If you’re a regular reader of the journal CHEST^®, you may have noticed an exciting new initiative for clinicians looking to enhance their understanding of the latest advances in research, improve their clinical knowledge, and earn credits toward certification: the opportunity to earn continuing medical education (CME) credits from monthly journal issues. Launched in late 2022, this new initiative was inspired by the desire to complement the excellent clinical work already being done by readers of the journal.

“Essentially, the idea was that CHEST journal readers are doing the work to keep themselves current and stay excellent doctors, and they should get credit for that work,” said Amy Morris, MD, FCCP, Chair of the CHEST Journal CME Editorial Board. “We all have to do CME, so why not get some credit for the reading that we do on a regular basis to stay current, and add some additional value for journal readers?”

But the initiative isn’t just an opportunity to offer free credits. The goal of the CME Editorial Board is to create greater awareness of important research and offer readers regular opportunities to improve their knowledge in a wide variety of specialties and clinical areas.

“We try to rotate topics month to month, but more than that, we look for articles that either have a broad impact on current clinical practice for a lot of providers, or convey some particular new interest – a way for our readers to learn about something new and interesting,” she said. “We avoid trivia, essentially “gotcha” questions that simply ensure you read the article, but rather focus on questions that reinforce key points in the article.”

To ensure the content covers a wide breadth of topics, the CME Editorial Board – comprising leaders from pulmonary, critical care, and sleep medicine to ensure the process meets a high clinical standard – reviews articles that are slated for publication monthly and selects one or more manuscripts with impactful findings. Once the articles are selected, they are sent to a cohort of experienced question writers sourced from the Network specialty areas within CHEST to draft clinically relevant questions. The final questions and answers then are returned to the Board for a careful review of their accuracy, quality, and relevancy.

Readers can visit chestnet.org/journalcme every month to see a new selection of CME-eligible articles and access questions from past issues – an offering that will only grow more robust as the initiative progresses.

“We have a regularly accumulating collection of questions such that folks who read the journal every month will always have questions to answer, and those who prefer to do some reading and CME acquisition in bulk can find a rich database of useful, interesting articles that maybe they didn’t have a chance to read when they first came out,” said Dr. Morris.

As the initiative evolves, so too will the content selected and the questions offered – a process readers will have an integral role in guiding. After answering the questions, readers will have the opportunity to provide feedback on whether the activity achieved its learning objectives, future topics to cover, and more.

Although the initiative will evolve with this feedback, said Dr. Morris, one thing remains constant: the commitment of the team developing these resources to their fellow clinicians. “We couldn’t do this without a dedicated team and a lot of volunteer time from individuals who really care about education and clinical practice, and making the literature relevant to clinical practice. It takes a lot of time and effort, and I so appreciate the work those individuals are doing.”

To access the latest CME-eligible research, and review past questions, visit chestnet.org/journalcme.

If you’re a regular reader of the journal CHEST^®, you may have noticed an exciting new initiative for clinicians looking to enhance their understanding of the latest advances in research, improve their clinical knowledge, and earn credits toward certification: the opportunity to earn continuing medical education (CME) credits from monthly journal issues. Launched in late 2022, this new initiative was inspired by the desire to complement the excellent clinical work already being done by readers of the journal.

“Essentially, the idea was that CHEST journal readers are doing the work to keep themselves current and stay excellent doctors, and they should get credit for that work,” said Amy Morris, MD, FCCP, Chair of the CHEST Journal CME Editorial Board. “We all have to do CME, so why not get some credit for the reading that we do on a regular basis to stay current, and add some additional value for journal readers?”

But the initiative isn’t just an opportunity to offer free credits. The goal of the CME Editorial Board is to create greater awareness of important research and offer readers regular opportunities to improve their knowledge in a wide variety of specialties and clinical areas.

“We try to rotate topics month to month, but more than that, we look for articles that either have a broad impact on current clinical practice for a lot of providers, or convey some particular new interest – a way for our readers to learn about something new and interesting,” she said. “We avoid trivia, essentially “gotcha” questions that simply ensure you read the article, but rather focus on questions that reinforce key points in the article.”

To ensure the content covers a wide breadth of topics, the CME Editorial Board – comprising leaders from pulmonary, critical care, and sleep medicine to ensure the process meets a high clinical standard – reviews articles that are slated for publication monthly and selects one or more manuscripts with impactful findings. Once the articles are selected, they are sent to a cohort of experienced question writers sourced from the Network specialty areas within CHEST to draft clinically relevant questions. The final questions and answers then are returned to the Board for a careful review of their accuracy, quality, and relevancy.

Readers can visit chestnet.org/journalcme every month to see a new selection of CME-eligible articles and access questions from past issues – an offering that will only grow more robust as the initiative progresses.

“We have a regularly accumulating collection of questions such that folks who read the journal every month will always have questions to answer, and those who prefer to do some reading and CME acquisition in bulk can find a rich database of useful, interesting articles that maybe they didn’t have a chance to read when they first came out,” said Dr. Morris.

As the initiative evolves, so too will the content selected and the questions offered – a process readers will have an integral role in guiding. After answering the questions, readers will have the opportunity to provide feedback on whether the activity achieved its learning objectives, future topics to cover, and more.

Although the initiative will evolve with this feedback, said Dr. Morris, one thing remains constant: the commitment of the team developing these resources to their fellow clinicians. “We couldn’t do this without a dedicated team and a lot of volunteer time from individuals who really care about education and clinical practice, and making the literature relevant to clinical practice. It takes a lot of time and effort, and I so appreciate the work those individuals are doing.”

To access the latest CME-eligible research, and review past questions, visit chestnet.org/journalcme.

If you’re a regular reader of the journal CHEST^®, you may have noticed an exciting new initiative for clinicians looking to enhance their understanding of the latest advances in research, improve their clinical knowledge, and earn credits toward certification: the opportunity to earn continuing medical education (CME) credits from monthly journal issues. Launched in late 2022, this new initiative was inspired by the desire to complement the excellent clinical work already being done by readers of the journal.

“Essentially, the idea was that CHEST journal readers are doing the work to keep themselves current and stay excellent doctors, and they should get credit for that work,” said Amy Morris, MD, FCCP, Chair of the CHEST Journal CME Editorial Board. “We all have to do CME, so why not get some credit for the reading that we do on a regular basis to stay current, and add some additional value for journal readers?”

But the initiative isn’t just an opportunity to offer free credits. The goal of the CME Editorial Board is to create greater awareness of important research and offer readers regular opportunities to improve their knowledge in a wide variety of specialties and clinical areas.

“We try to rotate topics month to month, but more than that, we look for articles that either have a broad impact on current clinical practice for a lot of providers, or convey some particular new interest – a way for our readers to learn about something new and interesting,” she said. “We avoid trivia, essentially “gotcha” questions that simply ensure you read the article, but rather focus on questions that reinforce key points in the article.”

To ensure the content covers a wide breadth of topics, the CME Editorial Board – comprising leaders from pulmonary, critical care, and sleep medicine to ensure the process meets a high clinical standard – reviews articles that are slated for publication monthly and selects one or more manuscripts with impactful findings. Once the articles are selected, they are sent to a cohort of experienced question writers sourced from the Network specialty areas within CHEST to draft clinically relevant questions. The final questions and answers then are returned to the Board for a careful review of their accuracy, quality, and relevancy.

Readers can visit chestnet.org/journalcme every month to see a new selection of CME-eligible articles and access questions from past issues – an offering that will only grow more robust as the initiative progresses.

“We have a regularly accumulating collection of questions such that folks who read the journal every month will always have questions to answer, and those who prefer to do some reading and CME acquisition in bulk can find a rich database of useful, interesting articles that maybe they didn’t have a chance to read when they first came out,” said Dr. Morris.

As the initiative evolves, so too will the content selected and the questions offered – a process readers will have an integral role in guiding. After answering the questions, readers will have the opportunity to provide feedback on whether the activity achieved its learning objectives, future topics to cover, and more.

Although the initiative will evolve with this feedback, said Dr. Morris, one thing remains constant: the commitment of the team developing these resources to their fellow clinicians. “We couldn’t do this without a dedicated team and a lot of volunteer time from individuals who really care about education and clinical practice, and making the literature relevant to clinical practice. It takes a lot of time and effort, and I so appreciate the work those individuals are doing.”

To access the latest CME-eligible research, and review past questions, visit chestnet.org/journalcme.

Maximize your learning experiences at CHEST 2023 (October 8-11 in Hawai’i) by attending a Master Class. Taking place before and after the annual meeting, these advanced-level courses on October 7, 12, and 13 will give you a deep dive into specific clinical areas with the guidance of distinguished faculty.

Replacing the “postgraduate courses” offered in previous years, the new Master Classes are open to both CHEST 2023 registrants and nonregistrants. Faculty will explore complex topics, and you will have the opportunity to participate in intensive case-based discussions with master clinicians.

“At CHEST, we’re always looking for ways to tailor the learning experience for the folks who come to the annual meeting. These Master Classes will be particularly useful for seasoned providers who are looking for a challenging education experience,” said Education Committee Chair, Amy E. Morris, MD, FCCP.

These classes will have some didactic elements, but a lot of time will be spent reviewing challenging cases that aren’t easily addressed by guidelines or a quick read of the literature and will go beyond what’s easily found online.

“Master Classes will focus on deeper-dive learning, in-depth pathophysiology and research, and conversational, interactive discussions,” Dr. Morris said.

She encourages everyone to seize the opportunity to attend these classes taught by “true masters of clinical medicine” in Hawai’i after years of strictly virtual learning that didn’t allow for as much interactivity.

“That’s why we’re in medicine – to learn from each other. This is an opportunity not just to learn facts or new ways of doing things, but a chance to interact on a personal level with providers from around the globe and master clinicians who are not always available to us in person,” she said. “In an increasingly digital world, an opportunity like this is harder to come by these days.”

Make the most of your trip to Hawai’i with advanced learning taught by highly regarded speakers. Take a look at the Master Classes available to you this year, and add a course to your meeting registration. For more information on CHEST 2023 educational offerings, browse the preliminary program at chestmeeting.chestnet.org.
 

October 7 (held in Honolulu on O’ahu)

How I Do It – Challenging Cases in Sleep Medicine

Faculty: Babak Mokhlesi, MD, FCCP; Timothy Morgenthaler, MD, FCCP; Lauren A. Tobias, MD, FCCP; and Lisa F. Wolfe, MD.

Interstitial Lung Disease

Faculty: Ayodeji Adegunsoye, MD, FCCP; Jonathan H. Chung, MD; Tejaswini Kulkarni, MD, MBBS, FCCP; Ganesh Raghu, MD; and Mary Beth Scholand, MD, FCCP.

Advances in Lung Cancer – Rocketing Forward With the Cancer Moonshot

Faculty: A. Christine Argento, MD, FCCP; Frank C. Detterbeck, MD, FCCP; Gerard A. Silvestri, MD, Master FCCP; and Lynn T. Tanoue, MD, FCCP.

Pulmonary Hypertension – Expert Didactics and Discussion

Faculty: Jean M. Elwing, MD, FCCP; Peter Leary, MD, PhD; and Namita Sood, MBBCh, FCCP.

October 12-13 (held in Wailea on Maui)

2023 Pulmonary Literature Review and Complex Case Presentations – An Interactive Course With the Masters in Pulmonology

Faculty: Doreen Addrizzo-Harris, MD, FCCP; Kevin M. Chan, MD, FCCP; Stephanie M. Levine, MD, FCCP; Diego J. Maselli, MD, FCCP; Marcos I. Restrepo, MD, PhD, FCCP; Linda Rogers, MD, FCCP; Gerard A. Silvestri, MD, Master FCCP; and David J. Steiger, MBChB, FCCP.

Avoiding Catastrophic Crisis in the ICU and Mastering Critical Care

Faculty: Kristin Burkart, MD, MS, FCCP; David Janz, MD; Patricia A. Kritek, MD; Matthew E. Prekker, MD; Nida Qadir, MD; Todd W. Rice, MD, FCCP; and Jonathan Sevransky, MD, FCCP.

CHEST 2023 hands-on and inter­active learning opportunities

By experiencing the latest developments for yourself through several different kinds of interactive sessions, you’ll take home actionable information that you can apply directly to your patient care. Explore the many ticketed sessions available to add on to your CHEST 2023 registration.

Simulation sessions

Choose from 25 different sessions offering hands-on experience with procedures relevant to your clinical practice.

Problem-based learning sessions

Supplement your schedule with these unique sessions, where you’ll solve real-world clinical problems in small groups and refine your expertise on clinical topics.

Meet the Professor sessions

Connect with leading chest medicine experts during these limited-capacity discussions capped at 24 registrants per session.

Maximize your learning experiences at CHEST 2023 (October 8-11 in Hawai’i) by attending a Master Class. Taking place before and after the annual meeting, these advanced-level courses on October 7, 12, and 13 will give you a deep dive into specific clinical areas with the guidance of distinguished faculty.

Replacing the “postgraduate courses” offered in previous years, the new Master Classes are open to both CHEST 2023 registrants and nonregistrants. Faculty will explore complex topics, and you will have the opportunity to participate in intensive case-based discussions with master clinicians.

“At CHEST, we’re always looking for ways to tailor the learning experience for the folks who come to the annual meeting. These Master Classes will be particularly useful for seasoned providers who are looking for a challenging education experience,” said Education Committee Chair, Amy E. Morris, MD, FCCP.

These classes will have some didactic elements, but a lot of time will be spent reviewing challenging cases that aren’t easily addressed by guidelines or a quick read of the literature and will go beyond what’s easily found online.

“Master Classes will focus on deeper-dive learning, in-depth pathophysiology and research, and conversational, interactive discussions,” Dr. Morris said.

She encourages everyone to seize the opportunity to attend these classes taught by “true masters of clinical medicine” in Hawai’i after years of strictly virtual learning that didn’t allow for as much interactivity.

“That’s why we’re in medicine – to learn from each other. This is an opportunity not just to learn facts or new ways of doing things, but a chance to interact on a personal level with providers from around the globe and master clinicians who are not always available to us in person,” she said. “In an increasingly digital world, an opportunity like this is harder to come by these days.”

Make the most of your trip to Hawai’i with advanced learning taught by highly regarded speakers. Take a look at the Master Classes available to you this year, and add a course to your meeting registration. For more information on CHEST 2023 educational offerings, browse the preliminary program at chestmeeting.chestnet.org.
 

October 7 (held in Honolulu on O’ahu)

How I Do It – Challenging Cases in Sleep Medicine

Faculty: Babak Mokhlesi, MD, FCCP; Timothy Morgenthaler, MD, FCCP; Lauren A. Tobias, MD, FCCP; and Lisa F. Wolfe, MD.

Interstitial Lung Disease

Faculty: Ayodeji Adegunsoye, MD, FCCP; Jonathan H. Chung, MD; Tejaswini Kulkarni, MD, MBBS, FCCP; Ganesh Raghu, MD; and Mary Beth Scholand, MD, FCCP.

Advances in Lung Cancer – Rocketing Forward With the Cancer Moonshot

Faculty: A. Christine Argento, MD, FCCP; Frank C. Detterbeck, MD, FCCP; Gerard A. Silvestri, MD, Master FCCP; and Lynn T. Tanoue, MD, FCCP.

Pulmonary Hypertension – Expert Didactics and Discussion

Faculty: Jean M. Elwing, MD, FCCP; Peter Leary, MD, PhD; and Namita Sood, MBBCh, FCCP.

October 12-13 (held in Wailea on Maui)

2023 Pulmonary Literature Review and Complex Case Presentations – An Interactive Course With the Masters in Pulmonology

Faculty: Doreen Addrizzo-Harris, MD, FCCP; Kevin M. Chan, MD, FCCP; Stephanie M. Levine, MD, FCCP; Diego J. Maselli, MD, FCCP; Marcos I. Restrepo, MD, PhD, FCCP; Linda Rogers, MD, FCCP; Gerard A. Silvestri, MD, Master FCCP; and David J. Steiger, MBChB, FCCP.

Avoiding Catastrophic Crisis in the ICU and Mastering Critical Care

Faculty: Kristin Burkart, MD, MS, FCCP; David Janz, MD; Patricia A. Kritek, MD; Matthew E. Prekker, MD; Nida Qadir, MD; Todd W. Rice, MD, FCCP; and Jonathan Sevransky, MD, FCCP.

CHEST 2023 hands-on and inter­active learning opportunities

By experiencing the latest developments for yourself through several different kinds of interactive sessions, you’ll take home actionable information that you can apply directly to your patient care. Explore the many ticketed sessions available to add on to your CHEST 2023 registration.

Simulation sessions

Choose from 25 different sessions offering hands-on experience with procedures relevant to your clinical practice.

Problem-based learning sessions

Supplement your schedule with these unique sessions, where you’ll solve real-world clinical problems in small groups and refine your expertise on clinical topics.

Meet the Professor sessions

Connect with leading chest medicine experts during these limited-capacity discussions capped at 24 registrants per session.

Maximize your learning experiences at CHEST 2023 (October 8-11 in Hawai’i) by attending a Master Class. Taking place before and after the annual meeting, these advanced-level courses on October 7, 12, and 13 will give you a deep dive into specific clinical areas with the guidance of distinguished faculty.

Replacing the “postgraduate courses” offered in previous years, the new Master Classes are open to both CHEST 2023 registrants and nonregistrants. Faculty will explore complex topics, and you will have the opportunity to participate in intensive case-based discussions with master clinicians.

“At CHEST, we’re always looking for ways to tailor the learning experience for the folks who come to the annual meeting. These Master Classes will be particularly useful for seasoned providers who are looking for a challenging education experience,” said Education Committee Chair, Amy E. Morris, MD, FCCP.

These classes will have some didactic elements, but a lot of time will be spent reviewing challenging cases that aren’t easily addressed by guidelines or a quick read of the literature and will go beyond what’s easily found online.

“Master Classes will focus on deeper-dive learning, in-depth pathophysiology and research, and conversational, interactive discussions,” Dr. Morris said.

She encourages everyone to seize the opportunity to attend these classes taught by “true masters of clinical medicine” in Hawai’i after years of strictly virtual learning that didn’t allow for as much interactivity.

“That’s why we’re in medicine – to learn from each other. This is an opportunity not just to learn facts or new ways of doing things, but a chance to interact on a personal level with providers from around the globe and master clinicians who are not always available to us in person,” she said. “In an increasingly digital world, an opportunity like this is harder to come by these days.”

Make the most of your trip to Hawai’i with advanced learning taught by highly regarded speakers. Take a look at the Master Classes available to you this year, and add a course to your meeting registration. For more information on CHEST 2023 educational offerings, browse the preliminary program at chestmeeting.chestnet.org.
 

October 7 (held in Honolulu on O’ahu)

How I Do It – Challenging Cases in Sleep Medicine

Faculty: Babak Mokhlesi, MD, FCCP; Timothy Morgenthaler, MD, FCCP; Lauren A. Tobias, MD, FCCP; and Lisa F. Wolfe, MD.

Interstitial Lung Disease

Faculty: Ayodeji Adegunsoye, MD, FCCP; Jonathan H. Chung, MD; Tejaswini Kulkarni, MD, MBBS, FCCP; Ganesh Raghu, MD; and Mary Beth Scholand, MD, FCCP.

Advances in Lung Cancer – Rocketing Forward With the Cancer Moonshot

Faculty: A. Christine Argento, MD, FCCP; Frank C. Detterbeck, MD, FCCP; Gerard A. Silvestri, MD, Master FCCP; and Lynn T. Tanoue, MD, FCCP.

Pulmonary Hypertension – Expert Didactics and Discussion

Faculty: Jean M. Elwing, MD, FCCP; Peter Leary, MD, PhD; and Namita Sood, MBBCh, FCCP.

October 12-13 (held in Wailea on Maui)

2023 Pulmonary Literature Review and Complex Case Presentations – An Interactive Course With the Masters in Pulmonology

Faculty: Doreen Addrizzo-Harris, MD, FCCP; Kevin M. Chan, MD, FCCP; Stephanie M. Levine, MD, FCCP; Diego J. Maselli, MD, FCCP; Marcos I. Restrepo, MD, PhD, FCCP; Linda Rogers, MD, FCCP; Gerard A. Silvestri, MD, Master FCCP; and David J. Steiger, MBChB, FCCP.

Avoiding Catastrophic Crisis in the ICU and Mastering Critical Care

Faculty: Kristin Burkart, MD, MS, FCCP; David Janz, MD; Patricia A. Kritek, MD; Matthew E. Prekker, MD; Nida Qadir, MD; Todd W. Rice, MD, FCCP; and Jonathan Sevransky, MD, FCCP.

CHEST 2023 hands-on and inter­active learning opportunities

By experiencing the latest developments for yourself through several different kinds of interactive sessions, you’ll take home actionable information that you can apply directly to your patient care. Explore the many ticketed sessions available to add on to your CHEST 2023 registration.

Simulation sessions

Choose from 25 different sessions offering hands-on experience with procedures relevant to your clinical practice.

Problem-based learning sessions

Supplement your schedule with these unique sessions, where you’ll solve real-world clinical problems in small groups and refine your expertise on clinical topics.

Meet the Professor sessions

Connect with leading chest medicine experts during these limited-capacity discussions capped at 24 registrants per session.

When we celebrated Women’s History Month in March, Drs. Carolyn D’Ambrosio, Aneesa Das, and I discussed our experiences as women in chest medicine and why connecting is so important. We touched on the critical role of mentors. This conversation prompted me to dedicate this President’s column to the value of mentorship. The conversation is available on the CHEST YouTube for viewing.

Pursuing a career in medicine is not something you do on your own, and I have been fortunate to have had a strong support system. I think many of us who have been successful and fulfilled in our careers can say we were blessed by having great mentors along the way.

I have been blessed in having mentors who were both within my institution and outside, but one of the most important places that I found mentors was through my involvement with CHEST. It is critically important to find a mentor or mentors who can guide you through the initial phases of your career. It is also very important to allow yourself time to be a mentor to those who need you.

To the junior faculty or trainees who have yet to connect with someone to provide guidance, I cannot stress enough the importance of getting involved in an organization like CHEST.

The best way to begin is to attend the annual meeting. Know that you are invited to approach any member of CHEST leadership, introduce yourself, and tell us that you want to get involved. (Conveniently, registration for CHEST 2023 in Hawaii just opened.)

I genuinely believe our community would say yes to anyone looking for guidance.

To my colleagues who are established in their careers, I am issuing a personal request (and a bit of a challenge). Before the upcoming annual meeting, consider who among your newer colleagues could benefit from having a mentor.

Take the time to tell them that you are there to support their development. Making that connection could mean re-establishing a relationship that got off track and that you want to re-engage.

Show how the commitment to mentorship matters by sharing a post (with a picture, if possible) on social media. Tag your post using the hashtags #CHESTMentee and #CHEST2023 to introduce them to your network. This type of exposure and support can have a lasting impact.

While attending CHEST 2023 – ideally with your mentee – be sure to add the mentoring ribbons to your badge. We will be heavily socializing these ribbons, sharing that anyone wearing the “I’m a mentor” ribbon is either open to accepting new mentees or will help facilitate a conversation that may lead to mentorship.

Beyond its incredible education opportunities, the CHEST Annual Meeting is well-known for being a welcoming environment. It’s up to us to take the extra steps to help earlier-career clinicians succeed by providing the best possible education and guidance for years to come.



Until next time,

Doreen J. Addrizzo- Harris, MD, FCCP

When we celebrated Women’s History Month in March, Drs. Carolyn D’Ambrosio, Aneesa Das, and I discussed our experiences as women in chest medicine and why connecting is so important. We touched on the critical role of mentors. This conversation prompted me to dedicate this President’s column to the value of mentorship. The conversation is available on the CHEST YouTube for viewing.

Pursuing a career in medicine is not something you do on your own, and I have been fortunate to have had a strong support system. I think many of us who have been successful and fulfilled in our careers can say we were blessed by having great mentors along the way.

I have been blessed in having mentors who were both within my institution and outside, but one of the most important places that I found mentors was through my involvement with CHEST. It is critically important to find a mentor or mentors who can guide you through the initial phases of your career. It is also very important to allow yourself time to be a mentor to those who need you.

To the junior faculty or trainees who have yet to connect with someone to provide guidance, I cannot stress enough the importance of getting involved in an organization like CHEST.

The best way to begin is to attend the annual meeting. Know that you are invited to approach any member of CHEST leadership, introduce yourself, and tell us that you want to get involved. (Conveniently, registration for CHEST 2023 in Hawaii just opened.)

I genuinely believe our community would say yes to anyone looking for guidance.

To my colleagues who are established in their careers, I am issuing a personal request (and a bit of a challenge). Before the upcoming annual meeting, consider who among your newer colleagues could benefit from having a mentor.

Take the time to tell them that you are there to support their development. Making that connection could mean re-establishing a relationship that got off track and that you want to re-engage.

Show how the commitment to mentorship matters by sharing a post (with a picture, if possible) on social media. Tag your post using the hashtags #CHESTMentee and #CHEST2023 to introduce them to your network. This type of exposure and support can have a lasting impact.

While attending CHEST 2023 – ideally with your mentee – be sure to add the mentoring ribbons to your badge. We will be heavily socializing these ribbons, sharing that anyone wearing the “I’m a mentor” ribbon is either open to accepting new mentees or will help facilitate a conversation that may lead to mentorship.

Beyond its incredible education opportunities, the CHEST Annual Meeting is well-known for being a welcoming environment. It’s up to us to take the extra steps to help earlier-career clinicians succeed by providing the best possible education and guidance for years to come.



Until next time,

Doreen J. Addrizzo- Harris, MD, FCCP

When we celebrated Women’s History Month in March, Drs. Carolyn D’Ambrosio, Aneesa Das, and I discussed our experiences as women in chest medicine and why connecting is so important. We touched on the critical role of mentors. This conversation prompted me to dedicate this President’s column to the value of mentorship. The conversation is available on the CHEST YouTube for viewing.

Pursuing a career in medicine is not something you do on your own, and I have been fortunate to have had a strong support system. I think many of us who have been successful and fulfilled in our careers can say we were blessed by having great mentors along the way.

I have been blessed in having mentors who were both within my institution and outside, but one of the most important places that I found mentors was through my involvement with CHEST. It is critically important to find a mentor or mentors who can guide you through the initial phases of your career. It is also very important to allow yourself time to be a mentor to those who need you.

To the junior faculty or trainees who have yet to connect with someone to provide guidance, I cannot stress enough the importance of getting involved in an organization like CHEST.

The best way to begin is to attend the annual meeting. Know that you are invited to approach any member of CHEST leadership, introduce yourself, and tell us that you want to get involved. (Conveniently, registration for CHEST 2023 in Hawaii just opened.)

I genuinely believe our community would say yes to anyone looking for guidance.

To my colleagues who are established in their careers, I am issuing a personal request (and a bit of a challenge). Before the upcoming annual meeting, consider who among your newer colleagues could benefit from having a mentor.

Take the time to tell them that you are there to support their development. Making that connection could mean re-establishing a relationship that got off track and that you want to re-engage.

Show how the commitment to mentorship matters by sharing a post (with a picture, if possible) on social media. Tag your post using the hashtags #CHESTMentee and #CHEST2023 to introduce them to your network. This type of exposure and support can have a lasting impact.

While attending CHEST 2023 – ideally with your mentee – be sure to add the mentoring ribbons to your badge. We will be heavily socializing these ribbons, sharing that anyone wearing the “I’m a mentor” ribbon is either open to accepting new mentees or will help facilitate a conversation that may lead to mentorship.

Beyond its incredible education opportunities, the CHEST Annual Meeting is well-known for being a welcoming environment. It’s up to us to take the extra steps to help earlier-career clinicians succeed by providing the best possible education and guidance for years to come.



Until next time,

Doreen J. Addrizzo- Harris, MD, FCCP

Obstructive sleep apnea (OSA) affects roughly 1 billion people worldwide, according to a report by the American Academy of Sleep Medicine. Severe OSA has been associated with an elevated risk of all-cause and cardiovascular-specific mortality. Studies support an association between OSA and a host of comorbidities, including hypertension, stroke, atrial fibrillation, mood disorders, and neurocognitive outcomes. Undiagnosed and untreated OSA also has major economic and societal costs, reducing workplace productivity and increasing one’s risk of accidents both on the job and while driving.

Positive airway pressure (PAP) is widely considered the most effective treatment for OSA. The majority of patients tolerate CPAP: real-world estimates using international big data show good adherence in over 70% of patients. Robust evidence shows that PAP reduces snoring, decreases daytime sleepiness, and improves quality of life in a dose-dependent manner. Economic analyses have also found CPAP to be cost-effective (Streatfeild, et al. Sleep. 2019;42[12]:zsz181).

But what do we know about the impact of PAP on health outcomes? Perhaps the best studied outcome is cardiovascular disease. Results of observational trials have suggested that CPAP adherence was associated with survival (Pepin JL et al. Chest. 2022;161[6]:1657). However, it has been speculated that these findings may have been driven, at least in part, by the “healthy user effect.” This phenomenon refers to the tendency for people who engage in one health-promoting behavior (eg, CPAP adherence) to engage in another as well (eg, eating well, exercising, taking prescribed medications). When we observe that patients who use CPAP live longer, we must ask ourselves whether perhaps their better outcomes resulted from healthy habits in general, as opposed to their CPAP usage per se.

Randomization eliminates the potential for the healthy user effect, by assigning patients to a certain intervention as opposed to simply observing whether they choose to use it. And herein lies one of the great disappointments for our field over the past decade: multiple large-scale randomized controlled trials have failed to demonstrate that CPAP reduces cardiovascular mortality, even in patients with pre-existing CAD. The first two of these were the SAVE (Sleep Apnea Cardiovascular Endpoints) (McEvoy R, et al.  N Engl J Med. 2016;375[10]:919) and RICCADSA (Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA) (Peker Y, et al. Am J Respir Crit Care Med. 2016;194[5]:613) trials evaluating the effects of PAP on a composite endpoint that included cardiovascular death and nonfatal cardiovascular events. Both trials found no difference between PAP and control groups, leading to a conclusion that PAP did not prevent cardiovascular events in patients with moderate-to-severe OSA and established cardiovascular disease. The ISAAC study (Impact of Sleep Apnea syndrome in the evolution of Acute Coronary syndrome) also failed to show a benefit of CPAP for secondary prevention of cardiovascular events in patients with moderate to severe OSA.

These negative findings were echoed in a recent report by the Agency for Healthcare Research and Quality evaluating a variety of long-term health outcomes in obstructive sleep apnea. The authors stated that “RCTs do not provide evidence that CPAP prescription affects long-term, clinically important outcomes. Specifically, with low strength of evidence, RCTs do not demonstrate that CPAP affects all-cause mortality, various CV outcomes, clinically important changes in psychosocial measures, or other clinical events” (AHRQ, Project ID: SLPT0919, 12/1/2022).

What plausible explanations have been offered for these negative results? Perhaps trials were underpowered. Perhaps patients did not use PAP for a sufficient duration to achieve benefit (usage was under 3 hours in most studies). Perhaps the patients selected for these trials were at such low-risk of adverse outcomes in the first place that treating their OSA didn’t have much impact. Many trials have excluded sleepy patients due to ethical concerns about withholding treatment from this population. But this may have effectively excluded the patients most likely to benefit; in other studies, sleepy patients seem to experience the greatest cardiovascular risk reduction with CPAP. For example, a meta-analysis showed that CPAP is most strongly associated with blood pressure reduction in patients who are sleepy, compared with those with minimally symptomatic OSA (Bratton D, et al. Thorax. 2014;69[12]:1128). And, recent work suggests that even among non-sleepy patients, it might be possible to identify a subset who could benefit from CPAP. A recent analysis suggested that non-sleepy patients who exhibit a higher change in heart rate following a respiratory event may derive greater cardiovascular benefit from CPAP therapy (Azarbarzin, et al. Am J Respir Crit Care Med. 2022;206[6]:767).

We are moving toward a more personalized approach to characterizing OSA, which eventually may allow for more nuanced, individualized counseling rather than a “one-size -called-CPAP-fits-all” approach. Until we are there, a patient-centered approach that elicits the presence of sleep-related symptoms and daytime impairment, as opposed to isolated comorbidities, provides the most compelling justification for CPAP.

Obstructive sleep apnea (OSA) affects roughly 1 billion people worldwide, according to a report by the American Academy of Sleep Medicine. Severe OSA has been associated with an elevated risk of all-cause and cardiovascular-specific mortality. Studies support an association between OSA and a host of comorbidities, including hypertension, stroke, atrial fibrillation, mood disorders, and neurocognitive outcomes. Undiagnosed and untreated OSA also has major economic and societal costs, reducing workplace productivity and increasing one’s risk of accidents both on the job and while driving.

Positive airway pressure (PAP) is widely considered the most effective treatment for OSA. The majority of patients tolerate CPAP: real-world estimates using international big data show good adherence in over 70% of patients. Robust evidence shows that PAP reduces snoring, decreases daytime sleepiness, and improves quality of life in a dose-dependent manner. Economic analyses have also found CPAP to be cost-effective (Streatfeild, et al. Sleep. 2019;42[12]:zsz181).

But what do we know about the impact of PAP on health outcomes? Perhaps the best studied outcome is cardiovascular disease. Results of observational trials have suggested that CPAP adherence was associated with survival (Pepin JL et al. Chest. 2022;161[6]:1657). However, it has been speculated that these findings may have been driven, at least in part, by the “healthy user effect.” This phenomenon refers to the tendency for people who engage in one health-promoting behavior (eg, CPAP adherence) to engage in another as well (eg, eating well, exercising, taking prescribed medications). When we observe that patients who use CPAP live longer, we must ask ourselves whether perhaps their better outcomes resulted from healthy habits in general, as opposed to their CPAP usage per se.

Randomization eliminates the potential for the healthy user effect, by assigning patients to a certain intervention as opposed to simply observing whether they choose to use it. And herein lies one of the great disappointments for our field over the past decade: multiple large-scale randomized controlled trials have failed to demonstrate that CPAP reduces cardiovascular mortality, even in patients with pre-existing CAD. The first two of these were the SAVE (Sleep Apnea Cardiovascular Endpoints) (McEvoy R, et al.  N Engl J Med. 2016;375[10]:919) and RICCADSA (Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA) (Peker Y, et al. Am J Respir Crit Care Med. 2016;194[5]:613) trials evaluating the effects of PAP on a composite endpoint that included cardiovascular death and nonfatal cardiovascular events. Both trials found no difference between PAP and control groups, leading to a conclusion that PAP did not prevent cardiovascular events in patients with moderate-to-severe OSA and established cardiovascular disease. The ISAAC study (Impact of Sleep Apnea syndrome in the evolution of Acute Coronary syndrome) also failed to show a benefit of CPAP for secondary prevention of cardiovascular events in patients with moderate to severe OSA.

These negative findings were echoed in a recent report by the Agency for Healthcare Research and Quality evaluating a variety of long-term health outcomes in obstructive sleep apnea. The authors stated that “RCTs do not provide evidence that CPAP prescription affects long-term, clinically important outcomes. Specifically, with low strength of evidence, RCTs do not demonstrate that CPAP affects all-cause mortality, various CV outcomes, clinically important changes in psychosocial measures, or other clinical events” (AHRQ, Project ID: SLPT0919, 12/1/2022).

What plausible explanations have been offered for these negative results? Perhaps trials were underpowered. Perhaps patients did not use PAP for a sufficient duration to achieve benefit (usage was under 3 hours in most studies). Perhaps the patients selected for these trials were at such low-risk of adverse outcomes in the first place that treating their OSA didn’t have much impact. Many trials have excluded sleepy patients due to ethical concerns about withholding treatment from this population. But this may have effectively excluded the patients most likely to benefit; in other studies, sleepy patients seem to experience the greatest cardiovascular risk reduction with CPAP. For example, a meta-analysis showed that CPAP is most strongly associated with blood pressure reduction in patients who are sleepy, compared with those with minimally symptomatic OSA (Bratton D, et al. Thorax. 2014;69[12]:1128). And, recent work suggests that even among non-sleepy patients, it might be possible to identify a subset who could benefit from CPAP. A recent analysis suggested that non-sleepy patients who exhibit a higher change in heart rate following a respiratory event may derive greater cardiovascular benefit from CPAP therapy (Azarbarzin, et al. Am J Respir Crit Care Med. 2022;206[6]:767).

We are moving toward a more personalized approach to characterizing OSA, which eventually may allow for more nuanced, individualized counseling rather than a “one-size -called-CPAP-fits-all” approach. Until we are there, a patient-centered approach that elicits the presence of sleep-related symptoms and daytime impairment, as opposed to isolated comorbidities, provides the most compelling justification for CPAP.

Obstructive sleep apnea (OSA) affects roughly 1 billion people worldwide, according to a report by the American Academy of Sleep Medicine. Severe OSA has been associated with an elevated risk of all-cause and cardiovascular-specific mortality. Studies support an association between OSA and a host of comorbidities, including hypertension, stroke, atrial fibrillation, mood disorders, and neurocognitive outcomes. Undiagnosed and untreated OSA also has major economic and societal costs, reducing workplace productivity and increasing one’s risk of accidents both on the job and while driving.

Positive airway pressure (PAP) is widely considered the most effective treatment for OSA. The majority of patients tolerate CPAP: real-world estimates using international big data show good adherence in over 70% of patients. Robust evidence shows that PAP reduces snoring, decreases daytime sleepiness, and improves quality of life in a dose-dependent manner. Economic analyses have also found CPAP to be cost-effective (Streatfeild, et al. Sleep. 2019;42[12]:zsz181).

But what do we know about the impact of PAP on health outcomes? Perhaps the best studied outcome is cardiovascular disease. Results of observational trials have suggested that CPAP adherence was associated with survival (Pepin JL et al. Chest. 2022;161[6]:1657). However, it has been speculated that these findings may have been driven, at least in part, by the “healthy user effect.” This phenomenon refers to the tendency for people who engage in one health-promoting behavior (eg, CPAP adherence) to engage in another as well (eg, eating well, exercising, taking prescribed medications). When we observe that patients who use CPAP live longer, we must ask ourselves whether perhaps their better outcomes resulted from healthy habits in general, as opposed to their CPAP usage per se.

Randomization eliminates the potential for the healthy user effect, by assigning patients to a certain intervention as opposed to simply observing whether they choose to use it. And herein lies one of the great disappointments for our field over the past decade: multiple large-scale randomized controlled trials have failed to demonstrate that CPAP reduces cardiovascular mortality, even in patients with pre-existing CAD. The first two of these were the SAVE (Sleep Apnea Cardiovascular Endpoints) (McEvoy R, et al.  N Engl J Med. 2016;375[10]:919) and RICCADSA (Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA) (Peker Y, et al. Am J Respir Crit Care Med. 2016;194[5]:613) trials evaluating the effects of PAP on a composite endpoint that included cardiovascular death and nonfatal cardiovascular events. Both trials found no difference between PAP and control groups, leading to a conclusion that PAP did not prevent cardiovascular events in patients with moderate-to-severe OSA and established cardiovascular disease. The ISAAC study (Impact of Sleep Apnea syndrome in the evolution of Acute Coronary syndrome) also failed to show a benefit of CPAP for secondary prevention of cardiovascular events in patients with moderate to severe OSA.

These negative findings were echoed in a recent report by the Agency for Healthcare Research and Quality evaluating a variety of long-term health outcomes in obstructive sleep apnea. The authors stated that “RCTs do not provide evidence that CPAP prescription affects long-term, clinically important outcomes. Specifically, with low strength of evidence, RCTs do not demonstrate that CPAP affects all-cause mortality, various CV outcomes, clinically important changes in psychosocial measures, or other clinical events” (AHRQ, Project ID: SLPT0919, 12/1/2022).

What plausible explanations have been offered for these negative results? Perhaps trials were underpowered. Perhaps patients did not use PAP for a sufficient duration to achieve benefit (usage was under 3 hours in most studies). Perhaps the patients selected for these trials were at such low-risk of adverse outcomes in the first place that treating their OSA didn’t have much impact. Many trials have excluded sleepy patients due to ethical concerns about withholding treatment from this population. But this may have effectively excluded the patients most likely to benefit; in other studies, sleepy patients seem to experience the greatest cardiovascular risk reduction with CPAP. For example, a meta-analysis showed that CPAP is most strongly associated with blood pressure reduction in patients who are sleepy, compared with those with minimally symptomatic OSA (Bratton D, et al. Thorax. 2014;69[12]:1128). And, recent work suggests that even among non-sleepy patients, it might be possible to identify a subset who could benefit from CPAP. A recent analysis suggested that non-sleepy patients who exhibit a higher change in heart rate following a respiratory event may derive greater cardiovascular benefit from CPAP therapy (Azarbarzin, et al. Am J Respir Crit Care Med. 2022;206[6]:767).

We are moving toward a more personalized approach to characterizing OSA, which eventually may allow for more nuanced, individualized counseling rather than a “one-size -called-CPAP-fits-all” approach. Until we are there, a patient-centered approach that elicits the presence of sleep-related symptoms and daytime impairment, as opposed to isolated comorbidities, provides the most compelling justification for CPAP.

Our fear of death is exposed often in medicine. It is not uncommon to hear the last moments of a patient’s life described as a series of futile, sterile medical interventions that attempt to prolong that life in quasi-sadistic fashion. So much effort is placed in making sure that “everything necessary” is tried that less emphasis is made on providing a comfortable death.

It seems obvious that a profession dedicated to prolonging health would have difficulty confronting death. But it should also be natural for psychiatry to be the specialty able to integrate this discomfort within the medical psyche.

Dr. Neha Akkoor

Yet, in training, we have noted much more time spent on the assessment of capacity in patients in order to refuse medical intervention than on time spent educating about the importance to die at the right time, as suggested by Friedrich Nietzsche.¹ A psychiatry resident may graduate knowing dozens of questions to assess the ability of a family member to consider the risk, benefits, and alternatives of continued intubation in a comatose patient, but may feel very ill-equipped in discussing the meaning of a rightful life and a rightful death.

Death anxiety can also come outside the context of not having endured enough traumas or successes in one’s life, or not having lived life right. As poignantly described by Dostoevsky in his 1864 novella, “Notes from the Underground,” death anxiety can manifest as a result of the deterministic nature of life.² Doing everything which is expected of us can feel like a betrayal of our one chance to have lived life authentically. This concept is also particularly familiar to physicians, who may have – in part – chosen their career path in response to a recommendation from their parents, rather than a more authentic feeling. Dostoevsky goads us to transgress, to act in a rebellious way, to truly feel alive. This can serve as a solution for death anxiety – if you are scared to die then live, live your fullest. Even if that means doing the unexpected or changing your path.

The fear of being forgotten after death can also drive many to pursue a legacy. Even a parent choosing to have children and teaching them values and belief systems is a way of leaving behind a mark on the world. For some, finding ways for being remembered after death – whether through fame, fortune, or having children, is a way of dealing with death anxiety.

The Mexican holiday “Dia de los Muertos,” or Day of the Dead, and the Japanese holiday “Obon” are examples from cultures where deceased ancestors are celebrated through rituals and offerings. Such cultures may relieve the anxiety of death by suggesting that one’s descendants will still care for the departed, and their legacy may remain.
 

Coping with death anxiety

For others, the road to recovery from death anxiety may take a completely different approach. Some may find comfort in the position that, to extinguish death anxiety, one should not live to the fullest but accept the tragic and mostly inconsequential aspects of life. The philosophical movement of “absurdism” addresses this perspective.

In our modern world, where we are so deeply attached to finding the cause and reason for things, absurdism reminds us that most of our lives and world do not have to make sense. While Albert Camus, arguably the most famous of the absurdist philosophers, encourages us to create meaning and transcend the tragedy and randomness of life,³ some patients can also find comfort in the idea that life is absurd, and thus one should not judge one’s own life and not fear own’s inevitable death.

Death anxiety can also be therapeutic. Especially in the existential tradition, one can enlist the fear of death for motivation. Many patients come to see us with a lack of motivation or drive. They feel paralyzed by their predicament and mental illness. As in the experiments of Martin Seligman, PhD, who shocked animals at random, a human exposed to repeated failure and abuse can get a sense of learned helplessness.⁴ Such patients can be very hard to reach, yet ultimately their despondence is no match for the reality that life will end. Reminding a patient that any day spent not feeling alive might as well be a metaphor for death is a challenging interpretation, but one that can lead to significant growth.

When considering the fear of death, psychiatry has generally taken the position that it is pathological, a form of anxiety. Psychiatry argues that one should strive to find fulfillment and joy in life. It thus may be a surprise to find that this is not a universally shared perspective.

In his 2010 book, author Thomas Ligotti argues on behalf of pessimistic and antinatalist views.⁵ Throughout the book he emphasizes the suffering that life can offer and argues against the endless pursuit of more life. To some psychiatrists, such arguments will be understood as insulting to our profession. Some may even interpret his texts as an argument in favor of ending one’s life.

However, psychiatrists must ask themselves “what are my answers to those arguments?” Mr. Ligotti’s book is a series of arguments against the idea that life will be pleasurable. Understanding those arguments and formulating a rebuttal would be an important process for any mental health provider. It is foolish to think that our patients do not have a rich and complicated relationship to death, and that none of our patients find death attractive in some ways. After all, accepting our fears as an important part of our body is a natural coping skill, which can also be taught.⁶

Part of the difficulty in discussing death and the fear of death may come from society’s resistance at having complicated conversations. It is not uncommon, currently, to include trigger warnings at the mention of discussions about death, even abstract ones. While we appreciate and encourage the articulation of feelings that a discussion about death may raise, we worry that such trigger warnings may be a form of censure that only makes society more resistant to talk about those important topics.

For another example of the avoidance of discussions about death, recall the “death panel” debates of 2009.⁷ When the U.S. government considered encouraging physicians to have discussions with their patients about end-of-life care, politicians and pundits decried that such discussions were “death panels,” and claimed they were an encouragement to patients to “cut [their] life short.” Such public projection of one’s anxiety about death has made it particularly difficult for psychiatry to make meaningful progress.
 

Acknowledging and addressing the fear

Death anxiety is such a common aspect of human life that most religions make some effort to address this fear. Many do so by offering a form of afterlife, often one described in idyllic fashion without anxiety.

Heaven, if one believes in it, is appealing for the person dreading death anxiety. Heaven is often described as being offered to those who have lived a rightful life, thus relieving the anxiety regarding the decisions one has made. Reincarnation can also be interpreted as another way of calming death anxiety, by promising a continual repetition of chances at getting life right. However, for many patients, religion doesn’t have the appeal that it once had.

Ultimately, the fear of death is a complex and multifaceted issue that can manifest in various ways. The medical profession, especially psychiatry, has a responsibility to address this fear in patients, but it also struggles with its own discomfort with the topic. The importance of providing a comfortable death is often overshadowed by the emphasis on prolonging life, which may manifest as a series of futile medical interventions.

The fear of death can be therapeutic and motivating, but it can also be pathological and lead to a lack of motivation or drive. The philosophical movements of absurdism and antinatalism offer alternative perspectives on death and life, and it is important for mental health providers to understand and engage with these views.

Society’s resistance to having a meaningful conversation about death only perpetuates the fear and makes progress difficult. Yet acknowledging and addressing the fear of death is an important aspect of mental health care and a crucial part of the human experience.

Dr. Akkoor is a psychiatry resident at the University of California, San Diego. She is interested in immigrant mental health, ethics, consultation-liaison psychiatry, and medical education. Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. Dr. Badre and Dr. Akkoor have no conflicts of interest.

References

1. Nietzsche F. Thus Spoke Zarathustra. 1883-1892.

2. Dostoevsky F. Notes from the Underground. 1864.

3. Camus A. The Plague. 1947.

4. Seligman M. Helplessness: On depression, development, and death. 1975.

5. Ligotti T. The Conspiracy Against the Human Race. 2010.

6. Hayes SC. Behav Ther. 2016 Nov;47(6):869-85. doi: 10.1016/j.beth.2016.11.006.

7. Nyhan B. The Forum. 2010 April 27;8(1). doi: 10.2202/1540-8884.1354.

Our fear of death is exposed often in medicine. It is not uncommon to hear the last moments of a patient’s life described as a series of futile, sterile medical interventions that attempt to prolong that life in quasi-sadistic fashion. So much effort is placed in making sure that “everything necessary” is tried that less emphasis is made on providing a comfortable death.

It seems obvious that a profession dedicated to prolonging health would have difficulty confronting death. But it should also be natural for psychiatry to be the specialty able to integrate this discomfort within the medical psyche.

Dr. Neha Akkoor

Yet, in training, we have noted much more time spent on the assessment of capacity in patients in order to refuse medical intervention than on time spent educating about the importance to die at the right time, as suggested by Friedrich Nietzsche.¹ A psychiatry resident may graduate knowing dozens of questions to assess the ability of a family member to consider the risk, benefits, and alternatives of continued intubation in a comatose patient, but may feel very ill-equipped in discussing the meaning of a rightful life and a rightful death.

Death anxiety can also come outside the context of not having endured enough traumas or successes in one’s life, or not having lived life right. As poignantly described by Dostoevsky in his 1864 novella, “Notes from the Underground,” death anxiety can manifest as a result of the deterministic nature of life.² Doing everything which is expected of us can feel like a betrayal of our one chance to have lived life authentically. This concept is also particularly familiar to physicians, who may have – in part – chosen their career path in response to a recommendation from their parents, rather than a more authentic feeling. Dostoevsky goads us to transgress, to act in a rebellious way, to truly feel alive. This can serve as a solution for death anxiety – if you are scared to die then live, live your fullest. Even if that means doing the unexpected or changing your path.

The fear of being forgotten after death can also drive many to pursue a legacy. Even a parent choosing to have children and teaching them values and belief systems is a way of leaving behind a mark on the world. For some, finding ways for being remembered after death – whether through fame, fortune, or having children, is a way of dealing with death anxiety.

The Mexican holiday “Dia de los Muertos,” or Day of the Dead, and the Japanese holiday “Obon” are examples from cultures where deceased ancestors are celebrated through rituals and offerings. Such cultures may relieve the anxiety of death by suggesting that one’s descendants will still care for the departed, and their legacy may remain.
 

Coping with death anxiety

For others, the road to recovery from death anxiety may take a completely different approach. Some may find comfort in the position that, to extinguish death anxiety, one should not live to the fullest but accept the tragic and mostly inconsequential aspects of life. The philosophical movement of “absurdism” addresses this perspective.

In our modern world, where we are so deeply attached to finding the cause and reason for things, absurdism reminds us that most of our lives and world do not have to make sense. While Albert Camus, arguably the most famous of the absurdist philosophers, encourages us to create meaning and transcend the tragedy and randomness of life,³ some patients can also find comfort in the idea that life is absurd, and thus one should not judge one’s own life and not fear own’s inevitable death.

Death anxiety can also be therapeutic. Especially in the existential tradition, one can enlist the fear of death for motivation. Many patients come to see us with a lack of motivation or drive. They feel paralyzed by their predicament and mental illness. As in the experiments of Martin Seligman, PhD, who shocked animals at random, a human exposed to repeated failure and abuse can get a sense of learned helplessness.⁴ Such patients can be very hard to reach, yet ultimately their despondence is no match for the reality that life will end. Reminding a patient that any day spent not feeling alive might as well be a metaphor for death is a challenging interpretation, but one that can lead to significant growth.

When considering the fear of death, psychiatry has generally taken the position that it is pathological, a form of anxiety. Psychiatry argues that one should strive to find fulfillment and joy in life. It thus may be a surprise to find that this is not a universally shared perspective.

In his 2010 book, author Thomas Ligotti argues on behalf of pessimistic and antinatalist views.⁵ Throughout the book he emphasizes the suffering that life can offer and argues against the endless pursuit of more life. To some psychiatrists, such arguments will be understood as insulting to our profession. Some may even interpret his texts as an argument in favor of ending one’s life.

However, psychiatrists must ask themselves “what are my answers to those arguments?” Mr. Ligotti’s book is a series of arguments against the idea that life will be pleasurable. Understanding those arguments and formulating a rebuttal would be an important process for any mental health provider. It is foolish to think that our patients do not have a rich and complicated relationship to death, and that none of our patients find death attractive in some ways. After all, accepting our fears as an important part of our body is a natural coping skill, which can also be taught.⁶

Part of the difficulty in discussing death and the fear of death may come from society’s resistance at having complicated conversations. It is not uncommon, currently, to include trigger warnings at the mention of discussions about death, even abstract ones. While we appreciate and encourage the articulation of feelings that a discussion about death may raise, we worry that such trigger warnings may be a form of censure that only makes society more resistant to talk about those important topics.

For another example of the avoidance of discussions about death, recall the “death panel” debates of 2009.⁷ When the U.S. government considered encouraging physicians to have discussions with their patients about end-of-life care, politicians and pundits decried that such discussions were “death panels,” and claimed they were an encouragement to patients to “cut [their] life short.” Such public projection of one’s anxiety about death has made it particularly difficult for psychiatry to make meaningful progress.
 

Acknowledging and addressing the fear

Death anxiety is such a common aspect of human life that most religions make some effort to address this fear. Many do so by offering a form of afterlife, often one described in idyllic fashion without anxiety.

Heaven, if one believes in it, is appealing for the person dreading death anxiety. Heaven is often described as being offered to those who have lived a rightful life, thus relieving the anxiety regarding the decisions one has made. Reincarnation can also be interpreted as another way of calming death anxiety, by promising a continual repetition of chances at getting life right. However, for many patients, religion doesn’t have the appeal that it once had.

Ultimately, the fear of death is a complex and multifaceted issue that can manifest in various ways. The medical profession, especially psychiatry, has a responsibility to address this fear in patients, but it also struggles with its own discomfort with the topic. The importance of providing a comfortable death is often overshadowed by the emphasis on prolonging life, which may manifest as a series of futile medical interventions.

The fear of death can be therapeutic and motivating, but it can also be pathological and lead to a lack of motivation or drive. The philosophical movements of absurdism and antinatalism offer alternative perspectives on death and life, and it is important for mental health providers to understand and engage with these views.

Society’s resistance to having a meaningful conversation about death only perpetuates the fear and makes progress difficult. Yet acknowledging and addressing the fear of death is an important aspect of mental health care and a crucial part of the human experience.

Dr. Akkoor is a psychiatry resident at the University of California, San Diego. She is interested in immigrant mental health, ethics, consultation-liaison psychiatry, and medical education. Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. Dr. Badre and Dr. Akkoor have no conflicts of interest.

References

1. Nietzsche F. Thus Spoke Zarathustra. 1883-1892.

2. Dostoevsky F. Notes from the Underground. 1864.

3. Camus A. The Plague. 1947.

4. Seligman M. Helplessness: On depression, development, and death. 1975.

5. Ligotti T. The Conspiracy Against the Human Race. 2010.

6. Hayes SC. Behav Ther. 2016 Nov;47(6):869-85. doi: 10.1016/j.beth.2016.11.006.

7. Nyhan B. The Forum. 2010 April 27;8(1). doi: 10.2202/1540-8884.1354.

Our fear of death is exposed often in medicine. It is not uncommon to hear the last moments of a patient’s life described as a series of futile, sterile medical interventions that attempt to prolong that life in quasi-sadistic fashion. So much effort is placed in making sure that “everything necessary” is tried that less emphasis is made on providing a comfortable death.

It seems obvious that a profession dedicated to prolonging health would have difficulty confronting death. But it should also be natural for psychiatry to be the specialty able to integrate this discomfort within the medical psyche.

Dr. Neha Akkoor

Yet, in training, we have noted much more time spent on the assessment of capacity in patients in order to refuse medical intervention than on time spent educating about the importance to die at the right time, as suggested by Friedrich Nietzsche.¹ A psychiatry resident may graduate knowing dozens of questions to assess the ability of a family member to consider the risk, benefits, and alternatives of continued intubation in a comatose patient, but may feel very ill-equipped in discussing the meaning of a rightful life and a rightful death.

Death anxiety can also come outside the context of not having endured enough traumas or successes in one’s life, or not having lived life right. As poignantly described by Dostoevsky in his 1864 novella, “Notes from the Underground,” death anxiety can manifest as a result of the deterministic nature of life.² Doing everything which is expected of us can feel like a betrayal of our one chance to have lived life authentically. This concept is also particularly familiar to physicians, who may have – in part – chosen their career path in response to a recommendation from their parents, rather than a more authentic feeling. Dostoevsky goads us to transgress, to act in a rebellious way, to truly feel alive. This can serve as a solution for death anxiety – if you are scared to die then live, live your fullest. Even if that means doing the unexpected or changing your path.

The fear of being forgotten after death can also drive many to pursue a legacy. Even a parent choosing to have children and teaching them values and belief systems is a way of leaving behind a mark on the world. For some, finding ways for being remembered after death – whether through fame, fortune, or having children, is a way of dealing with death anxiety.

The Mexican holiday “Dia de los Muertos,” or Day of the Dead, and the Japanese holiday “Obon” are examples from cultures where deceased ancestors are celebrated through rituals and offerings. Such cultures may relieve the anxiety of death by suggesting that one’s descendants will still care for the departed, and their legacy may remain.
 

Coping with death anxiety

For others, the road to recovery from death anxiety may take a completely different approach. Some may find comfort in the position that, to extinguish death anxiety, one should not live to the fullest but accept the tragic and mostly inconsequential aspects of life. The philosophical movement of “absurdism” addresses this perspective.

In our modern world, where we are so deeply attached to finding the cause and reason for things, absurdism reminds us that most of our lives and world do not have to make sense. While Albert Camus, arguably the most famous of the absurdist philosophers, encourages us to create meaning and transcend the tragedy and randomness of life,³ some patients can also find comfort in the idea that life is absurd, and thus one should not judge one’s own life and not fear own’s inevitable death.

Death anxiety can also be therapeutic. Especially in the existential tradition, one can enlist the fear of death for motivation. Many patients come to see us with a lack of motivation or drive. They feel paralyzed by their predicament and mental illness. As in the experiments of Martin Seligman, PhD, who shocked animals at random, a human exposed to repeated failure and abuse can get a sense of learned helplessness.⁴ Such patients can be very hard to reach, yet ultimately their despondence is no match for the reality that life will end. Reminding a patient that any day spent not feeling alive might as well be a metaphor for death is a challenging interpretation, but one that can lead to significant growth.

When considering the fear of death, psychiatry has generally taken the position that it is pathological, a form of anxiety. Psychiatry argues that one should strive to find fulfillment and joy in life. It thus may be a surprise to find that this is not a universally shared perspective.

In his 2010 book, author Thomas Ligotti argues on behalf of pessimistic and antinatalist views.⁵ Throughout the book he emphasizes the suffering that life can offer and argues against the endless pursuit of more life. To some psychiatrists, such arguments will be understood as insulting to our profession. Some may even interpret his texts as an argument in favor of ending one’s life.

However, psychiatrists must ask themselves “what are my answers to those arguments?” Mr. Ligotti’s book is a series of arguments against the idea that life will be pleasurable. Understanding those arguments and formulating a rebuttal would be an important process for any mental health provider. It is foolish to think that our patients do not have a rich and complicated relationship to death, and that none of our patients find death attractive in some ways. After all, accepting our fears as an important part of our body is a natural coping skill, which can also be taught.⁶

Part of the difficulty in discussing death and the fear of death may come from society’s resistance at having complicated conversations. It is not uncommon, currently, to include trigger warnings at the mention of discussions about death, even abstract ones. While we appreciate and encourage the articulation of feelings that a discussion about death may raise, we worry that such trigger warnings may be a form of censure that only makes society more resistant to talk about those important topics.

For another example of the avoidance of discussions about death, recall the “death panel” debates of 2009.⁷ When the U.S. government considered encouraging physicians to have discussions with their patients about end-of-life care, politicians and pundits decried that such discussions were “death panels,” and claimed they were an encouragement to patients to “cut [their] life short.” Such public projection of one’s anxiety about death has made it particularly difficult for psychiatry to make meaningful progress.
 

Acknowledging and addressing the fear

Death anxiety is such a common aspect of human life that most religions make some effort to address this fear. Many do so by offering a form of afterlife, often one described in idyllic fashion without anxiety.

Heaven, if one believes in it, is appealing for the person dreading death anxiety. Heaven is often described as being offered to those who have lived a rightful life, thus relieving the anxiety regarding the decisions one has made. Reincarnation can also be interpreted as another way of calming death anxiety, by promising a continual repetition of chances at getting life right. However, for many patients, religion doesn’t have the appeal that it once had.

Ultimately, the fear of death is a complex and multifaceted issue that can manifest in various ways. The medical profession, especially psychiatry, has a responsibility to address this fear in patients, but it also struggles with its own discomfort with the topic. The importance of providing a comfortable death is often overshadowed by the emphasis on prolonging life, which may manifest as a series of futile medical interventions.

The fear of death can be therapeutic and motivating, but it can also be pathological and lead to a lack of motivation or drive. The philosophical movements of absurdism and antinatalism offer alternative perspectives on death and life, and it is important for mental health providers to understand and engage with these views.

Society’s resistance to having a meaningful conversation about death only perpetuates the fear and makes progress difficult. Yet acknowledging and addressing the fear of death is an important aspect of mental health care and a crucial part of the human experience.

Dr. Akkoor is a psychiatry resident at the University of California, San Diego. She is interested in immigrant mental health, ethics, consultation-liaison psychiatry, and medical education. Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. Dr. Badre and Dr. Akkoor have no conflicts of interest.

References

1. Nietzsche F. Thus Spoke Zarathustra. 1883-1892.

2. Dostoevsky F. Notes from the Underground. 1864.

3. Camus A. The Plague. 1947.

4. Seligman M. Helplessness: On depression, development, and death. 1975.

5. Ligotti T. The Conspiracy Against the Human Race. 2010.

6. Hayes SC. Behav Ther. 2016 Nov;47(6):869-85. doi: 10.1016/j.beth.2016.11.006.

7. Nyhan B. The Forum. 2010 April 27;8(1). doi: 10.2202/1540-8884.1354.

Roughly 3.7 million adults have a history of schizophrenia spectrum disorders – a figure two to three times higher than previously assumed, according to the first study to estimate the national prevalence of schizophrenia spectrum disorders.

This finding is “especially important,” given that people with schizophrenia spectrum disorders experience “high levels of disability that present significant challenges in all aspects of their life,” principal investigator Heather Ringeisen, PhD, with RTI International, a nonprofit research institute based on Research Triangle Park, N.C., said in a statement.

The results “highlight the need to improve systems of care and access to treatment for people with schizophrenia and other mental health disorders,” added co–principal investigator Mark J. Edlund, MD, PhD, also with RTI.

The study also found that prevalence rates of many other nonpsychotic disorders were generally within an expected range in light of findings from prior research – with three exceptions.

Rates of major depressive disorder (MDD), generalized anxiety disorder (GAD), and obsessive-compulsive disorder (OCD) were higher than reported in past nationally representative samples.

The new data come from the Mental and Substance Use Disorder Prevalence Study (MDPS), a pilot program funded by the Substance Abuse and Mental Health Services Administration (SAMHSA).

A nationally representative sample of 5,679 adults aged 18-65 residing in U.S. households, prisons, homeless shelters, and state psychiatric hospitals were interviewed, virtually or in person, between October 2020 and October 2022.

The research team used a population-based version of the Structured Clinical Interview of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; SCID-5) for mental health and substance use disorder diagnostic assessment.

Among the key findings in the report:

• Nearly 2% of adults (about 3.7 million) had a lifetime history of schizophrenia spectrum disorders, which include schizophrenia, schizoaffective disorder, and schizophreniform disorder.
• Roughly 2.5 million adults (1.2%) met diagnostic criteria for a schizophrenia spectrum disorder in the past year.
• The two most common mental disorders among adults were MDD (15.5%, or about 31.4 million) and GAD (10.0%, or about 20.2 million).
• Approximately 8.2 million adults (4.1%) had past-year posttraumatic stress disorder, about 5.0 million (2.5%) had OCD, and roughly 3.1 million (1.5%) had bipolar I disorder.
• Alcohol use disorder (AUD) was the most common substance use disorder among adults aged 18-65; roughly 13.4 million adults (6.7%) met criteria for AUD in the past year.
• About 7.7 million adults (3.8%) had cannabis use disorder, about 3.2 million (1.6%) had stimulant use disorder, and about 1 million (0.5%) had opioid use disorder.

Multiple comorbidities

The data also show that one in four adults had at least one mental health disorder in the past year, most commonly MDD and GAD.

About 11% of adults met the criteria for at least one substance use disorder, with AUD and cannabis use disorder the most common.

In addition, an estimated 11 million adults aged 18-65 had both a mental health disorder and a substance use disorder in the past year.

Encouragingly, the findings suggest that more individuals are seeking and accessing treatment compared with previous studies, the authors noted; 61% of adults with a mental health disorder reported having at least one visit with a treatment provider in the past year.

However, considerable treatment gaps still exist for the most common mental health disorders, they reported. Within the past year, more than 40% of adults with MDD and more than 30% of those with GAD did not receive any treatment services.

The full report is available online.

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

Roughly 3.7 million adults have a history of schizophrenia spectrum disorders – a figure two to three times higher than previously assumed, according to the first study to estimate the national prevalence of schizophrenia spectrum disorders.

This finding is “especially important,” given that people with schizophrenia spectrum disorders experience “high levels of disability that present significant challenges in all aspects of their life,” principal investigator Heather Ringeisen, PhD, with RTI International, a nonprofit research institute based on Research Triangle Park, N.C., said in a statement.

The results “highlight the need to improve systems of care and access to treatment for people with schizophrenia and other mental health disorders,” added co–principal investigator Mark J. Edlund, MD, PhD, also with RTI.

The study also found that prevalence rates of many other nonpsychotic disorders were generally within an expected range in light of findings from prior research – with three exceptions.

Rates of major depressive disorder (MDD), generalized anxiety disorder (GAD), and obsessive-compulsive disorder (OCD) were higher than reported in past nationally representative samples.

The new data come from the Mental and Substance Use Disorder Prevalence Study (MDPS), a pilot program funded by the Substance Abuse and Mental Health Services Administration (SAMHSA).

A nationally representative sample of 5,679 adults aged 18-65 residing in U.S. households, prisons, homeless shelters, and state psychiatric hospitals were interviewed, virtually or in person, between October 2020 and October 2022.

The research team used a population-based version of the Structured Clinical Interview of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; SCID-5) for mental health and substance use disorder diagnostic assessment.

Among the key findings in the report:

• Nearly 2% of adults (about 3.7 million) had a lifetime history of schizophrenia spectrum disorders, which include schizophrenia, schizoaffective disorder, and schizophreniform disorder.
• Roughly 2.5 million adults (1.2%) met diagnostic criteria for a schizophrenia spectrum disorder in the past year.
• The two most common mental disorders among adults were MDD (15.5%, or about 31.4 million) and GAD (10.0%, or about 20.2 million).
• Approximately 8.2 million adults (4.1%) had past-year posttraumatic stress disorder, about 5.0 million (2.5%) had OCD, and roughly 3.1 million (1.5%) had bipolar I disorder.
• Alcohol use disorder (AUD) was the most common substance use disorder among adults aged 18-65; roughly 13.4 million adults (6.7%) met criteria for AUD in the past year.
• About 7.7 million adults (3.8%) had cannabis use disorder, about 3.2 million (1.6%) had stimulant use disorder, and about 1 million (0.5%) had opioid use disorder.

Multiple comorbidities

The data also show that one in four adults had at least one mental health disorder in the past year, most commonly MDD and GAD.

About 11% of adults met the criteria for at least one substance use disorder, with AUD and cannabis use disorder the most common.

In addition, an estimated 11 million adults aged 18-65 had both a mental health disorder and a substance use disorder in the past year.

Encouragingly, the findings suggest that more individuals are seeking and accessing treatment compared with previous studies, the authors noted; 61% of adults with a mental health disorder reported having at least one visit with a treatment provider in the past year.

However, considerable treatment gaps still exist for the most common mental health disorders, they reported. Within the past year, more than 40% of adults with MDD and more than 30% of those with GAD did not receive any treatment services.

The full report is available online.

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

Roughly 3.7 million adults have a history of schizophrenia spectrum disorders – a figure two to three times higher than previously assumed, according to the first study to estimate the national prevalence of schizophrenia spectrum disorders.

This finding is “especially important,” given that people with schizophrenia spectrum disorders experience “high levels of disability that present significant challenges in all aspects of their life,” principal investigator Heather Ringeisen, PhD, with RTI International, a nonprofit research institute based on Research Triangle Park, N.C., said in a statement.

The results “highlight the need to improve systems of care and access to treatment for people with schizophrenia and other mental health disorders,” added co–principal investigator Mark J. Edlund, MD, PhD, also with RTI.

The study also found that prevalence rates of many other nonpsychotic disorders were generally within an expected range in light of findings from prior research – with three exceptions.

Rates of major depressive disorder (MDD), generalized anxiety disorder (GAD), and obsessive-compulsive disorder (OCD) were higher than reported in past nationally representative samples.

The new data come from the Mental and Substance Use Disorder Prevalence Study (MDPS), a pilot program funded by the Substance Abuse and Mental Health Services Administration (SAMHSA).

A nationally representative sample of 5,679 adults aged 18-65 residing in U.S. households, prisons, homeless shelters, and state psychiatric hospitals were interviewed, virtually or in person, between October 2020 and October 2022.

The research team used a population-based version of the Structured Clinical Interview of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; SCID-5) for mental health and substance use disorder diagnostic assessment.

Among the key findings in the report:

• Nearly 2% of adults (about 3.7 million) had a lifetime history of schizophrenia spectrum disorders, which include schizophrenia, schizoaffective disorder, and schizophreniform disorder.
• Roughly 2.5 million adults (1.2%) met diagnostic criteria for a schizophrenia spectrum disorder in the past year.
• The two most common mental disorders among adults were MDD (15.5%, or about 31.4 million) and GAD (10.0%, or about 20.2 million).
• Approximately 8.2 million adults (4.1%) had past-year posttraumatic stress disorder, about 5.0 million (2.5%) had OCD, and roughly 3.1 million (1.5%) had bipolar I disorder.
• Alcohol use disorder (AUD) was the most common substance use disorder among adults aged 18-65; roughly 13.4 million adults (6.7%) met criteria for AUD in the past year.
• About 7.7 million adults (3.8%) had cannabis use disorder, about 3.2 million (1.6%) had stimulant use disorder, and about 1 million (0.5%) had opioid use disorder.

Multiple comorbidities

The data also show that one in four adults had at least one mental health disorder in the past year, most commonly MDD and GAD.

About 11% of adults met the criteria for at least one substance use disorder, with AUD and cannabis use disorder the most common.

In addition, an estimated 11 million adults aged 18-65 had both a mental health disorder and a substance use disorder in the past year.

Encouragingly, the findings suggest that more individuals are seeking and accessing treatment compared with previous studies, the authors noted; 61% of adults with a mental health disorder reported having at least one visit with a treatment provider in the past year.

However, considerable treatment gaps still exist for the most common mental health disorders, they reported. Within the past year, more than 40% of adults with MDD and more than 30% of those with GAD did not receive any treatment services.

The full report is available online.

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

Flares of systemic lupus erythematosus (SLE), particularly those involving severe kidney disease, were associated with growth spikes of the gut bacteria Ruminococcus blautia gnavus in a small, 4-year observational study that also demonstrated an underlying, inherent instability in the gut microbiome of patients with SLE.

Of 16 patients with SLE studied during the provision of routine care and monitoring, 5 had R. gnavus blooms that were “strikingly concordant with periods of raised disease activity,” Gregg J. Silverman, MD, of NYU Grossman School of Medicine, New York, and coinvestigators reported in Annals of the Rheumatic Diseases.

Four of the five patients with flare-associated R. gnavus blooms had lupus nephritis (LN); the other had a flare involving inflammation in multiple joints. The four patients with concurrent LN and spikes in R. gnavus also represented almost half of patients who had LN disease flares (four of nine) during the study period. The nine patients in the study with renal involvement, and the four with concurrent R. gnavus spikes and flares, represented different races and ethnicities.

The findings build upon research published by the NYU group several years ago showing that patients with SLE had more R. gnavus in the gut than similar patients without the disease, and that flares closely tracked major increases in R. gnavus growth. Evidence of R. gnavus expansions in patients with SLE now comes from several cohorts in the United States as well as cohorts in Europe and China, the researchers noted in their new paper.
 

An underlying, unstable microbiome

The new study at NYU took a “deeper dive” than previous research, looking at individuals over a longer period of time, Dr. Silverman, the study’s senior investigator and associate director of rheumatology at NYU Langone Health, said in an interview. Blood and a total of 44 stool samples from the 16 patients were analyzed, as were a total of 72 stool samples from 22 healthy control volunteers.

Importantly, he said, the gut microbiome in patients with SLE was found to be inherently unstable over time, compared with the microbiota communities of the controls. “There was an instability, a shifting dynamic composition of the microbiome [in patients with lupus]. ... Healthy individuals had more of a balance, with small changes over time” and a stable, low abundance of R. gnavus, Dr. Silverman said.

Transient expansions of several pathogenic species occurred in some of the patients with lupus (and not in controls), but blooms of R. gnavus were the most common. The researchers said in their paper that they “speculate that susceptibility for specific clinical features during R. gnavus blooms reflect in part differences in genetic susceptibility of the patient.”

Patients on cytotoxic agents or antibiotics were excluded from the study, but the study was not designed to disentangle the potential influence of diet or prior antibiotic exposure, they noted. Larger studies are needed that are better controlled and that include more frequent assessments, Dr. Silverman added.
 

A sure association and probable cause

“There seems to be a special connection [of R. gnavus] to lupus nephritis, which is an important, major subset of disease,” said Martin Kriegel, MD, PhD, chief or rheumatology and clinical immunology at the University of Munster (Germany). Dr. Kriegel also researches the gut microbiome in lupus and was asked to comment on the new findings from NYU.

The “difficult question is, is the bug driving the flare [as the NYU paper proposes], or is it the lupus nephritis that leads to overgrowth?” he said, noting that it “is well known that kidney disease, whether from lupus or other causes, creates disturbances in the microbiome.”

It’s “likely the case” that the pathobiome – with R. gnavus being an important pathobiont – helps to drive flares, he said. The new research shows only an association, but studies done in mice – including prior research by Dr. Silverman – support a mechanistic link, said Dr. Kriegel, also adjunct associate professor of immunobiology and of medicine at Yale University, New Haven, Conn.

Investigators in the microbiome space are moving toward more strain-level analysis – “not only measuring what organisms are there, but culturing them and sequencing them,” Dr. Kriegel noted, and the new study does just this.

The R. gnavus strains isolated during lupus flares were distinguishable from strains found in healthy people – and from strains found by other researchers in patients with inflammatory bowel disease – by their common expression of a novel type of cell membrane–associated lipoglycan. The lipoglycans were recognized by specific serum IgG2 antibodies that were detected concurrently with R. gnavus blooms and lupus flares, Dr. Silverman and his colleagues reported.

Dr. Silverman and Dr. Kriegel both study the paradigm of a gut-barrier breach, whereby pathogenic bacteria cause intestinal permeability, allowing bacterial leakages that trigger inflammation and immune responses. “We think that in lupus and other rheumatic diseases like rheumatoid arthritis, a leaky gut barrier is an important mechanism, even though these patients don’t have gastrointestinal symptoms,” said Dr. Kriegel, who has studied the role of another potentially pathogenic bacteria, Enterococcus gallinarum, in SLE.

Strengthening the gut barrier may be a plausible, general approach to reducing the severity of diseases like SLE and RA until more personalized approaches targeting individuals’ microbiome are developed, he noted.

Future treatments involving antibacterial agents, probiotics or dietary regimens that prevent imbalances in the gut microbiome would be “benign,” compared with currently utilized immunosuppressive medications, Dr. Silverman said.

The NYU study was funded in part by grants from the National Institutes of Health and the Lupus Research Alliance. Dr. Silverman disclosed that NYU has filed a patent application for an antibody test to detect serum antibodies to the lipoglycan made by some strains of R. gnavus. Dr. Kriegel disclosed that he holds a patent at Yale related to the Enterococcus bacteria he studies, and that he consults for Roche, Enterome, and Eligo Biosciences.

Flares of systemic lupus erythematosus (SLE), particularly those involving severe kidney disease, were associated with growth spikes of the gut bacteria Ruminococcus blautia gnavus in a small, 4-year observational study that also demonstrated an underlying, inherent instability in the gut microbiome of patients with SLE.

Of 16 patients with SLE studied during the provision of routine care and monitoring, 5 had R. gnavus blooms that were “strikingly concordant with periods of raised disease activity,” Gregg J. Silverman, MD, of NYU Grossman School of Medicine, New York, and coinvestigators reported in Annals of the Rheumatic Diseases.

Four of the five patients with flare-associated R. gnavus blooms had lupus nephritis (LN); the other had a flare involving inflammation in multiple joints. The four patients with concurrent LN and spikes in R. gnavus also represented almost half of patients who had LN disease flares (four of nine) during the study period. The nine patients in the study with renal involvement, and the four with concurrent R. gnavus spikes and flares, represented different races and ethnicities.

The findings build upon research published by the NYU group several years ago showing that patients with SLE had more R. gnavus in the gut than similar patients without the disease, and that flares closely tracked major increases in R. gnavus growth. Evidence of R. gnavus expansions in patients with SLE now comes from several cohorts in the United States as well as cohorts in Europe and China, the researchers noted in their new paper.
 

An underlying, unstable microbiome

The new study at NYU took a “deeper dive” than previous research, looking at individuals over a longer period of time, Dr. Silverman, the study’s senior investigator and associate director of rheumatology at NYU Langone Health, said in an interview. Blood and a total of 44 stool samples from the 16 patients were analyzed, as were a total of 72 stool samples from 22 healthy control volunteers.

Importantly, he said, the gut microbiome in patients with SLE was found to be inherently unstable over time, compared with the microbiota communities of the controls. “There was an instability, a shifting dynamic composition of the microbiome [in patients with lupus]. ... Healthy individuals had more of a balance, with small changes over time” and a stable, low abundance of R. gnavus, Dr. Silverman said.

Transient expansions of several pathogenic species occurred in some of the patients with lupus (and not in controls), but blooms of R. gnavus were the most common. The researchers said in their paper that they “speculate that susceptibility for specific clinical features during R. gnavus blooms reflect in part differences in genetic susceptibility of the patient.”

Patients on cytotoxic agents or antibiotics were excluded from the study, but the study was not designed to disentangle the potential influence of diet or prior antibiotic exposure, they noted. Larger studies are needed that are better controlled and that include more frequent assessments, Dr. Silverman added.
 

A sure association and probable cause

“There seems to be a special connection [of R. gnavus] to lupus nephritis, which is an important, major subset of disease,” said Martin Kriegel, MD, PhD, chief or rheumatology and clinical immunology at the University of Munster (Germany). Dr. Kriegel also researches the gut microbiome in lupus and was asked to comment on the new findings from NYU.

The “difficult question is, is the bug driving the flare [as the NYU paper proposes], or is it the lupus nephritis that leads to overgrowth?” he said, noting that it “is well known that kidney disease, whether from lupus or other causes, creates disturbances in the microbiome.”

It’s “likely the case” that the pathobiome – with R. gnavus being an important pathobiont – helps to drive flares, he said. The new research shows only an association, but studies done in mice – including prior research by Dr. Silverman – support a mechanistic link, said Dr. Kriegel, also adjunct associate professor of immunobiology and of medicine at Yale University, New Haven, Conn.

Investigators in the microbiome space are moving toward more strain-level analysis – “not only measuring what organisms are there, but culturing them and sequencing them,” Dr. Kriegel noted, and the new study does just this.

The R. gnavus strains isolated during lupus flares were distinguishable from strains found in healthy people – and from strains found by other researchers in patients with inflammatory bowel disease – by their common expression of a novel type of cell membrane–associated lipoglycan. The lipoglycans were recognized by specific serum IgG2 antibodies that were detected concurrently with R. gnavus blooms and lupus flares, Dr. Silverman and his colleagues reported.

Dr. Silverman and Dr. Kriegel both study the paradigm of a gut-barrier breach, whereby pathogenic bacteria cause intestinal permeability, allowing bacterial leakages that trigger inflammation and immune responses. “We think that in lupus and other rheumatic diseases like rheumatoid arthritis, a leaky gut barrier is an important mechanism, even though these patients don’t have gastrointestinal symptoms,” said Dr. Kriegel, who has studied the role of another potentially pathogenic bacteria, Enterococcus gallinarum, in SLE.

Strengthening the gut barrier may be a plausible, general approach to reducing the severity of diseases like SLE and RA until more personalized approaches targeting individuals’ microbiome are developed, he noted.

Future treatments involving antibacterial agents, probiotics or dietary regimens that prevent imbalances in the gut microbiome would be “benign,” compared with currently utilized immunosuppressive medications, Dr. Silverman said.

The NYU study was funded in part by grants from the National Institutes of Health and the Lupus Research Alliance. Dr. Silverman disclosed that NYU has filed a patent application for an antibody test to detect serum antibodies to the lipoglycan made by some strains of R. gnavus. Dr. Kriegel disclosed that he holds a patent at Yale related to the Enterococcus bacteria he studies, and that he consults for Roche, Enterome, and Eligo Biosciences.

Flares of systemic lupus erythematosus (SLE), particularly those involving severe kidney disease, were associated with growth spikes of the gut bacteria Ruminococcus blautia gnavus in a small, 4-year observational study that also demonstrated an underlying, inherent instability in the gut microbiome of patients with SLE.

Of 16 patients with SLE studied during the provision of routine care and monitoring, 5 had R. gnavus blooms that were “strikingly concordant with periods of raised disease activity,” Gregg J. Silverman, MD, of NYU Grossman School of Medicine, New York, and coinvestigators reported in Annals of the Rheumatic Diseases.

Four of the five patients with flare-associated R. gnavus blooms had lupus nephritis (LN); the other had a flare involving inflammation in multiple joints. The four patients with concurrent LN and spikes in R. gnavus also represented almost half of patients who had LN disease flares (four of nine) during the study period. The nine patients in the study with renal involvement, and the four with concurrent R. gnavus spikes and flares, represented different races and ethnicities.

The findings build upon research published by the NYU group several years ago showing that patients with SLE had more R. gnavus in the gut than similar patients without the disease, and that flares closely tracked major increases in R. gnavus growth. Evidence of R. gnavus expansions in patients with SLE now comes from several cohorts in the United States as well as cohorts in Europe and China, the researchers noted in their new paper.
 

An underlying, unstable microbiome

The new study at NYU took a “deeper dive” than previous research, looking at individuals over a longer period of time, Dr. Silverman, the study’s senior investigator and associate director of rheumatology at NYU Langone Health, said in an interview. Blood and a total of 44 stool samples from the 16 patients were analyzed, as were a total of 72 stool samples from 22 healthy control volunteers.

Importantly, he said, the gut microbiome in patients with SLE was found to be inherently unstable over time, compared with the microbiota communities of the controls. “There was an instability, a shifting dynamic composition of the microbiome [in patients with lupus]. ... Healthy individuals had more of a balance, with small changes over time” and a stable, low abundance of R. gnavus, Dr. Silverman said.

Transient expansions of several pathogenic species occurred in some of the patients with lupus (and not in controls), but blooms of R. gnavus were the most common. The researchers said in their paper that they “speculate that susceptibility for specific clinical features during R. gnavus blooms reflect in part differences in genetic susceptibility of the patient.”

Patients on cytotoxic agents or antibiotics were excluded from the study, but the study was not designed to disentangle the potential influence of diet or prior antibiotic exposure, they noted. Larger studies are needed that are better controlled and that include more frequent assessments, Dr. Silverman added.
 

A sure association and probable cause

“There seems to be a special connection [of R. gnavus] to lupus nephritis, which is an important, major subset of disease,” said Martin Kriegel, MD, PhD, chief or rheumatology and clinical immunology at the University of Munster (Germany). Dr. Kriegel also researches the gut microbiome in lupus and was asked to comment on the new findings from NYU.

The “difficult question is, is the bug driving the flare [as the NYU paper proposes], or is it the lupus nephritis that leads to overgrowth?” he said, noting that it “is well known that kidney disease, whether from lupus or other causes, creates disturbances in the microbiome.”

It’s “likely the case” that the pathobiome – with R. gnavus being an important pathobiont – helps to drive flares, he said. The new research shows only an association, but studies done in mice – including prior research by Dr. Silverman – support a mechanistic link, said Dr. Kriegel, also adjunct associate professor of immunobiology and of medicine at Yale University, New Haven, Conn.

Investigators in the microbiome space are moving toward more strain-level analysis – “not only measuring what organisms are there, but culturing them and sequencing them,” Dr. Kriegel noted, and the new study does just this.

The R. gnavus strains isolated during lupus flares were distinguishable from strains found in healthy people – and from strains found by other researchers in patients with inflammatory bowel disease – by their common expression of a novel type of cell membrane–associated lipoglycan. The lipoglycans were recognized by specific serum IgG2 antibodies that were detected concurrently with R. gnavus blooms and lupus flares, Dr. Silverman and his colleagues reported.

Dr. Silverman and Dr. Kriegel both study the paradigm of a gut-barrier breach, whereby pathogenic bacteria cause intestinal permeability, allowing bacterial leakages that trigger inflammation and immune responses. “We think that in lupus and other rheumatic diseases like rheumatoid arthritis, a leaky gut barrier is an important mechanism, even though these patients don’t have gastrointestinal symptoms,” said Dr. Kriegel, who has studied the role of another potentially pathogenic bacteria, Enterococcus gallinarum, in SLE.

Strengthening the gut barrier may be a plausible, general approach to reducing the severity of diseases like SLE and RA until more personalized approaches targeting individuals’ microbiome are developed, he noted.

Future treatments involving antibacterial agents, probiotics or dietary regimens that prevent imbalances in the gut microbiome would be “benign,” compared with currently utilized immunosuppressive medications, Dr. Silverman said.

The NYU study was funded in part by grants from the National Institutes of Health and the Lupus Research Alliance. Dr. Silverman disclosed that NYU has filed a patent application for an antibody test to detect serum antibodies to the lipoglycan made by some strains of R. gnavus. Dr. Kriegel disclosed that he holds a patent at Yale related to the Enterococcus bacteria he studies, and that he consults for Roche, Enterome, and Eligo Biosciences.

The current standard for breast cancer screening (for non–high-risk patients) is an annual or semiannual mammogram for women aged 40 and older.¹ However, mammography-based screening can give false-positive or false-negative results. This can lead to excessive use of invasive tissue biopsies and unnecessary exposure to ionizing radiation—which can also become expensive and time-consuming for patients.²

Both normal and cancerous cells shed cell-free DNA (cfDNA) into the blood circulation.³ Circulating tumor DNA (ctDNA) are fragments of DNA derived from tumor cells that circulate in the blood together with cfDNA. The ctDNA originates directly from a tumor or from circulating tumor cells (and carries information from the tumor cell genome), whereas cfDNA enters the bloodstream after apoptosis or necrosis and carries genome-wide DNA information. The amount of ctDNA in the blood has been shown to be elevated in patients with cancer.³ Different cancers release varying levels of ctDNA; the amount of ctDNA released depends on the number of tumor cells that are in senescence vs undergoing apoptosis.⁴ 

The possibility of incorporating this biomarker obtained from a “liquid biopsy” is currently being studied and will hopefully become a standard of care for breast cancer screening and monitoring. The liquid biopsy detects ctDNA that has been released into the bloodstream from tumor regions and helps identify intratumoral heterogeneity and clonal        evolution.⁵ Additionally, sequencing tumor DNA has opened new possibilities for precision oncology.⁶ Detection of somatic gene mutations, amplifications, and gene fusions helps to deliver targeted therapies.⁶ Analysis of potential somatic mutations in ctDNA, in combination with cfDNA levels, can help capture clinically relevant information beyond single genetic alterations and tumor fraction, potentially improving the accuracy of early detection and screening for breast cancer.

Recent advances in ctDNA testing technology have made it more accurate and reliable. ctDNA testing has several benefits, including early detection of cancer (detecting ctDNA at low levels⁾⁷; monitoring of tumor dynamics, therapeutic response, and residual disease⁸; as well as analysis of the evolution of genetic or epigenetic alterations characterizing the tumor.⁹ Its noninvasiveness, rapidity, and low cost allow for longitudinal monitoring of cancer in real time, potentially capturing tumor heterogeneity.^10,11 

The liquid biopsy potentially can give more options for therapeutic monitoring for breast cancer and may mirror clinically relevant genetic alterations that occur in all tumor tissues. Liquid biopsy offers many advantages. It allows for the detection of minimal residual disease and micrometastatic disease that may be difficult to detect with a traditional tissue biopsy.¹² Liquid biopsy detects ctDNA that has been released into the bloodstream from multiple tumor regions and allows the possibility of identifying intratumoral heterogeneity and  clonal evolution.⁵ It can also detect small quantitative variations within the blood, enabling real-time surveillance.

The liquid biopsy can offer earlier and easier access to some tumor-based genetic information at any given timepoint and can replace a tumor tissue biopsy in some cases, helping to avoid delays and complications of a solid tumor invasive biopsy procedure. This is especially relevant in the metastatic setting, in which ctDNA might be the only available genetic material from tumors.¹³ Tissue biopsy can only provide a static and spatially limited view of the disease at the time of sampling; ctDNA analysis could potentially reflect the genetic alterations that occur in all metastatic breast cancer sites over time.^14,15 Furthermore, machine learning of multi-gene signatures, obtained from ctDNA, can possibly identify complex biological features, including measures of tumor proliferation and estrogen receptor signaling, similar to direct tumor tissue DNA or RNA profiling.¹⁶

ctDNA testing is currently being studied to monitor patients who have been diagnosed with breast cancer. Small retrospective studies have shown that detection of ctDNA in plasma, after patients have completed therapy for early-stage breast cancer, is associated with a very high risk of relapse.¹⁷

Ongoing studies are examining the tailoring of adjuvant treatment based on ctDNA. If these trials are successful, certain aspects of adjuvant treatment could be lessened, or omitted, for patients who have undetectable ctDNA or intensified for patients who have detectable ctDNA after definitive treatments. This could personalize treatment specifically to the patient.

The detection and persistence of ctDNA in the middle of neoadjuvant systemic therapy may have the potential to negatively predict response to treatment and identify patients who will not achieve pathologic complete response. This may have the potential to aid in clinical decision-making for treatment escalation in these nonresponders.¹⁸ 

Despite these distinct characteristics, the low levels of ctDNA found in early-stage disease, along with the lack of ctDNA shedding from some tumors, can further complicate or impede detection of recurrence in early-stage breast cancer. Testing is further complicated by hematologic genetic alterations.⁵ The limitation of ctDNA approaches is that these techniques only detect known mutations in certain genes, so patients without these mutations could be overlooked, limiting the application of this technology.¹⁹

Overall, ctDNA testing represents a promising area of research for the diagnosis, treatment, and monitoring of breast cancer. While more research is needed to fully understand its potential, the advances in this technology are certainly exciting and could lead to significant improvements in patient outcomes. It is hopeful that in the near future, ctDNA testing from liquid biopsy could become a standard of care in breast cancer screening, ultimately helping clinicians to personalize treatment therapies and improve patient outcomes when treating patients with breast cancer.

The current standard for breast cancer screening (for non–high-risk patients) is an annual or semiannual mammogram for women aged 40 and older.¹ However, mammography-based screening can give false-positive or false-negative results. This can lead to excessive use of invasive tissue biopsies and unnecessary exposure to ionizing radiation—which can also become expensive and time-consuming for patients.²

Both normal and cancerous cells shed cell-free DNA (cfDNA) into the blood circulation.³ Circulating tumor DNA (ctDNA) are fragments of DNA derived from tumor cells that circulate in the blood together with cfDNA. The ctDNA originates directly from a tumor or from circulating tumor cells (and carries information from the tumor cell genome), whereas cfDNA enters the bloodstream after apoptosis or necrosis and carries genome-wide DNA information. The amount of ctDNA in the blood has been shown to be elevated in patients with cancer.³ Different cancers release varying levels of ctDNA; the amount of ctDNA released depends on the number of tumor cells that are in senescence vs undergoing apoptosis.⁴ 

The possibility of incorporating this biomarker obtained from a “liquid biopsy” is currently being studied and will hopefully become a standard of care for breast cancer screening and monitoring. The liquid biopsy detects ctDNA that has been released into the bloodstream from tumor regions and helps identify intratumoral heterogeneity and clonal        evolution.⁵ Additionally, sequencing tumor DNA has opened new possibilities for precision oncology.⁶ Detection of somatic gene mutations, amplifications, and gene fusions helps to deliver targeted therapies.⁶ Analysis of potential somatic mutations in ctDNA, in combination with cfDNA levels, can help capture clinically relevant information beyond single genetic alterations and tumor fraction, potentially improving the accuracy of early detection and screening for breast cancer.

Recent advances in ctDNA testing technology have made it more accurate and reliable. ctDNA testing has several benefits, including early detection of cancer (detecting ctDNA at low levels⁾⁷; monitoring of tumor dynamics, therapeutic response, and residual disease⁸; as well as analysis of the evolution of genetic or epigenetic alterations characterizing the tumor.⁹ Its noninvasiveness, rapidity, and low cost allow for longitudinal monitoring of cancer in real time, potentially capturing tumor heterogeneity.^10,11 

The liquid biopsy potentially can give more options for therapeutic monitoring for breast cancer and may mirror clinically relevant genetic alterations that occur in all tumor tissues. Liquid biopsy offers many advantages. It allows for the detection of minimal residual disease and micrometastatic disease that may be difficult to detect with a traditional tissue biopsy.¹² Liquid biopsy detects ctDNA that has been released into the bloodstream from multiple tumor regions and allows the possibility of identifying intratumoral heterogeneity and  clonal evolution.⁵ It can also detect small quantitative variations within the blood, enabling real-time surveillance.

The liquid biopsy can offer earlier and easier access to some tumor-based genetic information at any given timepoint and can replace a tumor tissue biopsy in some cases, helping to avoid delays and complications of a solid tumor invasive biopsy procedure. This is especially relevant in the metastatic setting, in which ctDNA might be the only available genetic material from tumors.¹³ Tissue biopsy can only provide a static and spatially limited view of the disease at the time of sampling; ctDNA analysis could potentially reflect the genetic alterations that occur in all metastatic breast cancer sites over time.^14,15 Furthermore, machine learning of multi-gene signatures, obtained from ctDNA, can possibly identify complex biological features, including measures of tumor proliferation and estrogen receptor signaling, similar to direct tumor tissue DNA or RNA profiling.¹⁶

ctDNA testing is currently being studied to monitor patients who have been diagnosed with breast cancer. Small retrospective studies have shown that detection of ctDNA in plasma, after patients have completed therapy for early-stage breast cancer, is associated with a very high risk of relapse.¹⁷

Ongoing studies are examining the tailoring of adjuvant treatment based on ctDNA. If these trials are successful, certain aspects of adjuvant treatment could be lessened, or omitted, for patients who have undetectable ctDNA or intensified for patients who have detectable ctDNA after definitive treatments. This could personalize treatment specifically to the patient.

The detection and persistence of ctDNA in the middle of neoadjuvant systemic therapy may have the potential to negatively predict response to treatment and identify patients who will not achieve pathologic complete response. This may have the potential to aid in clinical decision-making for treatment escalation in these nonresponders.¹⁸ 

Despite these distinct characteristics, the low levels of ctDNA found in early-stage disease, along with the lack of ctDNA shedding from some tumors, can further complicate or impede detection of recurrence in early-stage breast cancer. Testing is further complicated by hematologic genetic alterations.⁵ The limitation of ctDNA approaches is that these techniques only detect known mutations in certain genes, so patients without these mutations could be overlooked, limiting the application of this technology.¹⁹

Overall, ctDNA testing represents a promising area of research for the diagnosis, treatment, and monitoring of breast cancer. While more research is needed to fully understand its potential, the advances in this technology are certainly exciting and could lead to significant improvements in patient outcomes. It is hopeful that in the near future, ctDNA testing from liquid biopsy could become a standard of care in breast cancer screening, ultimately helping clinicians to personalize treatment therapies and improve patient outcomes when treating patients with breast cancer.

The current standard for breast cancer screening (for non–high-risk patients) is an annual or semiannual mammogram for women aged 40 and older.¹ However, mammography-based screening can give false-positive or false-negative results. This can lead to excessive use of invasive tissue biopsies and unnecessary exposure to ionizing radiation—which can also become expensive and time-consuming for patients.²

Both normal and cancerous cells shed cell-free DNA (cfDNA) into the blood circulation.³ Circulating tumor DNA (ctDNA) are fragments of DNA derived from tumor cells that circulate in the blood together with cfDNA. The ctDNA originates directly from a tumor or from circulating tumor cells (and carries information from the tumor cell genome), whereas cfDNA enters the bloodstream after apoptosis or necrosis and carries genome-wide DNA information. The amount of ctDNA in the blood has been shown to be elevated in patients with cancer.³ Different cancers release varying levels of ctDNA; the amount of ctDNA released depends on the number of tumor cells that are in senescence vs undergoing apoptosis.⁴ 

The possibility of incorporating this biomarker obtained from a “liquid biopsy” is currently being studied and will hopefully become a standard of care for breast cancer screening and monitoring. The liquid biopsy detects ctDNA that has been released into the bloodstream from tumor regions and helps identify intratumoral heterogeneity and clonal        evolution.⁵ Additionally, sequencing tumor DNA has opened new possibilities for precision oncology.⁶ Detection of somatic gene mutations, amplifications, and gene fusions helps to deliver targeted therapies.⁶ Analysis of potential somatic mutations in ctDNA, in combination with cfDNA levels, can help capture clinically relevant information beyond single genetic alterations and tumor fraction, potentially improving the accuracy of early detection and screening for breast cancer.

Recent advances in ctDNA testing technology have made it more accurate and reliable. ctDNA testing has several benefits, including early detection of cancer (detecting ctDNA at low levels⁾⁷; monitoring of tumor dynamics, therapeutic response, and residual disease⁸; as well as analysis of the evolution of genetic or epigenetic alterations characterizing the tumor.⁹ Its noninvasiveness, rapidity, and low cost allow for longitudinal monitoring of cancer in real time, potentially capturing tumor heterogeneity.^10,11 

The liquid biopsy potentially can give more options for therapeutic monitoring for breast cancer and may mirror clinically relevant genetic alterations that occur in all tumor tissues. Liquid biopsy offers many advantages. It allows for the detection of minimal residual disease and micrometastatic disease that may be difficult to detect with a traditional tissue biopsy.¹² Liquid biopsy detects ctDNA that has been released into the bloodstream from multiple tumor regions and allows the possibility of identifying intratumoral heterogeneity and  clonal evolution.⁵ It can also detect small quantitative variations within the blood, enabling real-time surveillance.

The liquid biopsy can offer earlier and easier access to some tumor-based genetic information at any given timepoint and can replace a tumor tissue biopsy in some cases, helping to avoid delays and complications of a solid tumor invasive biopsy procedure. This is especially relevant in the metastatic setting, in which ctDNA might be the only available genetic material from tumors.¹³ Tissue biopsy can only provide a static and spatially limited view of the disease at the time of sampling; ctDNA analysis could potentially reflect the genetic alterations that occur in all metastatic breast cancer sites over time.^14,15 Furthermore, machine learning of multi-gene signatures, obtained from ctDNA, can possibly identify complex biological features, including measures of tumor proliferation and estrogen receptor signaling, similar to direct tumor tissue DNA or RNA profiling.¹⁶

ctDNA testing is currently being studied to monitor patients who have been diagnosed with breast cancer. Small retrospective studies have shown that detection of ctDNA in plasma, after patients have completed therapy for early-stage breast cancer, is associated with a very high risk of relapse.¹⁷

Ongoing studies are examining the tailoring of adjuvant treatment based on ctDNA. If these trials are successful, certain aspects of adjuvant treatment could be lessened, or omitted, for patients who have undetectable ctDNA or intensified for patients who have detectable ctDNA after definitive treatments. This could personalize treatment specifically to the patient.

The detection and persistence of ctDNA in the middle of neoadjuvant systemic therapy may have the potential to negatively predict response to treatment and identify patients who will not achieve pathologic complete response. This may have the potential to aid in clinical decision-making for treatment escalation in these nonresponders.¹⁸ 

Despite these distinct characteristics, the low levels of ctDNA found in early-stage disease, along with the lack of ctDNA shedding from some tumors, can further complicate or impede detection of recurrence in early-stage breast cancer. Testing is further complicated by hematologic genetic alterations.⁵ The limitation of ctDNA approaches is that these techniques only detect known mutations in certain genes, so patients without these mutations could be overlooked, limiting the application of this technology.¹⁹

Overall, ctDNA testing represents a promising area of research for the diagnosis, treatment, and monitoring of breast cancer. While more research is needed to fully understand its potential, the advances in this technology are certainly exciting and could lead to significant improvements in patient outcomes. It is hopeful that in the near future, ctDNA testing from liquid biopsy could become a standard of care in breast cancer screening, ultimately helping clinicians to personalize treatment therapies and improve patient outcomes when treating patients with breast cancer.

Obesity is a major health problem in the United States. The Centers for Disease Control and Prevention (CDC) defines the problem as weight that is higher than what is healthy for a given height, with quantitative definitions of overweight and obesity as body mass indices (BMIs) of 25 to 29.9 kg/m² and ≥ 30 kg/m², respectively.¹ The prevalence of obesity among adults in 2017 ̶ 2018 was reported by the CDC to be 42.4%.² Among women, the reported prevalence of obesity was lowest among Asian individuals (17.2%) and greatest among non-Hispanic Black individuals (56.9%), with White (39.8%) and Hispanic individuals (43.7%) having rates in between.² In a meta-analysis of prospective studies that included 4 million people who were never smokers and had no chronic disease at baseline, age- and sex-adjusted mortality rates were studied over a median of 14 years of follow-up.³ Compared with those with a BMI of 20 to 25 kg/m², people with a BMI of 30 to 34.9 kg/m² or a BMI of 35 to 39.9 kg/m² had increased risks of death of 46% and 94%, respectively, demonstrating that obesity increases this risk.³

The increased risk of death associated with obesity is caused by obesity-related diseases that cause early mortality, including diabetes mellitus (DM), dyslipidemia, hypertension, coronary heart disease, heart failure, atrial fibrillation, stroke, and venous thromboembolic events.⁴ Obesity is also associated with an increased risk of many cancers, including cancer of the endometrium, kidney, esophagus, stomach, colon, rectum, gallbladder, pancreas, liver, and breast.⁵ With regard to gynecologic disease, obesity is associated with an increased risk of fibroids and heavy menstrual bleeding.⁶ For pregnant patients, obesity is associated with increased risks of⁷:

• miscarriage and stillbirth
• preeclampsia and gestational hypertension
• gestational diabetes
• severe maternal morbidity
• postterm pregnancy
• venous thromboembolism
• endometritis.

For obese patients, weight loss can normalize blood pressure, reduce the risk of cardiovascular events, decrease the risk of cancer, and cure type 2 DM.⁸

Bariatric surgery: The gold standard treatment for reliable and sustained weight loss

All patients with obesity should be counseled to reduce caloric intake and increase physical activity. Dietary counseling provided by a nutritionist may help reinforce advice given by a provider. However, lifestyle interventions are associated with modest weight loss (<5% of bodyweight; FIGURE).⁹ The gold standard treatment for reliable and sustained weight loss is bariatric surgery.

In the Swedish Obese Subjects study, involving 2,010 people, following bariatric surgery the mean decrease in bodyweight was 23% at 2 years, with a slow increase in weight thereafter, resulting in a sustained mean weight loss of 18% at 10 years.⁸ In this study, people in the diet and exercise control group had no change in bodyweight over 10 years of follow-up.⁸ Not all eligible obese patients want to undergo bariatric surgery because it is an arduous sequential process involving 6 months of intensive preoperative preparation, bariatric surgery, recovery, and intensive postoperative follow-up. The perioperative mortality rate is 0.03% to 0.2%.¹⁰ Following bariatric surgery, additional operations may be necessary for more than 10% of patients.¹⁰ With recent breakthroughs in the medication management of obesity, patients who do not want bariatric surgery can achieve reliable weight loss of greater than 10% of body weight with glucagon-like peptide -1 (GLP-1) agonists.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

GLP-1 agonist analogues: Practice-changing breakthrough in medication treatment

GLP-1, a 30 amino acid peptide, is produced by intestinal enteroendocrine cells and neurons in the medulla and hypothalamus.¹¹ GLP-1 reduces hunger cravings and causes satiety, reducing daily food intake.¹² GLP-1 also enhances the secretion of insulin, making GLP-1 agonists an effective treatment for type 2 DM. In humans and experimental animals, the administration of exogenous GLP-1 agonists decreases hunger cravings and causes satiety, reducing food intake, resulting in weight loss.¹² The synthetic GLP-1 agonists, liraglutide (Saxenda) and semaglutide (Wegovy) are approved by the US Food and Drug Administration (FDA) as anti-obesity medications.

Native GLP-1 has a short circulating half-life of approximately 2 minutes. The synthetic GLP-1 agonist medications liraglutide and semaglutide are modified to significantly increase their half-life. Liraglutide is a modified version of GLP-1 with a palmitic acid side chain and an amino acid spacer resulting in reduced degradation and a 15-hour half-life, necessitating daily administration. Semaglutide has a steric acid diacid at Lys26, a large synthetic spacer, a modification of amino acid 8 with the addition of α-aminobutyric acid and a 165-hour half-life, permitting weekly administration.¹³ For weight loss, liraglutide and semaglultide are administered by subcutaneous injection. Tirzepatide (Mounjaro) is a novel GLP-1 agonist. It is also a gastric inhibitory peptide, is FDA approved to treat type 2 DM, and is awaiting FDA approval as a weight loss medication.Tirzepatide causes substantial weight loss, similar to the effect of semaglutide.¹⁴

Semaglutide and weight loss

Semaglutide is approved by the FDA for chronic weight management as an adjunct to a reduced-calorie diet and increased physical activity in adults with a BMI ≥ 30 kg/m² or ≥ 27 kg/m² in the presence of a weight-related comorbidity. It is also FDA approved to treat type 2 DM.

In a weight loss trial, 1,961 overweight and obese patients with a mean BMI of 38 kg/m², were randomly assigned to semaglutide or placebo treatment for 68 weeks. All the participants were following a regimen that included a calorie-reduced diet and increased physical activity. The mean changes in body weight for the patients in the semaglutide and placebo treatment groups were -14.9% and -2.4%, respectively. The treatment difference was -12.4% (95% confidence interval [CI], -13.4% to -11.5%; P <.001). In this study, compared with placebo, semaglutide treatment resulted in a greater decrease in waist circumference, -5.3 in versus -1.6 in.¹⁵ A network meta-analysis of the efficacy of weight loss medicines indicates that semaglutide is the most effective medication currently FDA approved for weight loss, reliably producing substantial weight loss (FIGURE).⁹

In one randomized clinical trial, investigators directly compared the efficacy of semaglutide and liraglutide in achieving weight loss. In this trial, 338 patients were assigned randomly to treatment with semaglutide 2.4 mg weekly subcutaneous injection, liraglutide 3.0 mg daily subcutaneous injection, or placebo. All the participants were following a regimen that included a calorie-reduced diet and increased physical activity.¹⁶ After 68 weeks of treatment, the mean weight changes were -15.8%, -6.4%, and -1.9% in the semaglutide, liraglutide, and placebo groups, respectively. The difference between the semaglutide and liraglutide groups was -9.4% (95% CI, -12% to -6.8%; P <.001).¹⁶

Continue to: Semaglutide dose-escalation and contraindications...

For weight loss, the target dose of semaglutide is 2.4 mg once weekly subcutaneous injection achieved by sequential dose escalation. To give patients time to adjust to adverse effects caused by the medication, a standardized dose-escalation regimen is recommended. The FDA-approved escalation regimen for semaglutide treatment begins with a weekly subcutaneous dose of 0.25 mg for 4 weeks, followed by an increase in the weekly dosage every 4 weeks: 0.5 mg, 1.0 mg, 1.7 mg, and 2.4 mg.¹⁷ To support the dose-escalation process there are 5 unique autoinjectors that deliver the appropriate dose for the current step.

Semaglutide is contraindicated if the patient has an allergy to the medication or if there is a personal or family history of medullary thyroid cancer.¹⁷ In animal toxicology studies, semaglutide at clinically relevant dosing was associated with an increased risk of developing medullary thyroid cancer. Patients with a personal history of multiple endocrine neoplasia syndrome type 2, (medullary thyroid cancer, pheochromocytoma, and primary hyperparathyroidism) should not take semaglutide. Semaglutide may cause fetal harm and the FDA recommends discontinuing semaglutide at least 2 months before pregnancy.¹⁷ According to the FDA, the safety of semaglutide during breastfeeding has not been established. In Canada, breastfeeding is a contraindication to semaglutide treatment.¹⁸

Limitations of medication treatment of obesity

There are important limitations to semaglutide treatment of obesity, including:

• weight gain after stopping treatment
• limited medical insurance supportfor an expensive medication treatment
• bothersome adverse effects.

Weight gain posttreatment. After stopping medication treatment of obesity, weight gain occurs in most patients. However, patients may remain below baseline weight for a long time after stopping medication therapy. In one trial of 803 patients, after 20 weeks of semaglutide treatment (16-week dose-escalation phase, followed by 4 weeks on a weekly dose of 2.4 mg), the participants were randomized to 48 additional weeks of semaglutide or placebo.¹⁹ All the participants were following a regimen that included a calorie-reduced diet and increased physical activity. At the initial 20 weeks of treatment time point the mean weight change was -10.6%. Over the following 48 weeks, the patients treated with semaglutidehad an additional mean weight change of -7.9%, while the mean weight change for the placebo group was +6.9%.

Medical insurance coverage. A major barrier to semaglutide treatment of obesity is the medication’s cost. At the website GoodRx (https://www.goodrx.com/), the estimated price for a 1-month supply of semaglutide (Wegovy) is $1,350.²⁰ By contrast, a 1-month supply of phentermine-topiramate (Qsymia) is approximately $205. Currently, many medical insurance plans do not cover the cost of semaglutide treatment for weight loss. Patent protection for liraglutide may expire in the next few years, permitting the marketing of a lower-cost generic formulation, increasing the availability of the medication. However, as noted above, compared with liraglutide, semaglutide treatment results in much greater weight loss.

The most common adverse effects associated with semaglutide treatment are nausea, vomiting, diarrhea, and constipation. In one randomized clinical trial involving 1,961 patients, the frequency of adverse effects reported by patients taking semaglutide incrementally above the frequency of the same adverse effect reported by patients on placebo was: nausea (27%), vomiting (18%), diarrhea (16%), constipation (14%), dyspepsia (7%), and abdominal pain (5%).¹⁵ In this study, treatment was discontinued due to adverse effects in 7% and 3% of the patients in the semaglutide and placebo groups, respectively. Experts believe that adverse effects can be minimized by increasing the dose slowly and decreasing the dose if adverse effects are bothersome to the patient.

Measuring the benefits of semaglutide weight loss

Overweight and obesity are prevalent problems with many adverse consequences, including an increased risk of death. In population studies, weight loss following bariatric surgery is associated with a substantial reduction in mortality, cancer, and heart disease compared with conventional therapy.²¹ Over the next few years, the effect of semaglutide-induced weight loss on the rate of cancer and heart disease should become clear. If semaglutide treatment of obesity is associated with a reduction in cancer and heart disease, it would be a truly breakthrough medication. ●

Obesity is a major health problem in the United States. The Centers for Disease Control and Prevention (CDC) defines the problem as weight that is higher than what is healthy for a given height, with quantitative definitions of overweight and obesity as body mass indices (BMIs) of 25 to 29.9 kg/m² and ≥ 30 kg/m², respectively.¹ The prevalence of obesity among adults in 2017 ̶ 2018 was reported by the CDC to be 42.4%.² Among women, the reported prevalence of obesity was lowest among Asian individuals (17.2%) and greatest among non-Hispanic Black individuals (56.9%), with White (39.8%) and Hispanic individuals (43.7%) having rates in between.² In a meta-analysis of prospective studies that included 4 million people who were never smokers and had no chronic disease at baseline, age- and sex-adjusted mortality rates were studied over a median of 14 years of follow-up.³ Compared with those with a BMI of 20 to 25 kg/m², people with a BMI of 30 to 34.9 kg/m² or a BMI of 35 to 39.9 kg/m² had increased risks of death of 46% and 94%, respectively, demonstrating that obesity increases this risk.³

The increased risk of death associated with obesity is caused by obesity-related diseases that cause early mortality, including diabetes mellitus (DM), dyslipidemia, hypertension, coronary heart disease, heart failure, atrial fibrillation, stroke, and venous thromboembolic events.⁴ Obesity is also associated with an increased risk of many cancers, including cancer of the endometrium, kidney, esophagus, stomach, colon, rectum, gallbladder, pancreas, liver, and breast.⁵ With regard to gynecologic disease, obesity is associated with an increased risk of fibroids and heavy menstrual bleeding.⁶ For pregnant patients, obesity is associated with increased risks of⁷:

• miscarriage and stillbirth
• preeclampsia and gestational hypertension
• gestational diabetes
• severe maternal morbidity
• postterm pregnancy
• venous thromboembolism
• endometritis.

For obese patients, weight loss can normalize blood pressure, reduce the risk of cardiovascular events, decrease the risk of cancer, and cure type 2 DM.⁸

Bariatric surgery: The gold standard treatment for reliable and sustained weight loss

All patients with obesity should be counseled to reduce caloric intake and increase physical activity. Dietary counseling provided by a nutritionist may help reinforce advice given by a provider. However, lifestyle interventions are associated with modest weight loss (<5% of bodyweight; FIGURE).⁹ The gold standard treatment for reliable and sustained weight loss is bariatric surgery.

In the Swedish Obese Subjects study, involving 2,010 people, following bariatric surgery the mean decrease in bodyweight was 23% at 2 years, with a slow increase in weight thereafter, resulting in a sustained mean weight loss of 18% at 10 years.⁸ In this study, people in the diet and exercise control group had no change in bodyweight over 10 years of follow-up.⁸ Not all eligible obese patients want to undergo bariatric surgery because it is an arduous sequential process involving 6 months of intensive preoperative preparation, bariatric surgery, recovery, and intensive postoperative follow-up. The perioperative mortality rate is 0.03% to 0.2%.¹⁰ Following bariatric surgery, additional operations may be necessary for more than 10% of patients.¹⁰ With recent breakthroughs in the medication management of obesity, patients who do not want bariatric surgery can achieve reliable weight loss of greater than 10% of body weight with glucagon-like peptide -1 (GLP-1) agonists.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

GLP-1 agonist analogues: Practice-changing breakthrough in medication treatment

GLP-1, a 30 amino acid peptide, is produced by intestinal enteroendocrine cells and neurons in the medulla and hypothalamus.¹¹ GLP-1 reduces hunger cravings and causes satiety, reducing daily food intake.¹² GLP-1 also enhances the secretion of insulin, making GLP-1 agonists an effective treatment for type 2 DM. In humans and experimental animals, the administration of exogenous GLP-1 agonists decreases hunger cravings and causes satiety, reducing food intake, resulting in weight loss.¹² The synthetic GLP-1 agonists, liraglutide (Saxenda) and semaglutide (Wegovy) are approved by the US Food and Drug Administration (FDA) as anti-obesity medications.

Native GLP-1 has a short circulating half-life of approximately 2 minutes. The synthetic GLP-1 agonist medications liraglutide and semaglutide are modified to significantly increase their half-life. Liraglutide is a modified version of GLP-1 with a palmitic acid side chain and an amino acid spacer resulting in reduced degradation and a 15-hour half-life, necessitating daily administration. Semaglutide has a steric acid diacid at Lys26, a large synthetic spacer, a modification of amino acid 8 with the addition of α-aminobutyric acid and a 165-hour half-life, permitting weekly administration.¹³ For weight loss, liraglutide and semaglultide are administered by subcutaneous injection. Tirzepatide (Mounjaro) is a novel GLP-1 agonist. It is also a gastric inhibitory peptide, is FDA approved to treat type 2 DM, and is awaiting FDA approval as a weight loss medication.Tirzepatide causes substantial weight loss, similar to the effect of semaglutide.¹⁴

Semaglutide and weight loss

Semaglutide is approved by the FDA for chronic weight management as an adjunct to a reduced-calorie diet and increased physical activity in adults with a BMI ≥ 30 kg/m² or ≥ 27 kg/m² in the presence of a weight-related comorbidity. It is also FDA approved to treat type 2 DM.

In a weight loss trial, 1,961 overweight and obese patients with a mean BMI of 38 kg/m², were randomly assigned to semaglutide or placebo treatment for 68 weeks. All the participants were following a regimen that included a calorie-reduced diet and increased physical activity. The mean changes in body weight for the patients in the semaglutide and placebo treatment groups were -14.9% and -2.4%, respectively. The treatment difference was -12.4% (95% confidence interval [CI], -13.4% to -11.5%; P <.001). In this study, compared with placebo, semaglutide treatment resulted in a greater decrease in waist circumference, -5.3 in versus -1.6 in.¹⁵ A network meta-analysis of the efficacy of weight loss medicines indicates that semaglutide is the most effective medication currently FDA approved for weight loss, reliably producing substantial weight loss (FIGURE).⁹

In one randomized clinical trial, investigators directly compared the efficacy of semaglutide and liraglutide in achieving weight loss. In this trial, 338 patients were assigned randomly to treatment with semaglutide 2.4 mg weekly subcutaneous injection, liraglutide 3.0 mg daily subcutaneous injection, or placebo. All the participants were following a regimen that included a calorie-reduced diet and increased physical activity.¹⁶ After 68 weeks of treatment, the mean weight changes were -15.8%, -6.4%, and -1.9% in the semaglutide, liraglutide, and placebo groups, respectively. The difference between the semaglutide and liraglutide groups was -9.4% (95% CI, -12% to -6.8%; P <.001).¹⁶

Continue to: Semaglutide dose-escalation and contraindications...

For weight loss, the target dose of semaglutide is 2.4 mg once weekly subcutaneous injection achieved by sequential dose escalation. To give patients time to adjust to adverse effects caused by the medication, a standardized dose-escalation regimen is recommended. The FDA-approved escalation regimen for semaglutide treatment begins with a weekly subcutaneous dose of 0.25 mg for 4 weeks, followed by an increase in the weekly dosage every 4 weeks: 0.5 mg, 1.0 mg, 1.7 mg, and 2.4 mg.¹⁷ To support the dose-escalation process there are 5 unique autoinjectors that deliver the appropriate dose for the current step.

Semaglutide is contraindicated if the patient has an allergy to the medication or if there is a personal or family history of medullary thyroid cancer.¹⁷ In animal toxicology studies, semaglutide at clinically relevant dosing was associated with an increased risk of developing medullary thyroid cancer. Patients with a personal history of multiple endocrine neoplasia syndrome type 2, (medullary thyroid cancer, pheochromocytoma, and primary hyperparathyroidism) should not take semaglutide. Semaglutide may cause fetal harm and the FDA recommends discontinuing semaglutide at least 2 months before pregnancy.¹⁷ According to the FDA, the safety of semaglutide during breastfeeding has not been established. In Canada, breastfeeding is a contraindication to semaglutide treatment.¹⁸

Limitations of medication treatment of obesity

There are important limitations to semaglutide treatment of obesity, including:

• weight gain after stopping treatment
• limited medical insurance supportfor an expensive medication treatment
• bothersome adverse effects.

Weight gain posttreatment. After stopping medication treatment of obesity, weight gain occurs in most patients. However, patients may remain below baseline weight for a long time after stopping medication therapy. In one trial of 803 patients, after 20 weeks of semaglutide treatment (16-week dose-escalation phase, followed by 4 weeks on a weekly dose of 2.4 mg), the participants were randomized to 48 additional weeks of semaglutide or placebo.¹⁹ All the participants were following a regimen that included a calorie-reduced diet and increased physical activity. At the initial 20 weeks of treatment time point the mean weight change was -10.6%. Over the following 48 weeks, the patients treated with semaglutidehad an additional mean weight change of -7.9%, while the mean weight change for the placebo group was +6.9%.

Medical insurance coverage. A major barrier to semaglutide treatment of obesity is the medication’s cost. At the website GoodRx (https://www.goodrx.com/), the estimated price for a 1-month supply of semaglutide (Wegovy) is $1,350.²⁰ By contrast, a 1-month supply of phentermine-topiramate (Qsymia) is approximately $205. Currently, many medical insurance plans do not cover the cost of semaglutide treatment for weight loss. Patent protection for liraglutide may expire in the next few years, permitting the marketing of a lower-cost generic formulation, increasing the availability of the medication. However, as noted above, compared with liraglutide, semaglutide treatment results in much greater weight loss.

The most common adverse effects associated with semaglutide treatment are nausea, vomiting, diarrhea, and constipation. In one randomized clinical trial involving 1,961 patients, the frequency of adverse effects reported by patients taking semaglutide incrementally above the frequency of the same adverse effect reported by patients on placebo was: nausea (27%), vomiting (18%), diarrhea (16%), constipation (14%), dyspepsia (7%), and abdominal pain (5%).¹⁵ In this study, treatment was discontinued due to adverse effects in 7% and 3% of the patients in the semaglutide and placebo groups, respectively. Experts believe that adverse effects can be minimized by increasing the dose slowly and decreasing the dose if adverse effects are bothersome to the patient.

Measuring the benefits of semaglutide weight loss

Overweight and obesity are prevalent problems with many adverse consequences, including an increased risk of death. In population studies, weight loss following bariatric surgery is associated with a substantial reduction in mortality, cancer, and heart disease compared with conventional therapy.²¹ Over the next few years, the effect of semaglutide-induced weight loss on the rate of cancer and heart disease should become clear. If semaglutide treatment of obesity is associated with a reduction in cancer and heart disease, it would be a truly breakthrough medication. ●

Obesity is a major health problem in the United States. The Centers for Disease Control and Prevention (CDC) defines the problem as weight that is higher than what is healthy for a given height, with quantitative definitions of overweight and obesity as body mass indices (BMIs) of 25 to 29.9 kg/m² and ≥ 30 kg/m², respectively.¹ The prevalence of obesity among adults in 2017 ̶ 2018 was reported by the CDC to be 42.4%.² Among women, the reported prevalence of obesity was lowest among Asian individuals (17.2%) and greatest among non-Hispanic Black individuals (56.9%), with White (39.8%) and Hispanic individuals (43.7%) having rates in between.² In a meta-analysis of prospective studies that included 4 million people who were never smokers and had no chronic disease at baseline, age- and sex-adjusted mortality rates were studied over a median of 14 years of follow-up.³ Compared with those with a BMI of 20 to 25 kg/m², people with a BMI of 30 to 34.9 kg/m² or a BMI of 35 to 39.9 kg/m² had increased risks of death of 46% and 94%, respectively, demonstrating that obesity increases this risk.³

The increased risk of death associated with obesity is caused by obesity-related diseases that cause early mortality, including diabetes mellitus (DM), dyslipidemia, hypertension, coronary heart disease, heart failure, atrial fibrillation, stroke, and venous thromboembolic events.⁴ Obesity is also associated with an increased risk of many cancers, including cancer of the endometrium, kidney, esophagus, stomach, colon, rectum, gallbladder, pancreas, liver, and breast.⁵ With regard to gynecologic disease, obesity is associated with an increased risk of fibroids and heavy menstrual bleeding.⁶ For pregnant patients, obesity is associated with increased risks of⁷:

• miscarriage and stillbirth
• preeclampsia and gestational hypertension
• gestational diabetes
• severe maternal morbidity
• postterm pregnancy
• venous thromboembolism
• endometritis.

For obese patients, weight loss can normalize blood pressure, reduce the risk of cardiovascular events, decrease the risk of cancer, and cure type 2 DM.⁸

Bariatric surgery: The gold standard treatment for reliable and sustained weight loss

All patients with obesity should be counseled to reduce caloric intake and increase physical activity. Dietary counseling provided by a nutritionist may help reinforce advice given by a provider. However, lifestyle interventions are associated with modest weight loss (<5% of bodyweight; FIGURE).⁹ The gold standard treatment for reliable and sustained weight loss is bariatric surgery.

In the Swedish Obese Subjects study, involving 2,010 people, following bariatric surgery the mean decrease in bodyweight was 23% at 2 years, with a slow increase in weight thereafter, resulting in a sustained mean weight loss of 18% at 10 years.⁸ In this study, people in the diet and exercise control group had no change in bodyweight over 10 years of follow-up.⁸ Not all eligible obese patients want to undergo bariatric surgery because it is an arduous sequential process involving 6 months of intensive preoperative preparation, bariatric surgery, recovery, and intensive postoperative follow-up. The perioperative mortality rate is 0.03% to 0.2%.¹⁰ Following bariatric surgery, additional operations may be necessary for more than 10% of patients.¹⁰ With recent breakthroughs in the medication management of obesity, patients who do not want bariatric surgery can achieve reliable weight loss of greater than 10% of body weight with glucagon-like peptide -1 (GLP-1) agonists.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

GLP-1 agonist analogues: Practice-changing breakthrough in medication treatment

GLP-1, a 30 amino acid peptide, is produced by intestinal enteroendocrine cells and neurons in the medulla and hypothalamus.¹¹ GLP-1 reduces hunger cravings and causes satiety, reducing daily food intake.¹² GLP-1 also enhances the secretion of insulin, making GLP-1 agonists an effective treatment for type 2 DM. In humans and experimental animals, the administration of exogenous GLP-1 agonists decreases hunger cravings and causes satiety, reducing food intake, resulting in weight loss.¹² The synthetic GLP-1 agonists, liraglutide (Saxenda) and semaglutide (Wegovy) are approved by the US Food and Drug Administration (FDA) as anti-obesity medications.

Native GLP-1 has a short circulating half-life of approximately 2 minutes. The synthetic GLP-1 agonist medications liraglutide and semaglutide are modified to significantly increase their half-life. Liraglutide is a modified version of GLP-1 with a palmitic acid side chain and an amino acid spacer resulting in reduced degradation and a 15-hour half-life, necessitating daily administration. Semaglutide has a steric acid diacid at Lys26, a large synthetic spacer, a modification of amino acid 8 with the addition of α-aminobutyric acid and a 165-hour half-life, permitting weekly administration.¹³ For weight loss, liraglutide and semaglultide are administered by subcutaneous injection. Tirzepatide (Mounjaro) is a novel GLP-1 agonist. It is also a gastric inhibitory peptide, is FDA approved to treat type 2 DM, and is awaiting FDA approval as a weight loss medication.Tirzepatide causes substantial weight loss, similar to the effect of semaglutide.¹⁴

Semaglutide and weight loss

Semaglutide is approved by the FDA for chronic weight management as an adjunct to a reduced-calorie diet and increased physical activity in adults with a BMI ≥ 30 kg/m² or ≥ 27 kg/m² in the presence of a weight-related comorbidity. It is also FDA approved to treat type 2 DM.

In a weight loss trial, 1,961 overweight and obese patients with a mean BMI of 38 kg/m², were randomly assigned to semaglutide or placebo treatment for 68 weeks. All the participants were following a regimen that included a calorie-reduced diet and increased physical activity. The mean changes in body weight for the patients in the semaglutide and placebo treatment groups were -14.9% and -2.4%, respectively. The treatment difference was -12.4% (95% confidence interval [CI], -13.4% to -11.5%; P <.001). In this study, compared with placebo, semaglutide treatment resulted in a greater decrease in waist circumference, -5.3 in versus -1.6 in.¹⁵ A network meta-analysis of the efficacy of weight loss medicines indicates that semaglutide is the most effective medication currently FDA approved for weight loss, reliably producing substantial weight loss (FIGURE).⁹

In one randomized clinical trial, investigators directly compared the efficacy of semaglutide and liraglutide in achieving weight loss. In this trial, 338 patients were assigned randomly to treatment with semaglutide 2.4 mg weekly subcutaneous injection, liraglutide 3.0 mg daily subcutaneous injection, or placebo. All the participants were following a regimen that included a calorie-reduced diet and increased physical activity.¹⁶ After 68 weeks of treatment, the mean weight changes were -15.8%, -6.4%, and -1.9% in the semaglutide, liraglutide, and placebo groups, respectively. The difference between the semaglutide and liraglutide groups was -9.4% (95% CI, -12% to -6.8%; P <.001).¹⁶

Continue to: Semaglutide dose-escalation and contraindications...

For weight loss, the target dose of semaglutide is 2.4 mg once weekly subcutaneous injection achieved by sequential dose escalation. To give patients time to adjust to adverse effects caused by the medication, a standardized dose-escalation regimen is recommended. The FDA-approved escalation regimen for semaglutide treatment begins with a weekly subcutaneous dose of 0.25 mg for 4 weeks, followed by an increase in the weekly dosage every 4 weeks: 0.5 mg, 1.0 mg, 1.7 mg, and 2.4 mg.¹⁷ To support the dose-escalation process there are 5 unique autoinjectors that deliver the appropriate dose for the current step.

Semaglutide is contraindicated if the patient has an allergy to the medication or if there is a personal or family history of medullary thyroid cancer.¹⁷ In animal toxicology studies, semaglutide at clinically relevant dosing was associated with an increased risk of developing medullary thyroid cancer. Patients with a personal history of multiple endocrine neoplasia syndrome type 2, (medullary thyroid cancer, pheochromocytoma, and primary hyperparathyroidism) should not take semaglutide. Semaglutide may cause fetal harm and the FDA recommends discontinuing semaglutide at least 2 months before pregnancy.¹⁷ According to the FDA, the safety of semaglutide during breastfeeding has not been established. In Canada, breastfeeding is a contraindication to semaglutide treatment.¹⁸

Limitations of medication treatment of obesity

There are important limitations to semaglutide treatment of obesity, including:

• weight gain after stopping treatment
• limited medical insurance supportfor an expensive medication treatment
• bothersome adverse effects.

Weight gain posttreatment. After stopping medication treatment of obesity, weight gain occurs in most patients. However, patients may remain below baseline weight for a long time after stopping medication therapy. In one trial of 803 patients, after 20 weeks of semaglutide treatment (16-week dose-escalation phase, followed by 4 weeks on a weekly dose of 2.4 mg), the participants were randomized to 48 additional weeks of semaglutide or placebo.¹⁹ All the participants were following a regimen that included a calorie-reduced diet and increased physical activity. At the initial 20 weeks of treatment time point the mean weight change was -10.6%. Over the following 48 weeks, the patients treated with semaglutidehad an additional mean weight change of -7.9%, while the mean weight change for the placebo group was +6.9%.

Medical insurance coverage. A major barrier to semaglutide treatment of obesity is the medication’s cost. At the website GoodRx (https://www.goodrx.com/), the estimated price for a 1-month supply of semaglutide (Wegovy) is $1,350.²⁰ By contrast, a 1-month supply of phentermine-topiramate (Qsymia) is approximately $205. Currently, many medical insurance plans do not cover the cost of semaglutide treatment for weight loss. Patent protection for liraglutide may expire in the next few years, permitting the marketing of a lower-cost generic formulation, increasing the availability of the medication. However, as noted above, compared with liraglutide, semaglutide treatment results in much greater weight loss.

The most common adverse effects associated with semaglutide treatment are nausea, vomiting, diarrhea, and constipation. In one randomized clinical trial involving 1,961 patients, the frequency of adverse effects reported by patients taking semaglutide incrementally above the frequency of the same adverse effect reported by patients on placebo was: nausea (27%), vomiting (18%), diarrhea (16%), constipation (14%), dyspepsia (7%), and abdominal pain (5%).¹⁵ In this study, treatment was discontinued due to adverse effects in 7% and 3% of the patients in the semaglutide and placebo groups, respectively. Experts believe that adverse effects can be minimized by increasing the dose slowly and decreasing the dose if adverse effects are bothersome to the patient.

Measuring the benefits of semaglutide weight loss

Overweight and obesity are prevalent problems with many adverse consequences, including an increased risk of death. In population studies, weight loss following bariatric surgery is associated with a substantial reduction in mortality, cancer, and heart disease compared with conventional therapy.²¹ Over the next few years, the effect of semaglutide-induced weight loss on the rate of cancer and heart disease should become clear. If semaglutide treatment of obesity is associated with a reduction in cancer and heart disease, it would be a truly breakthrough medication. ●

McElwee ER, Oliver EA, McFarling K, et al. Risk of stillbirth in pregnancies complicated by diabetes, stratified by fetal growth. Obstet Gynecol. 2023;141:801-809. doi:10.1097/AOG.0000000000005102.

EXPERT COMMENTARY 

Stillbirth is defined as intrauterine demise at or beyond 20 weeks’ gestation. Pregestational DM and GDM significantly increase the risk of stillbirth. Both fetal growth restriction and macrosomia are common complications of pregnancies affected by diabetes, and they further increase the risk of stillbirth. While maternal variables such as glycemic control and medication requirement are currently used to assess the risks of expectant management and inform delivery timing, abnormal fetal growth is not.

Investigators sought to evaluate the stillbirth rates per week of expectant management during the late third trimester stratified by birth weight (as a surrogate for fetal growth) in pregnancies complicated by PG-DM or GDM.

Details of the study

McElwee and colleagues used the US National Vital Statistics System to identify nonanomalous singleton pregnancies complicated by PG-DM or GDM from 2014 to 2017.¹ Pregnancies were stratified by birth weight and categorized as being LGA (birth weight > 90th percentile for gestational age), SGA (birth weight < 10th percentile for gestational age), or AGA. Stillbirths were identified from 34 0/7 through 39 6/7 weeks of gestation, and conditional stillbirth rates per 10,000 pregnancies were calculated for each week of gestation.

Results. Among 834,631 pregnancies complicated by PG-DM (13.1%) or GDM (86.9%), there were 3,033 stillbirths, of which 61% were in pregnancies with PG-DM. Stillbirth rates increased with advancing gestational age for both PG-DM and GDM regardless of birth weight. In pregnancies with PG-DM, fetuses that were LGA or SGA had a higher relative risk of stillbirth compared with their AGA counterparts at each gestational age. This stillbirth risk was highest in pregnancies with PG-DM that were LGA. At 39 weeks, the stillbirth rate in this population was 96.9/10,000 ongoing pregnancies and was 5 times higher than pregnancies with PG-DM that were AGA. When the GDM-related AGA group was selected as the referent (as the lowest-risk comparison group), pregnancies with PG-DM that were LGA had a 21-times higher relative risk of stillbirth at 37 and 38 weeks of gestation.

Study strengths and limitations

Decisions on the optimal timing of delivery seek to strike a balance between the increased neonatal morbidity with delivery before 39 weeks’ gestation and the increased risk of stillbirth with expectant management. In pregnancies complicated by diabetes, current guidelines from the American College of Obstetricians and Gynecologists recommend consideration of maternal variables, such as medication requirement, glycemic control, and vascular sequelae, to inform decisions on delivery timing, as these factors have been postulated to influence the risk of stillbirth with pregnancy prolongation.² These recommendations are based largely on expert opinion and retrospective data.

The question of how fetal growth abnormalities factor into this complicated decision making is also an area of low-quality evidence despite studies that demonstrate that both SGA and LGA fetuses in pregnancies complicated by diabetes are at increased risk of stillbirth.³

The large population-based study design by McElwee and colleagues allowed the investigators to examine a rare event (stillbirth) with multiple stratification levels and sufficient statistical power and to contribute to this literature.

Significant limitations, however, must be considered before generalizing these results. The data were restricted to variables available on birth and death certificates, and more granular information—such as the type of DM, level of glycemic control, frequency of antenatal testing, and stillbirth work-up—could not be assessed. Ultrasonographic estimations of fetal weight also were not included. Birth weight data were used as a proxy, although we know that these variables do not always correlate well given the limited accuracy of ultrasonography in assessing projected birth weight, particularly later in pregnancy. The authors also did not control for highly prevalent variables (for example, hypertension, obesity) that are likely associated with abnormal fetal growth and stillbirth in these populations. ●

McElwee ER, Oliver EA, McFarling K, et al. Risk of stillbirth in pregnancies complicated by diabetes, stratified by fetal growth. Obstet Gynecol. 2023;141:801-809. doi:10.1097/AOG.0000000000005102.

EXPERT COMMENTARY 

Stillbirth is defined as intrauterine demise at or beyond 20 weeks’ gestation. Pregestational DM and GDM significantly increase the risk of stillbirth. Both fetal growth restriction and macrosomia are common complications of pregnancies affected by diabetes, and they further increase the risk of stillbirth. While maternal variables such as glycemic control and medication requirement are currently used to assess the risks of expectant management and inform delivery timing, abnormal fetal growth is not.

Investigators sought to evaluate the stillbirth rates per week of expectant management during the late third trimester stratified by birth weight (as a surrogate for fetal growth) in pregnancies complicated by PG-DM or GDM.

Details of the study

McElwee and colleagues used the US National Vital Statistics System to identify nonanomalous singleton pregnancies complicated by PG-DM or GDM from 2014 to 2017.¹ Pregnancies were stratified by birth weight and categorized as being LGA (birth weight > 90th percentile for gestational age), SGA (birth weight < 10th percentile for gestational age), or AGA. Stillbirths were identified from 34 0/7 through 39 6/7 weeks of gestation, and conditional stillbirth rates per 10,000 pregnancies were calculated for each week of gestation.

Results. Among 834,631 pregnancies complicated by PG-DM (13.1%) or GDM (86.9%), there were 3,033 stillbirths, of which 61% were in pregnancies with PG-DM. Stillbirth rates increased with advancing gestational age for both PG-DM and GDM regardless of birth weight. In pregnancies with PG-DM, fetuses that were LGA or SGA had a higher relative risk of stillbirth compared with their AGA counterparts at each gestational age. This stillbirth risk was highest in pregnancies with PG-DM that were LGA. At 39 weeks, the stillbirth rate in this population was 96.9/10,000 ongoing pregnancies and was 5 times higher than pregnancies with PG-DM that were AGA. When the GDM-related AGA group was selected as the referent (as the lowest-risk comparison group), pregnancies with PG-DM that were LGA had a 21-times higher relative risk of stillbirth at 37 and 38 weeks of gestation.

Study strengths and limitations

Decisions on the optimal timing of delivery seek to strike a balance between the increased neonatal morbidity with delivery before 39 weeks’ gestation and the increased risk of stillbirth with expectant management. In pregnancies complicated by diabetes, current guidelines from the American College of Obstetricians and Gynecologists recommend consideration of maternal variables, such as medication requirement, glycemic control, and vascular sequelae, to inform decisions on delivery timing, as these factors have been postulated to influence the risk of stillbirth with pregnancy prolongation.² These recommendations are based largely on expert opinion and retrospective data.

The question of how fetal growth abnormalities factor into this complicated decision making is also an area of low-quality evidence despite studies that demonstrate that both SGA and LGA fetuses in pregnancies complicated by diabetes are at increased risk of stillbirth.³

The large population-based study design by McElwee and colleagues allowed the investigators to examine a rare event (stillbirth) with multiple stratification levels and sufficient statistical power and to contribute to this literature.

Significant limitations, however, must be considered before generalizing these results. The data were restricted to variables available on birth and death certificates, and more granular information—such as the type of DM, level of glycemic control, frequency of antenatal testing, and stillbirth work-up—could not be assessed. Ultrasonographic estimations of fetal weight also were not included. Birth weight data were used as a proxy, although we know that these variables do not always correlate well given the limited accuracy of ultrasonography in assessing projected birth weight, particularly later in pregnancy. The authors also did not control for highly prevalent variables (for example, hypertension, obesity) that are likely associated with abnormal fetal growth and stillbirth in these populations. ●

McElwee ER, Oliver EA, McFarling K, et al. Risk of stillbirth in pregnancies complicated by diabetes, stratified by fetal growth. Obstet Gynecol. 2023;141:801-809. doi:10.1097/AOG.0000000000005102.

EXPERT COMMENTARY 

Stillbirth is defined as intrauterine demise at or beyond 20 weeks’ gestation. Pregestational DM and GDM significantly increase the risk of stillbirth. Both fetal growth restriction and macrosomia are common complications of pregnancies affected by diabetes, and they further increase the risk of stillbirth. While maternal variables such as glycemic control and medication requirement are currently used to assess the risks of expectant management and inform delivery timing, abnormal fetal growth is not.

Investigators sought to evaluate the stillbirth rates per week of expectant management during the late third trimester stratified by birth weight (as a surrogate for fetal growth) in pregnancies complicated by PG-DM or GDM.

Details of the study

McElwee and colleagues used the US National Vital Statistics System to identify nonanomalous singleton pregnancies complicated by PG-DM or GDM from 2014 to 2017.¹ Pregnancies were stratified by birth weight and categorized as being LGA (birth weight > 90th percentile for gestational age), SGA (birth weight < 10th percentile for gestational age), or AGA. Stillbirths were identified from 34 0/7 through 39 6/7 weeks of gestation, and conditional stillbirth rates per 10,000 pregnancies were calculated for each week of gestation.

Results. Among 834,631 pregnancies complicated by PG-DM (13.1%) or GDM (86.9%), there were 3,033 stillbirths, of which 61% were in pregnancies with PG-DM. Stillbirth rates increased with advancing gestational age for both PG-DM and GDM regardless of birth weight. In pregnancies with PG-DM, fetuses that were LGA or SGA had a higher relative risk of stillbirth compared with their AGA counterparts at each gestational age. This stillbirth risk was highest in pregnancies with PG-DM that were LGA. At 39 weeks, the stillbirth rate in this population was 96.9/10,000 ongoing pregnancies and was 5 times higher than pregnancies with PG-DM that were AGA. When the GDM-related AGA group was selected as the referent (as the lowest-risk comparison group), pregnancies with PG-DM that were LGA had a 21-times higher relative risk of stillbirth at 37 and 38 weeks of gestation.

Study strengths and limitations

Decisions on the optimal timing of delivery seek to strike a balance between the increased neonatal morbidity with delivery before 39 weeks’ gestation and the increased risk of stillbirth with expectant management. In pregnancies complicated by diabetes, current guidelines from the American College of Obstetricians and Gynecologists recommend consideration of maternal variables, such as medication requirement, glycemic control, and vascular sequelae, to inform decisions on delivery timing, as these factors have been postulated to influence the risk of stillbirth with pregnancy prolongation.² These recommendations are based largely on expert opinion and retrospective data.

The question of how fetal growth abnormalities factor into this complicated decision making is also an area of low-quality evidence despite studies that demonstrate that both SGA and LGA fetuses in pregnancies complicated by diabetes are at increased risk of stillbirth.³

The large population-based study design by McElwee and colleagues allowed the investigators to examine a rare event (stillbirth) with multiple stratification levels and sufficient statistical power and to contribute to this literature.

Significant limitations, however, must be considered before generalizing these results. The data were restricted to variables available on birth and death certificates, and more granular information—such as the type of DM, level of glycemic control, frequency of antenatal testing, and stillbirth work-up—could not be assessed. Ultrasonographic estimations of fetal weight also were not included. Birth weight data were used as a proxy, although we know that these variables do not always correlate well given the limited accuracy of ultrasonography in assessing projected birth weight, particularly later in pregnancy. The authors also did not control for highly prevalent variables (for example, hypertension, obesity) that are likely associated with abnormal fetal growth and stillbirth in these populations. ●