGM “gives us the opportunity,” she said, “to think about nocturnal glucose as a possible target” for further optimizing diabetes management during pregnancy.

CGM in Type 2, GDM

CGM in type 2 diabetes in pregnancy was addressed in a recently published systematic review and meta-analysis, which found only three qualifying randomized controlled trials and concluded that CGM use was not associated with improvements in perinatal outcomes, as assessed by LGA and preeclampsia (Am J Obstet Gynecol MFM. 2023;5:100969). “It’s very limited by the small sample size and the fact that most [patients] were using intermittent CGM,” Dr. Durnwald said. “It highlights how important it is to perform larger studies with continuous CGM.”

While the 2024 ADA standards say there are insufficient data to support the use of CGM in all patients with type 2 diabetes or GDM — and that the decision should be individualized “based on treatment regimen, circumstance, preferences, and needs” — real-world access to CGM for type 2, and even a bit for GDM, is improving, she said.

Some insurers require patients to be on insulin, but the trends are such that “we certainly talk about CGM to all our patients with type 2 diabetes and even our patients with GDM,” Dr. Durnwald said in a later interview. “CGMs are being advertised so we definitely have people who ask about them upon diagnosis, and we try to make it work for them.”
 

Is Preventing Maternal Hypoglycemia Possible?

Advancements in technology and pharmacology aimed at optimizing glycemic control — increased adoption of CGM, the use of insulin pump therapy, and the use of more rapid insulin analogs — appear to have had little to no impact on rates of severe maternal hypoglycemia in type 1 diabetes in pregnancy, said Dr. Rosenn, referring to several published studies.

The CONCEPTT study in type 1 diabetes, for instance, “gave us the best data we have on the use of CGM,” but differences in the percentage of patients with severe hypoglycemia and the total number of severe hypoglycemia episodes were basically the same whether patients used CGM or not, he said.

Closed-loop insulin delivery systems have been found in nonpregnant patients with type 1 diabetes to “be helpful in keeping people in range and also possibly [decreasing nocturnal hypoglycemia],” but the systems are not approved for use in pregnancy. “There’s not enough data on use in pregnancy, but probably more important, the algorithms used in the closed-loop systems are not directed to the targets we consider ideal for pregnancy,” Dr. Rosenn said.

In a pilot study of a closed-loop delivery system customized for pregnancies complicated by type 1 diabetes, 10 pregnant women were recruited at 14-32 weeks and, after a 1- to 2-week run-in period using a regular CGM-augmented pump, they used the closed-loop system targeting a daytime glucose of 80-110 mg/dL and nocturnal glucose of 80-100 mg/dL.

Mean TIR (a target range of 63-140 mg/dL) increased from 65% during the run-in period to 79% on the closed-loop system, and there were significant decreases in both time above range and time in the hypoglycemic ranges of < 63 mg/dL and < 54 mg/dL. Hypoglycemic events per week (defined as < 54 mg/dL for over 15 minutes) decreased from 4 to 0.7 (Diabetes Care. 2023;46:1425-31).

The investigators are continuing their research, and there are currently two randomized controlled trials underway examining use of closed-loop systems designed for pregnancy, said Dr. Rosenn, who was involved in feasibility research leading up to the pilot study. “So I’m hopeful we’ll see some encouraging information in the future.”

Maternal hypoglycemia during pregnancy is more common in type 1 diabetes, but it also affects pregnancies complicated by type 2 diabetes and GDM. In addition to the strict glycemic control imposed to improve maternal and fetal outcomes, pregnancy itself plays a role.

Research several decades ago from the Diabetes in Pregnancy Program Project, a prospective cohort in Cincinnati which Dr. Rosenn co-led, documented impaired counterregulatory physiology in pregnancy. Even in nondiabetic patients, there are declines in secretion of glucagon and growth hormone in response to hypoglycemia, for instance. In patients with type 1 diabetes, the diminishment in counterregulatory response is more severe.

Rethinking Intrapartum Care

Guidance for tight blood glucose control during labor and delivery for insulin-treated individuals — as reflected in the American College of Obstetricians and Gynecologists Practice Bulletin No. 201 on Pregestational Diabetes and in recommendations from the United Kingdom’s National Institute for Health and Care Excellence (NICE) — is based on small case series and overall “poor-quality” evidence that more recent research has failed to back up, Dr. Bartal said.

A systematic review published in 2018, for example, concluded there is a paucity of high-quality data supporting the association of glucose during labor and delivery with neonatal hypoglycemia in pregnancies complicated by diabetes (Diabet Med. 2018;35:173-83). And in a subsequent retrospective cohort study of pregnant women with type 1/type 2/GDM and their neonates, the same investigators reported no difference in the target glucose in labor between those with and without neonatal hypotension, after adjustment for important neonatal factors such as LGA and preterm delivery (Diabet Med. 2020;37:138-46).

Also exemplifying the body of research, Dr. Bartal said, is another single-center retrospective study published in 2020 that evaluated outcomes in the years before and after the institution of a formal intrapartum insulin regimen (a standardized protocol for titration of insulin and glucose infusions) for women with pregestational or gestational diabetes. The protocol was associated with improved maternal glucose control, but an increased frequency of neonatal hypoglycemia (Obstet Gynecol. 2020;136:411-6).

Her own group at the University of Texas in Houston looked retrospectively at 233 insulin-treated pregnancies complicated by type 2 diabetes and found no significant difference in the rate of neonatal hypoglycemia between those placed on a drip and those who were not, Dr. Bartal said. Over 40% of the newborns had hypoglycemia; it occurred irrespective of the route of delivery as well (J Matern Fetal Neonatal Med. 2022;35:7445-51).

Only two published randomized controlled trials have evaluated blood sugar control in labor, she said. The first, published in 2006, compared a continuous insulin drip with a rotation of glucose and non–glucose-containing fluids in insulin-requiring diabetes and found no differences in maternal blood glucose (the primary outcome) and a similar risk of neonatal hypoglycemia (Am J Obstet Gynecol. 2006;195;1095-9).

The second RCT, published in 2019, evaluated tight versus liberalized control (60-100 mg/dL, checking every hour, versus 60-120 mg/dL, checking every 4 hours) in laboring women with GDM. The first neonatal blood glucose level was similar in both groups, while the mean neonatal blood glucose level in the first 24 hours of life was lower with tight control (54 vs 58 mg/dL, P = .49) (Obstet Gynecol. 2019;133:1171-7). Findings from a new RCT conducted at the University of Texas in Houston of usual care versus more permissive glucose control will be presented at the SMFM Pregnancy Meeting in February 2024, she said.

Neonatal hypoglycemia is associated with increased risk of NICU admission, “but it’s also associated with possible long-term developmental deficit,” Dr. Bartal said, with the risk highest in children exposed to severe, recurrent, or clinically undetected hypoglycemia. Research has documented significantly increased risks of low executive function and visual motor function, for instance, in children who experienced neonatal hypoglycemia.

The risk of neonatal hypoglycemia has been linked to a variety of factors outside of the intrapartum period such as diabetes control and weight gain during pregnancy, neonatal birth weight/LGA, neonatal adiposity, gestational age at delivery, maternal body mass index, smoking, and diabetes control prior to pregnancy, Dr. Bartal noted. Also challenging is the reality that neonatal hypoglycemia as a research outcome is not standardized; definitions have varied across studies.

Tight intrapartum control comes with “costs,” from close monitoring of labor to increased resource utilization, and it may affect the labor experience/satisfaction, Dr. Bartal said. “But furthermore,” she said, “there are studies coming out, especially in the anesthesiology journals, that show there may be possible harm,” such as the risk of maternal and neonatal hyponatremia, and maternal hypoglycemia. A 2016 editorial in Anaesthesia (2016;71:750) describes these concerns, she noted.

“I do think we need to rethink our current recommendations,” she said.

Dr. Durnwald reported serving on the Dexcom GDM advisory board and receiving funding from United Health Group and the Helmsley Charitable Trust. Dr. Bartal and Dr. Rosenn reported no conflicts of interest.

WASHINGTON — Continuous glucose monitoring (CGM) is widely used during pregnancy for individuals with type 1 diabetes — with pregnancy-specific target metrics now chosen and benefits on perinatal outcomes demonstrated — but more research is needed to elucidate its role in the growing population of pregnant people with type 2 diabetes and gestational diabetes (GDM). And overall, there are still “many more questions unanswered about CGM use in pregnancy than what we have answered,” Celeste Durnwald, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

There’s much to learn about how to best interpret “the detailed and complex data that CGM provides,” and what targets in addition to time in range (TIR) are most important, said Dr. Durnwald, director of the perinatal diabetes program and associate professor of ob.gyn. at the Hospital of the University of Pennsylvania, Philadelphia, in a presentation on CGM.

Among other questions are whether fasting glucose is “as important in the era of CGM,” and whether there should be different glycemic targets for nocturnal versus daytime TIR, she said. Moreover, questions justifiably remain about whether the TIR targets for type 1 diabetes in pregnancy are indeed optimal, she said in a discussion period.

Ongoing research is looking at whether CGM can motivate and guide patients with GDM through diet and lifestyle changes such that “we can see changes in amounts of medication we use,” Dr. Durnwald noted in her presentation. “There’s a whole breadth of research looking at whether CGM can help predict diagnosis of GDM, large for gestational age, or preeclampsia, and what are the targets.”

Maternal hypoglycemia during pregnancy — a time when strict glycemic control is recommended to reduce the risk of congenital malformations and other fetal and neonatal morbidity — remains a concern in type 1 diabetes, even with widespread use of CGM in this population, said Barak Rosenn, MD, during a presentation on glycemic control in type 1 diabetes.

A pilot study of a newly designed pregnancy-specific closed-loop insulin delivery system, published last year (Diabetes Care. 2023;46:1425-31), has offered the first “really encouraging information about the ability to use our most up-to-date technology to help our type 1 patients maintain strict control and at the same time decrease their risk of severe hypoglycemia,” said Dr. Rosenn, a maternal-fetal medicine specialist at the Jersey City Medical Center, Jersey City, New Jersey.

Guidance for tight intrapartum glucose control, meanwhile, has been backed by little evidence, said Michal Fishel Bartal, MD, MS, and some recent studies and reviews have shown little to no effect of such tight control on neonatal hypoglycemia, which is the aim of the guidance.

“We need to reexamine current recommendations,” said Dr. Bartal, assistant professor in the division of maternal-fetal medicine at the University of Texas Health Science Center, Houston, during a presentation on intrapartum care. “There’s very limited evidence-based data for the way we manage people with diabetes [during labor and delivery].”

The Knowns And Unknowns of CGM in Pregnancy

The multicenter, international CONCEPTT trial (Continuous Glucose Monitoring in Pregnant Women With Type 1 Diabetes), published in 2017, was the first trial to demonstrate improvements in perinatal outcomes, and it “brought CGM to the forefront in terms of widespread use,” Dr. Durnwald said.

The trial randomized more than 300 patients with type 1 diabetes who were pregnant or planning pregnancy (both users of insulin pumps and users of multiple insulin injections) to continuous, real-time CGM in addition to finger-stick glucose monitoring, or standard finger-stick glucose tests alone. In addition to small improvements in A1c and 7% more TIR (without an increase in hypoglycemia), pregnant CGM users had reductions in large-for-gestational age (LGA) births (53% vs 69%, P = .0489), neonatal intensive care admissions lasting more than 24 hours, and severe neonatal hypoglycemia.

Numbers needed to treat to prevent adverse outcomes in the CONCEPTT trial were six for LGA, six for NICU admission, and eight for neonatal hypoglycemia.

Data from the CONCEPTT trial featured prominently in the development of consensus recommendations for CGM targets in pregnancy by an international expert panel endorsed by the American Diabetes Association. In its 2019 report, the group recommended a target range of 63-140 mg/dL for type 1 and type 2 diabetes during pregnancy (compared with 70-180 mg/dL outside of pregnancy), and a TIR > 70% for pregnant people with type 1 diabetes. (Targets for time below range and time above range are also defined for type 1.)

More data are needed, the group said, in order to recommend TIR targets for type 2 diabetes in pregnancy or GDM (Diabetes Care. 2019;42:1593-603). “Many argue,” Dr. Durnwald said, “that there could be more stringent targets for those at less risk for [maternal] hypoglycemia, especially our GDM population.”

There’s a question of whether even higher TIR would further improve perinatal outcomes, she said, “or will we reach a threshold where higher TIR doesn’t get us a [further] reduction in LGA or preeclampsia.”

And while TIR is “certainly our buzzword,” lower mean glucose levels have also been associated with a lower risk of LGA and other adverse neonatal outcomes. A 2019 retrospective study from Sweden, for instance, analyzed patterns of CGM data from 186 pregnant women with type 1 diabetes and found significant associations between elevated mean glucose levels (in the second and third trimesters) and both LGA and an adverse neonatal composite outcome (Diabetologia. 2019;62:1143-53).

Elevated TIR was also associated with LGA, but “mean glucose had the strongest association with the rate of LGA,” Dr. Durnwald said.

Similarly, a 2020 subanalysis of the CONCEPTT trial data found that a higher mean glucose at both 24 and 34 weeks of gestation was significantly associated with a greater risk of LGA (Diabetes Care. 2020;43:1178-84), and a smaller 2015 analysis of data from two randomized controlled trials of CGM in pregnant women with type 1 and type 2 diabetes found this association in trimesters 2 and 3 (Diabetes Care. 2015;38;1319-25).

The ADA’s Standards of Care in Diabetes (Diabetes Care. 2024;47:S282-S294) endorse CGM as an adjunctive tool in pregnancy — not as a replacement for all traditional blood glucose monitoring — and advise that the use of CGM-reported mean glucose is superior to the use of estimated A1c, glucose management indicator, and other calculations to estimate A1c. Changes occur in pregnancy, Dr. Durnwald pointed out. “Most experts will identify a [target] mean glucose < 120 mg/dL in those with type 1, but there’s potential to have a mean glucose closer to 100 in certainly our patients with GDM and some of our patients with type 2,” she said. To a lesser extent, researchers have also looked at the effect of CMG-reported glycemic variability on outcomes such as LGA, with at least two studies finding some association, and there has been some research on nocturnal glucose and LGA, Dr. Durnwald said. CGM “gives us the opportunity,” she said, “to think about nocturnal glucose as a possible target” for further optimizing diabetes management during pregnancy.

CGM in Type 2, GDM

CGM in type 2 diabetes in pregnancy was addressed in a recently published systematic review and meta-analysis, which found only three qualifying randomized controlled trials and concluded that CGM use was not associated with improvements in perinatal outcomes, as assessed by LGA and preeclampsia (Am J Obstet Gynecol MFM. 2023;5:100969). “It’s very limited by the small sample size and the fact that most [patients] were using intermittent CGM,” Dr. Durnwald said. “It highlights how important it is to perform larger studies with continuous CGM.”

While the 2024 ADA standards say there are insufficient data to support the use of CGM in all patients with type 2 diabetes or GDM — and that the decision should be individualized “based on treatment regimen, circumstance, preferences, and needs” — real-world access to CGM for type 2, and even a bit for GDM, is improving, she said.

Some insurers require patients to be on insulin, but the trends are such that “we certainly talk about CGM to all our patients with type 2 diabetes and even our patients with GDM,” Dr. Durnwald said in a later interview. “CGMs are being advertised so we definitely have people who ask about them upon diagnosis, and we try to make it work for them.”
 

Is Preventing Maternal Hypoglycemia Possible?

Advancements in technology and pharmacology aimed at optimizing glycemic control — increased adoption of CGM, the use of insulin pump therapy, and the use of more rapid insulin analogs — appear to have had little to no impact on rates of severe maternal hypoglycemia in type 1 diabetes in pregnancy, said Dr. Rosenn, referring to several published studies.

The CONCEPTT study in type 1 diabetes, for instance, “gave us the best data we have on the use of CGM,” but differences in the percentage of patients with severe hypoglycemia and the total number of severe hypoglycemia episodes were basically the same whether patients used CGM or not, he said.

Closed-loop insulin delivery systems have been found in nonpregnant patients with type 1 diabetes to “be helpful in keeping people in range and also possibly [decreasing nocturnal hypoglycemia],” but the systems are not approved for use in pregnancy. “There’s not enough data on use in pregnancy, but probably more important, the algorithms used in the closed-loop systems are not directed to the targets we consider ideal for pregnancy,” Dr. Rosenn said.

In a pilot study of a closed-loop delivery system customized for pregnancies complicated by type 1 diabetes, 10 pregnant women were recruited at 14-32 weeks and, after a 1- to 2-week run-in period using a regular CGM-augmented pump, they used the closed-loop system targeting a daytime glucose of 80-110 mg/dL and nocturnal glucose of 80-100 mg/dL.

Mean TIR (a target range of 63-140 mg/dL) increased from 65% during the run-in period to 79% on the closed-loop system, and there were significant decreases in both time above range and time in the hypoglycemic ranges of < 63 mg/dL and < 54 mg/dL. Hypoglycemic events per week (defined as < 54 mg/dL for over 15 minutes) decreased from 4 to 0.7 (Diabetes Care. 2023;46:1425-31).

The investigators are continuing their research, and there are currently two randomized controlled trials underway examining use of closed-loop systems designed for pregnancy, said Dr. Rosenn, who was involved in feasibility research leading up to the pilot study. “So I’m hopeful we’ll see some encouraging information in the future.”

Maternal hypoglycemia during pregnancy is more common in type 1 diabetes, but it also affects pregnancies complicated by type 2 diabetes and GDM. In addition to the strict glycemic control imposed to improve maternal and fetal outcomes, pregnancy itself plays a role.

Research several decades ago from the Diabetes in Pregnancy Program Project, a prospective cohort in Cincinnati which Dr. Rosenn co-led, documented impaired counterregulatory physiology in pregnancy. Even in nondiabetic patients, there are declines in secretion of glucagon and growth hormone in response to hypoglycemia, for instance. In patients with type 1 diabetes, the diminishment in counterregulatory response is more severe.

Rethinking Intrapartum Care

Guidance for tight blood glucose control during labor and delivery for insulin-treated individuals — as reflected in the American College of Obstetricians and Gynecologists Practice Bulletin No. 201 on Pregestational Diabetes and in recommendations from the United Kingdom’s National Institute for Health and Care Excellence (NICE) — is based on small case series and overall “poor-quality” evidence that more recent research has failed to back up, Dr. Bartal said.

A systematic review published in 2018, for example, concluded there is a paucity of high-quality data supporting the association of glucose during labor and delivery with neonatal hypoglycemia in pregnancies complicated by diabetes (Diabet Med. 2018;35:173-83). And in a subsequent retrospective cohort study of pregnant women with type 1/type 2/GDM and their neonates, the same investigators reported no difference in the target glucose in labor between those with and without neonatal hypotension, after adjustment for important neonatal factors such as LGA and preterm delivery (Diabet Med. 2020;37:138-46).

Also exemplifying the body of research, Dr. Bartal said, is another single-center retrospective study published in 2020 that evaluated outcomes in the years before and after the institution of a formal intrapartum insulin regimen (a standardized protocol for titration of insulin and glucose infusions) for women with pregestational or gestational diabetes. The protocol was associated with improved maternal glucose control, but an increased frequency of neonatal hypoglycemia (Obstet Gynecol. 2020;136:411-6).

Her own group at the University of Texas in Houston looked retrospectively at 233 insulin-treated pregnancies complicated by type 2 diabetes and found no significant difference in the rate of neonatal hypoglycemia between those placed on a drip and those who were not, Dr. Bartal said. Over 40% of the newborns had hypoglycemia; it occurred irrespective of the route of delivery as well (J Matern Fetal Neonatal Med. 2022;35:7445-51).

Only two published randomized controlled trials have evaluated blood sugar control in labor, she said. The first, published in 2006, compared a continuous insulin drip with a rotation of glucose and non–glucose-containing fluids in insulin-requiring diabetes and found no differences in maternal blood glucose (the primary outcome) and a similar risk of neonatal hypoglycemia (Am J Obstet Gynecol. 2006;195;1095-9).

The second RCT, published in 2019, evaluated tight versus liberalized control (60-100 mg/dL, checking every hour, versus 60-120 mg/dL, checking every 4 hours) in laboring women with GDM. The first neonatal blood glucose level was similar in both groups, while the mean neonatal blood glucose level in the first 24 hours of life was lower with tight control (54 vs 58 mg/dL, P = .49) (Obstet Gynecol. 2019;133:1171-7). Findings from a new RCT conducted at the University of Texas in Houston of usual care versus more permissive glucose control will be presented at the SMFM Pregnancy Meeting in February 2024, she said.

Neonatal hypoglycemia is associated with increased risk of NICU admission, “but it’s also associated with possible long-term developmental deficit,” Dr. Bartal said, with the risk highest in children exposed to severe, recurrent, or clinically undetected hypoglycemia. Research has documented significantly increased risks of low executive function and visual motor function, for instance, in children who experienced neonatal hypoglycemia.

The risk of neonatal hypoglycemia has been linked to a variety of factors outside of the intrapartum period such as diabetes control and weight gain during pregnancy, neonatal birth weight/LGA, neonatal adiposity, gestational age at delivery, maternal body mass index, smoking, and diabetes control prior to pregnancy, Dr. Bartal noted. Also challenging is the reality that neonatal hypoglycemia as a research outcome is not standardized; definitions have varied across studies.

Tight intrapartum control comes with “costs,” from close monitoring of labor to increased resource utilization, and it may affect the labor experience/satisfaction, Dr. Bartal said. “But furthermore,” she said, “there are studies coming out, especially in the anesthesiology journals, that show there may be possible harm,” such as the risk of maternal and neonatal hyponatremia, and maternal hypoglycemia. A 2016 editorial in Anaesthesia (2016;71:750) describes these concerns, she noted.

“I do think we need to rethink our current recommendations,” she said.

Dr. Durnwald reported serving on the Dexcom GDM advisory board and receiving funding from United Health Group and the Helmsley Charitable Trust. Dr. Bartal and Dr. Rosenn reported no conflicts of interest.

WASHINGTON — Continuous glucose monitoring (CGM) is widely used during pregnancy for individuals with type 1 diabetes — with pregnancy-specific target metrics now chosen and benefits on perinatal outcomes demonstrated — but more research is needed to elucidate its role in the growing population of pregnant people with type 2 diabetes and gestational diabetes (GDM). And overall, there are still “many more questions unanswered about CGM use in pregnancy than what we have answered,” Celeste Durnwald, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

There’s much to learn about how to best interpret “the detailed and complex data that CGM provides,” and what targets in addition to time in range (TIR) are most important, said Dr. Durnwald, director of the perinatal diabetes program and associate professor of ob.gyn. at the Hospital of the University of Pennsylvania, Philadelphia, in a presentation on CGM.

Among other questions are whether fasting glucose is “as important in the era of CGM,” and whether there should be different glycemic targets for nocturnal versus daytime TIR, she said. Moreover, questions justifiably remain about whether the TIR targets for type 1 diabetes in pregnancy are indeed optimal, she said in a discussion period.

Ongoing research is looking at whether CGM can motivate and guide patients with GDM through diet and lifestyle changes such that “we can see changes in amounts of medication we use,” Dr. Durnwald noted in her presentation. “There’s a whole breadth of research looking at whether CGM can help predict diagnosis of GDM, large for gestational age, or preeclampsia, and what are the targets.”

Maternal hypoglycemia during pregnancy — a time when strict glycemic control is recommended to reduce the risk of congenital malformations and other fetal and neonatal morbidity — remains a concern in type 1 diabetes, even with widespread use of CGM in this population, said Barak Rosenn, MD, during a presentation on glycemic control in type 1 diabetes.

A pilot study of a newly designed pregnancy-specific closed-loop insulin delivery system, published last year (Diabetes Care. 2023;46:1425-31), has offered the first “really encouraging information about the ability to use our most up-to-date technology to help our type 1 patients maintain strict control and at the same time decrease their risk of severe hypoglycemia,” said Dr. Rosenn, a maternal-fetal medicine specialist at the Jersey City Medical Center, Jersey City, New Jersey.

Guidance for tight intrapartum glucose control, meanwhile, has been backed by little evidence, said Michal Fishel Bartal, MD, MS, and some recent studies and reviews have shown little to no effect of such tight control on neonatal hypoglycemia, which is the aim of the guidance.

“We need to reexamine current recommendations,” said Dr. Bartal, assistant professor in the division of maternal-fetal medicine at the University of Texas Health Science Center, Houston, during a presentation on intrapartum care. “There’s very limited evidence-based data for the way we manage people with diabetes [during labor and delivery].”

The Knowns And Unknowns of CGM in Pregnancy

The multicenter, international CONCEPTT trial (Continuous Glucose Monitoring in Pregnant Women With Type 1 Diabetes), published in 2017, was the first trial to demonstrate improvements in perinatal outcomes, and it “brought CGM to the forefront in terms of widespread use,” Dr. Durnwald said.

The trial randomized more than 300 patients with type 1 diabetes who were pregnant or planning pregnancy (both users of insulin pumps and users of multiple insulin injections) to continuous, real-time CGM in addition to finger-stick glucose monitoring, or standard finger-stick glucose tests alone. In addition to small improvements in A1c and 7% more TIR (without an increase in hypoglycemia), pregnant CGM users had reductions in large-for-gestational age (LGA) births (53% vs 69%, P = .0489), neonatal intensive care admissions lasting more than 24 hours, and severe neonatal hypoglycemia.

Numbers needed to treat to prevent adverse outcomes in the CONCEPTT trial were six for LGA, six for NICU admission, and eight for neonatal hypoglycemia.

Data from the CONCEPTT trial featured prominently in the development of consensus recommendations for CGM targets in pregnancy by an international expert panel endorsed by the American Diabetes Association. In its 2019 report, the group recommended a target range of 63-140 mg/dL for type 1 and type 2 diabetes during pregnancy (compared with 70-180 mg/dL outside of pregnancy), and a TIR > 70% for pregnant people with type 1 diabetes. (Targets for time below range and time above range are also defined for type 1.)

More data are needed, the group said, in order to recommend TIR targets for type 2 diabetes in pregnancy or GDM (Diabetes Care. 2019;42:1593-603). “Many argue,” Dr. Durnwald said, “that there could be more stringent targets for those at less risk for [maternal] hypoglycemia, especially our GDM population.”

There’s a question of whether even higher TIR would further improve perinatal outcomes, she said, “or will we reach a threshold where higher TIR doesn’t get us a [further] reduction in LGA or preeclampsia.”

And while TIR is “certainly our buzzword,” lower mean glucose levels have also been associated with a lower risk of LGA and other adverse neonatal outcomes. A 2019 retrospective study from Sweden, for instance, analyzed patterns of CGM data from 186 pregnant women with type 1 diabetes and found significant associations between elevated mean glucose levels (in the second and third trimesters) and both LGA and an adverse neonatal composite outcome (Diabetologia. 2019;62:1143-53).

Elevated TIR was also associated with LGA, but “mean glucose had the strongest association with the rate of LGA,” Dr. Durnwald said.

Similarly, a 2020 subanalysis of the CONCEPTT trial data found that a higher mean glucose at both 24 and 34 weeks of gestation was significantly associated with a greater risk of LGA (Diabetes Care. 2020;43:1178-84), and a smaller 2015 analysis of data from two randomized controlled trials of CGM in pregnant women with type 1 and type 2 diabetes found this association in trimesters 2 and 3 (Diabetes Care. 2015;38;1319-25).

The ADA’s Standards of Care in Diabetes (Diabetes Care. 2024;47:S282-S294) endorse CGM as an adjunctive tool in pregnancy — not as a replacement for all traditional blood glucose monitoring — and advise that the use of CGM-reported mean glucose is superior to the use of estimated A1c, glucose management indicator, and other calculations to estimate A1c. Changes occur in pregnancy, Dr. Durnwald pointed out. “Most experts will identify a [target] mean glucose < 120 mg/dL in those with type 1, but there’s potential to have a mean glucose closer to 100 in certainly our patients with GDM and some of our patients with type 2,” she said. To a lesser extent, researchers have also looked at the effect of CMG-reported glycemic variability on outcomes such as LGA, with at least two studies finding some association, and there has been some research on nocturnal glucose and LGA, Dr. Durnwald said. CGM “gives us the opportunity,” she said, “to think about nocturnal glucose as a possible target” for further optimizing diabetes management during pregnancy.

CGM in Type 2, GDM

CGM in type 2 diabetes in pregnancy was addressed in a recently published systematic review and meta-analysis, which found only three qualifying randomized controlled trials and concluded that CGM use was not associated with improvements in perinatal outcomes, as assessed by LGA and preeclampsia (Am J Obstet Gynecol MFM. 2023;5:100969). “It’s very limited by the small sample size and the fact that most [patients] were using intermittent CGM,” Dr. Durnwald said. “It highlights how important it is to perform larger studies with continuous CGM.”

While the 2024 ADA standards say there are insufficient data to support the use of CGM in all patients with type 2 diabetes or GDM — and that the decision should be individualized “based on treatment regimen, circumstance, preferences, and needs” — real-world access to CGM for type 2, and even a bit for GDM, is improving, she said.

Some insurers require patients to be on insulin, but the trends are such that “we certainly talk about CGM to all our patients with type 2 diabetes and even our patients with GDM,” Dr. Durnwald said in a later interview. “CGMs are being advertised so we definitely have people who ask about them upon diagnosis, and we try to make it work for them.”
 

Is Preventing Maternal Hypoglycemia Possible?

Advancements in technology and pharmacology aimed at optimizing glycemic control — increased adoption of CGM, the use of insulin pump therapy, and the use of more rapid insulin analogs — appear to have had little to no impact on rates of severe maternal hypoglycemia in type 1 diabetes in pregnancy, said Dr. Rosenn, referring to several published studies.

The CONCEPTT study in type 1 diabetes, for instance, “gave us the best data we have on the use of CGM,” but differences in the percentage of patients with severe hypoglycemia and the total number of severe hypoglycemia episodes were basically the same whether patients used CGM or not, he said.

Closed-loop insulin delivery systems have been found in nonpregnant patients with type 1 diabetes to “be helpful in keeping people in range and also possibly [decreasing nocturnal hypoglycemia],” but the systems are not approved for use in pregnancy. “There’s not enough data on use in pregnancy, but probably more important, the algorithms used in the closed-loop systems are not directed to the targets we consider ideal for pregnancy,” Dr. Rosenn said.

In a pilot study of a closed-loop delivery system customized for pregnancies complicated by type 1 diabetes, 10 pregnant women were recruited at 14-32 weeks and, after a 1- to 2-week run-in period using a regular CGM-augmented pump, they used the closed-loop system targeting a daytime glucose of 80-110 mg/dL and nocturnal glucose of 80-100 mg/dL.

Mean TIR (a target range of 63-140 mg/dL) increased from 65% during the run-in period to 79% on the closed-loop system, and there were significant decreases in both time above range and time in the hypoglycemic ranges of < 63 mg/dL and < 54 mg/dL. Hypoglycemic events per week (defined as < 54 mg/dL for over 15 minutes) decreased from 4 to 0.7 (Diabetes Care. 2023;46:1425-31).

The investigators are continuing their research, and there are currently two randomized controlled trials underway examining use of closed-loop systems designed for pregnancy, said Dr. Rosenn, who was involved in feasibility research leading up to the pilot study. “So I’m hopeful we’ll see some encouraging information in the future.”

Maternal hypoglycemia during pregnancy is more common in type 1 diabetes, but it also affects pregnancies complicated by type 2 diabetes and GDM. In addition to the strict glycemic control imposed to improve maternal and fetal outcomes, pregnancy itself plays a role.

Research several decades ago from the Diabetes in Pregnancy Program Project, a prospective cohort in Cincinnati which Dr. Rosenn co-led, documented impaired counterregulatory physiology in pregnancy. Even in nondiabetic patients, there are declines in secretion of glucagon and growth hormone in response to hypoglycemia, for instance. In patients with type 1 diabetes, the diminishment in counterregulatory response is more severe.

Rethinking Intrapartum Care

Guidance for tight blood glucose control during labor and delivery for insulin-treated individuals — as reflected in the American College of Obstetricians and Gynecologists Practice Bulletin No. 201 on Pregestational Diabetes and in recommendations from the United Kingdom’s National Institute for Health and Care Excellence (NICE) — is based on small case series and overall “poor-quality” evidence that more recent research has failed to back up, Dr. Bartal said.

A systematic review published in 2018, for example, concluded there is a paucity of high-quality data supporting the association of glucose during labor and delivery with neonatal hypoglycemia in pregnancies complicated by diabetes (Diabet Med. 2018;35:173-83). And in a subsequent retrospective cohort study of pregnant women with type 1/type 2/GDM and their neonates, the same investigators reported no difference in the target glucose in labor between those with and without neonatal hypotension, after adjustment for important neonatal factors such as LGA and preterm delivery (Diabet Med. 2020;37:138-46).

Also exemplifying the body of research, Dr. Bartal said, is another single-center retrospective study published in 2020 that evaluated outcomes in the years before and after the institution of a formal intrapartum insulin regimen (a standardized protocol for titration of insulin and glucose infusions) for women with pregestational or gestational diabetes. The protocol was associated with improved maternal glucose control, but an increased frequency of neonatal hypoglycemia (Obstet Gynecol. 2020;136:411-6).

Her own group at the University of Texas in Houston looked retrospectively at 233 insulin-treated pregnancies complicated by type 2 diabetes and found no significant difference in the rate of neonatal hypoglycemia between those placed on a drip and those who were not, Dr. Bartal said. Over 40% of the newborns had hypoglycemia; it occurred irrespective of the route of delivery as well (J Matern Fetal Neonatal Med. 2022;35:7445-51).

Only two published randomized controlled trials have evaluated blood sugar control in labor, she said. The first, published in 2006, compared a continuous insulin drip with a rotation of glucose and non–glucose-containing fluids in insulin-requiring diabetes and found no differences in maternal blood glucose (the primary outcome) and a similar risk of neonatal hypoglycemia (Am J Obstet Gynecol. 2006;195;1095-9).

The second RCT, published in 2019, evaluated tight versus liberalized control (60-100 mg/dL, checking every hour, versus 60-120 mg/dL, checking every 4 hours) in laboring women with GDM. The first neonatal blood glucose level was similar in both groups, while the mean neonatal blood glucose level in the first 24 hours of life was lower with tight control (54 vs 58 mg/dL, P = .49) (Obstet Gynecol. 2019;133:1171-7). Findings from a new RCT conducted at the University of Texas in Houston of usual care versus more permissive glucose control will be presented at the SMFM Pregnancy Meeting in February 2024, she said.

Neonatal hypoglycemia is associated with increased risk of NICU admission, “but it’s also associated with possible long-term developmental deficit,” Dr. Bartal said, with the risk highest in children exposed to severe, recurrent, or clinically undetected hypoglycemia. Research has documented significantly increased risks of low executive function and visual motor function, for instance, in children who experienced neonatal hypoglycemia.

The risk of neonatal hypoglycemia has been linked to a variety of factors outside of the intrapartum period such as diabetes control and weight gain during pregnancy, neonatal birth weight/LGA, neonatal adiposity, gestational age at delivery, maternal body mass index, smoking, and diabetes control prior to pregnancy, Dr. Bartal noted. Also challenging is the reality that neonatal hypoglycemia as a research outcome is not standardized; definitions have varied across studies.

Tight intrapartum control comes with “costs,” from close monitoring of labor to increased resource utilization, and it may affect the labor experience/satisfaction, Dr. Bartal said. “But furthermore,” she said, “there are studies coming out, especially in the anesthesiology journals, that show there may be possible harm,” such as the risk of maternal and neonatal hyponatremia, and maternal hypoglycemia. A 2016 editorial in Anaesthesia (2016;71:750) describes these concerns, she noted.

“I do think we need to rethink our current recommendations,” she said.

Dr. Durnwald reported serving on the Dexcom GDM advisory board and receiving funding from United Health Group and the Helmsley Charitable Trust. Dr. Bartal and Dr. Rosenn reported no conflicts of interest.

Testosterone replacement therapy in the treatment of hypogonadism showed no benefit in slowing the progression of prediabetes or diabetes, contrary to previous evidence that suggested potential improvements in insulin sensitivity and metabolism.

“The findings of this study suggest that testosterone replacement therapy alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism,” reported the authors of research published this month in JAMA Internal Medicine.

The suggestion that testosterone replacement could prevent or slow diabetes stems from numerous studies linking testosterone deficiency to a host of adverse effects that include increases in insulin resistance and an increased risk for prediabetes and type 2 diabetes.

Furthermore, one recent uncontrolled study showed a lower rate of progression from prediabetes to diabetes in testosterone-treated vs untreated men with hypogonadism.

But with no known randomized clinical trials evaluating the effects of testosterone on diabetes in the absence of a concurrent lifestyle intervention, Shalender Bhasin, MB, of the Research Program in Men’s Health: Aging and Metabolism, at Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues conducted a substudy of the randomized TRAVERSE trial, which was conducted at 316 sites in the United States.

“We hypothesized that testosterone replacement therapy for men with hypogonadism and prediabetes would be associated with a significantly lower rate of progression to diabetes,” they wrote.

In the study, named the TRAVERSE Diabetes Study, 5204 participants aged between 40 and 85 years with hypogonadism as well as prediabetes (n = 1175) or diabetes (n = 3880) were randomized 1:1 to receive treatment either with 1.62% testosterone gel or placebo gel.

The participants had a mean age of 63.2 years, and the mean A1c among those with prediabetes was 5.8%.

For the primary outcome, the risk for progression to diabetes did not differ significantly between the testosterone-treated and placebo groups at 6 months (0.7% vs 1.4%), 12 months (7.8% vs 10.7%), 24 months (10.1% vs 14.6%), 36 months (12.8% vs 15.8%), or 48 months (13.4% vs 15.7%; omnibus test P = .49).

There were also no significant differences in terms of glycemic remission and the changes in glucose and A1c levels between the testosterone- and placebo-treated men with prediabetes or diabetes, consistent with findings from previous smaller trials.

The authors pointed out that the participants in the TRAVERSE trial had mild to moderate testosterone deficiency, and “it is possible that greater improvements in insulin sensitivity may be observed in men with severe testosterone deficiency.”

However, they noted that most men with hypogonadism who are treated with testosterone replacement therapy have only mild testosterone deficiency.

The parent TRAVERSE study did show testosterone replacement therapy to be associated with higher incidences of venous thromboembolism, atrial fibrillation, and acute kidney injury; however, no additional between-group differences were observed based on diabetes or prediabetes status.

“The findings of this study do not support the use of testosterone replacement therapy alone to prevent or to treat diabetes in men with hypogonadism,” the authors concluded.
 

Study ‘Overcomes Limitations of Prior Studies’

In an editorial published concurrently with the study, Lona Mody, MD, of the Division of Geriatric and Palliative Care Medicine, University of Michigan Medical School, in Ann Arbor, and colleagues underscored that “the results of this study suggest that testosterone replacement therapy will not benefit glycemic control in men without hypogonadism despite the inappropriately high rates of use in this group.”

Further commenting, Dr. Mody elaborated on the high rates of use, noting that data have shown androgen use among men over 40 years increased more than threefold from 0.81% in 2001 to 2.91% in 2011.

“Based on sales data, testosterone prescribing has increased 100-fold from $18 million in the late 1980s to $1.8 billion over three decades,” Dr. Mody said.

She noted that while some previous research has shown a similar lack of benefits, “the current study overcomes some limitations of prior studies.”

Ultimately, the evidence indicated that “the only major indication for testosterone replacement therapy remains to treat bothersome symptoms of hypogonadism,” Dr. Mody said. “It does not appear to have metabolic benefits.”

This trial was funded by a consortium of testosterone manufacturers led by AbbVie Inc., with additional financial support provided by Endo Pharmaceuticals, Acerus Pharmaceuticals Corporation, and Upsher-Smith Laboratories, LLC.
 

A version of this article appeared on Medscape.com.

Testosterone replacement therapy in the treatment of hypogonadism showed no benefit in slowing the progression of prediabetes or diabetes, contrary to previous evidence that suggested potential improvements in insulin sensitivity and metabolism.

“The findings of this study suggest that testosterone replacement therapy alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism,” reported the authors of research published this month in JAMA Internal Medicine.

The suggestion that testosterone replacement could prevent or slow diabetes stems from numerous studies linking testosterone deficiency to a host of adverse effects that include increases in insulin resistance and an increased risk for prediabetes and type 2 diabetes.

Furthermore, one recent uncontrolled study showed a lower rate of progression from prediabetes to diabetes in testosterone-treated vs untreated men with hypogonadism.

But with no known randomized clinical trials evaluating the effects of testosterone on diabetes in the absence of a concurrent lifestyle intervention, Shalender Bhasin, MB, of the Research Program in Men’s Health: Aging and Metabolism, at Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues conducted a substudy of the randomized TRAVERSE trial, which was conducted at 316 sites in the United States.

“We hypothesized that testosterone replacement therapy for men with hypogonadism and prediabetes would be associated with a significantly lower rate of progression to diabetes,” they wrote.

In the study, named the TRAVERSE Diabetes Study, 5204 participants aged between 40 and 85 years with hypogonadism as well as prediabetes (n = 1175) or diabetes (n = 3880) were randomized 1:1 to receive treatment either with 1.62% testosterone gel or placebo gel.

The participants had a mean age of 63.2 years, and the mean A1c among those with prediabetes was 5.8%.

For the primary outcome, the risk for progression to diabetes did not differ significantly between the testosterone-treated and placebo groups at 6 months (0.7% vs 1.4%), 12 months (7.8% vs 10.7%), 24 months (10.1% vs 14.6%), 36 months (12.8% vs 15.8%), or 48 months (13.4% vs 15.7%; omnibus test P = .49).

There were also no significant differences in terms of glycemic remission and the changes in glucose and A1c levels between the testosterone- and placebo-treated men with prediabetes or diabetes, consistent with findings from previous smaller trials.

The authors pointed out that the participants in the TRAVERSE trial had mild to moderate testosterone deficiency, and “it is possible that greater improvements in insulin sensitivity may be observed in men with severe testosterone deficiency.”

However, they noted that most men with hypogonadism who are treated with testosterone replacement therapy have only mild testosterone deficiency.

The parent TRAVERSE study did show testosterone replacement therapy to be associated with higher incidences of venous thromboembolism, atrial fibrillation, and acute kidney injury; however, no additional between-group differences were observed based on diabetes or prediabetes status.

“The findings of this study do not support the use of testosterone replacement therapy alone to prevent or to treat diabetes in men with hypogonadism,” the authors concluded.
 

Study ‘Overcomes Limitations of Prior Studies’

In an editorial published concurrently with the study, Lona Mody, MD, of the Division of Geriatric and Palliative Care Medicine, University of Michigan Medical School, in Ann Arbor, and colleagues underscored that “the results of this study suggest that testosterone replacement therapy will not benefit glycemic control in men without hypogonadism despite the inappropriately high rates of use in this group.”

Further commenting, Dr. Mody elaborated on the high rates of use, noting that data have shown androgen use among men over 40 years increased more than threefold from 0.81% in 2001 to 2.91% in 2011.

“Based on sales data, testosterone prescribing has increased 100-fold from $18 million in the late 1980s to $1.8 billion over three decades,” Dr. Mody said.

She noted that while some previous research has shown a similar lack of benefits, “the current study overcomes some limitations of prior studies.”

Ultimately, the evidence indicated that “the only major indication for testosterone replacement therapy remains to treat bothersome symptoms of hypogonadism,” Dr. Mody said. “It does not appear to have metabolic benefits.”

This trial was funded by a consortium of testosterone manufacturers led by AbbVie Inc., with additional financial support provided by Endo Pharmaceuticals, Acerus Pharmaceuticals Corporation, and Upsher-Smith Laboratories, LLC.
 

A version of this article appeared on Medscape.com.

Testosterone replacement therapy in the treatment of hypogonadism showed no benefit in slowing the progression of prediabetes or diabetes, contrary to previous evidence that suggested potential improvements in insulin sensitivity and metabolism.

“The findings of this study suggest that testosterone replacement therapy alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism,” reported the authors of research published this month in JAMA Internal Medicine.

The suggestion that testosterone replacement could prevent or slow diabetes stems from numerous studies linking testosterone deficiency to a host of adverse effects that include increases in insulin resistance and an increased risk for prediabetes and type 2 diabetes.

Furthermore, one recent uncontrolled study showed a lower rate of progression from prediabetes to diabetes in testosterone-treated vs untreated men with hypogonadism.

But with no known randomized clinical trials evaluating the effects of testosterone on diabetes in the absence of a concurrent lifestyle intervention, Shalender Bhasin, MB, of the Research Program in Men’s Health: Aging and Metabolism, at Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues conducted a substudy of the randomized TRAVERSE trial, which was conducted at 316 sites in the United States.

“We hypothesized that testosterone replacement therapy for men with hypogonadism and prediabetes would be associated with a significantly lower rate of progression to diabetes,” they wrote.

In the study, named the TRAVERSE Diabetes Study, 5204 participants aged between 40 and 85 years with hypogonadism as well as prediabetes (n = 1175) or diabetes (n = 3880) were randomized 1:1 to receive treatment either with 1.62% testosterone gel or placebo gel.

The participants had a mean age of 63.2 years, and the mean A1c among those with prediabetes was 5.8%.

For the primary outcome, the risk for progression to diabetes did not differ significantly between the testosterone-treated and placebo groups at 6 months (0.7% vs 1.4%), 12 months (7.8% vs 10.7%), 24 months (10.1% vs 14.6%), 36 months (12.8% vs 15.8%), or 48 months (13.4% vs 15.7%; omnibus test P = .49).

There were also no significant differences in terms of glycemic remission and the changes in glucose and A1c levels between the testosterone- and placebo-treated men with prediabetes or diabetes, consistent with findings from previous smaller trials.

The authors pointed out that the participants in the TRAVERSE trial had mild to moderate testosterone deficiency, and “it is possible that greater improvements in insulin sensitivity may be observed in men with severe testosterone deficiency.”

However, they noted that most men with hypogonadism who are treated with testosterone replacement therapy have only mild testosterone deficiency.

The parent TRAVERSE study did show testosterone replacement therapy to be associated with higher incidences of venous thromboembolism, atrial fibrillation, and acute kidney injury; however, no additional between-group differences were observed based on diabetes or prediabetes status.

“The findings of this study do not support the use of testosterone replacement therapy alone to prevent or to treat diabetes in men with hypogonadism,” the authors concluded.
 

Study ‘Overcomes Limitations of Prior Studies’

In an editorial published concurrently with the study, Lona Mody, MD, of the Division of Geriatric and Palliative Care Medicine, University of Michigan Medical School, in Ann Arbor, and colleagues underscored that “the results of this study suggest that testosterone replacement therapy will not benefit glycemic control in men without hypogonadism despite the inappropriately high rates of use in this group.”

Further commenting, Dr. Mody elaborated on the high rates of use, noting that data have shown androgen use among men over 40 years increased more than threefold from 0.81% in 2001 to 2.91% in 2011.

“Based on sales data, testosterone prescribing has increased 100-fold from $18 million in the late 1980s to $1.8 billion over three decades,” Dr. Mody said.

She noted that while some previous research has shown a similar lack of benefits, “the current study overcomes some limitations of prior studies.”

Ultimately, the evidence indicated that “the only major indication for testosterone replacement therapy remains to treat bothersome symptoms of hypogonadism,” Dr. Mody said. “It does not appear to have metabolic benefits.”

This trial was funded by a consortium of testosterone manufacturers led by AbbVie Inc., with additional financial support provided by Endo Pharmaceuticals, Acerus Pharmaceuticals Corporation, and Upsher-Smith Laboratories, LLC.
 

A version of this article appeared on Medscape.com.

Less than half of the dermatology residents surveyed reported specific training on management of sensitive skin, according to a survey of approximately 200 residents.

Although sensitive skin affects an estimated 40%-70% of the population, knowledge of the pathophysiology of sensitive skin is incomplete, and consensus is lacking as to the best diagnosis and treatment strategies, and the inclusion of sensitive skin education in dermatology curricula has not been examined, according to Erika T. McCormick, BS, and Adam Friedman, MD, of George Washington University, Washington, DC.

For the study, published in the Journal of Drugs in Dermatology, they developed a 26-question survey for dermatology residents that asked about sensitive skin in dermatology residency training. Participants came from the Orlando Dermatology, Aesthetic, and Surgical Conference email list.

Survey respondents included 214 residents at various levels of training at programs across the United States; 67.1% were female, 92.1% were aged 25-34 years, and 85.5% were in academic or university programs.

Overall, 99% of respondents believed that sensitive skin issues should be part of their residency training to some extent, and 84% reported experiences with patients for whom the chief presenting complaint was sensitive skin.

However, fewer than half (48%) of the residents reported specific resident education in sensitive skin, while 51% reported nonspecific education about sensitive skin education in the context of other skin diseases, and 1% reported no education about sensitive skin.

Less than one-quarter of the respondents who received any sensitive skin education reported feeling comfortable in their ability to diagnose, evaluate, and manage sensitive skin, while those with sensitive skin–specific education were significantly more likely to describe themselves as “very knowledgeable.”

As for treatment approaches, residents with specific sensitive skin education were more likely than were those without sensitive skin–specific training to ask patients about allergies and past reactions to skin products, and to counsel them about environmental triggers.

Notably, 96% of the respondents were not familiar with the Sensitive Skin (SS) Scale–10, a validated measure of sensitive skin severity.

The most common challenges in care of patients with sensitive skin were assessing improvement over time, reported by 25% of respondents, recommending products (23%), and prescribing/medical management (22%). The topics residents expressed most interest in learning about were product recommendations (78%), patient counseling (77%), reviewing research on sensitive skin (70%), diagnosing sensitive skin (67%), using the SS-10 (48%), and clinical research updates (40%).

The findings were limited by several factors including the reliance on self-reports, the researchers noted. However, the results highlight the lack of consensus in treatment of sensitive skin and the need to address this knowledge gap at the residency level, they said.
 

Improving Tools for Practice

“Many practice patterns and approaches are forged in the fires of training,” corresponding author Dr. Friedman, professor and chair of dermatology and residency program director at George Washington University, said in an interview. “Identifying gaps, especially for heavily prevalent issues, questions, and concerns such as sensitive skin that residents will encounter in practice is important to ensure an educated workforce,” he said.

Education on sensitive skin is lacking because, until recently, research and clinical guidance have been lacking, Dr. Friedman said. The root of the problem is that sensitive skin is mainly considered a symptom, rather than an independent condition, he explained. “Depending on the study, the prevalence of sensitive skin has been reported as high as 70%, with roughly 40% of these patients having no primary skin condition,” he said. This means sensitive skin can be both a symptom and a condition, which causes confusion for clinicians and patients, he added.

“Therefore, in order to overcome this gap, the condition itself at a minimum needs a standard definition and a way to diagnosis, which we fortunately have in the validated research tool known as the SS-10,” said Dr. Friedman.

Almost all residents surveyed in the current study had never heard of the SS-10, but more than half found it to be useful after learning of it through the study survey, he noted.

Looking ahead, greater elucidation of the pathophysiology of sensitive skin is needed to effectively pursue studies of products and treatments for these patients, but the SS-10 can be used to define and monitor the condition to evaluate improvement, he added.

The study was funded by an independent fellowship grant from Galderma. Ms. McCormick is supported by an unrestricted fellowship grant funded by Galderma. Dr. Friedman has served as a consultant for Galderma.

Less than half of the dermatology residents surveyed reported specific training on management of sensitive skin, according to a survey of approximately 200 residents.

Although sensitive skin affects an estimated 40%-70% of the population, knowledge of the pathophysiology of sensitive skin is incomplete, and consensus is lacking as to the best diagnosis and treatment strategies, and the inclusion of sensitive skin education in dermatology curricula has not been examined, according to Erika T. McCormick, BS, and Adam Friedman, MD, of George Washington University, Washington, DC.

For the study, published in the Journal of Drugs in Dermatology, they developed a 26-question survey for dermatology residents that asked about sensitive skin in dermatology residency training. Participants came from the Orlando Dermatology, Aesthetic, and Surgical Conference email list.

Survey respondents included 214 residents at various levels of training at programs across the United States; 67.1% were female, 92.1% were aged 25-34 years, and 85.5% were in academic or university programs.

Overall, 99% of respondents believed that sensitive skin issues should be part of their residency training to some extent, and 84% reported experiences with patients for whom the chief presenting complaint was sensitive skin.

However, fewer than half (48%) of the residents reported specific resident education in sensitive skin, while 51% reported nonspecific education about sensitive skin education in the context of other skin diseases, and 1% reported no education about sensitive skin.

Less than one-quarter of the respondents who received any sensitive skin education reported feeling comfortable in their ability to diagnose, evaluate, and manage sensitive skin, while those with sensitive skin–specific education were significantly more likely to describe themselves as “very knowledgeable.”

As for treatment approaches, residents with specific sensitive skin education were more likely than were those without sensitive skin–specific training to ask patients about allergies and past reactions to skin products, and to counsel them about environmental triggers.

Notably, 96% of the respondents were not familiar with the Sensitive Skin (SS) Scale–10, a validated measure of sensitive skin severity.

The most common challenges in care of patients with sensitive skin were assessing improvement over time, reported by 25% of respondents, recommending products (23%), and prescribing/medical management (22%). The topics residents expressed most interest in learning about were product recommendations (78%), patient counseling (77%), reviewing research on sensitive skin (70%), diagnosing sensitive skin (67%), using the SS-10 (48%), and clinical research updates (40%).

The findings were limited by several factors including the reliance on self-reports, the researchers noted. However, the results highlight the lack of consensus in treatment of sensitive skin and the need to address this knowledge gap at the residency level, they said.
 

Improving Tools for Practice

“Many practice patterns and approaches are forged in the fires of training,” corresponding author Dr. Friedman, professor and chair of dermatology and residency program director at George Washington University, said in an interview. “Identifying gaps, especially for heavily prevalent issues, questions, and concerns such as sensitive skin that residents will encounter in practice is important to ensure an educated workforce,” he said.

Education on sensitive skin is lacking because, until recently, research and clinical guidance have been lacking, Dr. Friedman said. The root of the problem is that sensitive skin is mainly considered a symptom, rather than an independent condition, he explained. “Depending on the study, the prevalence of sensitive skin has been reported as high as 70%, with roughly 40% of these patients having no primary skin condition,” he said. This means sensitive skin can be both a symptom and a condition, which causes confusion for clinicians and patients, he added.

“Therefore, in order to overcome this gap, the condition itself at a minimum needs a standard definition and a way to diagnosis, which we fortunately have in the validated research tool known as the SS-10,” said Dr. Friedman.

Almost all residents surveyed in the current study had never heard of the SS-10, but more than half found it to be useful after learning of it through the study survey, he noted.

Looking ahead, greater elucidation of the pathophysiology of sensitive skin is needed to effectively pursue studies of products and treatments for these patients, but the SS-10 can be used to define and monitor the condition to evaluate improvement, he added.

The study was funded by an independent fellowship grant from Galderma. Ms. McCormick is supported by an unrestricted fellowship grant funded by Galderma. Dr. Friedman has served as a consultant for Galderma.

Less than half of the dermatology residents surveyed reported specific training on management of sensitive skin, according to a survey of approximately 200 residents.

Although sensitive skin affects an estimated 40%-70% of the population, knowledge of the pathophysiology of sensitive skin is incomplete, and consensus is lacking as to the best diagnosis and treatment strategies, and the inclusion of sensitive skin education in dermatology curricula has not been examined, according to Erika T. McCormick, BS, and Adam Friedman, MD, of George Washington University, Washington, DC.

For the study, published in the Journal of Drugs in Dermatology, they developed a 26-question survey for dermatology residents that asked about sensitive skin in dermatology residency training. Participants came from the Orlando Dermatology, Aesthetic, and Surgical Conference email list.

Survey respondents included 214 residents at various levels of training at programs across the United States; 67.1% were female, 92.1% were aged 25-34 years, and 85.5% were in academic or university programs.

Overall, 99% of respondents believed that sensitive skin issues should be part of their residency training to some extent, and 84% reported experiences with patients for whom the chief presenting complaint was sensitive skin.

However, fewer than half (48%) of the residents reported specific resident education in sensitive skin, while 51% reported nonspecific education about sensitive skin education in the context of other skin diseases, and 1% reported no education about sensitive skin.

Less than one-quarter of the respondents who received any sensitive skin education reported feeling comfortable in their ability to diagnose, evaluate, and manage sensitive skin, while those with sensitive skin–specific education were significantly more likely to describe themselves as “very knowledgeable.”

As for treatment approaches, residents with specific sensitive skin education were more likely than were those without sensitive skin–specific training to ask patients about allergies and past reactions to skin products, and to counsel them about environmental triggers.

Notably, 96% of the respondents were not familiar with the Sensitive Skin (SS) Scale–10, a validated measure of sensitive skin severity.

The most common challenges in care of patients with sensitive skin were assessing improvement over time, reported by 25% of respondents, recommending products (23%), and prescribing/medical management (22%). The topics residents expressed most interest in learning about were product recommendations (78%), patient counseling (77%), reviewing research on sensitive skin (70%), diagnosing sensitive skin (67%), using the SS-10 (48%), and clinical research updates (40%).

The findings were limited by several factors including the reliance on self-reports, the researchers noted. However, the results highlight the lack of consensus in treatment of sensitive skin and the need to address this knowledge gap at the residency level, they said.
 

Improving Tools for Practice

“Many practice patterns and approaches are forged in the fires of training,” corresponding author Dr. Friedman, professor and chair of dermatology and residency program director at George Washington University, said in an interview. “Identifying gaps, especially for heavily prevalent issues, questions, and concerns such as sensitive skin that residents will encounter in practice is important to ensure an educated workforce,” he said.

Education on sensitive skin is lacking because, until recently, research and clinical guidance have been lacking, Dr. Friedman said. The root of the problem is that sensitive skin is mainly considered a symptom, rather than an independent condition, he explained. “Depending on the study, the prevalence of sensitive skin has been reported as high as 70%, with roughly 40% of these patients having no primary skin condition,” he said. This means sensitive skin can be both a symptom and a condition, which causes confusion for clinicians and patients, he added.

“Therefore, in order to overcome this gap, the condition itself at a minimum needs a standard definition and a way to diagnosis, which we fortunately have in the validated research tool known as the SS-10,” said Dr. Friedman.

Almost all residents surveyed in the current study had never heard of the SS-10, but more than half found it to be useful after learning of it through the study survey, he noted.

Looking ahead, greater elucidation of the pathophysiology of sensitive skin is needed to effectively pursue studies of products and treatments for these patients, but the SS-10 can be used to define and monitor the condition to evaluate improvement, he added.

The study was funded by an independent fellowship grant from Galderma. Ms. McCormick is supported by an unrestricted fellowship grant funded by Galderma. Dr. Friedman has served as a consultant for Galderma.

Blue Hill is a small idyllic town a little less than two and a half hours Down East the coast from where I am sitting here in Harpswell. Thanks to gentrification it tends to lean left politically, but like the rest of Maine most folks in the surrounding communities often don’t know or care much about their neighbor’s party affiliation. Its library, founded in 1796, is well funded and a source of civic pride.

One day a couple of years ago, the library director received a donated book from a patron. Although he personally didn’t agree with the book’s message, he felt it deserved a space in their collection dealing with the subject. What happened in the wake of this donation is an ugly tale. Some community members objected to the book and asked that it be removed from the shelves, or at least kept under the desk and loaned out only on request.

The objectors, many of whom knew the director, were confrontational. The collections committee unanimously supported his decision. Some committee members also received similar responses from community members. Remember, this is a small town.

A request for support sent to the American Library Association was basically ignored. Over the next 2 years things have quieted, but fractured friendships and relationships in this quiet coastal Maine town have not been repaired. However, as the librarian has observed, “intellectual freedom or the freedom of speech isn’t there just to protect the ideas that we like.”

While the title of the book may feel inflammatory to some, every publisher hopes to grab the market’s attention with a hot title. The cause of this sad situation in Blue Hill was not a white supremacist’s polemic offering specific ways to create genocide. This was a book suggesting that gender dysphoria presenting in adolescence may have multiple causes and raises concerns about the wisdom of the pace of some gender-affirming care.

Clearly the topic of gender dysphoria in adolescence has become a third rail that must be approached with caution or completely avoided. A recent opinion piece in the New York Times provides even more concerning examples of this peril. Again, the eye-catching title of the article — As Kids, They Thought They Were Trans. They No Longer Do — draws in the audience eager to read about some unfortunate individuals who have regretted their decision to transition and are now detransitioning.

If you are interested in hearing anecdotal evidence and opinions supporting the notion that there is such a thing as rapid-onset gender dysphoria, I suggest you read the entire piece. However, the article’s most troubling message for me comes when I read about the professionals who were former gender-related care providers who left the field because of “pushback, the accusations of being transphobic, from being pro-assessment and wanting a more thorough process.”

One therapist trained in gender-affirming care who began to have doubts about the model and spoke out in favor of a more measured approach was investigated by her licensing board after transgender advocates threatened to report her. Ultimately, her case was dismissed, but she continues to fear for her safety.

Gender-related healthcare is another sad example of how in this country it is the noise coming from the advocates on the extremes of the issue that is drowning out the “vast ideological middle” that is seeking civil and rational discussions.

In this situation there are those who want to make it illegal for the healthcare providers to help patients who might benefit from transitioning. On the other end of the spectrum are those advocates who are unwilling to acknowledge that there may be some adolescents with what has been called by some “rapid-onset gender dysphoria.”

The landscape on which this tragedy is being played out is changing so quickly that there will be no correct answers in the short term. There just isn’t enough data. However, there is enough anecdotal evidence from professionals who were and still are practicing gender-related care to raise a concern that something is happening in the adolescent population that suggests some individuals with gender dysphoria should be managed in a different way than the currently accepted gender-affirming model. The size of this subgroup is up for debate and we may never learn it because of reporting bias and privacy concerns.

The American Academy of Pediatrics has recently authorized a systematic review of gender-affirming care. I hope that, like the librarian in Blue Hill, it will have the courage to include all the evidence available even though, as we have seen here in Maine, some of it may spark a firestorm of vehement responses.

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

Blue Hill is a small idyllic town a little less than two and a half hours Down East the coast from where I am sitting here in Harpswell. Thanks to gentrification it tends to lean left politically, but like the rest of Maine most folks in the surrounding communities often don’t know or care much about their neighbor’s party affiliation. Its library, founded in 1796, is well funded and a source of civic pride.

One day a couple of years ago, the library director received a donated book from a patron. Although he personally didn’t agree with the book’s message, he felt it deserved a space in their collection dealing with the subject. What happened in the wake of this donation is an ugly tale. Some community members objected to the book and asked that it be removed from the shelves, or at least kept under the desk and loaned out only on request.

The objectors, many of whom knew the director, were confrontational. The collections committee unanimously supported his decision. Some committee members also received similar responses from community members. Remember, this is a small town.

A request for support sent to the American Library Association was basically ignored. Over the next 2 years things have quieted, but fractured friendships and relationships in this quiet coastal Maine town have not been repaired. However, as the librarian has observed, “intellectual freedom or the freedom of speech isn’t there just to protect the ideas that we like.”

While the title of the book may feel inflammatory to some, every publisher hopes to grab the market’s attention with a hot title. The cause of this sad situation in Blue Hill was not a white supremacist’s polemic offering specific ways to create genocide. This was a book suggesting that gender dysphoria presenting in adolescence may have multiple causes and raises concerns about the wisdom of the pace of some gender-affirming care.

Clearly the topic of gender dysphoria in adolescence has become a third rail that must be approached with caution or completely avoided. A recent opinion piece in the New York Times provides even more concerning examples of this peril. Again, the eye-catching title of the article — As Kids, They Thought They Were Trans. They No Longer Do — draws in the audience eager to read about some unfortunate individuals who have regretted their decision to transition and are now detransitioning.

If you are interested in hearing anecdotal evidence and opinions supporting the notion that there is such a thing as rapid-onset gender dysphoria, I suggest you read the entire piece. However, the article’s most troubling message for me comes when I read about the professionals who were former gender-related care providers who left the field because of “pushback, the accusations of being transphobic, from being pro-assessment and wanting a more thorough process.”

One therapist trained in gender-affirming care who began to have doubts about the model and spoke out in favor of a more measured approach was investigated by her licensing board after transgender advocates threatened to report her. Ultimately, her case was dismissed, but she continues to fear for her safety.

Gender-related healthcare is another sad example of how in this country it is the noise coming from the advocates on the extremes of the issue that is drowning out the “vast ideological middle” that is seeking civil and rational discussions.

In this situation there are those who want to make it illegal for the healthcare providers to help patients who might benefit from transitioning. On the other end of the spectrum are those advocates who are unwilling to acknowledge that there may be some adolescents with what has been called by some “rapid-onset gender dysphoria.”

The landscape on which this tragedy is being played out is changing so quickly that there will be no correct answers in the short term. There just isn’t enough data. However, there is enough anecdotal evidence from professionals who were and still are practicing gender-related care to raise a concern that something is happening in the adolescent population that suggests some individuals with gender dysphoria should be managed in a different way than the currently accepted gender-affirming model. The size of this subgroup is up for debate and we may never learn it because of reporting bias and privacy concerns.

The American Academy of Pediatrics has recently authorized a systematic review of gender-affirming care. I hope that, like the librarian in Blue Hill, it will have the courage to include all the evidence available even though, as we have seen here in Maine, some of it may spark a firestorm of vehement responses.

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

Blue Hill is a small idyllic town a little less than two and a half hours Down East the coast from where I am sitting here in Harpswell. Thanks to gentrification it tends to lean left politically, but like the rest of Maine most folks in the surrounding communities often don’t know or care much about their neighbor’s party affiliation. Its library, founded in 1796, is well funded and a source of civic pride.

One day a couple of years ago, the library director received a donated book from a patron. Although he personally didn’t agree with the book’s message, he felt it deserved a space in their collection dealing with the subject. What happened in the wake of this donation is an ugly tale. Some community members objected to the book and asked that it be removed from the shelves, or at least kept under the desk and loaned out only on request.

The objectors, many of whom knew the director, were confrontational. The collections committee unanimously supported his decision. Some committee members also received similar responses from community members. Remember, this is a small town.

A request for support sent to the American Library Association was basically ignored. Over the next 2 years things have quieted, but fractured friendships and relationships in this quiet coastal Maine town have not been repaired. However, as the librarian has observed, “intellectual freedom or the freedom of speech isn’t there just to protect the ideas that we like.”

While the title of the book may feel inflammatory to some, every publisher hopes to grab the market’s attention with a hot title. The cause of this sad situation in Blue Hill was not a white supremacist’s polemic offering specific ways to create genocide. This was a book suggesting that gender dysphoria presenting in adolescence may have multiple causes and raises concerns about the wisdom of the pace of some gender-affirming care.

Clearly the topic of gender dysphoria in adolescence has become a third rail that must be approached with caution or completely avoided. A recent opinion piece in the New York Times provides even more concerning examples of this peril. Again, the eye-catching title of the article — As Kids, They Thought They Were Trans. They No Longer Do — draws in the audience eager to read about some unfortunate individuals who have regretted their decision to transition and are now detransitioning.

If you are interested in hearing anecdotal evidence and opinions supporting the notion that there is such a thing as rapid-onset gender dysphoria, I suggest you read the entire piece. However, the article’s most troubling message for me comes when I read about the professionals who were former gender-related care providers who left the field because of “pushback, the accusations of being transphobic, from being pro-assessment and wanting a more thorough process.”

One therapist trained in gender-affirming care who began to have doubts about the model and spoke out in favor of a more measured approach was investigated by her licensing board after transgender advocates threatened to report her. Ultimately, her case was dismissed, but she continues to fear for her safety.

Gender-related healthcare is another sad example of how in this country it is the noise coming from the advocates on the extremes of the issue that is drowning out the “vast ideological middle” that is seeking civil and rational discussions.

In this situation there are those who want to make it illegal for the healthcare providers to help patients who might benefit from transitioning. On the other end of the spectrum are those advocates who are unwilling to acknowledge that there may be some adolescents with what has been called by some “rapid-onset gender dysphoria.”

The landscape on which this tragedy is being played out is changing so quickly that there will be no correct answers in the short term. There just isn’t enough data. However, there is enough anecdotal evidence from professionals who were and still are practicing gender-related care to raise a concern that something is happening in the adolescent population that suggests some individuals with gender dysphoria should be managed in a different way than the currently accepted gender-affirming model. The size of this subgroup is up for debate and we may never learn it because of reporting bias and privacy concerns.

The American Academy of Pediatrics has recently authorized a systematic review of gender-affirming care. I hope that, like the librarian in Blue Hill, it will have the courage to include all the evidence available even though, as we have seen here in Maine, some of it may spark a firestorm of vehement responses.

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

Patients with quiescent systemic lupus erythematosus (SLE) who are on maintenance therapy with mycophenolate mofetil (MMF) may be able to be safely weaned off the drug with the understanding that disease flare may occur and may require restarting immunosuppressive therapy.

That’s the conclusion of investigators in a multicenter randomized trial conducted at 19 US centers and published in The Lancet Rheumatology. They found that among 100 patients with stable SLE who were on MMF for at least 2 years for renal indications or at least 1 year for nonrenal indications, MMF withdrawal was not significantly inferior to MMF maintenance in terms of clinically significant disease reactivation within at least 1 year.

Oklahoma Medical Research Foundation

“Our findings suggest that mycophenolate mofetil could be safely withdrawn in patients with stable SLE. However, larger studies with a longer follow-up are still needed,” wrote Eliza F. Chakravarty, MD, MS, from the University of Oklahoma College of Medicine in Oklahoma City, and colleagues.

“Our study was only for 60 weeks, so we don’t have long-term data on what happens when patients taper off, but my recommendation — and I think the data support this — is that even if you do have a history of lupus nephritis, if you had stable disease or very little to no activity for a year or 2, then I think it’s worth stopping the medication and following for any signs of disease flare,” Dr. Chakravarty said in an interview with this news organization. 

She added that “in clinical practice, we would follow patients regularly no matter what they’re on, even if they’re in remission, looking for clinical signs or laboratory evidence of flare, and then if they look like they might be having flare, treat them accordingly.”
 

Toxicities a Concern

Although MMF is effective for inducing prolonged disease quiescence, it is a known teratogen and has significant toxicities, and it’s desirable to wean patients off the drug if it can be done safely, Dr. Chakravarty said.

The optimal duration of maintenance therapy with MMF is not known, however, which prompted the researchers to conduct the open-label study.

Patients aged 18-70 years who met the American College of Rheumatology (ACR) 1997 SLE criteria and had a clinical SLE Disease Activity Index (SLEDAI) score ≤ 4 at screening and who also had been on stable or tapering MMF therapy for 2 or more years for renal indications or 1 or more year for nonrenal indications were eligible. All patients were on a background regimen of hydroxychloroquine.

Patients were randomly assigned on an equal basis to either withdrawal with a 12-week taper or to continued maintenance at their baseline dose, ranging from 1 to 3 g/day for 60 weeks. 

The investigators used an adaptive random-allocation strategy to ensure that the groups were balanced for study site, renal vs nonrenal disease, and baseline MMF dose (≥ 2 g/day vs < 2 g/day).

A total of 100 patients with an average age of 42 years were included in a modified intention-to-treat analysis: 49 were randomly assigned to maintenance and 51 to withdrawal.

Overall, 84% of patients were women, 40% were White, and 41% were Black. Most patients, 76%, had a history of lupus nephritis. 

Significant disease reactivation, the primary endpoints, was defined as the need to increase prednisone to ≥ 15 mg/day for 4 weeks, the need for two or more short steroid bursts, or the need to resume MMF or start patients on another immunosuppressive therapy.

By week 60, 18% of patients in the withdrawal group had clinically significant disease reactivation compared with 10% of patients in the maintenance group.

“Although the differences were not significant, this study used an estimation-based design to determine estimated increases in clinically significant disease reactivation risk with 75%, 85%, and 95% confidence limits to assist clinicians and patients in making informed treatment decisions. We found a 6%-8% increase with upper 85% confidence limits of 11%-19% in clinically significant disease reactivation and flare risk following mycophenolate mofetil withdrawal,” the investigators wrote.

Rates of adverse events were similar between the groups, occurring in 90% of patients in the maintenance arm and 88% of those in the withdrawal arm. Infections occurred more frequently among patients in the maintenance group, at 64% vs 46%.
 

Encouraging Data

In an accompanying editorial, Noémie Jourde-Chiche, MD, PhD, from Aix-Marseille University in Marseille, France, and Laurent Chiche, MD, from Hopital Europeen de Marseille, wrote that the study data “were clearly encouraging.” They noted that the results show that it’s feasible to wean select patients off immunosuppressive therapy and keep SLE in check and that the quantified risk assessment strategy will allow shared decision-making for each patient.

“Overall, the prospect of a time-limited (versus lifelong) treatment may favor compliance, as observed in other disease fields, which might consolidate remission and reduce the risk of subsequent relapse, using sequentially treat-to-target and think-to-untreat strategies for a win-wean era in SLE,” they wrote.

“We’ve been awaiting the results of this trial for quite a while, and so it is nice to see it out,” commented Karen H. Costenbader, MD, MPH, professor of medicine at Harvard Medical School, and chair of the division of rheumatology and director of the Lupus Program at Brigham and Women’s Hospital in Boston, Massachusetts.

“It does provide some data to address a question that comes up in discussions with patients all the time: A person with lupus has been doing really well, in what we call low disease activity state or remission, but on mycophenolate, possibly for several years,” she said in a reply to a request for objective commentary.

“The question is how and when to taper and can MMF be safely discontinued,” she said. “Personally, I always review the severity of the underlying disease and indication for the MMF in the first place. Really active SLE with rapidly progressing kidney or other organ damage has to be treated with tremendous respect and no one wants to go back there. I also think about how long it has been, which other medications are still being taken (hydroxychloroquine, belimumab [Benlysta], etc.) and whether the labs and symptoms have really returned to completely normal. Then I have discussions about all this with my patient and we often try a long, slow, gingerly taper with a lot of interim monitoring.”

The study was funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Chakravarty and Dr. Costenbader report no relevant financial relationships. Dr. Jourde-Chiche declares personal consulting fees from Otsuka and AstraZeneca, personal speaking fees from GlaxoSmithKline and Otsuka, and personal payment for expert testimony from Otsuka. Dr. Chiche declares research grants paid to his institution from AstraZeneca and GlaxoSmithKline, personal consulting fees from Novartis and AstraZeneca, and personal speaking fees from GlaxoSmithKline and Novartis.

A version of this article appeared on Medscape.com . 

Patients with quiescent systemic lupus erythematosus (SLE) who are on maintenance therapy with mycophenolate mofetil (MMF) may be able to be safely weaned off the drug with the understanding that disease flare may occur and may require restarting immunosuppressive therapy.

That’s the conclusion of investigators in a multicenter randomized trial conducted at 19 US centers and published in The Lancet Rheumatology. They found that among 100 patients with stable SLE who were on MMF for at least 2 years for renal indications or at least 1 year for nonrenal indications, MMF withdrawal was not significantly inferior to MMF maintenance in terms of clinically significant disease reactivation within at least 1 year.

Oklahoma Medical Research Foundation

“Our findings suggest that mycophenolate mofetil could be safely withdrawn in patients with stable SLE. However, larger studies with a longer follow-up are still needed,” wrote Eliza F. Chakravarty, MD, MS, from the University of Oklahoma College of Medicine in Oklahoma City, and colleagues.

“Our study was only for 60 weeks, so we don’t have long-term data on what happens when patients taper off, but my recommendation — and I think the data support this — is that even if you do have a history of lupus nephritis, if you had stable disease or very little to no activity for a year or 2, then I think it’s worth stopping the medication and following for any signs of disease flare,” Dr. Chakravarty said in an interview with this news organization. 

She added that “in clinical practice, we would follow patients regularly no matter what they’re on, even if they’re in remission, looking for clinical signs or laboratory evidence of flare, and then if they look like they might be having flare, treat them accordingly.”
 

Toxicities a Concern

Although MMF is effective for inducing prolonged disease quiescence, it is a known teratogen and has significant toxicities, and it’s desirable to wean patients off the drug if it can be done safely, Dr. Chakravarty said.

The optimal duration of maintenance therapy with MMF is not known, however, which prompted the researchers to conduct the open-label study.

Patients aged 18-70 years who met the American College of Rheumatology (ACR) 1997 SLE criteria and had a clinical SLE Disease Activity Index (SLEDAI) score ≤ 4 at screening and who also had been on stable or tapering MMF therapy for 2 or more years for renal indications or 1 or more year for nonrenal indications were eligible. All patients were on a background regimen of hydroxychloroquine.

Patients were randomly assigned on an equal basis to either withdrawal with a 12-week taper or to continued maintenance at their baseline dose, ranging from 1 to 3 g/day for 60 weeks. 

The investigators used an adaptive random-allocation strategy to ensure that the groups were balanced for study site, renal vs nonrenal disease, and baseline MMF dose (≥ 2 g/day vs < 2 g/day).

A total of 100 patients with an average age of 42 years were included in a modified intention-to-treat analysis: 49 were randomly assigned to maintenance and 51 to withdrawal.

Overall, 84% of patients were women, 40% were White, and 41% were Black. Most patients, 76%, had a history of lupus nephritis. 

Significant disease reactivation, the primary endpoints, was defined as the need to increase prednisone to ≥ 15 mg/day for 4 weeks, the need for two or more short steroid bursts, or the need to resume MMF or start patients on another immunosuppressive therapy.

By week 60, 18% of patients in the withdrawal group had clinically significant disease reactivation compared with 10% of patients in the maintenance group.

“Although the differences were not significant, this study used an estimation-based design to determine estimated increases in clinically significant disease reactivation risk with 75%, 85%, and 95% confidence limits to assist clinicians and patients in making informed treatment decisions. We found a 6%-8% increase with upper 85% confidence limits of 11%-19% in clinically significant disease reactivation and flare risk following mycophenolate mofetil withdrawal,” the investigators wrote.

Rates of adverse events were similar between the groups, occurring in 90% of patients in the maintenance arm and 88% of those in the withdrawal arm. Infections occurred more frequently among patients in the maintenance group, at 64% vs 46%.
 

Encouraging Data

In an accompanying editorial, Noémie Jourde-Chiche, MD, PhD, from Aix-Marseille University in Marseille, France, and Laurent Chiche, MD, from Hopital Europeen de Marseille, wrote that the study data “were clearly encouraging.” They noted that the results show that it’s feasible to wean select patients off immunosuppressive therapy and keep SLE in check and that the quantified risk assessment strategy will allow shared decision-making for each patient.

“Overall, the prospect of a time-limited (versus lifelong) treatment may favor compliance, as observed in other disease fields, which might consolidate remission and reduce the risk of subsequent relapse, using sequentially treat-to-target and think-to-untreat strategies for a win-wean era in SLE,” they wrote.

“We’ve been awaiting the results of this trial for quite a while, and so it is nice to see it out,” commented Karen H. Costenbader, MD, MPH, professor of medicine at Harvard Medical School, and chair of the division of rheumatology and director of the Lupus Program at Brigham and Women’s Hospital in Boston, Massachusetts.

“It does provide some data to address a question that comes up in discussions with patients all the time: A person with lupus has been doing really well, in what we call low disease activity state or remission, but on mycophenolate, possibly for several years,” she said in a reply to a request for objective commentary.

“The question is how and when to taper and can MMF be safely discontinued,” she said. “Personally, I always review the severity of the underlying disease and indication for the MMF in the first place. Really active SLE with rapidly progressing kidney or other organ damage has to be treated with tremendous respect and no one wants to go back there. I also think about how long it has been, which other medications are still being taken (hydroxychloroquine, belimumab [Benlysta], etc.) and whether the labs and symptoms have really returned to completely normal. Then I have discussions about all this with my patient and we often try a long, slow, gingerly taper with a lot of interim monitoring.”

The study was funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Chakravarty and Dr. Costenbader report no relevant financial relationships. Dr. Jourde-Chiche declares personal consulting fees from Otsuka and AstraZeneca, personal speaking fees from GlaxoSmithKline and Otsuka, and personal payment for expert testimony from Otsuka. Dr. Chiche declares research grants paid to his institution from AstraZeneca and GlaxoSmithKline, personal consulting fees from Novartis and AstraZeneca, and personal speaking fees from GlaxoSmithKline and Novartis.

A version of this article appeared on Medscape.com . 

Patients with quiescent systemic lupus erythematosus (SLE) who are on maintenance therapy with mycophenolate mofetil (MMF) may be able to be safely weaned off the drug with the understanding that disease flare may occur and may require restarting immunosuppressive therapy.

That’s the conclusion of investigators in a multicenter randomized trial conducted at 19 US centers and published in The Lancet Rheumatology. They found that among 100 patients with stable SLE who were on MMF for at least 2 years for renal indications or at least 1 year for nonrenal indications, MMF withdrawal was not significantly inferior to MMF maintenance in terms of clinically significant disease reactivation within at least 1 year.

Oklahoma Medical Research Foundation

“Our findings suggest that mycophenolate mofetil could be safely withdrawn in patients with stable SLE. However, larger studies with a longer follow-up are still needed,” wrote Eliza F. Chakravarty, MD, MS, from the University of Oklahoma College of Medicine in Oklahoma City, and colleagues.

“Our study was only for 60 weeks, so we don’t have long-term data on what happens when patients taper off, but my recommendation — and I think the data support this — is that even if you do have a history of lupus nephritis, if you had stable disease or very little to no activity for a year or 2, then I think it’s worth stopping the medication and following for any signs of disease flare,” Dr. Chakravarty said in an interview with this news organization. 

She added that “in clinical practice, we would follow patients regularly no matter what they’re on, even if they’re in remission, looking for clinical signs or laboratory evidence of flare, and then if they look like they might be having flare, treat them accordingly.”
 

Toxicities a Concern

Although MMF is effective for inducing prolonged disease quiescence, it is a known teratogen and has significant toxicities, and it’s desirable to wean patients off the drug if it can be done safely, Dr. Chakravarty said.

The optimal duration of maintenance therapy with MMF is not known, however, which prompted the researchers to conduct the open-label study.

Patients aged 18-70 years who met the American College of Rheumatology (ACR) 1997 SLE criteria and had a clinical SLE Disease Activity Index (SLEDAI) score ≤ 4 at screening and who also had been on stable or tapering MMF therapy for 2 or more years for renal indications or 1 or more year for nonrenal indications were eligible. All patients were on a background regimen of hydroxychloroquine.

Patients were randomly assigned on an equal basis to either withdrawal with a 12-week taper or to continued maintenance at their baseline dose, ranging from 1 to 3 g/day for 60 weeks. 

The investigators used an adaptive random-allocation strategy to ensure that the groups were balanced for study site, renal vs nonrenal disease, and baseline MMF dose (≥ 2 g/day vs < 2 g/day).

A total of 100 patients with an average age of 42 years were included in a modified intention-to-treat analysis: 49 were randomly assigned to maintenance and 51 to withdrawal.

Overall, 84% of patients were women, 40% were White, and 41% were Black. Most patients, 76%, had a history of lupus nephritis. 

Significant disease reactivation, the primary endpoints, was defined as the need to increase prednisone to ≥ 15 mg/day for 4 weeks, the need for two or more short steroid bursts, or the need to resume MMF or start patients on another immunosuppressive therapy.

By week 60, 18% of patients in the withdrawal group had clinically significant disease reactivation compared with 10% of patients in the maintenance group.

“Although the differences were not significant, this study used an estimation-based design to determine estimated increases in clinically significant disease reactivation risk with 75%, 85%, and 95% confidence limits to assist clinicians and patients in making informed treatment decisions. We found a 6%-8% increase with upper 85% confidence limits of 11%-19% in clinically significant disease reactivation and flare risk following mycophenolate mofetil withdrawal,” the investigators wrote.

Rates of adverse events were similar between the groups, occurring in 90% of patients in the maintenance arm and 88% of those in the withdrawal arm. Infections occurred more frequently among patients in the maintenance group, at 64% vs 46%.
 

Encouraging Data

In an accompanying editorial, Noémie Jourde-Chiche, MD, PhD, from Aix-Marseille University in Marseille, France, and Laurent Chiche, MD, from Hopital Europeen de Marseille, wrote that the study data “were clearly encouraging.” They noted that the results show that it’s feasible to wean select patients off immunosuppressive therapy and keep SLE in check and that the quantified risk assessment strategy will allow shared decision-making for each patient.

“Overall, the prospect of a time-limited (versus lifelong) treatment may favor compliance, as observed in other disease fields, which might consolidate remission and reduce the risk of subsequent relapse, using sequentially treat-to-target and think-to-untreat strategies for a win-wean era in SLE,” they wrote.

“We’ve been awaiting the results of this trial for quite a while, and so it is nice to see it out,” commented Karen H. Costenbader, MD, MPH, professor of medicine at Harvard Medical School, and chair of the division of rheumatology and director of the Lupus Program at Brigham and Women’s Hospital in Boston, Massachusetts.

“It does provide some data to address a question that comes up in discussions with patients all the time: A person with lupus has been doing really well, in what we call low disease activity state or remission, but on mycophenolate, possibly for several years,” she said in a reply to a request for objective commentary.

“The question is how and when to taper and can MMF be safely discontinued,” she said. “Personally, I always review the severity of the underlying disease and indication for the MMF in the first place. Really active SLE with rapidly progressing kidney or other organ damage has to be treated with tremendous respect and no one wants to go back there. I also think about how long it has been, which other medications are still being taken (hydroxychloroquine, belimumab [Benlysta], etc.) and whether the labs and symptoms have really returned to completely normal. Then I have discussions about all this with my patient and we often try a long, slow, gingerly taper with a lot of interim monitoring.”

The study was funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Chakravarty and Dr. Costenbader report no relevant financial relationships. Dr. Jourde-Chiche declares personal consulting fees from Otsuka and AstraZeneca, personal speaking fees from GlaxoSmithKline and Otsuka, and personal payment for expert testimony from Otsuka. Dr. Chiche declares research grants paid to his institution from AstraZeneca and GlaxoSmithKline, personal consulting fees from Novartis and AstraZeneca, and personal speaking fees from GlaxoSmithKline and Novartis.

A version of this article appeared on Medscape.com . 

Circulating tumor cells (CTCs), the cells shed from a solid tumor into the bloodstream, may help doctors avoid having to do repeat needle biopsies on patients with unresectable non–small cell lung cancer.

Challenges to using CTCs clinically are that they are not abundant in the blood and have been difficult to isolate in patients with this type of cancer with commercially available assays.

New research published in Cell Reports may bring doctors closer to using CTCs as a biomarker for patients with non–small cell lung cancer (NSCLC) in clinic. In their paper, the authors show that an experimental nanotechnology can effectively isolate and measure CTCs in patients with stage 3 NSCLC. They also found that a precipitous drop in CTCs during chemoradiation treatment predicted significantly longer progression-free survival in those patients.
 

Study Results and Methods

For their research, study coauthors Shruti Jolly, MD, and Sunitha Nagrath, PhD, used a novel graphene oxide technology called the GO chip, developed more than a decade ago by Dr. Nagrath and her colleagues, to isolate CTCs from patients with stage 3 NSCLC. While a different technology, which is approved by the US Food and Drug Administration (FDA), uses a single antibody to pick up CTCs, the GO chip uses a cocktail of three antibodies to CTC proteins, making it more sensitive.

The 26 patients in the study (mean age 67, 27% female) all received radiation treatment for 6 weeks, plus weekly carboplatin and paclitaxel chemotherapy. Sixteen of the patients afterward went on to have immunotherapy with durvalumab. Blood was drawn at six fixed time points: before treatment, and at weeks 1, 4, 10, 18, and 30. CTCs were measured and analyzed with every draw.

Previous studies showed that absolute number of CTCs did not correlate with either tumor volume or progression-free survival in NSCLC.

Dr. Jolly and Dr. Nagrath sought to measure change in CTCs from baseline for each patient, having the patient serve as his or her own control. They found that patients whose individual CTC counts dropped by 75% or more between pretreatment and week 4 of chemoradiation saw a mean 21 months of progression-free survival compared with 7 months for patients whose CTCs dropped by less than 75% in the same period (P = .0076).

Dr. Jolly and Dr. Nagrath also aimed to determine, as an exploratory outcome of their study, whether other information collected from the CTCs could predict response to treatment with durvalumab immunotherapy. They found that having more than 50% of CTCs positive for the protein PD-L1 correlated to shorter progression-free survival among the 16 patients receiving durvalumab (P = .04).

“Every person’s tumor is unique in terms of its response to treatment,” said Dr. Jolly, a radiation oncologist and professor and associate chair of community practices in the Department of Radiation Oncology at the University of Michigan, Ann Arbor.

“Two people with a three-centimeter lung tumor will not necessarily shed the same amount of tumor cells into circulation. CTCs are reflective of disease burden; however, this is not related to the absolute numbers. That’s why we decided to use individualized baselines and look at the percentage of decrease,” she said.

Dr. Nagrath, professor of chemical and biomedical engineering at the University of Michigan, noted, in the same interview, that the findings argue for CTCs as a biomarker in stage 3 NSCLC.

“A lot of researchers who do lung cancer studies struggle with isolating lung cancer CTCs,” Dr. Nagrath said. “We showed, with repeated blood draws during treatment, what is changing at a molecular level and that you can see it with a simple blood draw. It also gives the proof of concept that if these cells are present, this is a good way to monitor and see if a treatment is working, even early in the treatment.” Moreover, she added, “many studies in lung cancer are in stage 4.”

Our study is unique as it followed patients with locally advanced tumors from their being treatment naive to all the way through immunotherapy,” she continued.

The University of Michigan has a patent on the GO chip technology, but thus far no company has made efforts to license it and submit it for approval. While “liquid biopsy” is an important emerging concept in lung cancer, there is little consensus yet as to which blood biomarkers — whether CTCs, circulating tumor DNA (ctDNA), or extracellular vesicles (EVs) — are most clinically relevant, Dr. Nagrath said.

The study’s small size is one of its weaknesses, according to the authors.
 

Findings are ‘Particularly Intriguing’

Majid Ebrahimi Warkiani, PhD, who was not involved in the study, described the new findings as “particularly intriguing [and] highlighting the efficacy of liquid biopsy using CTCs for predicting treatment outcomes.”

A challenge within the realm of CTCs lies in the community’s ongoing struggle to define and classify these cells accurately, Dr. Warkiani said in an interview.

“While surface protein markers offer valuable insights, emerging layers of analysis, such as metabolomics, are increasingly entering the scene to bolster the identification of putative cancer cells, alongside molecular tests like fluorescence in situ hybridization (FISH),” said Dr. Warkiani of the University of Technology Sydney in Australia. “The amalgamation of these approaches simultaneously presents a significant challenge, particularly in terms of standardization for patient care, unlike ctDNA, which faces fewer bottlenecks.

“The robustness of the research in this study is commendable. However, further clinical testing and randomized trials are imperative,” Dr. Warkiani continued. “Companies like Epic Sciences are actively engaged in advancing research and standardization in this field.”

The study by Dr. Jolly and Dr. Nagrath was funded by the National Institutes of Health. None of the study authors reported financial conflicts of interest. Dr. Warkiani reported no conflicts of interest related to his comment.

Circulating tumor cells (CTCs), the cells shed from a solid tumor into the bloodstream, may help doctors avoid having to do repeat needle biopsies on patients with unresectable non–small cell lung cancer.

Challenges to using CTCs clinically are that they are not abundant in the blood and have been difficult to isolate in patients with this type of cancer with commercially available assays.

New research published in Cell Reports may bring doctors closer to using CTCs as a biomarker for patients with non–small cell lung cancer (NSCLC) in clinic. In their paper, the authors show that an experimental nanotechnology can effectively isolate and measure CTCs in patients with stage 3 NSCLC. They also found that a precipitous drop in CTCs during chemoradiation treatment predicted significantly longer progression-free survival in those patients.
 

Study Results and Methods

For their research, study coauthors Shruti Jolly, MD, and Sunitha Nagrath, PhD, used a novel graphene oxide technology called the GO chip, developed more than a decade ago by Dr. Nagrath and her colleagues, to isolate CTCs from patients with stage 3 NSCLC. While a different technology, which is approved by the US Food and Drug Administration (FDA), uses a single antibody to pick up CTCs, the GO chip uses a cocktail of three antibodies to CTC proteins, making it more sensitive.

The 26 patients in the study (mean age 67, 27% female) all received radiation treatment for 6 weeks, plus weekly carboplatin and paclitaxel chemotherapy. Sixteen of the patients afterward went on to have immunotherapy with durvalumab. Blood was drawn at six fixed time points: before treatment, and at weeks 1, 4, 10, 18, and 30. CTCs were measured and analyzed with every draw.

Previous studies showed that absolute number of CTCs did not correlate with either tumor volume or progression-free survival in NSCLC.

Dr. Jolly and Dr. Nagrath sought to measure change in CTCs from baseline for each patient, having the patient serve as his or her own control. They found that patients whose individual CTC counts dropped by 75% or more between pretreatment and week 4 of chemoradiation saw a mean 21 months of progression-free survival compared with 7 months for patients whose CTCs dropped by less than 75% in the same period (P = .0076).

Dr. Jolly and Dr. Nagrath also aimed to determine, as an exploratory outcome of their study, whether other information collected from the CTCs could predict response to treatment with durvalumab immunotherapy. They found that having more than 50% of CTCs positive for the protein PD-L1 correlated to shorter progression-free survival among the 16 patients receiving durvalumab (P = .04).

“Every person’s tumor is unique in terms of its response to treatment,” said Dr. Jolly, a radiation oncologist and professor and associate chair of community practices in the Department of Radiation Oncology at the University of Michigan, Ann Arbor.

“Two people with a three-centimeter lung tumor will not necessarily shed the same amount of tumor cells into circulation. CTCs are reflective of disease burden; however, this is not related to the absolute numbers. That’s why we decided to use individualized baselines and look at the percentage of decrease,” she said.

Dr. Nagrath, professor of chemical and biomedical engineering at the University of Michigan, noted, in the same interview, that the findings argue for CTCs as a biomarker in stage 3 NSCLC.

“A lot of researchers who do lung cancer studies struggle with isolating lung cancer CTCs,” Dr. Nagrath said. “We showed, with repeated blood draws during treatment, what is changing at a molecular level and that you can see it with a simple blood draw. It also gives the proof of concept that if these cells are present, this is a good way to monitor and see if a treatment is working, even early in the treatment.” Moreover, she added, “many studies in lung cancer are in stage 4.”

Our study is unique as it followed patients with locally advanced tumors from their being treatment naive to all the way through immunotherapy,” she continued.

The University of Michigan has a patent on the GO chip technology, but thus far no company has made efforts to license it and submit it for approval. While “liquid biopsy” is an important emerging concept in lung cancer, there is little consensus yet as to which blood biomarkers — whether CTCs, circulating tumor DNA (ctDNA), or extracellular vesicles (EVs) — are most clinically relevant, Dr. Nagrath said.

The study’s small size is one of its weaknesses, according to the authors.
 

Findings are ‘Particularly Intriguing’

Majid Ebrahimi Warkiani, PhD, who was not involved in the study, described the new findings as “particularly intriguing [and] highlighting the efficacy of liquid biopsy using CTCs for predicting treatment outcomes.”

A challenge within the realm of CTCs lies in the community’s ongoing struggle to define and classify these cells accurately, Dr. Warkiani said in an interview.

“While surface protein markers offer valuable insights, emerging layers of analysis, such as metabolomics, are increasingly entering the scene to bolster the identification of putative cancer cells, alongside molecular tests like fluorescence in situ hybridization (FISH),” said Dr. Warkiani of the University of Technology Sydney in Australia. “The amalgamation of these approaches simultaneously presents a significant challenge, particularly in terms of standardization for patient care, unlike ctDNA, which faces fewer bottlenecks.

“The robustness of the research in this study is commendable. However, further clinical testing and randomized trials are imperative,” Dr. Warkiani continued. “Companies like Epic Sciences are actively engaged in advancing research and standardization in this field.”

The study by Dr. Jolly and Dr. Nagrath was funded by the National Institutes of Health. None of the study authors reported financial conflicts of interest. Dr. Warkiani reported no conflicts of interest related to his comment.

Circulating tumor cells (CTCs), the cells shed from a solid tumor into the bloodstream, may help doctors avoid having to do repeat needle biopsies on patients with unresectable non–small cell lung cancer.

Challenges to using CTCs clinically are that they are not abundant in the blood and have been difficult to isolate in patients with this type of cancer with commercially available assays.

New research published in Cell Reports may bring doctors closer to using CTCs as a biomarker for patients with non–small cell lung cancer (NSCLC) in clinic. In their paper, the authors show that an experimental nanotechnology can effectively isolate and measure CTCs in patients with stage 3 NSCLC. They also found that a precipitous drop in CTCs during chemoradiation treatment predicted significantly longer progression-free survival in those patients.
 

Study Results and Methods

For their research, study coauthors Shruti Jolly, MD, and Sunitha Nagrath, PhD, used a novel graphene oxide technology called the GO chip, developed more than a decade ago by Dr. Nagrath and her colleagues, to isolate CTCs from patients with stage 3 NSCLC. While a different technology, which is approved by the US Food and Drug Administration (FDA), uses a single antibody to pick up CTCs, the GO chip uses a cocktail of three antibodies to CTC proteins, making it more sensitive.

The 26 patients in the study (mean age 67, 27% female) all received radiation treatment for 6 weeks, plus weekly carboplatin and paclitaxel chemotherapy. Sixteen of the patients afterward went on to have immunotherapy with durvalumab. Blood was drawn at six fixed time points: before treatment, and at weeks 1, 4, 10, 18, and 30. CTCs were measured and analyzed with every draw.

Previous studies showed that absolute number of CTCs did not correlate with either tumor volume or progression-free survival in NSCLC.

Dr. Jolly and Dr. Nagrath sought to measure change in CTCs from baseline for each patient, having the patient serve as his or her own control. They found that patients whose individual CTC counts dropped by 75% or more between pretreatment and week 4 of chemoradiation saw a mean 21 months of progression-free survival compared with 7 months for patients whose CTCs dropped by less than 75% in the same period (P = .0076).

Dr. Jolly and Dr. Nagrath also aimed to determine, as an exploratory outcome of their study, whether other information collected from the CTCs could predict response to treatment with durvalumab immunotherapy. They found that having more than 50% of CTCs positive for the protein PD-L1 correlated to shorter progression-free survival among the 16 patients receiving durvalumab (P = .04).

“Every person’s tumor is unique in terms of its response to treatment,” said Dr. Jolly, a radiation oncologist and professor and associate chair of community practices in the Department of Radiation Oncology at the University of Michigan, Ann Arbor.

“Two people with a three-centimeter lung tumor will not necessarily shed the same amount of tumor cells into circulation. CTCs are reflective of disease burden; however, this is not related to the absolute numbers. That’s why we decided to use individualized baselines and look at the percentage of decrease,” she said.

Dr. Nagrath, professor of chemical and biomedical engineering at the University of Michigan, noted, in the same interview, that the findings argue for CTCs as a biomarker in stage 3 NSCLC.

“A lot of researchers who do lung cancer studies struggle with isolating lung cancer CTCs,” Dr. Nagrath said. “We showed, with repeated blood draws during treatment, what is changing at a molecular level and that you can see it with a simple blood draw. It also gives the proof of concept that if these cells are present, this is a good way to monitor and see if a treatment is working, even early in the treatment.” Moreover, she added, “many studies in lung cancer are in stage 4.”

Our study is unique as it followed patients with locally advanced tumors from their being treatment naive to all the way through immunotherapy,” she continued.

The University of Michigan has a patent on the GO chip technology, but thus far no company has made efforts to license it and submit it for approval. While “liquid biopsy” is an important emerging concept in lung cancer, there is little consensus yet as to which blood biomarkers — whether CTCs, circulating tumor DNA (ctDNA), or extracellular vesicles (EVs) — are most clinically relevant, Dr. Nagrath said.

The study’s small size is one of its weaknesses, according to the authors.
 

Findings are ‘Particularly Intriguing’

Majid Ebrahimi Warkiani, PhD, who was not involved in the study, described the new findings as “particularly intriguing [and] highlighting the efficacy of liquid biopsy using CTCs for predicting treatment outcomes.”

A challenge within the realm of CTCs lies in the community’s ongoing struggle to define and classify these cells accurately, Dr. Warkiani said in an interview.

“While surface protein markers offer valuable insights, emerging layers of analysis, such as metabolomics, are increasingly entering the scene to bolster the identification of putative cancer cells, alongside molecular tests like fluorescence in situ hybridization (FISH),” said Dr. Warkiani of the University of Technology Sydney in Australia. “The amalgamation of these approaches simultaneously presents a significant challenge, particularly in terms of standardization for patient care, unlike ctDNA, which faces fewer bottlenecks.

“The robustness of the research in this study is commendable. However, further clinical testing and randomized trials are imperative,” Dr. Warkiani continued. “Companies like Epic Sciences are actively engaged in advancing research and standardization in this field.”

The study by Dr. Jolly and Dr. Nagrath was funded by the National Institutes of Health. None of the study authors reported financial conflicts of interest. Dr. Warkiani reported no conflicts of interest related to his comment.

Emergencies happen anywhere and anytime, and sometimes, medical professionals find themselves in situations where they are the only ones who can help. 'Is There a Doctor in the House?' is a Medscape Medical News series telling these stories.

Bill Madden, MD: It was a Saturday in October of 1996. I had gone to my favorite plant nursery in Tucson with my wife, Beth, and two of my kids, Zach and Katya, who were 9 years old. I went to the back of the nursery to use the bathroom, and I heard two of the workers yelling at each other. The tone was angry. 

I went back up to the front, and Zach said that he was bored. He asked if he could go to the car and get a book, so I gave him my car keys and told him to be careful crossing the street. 

Ron Quintia, DDS: It was late in the afternoon, probably close to 4 PM. I was also at the nursery picking up some plants. 

The noise came out of nowhere. Boom! Boom! Boom! I thought, Wow, that sounds like a gun. But no, it can’t be a gun. This is a plant nursery. 

BM: When I heard the rounds being fired, I knew what that sound meant. I was in the Army for 20 years doing critical care for kids. 

I turned and a young man came running toward me out of the sun. It was hard to see, but I realized a second guy was running about 10 feet behind him. Both men were screaming. 

My wife was about 10 feet away behind a raised planter with Katya. I yelled for them to get down as I dove for the ground.

The first guy, a young Hispanic man, tried to escape through some bushes. But the shooter was catching up. I recognized him. He was from Ethiopia and worked at the nursery. I had talked to him a week earlier about his life; he used to be a farmer.

Now, he was holding a 9-mm automatic — silver, very shiny. He shot the Hispanic man twice in the chest. Then he ran toward the back of the nursery. 

RQ: When I realized what was happening, I crouched down, so I couldn’t see very much. But I heard someone screaming, “He has a gun! He has a gun!” And then I heard more shots. 

BM: I yelled at my wife, “Get out!” Then I ran for the phone at the kiosk desk to call 911. This was before most people had cell phones. But the phone was hooked up to the paging system for the nursery, and I couldn’t get it to work. I turned and ran for the wounded man.

RQ: I got to the victim first. Both lungs had been hit, and I could hear he had sucking chest wounds. He was bleeding out of his mouth, saying, “I’m going to die. I’m going to die.” I told him, “You’re not going to die,” while thinking to myself, He’s going to die. 

BM: I had never met Ron before, but we started working on the patient together. Both of his lungs were collapsing. With sucking chest wounds, the critical issue is to seal up the holes. So normally, you slap a Vaseline dressing on and tape it up real good. But obviously, we didn’t have anything. 

Ron and I took off our shirts and used them to bandage the man’s chest. He wasn’t looking good, starting to turn blue. He was dying. We were yelling for someone to call an ambulance. 

And then suddenly, the shooter was back. He was standing there yelling at us to leave so he could kill the man we were helping. The 9-mil was in his hand, ready to fire. He kept screaming, “I’m not a monkey! I’m not a monkey!”

RQ: The guy was less than 10 feet from us, and we were facing down this gun that looked like a cannon. I thought, This is it. It’s curtains. I’m going to die. We’re all going to die. 

BM: I had decided I would die too. I wasn’t frightened though. It’s hard to explain. Dying was okay because I’d gotten my family away. I just had to stay alive as long as I could in order to provide for the victim. 

It’s what I signed up for when I chose to be a doc — to do whatever was needed. And if I got killed in the process, that was just part of the story. So we started talking to the shooter.

I said, “No, you’re not a monkey. You’re a man, a human being. It’s okay.” We pleaded with him to put the weapon down and not to shoot. We did not leave the patient. Finally, the shooter ran off toward the back of the nursery.

RQ: About 30 seconds after that, we heard two more shots from that direction. 

Then there were sirens, and the place was suddenly crawling with police. The paramedics came and took over. I got up and got out of the way.

BM: A young woman ran up, her mouth covered with blood. She said that there was another victim in the back. I asked a police officer to go with us to check. We started for the back when suddenly, we heard yelling and many rounds being fired. The officer ran in the direction of the shooting. 

The woman and I kept walking through rows of plants and trees. It was like moving through a jungle. Finally, we reached the other victim, an American Indian man, lying on his back. He had a chest wound and a head wound. No respirations. No radial pulse. No carotid pulse. I pronounced him dead.

Then I heard a voice calling for help. There were two women hiding nearby in the bushes. I led them to where the police cars were.

Another officer came over and told me that they had the shooter. The police had shot him in the leg and arrested him.

RQ: The police kept us there for quite some time. Meanwhile, the TV crews arrived. I had a black Toyota 4Runner at the time. My family was home watching the news, and a bulletin came on about a shooting in Midtown. The camera panned around the area, and my wife saw our car on the street! They were all worried until I could call and let them know that I was okay.

BM: As we waited, the sun went down, and I was getting cold. My shirt was a bloody mess. Ron and I just sat there quietly, not saying a whole heck of a lot. 

Finally, an officer took our statements, a detective interviewed us, and they let us leave. I called Beth, and she and the kids came and got me. 

At home, we talked to the kids, letting them express their fears. We put them to bed. I didn’t sleep that night. 

RQ: I can’t describe how weird it was going home with this guy’s blood on my body. Needing to take a bath. Trying to get rid of the stench of what could have been a brutal killing. But it wasn’t. At least, not for our patient. 

Thankfully, there are three hospitals within a stone’s throw of the nursery. The paramedics got the man we helped to Tucson Medical Center and into the OR immediately. Then the general surgeons could get chest tubes in him to reinflate his lungs.

BM: The doctor who treated him called me later. He said that when they put the chest tubes in, they got a liter and a half of blood out of him. If it had taken another 10 minutes or so to get there, he very likely would’ve been dead on arrival in the emergency room. 

RQ: I checked on him at the hospital the next day, and he was doing okay. That was the last time I saw him. 

I only saw the shooter again in court. Dr. Madden and I were both called as witnesses at his trial. He was tried for capital murder and 12 charges of aggravated assault for every person who was at the nursery. He was found guilty on all of them and sentenced to 35 years to life in prison. 

BM: I don’t think the shooter was very well represented in court. It’s not that he didn’t kill one person and critically wound another. He did, and he deserves to be punished for that. But his story wasn’t told.

I knew that during the civil war in Ethiopia, his family had been killed by Cuban soldiers sent there to help the pro-communist government. In a way, I thought of him as two different people: the shooter and the farmer. They are both in prison, but only one of them deserves to be there.

After it happened, I wanted to visit the farmer in the hospital and tell him that, despite what he had done, he was not alone. Our family cared about him. The police wouldn’t let me see him, so I asked the Catholic chaplain of the hospital to go. He gave him my message: that despite all the sorrow and pain, in some distant way, I understood. I respected him as a human being. And I was praying for him.

RQ: It’s safe to say that the experience will affect me forever. For months, even years afterward, if somebody would ask me about what happened, I would start to cry. I would sit in the parking lot of my favorite running trail and worry about the people driving in. If I heard a car backfire, I thought about gunshots. 

It was terrifying. And thank God I’ve never found myself in that position again. But I suspect I’d probably react the same way. This is our calling. It’s what we do — protecting other people and taking care of them.

BM: I’d always wondered what I would do in a situation like this. I knew I could function in a critical care situation, a child in a hospital or in the back of an ambulance. But could I do it when my own life was threatened? I found out that I could, and that was really important to me. 

RQ: It was one of those great lessons in life. You realize how lucky you are and that your life can be snatched away from you in a millisecond. I went to a nursery to buy plants for my yard, and instead I ended up helping to save a life.Bill Madden, MD, is a retired US Army colonel and pediatrician, formerly an associate professor of Clinical Pediatrics at the College of Medicine of the University of Arizona, Tucson. 

Ron Quintia, DDS, is an oral and maxillofacial surgeon at Southern Arizona Oral & Maxillofacial Surgery in Tucson, Arizona. 

A version of this article appeared on Medscape.com .

Emergencies happen anywhere and anytime, and sometimes, medical professionals find themselves in situations where they are the only ones who can help. 'Is There a Doctor in the House?' is a Medscape Medical News series telling these stories.

Bill Madden, MD: It was a Saturday in October of 1996. I had gone to my favorite plant nursery in Tucson with my wife, Beth, and two of my kids, Zach and Katya, who were 9 years old. I went to the back of the nursery to use the bathroom, and I heard two of the workers yelling at each other. The tone was angry. 

I went back up to the front, and Zach said that he was bored. He asked if he could go to the car and get a book, so I gave him my car keys and told him to be careful crossing the street. 

Ron Quintia, DDS: It was late in the afternoon, probably close to 4 PM. I was also at the nursery picking up some plants. 

The noise came out of nowhere. Boom! Boom! Boom! I thought, Wow, that sounds like a gun. But no, it can’t be a gun. This is a plant nursery. 

BM: When I heard the rounds being fired, I knew what that sound meant. I was in the Army for 20 years doing critical care for kids. 

I turned and a young man came running toward me out of the sun. It was hard to see, but I realized a second guy was running about 10 feet behind him. Both men were screaming. 

My wife was about 10 feet away behind a raised planter with Katya. I yelled for them to get down as I dove for the ground.

The first guy, a young Hispanic man, tried to escape through some bushes. But the shooter was catching up. I recognized him. He was from Ethiopia and worked at the nursery. I had talked to him a week earlier about his life; he used to be a farmer.

Now, he was holding a 9-mm automatic — silver, very shiny. He shot the Hispanic man twice in the chest. Then he ran toward the back of the nursery. 

RQ: When I realized what was happening, I crouched down, so I couldn’t see very much. But I heard someone screaming, “He has a gun! He has a gun!” And then I heard more shots. 

BM: I yelled at my wife, “Get out!” Then I ran for the phone at the kiosk desk to call 911. This was before most people had cell phones. But the phone was hooked up to the paging system for the nursery, and I couldn’t get it to work. I turned and ran for the wounded man.

RQ: I got to the victim first. Both lungs had been hit, and I could hear he had sucking chest wounds. He was bleeding out of his mouth, saying, “I’m going to die. I’m going to die.” I told him, “You’re not going to die,” while thinking to myself, He’s going to die. 

BM: I had never met Ron before, but we started working on the patient together. Both of his lungs were collapsing. With sucking chest wounds, the critical issue is to seal up the holes. So normally, you slap a Vaseline dressing on and tape it up real good. But obviously, we didn’t have anything. 

Ron and I took off our shirts and used them to bandage the man’s chest. He wasn’t looking good, starting to turn blue. He was dying. We were yelling for someone to call an ambulance. 

And then suddenly, the shooter was back. He was standing there yelling at us to leave so he could kill the man we were helping. The 9-mil was in his hand, ready to fire. He kept screaming, “I’m not a monkey! I’m not a monkey!”

RQ: The guy was less than 10 feet from us, and we were facing down this gun that looked like a cannon. I thought, This is it. It’s curtains. I’m going to die. We’re all going to die. 

BM: I had decided I would die too. I wasn’t frightened though. It’s hard to explain. Dying was okay because I’d gotten my family away. I just had to stay alive as long as I could in order to provide for the victim. 

It’s what I signed up for when I chose to be a doc — to do whatever was needed. And if I got killed in the process, that was just part of the story. So we started talking to the shooter.

I said, “No, you’re not a monkey. You’re a man, a human being. It’s okay.” We pleaded with him to put the weapon down and not to shoot. We did not leave the patient. Finally, the shooter ran off toward the back of the nursery.

RQ: About 30 seconds after that, we heard two more shots from that direction. 

Then there were sirens, and the place was suddenly crawling with police. The paramedics came and took over. I got up and got out of the way.

BM: A young woman ran up, her mouth covered with blood. She said that there was another victim in the back. I asked a police officer to go with us to check. We started for the back when suddenly, we heard yelling and many rounds being fired. The officer ran in the direction of the shooting. 

The woman and I kept walking through rows of plants and trees. It was like moving through a jungle. Finally, we reached the other victim, an American Indian man, lying on his back. He had a chest wound and a head wound. No respirations. No radial pulse. No carotid pulse. I pronounced him dead.

Then I heard a voice calling for help. There were two women hiding nearby in the bushes. I led them to where the police cars were.

Another officer came over and told me that they had the shooter. The police had shot him in the leg and arrested him.

RQ: The police kept us there for quite some time. Meanwhile, the TV crews arrived. I had a black Toyota 4Runner at the time. My family was home watching the news, and a bulletin came on about a shooting in Midtown. The camera panned around the area, and my wife saw our car on the street! They were all worried until I could call and let them know that I was okay.

BM: As we waited, the sun went down, and I was getting cold. My shirt was a bloody mess. Ron and I just sat there quietly, not saying a whole heck of a lot. 

Finally, an officer took our statements, a detective interviewed us, and they let us leave. I called Beth, and she and the kids came and got me. 

At home, we talked to the kids, letting them express their fears. We put them to bed. I didn’t sleep that night. 

RQ: I can’t describe how weird it was going home with this guy’s blood on my body. Needing to take a bath. Trying to get rid of the stench of what could have been a brutal killing. But it wasn’t. At least, not for our patient. 

Thankfully, there are three hospitals within a stone’s throw of the nursery. The paramedics got the man we helped to Tucson Medical Center and into the OR immediately. Then the general surgeons could get chest tubes in him to reinflate his lungs.

BM: The doctor who treated him called me later. He said that when they put the chest tubes in, they got a liter and a half of blood out of him. If it had taken another 10 minutes or so to get there, he very likely would’ve been dead on arrival in the emergency room. 

RQ: I checked on him at the hospital the next day, and he was doing okay. That was the last time I saw him. 

I only saw the shooter again in court. Dr. Madden and I were both called as witnesses at his trial. He was tried for capital murder and 12 charges of aggravated assault for every person who was at the nursery. He was found guilty on all of them and sentenced to 35 years to life in prison. 

BM: I don’t think the shooter was very well represented in court. It’s not that he didn’t kill one person and critically wound another. He did, and he deserves to be punished for that. But his story wasn’t told.

I knew that during the civil war in Ethiopia, his family had been killed by Cuban soldiers sent there to help the pro-communist government. In a way, I thought of him as two different people: the shooter and the farmer. They are both in prison, but only one of them deserves to be there.

After it happened, I wanted to visit the farmer in the hospital and tell him that, despite what he had done, he was not alone. Our family cared about him. The police wouldn’t let me see him, so I asked the Catholic chaplain of the hospital to go. He gave him my message: that despite all the sorrow and pain, in some distant way, I understood. I respected him as a human being. And I was praying for him.

RQ: It’s safe to say that the experience will affect me forever. For months, even years afterward, if somebody would ask me about what happened, I would start to cry. I would sit in the parking lot of my favorite running trail and worry about the people driving in. If I heard a car backfire, I thought about gunshots. 

It was terrifying. And thank God I’ve never found myself in that position again. But I suspect I’d probably react the same way. This is our calling. It’s what we do — protecting other people and taking care of them.

BM: I’d always wondered what I would do in a situation like this. I knew I could function in a critical care situation, a child in a hospital or in the back of an ambulance. But could I do it when my own life was threatened? I found out that I could, and that was really important to me. 

RQ: It was one of those great lessons in life. You realize how lucky you are and that your life can be snatched away from you in a millisecond. I went to a nursery to buy plants for my yard, and instead I ended up helping to save a life.Bill Madden, MD, is a retired US Army colonel and pediatrician, formerly an associate professor of Clinical Pediatrics at the College of Medicine of the University of Arizona, Tucson. 

Ron Quintia, DDS, is an oral and maxillofacial surgeon at Southern Arizona Oral & Maxillofacial Surgery in Tucson, Arizona. 

A version of this article appeared on Medscape.com .

Emergencies happen anywhere and anytime, and sometimes, medical professionals find themselves in situations where they are the only ones who can help. 'Is There a Doctor in the House?' is a Medscape Medical News series telling these stories.

Bill Madden, MD: It was a Saturday in October of 1996. I had gone to my favorite plant nursery in Tucson with my wife, Beth, and two of my kids, Zach and Katya, who were 9 years old. I went to the back of the nursery to use the bathroom, and I heard two of the workers yelling at each other. The tone was angry. 

I went back up to the front, and Zach said that he was bored. He asked if he could go to the car and get a book, so I gave him my car keys and told him to be careful crossing the street. 

Ron Quintia, DDS: It was late in the afternoon, probably close to 4 PM. I was also at the nursery picking up some plants. 

The noise came out of nowhere. Boom! Boom! Boom! I thought, Wow, that sounds like a gun. But no, it can’t be a gun. This is a plant nursery. 

BM: When I heard the rounds being fired, I knew what that sound meant. I was in the Army for 20 years doing critical care for kids. 

I turned and a young man came running toward me out of the sun. It was hard to see, but I realized a second guy was running about 10 feet behind him. Both men were screaming. 

My wife was about 10 feet away behind a raised planter with Katya. I yelled for them to get down as I dove for the ground.

The first guy, a young Hispanic man, tried to escape through some bushes. But the shooter was catching up. I recognized him. He was from Ethiopia and worked at the nursery. I had talked to him a week earlier about his life; he used to be a farmer.

Now, he was holding a 9-mm automatic — silver, very shiny. He shot the Hispanic man twice in the chest. Then he ran toward the back of the nursery. 

RQ: When I realized what was happening, I crouched down, so I couldn’t see very much. But I heard someone screaming, “He has a gun! He has a gun!” And then I heard more shots. 

BM: I yelled at my wife, “Get out!” Then I ran for the phone at the kiosk desk to call 911. This was before most people had cell phones. But the phone was hooked up to the paging system for the nursery, and I couldn’t get it to work. I turned and ran for the wounded man.

RQ: I got to the victim first. Both lungs had been hit, and I could hear he had sucking chest wounds. He was bleeding out of his mouth, saying, “I’m going to die. I’m going to die.” I told him, “You’re not going to die,” while thinking to myself, He’s going to die. 

BM: I had never met Ron before, but we started working on the patient together. Both of his lungs were collapsing. With sucking chest wounds, the critical issue is to seal up the holes. So normally, you slap a Vaseline dressing on and tape it up real good. But obviously, we didn’t have anything. 

Ron and I took off our shirts and used them to bandage the man’s chest. He wasn’t looking good, starting to turn blue. He was dying. We were yelling for someone to call an ambulance. 

And then suddenly, the shooter was back. He was standing there yelling at us to leave so he could kill the man we were helping. The 9-mil was in his hand, ready to fire. He kept screaming, “I’m not a monkey! I’m not a monkey!”

RQ: The guy was less than 10 feet from us, and we were facing down this gun that looked like a cannon. I thought, This is it. It’s curtains. I’m going to die. We’re all going to die. 

BM: I had decided I would die too. I wasn’t frightened though. It’s hard to explain. Dying was okay because I’d gotten my family away. I just had to stay alive as long as I could in order to provide for the victim. 

It’s what I signed up for when I chose to be a doc — to do whatever was needed. And if I got killed in the process, that was just part of the story. So we started talking to the shooter.

I said, “No, you’re not a monkey. You’re a man, a human being. It’s okay.” We pleaded with him to put the weapon down and not to shoot. We did not leave the patient. Finally, the shooter ran off toward the back of the nursery.

RQ: About 30 seconds after that, we heard two more shots from that direction. 

Then there were sirens, and the place was suddenly crawling with police. The paramedics came and took over. I got up and got out of the way.

BM: A young woman ran up, her mouth covered with blood. She said that there was another victim in the back. I asked a police officer to go with us to check. We started for the back when suddenly, we heard yelling and many rounds being fired. The officer ran in the direction of the shooting. 

The woman and I kept walking through rows of plants and trees. It was like moving through a jungle. Finally, we reached the other victim, an American Indian man, lying on his back. He had a chest wound and a head wound. No respirations. No radial pulse. No carotid pulse. I pronounced him dead.

Then I heard a voice calling for help. There were two women hiding nearby in the bushes. I led them to where the police cars were.

Another officer came over and told me that they had the shooter. The police had shot him in the leg and arrested him.

RQ: The police kept us there for quite some time. Meanwhile, the TV crews arrived. I had a black Toyota 4Runner at the time. My family was home watching the news, and a bulletin came on about a shooting in Midtown. The camera panned around the area, and my wife saw our car on the street! They were all worried until I could call and let them know that I was okay.

BM: As we waited, the sun went down, and I was getting cold. My shirt was a bloody mess. Ron and I just sat there quietly, not saying a whole heck of a lot. 

Finally, an officer took our statements, a detective interviewed us, and they let us leave. I called Beth, and she and the kids came and got me. 

At home, we talked to the kids, letting them express their fears. We put them to bed. I didn’t sleep that night. 

RQ: I can’t describe how weird it was going home with this guy’s blood on my body. Needing to take a bath. Trying to get rid of the stench of what could have been a brutal killing. But it wasn’t. At least, not for our patient. 

Thankfully, there are three hospitals within a stone’s throw of the nursery. The paramedics got the man we helped to Tucson Medical Center and into the OR immediately. Then the general surgeons could get chest tubes in him to reinflate his lungs.

BM: The doctor who treated him called me later. He said that when they put the chest tubes in, they got a liter and a half of blood out of him. If it had taken another 10 minutes or so to get there, he very likely would’ve been dead on arrival in the emergency room. 

RQ: I checked on him at the hospital the next day, and he was doing okay. That was the last time I saw him. 

I only saw the shooter again in court. Dr. Madden and I were both called as witnesses at his trial. He was tried for capital murder and 12 charges of aggravated assault for every person who was at the nursery. He was found guilty on all of them and sentenced to 35 years to life in prison. 

BM: I don’t think the shooter was very well represented in court. It’s not that he didn’t kill one person and critically wound another. He did, and he deserves to be punished for that. But his story wasn’t told.

I knew that during the civil war in Ethiopia, his family had been killed by Cuban soldiers sent there to help the pro-communist government. In a way, I thought of him as two different people: the shooter and the farmer. They are both in prison, but only one of them deserves to be there.

After it happened, I wanted to visit the farmer in the hospital and tell him that, despite what he had done, he was not alone. Our family cared about him. The police wouldn’t let me see him, so I asked the Catholic chaplain of the hospital to go. He gave him my message: that despite all the sorrow and pain, in some distant way, I understood. I respected him as a human being. And I was praying for him.

RQ: It’s safe to say that the experience will affect me forever. For months, even years afterward, if somebody would ask me about what happened, I would start to cry. I would sit in the parking lot of my favorite running trail and worry about the people driving in. If I heard a car backfire, I thought about gunshots. 

It was terrifying. And thank God I’ve never found myself in that position again. But I suspect I’d probably react the same way. This is our calling. It’s what we do — protecting other people and taking care of them.

BM: I’d always wondered what I would do in a situation like this. I knew I could function in a critical care situation, a child in a hospital or in the back of an ambulance. But could I do it when my own life was threatened? I found out that I could, and that was really important to me. 

RQ: It was one of those great lessons in life. You realize how lucky you are and that your life can be snatched away from you in a millisecond. I went to a nursery to buy plants for my yard, and instead I ended up helping to save a life.Bill Madden, MD, is a retired US Army colonel and pediatrician, formerly an associate professor of Clinical Pediatrics at the College of Medicine of the University of Arizona, Tucson. 

Ron Quintia, DDS, is an oral and maxillofacial surgeon at Southern Arizona Oral & Maxillofacial Surgery in Tucson, Arizona. 

A version of this article appeared on Medscape.com .

Patients with lactose intolerance are usually advised to avoid milk. However, many still consume dairy products despite experiencing gastrointestinal symptoms. Surprisingly, this "unreasonable" strategy may have the benefit of reducing the risk for type 2 diabetes, as shown in a recent American study.

“At first glance, the statement of the study seems counterintuitive,” said Robert Wagner, MD, head of the Clinical Studies Center at the German Diabetes Center-Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany. “However, lactose intolerance has different manifestations.” Less severely affected individuals often consume milk and tolerate discomfort such as bloating or abdominal pain. “It is precisely these individuals that the study clearly shows have a lower incidence of diabetes associated with milk consumption,” said Dr. Wagner.
 

Milk’s Heterogeneous Effect

The effect of milk consumption on diabetes, among other factors, has been repeatedly studied in nutritional studies, with sometimes heterogeneous results in different countries. The reason for this is presumed to be that in Asia, most people — 60%-100% — are lactose intolerant, whereas in Europe, only as much as 40% of the population has lactose intolerance.

The authors, led by Kai Luo, PhD, research fellow in the Department of Epidemiology and Population Health at Albert Einstein College of Medicine in Bronx, New York, did not mention lactose tolerance and intolerance in their paper in Nature Metabolism. Instead, they divided the study population into lactase-persistent and non-lactase-persistent participants.

“Not being lactase-persistent does not necessarily exclude the ability to consume a certain amount of lactose,” said Lonneke Janssen Duijghuijsen, PhD, a nutrition scientist at Wageningen University, Wageningen, the Netherlands. “Studies have shown that many individuals who lack lactase can still consume up to 12 g of lactose per day — equivalent to the amount in a large glass of milk — without experiencing intolerance symptoms.”
 

Gut Microbiome and Metabolites

Dr. Luo and his colleagues analyzed data from 12,653 participants in the Hispanic Community Health Study/Study of Latinos, an ongoing prospective cohort study involving adults with Hispanic backgrounds. It collects detailed information on nutrition and the occurrence of diseases.

The authors examined whether the study participants were lactase-persistent or non-lactase-persistent and how frequently they consumed milk. They also analyzed the gut microbiome and various metabolites in the blood over a median follow-up period of 6 years.

The data analysis showed that higher milk consumption in non-lactase-persistent participants — but not in lactase-persistent participants — is associated with about a 30% reduced risk for type 2 diabetes when socioeconomic, demographic, and behavioral factors are accounted for. Comparable results were obtained by Dr. Luo and his colleagues with data from the UK Biobank, which served as validation.

A higher milk consumption was associated not only with a lower diabetes risk in non-lactase-persistent individuals but also with a lower body mass index. “This could be one of the factors behind the diabetes protection,” said Dr. Wagner. “However, no formal mediation analyses were conducted in the study.”

Dr. Luo’s team primarily attributed the cause of the observed association between milk consumption and diabetes risk to the gut. Increased milk intake was also associated with changes in the gut microbiome. For example, there was an enrichment of Bifidobacterium, while Prevotella decreased. Changes were also observed in the circulating metabolites in the blood, such as an increase in indole-3-propionate and a decrease in branched-chain amino acids.

These metabolites, speculated the authors, could be more intensely produced by milk-associated bacteria and might be causally related to the association between milk consumption and reduced risk for type 2 diabetes in non-lactase-persistent individuals. “The authors have not been able to provide precise evidence of these mediators, but one possible mediator of these effects could be short-chain fatty acids, which can directly or indirectly influence appetite, insulin action, or liver fat beneficially,” said Dr. Wagner.
 

Bacteria in the Colon

For Dr. Janssen Duijghuijsen, the conclusion that milk consumption can influence the composition of the microbiome and thus the metabolic profile, especially in individuals without lactase persistence, is plausible.

“Individuals with lactase persistence efficiently digest lactose and absorb the resulting galactose and glucose molecules in the small intestine. In contrast, in non-lactase-persistent individuals, lactase is not expressed in the brush border of the small intestine. As a result, lactose remains undigested in the colon and can serve as an energy source for gut bacteria. This can influence the composition of the microbiome, which in turn can alter the concentration of circulating metabolites,” she said.

Dr. Janssen Duijghuijsen has investigated the effect of lactose intake on the microbiome. In a recently published study, she also showed that increasing lactose intake by non-lactase-persistent individuals leads to changes in the microbiome, including an increase in Bifidobacteria.

“In line with the current study, we also found a significant increase in fecal beta-galactosidase activity. Given the close relationship between the composition of the gut microbiome and the metabolite profile, it is likely that changes in one can affect the other,” said Dr. Janssen Duijghuijsen.
 

Nutritional Recommendations

The nutrition scientist warned against concluding that milk consumption can protect against type 2 diabetes in non-lactase-persistent individuals, however. “The study suggests a statistical association between milk consumption, certain metabolites, and the frequency of type 2 diabetes. These associations do not provide definitive evidence of a causal relationship,” she said. Any dietary recommendations cannot be derived from the study; much more research is needed for that.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Patients with lactose intolerance are usually advised to avoid milk. However, many still consume dairy products despite experiencing gastrointestinal symptoms. Surprisingly, this "unreasonable" strategy may have the benefit of reducing the risk for type 2 diabetes, as shown in a recent American study.

“At first glance, the statement of the study seems counterintuitive,” said Robert Wagner, MD, head of the Clinical Studies Center at the German Diabetes Center-Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany. “However, lactose intolerance has different manifestations.” Less severely affected individuals often consume milk and tolerate discomfort such as bloating or abdominal pain. “It is precisely these individuals that the study clearly shows have a lower incidence of diabetes associated with milk consumption,” said Dr. Wagner.
 

Milk’s Heterogeneous Effect

The effect of milk consumption on diabetes, among other factors, has been repeatedly studied in nutritional studies, with sometimes heterogeneous results in different countries. The reason for this is presumed to be that in Asia, most people — 60%-100% — are lactose intolerant, whereas in Europe, only as much as 40% of the population has lactose intolerance.

The authors, led by Kai Luo, PhD, research fellow in the Department of Epidemiology and Population Health at Albert Einstein College of Medicine in Bronx, New York, did not mention lactose tolerance and intolerance in their paper in Nature Metabolism. Instead, they divided the study population into lactase-persistent and non-lactase-persistent participants.

“Not being lactase-persistent does not necessarily exclude the ability to consume a certain amount of lactose,” said Lonneke Janssen Duijghuijsen, PhD, a nutrition scientist at Wageningen University, Wageningen, the Netherlands. “Studies have shown that many individuals who lack lactase can still consume up to 12 g of lactose per day — equivalent to the amount in a large glass of milk — without experiencing intolerance symptoms.”
 

Gut Microbiome and Metabolites

Dr. Luo and his colleagues analyzed data from 12,653 participants in the Hispanic Community Health Study/Study of Latinos, an ongoing prospective cohort study involving adults with Hispanic backgrounds. It collects detailed information on nutrition and the occurrence of diseases.

The authors examined whether the study participants were lactase-persistent or non-lactase-persistent and how frequently they consumed milk. They also analyzed the gut microbiome and various metabolites in the blood over a median follow-up period of 6 years.

The data analysis showed that higher milk consumption in non-lactase-persistent participants — but not in lactase-persistent participants — is associated with about a 30% reduced risk for type 2 diabetes when socioeconomic, demographic, and behavioral factors are accounted for. Comparable results were obtained by Dr. Luo and his colleagues with data from the UK Biobank, which served as validation.

A higher milk consumption was associated not only with a lower diabetes risk in non-lactase-persistent individuals but also with a lower body mass index. “This could be one of the factors behind the diabetes protection,” said Dr. Wagner. “However, no formal mediation analyses were conducted in the study.”

Dr. Luo’s team primarily attributed the cause of the observed association between milk consumption and diabetes risk to the gut. Increased milk intake was also associated with changes in the gut microbiome. For example, there was an enrichment of Bifidobacterium, while Prevotella decreased. Changes were also observed in the circulating metabolites in the blood, such as an increase in indole-3-propionate and a decrease in branched-chain amino acids.

These metabolites, speculated the authors, could be more intensely produced by milk-associated bacteria and might be causally related to the association between milk consumption and reduced risk for type 2 diabetes in non-lactase-persistent individuals. “The authors have not been able to provide precise evidence of these mediators, but one possible mediator of these effects could be short-chain fatty acids, which can directly or indirectly influence appetite, insulin action, or liver fat beneficially,” said Dr. Wagner.
 

Bacteria in the Colon

For Dr. Janssen Duijghuijsen, the conclusion that milk consumption can influence the composition of the microbiome and thus the metabolic profile, especially in individuals without lactase persistence, is plausible.

“Individuals with lactase persistence efficiently digest lactose and absorb the resulting galactose and glucose molecules in the small intestine. In contrast, in non-lactase-persistent individuals, lactase is not expressed in the brush border of the small intestine. As a result, lactose remains undigested in the colon and can serve as an energy source for gut bacteria. This can influence the composition of the microbiome, which in turn can alter the concentration of circulating metabolites,” she said.

Dr. Janssen Duijghuijsen has investigated the effect of lactose intake on the microbiome. In a recently published study, she also showed that increasing lactose intake by non-lactase-persistent individuals leads to changes in the microbiome, including an increase in Bifidobacteria.

“In line with the current study, we also found a significant increase in fecal beta-galactosidase activity. Given the close relationship between the composition of the gut microbiome and the metabolite profile, it is likely that changes in one can affect the other,” said Dr. Janssen Duijghuijsen.
 

Nutritional Recommendations

The nutrition scientist warned against concluding that milk consumption can protect against type 2 diabetes in non-lactase-persistent individuals, however. “The study suggests a statistical association between milk consumption, certain metabolites, and the frequency of type 2 diabetes. These associations do not provide definitive evidence of a causal relationship,” she said. Any dietary recommendations cannot be derived from the study; much more research is needed for that.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Patients with lactose intolerance are usually advised to avoid milk. However, many still consume dairy products despite experiencing gastrointestinal symptoms. Surprisingly, this "unreasonable" strategy may have the benefit of reducing the risk for type 2 diabetes, as shown in a recent American study.

“At first glance, the statement of the study seems counterintuitive,” said Robert Wagner, MD, head of the Clinical Studies Center at the German Diabetes Center-Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany. “However, lactose intolerance has different manifestations.” Less severely affected individuals often consume milk and tolerate discomfort such as bloating or abdominal pain. “It is precisely these individuals that the study clearly shows have a lower incidence of diabetes associated with milk consumption,” said Dr. Wagner.
 

Milk’s Heterogeneous Effect

The effect of milk consumption on diabetes, among other factors, has been repeatedly studied in nutritional studies, with sometimes heterogeneous results in different countries. The reason for this is presumed to be that in Asia, most people — 60%-100% — are lactose intolerant, whereas in Europe, only as much as 40% of the population has lactose intolerance.

The authors, led by Kai Luo, PhD, research fellow in the Department of Epidemiology and Population Health at Albert Einstein College of Medicine in Bronx, New York, did not mention lactose tolerance and intolerance in their paper in Nature Metabolism. Instead, they divided the study population into lactase-persistent and non-lactase-persistent participants.

“Not being lactase-persistent does not necessarily exclude the ability to consume a certain amount of lactose,” said Lonneke Janssen Duijghuijsen, PhD, a nutrition scientist at Wageningen University, Wageningen, the Netherlands. “Studies have shown that many individuals who lack lactase can still consume up to 12 g of lactose per day — equivalent to the amount in a large glass of milk — without experiencing intolerance symptoms.”
 

Gut Microbiome and Metabolites

Dr. Luo and his colleagues analyzed data from 12,653 participants in the Hispanic Community Health Study/Study of Latinos, an ongoing prospective cohort study involving adults with Hispanic backgrounds. It collects detailed information on nutrition and the occurrence of diseases.

The authors examined whether the study participants were lactase-persistent or non-lactase-persistent and how frequently they consumed milk. They also analyzed the gut microbiome and various metabolites in the blood over a median follow-up period of 6 years.

The data analysis showed that higher milk consumption in non-lactase-persistent participants — but not in lactase-persistent participants — is associated with about a 30% reduced risk for type 2 diabetes when socioeconomic, demographic, and behavioral factors are accounted for. Comparable results were obtained by Dr. Luo and his colleagues with data from the UK Biobank, which served as validation.

A higher milk consumption was associated not only with a lower diabetes risk in non-lactase-persistent individuals but also with a lower body mass index. “This could be one of the factors behind the diabetes protection,” said Dr. Wagner. “However, no formal mediation analyses were conducted in the study.”

Dr. Luo’s team primarily attributed the cause of the observed association between milk consumption and diabetes risk to the gut. Increased milk intake was also associated with changes in the gut microbiome. For example, there was an enrichment of Bifidobacterium, while Prevotella decreased. Changes were also observed in the circulating metabolites in the blood, such as an increase in indole-3-propionate and a decrease in branched-chain amino acids.

These metabolites, speculated the authors, could be more intensely produced by milk-associated bacteria and might be causally related to the association between milk consumption and reduced risk for type 2 diabetes in non-lactase-persistent individuals. “The authors have not been able to provide precise evidence of these mediators, but one possible mediator of these effects could be short-chain fatty acids, which can directly or indirectly influence appetite, insulin action, or liver fat beneficially,” said Dr. Wagner.
 

Bacteria in the Colon

For Dr. Janssen Duijghuijsen, the conclusion that milk consumption can influence the composition of the microbiome and thus the metabolic profile, especially in individuals without lactase persistence, is plausible.

“Individuals with lactase persistence efficiently digest lactose and absorb the resulting galactose and glucose molecules in the small intestine. In contrast, in non-lactase-persistent individuals, lactase is not expressed in the brush border of the small intestine. As a result, lactose remains undigested in the colon and can serve as an energy source for gut bacteria. This can influence the composition of the microbiome, which in turn can alter the concentration of circulating metabolites,” she said.

Dr. Janssen Duijghuijsen has investigated the effect of lactose intake on the microbiome. In a recently published study, she also showed that increasing lactose intake by non-lactase-persistent individuals leads to changes in the microbiome, including an increase in Bifidobacteria.

“In line with the current study, we also found a significant increase in fecal beta-galactosidase activity. Given the close relationship between the composition of the gut microbiome and the metabolite profile, it is likely that changes in one can affect the other,” said Dr. Janssen Duijghuijsen.
 

Nutritional Recommendations

The nutrition scientist warned against concluding that milk consumption can protect against type 2 diabetes in non-lactase-persistent individuals, however. “The study suggests a statistical association between milk consumption, certain metabolites, and the frequency of type 2 diabetes. These associations do not provide definitive evidence of a causal relationship,” she said. Any dietary recommendations cannot be derived from the study; much more research is needed for that.

This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.