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Waiting for Therapy? There’s an App for That
TOPLINE:
Smartphone apps, including those using cognitive-behavioral therapy (CBT) and mindfulness techniques, showed comparable efficacy in reducing depression, anxiety, and suicidality in patients with psychiatric conditions waiting for appointments with psychiatrists or therapists.
METHODOLOGY:
- Participants were adults aged 18 years or older seeking outpatient psychiatric services from several mental and behavioral health clinics within the University of Michigan Health System.
- Eligible participants were those with either a scheduled future mental health appointment or an initial appointment completed within the past 60 days and daily access to a smartphone.
- After completing a baseline survey that gathered data on participants’ depression, anxiety, and suicidality scores, 2080 participants were randomly assigned to one of five groups:
- Enhanced personalized feedback (EPF) only (n = 690)
- SilverCloud only (SilverCloud, a mobile application designed to deliver CBT strategies; n = 345)
- SilverCloud plus EPF (n = 346)
- Headspace only (Headspace, a mobile application designed to train users in mindfulness practices; n = 349)
- Headspace plus EPF (n = 349)
TAKEAWAY:
- The mean baseline Patient Health Questionnaire-9 depression score was 12.7 (6.4% patients). Overall, depression scores significantly decreased by 2.5 points from baseline to the 6-week follow-up for all five arms, with marginal mean differences in mean change ranging from −2.1 to −2.9 (P < .001).
- The magnitude of change was not significantly different across the five arms on most measures (P = .31). Additionally, the groups did not differ in decrease of anxiety or substance use symptoms.
- The Headspace arms reported significantly greater improvements on a suicidality measure subscale than the SilverCloud arms (mean difference in mean change, 0.63; P = .004).
IN PRACTICE:
“Having this type of option, especially for people who are motivated enough to seek an appointment and wait for it, could be very valuable when providers have long wait lists,” lead author Adam Horwitz, PhD, University of Michigan, Ann Arbor, said in a press release.
“These individuals want to be doing something about their mental health but don’t yet have access, so this suggests that providing them with some sort of digital option when their motivation is already high, and they are ready to do something, could begin to make a difference.”
SOURCE:
Dr. Horwitz led the study, which was published online in JAMA Network Open.
LIMITATIONS:
There may have been aspects of formal or in-person care that contributed to the improvement in symptoms across groups and diluted the ability to identify differences between applications in effects on symptom reduction.
DISCLOSURES:
This study was funded by a grant from Precision Health, the Eisenberg Family Depression Center, and the National Institute of Mental Health. Disclosures are noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.A version of this article first appeared on Medscape.com.
TOPLINE:
Smartphone apps, including those using cognitive-behavioral therapy (CBT) and mindfulness techniques, showed comparable efficacy in reducing depression, anxiety, and suicidality in patients with psychiatric conditions waiting for appointments with psychiatrists or therapists.
METHODOLOGY:
- Participants were adults aged 18 years or older seeking outpatient psychiatric services from several mental and behavioral health clinics within the University of Michigan Health System.
- Eligible participants were those with either a scheduled future mental health appointment or an initial appointment completed within the past 60 days and daily access to a smartphone.
- After completing a baseline survey that gathered data on participants’ depression, anxiety, and suicidality scores, 2080 participants were randomly assigned to one of five groups:
- Enhanced personalized feedback (EPF) only (n = 690)
- SilverCloud only (SilverCloud, a mobile application designed to deliver CBT strategies; n = 345)
- SilverCloud plus EPF (n = 346)
- Headspace only (Headspace, a mobile application designed to train users in mindfulness practices; n = 349)
- Headspace plus EPF (n = 349)
TAKEAWAY:
- The mean baseline Patient Health Questionnaire-9 depression score was 12.7 (6.4% patients). Overall, depression scores significantly decreased by 2.5 points from baseline to the 6-week follow-up for all five arms, with marginal mean differences in mean change ranging from −2.1 to −2.9 (P < .001).
- The magnitude of change was not significantly different across the five arms on most measures (P = .31). Additionally, the groups did not differ in decrease of anxiety or substance use symptoms.
- The Headspace arms reported significantly greater improvements on a suicidality measure subscale than the SilverCloud arms (mean difference in mean change, 0.63; P = .004).
IN PRACTICE:
“Having this type of option, especially for people who are motivated enough to seek an appointment and wait for it, could be very valuable when providers have long wait lists,” lead author Adam Horwitz, PhD, University of Michigan, Ann Arbor, said in a press release.
“These individuals want to be doing something about their mental health but don’t yet have access, so this suggests that providing them with some sort of digital option when their motivation is already high, and they are ready to do something, could begin to make a difference.”
SOURCE:
Dr. Horwitz led the study, which was published online in JAMA Network Open.
LIMITATIONS:
There may have been aspects of formal or in-person care that contributed to the improvement in symptoms across groups and diluted the ability to identify differences between applications in effects on symptom reduction.
DISCLOSURES:
This study was funded by a grant from Precision Health, the Eisenberg Family Depression Center, and the National Institute of Mental Health. Disclosures are noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.A version of this article first appeared on Medscape.com.
TOPLINE:
Smartphone apps, including those using cognitive-behavioral therapy (CBT) and mindfulness techniques, showed comparable efficacy in reducing depression, anxiety, and suicidality in patients with psychiatric conditions waiting for appointments with psychiatrists or therapists.
METHODOLOGY:
- Participants were adults aged 18 years or older seeking outpatient psychiatric services from several mental and behavioral health clinics within the University of Michigan Health System.
- Eligible participants were those with either a scheduled future mental health appointment or an initial appointment completed within the past 60 days and daily access to a smartphone.
- After completing a baseline survey that gathered data on participants’ depression, anxiety, and suicidality scores, 2080 participants were randomly assigned to one of five groups:
- Enhanced personalized feedback (EPF) only (n = 690)
- SilverCloud only (SilverCloud, a mobile application designed to deliver CBT strategies; n = 345)
- SilverCloud plus EPF (n = 346)
- Headspace only (Headspace, a mobile application designed to train users in mindfulness practices; n = 349)
- Headspace plus EPF (n = 349)
TAKEAWAY:
- The mean baseline Patient Health Questionnaire-9 depression score was 12.7 (6.4% patients). Overall, depression scores significantly decreased by 2.5 points from baseline to the 6-week follow-up for all five arms, with marginal mean differences in mean change ranging from −2.1 to −2.9 (P < .001).
- The magnitude of change was not significantly different across the five arms on most measures (P = .31). Additionally, the groups did not differ in decrease of anxiety or substance use symptoms.
- The Headspace arms reported significantly greater improvements on a suicidality measure subscale than the SilverCloud arms (mean difference in mean change, 0.63; P = .004).
IN PRACTICE:
“Having this type of option, especially for people who are motivated enough to seek an appointment and wait for it, could be very valuable when providers have long wait lists,” lead author Adam Horwitz, PhD, University of Michigan, Ann Arbor, said in a press release.
“These individuals want to be doing something about their mental health but don’t yet have access, so this suggests that providing them with some sort of digital option when their motivation is already high, and they are ready to do something, could begin to make a difference.”
SOURCE:
Dr. Horwitz led the study, which was published online in JAMA Network Open.
LIMITATIONS:
There may have been aspects of formal or in-person care that contributed to the improvement in symptoms across groups and diluted the ability to identify differences between applications in effects on symptom reduction.
DISCLOSURES:
This study was funded by a grant from Precision Health, the Eisenberg Family Depression Center, and the National Institute of Mental Health. Disclosures are noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.A version of this article first appeared on Medscape.com.
Navigating and Negotiating Maternity/Paternity Leave in Private Practice
Marybeth Spanarkel, MD, a Duke University School of Medicine alumna (1979), completed her internal medicine and gastroenterology training at the University of Pennsylvania, National Institutes of Health, and Johns Hopkins. Initially groomed for an academic role, she chose a clinical position in private practice at Duke Regional Hospital in Durham, North Carolina, where she worked for 25 years.
At age 59, Dr. Spanarkel suffered a neck injury leading to permanent C5-6 radiculopathy, which abruptly ended her career as a clinical gastroenterologist. Since then, she has been a passionate advocate for ergonomic reform in endoscopy. Currently, she is the senior medical adviser and cofounder of ColoWrap, a device designed to improve colonoscopy procedures and reduce ergonomic risk.
Dr. Spanarkel spoke with GI & Hepatology News about the issues that gastroenterologists should consider when negotiating maternity/paternity leave in private practice.
Would you share with the readers your experience with maternity leave in private practice?
As a mother of four, I had two children during my GI fellowship, and received my full salary each time for a 3-month maternity leave. My third child arrived in the time period between leaving my academic position and starting in private practice. My fourth child was born after 2 years in private practice, and I took 3 weeks off. Fortunately, I was not asked to pay upfront overhead fees in my 15-person practice. However, my reduced productivity during that time was factored into my salary calculations, leading to a decreased income for the following 6 months.
How does pregnancy affect your performance and productivity as a GI physician?
“We” may be having a baby, but “You” are pregnant. While some may experience few symptoms, most pregnant doctors deal with problems such as nausea and extreme fatigue, especially in the first trimester. The third trimester may result in reduced physical agility, particularly when performing procedures. Even in uncomplicated pregnancies, balancing the physiologic changes with the demands of a full-time GI role can be strenuous. And this doesn’t even take into account potential infertility issues, pregnancy complications, or newborn concerns that physicians may encounter.
And after childbirth?
Post childbirth, despite a supportive partner, the primary responsibilities such as feeding, nursing support, and bonding often fall on the biological mother. These duties are superimposed on the doctor’s own recovery and postpartum changes. While the United States commonly recognizes 3 months as a standard maternity leave, some European countries advocate for up to 12 months, demonstrating again that this is not an “overnight” transition.
In the past, GI doctors were mostly male, but now there’s a growing number of females in the field. Despite this shift, studies still highlight continued gender disparities in salaries and leadership opportunities, and support for pregnancy-related issues has been largely under-addressed.1,2,3
How do academic centers manage maternity leave?
In academic centers or large healthcare settings, maternity leave policies are more standardized compared with private practice. Doctors are salaried depending on their level of training and experience and then they are assigned a mix of clinical, research, teaching, and/or administrative duties.
Typically, maternity leave in these centers is a standard 3-month period, often combining paid time off (PTO) with unpaid or paid leave. In some cases, short- or long-term disability payments are available, especially for complications. But, the financial impact of a doctor’s maternity leave on the overall unit is usually minimal due to the number of participants in the system. The extra workload is diffused over a larger number of doctors, so the new schedule is generally manageable.4 And since the salary of the employee/physician includes a portion of nonclinical time (administrative, teaching, research), the actual decrease in revenue isn’t that dramatic.
How about maternity leave in private practice?
Maternity leave in private practice, especially if there is only a small number of partners, is handled entirely differently. Think of a household budget (rent, utilities, salaries, benefits, insurance) that is shared by “roommates,” the other partners in the group. To understand how maternity leave affects a private practice, you have to understand how your private practice operates.
Typically, newly hired private practice physicians receive a set salary, with the expectation that their patient revenue will eventually cover both their share of overhead and their salary. The practice might set a monthly quota, offering a bonus for exceeding it, or they may retain the extra revenue until the physician becomes a full partner.
Income in private practice is almost entirely generated by seeing patients and performing procedures, as opposed to non-reimbursable activities such as committee meetings or lectures. Physicians learn to be highly efficient with their time, a standard also expected of their employees. They have more control over their schedules, vacation time, and patient/procedure load. Since income is affected only after overhead costs are covered, each doctor’s approach to workload and pace doesn’t typically concern the other partners. Some physicians may be highly aggressive and efficient (and thus increase their salaries), while others may prefer a slower pace due to external responsibilities.
This arrangement is often seen as fair because the established practice helps you get started by providing the environment for you to generate revenue. This includes patient referrals, office space, and staff. In return, the practice not only hopes you will achieve its goals/quotas but may expect a return on its investment in you.
Additionally, access to shared passive revenue streams, such as a pathology lab, clinical research trials, or facility fees from an endoscopy center, may only be available once a certain level of productivity or full partnership is reached.
The initial years in private practice can be seen as a trial period. Your professional reputation, liability, and patient population are more directly in your own hands. Decision-making, patient management, and potential complications are more wholly your responsibility, which can feel isolating. However, providing excellent care can build your reputation, as satisfied patients will seek you out and generate more referrals. During this time, you need to demonstrate to your prospective partners your commitment to delivering high-quality patient care and to meeting certain minimum standards of volume. If clinical medicine is your passion, the right private practice role can be a fulfilling platform where you do what you love to do and simultaneously are well compensated for it.
How does taking maternity affect shared overhead?
Any physician requiring “leave” will affect the overall revenue of a practice. Issues regarding maternity leave in private practice can also be applied to adoption, paternity, surrogacy, foster care, or medical leave. For instance, if the cumulative overhead is $100k per month in a practice with five doctors, each doctor contributes $20k monthly, totaling $240k each annually.
For example, Dr. “Jones” generates $480k in charges/collections, so after paying his share of overhead, his salary is $240k for the year. In contrast, Dr. “Smith” works more intensely, doubling the patients and procedures of Dr. “Jones,” and generates $960k. After deducting the overhead, his salary is $720k, more than twice his partner’s salary.
Let’s say the practice is considering hiring a new doctor who is 2 months pregnant. If he/she generates $380k in charges in the first year but owes $240k in shared overhead, his/her salary would be $140k, which is not very attractive as a “starting salary” for a highly competent, well-trained GI physician. In extreme cases, with high overhead and low productivity, there might be no revenue for salary once the overhead is paid.
In private practice, is there hesitancy hiring a pregnant person?
While it’s illegal to inquire about pregnancy during employment interviews, partners in private practice might still hesitate to hire a pregnant person. Concerns include sharing overhead costs, handling extra calls or emergencies, and wanting new physicians to contribute equally.
However, this viewpoint can be shortsighted. , as older partners might also face personal or medical needs. Adopting a flexible, empathetic approach toward partners can foster goodwill, potentially enhancing revenue, teamwork, and patient care over a long-term career. The value of empathy should not be underestimated.
What should you consider when you are applying for a new private practice job?
When applying for a private practice position, here are some key points to consider:
- If possible, have your children while employed by a large healthcare system with an established leave policy.
- In a private practice job, ensure the employment contract clearly outlines the terms of medical leave (maternity, paternity, adoption, illness), including details on overhead, benefits, salary, call schedule, and the path to full partnership. Consider having a lawyer review the contract.
- Inquire about how other types of leave, like sabbatical, personal, family, military, or medical, are managed. Understand the implications for salary and overhead, for example, in cases of a partner needing extended leave for surgery or rehabilitation.
- Review the requirements for becoming a full partner, particularly if this includes potential future passive income sources. Does maternity leave (or other types of leave) alter this path?
- Examine the entire benefit package, with a focus on long-term disability policies, considering the statistics on both temporary and permanent disability among GI doctors.5
- Negotiate terms for overhead during leave. Options might include a long term or interest-free loan to cover the 3-month sum, a 50% reduction in overhead charges, or “overhead protection insurance” where a designated policy covers overhead for partners on medical leave.
Remember, a brief leave in a 30-year career is relatively minor. Prioritize taking enough time for yourself and your child. Concentrate on long term fairness when engaged in salary negotiations. Don’t rush back; there will be time later to compensate for a temporary decrease in salary, but limited opportunities to spend age-specific time with your young child.
References
1. Butkus R, et al. Achieving Gender Equity in Physician Compensation and Career Advancement: A Position Paper of the American College of Physicians. Ann Intern Med. 2018 May 15. doi: 10.7326/M17-3438.
2. American Medical Association. Advancing Gender Equity in Medicine: Resources for physicians. 2024 Feb 28.
3. Devi J, et al. Fixing the leaky pipeline: gender imbalance in gastroenterology in Asia-Pacific region. J Gastroenterol Hepatol. 2023 Sept. doi: 10.1111/jgh.16353.
4. Mahadevan U, et al. Closing the gender gap: building a successful career and leadership in research as a female gastroenterologist. Lancet Gastroenterol Hepatol. 2022 Jun. doi: 10.1016/S2468-1253(22)00135-2.
5. Murphy R. Know your maternity leave options. 2024 Apr 4.
Marybeth Spanarkel, MD, a Duke University School of Medicine alumna (1979), completed her internal medicine and gastroenterology training at the University of Pennsylvania, National Institutes of Health, and Johns Hopkins. Initially groomed for an academic role, she chose a clinical position in private practice at Duke Regional Hospital in Durham, North Carolina, where she worked for 25 years.
At age 59, Dr. Spanarkel suffered a neck injury leading to permanent C5-6 radiculopathy, which abruptly ended her career as a clinical gastroenterologist. Since then, she has been a passionate advocate for ergonomic reform in endoscopy. Currently, she is the senior medical adviser and cofounder of ColoWrap, a device designed to improve colonoscopy procedures and reduce ergonomic risk.
Dr. Spanarkel spoke with GI & Hepatology News about the issues that gastroenterologists should consider when negotiating maternity/paternity leave in private practice.
Would you share with the readers your experience with maternity leave in private practice?
As a mother of four, I had two children during my GI fellowship, and received my full salary each time for a 3-month maternity leave. My third child arrived in the time period between leaving my academic position and starting in private practice. My fourth child was born after 2 years in private practice, and I took 3 weeks off. Fortunately, I was not asked to pay upfront overhead fees in my 15-person practice. However, my reduced productivity during that time was factored into my salary calculations, leading to a decreased income for the following 6 months.
How does pregnancy affect your performance and productivity as a GI physician?
“We” may be having a baby, but “You” are pregnant. While some may experience few symptoms, most pregnant doctors deal with problems such as nausea and extreme fatigue, especially in the first trimester. The third trimester may result in reduced physical agility, particularly when performing procedures. Even in uncomplicated pregnancies, balancing the physiologic changes with the demands of a full-time GI role can be strenuous. And this doesn’t even take into account potential infertility issues, pregnancy complications, or newborn concerns that physicians may encounter.
And after childbirth?
Post childbirth, despite a supportive partner, the primary responsibilities such as feeding, nursing support, and bonding often fall on the biological mother. These duties are superimposed on the doctor’s own recovery and postpartum changes. While the United States commonly recognizes 3 months as a standard maternity leave, some European countries advocate for up to 12 months, demonstrating again that this is not an “overnight” transition.
In the past, GI doctors were mostly male, but now there’s a growing number of females in the field. Despite this shift, studies still highlight continued gender disparities in salaries and leadership opportunities, and support for pregnancy-related issues has been largely under-addressed.1,2,3
How do academic centers manage maternity leave?
In academic centers or large healthcare settings, maternity leave policies are more standardized compared with private practice. Doctors are salaried depending on their level of training and experience and then they are assigned a mix of clinical, research, teaching, and/or administrative duties.
Typically, maternity leave in these centers is a standard 3-month period, often combining paid time off (PTO) with unpaid or paid leave. In some cases, short- or long-term disability payments are available, especially for complications. But, the financial impact of a doctor’s maternity leave on the overall unit is usually minimal due to the number of participants in the system. The extra workload is diffused over a larger number of doctors, so the new schedule is generally manageable.4 And since the salary of the employee/physician includes a portion of nonclinical time (administrative, teaching, research), the actual decrease in revenue isn’t that dramatic.
How about maternity leave in private practice?
Maternity leave in private practice, especially if there is only a small number of partners, is handled entirely differently. Think of a household budget (rent, utilities, salaries, benefits, insurance) that is shared by “roommates,” the other partners in the group. To understand how maternity leave affects a private practice, you have to understand how your private practice operates.
Typically, newly hired private practice physicians receive a set salary, with the expectation that their patient revenue will eventually cover both their share of overhead and their salary. The practice might set a monthly quota, offering a bonus for exceeding it, or they may retain the extra revenue until the physician becomes a full partner.
Income in private practice is almost entirely generated by seeing patients and performing procedures, as opposed to non-reimbursable activities such as committee meetings or lectures. Physicians learn to be highly efficient with their time, a standard also expected of their employees. They have more control over their schedules, vacation time, and patient/procedure load. Since income is affected only after overhead costs are covered, each doctor’s approach to workload and pace doesn’t typically concern the other partners. Some physicians may be highly aggressive and efficient (and thus increase their salaries), while others may prefer a slower pace due to external responsibilities.
This arrangement is often seen as fair because the established practice helps you get started by providing the environment for you to generate revenue. This includes patient referrals, office space, and staff. In return, the practice not only hopes you will achieve its goals/quotas but may expect a return on its investment in you.
Additionally, access to shared passive revenue streams, such as a pathology lab, clinical research trials, or facility fees from an endoscopy center, may only be available once a certain level of productivity or full partnership is reached.
The initial years in private practice can be seen as a trial period. Your professional reputation, liability, and patient population are more directly in your own hands. Decision-making, patient management, and potential complications are more wholly your responsibility, which can feel isolating. However, providing excellent care can build your reputation, as satisfied patients will seek you out and generate more referrals. During this time, you need to demonstrate to your prospective partners your commitment to delivering high-quality patient care and to meeting certain minimum standards of volume. If clinical medicine is your passion, the right private practice role can be a fulfilling platform where you do what you love to do and simultaneously are well compensated for it.
How does taking maternity affect shared overhead?
Any physician requiring “leave” will affect the overall revenue of a practice. Issues regarding maternity leave in private practice can also be applied to adoption, paternity, surrogacy, foster care, or medical leave. For instance, if the cumulative overhead is $100k per month in a practice with five doctors, each doctor contributes $20k monthly, totaling $240k each annually.
For example, Dr. “Jones” generates $480k in charges/collections, so after paying his share of overhead, his salary is $240k for the year. In contrast, Dr. “Smith” works more intensely, doubling the patients and procedures of Dr. “Jones,” and generates $960k. After deducting the overhead, his salary is $720k, more than twice his partner’s salary.
Let’s say the practice is considering hiring a new doctor who is 2 months pregnant. If he/she generates $380k in charges in the first year but owes $240k in shared overhead, his/her salary would be $140k, which is not very attractive as a “starting salary” for a highly competent, well-trained GI physician. In extreme cases, with high overhead and low productivity, there might be no revenue for salary once the overhead is paid.
In private practice, is there hesitancy hiring a pregnant person?
While it’s illegal to inquire about pregnancy during employment interviews, partners in private practice might still hesitate to hire a pregnant person. Concerns include sharing overhead costs, handling extra calls or emergencies, and wanting new physicians to contribute equally.
However, this viewpoint can be shortsighted. , as older partners might also face personal or medical needs. Adopting a flexible, empathetic approach toward partners can foster goodwill, potentially enhancing revenue, teamwork, and patient care over a long-term career. The value of empathy should not be underestimated.
What should you consider when you are applying for a new private practice job?
When applying for a private practice position, here are some key points to consider:
- If possible, have your children while employed by a large healthcare system with an established leave policy.
- In a private practice job, ensure the employment contract clearly outlines the terms of medical leave (maternity, paternity, adoption, illness), including details on overhead, benefits, salary, call schedule, and the path to full partnership. Consider having a lawyer review the contract.
- Inquire about how other types of leave, like sabbatical, personal, family, military, or medical, are managed. Understand the implications for salary and overhead, for example, in cases of a partner needing extended leave for surgery or rehabilitation.
- Review the requirements for becoming a full partner, particularly if this includes potential future passive income sources. Does maternity leave (or other types of leave) alter this path?
- Examine the entire benefit package, with a focus on long-term disability policies, considering the statistics on both temporary and permanent disability among GI doctors.5
- Negotiate terms for overhead during leave. Options might include a long term or interest-free loan to cover the 3-month sum, a 50% reduction in overhead charges, or “overhead protection insurance” where a designated policy covers overhead for partners on medical leave.
Remember, a brief leave in a 30-year career is relatively minor. Prioritize taking enough time for yourself and your child. Concentrate on long term fairness when engaged in salary negotiations. Don’t rush back; there will be time later to compensate for a temporary decrease in salary, but limited opportunities to spend age-specific time with your young child.
References
1. Butkus R, et al. Achieving Gender Equity in Physician Compensation and Career Advancement: A Position Paper of the American College of Physicians. Ann Intern Med. 2018 May 15. doi: 10.7326/M17-3438.
2. American Medical Association. Advancing Gender Equity in Medicine: Resources for physicians. 2024 Feb 28.
3. Devi J, et al. Fixing the leaky pipeline: gender imbalance in gastroenterology in Asia-Pacific region. J Gastroenterol Hepatol. 2023 Sept. doi: 10.1111/jgh.16353.
4. Mahadevan U, et al. Closing the gender gap: building a successful career and leadership in research as a female gastroenterologist. Lancet Gastroenterol Hepatol. 2022 Jun. doi: 10.1016/S2468-1253(22)00135-2.
5. Murphy R. Know your maternity leave options. 2024 Apr 4.
Marybeth Spanarkel, MD, a Duke University School of Medicine alumna (1979), completed her internal medicine and gastroenterology training at the University of Pennsylvania, National Institutes of Health, and Johns Hopkins. Initially groomed for an academic role, she chose a clinical position in private practice at Duke Regional Hospital in Durham, North Carolina, where she worked for 25 years.
At age 59, Dr. Spanarkel suffered a neck injury leading to permanent C5-6 radiculopathy, which abruptly ended her career as a clinical gastroenterologist. Since then, she has been a passionate advocate for ergonomic reform in endoscopy. Currently, she is the senior medical adviser and cofounder of ColoWrap, a device designed to improve colonoscopy procedures and reduce ergonomic risk.
Dr. Spanarkel spoke with GI & Hepatology News about the issues that gastroenterologists should consider when negotiating maternity/paternity leave in private practice.
Would you share with the readers your experience with maternity leave in private practice?
As a mother of four, I had two children during my GI fellowship, and received my full salary each time for a 3-month maternity leave. My third child arrived in the time period between leaving my academic position and starting in private practice. My fourth child was born after 2 years in private practice, and I took 3 weeks off. Fortunately, I was not asked to pay upfront overhead fees in my 15-person practice. However, my reduced productivity during that time was factored into my salary calculations, leading to a decreased income for the following 6 months.
How does pregnancy affect your performance and productivity as a GI physician?
“We” may be having a baby, but “You” are pregnant. While some may experience few symptoms, most pregnant doctors deal with problems such as nausea and extreme fatigue, especially in the first trimester. The third trimester may result in reduced physical agility, particularly when performing procedures. Even in uncomplicated pregnancies, balancing the physiologic changes with the demands of a full-time GI role can be strenuous. And this doesn’t even take into account potential infertility issues, pregnancy complications, or newborn concerns that physicians may encounter.
And after childbirth?
Post childbirth, despite a supportive partner, the primary responsibilities such as feeding, nursing support, and bonding often fall on the biological mother. These duties are superimposed on the doctor’s own recovery and postpartum changes. While the United States commonly recognizes 3 months as a standard maternity leave, some European countries advocate for up to 12 months, demonstrating again that this is not an “overnight” transition.
In the past, GI doctors were mostly male, but now there’s a growing number of females in the field. Despite this shift, studies still highlight continued gender disparities in salaries and leadership opportunities, and support for pregnancy-related issues has been largely under-addressed.1,2,3
How do academic centers manage maternity leave?
In academic centers or large healthcare settings, maternity leave policies are more standardized compared with private practice. Doctors are salaried depending on their level of training and experience and then they are assigned a mix of clinical, research, teaching, and/or administrative duties.
Typically, maternity leave in these centers is a standard 3-month period, often combining paid time off (PTO) with unpaid or paid leave. In some cases, short- or long-term disability payments are available, especially for complications. But, the financial impact of a doctor’s maternity leave on the overall unit is usually minimal due to the number of participants in the system. The extra workload is diffused over a larger number of doctors, so the new schedule is generally manageable.4 And since the salary of the employee/physician includes a portion of nonclinical time (administrative, teaching, research), the actual decrease in revenue isn’t that dramatic.
How about maternity leave in private practice?
Maternity leave in private practice, especially if there is only a small number of partners, is handled entirely differently. Think of a household budget (rent, utilities, salaries, benefits, insurance) that is shared by “roommates,” the other partners in the group. To understand how maternity leave affects a private practice, you have to understand how your private practice operates.
Typically, newly hired private practice physicians receive a set salary, with the expectation that their patient revenue will eventually cover both their share of overhead and their salary. The practice might set a monthly quota, offering a bonus for exceeding it, or they may retain the extra revenue until the physician becomes a full partner.
Income in private practice is almost entirely generated by seeing patients and performing procedures, as opposed to non-reimbursable activities such as committee meetings or lectures. Physicians learn to be highly efficient with their time, a standard also expected of their employees. They have more control over their schedules, vacation time, and patient/procedure load. Since income is affected only after overhead costs are covered, each doctor’s approach to workload and pace doesn’t typically concern the other partners. Some physicians may be highly aggressive and efficient (and thus increase their salaries), while others may prefer a slower pace due to external responsibilities.
This arrangement is often seen as fair because the established practice helps you get started by providing the environment for you to generate revenue. This includes patient referrals, office space, and staff. In return, the practice not only hopes you will achieve its goals/quotas but may expect a return on its investment in you.
Additionally, access to shared passive revenue streams, such as a pathology lab, clinical research trials, or facility fees from an endoscopy center, may only be available once a certain level of productivity or full partnership is reached.
The initial years in private practice can be seen as a trial period. Your professional reputation, liability, and patient population are more directly in your own hands. Decision-making, patient management, and potential complications are more wholly your responsibility, which can feel isolating. However, providing excellent care can build your reputation, as satisfied patients will seek you out and generate more referrals. During this time, you need to demonstrate to your prospective partners your commitment to delivering high-quality patient care and to meeting certain minimum standards of volume. If clinical medicine is your passion, the right private practice role can be a fulfilling platform where you do what you love to do and simultaneously are well compensated for it.
How does taking maternity affect shared overhead?
Any physician requiring “leave” will affect the overall revenue of a practice. Issues regarding maternity leave in private practice can also be applied to adoption, paternity, surrogacy, foster care, or medical leave. For instance, if the cumulative overhead is $100k per month in a practice with five doctors, each doctor contributes $20k monthly, totaling $240k each annually.
For example, Dr. “Jones” generates $480k in charges/collections, so after paying his share of overhead, his salary is $240k for the year. In contrast, Dr. “Smith” works more intensely, doubling the patients and procedures of Dr. “Jones,” and generates $960k. After deducting the overhead, his salary is $720k, more than twice his partner’s salary.
Let’s say the practice is considering hiring a new doctor who is 2 months pregnant. If he/she generates $380k in charges in the first year but owes $240k in shared overhead, his/her salary would be $140k, which is not very attractive as a “starting salary” for a highly competent, well-trained GI physician. In extreme cases, with high overhead and low productivity, there might be no revenue for salary once the overhead is paid.
In private practice, is there hesitancy hiring a pregnant person?
While it’s illegal to inquire about pregnancy during employment interviews, partners in private practice might still hesitate to hire a pregnant person. Concerns include sharing overhead costs, handling extra calls or emergencies, and wanting new physicians to contribute equally.
However, this viewpoint can be shortsighted. , as older partners might also face personal or medical needs. Adopting a flexible, empathetic approach toward partners can foster goodwill, potentially enhancing revenue, teamwork, and patient care over a long-term career. The value of empathy should not be underestimated.
What should you consider when you are applying for a new private practice job?
When applying for a private practice position, here are some key points to consider:
- If possible, have your children while employed by a large healthcare system with an established leave policy.
- In a private practice job, ensure the employment contract clearly outlines the terms of medical leave (maternity, paternity, adoption, illness), including details on overhead, benefits, salary, call schedule, and the path to full partnership. Consider having a lawyer review the contract.
- Inquire about how other types of leave, like sabbatical, personal, family, military, or medical, are managed. Understand the implications for salary and overhead, for example, in cases of a partner needing extended leave for surgery or rehabilitation.
- Review the requirements for becoming a full partner, particularly if this includes potential future passive income sources. Does maternity leave (or other types of leave) alter this path?
- Examine the entire benefit package, with a focus on long-term disability policies, considering the statistics on both temporary and permanent disability among GI doctors.5
- Negotiate terms for overhead during leave. Options might include a long term or interest-free loan to cover the 3-month sum, a 50% reduction in overhead charges, or “overhead protection insurance” where a designated policy covers overhead for partners on medical leave.
Remember, a brief leave in a 30-year career is relatively minor. Prioritize taking enough time for yourself and your child. Concentrate on long term fairness when engaged in salary negotiations. Don’t rush back; there will be time later to compensate for a temporary decrease in salary, but limited opportunities to spend age-specific time with your young child.
References
1. Butkus R, et al. Achieving Gender Equity in Physician Compensation and Career Advancement: A Position Paper of the American College of Physicians. Ann Intern Med. 2018 May 15. doi: 10.7326/M17-3438.
2. American Medical Association. Advancing Gender Equity in Medicine: Resources for physicians. 2024 Feb 28.
3. Devi J, et al. Fixing the leaky pipeline: gender imbalance in gastroenterology in Asia-Pacific region. J Gastroenterol Hepatol. 2023 Sept. doi: 10.1111/jgh.16353.
4. Mahadevan U, et al. Closing the gender gap: building a successful career and leadership in research as a female gastroenterologist. Lancet Gastroenterol Hepatol. 2022 Jun. doi: 10.1016/S2468-1253(22)00135-2.
5. Murphy R. Know your maternity leave options. 2024 Apr 4.
LBCL: CAR T Benefits Both Young and Old
“This real-world study demonstrates that CD19 CAR-T cell therapy is feasible in a population of patients aged 75 years and older,” said senior author Pierre Bories, MD, PhD, of the Institute for Cancer Strasbourg-Europe, in Alsace, France. He presented the findings at the annual meeting of the European Hematology Association, held in Madrid, Spain.
Patients with R/R LBCL are often older, with many aged over 75, yet patients in those age groups are frequently underrepresented in clinical trials of CD19-directed CAR T-cell therapy, which has significantly improved outcomes for patients with R/R LBCL.
To further investigate differences in outcomes between older and younger patients with R/R LBCL treated with CAR-T cell therapy, Dr. Bories and colleagues conducted a retrospective analysis of 1,524 patients in the French DESCAR-T registry who were treated at treated at 31 centers in France and had at least two previous infusions of CAR-T cell therapy between April 2018 and September 2023.
Of the patients, 69.8% (n = 1065) were treated with axicabtagene ciloleucel (axi-cel), while 30.1% (n = 459) were treated with tisagenlecleucel (tisa-cel).
Among those patients, 125 were 75 years old or older, with a median age of 76, and the remaining 1399 were under the age of 75, with a median age of 62.
The two age groups had significant differences in terms of characteristics including gender, LBCL subset, number of prior lines of therapy, performance status, age-adjusted International Prognostic Index (IPI), rate of patients receiving a bridging therapy, response to the bridging therapy, and LDH at time of infusion.
Compared with patients aged 75 or younger, those who were 75 years or older had a higher hematopoietic cell transplantation–specific comorbidity index (HCT-CI) score, (31.2% high HCT-CI versus 16.8%, respectively; P < .001).
Patients over 75 also had fewer prior transplants than those under 75 (4.8% versus 21.8%, respectively; P < .001), and they more commonly received tisa-cel CAR-T cell therapy (43.2% versus 28.9%, respectively; P < .001).
Among 1457 patients with response data available, with a median follow-up of 12.7 months, there were no significant differences in terms of the best overall response rate (ORR) and complete response rates (CRR) between the two age groups, with rates of 74.8% for ORR and 62.6% for CRR among those 75 or older, compared with 78.0% and 60.8%, respectively, in the under 75 group (P = .425 and P = .699, respectively).
Likewise, the estimated median overall survival (OS) was 18.3 months in the 75 and older group and 24.0 months in the under 75 group (P = .12).
There were also no significant difference in terms of the estimated median progression-free survival, of 8.2 months in the 75 and older group versus 6.1 months in the under 75 group (P = .73).
In terms of safety, there were no significant differences in terms of grade 3 or higher cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) among patients 75 and older versus under 75, with 7.3% versus 7.4% developing CRS, respectively (P = .97), and 9.8% versus 12.4% developing ICANS (P = .39).
There were no significant differences between the age groups regarding ICU admissions, which occurred in about 24% of the cohorts, or the need for mechanical ventilation, which was necessary in about 3% of the entire cohort.
Of note, the overall rates of non-relapse mortality were more common in the 75 years and older group, among whom 19.5% of deaths were not related to lymphoma progression or relapse, compared with 8.1% in the under 75 group (P < .0001).
Early mortalities not related to relapse, defined as occurring before day 28 post-infusion, occurred among 3 patients aged 75 and older (2.4% of all patients 75 and older, representing 12.0% of all non-relapse mortality cases) compared with 16 patients under 75 (1.2% of those patients and 13.1% of all non-relapse mortality).
Infection was the main cause of non-relapse mortality in both groups, representing the cause in 57.7% of those under 75 and 54.2% of those aged 75 and older.
Patients 75 and older had a significantly higher risk of non-relapse mortality from infection (P = .0003), CRS (P = .022) or other causes, compared with those under 75 (P = .0004), but not from ICANS (P = .524).
“Our findings show a higher non-relapse mortality in this older population, which mainly relied on late infectious events, occurring after 28 days,” Dr. Bories said.
“There was also a higher rate of non-relapse mortality from infections, CRS or other causes in those 75 or older, but that did not translate to a lower overall survival in our patient sample,” he said.
Asked at the session about the implications of the higher infection risk in elderly patients, Dr. Bories said, “I think this deserves special attention and we have to be more careful with frail patients.
“This should obviously encourage the use of prophylaxis for a longer period of time.”
Dr. Bories noted that he and his team are currently conducting a more detailed propensity-matched comparison between axi-cel and tisa-cel in an older population.
The findings are consistent with those of other studies, among the latest including a 2024 real-world multicenter study of 172 diffuse LBCL (DLBCL) patients treated with CAR-T cell therapy (mostly axi-cel).
That study showed comparable median progression-free and OS rates between those over and under the age of 70, however, in contrast to the current study, that study showed no significant differences in non-relapse mortality.
The ORR in that study also did not differ between age groups, exceeding 75%.
Of note, in that study, tisa‐cel treatment was associated with an approximately 60% higher risk of relapse and/or death compared with axi‐cel treatment, which the authors report was driven primarily by less favorable survival outcomes among tisa‐cel patients younger than age 70 years.
“In this context, some reports showed that axi‐cel may offer enhanced effectiveness compared to tisa‐cel in patients aged 65 and older, despite higher rates of neurotoxicity,” they wrote.
Nevertheless, the study’s overall findings indicate that “CAR T-cell therapy should be not withheld for elderly patients with r/r DLBCL,” the authors concluded.
Low CAR T Utilization in Elderly Patients
Overall, utilization of CAR-T cell therapy among older patients reportedly remains low, as demonstrated in one recent real-world study on the issue, involving 551 older patients with DLBCL.
The study showed that 19% of patients aged 65-69 and 22% of those aged 70-74 years received CAR-T cell therapy, compared with only 13% of those aged 75 and older.
“While CAR T-cell therapy in older patients is associated with favorable event-free survival comparable to outcomes in younger patients, CAR T-cell usage is low in older patients with DLBCL, which suggests an unmet need for more accessible, effective, and tolerable therapy,” reported first author Dia Chihara, MD, PhD, of the Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, in Houston, Texas, and colleagues.
Noting that “the use of current CAR-T cell therapy products seemed to be limited to selected patients,” the authors added that “this may change in the future with next-generation CAR T-cell therapy products.”
Dr. Bories disclosed relationships with Kite Gilead, Novartis, BMD-Celgene, Abbvie, Servier, Janssen and the BMS foundation.
“This real-world study demonstrates that CD19 CAR-T cell therapy is feasible in a population of patients aged 75 years and older,” said senior author Pierre Bories, MD, PhD, of the Institute for Cancer Strasbourg-Europe, in Alsace, France. He presented the findings at the annual meeting of the European Hematology Association, held in Madrid, Spain.
Patients with R/R LBCL are often older, with many aged over 75, yet patients in those age groups are frequently underrepresented in clinical trials of CD19-directed CAR T-cell therapy, which has significantly improved outcomes for patients with R/R LBCL.
To further investigate differences in outcomes between older and younger patients with R/R LBCL treated with CAR-T cell therapy, Dr. Bories and colleagues conducted a retrospective analysis of 1,524 patients in the French DESCAR-T registry who were treated at treated at 31 centers in France and had at least two previous infusions of CAR-T cell therapy between April 2018 and September 2023.
Of the patients, 69.8% (n = 1065) were treated with axicabtagene ciloleucel (axi-cel), while 30.1% (n = 459) were treated with tisagenlecleucel (tisa-cel).
Among those patients, 125 were 75 years old or older, with a median age of 76, and the remaining 1399 were under the age of 75, with a median age of 62.
The two age groups had significant differences in terms of characteristics including gender, LBCL subset, number of prior lines of therapy, performance status, age-adjusted International Prognostic Index (IPI), rate of patients receiving a bridging therapy, response to the bridging therapy, and LDH at time of infusion.
Compared with patients aged 75 or younger, those who were 75 years or older had a higher hematopoietic cell transplantation–specific comorbidity index (HCT-CI) score, (31.2% high HCT-CI versus 16.8%, respectively; P < .001).
Patients over 75 also had fewer prior transplants than those under 75 (4.8% versus 21.8%, respectively; P < .001), and they more commonly received tisa-cel CAR-T cell therapy (43.2% versus 28.9%, respectively; P < .001).
Among 1457 patients with response data available, with a median follow-up of 12.7 months, there were no significant differences in terms of the best overall response rate (ORR) and complete response rates (CRR) between the two age groups, with rates of 74.8% for ORR and 62.6% for CRR among those 75 or older, compared with 78.0% and 60.8%, respectively, in the under 75 group (P = .425 and P = .699, respectively).
Likewise, the estimated median overall survival (OS) was 18.3 months in the 75 and older group and 24.0 months in the under 75 group (P = .12).
There were also no significant difference in terms of the estimated median progression-free survival, of 8.2 months in the 75 and older group versus 6.1 months in the under 75 group (P = .73).
In terms of safety, there were no significant differences in terms of grade 3 or higher cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) among patients 75 and older versus under 75, with 7.3% versus 7.4% developing CRS, respectively (P = .97), and 9.8% versus 12.4% developing ICANS (P = .39).
There were no significant differences between the age groups regarding ICU admissions, which occurred in about 24% of the cohorts, or the need for mechanical ventilation, which was necessary in about 3% of the entire cohort.
Of note, the overall rates of non-relapse mortality were more common in the 75 years and older group, among whom 19.5% of deaths were not related to lymphoma progression or relapse, compared with 8.1% in the under 75 group (P < .0001).
Early mortalities not related to relapse, defined as occurring before day 28 post-infusion, occurred among 3 patients aged 75 and older (2.4% of all patients 75 and older, representing 12.0% of all non-relapse mortality cases) compared with 16 patients under 75 (1.2% of those patients and 13.1% of all non-relapse mortality).
Infection was the main cause of non-relapse mortality in both groups, representing the cause in 57.7% of those under 75 and 54.2% of those aged 75 and older.
Patients 75 and older had a significantly higher risk of non-relapse mortality from infection (P = .0003), CRS (P = .022) or other causes, compared with those under 75 (P = .0004), but not from ICANS (P = .524).
“Our findings show a higher non-relapse mortality in this older population, which mainly relied on late infectious events, occurring after 28 days,” Dr. Bories said.
“There was also a higher rate of non-relapse mortality from infections, CRS or other causes in those 75 or older, but that did not translate to a lower overall survival in our patient sample,” he said.
Asked at the session about the implications of the higher infection risk in elderly patients, Dr. Bories said, “I think this deserves special attention and we have to be more careful with frail patients.
“This should obviously encourage the use of prophylaxis for a longer period of time.”
Dr. Bories noted that he and his team are currently conducting a more detailed propensity-matched comparison between axi-cel and tisa-cel in an older population.
The findings are consistent with those of other studies, among the latest including a 2024 real-world multicenter study of 172 diffuse LBCL (DLBCL) patients treated with CAR-T cell therapy (mostly axi-cel).
That study showed comparable median progression-free and OS rates between those over and under the age of 70, however, in contrast to the current study, that study showed no significant differences in non-relapse mortality.
The ORR in that study also did not differ between age groups, exceeding 75%.
Of note, in that study, tisa‐cel treatment was associated with an approximately 60% higher risk of relapse and/or death compared with axi‐cel treatment, which the authors report was driven primarily by less favorable survival outcomes among tisa‐cel patients younger than age 70 years.
“In this context, some reports showed that axi‐cel may offer enhanced effectiveness compared to tisa‐cel in patients aged 65 and older, despite higher rates of neurotoxicity,” they wrote.
Nevertheless, the study’s overall findings indicate that “CAR T-cell therapy should be not withheld for elderly patients with r/r DLBCL,” the authors concluded.
Low CAR T Utilization in Elderly Patients
Overall, utilization of CAR-T cell therapy among older patients reportedly remains low, as demonstrated in one recent real-world study on the issue, involving 551 older patients with DLBCL.
The study showed that 19% of patients aged 65-69 and 22% of those aged 70-74 years received CAR-T cell therapy, compared with only 13% of those aged 75 and older.
“While CAR T-cell therapy in older patients is associated with favorable event-free survival comparable to outcomes in younger patients, CAR T-cell usage is low in older patients with DLBCL, which suggests an unmet need for more accessible, effective, and tolerable therapy,” reported first author Dia Chihara, MD, PhD, of the Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, in Houston, Texas, and colleagues.
Noting that “the use of current CAR-T cell therapy products seemed to be limited to selected patients,” the authors added that “this may change in the future with next-generation CAR T-cell therapy products.”
Dr. Bories disclosed relationships with Kite Gilead, Novartis, BMD-Celgene, Abbvie, Servier, Janssen and the BMS foundation.
“This real-world study demonstrates that CD19 CAR-T cell therapy is feasible in a population of patients aged 75 years and older,” said senior author Pierre Bories, MD, PhD, of the Institute for Cancer Strasbourg-Europe, in Alsace, France. He presented the findings at the annual meeting of the European Hematology Association, held in Madrid, Spain.
Patients with R/R LBCL are often older, with many aged over 75, yet patients in those age groups are frequently underrepresented in clinical trials of CD19-directed CAR T-cell therapy, which has significantly improved outcomes for patients with R/R LBCL.
To further investigate differences in outcomes between older and younger patients with R/R LBCL treated with CAR-T cell therapy, Dr. Bories and colleagues conducted a retrospective analysis of 1,524 patients in the French DESCAR-T registry who were treated at treated at 31 centers in France and had at least two previous infusions of CAR-T cell therapy between April 2018 and September 2023.
Of the patients, 69.8% (n = 1065) were treated with axicabtagene ciloleucel (axi-cel), while 30.1% (n = 459) were treated with tisagenlecleucel (tisa-cel).
Among those patients, 125 were 75 years old or older, with a median age of 76, and the remaining 1399 were under the age of 75, with a median age of 62.
The two age groups had significant differences in terms of characteristics including gender, LBCL subset, number of prior lines of therapy, performance status, age-adjusted International Prognostic Index (IPI), rate of patients receiving a bridging therapy, response to the bridging therapy, and LDH at time of infusion.
Compared with patients aged 75 or younger, those who were 75 years or older had a higher hematopoietic cell transplantation–specific comorbidity index (HCT-CI) score, (31.2% high HCT-CI versus 16.8%, respectively; P < .001).
Patients over 75 also had fewer prior transplants than those under 75 (4.8% versus 21.8%, respectively; P < .001), and they more commonly received tisa-cel CAR-T cell therapy (43.2% versus 28.9%, respectively; P < .001).
Among 1457 patients with response data available, with a median follow-up of 12.7 months, there were no significant differences in terms of the best overall response rate (ORR) and complete response rates (CRR) between the two age groups, with rates of 74.8% for ORR and 62.6% for CRR among those 75 or older, compared with 78.0% and 60.8%, respectively, in the under 75 group (P = .425 and P = .699, respectively).
Likewise, the estimated median overall survival (OS) was 18.3 months in the 75 and older group and 24.0 months in the under 75 group (P = .12).
There were also no significant difference in terms of the estimated median progression-free survival, of 8.2 months in the 75 and older group versus 6.1 months in the under 75 group (P = .73).
In terms of safety, there were no significant differences in terms of grade 3 or higher cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) among patients 75 and older versus under 75, with 7.3% versus 7.4% developing CRS, respectively (P = .97), and 9.8% versus 12.4% developing ICANS (P = .39).
There were no significant differences between the age groups regarding ICU admissions, which occurred in about 24% of the cohorts, or the need for mechanical ventilation, which was necessary in about 3% of the entire cohort.
Of note, the overall rates of non-relapse mortality were more common in the 75 years and older group, among whom 19.5% of deaths were not related to lymphoma progression or relapse, compared with 8.1% in the under 75 group (P < .0001).
Early mortalities not related to relapse, defined as occurring before day 28 post-infusion, occurred among 3 patients aged 75 and older (2.4% of all patients 75 and older, representing 12.0% of all non-relapse mortality cases) compared with 16 patients under 75 (1.2% of those patients and 13.1% of all non-relapse mortality).
Infection was the main cause of non-relapse mortality in both groups, representing the cause in 57.7% of those under 75 and 54.2% of those aged 75 and older.
Patients 75 and older had a significantly higher risk of non-relapse mortality from infection (P = .0003), CRS (P = .022) or other causes, compared with those under 75 (P = .0004), but not from ICANS (P = .524).
“Our findings show a higher non-relapse mortality in this older population, which mainly relied on late infectious events, occurring after 28 days,” Dr. Bories said.
“There was also a higher rate of non-relapse mortality from infections, CRS or other causes in those 75 or older, but that did not translate to a lower overall survival in our patient sample,” he said.
Asked at the session about the implications of the higher infection risk in elderly patients, Dr. Bories said, “I think this deserves special attention and we have to be more careful with frail patients.
“This should obviously encourage the use of prophylaxis for a longer period of time.”
Dr. Bories noted that he and his team are currently conducting a more detailed propensity-matched comparison between axi-cel and tisa-cel in an older population.
The findings are consistent with those of other studies, among the latest including a 2024 real-world multicenter study of 172 diffuse LBCL (DLBCL) patients treated with CAR-T cell therapy (mostly axi-cel).
That study showed comparable median progression-free and OS rates between those over and under the age of 70, however, in contrast to the current study, that study showed no significant differences in non-relapse mortality.
The ORR in that study also did not differ between age groups, exceeding 75%.
Of note, in that study, tisa‐cel treatment was associated with an approximately 60% higher risk of relapse and/or death compared with axi‐cel treatment, which the authors report was driven primarily by less favorable survival outcomes among tisa‐cel patients younger than age 70 years.
“In this context, some reports showed that axi‐cel may offer enhanced effectiveness compared to tisa‐cel in patients aged 65 and older, despite higher rates of neurotoxicity,” they wrote.
Nevertheless, the study’s overall findings indicate that “CAR T-cell therapy should be not withheld for elderly patients with r/r DLBCL,” the authors concluded.
Low CAR T Utilization in Elderly Patients
Overall, utilization of CAR-T cell therapy among older patients reportedly remains low, as demonstrated in one recent real-world study on the issue, involving 551 older patients with DLBCL.
The study showed that 19% of patients aged 65-69 and 22% of those aged 70-74 years received CAR-T cell therapy, compared with only 13% of those aged 75 and older.
“While CAR T-cell therapy in older patients is associated with favorable event-free survival comparable to outcomes in younger patients, CAR T-cell usage is low in older patients with DLBCL, which suggests an unmet need for more accessible, effective, and tolerable therapy,” reported first author Dia Chihara, MD, PhD, of the Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, in Houston, Texas, and colleagues.
Noting that “the use of current CAR-T cell therapy products seemed to be limited to selected patients,” the authors added that “this may change in the future with next-generation CAR T-cell therapy products.”
Dr. Bories disclosed relationships with Kite Gilead, Novartis, BMD-Celgene, Abbvie, Servier, Janssen and the BMS foundation.
FROM EHA 2024
‘Doesn’t Fit Anything I Trained for’: Committee Examines Treatment for Chronic Illness After Lyme Disease
WASHINGTON — Advancing treatment for what has been variably called chronic Lyme and posttreatment Lyme disease (PTLD) is under the eyes of a National Academies of Science, Engineering, and Medicine (NASEM) committee of experts for the first time — a year after the NASEM shone a spotlight on the need to accelerate research on chronic illnesses that follow known or suspected infections.
The committee will not make recommendations on specific approaches to diagnosis and treatment when it issues a report in early 2025 but will instead present “consensus findings” on treatment for chronic illness associated with Lyme disease, including recommendations for advancing treatment.
It’s an area void of the US Food and Drug Administration–approved therapies, void of any consensus on the off-label use of medications, and without any current standard of care or proven mechanisms and pathophysiology, said John Aucott, MD, director of the Johns Hopkins Medicine Lyme Disease Clinical Research Center, Baltimore, one of the invited speakers at a public meeting held by the NASEM in Washington, DC.
“The best way to look at this illness is not from the silos of infectious disease or the silos of rheumatology; you have to look across disciplines,” Dr. Aucott, also associate professor of medicine in the Division of Rheumatology, told the committee. “The story doesn’t fit anything I trained for in my infectious disease fellowship. Even today, I’d posit that PTLD is like an island — it’s still not connected to a lot of the mainstream of medicine.”
Rhisa Parera, who wrote and directed a 2021 documentary, Your Labs Are Normal, was one of several invited speakers who amplified the patient voice. Starting around age 7, she had pain in her knees, spine, and hips and vivid nightmares. In high school, she developed gastrointestinal issues, and in college, she developed debilitating neurologic symptoms.
Depression was her eventual diagnosis after having seen “every specialist in the book,” she said. At age 29, she received a positive western blot test and a Lyme disease diagnosis, at which point “I was prescribed 4 weeks of doxycycline and left in the dark,” the 34-year-old Black patient told the committee. Her health improved only after she began working with an “LLMD,” or Lyme-literate medical doctor (a term used in the patient community), while she lived with her mother and did not work, she said.
“I don’t share my Lyme disease history with other doctors. It’s pointless when you have those who will laugh at you, say you’re fine if you were treated, or just deny the disease completely,” Ms. Parera said. “We need this to be taught in medical school. It’s a literal emergency.”
Incidence and Potential Mechanisms
Limited research has suggested that 10%-20% of patients with Lyme disease develop persistent symptoms after standard antibiotic treatment advised by the Infectious Diseases Society of America (IDSA), Dr. Aucott said. (On its web page on chronic symptoms, the Centers for Disease Control and Prevention presents a more conservative range of 5%-10%.)
His own prospective cohort study at Johns Hopkins, published in 2022, found that 13.7% of 234 patients with prior Lyme disease met symptom and functional impact criteria for PTLD, compared with 4.1% of 49 participants without a history of Lyme disease — a statistically significant difference that he said should “put to rest” the question of “is it real?”
PTLD is the research case definition proposed by the IDSA in 2006; it requires that patients have prior documented Lyme disease, no other specific comorbidities, and specific symptoms (fatigue, widespread musculoskeletal pain, and/or cognitive difficulties) causing significant functional impact at least 6 months from their initial diagnosis and treatment.
In the real world, however, where diagnostics for acute Lyme disease are often inaccurate, erythema migrans is often absent, and the symptomatology of Lyme IACI is variable (and where there is no approved laboratory test or objective biomarker for diagnosing Lyme IACI), PTLD represents only a subset of a broader, heterogeneous population with persistent symptoms.
The term “Lyme IACI,” pronounced “Lyme eye-ACK-ee” at the meeting, builds on conversations at the 2023 NASEM workshop on infection-associated chronic illnesses and “encompasses a variety of terms that are used,” including PTLD, PTLD syndrome, persistent Lyme disease, and chronic Lyme disease, according to committee documents. Symptoms are distinct from the known complications of Lyme disease, such as arthritis or carditis.
The findings from Dr. Aucott’s SLICE cohort likely represent “the best outcome,” he said. They’re “probably not generalizable to a community setting where we see lots of missed diagnoses and delayed diagnoses,” as well as other tick-borne coinfections.
One of the challenges in designing future trials, in fact, relates to enrollment criteria and whether to use strict inclusion and exclusion criteria associated with the IDSA definition or take a broader approach to trial enrollment, he and others said. “You want to enroll patients for whom there’s no controversy that they’ve had Lyme infection ... for a study people believe in,” Dr. Aucott said during a discussion period, noting that it’s typical to screen over 100 patients to find one enrollee. “But it’s a tension we’re having.”
Timothy Sellati, PhD, chief scientific officer of the Global Lyme Alliance, urged change. “It’s really important to try to figure out how to alter our thinking on identifying and diagnosing chronic Lyme patients because they need to be recruited into clinical trials,” he said during his presentation.
“We think the best way to do this is to [develop and] employ composite diagnostic testing” that looks at unique Borrelia signatures (eg, protein, DNA, RNA, or metabolites), genetic and/or epigenetic signatures, inflammation signatures, T-cell-independent antibody signatures, and other elements, Dr. Sellati said.
Researchers designing treatment trials also face unknowns, Dr. Aucott and others said, about the role of potential mechanisms of Lyme IACI, from persistent Borrelia burgdorferi (or Borrelia mayonii) infection or the persistence of bacterial remnants (eg, nucleic acids or peptidoglycans) to infection-triggered pathology such as persistent immune dysregulation, chronic inflammation, autoimmunity, microbiome alterations, and dysautonomia and other neural network alterations.
The NASEM’s spotlight on Lyme IACI follows its long COVID-driven push last year to advance a common research agenda in infection-associated chronic illnesses. Investigators see common symptoms and potential shared mechanisms between long COVID, Lyme IACI, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other complex chronic illnesses following infections.
At the Lyme IACI meeting, invited speakers described parts of the research landscape. Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, for instance, described a recently published deep phenotyping study of 17 patients with ME/CFS that found decreased central catecholamine synthesis, circuit dysfunction of integrative brain regions, and immune profiling differences (eg, defects in B-cell maturation or T-cell exhaustion), compared with matched controls, that suggest the persistence of microbial antigens.
And John Leong, MD, PhD, of Tufts University, Boston, described his lab’s focus on understanding the microbe-host interactions that enable bloodstream dissemination and tissue invasion of B burgdorferi to take hold, increasing the risk for persistent symptoms. Other research at Tufts, he noted during a discussion period, has demonstrated the persistence of B burgdorferi to antibiotics in microtiter dishes. “Those organisms that survive are really difficult to eradicate in vitro,” Dr. Leong said.
Other physician investigators described research on nociplastic pain — a category of pain that can be triggered by infections, causing both amplified sensory processing and augmented central nervous system pain — and on whether reactivation of the Epstein-Barr virus could potentiate autoimmunity in the context of Borrelia infection.
Researchers are ready to test therapies while pathophysiology is unraveled — provided there is funding, Dr. Aucott said. The Clinical Trials Network for Lyme and Other Tick-Borne Diseases, coordinated by Brian Fallon, MD, of Columbia University, New York City, and funded several years ago by the Steven & Alexandra Cohen Foundation, has a slate of small pilot studies underway or being planned that address potential mechanisms (eg, studies of pulse intravenous ceftriaxone, tetracycline, transauricular vagus nerve stimulation, and mast cell modulation). And should full multisite trials be designed and funded, the network is ready with an infrastructure.
Need for Patient-Centered Outcomes
Persistent symptomatology is on the NIH’s radar screen. Efforts to understand causes were part of a strategic tick-borne disease research plan developed by the NIH in 2019. And in 2023, the National Institute of Allergy and Infectious Diseases (NIAID) funded seven projects addressing persistent symptoms that will run through 2028, C. Benjamin Beard, PhD, deputy division director of the CDC’s Division of Vector-Borne Disease, said at the NASEM committee meeting.
Patient advocates maintained that too much emphasis is placed on tick biology and pathophysiology. When Wendy Adams, research grant director and advisory board member of the Bay Area Lyme Foundation, and a colleague analyzed NIAID tick-borne disease funding from 2013 to 2021, they found that 75% of the funding went toward basic research, 15% to translational research, and “only 3% went to clinical research,” Ms. Adams told the committee.
Only 3% of the basic research budget was spent on coinfections, she said, and only 1% was spent on neurologic disease associated with tick-borne infections, both of which are survey-defined patient priorities. Moreover, “12% of the overall NIAID [tick-borne diseases] budget was spent on tick biology,” she said.
Research needs to involve community physicians who are utilizing the guidelines and approaches of the International Lyme and Associated Diseases Society to treat most patients with Lyme IACI, Ms. Adams said. “They have data to be mined,” she said, as does LymeDisease.org, which maintains a patient registry, MyLymeData, with over 18,000 patients. The organization has published two treatment studies, including one on antibiotic treatment response.
Lorraine Johnson, JD, MBA, CEO of LymeDisease.org and principal investigator of MyLymeData, stressed the importance of using patient-centered outcomes that incorporate minimal clinically important differences (MCIDs). “A change in the SF-36 score [without consideration of MCIDs] is not inherently important or meaningful to patients,” she said, referring to the SF-36 survey of health-related quality of life.
“This may seem like an esoteric issue, but two of the four clinical trials done [on retreatment of] persistent Lyme disease used the SF-36 as their outcome measure, and those studies, led by [Mark] Klempner, concluded that retreatment was not effective,” Ms. Johnson said. “Patients have been and continue to be harmed by [this research] because they’re told by physicians that antibiotics don’t work.”
A 2012 biostatistical review of these four RCTs — trials that helped inform the 2006 IDSA treatment guidelines — concluded that the Klempner studies “set the bar for treatment success too high,” Ms. Johnson said. Three of the four trials were likely underpowered to detect clinically meaningful treatment effects, the review also found.
The NASEM committee will hold additional public meetings and review a wide range of literature through this year. The formation of the committee was recommended by the US Department of Health and Human Services Tick-Borne Disease Working Group that was established by Congress in 2016 and concluded its work in 2022. The committee’s work is funded by the Cohen Foundation.
A version of this article appeared on Medscape.com.
WASHINGTON — Advancing treatment for what has been variably called chronic Lyme and posttreatment Lyme disease (PTLD) is under the eyes of a National Academies of Science, Engineering, and Medicine (NASEM) committee of experts for the first time — a year after the NASEM shone a spotlight on the need to accelerate research on chronic illnesses that follow known or suspected infections.
The committee will not make recommendations on specific approaches to diagnosis and treatment when it issues a report in early 2025 but will instead present “consensus findings” on treatment for chronic illness associated with Lyme disease, including recommendations for advancing treatment.
It’s an area void of the US Food and Drug Administration–approved therapies, void of any consensus on the off-label use of medications, and without any current standard of care or proven mechanisms and pathophysiology, said John Aucott, MD, director of the Johns Hopkins Medicine Lyme Disease Clinical Research Center, Baltimore, one of the invited speakers at a public meeting held by the NASEM in Washington, DC.
“The best way to look at this illness is not from the silos of infectious disease or the silos of rheumatology; you have to look across disciplines,” Dr. Aucott, also associate professor of medicine in the Division of Rheumatology, told the committee. “The story doesn’t fit anything I trained for in my infectious disease fellowship. Even today, I’d posit that PTLD is like an island — it’s still not connected to a lot of the mainstream of medicine.”
Rhisa Parera, who wrote and directed a 2021 documentary, Your Labs Are Normal, was one of several invited speakers who amplified the patient voice. Starting around age 7, she had pain in her knees, spine, and hips and vivid nightmares. In high school, she developed gastrointestinal issues, and in college, she developed debilitating neurologic symptoms.
Depression was her eventual diagnosis after having seen “every specialist in the book,” she said. At age 29, she received a positive western blot test and a Lyme disease diagnosis, at which point “I was prescribed 4 weeks of doxycycline and left in the dark,” the 34-year-old Black patient told the committee. Her health improved only after she began working with an “LLMD,” or Lyme-literate medical doctor (a term used in the patient community), while she lived with her mother and did not work, she said.
“I don’t share my Lyme disease history with other doctors. It’s pointless when you have those who will laugh at you, say you’re fine if you were treated, or just deny the disease completely,” Ms. Parera said. “We need this to be taught in medical school. It’s a literal emergency.”
Incidence and Potential Mechanisms
Limited research has suggested that 10%-20% of patients with Lyme disease develop persistent symptoms after standard antibiotic treatment advised by the Infectious Diseases Society of America (IDSA), Dr. Aucott said. (On its web page on chronic symptoms, the Centers for Disease Control and Prevention presents a more conservative range of 5%-10%.)
His own prospective cohort study at Johns Hopkins, published in 2022, found that 13.7% of 234 patients with prior Lyme disease met symptom and functional impact criteria for PTLD, compared with 4.1% of 49 participants without a history of Lyme disease — a statistically significant difference that he said should “put to rest” the question of “is it real?”
PTLD is the research case definition proposed by the IDSA in 2006; it requires that patients have prior documented Lyme disease, no other specific comorbidities, and specific symptoms (fatigue, widespread musculoskeletal pain, and/or cognitive difficulties) causing significant functional impact at least 6 months from their initial diagnosis and treatment.
In the real world, however, where diagnostics for acute Lyme disease are often inaccurate, erythema migrans is often absent, and the symptomatology of Lyme IACI is variable (and where there is no approved laboratory test or objective biomarker for diagnosing Lyme IACI), PTLD represents only a subset of a broader, heterogeneous population with persistent symptoms.
The term “Lyme IACI,” pronounced “Lyme eye-ACK-ee” at the meeting, builds on conversations at the 2023 NASEM workshop on infection-associated chronic illnesses and “encompasses a variety of terms that are used,” including PTLD, PTLD syndrome, persistent Lyme disease, and chronic Lyme disease, according to committee documents. Symptoms are distinct from the known complications of Lyme disease, such as arthritis or carditis.
The findings from Dr. Aucott’s SLICE cohort likely represent “the best outcome,” he said. They’re “probably not generalizable to a community setting where we see lots of missed diagnoses and delayed diagnoses,” as well as other tick-borne coinfections.
One of the challenges in designing future trials, in fact, relates to enrollment criteria and whether to use strict inclusion and exclusion criteria associated with the IDSA definition or take a broader approach to trial enrollment, he and others said. “You want to enroll patients for whom there’s no controversy that they’ve had Lyme infection ... for a study people believe in,” Dr. Aucott said during a discussion period, noting that it’s typical to screen over 100 patients to find one enrollee. “But it’s a tension we’re having.”
Timothy Sellati, PhD, chief scientific officer of the Global Lyme Alliance, urged change. “It’s really important to try to figure out how to alter our thinking on identifying and diagnosing chronic Lyme patients because they need to be recruited into clinical trials,” he said during his presentation.
“We think the best way to do this is to [develop and] employ composite diagnostic testing” that looks at unique Borrelia signatures (eg, protein, DNA, RNA, or metabolites), genetic and/or epigenetic signatures, inflammation signatures, T-cell-independent antibody signatures, and other elements, Dr. Sellati said.
Researchers designing treatment trials also face unknowns, Dr. Aucott and others said, about the role of potential mechanisms of Lyme IACI, from persistent Borrelia burgdorferi (or Borrelia mayonii) infection or the persistence of bacterial remnants (eg, nucleic acids or peptidoglycans) to infection-triggered pathology such as persistent immune dysregulation, chronic inflammation, autoimmunity, microbiome alterations, and dysautonomia and other neural network alterations.
The NASEM’s spotlight on Lyme IACI follows its long COVID-driven push last year to advance a common research agenda in infection-associated chronic illnesses. Investigators see common symptoms and potential shared mechanisms between long COVID, Lyme IACI, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other complex chronic illnesses following infections.
At the Lyme IACI meeting, invited speakers described parts of the research landscape. Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, for instance, described a recently published deep phenotyping study of 17 patients with ME/CFS that found decreased central catecholamine synthesis, circuit dysfunction of integrative brain regions, and immune profiling differences (eg, defects in B-cell maturation or T-cell exhaustion), compared with matched controls, that suggest the persistence of microbial antigens.
And John Leong, MD, PhD, of Tufts University, Boston, described his lab’s focus on understanding the microbe-host interactions that enable bloodstream dissemination and tissue invasion of B burgdorferi to take hold, increasing the risk for persistent symptoms. Other research at Tufts, he noted during a discussion period, has demonstrated the persistence of B burgdorferi to antibiotics in microtiter dishes. “Those organisms that survive are really difficult to eradicate in vitro,” Dr. Leong said.
Other physician investigators described research on nociplastic pain — a category of pain that can be triggered by infections, causing both amplified sensory processing and augmented central nervous system pain — and on whether reactivation of the Epstein-Barr virus could potentiate autoimmunity in the context of Borrelia infection.
Researchers are ready to test therapies while pathophysiology is unraveled — provided there is funding, Dr. Aucott said. The Clinical Trials Network for Lyme and Other Tick-Borne Diseases, coordinated by Brian Fallon, MD, of Columbia University, New York City, and funded several years ago by the Steven & Alexandra Cohen Foundation, has a slate of small pilot studies underway or being planned that address potential mechanisms (eg, studies of pulse intravenous ceftriaxone, tetracycline, transauricular vagus nerve stimulation, and mast cell modulation). And should full multisite trials be designed and funded, the network is ready with an infrastructure.
Need for Patient-Centered Outcomes
Persistent symptomatology is on the NIH’s radar screen. Efforts to understand causes were part of a strategic tick-borne disease research plan developed by the NIH in 2019. And in 2023, the National Institute of Allergy and Infectious Diseases (NIAID) funded seven projects addressing persistent symptoms that will run through 2028, C. Benjamin Beard, PhD, deputy division director of the CDC’s Division of Vector-Borne Disease, said at the NASEM committee meeting.
Patient advocates maintained that too much emphasis is placed on tick biology and pathophysiology. When Wendy Adams, research grant director and advisory board member of the Bay Area Lyme Foundation, and a colleague analyzed NIAID tick-borne disease funding from 2013 to 2021, they found that 75% of the funding went toward basic research, 15% to translational research, and “only 3% went to clinical research,” Ms. Adams told the committee.
Only 3% of the basic research budget was spent on coinfections, she said, and only 1% was spent on neurologic disease associated with tick-borne infections, both of which are survey-defined patient priorities. Moreover, “12% of the overall NIAID [tick-borne diseases] budget was spent on tick biology,” she said.
Research needs to involve community physicians who are utilizing the guidelines and approaches of the International Lyme and Associated Diseases Society to treat most patients with Lyme IACI, Ms. Adams said. “They have data to be mined,” she said, as does LymeDisease.org, which maintains a patient registry, MyLymeData, with over 18,000 patients. The organization has published two treatment studies, including one on antibiotic treatment response.
Lorraine Johnson, JD, MBA, CEO of LymeDisease.org and principal investigator of MyLymeData, stressed the importance of using patient-centered outcomes that incorporate minimal clinically important differences (MCIDs). “A change in the SF-36 score [without consideration of MCIDs] is not inherently important or meaningful to patients,” she said, referring to the SF-36 survey of health-related quality of life.
“This may seem like an esoteric issue, but two of the four clinical trials done [on retreatment of] persistent Lyme disease used the SF-36 as their outcome measure, and those studies, led by [Mark] Klempner, concluded that retreatment was not effective,” Ms. Johnson said. “Patients have been and continue to be harmed by [this research] because they’re told by physicians that antibiotics don’t work.”
A 2012 biostatistical review of these four RCTs — trials that helped inform the 2006 IDSA treatment guidelines — concluded that the Klempner studies “set the bar for treatment success too high,” Ms. Johnson said. Three of the four trials were likely underpowered to detect clinically meaningful treatment effects, the review also found.
The NASEM committee will hold additional public meetings and review a wide range of literature through this year. The formation of the committee was recommended by the US Department of Health and Human Services Tick-Borne Disease Working Group that was established by Congress in 2016 and concluded its work in 2022. The committee’s work is funded by the Cohen Foundation.
A version of this article appeared on Medscape.com.
WASHINGTON — Advancing treatment for what has been variably called chronic Lyme and posttreatment Lyme disease (PTLD) is under the eyes of a National Academies of Science, Engineering, and Medicine (NASEM) committee of experts for the first time — a year after the NASEM shone a spotlight on the need to accelerate research on chronic illnesses that follow known or suspected infections.
The committee will not make recommendations on specific approaches to diagnosis and treatment when it issues a report in early 2025 but will instead present “consensus findings” on treatment for chronic illness associated with Lyme disease, including recommendations for advancing treatment.
It’s an area void of the US Food and Drug Administration–approved therapies, void of any consensus on the off-label use of medications, and without any current standard of care or proven mechanisms and pathophysiology, said John Aucott, MD, director of the Johns Hopkins Medicine Lyme Disease Clinical Research Center, Baltimore, one of the invited speakers at a public meeting held by the NASEM in Washington, DC.
“The best way to look at this illness is not from the silos of infectious disease or the silos of rheumatology; you have to look across disciplines,” Dr. Aucott, also associate professor of medicine in the Division of Rheumatology, told the committee. “The story doesn’t fit anything I trained for in my infectious disease fellowship. Even today, I’d posit that PTLD is like an island — it’s still not connected to a lot of the mainstream of medicine.”
Rhisa Parera, who wrote and directed a 2021 documentary, Your Labs Are Normal, was one of several invited speakers who amplified the patient voice. Starting around age 7, she had pain in her knees, spine, and hips and vivid nightmares. In high school, she developed gastrointestinal issues, and in college, she developed debilitating neurologic symptoms.
Depression was her eventual diagnosis after having seen “every specialist in the book,” she said. At age 29, she received a positive western blot test and a Lyme disease diagnosis, at which point “I was prescribed 4 weeks of doxycycline and left in the dark,” the 34-year-old Black patient told the committee. Her health improved only after she began working with an “LLMD,” or Lyme-literate medical doctor (a term used in the patient community), while she lived with her mother and did not work, she said.
“I don’t share my Lyme disease history with other doctors. It’s pointless when you have those who will laugh at you, say you’re fine if you were treated, or just deny the disease completely,” Ms. Parera said. “We need this to be taught in medical school. It’s a literal emergency.”
Incidence and Potential Mechanisms
Limited research has suggested that 10%-20% of patients with Lyme disease develop persistent symptoms after standard antibiotic treatment advised by the Infectious Diseases Society of America (IDSA), Dr. Aucott said. (On its web page on chronic symptoms, the Centers for Disease Control and Prevention presents a more conservative range of 5%-10%.)
His own prospective cohort study at Johns Hopkins, published in 2022, found that 13.7% of 234 patients with prior Lyme disease met symptom and functional impact criteria for PTLD, compared with 4.1% of 49 participants without a history of Lyme disease — a statistically significant difference that he said should “put to rest” the question of “is it real?”
PTLD is the research case definition proposed by the IDSA in 2006; it requires that patients have prior documented Lyme disease, no other specific comorbidities, and specific symptoms (fatigue, widespread musculoskeletal pain, and/or cognitive difficulties) causing significant functional impact at least 6 months from their initial diagnosis and treatment.
In the real world, however, where diagnostics for acute Lyme disease are often inaccurate, erythema migrans is often absent, and the symptomatology of Lyme IACI is variable (and where there is no approved laboratory test or objective biomarker for diagnosing Lyme IACI), PTLD represents only a subset of a broader, heterogeneous population with persistent symptoms.
The term “Lyme IACI,” pronounced “Lyme eye-ACK-ee” at the meeting, builds on conversations at the 2023 NASEM workshop on infection-associated chronic illnesses and “encompasses a variety of terms that are used,” including PTLD, PTLD syndrome, persistent Lyme disease, and chronic Lyme disease, according to committee documents. Symptoms are distinct from the known complications of Lyme disease, such as arthritis or carditis.
The findings from Dr. Aucott’s SLICE cohort likely represent “the best outcome,” he said. They’re “probably not generalizable to a community setting where we see lots of missed diagnoses and delayed diagnoses,” as well as other tick-borne coinfections.
One of the challenges in designing future trials, in fact, relates to enrollment criteria and whether to use strict inclusion and exclusion criteria associated with the IDSA definition or take a broader approach to trial enrollment, he and others said. “You want to enroll patients for whom there’s no controversy that they’ve had Lyme infection ... for a study people believe in,” Dr. Aucott said during a discussion period, noting that it’s typical to screen over 100 patients to find one enrollee. “But it’s a tension we’re having.”
Timothy Sellati, PhD, chief scientific officer of the Global Lyme Alliance, urged change. “It’s really important to try to figure out how to alter our thinking on identifying and diagnosing chronic Lyme patients because they need to be recruited into clinical trials,” he said during his presentation.
“We think the best way to do this is to [develop and] employ composite diagnostic testing” that looks at unique Borrelia signatures (eg, protein, DNA, RNA, or metabolites), genetic and/or epigenetic signatures, inflammation signatures, T-cell-independent antibody signatures, and other elements, Dr. Sellati said.
Researchers designing treatment trials also face unknowns, Dr. Aucott and others said, about the role of potential mechanisms of Lyme IACI, from persistent Borrelia burgdorferi (or Borrelia mayonii) infection or the persistence of bacterial remnants (eg, nucleic acids or peptidoglycans) to infection-triggered pathology such as persistent immune dysregulation, chronic inflammation, autoimmunity, microbiome alterations, and dysautonomia and other neural network alterations.
The NASEM’s spotlight on Lyme IACI follows its long COVID-driven push last year to advance a common research agenda in infection-associated chronic illnesses. Investigators see common symptoms and potential shared mechanisms between long COVID, Lyme IACI, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other complex chronic illnesses following infections.
At the Lyme IACI meeting, invited speakers described parts of the research landscape. Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke, for instance, described a recently published deep phenotyping study of 17 patients with ME/CFS that found decreased central catecholamine synthesis, circuit dysfunction of integrative brain regions, and immune profiling differences (eg, defects in B-cell maturation or T-cell exhaustion), compared with matched controls, that suggest the persistence of microbial antigens.
And John Leong, MD, PhD, of Tufts University, Boston, described his lab’s focus on understanding the microbe-host interactions that enable bloodstream dissemination and tissue invasion of B burgdorferi to take hold, increasing the risk for persistent symptoms. Other research at Tufts, he noted during a discussion period, has demonstrated the persistence of B burgdorferi to antibiotics in microtiter dishes. “Those organisms that survive are really difficult to eradicate in vitro,” Dr. Leong said.
Other physician investigators described research on nociplastic pain — a category of pain that can be triggered by infections, causing both amplified sensory processing and augmented central nervous system pain — and on whether reactivation of the Epstein-Barr virus could potentiate autoimmunity in the context of Borrelia infection.
Researchers are ready to test therapies while pathophysiology is unraveled — provided there is funding, Dr. Aucott said. The Clinical Trials Network for Lyme and Other Tick-Borne Diseases, coordinated by Brian Fallon, MD, of Columbia University, New York City, and funded several years ago by the Steven & Alexandra Cohen Foundation, has a slate of small pilot studies underway or being planned that address potential mechanisms (eg, studies of pulse intravenous ceftriaxone, tetracycline, transauricular vagus nerve stimulation, and mast cell modulation). And should full multisite trials be designed and funded, the network is ready with an infrastructure.
Need for Patient-Centered Outcomes
Persistent symptomatology is on the NIH’s radar screen. Efforts to understand causes were part of a strategic tick-borne disease research plan developed by the NIH in 2019. And in 2023, the National Institute of Allergy and Infectious Diseases (NIAID) funded seven projects addressing persistent symptoms that will run through 2028, C. Benjamin Beard, PhD, deputy division director of the CDC’s Division of Vector-Borne Disease, said at the NASEM committee meeting.
Patient advocates maintained that too much emphasis is placed on tick biology and pathophysiology. When Wendy Adams, research grant director and advisory board member of the Bay Area Lyme Foundation, and a colleague analyzed NIAID tick-borne disease funding from 2013 to 2021, they found that 75% of the funding went toward basic research, 15% to translational research, and “only 3% went to clinical research,” Ms. Adams told the committee.
Only 3% of the basic research budget was spent on coinfections, she said, and only 1% was spent on neurologic disease associated with tick-borne infections, both of which are survey-defined patient priorities. Moreover, “12% of the overall NIAID [tick-borne diseases] budget was spent on tick biology,” she said.
Research needs to involve community physicians who are utilizing the guidelines and approaches of the International Lyme and Associated Diseases Society to treat most patients with Lyme IACI, Ms. Adams said. “They have data to be mined,” she said, as does LymeDisease.org, which maintains a patient registry, MyLymeData, with over 18,000 patients. The organization has published two treatment studies, including one on antibiotic treatment response.
Lorraine Johnson, JD, MBA, CEO of LymeDisease.org and principal investigator of MyLymeData, stressed the importance of using patient-centered outcomes that incorporate minimal clinically important differences (MCIDs). “A change in the SF-36 score [without consideration of MCIDs] is not inherently important or meaningful to patients,” she said, referring to the SF-36 survey of health-related quality of life.
“This may seem like an esoteric issue, but two of the four clinical trials done [on retreatment of] persistent Lyme disease used the SF-36 as their outcome measure, and those studies, led by [Mark] Klempner, concluded that retreatment was not effective,” Ms. Johnson said. “Patients have been and continue to be harmed by [this research] because they’re told by physicians that antibiotics don’t work.”
A 2012 biostatistical review of these four RCTs — trials that helped inform the 2006 IDSA treatment guidelines — concluded that the Klempner studies “set the bar for treatment success too high,” Ms. Johnson said. Three of the four trials were likely underpowered to detect clinically meaningful treatment effects, the review also found.
The NASEM committee will hold additional public meetings and review a wide range of literature through this year. The formation of the committee was recommended by the US Department of Health and Human Services Tick-Borne Disease Working Group that was established by Congress in 2016 and concluded its work in 2022. The committee’s work is funded by the Cohen Foundation.
A version of this article appeared on Medscape.com.
High Blood Sugar May Drive Dementia, German Researchers Warn
On World Brain Day (July 22, 2024), the German Society of Neurology (DGN) and the German Brain Foundation pointed out that too much sugar can harm the brain. The current results of the Global Burden of Diseases study shows that stroke and dementia are among the top 10 causes of death. A healthy, active lifestyle with sufficient exercise and sleep, along with the avoidance of harmful substances like alcohol, nicotine, or excessive sugar, protects the brain.
“Of course, the dose makes the poison as the brain, being the body’s powerhouse, needs glucose to function,” said Frank Erbguth, MD, PhD, president of the German Brain Foundation, in a press release from DGN and the German Brain Foundation. “However, with a permanent increase in blood sugar levels due to too many, too lavish meals and constant snacking on the side, we overload the system and fuel the development of neurologic diseases, particularly dementia and stroke.”
The per capita consumption of sugar was 33.2 kg in 2021/2022, which is almost twice the recommended amount. The German Nutrition Society recommends that no more than 10% of energy come from sugar. With a goal of 2000 kilocalories, that’s 50 g per day, or 18 kg per year. This total includes not only added sugar but also naturally occurring sugar, such as in fruits, honey, or juices.
What’s the Mechanism?
In Germany, around 250,000 people are diagnosed with dementia annually, and 15%-25% have vascular dementia. That proportion represents between 40,000 and 60,000 new cases each year.
In addition, glycosaminoglycans, which are complex sugar molecules, can directly impair cognition. They affect the function of synapses between nerve cells and, thus, affect neuronal plasticity. Experimental data presented at the 2023 American Chemical Society Congress have shown this phenomenon.
Twenty years ago, a study provided evidence that a diet high in fat and sugar disrupts neuronal plasticity and can impair the function of the hippocampus in the long term. A recent meta-analysis confirms these findings: Although mental performance improves at 2-12 hours after sugar consumption, sustained sugar intake can permanently damage cognitive function.
Diabetes mellitus can indirectly cause brain damage. Since the 1990s, it has been known that patients with type 2 diabetes have a significantly higher risk for dementia. It is suspected that glucose metabolism is also disrupted in neurons, thus contributing to the development of Alzheimer’s disease. Insulin also plays a role in the formation of Alzheimer’s plaques.
The Max Planck Institute for Metabolism Research demonstrated in 2023 that regular consumption of high-sugar and high-fat foods can change the brain. This leads to an increased craving for high-sugar and high-fat foods, which in turn promotes the development of obesity and type 2 diabetes.
Reduce Sugar Consumption
DGN and the German Brain Foundation advise minimizing sugar consumption. This process is often challenging, as even a small dose of sugar can trigger the gut to send signals to the brain via the vagus nerve, thus causing a strong craving for more sugar. “This could be the reason why some people quickly eat a whole chocolate bar after just one piece,” said Dr. Erbguth. In addition, dopamine, a “feel-good hormone,” is released in the brain when consuming sugar, thus leading to a desire for more.
“It is wise to break free from this cycle by largely avoiding sugar,” said Peter Berlit, MD, secretary general and spokesperson for DGN. “The effort is worth it, as 40% of all dementia cases and 90% of all strokes are preventable, with many of them linked to industrial sugar,” said Dr. Berlit. DGN and the German Brain Foundation support the call for a tax on particularly sugary beverages. They also pointed out that foods like yogurt or tomato ketchup contain sugar, and alcohol can also significantly raise blood sugar levels.
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
On World Brain Day (July 22, 2024), the German Society of Neurology (DGN) and the German Brain Foundation pointed out that too much sugar can harm the brain. The current results of the Global Burden of Diseases study shows that stroke and dementia are among the top 10 causes of death. A healthy, active lifestyle with sufficient exercise and sleep, along with the avoidance of harmful substances like alcohol, nicotine, or excessive sugar, protects the brain.
“Of course, the dose makes the poison as the brain, being the body’s powerhouse, needs glucose to function,” said Frank Erbguth, MD, PhD, president of the German Brain Foundation, in a press release from DGN and the German Brain Foundation. “However, with a permanent increase in blood sugar levels due to too many, too lavish meals and constant snacking on the side, we overload the system and fuel the development of neurologic diseases, particularly dementia and stroke.”
The per capita consumption of sugar was 33.2 kg in 2021/2022, which is almost twice the recommended amount. The German Nutrition Society recommends that no more than 10% of energy come from sugar. With a goal of 2000 kilocalories, that’s 50 g per day, or 18 kg per year. This total includes not only added sugar but also naturally occurring sugar, such as in fruits, honey, or juices.
What’s the Mechanism?
In Germany, around 250,000 people are diagnosed with dementia annually, and 15%-25% have vascular dementia. That proportion represents between 40,000 and 60,000 new cases each year.
In addition, glycosaminoglycans, which are complex sugar molecules, can directly impair cognition. They affect the function of synapses between nerve cells and, thus, affect neuronal plasticity. Experimental data presented at the 2023 American Chemical Society Congress have shown this phenomenon.
Twenty years ago, a study provided evidence that a diet high in fat and sugar disrupts neuronal plasticity and can impair the function of the hippocampus in the long term. A recent meta-analysis confirms these findings: Although mental performance improves at 2-12 hours after sugar consumption, sustained sugar intake can permanently damage cognitive function.
Diabetes mellitus can indirectly cause brain damage. Since the 1990s, it has been known that patients with type 2 diabetes have a significantly higher risk for dementia. It is suspected that glucose metabolism is also disrupted in neurons, thus contributing to the development of Alzheimer’s disease. Insulin also plays a role in the formation of Alzheimer’s plaques.
The Max Planck Institute for Metabolism Research demonstrated in 2023 that regular consumption of high-sugar and high-fat foods can change the brain. This leads to an increased craving for high-sugar and high-fat foods, which in turn promotes the development of obesity and type 2 diabetes.
Reduce Sugar Consumption
DGN and the German Brain Foundation advise minimizing sugar consumption. This process is often challenging, as even a small dose of sugar can trigger the gut to send signals to the brain via the vagus nerve, thus causing a strong craving for more sugar. “This could be the reason why some people quickly eat a whole chocolate bar after just one piece,” said Dr. Erbguth. In addition, dopamine, a “feel-good hormone,” is released in the brain when consuming sugar, thus leading to a desire for more.
“It is wise to break free from this cycle by largely avoiding sugar,” said Peter Berlit, MD, secretary general and spokesperson for DGN. “The effort is worth it, as 40% of all dementia cases and 90% of all strokes are preventable, with many of them linked to industrial sugar,” said Dr. Berlit. DGN and the German Brain Foundation support the call for a tax on particularly sugary beverages. They also pointed out that foods like yogurt or tomato ketchup contain sugar, and alcohol can also significantly raise blood sugar levels.
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
On World Brain Day (July 22, 2024), the German Society of Neurology (DGN) and the German Brain Foundation pointed out that too much sugar can harm the brain. The current results of the Global Burden of Diseases study shows that stroke and dementia are among the top 10 causes of death. A healthy, active lifestyle with sufficient exercise and sleep, along with the avoidance of harmful substances like alcohol, nicotine, or excessive sugar, protects the brain.
“Of course, the dose makes the poison as the brain, being the body’s powerhouse, needs glucose to function,” said Frank Erbguth, MD, PhD, president of the German Brain Foundation, in a press release from DGN and the German Brain Foundation. “However, with a permanent increase in blood sugar levels due to too many, too lavish meals and constant snacking on the side, we overload the system and fuel the development of neurologic diseases, particularly dementia and stroke.”
The per capita consumption of sugar was 33.2 kg in 2021/2022, which is almost twice the recommended amount. The German Nutrition Society recommends that no more than 10% of energy come from sugar. With a goal of 2000 kilocalories, that’s 50 g per day, or 18 kg per year. This total includes not only added sugar but also naturally occurring sugar, such as in fruits, honey, or juices.
What’s the Mechanism?
In Germany, around 250,000 people are diagnosed with dementia annually, and 15%-25% have vascular dementia. That proportion represents between 40,000 and 60,000 new cases each year.
In addition, glycosaminoglycans, which are complex sugar molecules, can directly impair cognition. They affect the function of synapses between nerve cells and, thus, affect neuronal plasticity. Experimental data presented at the 2023 American Chemical Society Congress have shown this phenomenon.
Twenty years ago, a study provided evidence that a diet high in fat and sugar disrupts neuronal plasticity and can impair the function of the hippocampus in the long term. A recent meta-analysis confirms these findings: Although mental performance improves at 2-12 hours after sugar consumption, sustained sugar intake can permanently damage cognitive function.
Diabetes mellitus can indirectly cause brain damage. Since the 1990s, it has been known that patients with type 2 diabetes have a significantly higher risk for dementia. It is suspected that glucose metabolism is also disrupted in neurons, thus contributing to the development of Alzheimer’s disease. Insulin also plays a role in the formation of Alzheimer’s plaques.
The Max Planck Institute for Metabolism Research demonstrated in 2023 that regular consumption of high-sugar and high-fat foods can change the brain. This leads to an increased craving for high-sugar and high-fat foods, which in turn promotes the development of obesity and type 2 diabetes.
Reduce Sugar Consumption
DGN and the German Brain Foundation advise minimizing sugar consumption. This process is often challenging, as even a small dose of sugar can trigger the gut to send signals to the brain via the vagus nerve, thus causing a strong craving for more sugar. “This could be the reason why some people quickly eat a whole chocolate bar after just one piece,” said Dr. Erbguth. In addition, dopamine, a “feel-good hormone,” is released in the brain when consuming sugar, thus leading to a desire for more.
“It is wise to break free from this cycle by largely avoiding sugar,” said Peter Berlit, MD, secretary general and spokesperson for DGN. “The effort is worth it, as 40% of all dementia cases and 90% of all strokes are preventable, with many of them linked to industrial sugar,” said Dr. Berlit. DGN and the German Brain Foundation support the call for a tax on particularly sugary beverages. They also pointed out that foods like yogurt or tomato ketchup contain sugar, and alcohol can also significantly raise blood sugar levels.
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Black Women With Breast Cancer Face Clinical Inequities
Black metastatic breast cancer patients with PIK3CA mutations were less likely to receive targeted therapy and less likely to be enrolled in clinical trials than White patients and had shorter overall survival, according to a retrospective cohort study. Black and White patients were equally likely to receive other drugs that did not require genomic testing.
“These clinical inequities in the use of targeted therapies and clinical trials ... must be a focus going forward,” said lead investigator Emily Podany, MD, a clinical fellow in hematology-oncology at Washington University in St. Louis, Missouri. “Our consortium is looking for paths forward in order to try and decrease these striking inequities. And it’s a focus of future research for us and future implementation [of] science interventions, hopefully, across the country.”
The study results were presented at the annual meeting of the American Society of Clinical Oncology.
Black Women Underrepresented
Black women are generally underrepresented in clinical trials, noted Dr. Podany. “They make up about 2%-5% of the patients in breast cancer clinical trials, and there are documented inequities in treatment and in outcomes for Black patients with metastatic breast cancer. This includes longer treatment delays, it includes fewer sentinel lymph node biopsies, and unfortunately, they’re more likely to discontinue treatment early.”
In terms of PI3K inhibition, PIK3CA mutations are found in about 40% of patients with HR-positive HER2-negative metastatic breast cancer. Alpelisib is FDA-approved as a targeted therapy for these patients, she said.
The study evaluated records of 1327 patients with metastatic breast cancer who also had circulating tumor DNA (ctDNA) results and were treated at Washington University, Massachusetts General Hospital in Boston, and Northwestern University in Chicago. Of these, 795 had an ER-positive, HER2-negative subtype and were included in the analysis. Most (89%) of the patients were White (n = 708), while 11% (n = 87) were Black, and the only baseline difference between patients was that Black patients had significantly more de novo metastatic breast cancer (31% versus 22%).
Use of PI3K, CDK4/6, or mTOR inhibitors was evaluated using manual electronic medical review, and genomic differences were evaluated using logistic regression.
The analysis showed inequities in both treatment and clinical trial enrollment. There were no differences between groups in the use of CDK4/6 or mTOR inhibitors, which do not require a genomic profile, the researchers noted, but Black patients with PIK3CA single nucleotide variants (SNV) were significantly less likely than White patients to use PI3K inhibitors (5.9% versus 28.8%; P = .045), despite no difference in PIK3CA mutations between groups (36% and 34% respectively). Similarly, 11% of White patients with PIK3CA mutations were enrolled in clinical trials, but none of the Black patients was.
Genomic differences were also found, Dr. Podany reported. Black patients with estrogen/progesterone receptor (ER/PR) positive, HER2-negative disease were more likely to have a CCND1 copy number variant. And for ER-positive PR-negative HER2-negative patients, Black patients were more likely to have a GATA3 SNV, while White patients were more likely to have a KRAS copy number variant.
Black Survival Less Than Half
The analysis also found significant differences in overall survival from the time of the first liquid biopsy, with White ER-positive, PR-negative, HER2-negative patients living a median of 21 months, versus 9.1 months for Black patients.
There were several limitations to the study beyond its retrospective nature, “so, we may be underestimating the true inequity,” noted Dr. Podany. “These are large urban academic centers, so our patients have access to these treatments. They have access to care. They have access to ctDNA liquid biopsy testing. And the timing of ctDNA, especially the first ctDNA test, is variable and provider-dependant. We were also unable to assess receipt of PI3 kinase inhibitors at future time points after the end of this cohort study.”
Asked for comment, Giuseppe Del Priore, MD, MPH, from Morehouse School of Medicine in Atlanta, Georgia, approved of the study design “with subjects limited to three distinctive institutions. That parameter alone can control for several unknown variables among the studied comparison groups, ie, Black women versus others.”
However, Dr. Del Priore, who is adjunct professor of obstetrics and gynecology, with a specialty in oncology, added, “retrospective studies are not reliable except for generating hypotheses. Therefore, I would like to see a rapid implementation of an intervention trial at these same institutions to ensure equal consideration of, and access to, targeted therapies. Too often a retrospective correlation is reported, but the solution is elusive due to unknown factors. In this case, knowing there is a mutation is far from alleviating the disproportionate burden of disease that many communities face.”
Dr. Podany had no relevant disclosures. Dr. Del Priore reported no conflicts of interest and disclosed that he is chief medical officer at BriaCell.
Black metastatic breast cancer patients with PIK3CA mutations were less likely to receive targeted therapy and less likely to be enrolled in clinical trials than White patients and had shorter overall survival, according to a retrospective cohort study. Black and White patients were equally likely to receive other drugs that did not require genomic testing.
“These clinical inequities in the use of targeted therapies and clinical trials ... must be a focus going forward,” said lead investigator Emily Podany, MD, a clinical fellow in hematology-oncology at Washington University in St. Louis, Missouri. “Our consortium is looking for paths forward in order to try and decrease these striking inequities. And it’s a focus of future research for us and future implementation [of] science interventions, hopefully, across the country.”
The study results were presented at the annual meeting of the American Society of Clinical Oncology.
Black Women Underrepresented
Black women are generally underrepresented in clinical trials, noted Dr. Podany. “They make up about 2%-5% of the patients in breast cancer clinical trials, and there are documented inequities in treatment and in outcomes for Black patients with metastatic breast cancer. This includes longer treatment delays, it includes fewer sentinel lymph node biopsies, and unfortunately, they’re more likely to discontinue treatment early.”
In terms of PI3K inhibition, PIK3CA mutations are found in about 40% of patients with HR-positive HER2-negative metastatic breast cancer. Alpelisib is FDA-approved as a targeted therapy for these patients, she said.
The study evaluated records of 1327 patients with metastatic breast cancer who also had circulating tumor DNA (ctDNA) results and were treated at Washington University, Massachusetts General Hospital in Boston, and Northwestern University in Chicago. Of these, 795 had an ER-positive, HER2-negative subtype and were included in the analysis. Most (89%) of the patients were White (n = 708), while 11% (n = 87) were Black, and the only baseline difference between patients was that Black patients had significantly more de novo metastatic breast cancer (31% versus 22%).
Use of PI3K, CDK4/6, or mTOR inhibitors was evaluated using manual electronic medical review, and genomic differences were evaluated using logistic regression.
The analysis showed inequities in both treatment and clinical trial enrollment. There were no differences between groups in the use of CDK4/6 or mTOR inhibitors, which do not require a genomic profile, the researchers noted, but Black patients with PIK3CA single nucleotide variants (SNV) were significantly less likely than White patients to use PI3K inhibitors (5.9% versus 28.8%; P = .045), despite no difference in PIK3CA mutations between groups (36% and 34% respectively). Similarly, 11% of White patients with PIK3CA mutations were enrolled in clinical trials, but none of the Black patients was.
Genomic differences were also found, Dr. Podany reported. Black patients with estrogen/progesterone receptor (ER/PR) positive, HER2-negative disease were more likely to have a CCND1 copy number variant. And for ER-positive PR-negative HER2-negative patients, Black patients were more likely to have a GATA3 SNV, while White patients were more likely to have a KRAS copy number variant.
Black Survival Less Than Half
The analysis also found significant differences in overall survival from the time of the first liquid biopsy, with White ER-positive, PR-negative, HER2-negative patients living a median of 21 months, versus 9.1 months for Black patients.
There were several limitations to the study beyond its retrospective nature, “so, we may be underestimating the true inequity,” noted Dr. Podany. “These are large urban academic centers, so our patients have access to these treatments. They have access to care. They have access to ctDNA liquid biopsy testing. And the timing of ctDNA, especially the first ctDNA test, is variable and provider-dependant. We were also unable to assess receipt of PI3 kinase inhibitors at future time points after the end of this cohort study.”
Asked for comment, Giuseppe Del Priore, MD, MPH, from Morehouse School of Medicine in Atlanta, Georgia, approved of the study design “with subjects limited to three distinctive institutions. That parameter alone can control for several unknown variables among the studied comparison groups, ie, Black women versus others.”
However, Dr. Del Priore, who is adjunct professor of obstetrics and gynecology, with a specialty in oncology, added, “retrospective studies are not reliable except for generating hypotheses. Therefore, I would like to see a rapid implementation of an intervention trial at these same institutions to ensure equal consideration of, and access to, targeted therapies. Too often a retrospective correlation is reported, but the solution is elusive due to unknown factors. In this case, knowing there is a mutation is far from alleviating the disproportionate burden of disease that many communities face.”
Dr. Podany had no relevant disclosures. Dr. Del Priore reported no conflicts of interest and disclosed that he is chief medical officer at BriaCell.
Black metastatic breast cancer patients with PIK3CA mutations were less likely to receive targeted therapy and less likely to be enrolled in clinical trials than White patients and had shorter overall survival, according to a retrospective cohort study. Black and White patients were equally likely to receive other drugs that did not require genomic testing.
“These clinical inequities in the use of targeted therapies and clinical trials ... must be a focus going forward,” said lead investigator Emily Podany, MD, a clinical fellow in hematology-oncology at Washington University in St. Louis, Missouri. “Our consortium is looking for paths forward in order to try and decrease these striking inequities. And it’s a focus of future research for us and future implementation [of] science interventions, hopefully, across the country.”
The study results were presented at the annual meeting of the American Society of Clinical Oncology.
Black Women Underrepresented
Black women are generally underrepresented in clinical trials, noted Dr. Podany. “They make up about 2%-5% of the patients in breast cancer clinical trials, and there are documented inequities in treatment and in outcomes for Black patients with metastatic breast cancer. This includes longer treatment delays, it includes fewer sentinel lymph node biopsies, and unfortunately, they’re more likely to discontinue treatment early.”
In terms of PI3K inhibition, PIK3CA mutations are found in about 40% of patients with HR-positive HER2-negative metastatic breast cancer. Alpelisib is FDA-approved as a targeted therapy for these patients, she said.
The study evaluated records of 1327 patients with metastatic breast cancer who also had circulating tumor DNA (ctDNA) results and were treated at Washington University, Massachusetts General Hospital in Boston, and Northwestern University in Chicago. Of these, 795 had an ER-positive, HER2-negative subtype and were included in the analysis. Most (89%) of the patients were White (n = 708), while 11% (n = 87) were Black, and the only baseline difference between patients was that Black patients had significantly more de novo metastatic breast cancer (31% versus 22%).
Use of PI3K, CDK4/6, or mTOR inhibitors was evaluated using manual electronic medical review, and genomic differences were evaluated using logistic regression.
The analysis showed inequities in both treatment and clinical trial enrollment. There were no differences between groups in the use of CDK4/6 or mTOR inhibitors, which do not require a genomic profile, the researchers noted, but Black patients with PIK3CA single nucleotide variants (SNV) were significantly less likely than White patients to use PI3K inhibitors (5.9% versus 28.8%; P = .045), despite no difference in PIK3CA mutations between groups (36% and 34% respectively). Similarly, 11% of White patients with PIK3CA mutations were enrolled in clinical trials, but none of the Black patients was.
Genomic differences were also found, Dr. Podany reported. Black patients with estrogen/progesterone receptor (ER/PR) positive, HER2-negative disease were more likely to have a CCND1 copy number variant. And for ER-positive PR-negative HER2-negative patients, Black patients were more likely to have a GATA3 SNV, while White patients were more likely to have a KRAS copy number variant.
Black Survival Less Than Half
The analysis also found significant differences in overall survival from the time of the first liquid biopsy, with White ER-positive, PR-negative, HER2-negative patients living a median of 21 months, versus 9.1 months for Black patients.
There were several limitations to the study beyond its retrospective nature, “so, we may be underestimating the true inequity,” noted Dr. Podany. “These are large urban academic centers, so our patients have access to these treatments. They have access to care. They have access to ctDNA liquid biopsy testing. And the timing of ctDNA, especially the first ctDNA test, is variable and provider-dependant. We were also unable to assess receipt of PI3 kinase inhibitors at future time points after the end of this cohort study.”
Asked for comment, Giuseppe Del Priore, MD, MPH, from Morehouse School of Medicine in Atlanta, Georgia, approved of the study design “with subjects limited to three distinctive institutions. That parameter alone can control for several unknown variables among the studied comparison groups, ie, Black women versus others.”
However, Dr. Del Priore, who is adjunct professor of obstetrics and gynecology, with a specialty in oncology, added, “retrospective studies are not reliable except for generating hypotheses. Therefore, I would like to see a rapid implementation of an intervention trial at these same institutions to ensure equal consideration of, and access to, targeted therapies. Too often a retrospective correlation is reported, but the solution is elusive due to unknown factors. In this case, knowing there is a mutation is far from alleviating the disproportionate burden of disease that many communities face.”
Dr. Podany had no relevant disclosures. Dr. Del Priore reported no conflicts of interest and disclosed that he is chief medical officer at BriaCell.
FROM ASCO 2024
Gluconolactone
This derivative of oxidized glucose lactone is present naturally in bread, cheese, fruit juices, honey, tofu, and wine, and is used as a food additive in Europe.1,2 In dermatology, it is most often used in chemical peels.
Polyhydroxy acids (PHAs) were discovered about 3 decades ago to exert similar functions as alpha hydroxy acids without provoking sensory irritation reactions. Gluconolactone along with lactobionic acid were the identified PHAs and further characterized as delivering more humectant and moisturizing activity than alpha hydroxy acids and effective in combination with retinoic acid to treat adult acne and with retinyl acetate to confer antiaging benefits.3 It is typically added to products for its skin-conditioning qualities, resulting in smoother, brighter, more toned skin.4 This column focuses on recent studies using this bioactive agent for dermatologic purposes.
Split-Face Studies Show Various Benefits
In 2023, Jarząbek-Perz and colleagues conducted a split-face evaluation to assess the effects on various skin parameters (ie, hydration, pH, sebum, and transepidermal water loss [TEWL]) of gluconolactone and oxybrasion, compared with gluconolactone and microneedling. Twenty-one White women underwent a series of three split-face treatments at 1-week intervals. Chemical peels with 10% gluconolactone were performed on the whole face. The right side of the face was also treated with oxybrasion and the left with microneedle mesotherapy. Skin parameters were measured before the first and third treatments and 2 weeks following the final treatment. Photos were taken before and after the study. Both treatments resulted in improved hydration and reductions in sebum, pH, and TEWL. No statistically significant differences were noted between the treatment protocols. The researchers concluded that gluconolactone peels can be effectively combined with oxybrasion or microneedle mesotherapy to enhance skin hydration and to secure the hydrolipid barrier.5
Later that year, the same team evaluated pH, sebum levels, and TEWL before, during, and after several applications of 10% and 30% gluconolactone chemical peels in a split-face model in 16 female participants. The investigators conducted three procedures on both sides of the face, taking measurements on the forehead, periorbital area, on the cheek, and on the nose wing before, during, and 7 days after the final treatment. They found statistically significant improvements in sebum levels in the cheeks after the treatment series. Also, pH values were lower at each measurement site after each procedure. TEWL levels were significantly diminished around the eyes, as well as the left forehead and right cheek, with no significant discrepancy between gluconolactone concentrations. The researchers concluded that gluconolactone plays a major role in reducing cutaneous pH and TEWL and imparts a regulatory effect on sebum.1
Two years earlier, Jarząbek-Perz and colleagues assessed skin moisture in a split-face model in 16 healthy women after the application of 10% and 30% gluconolactone. Investigators measured skin moisture before and after each of three treatments and a week after the final treatment from the forehead, periorbital area, and on the cheek. They observed no significant discrepancies between the 10% and 30% formulations, but a significant elevation in facial skin hydration was found to be promoted by gluconolactone. The investigators concluded that gluconolactone is an effective moisturizer for care of dry skin.6
Topical Formulation
In 2023, Zerbinati and colleagues determined that a gluconolactone-based lotion that they had begun testing 2 years earlier was safe and effective for dermatologic applications, with the noncomedogenic formulation found suitable as an antiaging agent, particularly as it treats aging-related pore dilatation.7,8
Acne Treatment
In 2019, Kantikosum and colleagues conducted a double-blind, within-person comparative study to assess the efficacy of various cosmeceutical ingredients, including gluconolactone, glycolic acid, licochalcone A, and salicylic acid, combined with the acne treatment adapalene vs adapalene monotherapy for mild to moderate acne. Each of 25 subjects over 28 days applied a product mixed with 0.1% adapalene on one side of the face, and 0.1% adapalene alone on the other side of the face once nightly. The VISIA camera system spot score pointed to a statistically significant improvement on the combination sides. Differences in lesion reduction and severity were within acceptable margins, the authors reported. They concluded that the cosmeceutical combinations yielded similar benefits as adapalene alone, with the combination formulations decreasing acne complications.9
Potential Use as an Antifibrotic Agent
In 2018, Jayamani and colleagues investigated the antifibrotic characteristics of glucono-delta-lactone, a known acidifier, to ascertain if it could directly suppress collagen fibrils or even cause them to disintegrate. The researchers noted that collagen fibrillation is pH dependent, and that glucono-delta-lactone was found to exert a concentration-dependent suppression of fibrils and disintegration of preformed collagen fibrils with the antifibrotic function of the compound ascribed to its capacity to decrease pH. Further, glucono-delta-lactone appeared to emerge as an ideal antifibrotic agent as it left intact the triple helical structure of collagen after treatment. The investigators concluded that glucono-delta-lactone provides the foundation for developing antifibrotic agents intended to treat disorders characterized by collagen deposition.10
Conclusion
Gluconolactone emerged in the 1990s as a PHA useful in skin peels as an alternative to alpha hydroxy acids because of its nonirritating qualities. Since then, its soothing, hydrating, and, in particular, antiacne and antiaging qualities have become established. Wider applications of this versatile agent for dermatologic purposes are likely to be further investigated.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions, a SaaS company used to generate skin care routines in office and as a ecommerce solution. Write to her at [email protected].
References
1. Jarząbek-Perz S et al. J Cosmet Dermatol. 2023 Dec;22(12):3305-3312..
2. Qin X et al. Front Physiol. 2022 Mar 14;13:856699.
3. Grimes PE et al. Cutis. 2004 Feb;73(2 Suppl):3-13.
4. Glaser DA. Facial Plast Surg Clin North Am. 2003 May;11(2):219-227.
5. Jarząbek-Perz S et al. Skin Res Technol. 2023 Jun;29(6):e13353.
6. Jarząbek-Perz S et al. Skin Res Technol. 2021 Sep;27(5):925-930.
7. Zerbinati N et al. Molecules. 2021 Dec 15;26(24):7592.
8. Zerbinati Net al. Pharmaceuticals (Basel). 2023 Apr 27;16(5):655.
9. Kantikosum K et al. Clin Cosmet Investig Dermatol. 2019 Feb 19;12:151-161.
10. Jayamani J et al. Int J Biol Macromol. 2018 Feb;107(Pt A):175-185.
This derivative of oxidized glucose lactone is present naturally in bread, cheese, fruit juices, honey, tofu, and wine, and is used as a food additive in Europe.1,2 In dermatology, it is most often used in chemical peels.
Polyhydroxy acids (PHAs) were discovered about 3 decades ago to exert similar functions as alpha hydroxy acids without provoking sensory irritation reactions. Gluconolactone along with lactobionic acid were the identified PHAs and further characterized as delivering more humectant and moisturizing activity than alpha hydroxy acids and effective in combination with retinoic acid to treat adult acne and with retinyl acetate to confer antiaging benefits.3 It is typically added to products for its skin-conditioning qualities, resulting in smoother, brighter, more toned skin.4 This column focuses on recent studies using this bioactive agent for dermatologic purposes.
Split-Face Studies Show Various Benefits
In 2023, Jarząbek-Perz and colleagues conducted a split-face evaluation to assess the effects on various skin parameters (ie, hydration, pH, sebum, and transepidermal water loss [TEWL]) of gluconolactone and oxybrasion, compared with gluconolactone and microneedling. Twenty-one White women underwent a series of three split-face treatments at 1-week intervals. Chemical peels with 10% gluconolactone were performed on the whole face. The right side of the face was also treated with oxybrasion and the left with microneedle mesotherapy. Skin parameters were measured before the first and third treatments and 2 weeks following the final treatment. Photos were taken before and after the study. Both treatments resulted in improved hydration and reductions in sebum, pH, and TEWL. No statistically significant differences were noted between the treatment protocols. The researchers concluded that gluconolactone peels can be effectively combined with oxybrasion or microneedle mesotherapy to enhance skin hydration and to secure the hydrolipid barrier.5
Later that year, the same team evaluated pH, sebum levels, and TEWL before, during, and after several applications of 10% and 30% gluconolactone chemical peels in a split-face model in 16 female participants. The investigators conducted three procedures on both sides of the face, taking measurements on the forehead, periorbital area, on the cheek, and on the nose wing before, during, and 7 days after the final treatment. They found statistically significant improvements in sebum levels in the cheeks after the treatment series. Also, pH values were lower at each measurement site after each procedure. TEWL levels were significantly diminished around the eyes, as well as the left forehead and right cheek, with no significant discrepancy between gluconolactone concentrations. The researchers concluded that gluconolactone plays a major role in reducing cutaneous pH and TEWL and imparts a regulatory effect on sebum.1
Two years earlier, Jarząbek-Perz and colleagues assessed skin moisture in a split-face model in 16 healthy women after the application of 10% and 30% gluconolactone. Investigators measured skin moisture before and after each of three treatments and a week after the final treatment from the forehead, periorbital area, and on the cheek. They observed no significant discrepancies between the 10% and 30% formulations, but a significant elevation in facial skin hydration was found to be promoted by gluconolactone. The investigators concluded that gluconolactone is an effective moisturizer for care of dry skin.6
Topical Formulation
In 2023, Zerbinati and colleagues determined that a gluconolactone-based lotion that they had begun testing 2 years earlier was safe and effective for dermatologic applications, with the noncomedogenic formulation found suitable as an antiaging agent, particularly as it treats aging-related pore dilatation.7,8
Acne Treatment
In 2019, Kantikosum and colleagues conducted a double-blind, within-person comparative study to assess the efficacy of various cosmeceutical ingredients, including gluconolactone, glycolic acid, licochalcone A, and salicylic acid, combined with the acne treatment adapalene vs adapalene monotherapy for mild to moderate acne. Each of 25 subjects over 28 days applied a product mixed with 0.1% adapalene on one side of the face, and 0.1% adapalene alone on the other side of the face once nightly. The VISIA camera system spot score pointed to a statistically significant improvement on the combination sides. Differences in lesion reduction and severity were within acceptable margins, the authors reported. They concluded that the cosmeceutical combinations yielded similar benefits as adapalene alone, with the combination formulations decreasing acne complications.9
Potential Use as an Antifibrotic Agent
In 2018, Jayamani and colleagues investigated the antifibrotic characteristics of glucono-delta-lactone, a known acidifier, to ascertain if it could directly suppress collagen fibrils or even cause them to disintegrate. The researchers noted that collagen fibrillation is pH dependent, and that glucono-delta-lactone was found to exert a concentration-dependent suppression of fibrils and disintegration of preformed collagen fibrils with the antifibrotic function of the compound ascribed to its capacity to decrease pH. Further, glucono-delta-lactone appeared to emerge as an ideal antifibrotic agent as it left intact the triple helical structure of collagen after treatment. The investigators concluded that glucono-delta-lactone provides the foundation for developing antifibrotic agents intended to treat disorders characterized by collagen deposition.10
Conclusion
Gluconolactone emerged in the 1990s as a PHA useful in skin peels as an alternative to alpha hydroxy acids because of its nonirritating qualities. Since then, its soothing, hydrating, and, in particular, antiacne and antiaging qualities have become established. Wider applications of this versatile agent for dermatologic purposes are likely to be further investigated.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions, a SaaS company used to generate skin care routines in office and as a ecommerce solution. Write to her at [email protected].
References
1. Jarząbek-Perz S et al. J Cosmet Dermatol. 2023 Dec;22(12):3305-3312..
2. Qin X et al. Front Physiol. 2022 Mar 14;13:856699.
3. Grimes PE et al. Cutis. 2004 Feb;73(2 Suppl):3-13.
4. Glaser DA. Facial Plast Surg Clin North Am. 2003 May;11(2):219-227.
5. Jarząbek-Perz S et al. Skin Res Technol. 2023 Jun;29(6):e13353.
6. Jarząbek-Perz S et al. Skin Res Technol. 2021 Sep;27(5):925-930.
7. Zerbinati N et al. Molecules. 2021 Dec 15;26(24):7592.
8. Zerbinati Net al. Pharmaceuticals (Basel). 2023 Apr 27;16(5):655.
9. Kantikosum K et al. Clin Cosmet Investig Dermatol. 2019 Feb 19;12:151-161.
10. Jayamani J et al. Int J Biol Macromol. 2018 Feb;107(Pt A):175-185.
This derivative of oxidized glucose lactone is present naturally in bread, cheese, fruit juices, honey, tofu, and wine, and is used as a food additive in Europe.1,2 In dermatology, it is most often used in chemical peels.
Polyhydroxy acids (PHAs) were discovered about 3 decades ago to exert similar functions as alpha hydroxy acids without provoking sensory irritation reactions. Gluconolactone along with lactobionic acid were the identified PHAs and further characterized as delivering more humectant and moisturizing activity than alpha hydroxy acids and effective in combination with retinoic acid to treat adult acne and with retinyl acetate to confer antiaging benefits.3 It is typically added to products for its skin-conditioning qualities, resulting in smoother, brighter, more toned skin.4 This column focuses on recent studies using this bioactive agent for dermatologic purposes.
Split-Face Studies Show Various Benefits
In 2023, Jarząbek-Perz and colleagues conducted a split-face evaluation to assess the effects on various skin parameters (ie, hydration, pH, sebum, and transepidermal water loss [TEWL]) of gluconolactone and oxybrasion, compared with gluconolactone and microneedling. Twenty-one White women underwent a series of three split-face treatments at 1-week intervals. Chemical peels with 10% gluconolactone were performed on the whole face. The right side of the face was also treated with oxybrasion and the left with microneedle mesotherapy. Skin parameters were measured before the first and third treatments and 2 weeks following the final treatment. Photos were taken before and after the study. Both treatments resulted in improved hydration and reductions in sebum, pH, and TEWL. No statistically significant differences were noted between the treatment protocols. The researchers concluded that gluconolactone peels can be effectively combined with oxybrasion or microneedle mesotherapy to enhance skin hydration and to secure the hydrolipid barrier.5
Later that year, the same team evaluated pH, sebum levels, and TEWL before, during, and after several applications of 10% and 30% gluconolactone chemical peels in a split-face model in 16 female participants. The investigators conducted three procedures on both sides of the face, taking measurements on the forehead, periorbital area, on the cheek, and on the nose wing before, during, and 7 days after the final treatment. They found statistically significant improvements in sebum levels in the cheeks after the treatment series. Also, pH values were lower at each measurement site after each procedure. TEWL levels were significantly diminished around the eyes, as well as the left forehead and right cheek, with no significant discrepancy between gluconolactone concentrations. The researchers concluded that gluconolactone plays a major role in reducing cutaneous pH and TEWL and imparts a regulatory effect on sebum.1
Two years earlier, Jarząbek-Perz and colleagues assessed skin moisture in a split-face model in 16 healthy women after the application of 10% and 30% gluconolactone. Investigators measured skin moisture before and after each of three treatments and a week after the final treatment from the forehead, periorbital area, and on the cheek. They observed no significant discrepancies between the 10% and 30% formulations, but a significant elevation in facial skin hydration was found to be promoted by gluconolactone. The investigators concluded that gluconolactone is an effective moisturizer for care of dry skin.6
Topical Formulation
In 2023, Zerbinati and colleagues determined that a gluconolactone-based lotion that they had begun testing 2 years earlier was safe and effective for dermatologic applications, with the noncomedogenic formulation found suitable as an antiaging agent, particularly as it treats aging-related pore dilatation.7,8
Acne Treatment
In 2019, Kantikosum and colleagues conducted a double-blind, within-person comparative study to assess the efficacy of various cosmeceutical ingredients, including gluconolactone, glycolic acid, licochalcone A, and salicylic acid, combined with the acne treatment adapalene vs adapalene monotherapy for mild to moderate acne. Each of 25 subjects over 28 days applied a product mixed with 0.1% adapalene on one side of the face, and 0.1% adapalene alone on the other side of the face once nightly. The VISIA camera system spot score pointed to a statistically significant improvement on the combination sides. Differences in lesion reduction and severity were within acceptable margins, the authors reported. They concluded that the cosmeceutical combinations yielded similar benefits as adapalene alone, with the combination formulations decreasing acne complications.9
Potential Use as an Antifibrotic Agent
In 2018, Jayamani and colleagues investigated the antifibrotic characteristics of glucono-delta-lactone, a known acidifier, to ascertain if it could directly suppress collagen fibrils or even cause them to disintegrate. The researchers noted that collagen fibrillation is pH dependent, and that glucono-delta-lactone was found to exert a concentration-dependent suppression of fibrils and disintegration of preformed collagen fibrils with the antifibrotic function of the compound ascribed to its capacity to decrease pH. Further, glucono-delta-lactone appeared to emerge as an ideal antifibrotic agent as it left intact the triple helical structure of collagen after treatment. The investigators concluded that glucono-delta-lactone provides the foundation for developing antifibrotic agents intended to treat disorders characterized by collagen deposition.10
Conclusion
Gluconolactone emerged in the 1990s as a PHA useful in skin peels as an alternative to alpha hydroxy acids because of its nonirritating qualities. Since then, its soothing, hydrating, and, in particular, antiacne and antiaging qualities have become established. Wider applications of this versatile agent for dermatologic purposes are likely to be further investigated.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions, a SaaS company used to generate skin care routines in office and as a ecommerce solution. Write to her at [email protected].
References
1. Jarząbek-Perz S et al. J Cosmet Dermatol. 2023 Dec;22(12):3305-3312..
2. Qin X et al. Front Physiol. 2022 Mar 14;13:856699.
3. Grimes PE et al. Cutis. 2004 Feb;73(2 Suppl):3-13.
4. Glaser DA. Facial Plast Surg Clin North Am. 2003 May;11(2):219-227.
5. Jarząbek-Perz S et al. Skin Res Technol. 2023 Jun;29(6):e13353.
6. Jarząbek-Perz S et al. Skin Res Technol. 2021 Sep;27(5):925-930.
7. Zerbinati N et al. Molecules. 2021 Dec 15;26(24):7592.
8. Zerbinati Net al. Pharmaceuticals (Basel). 2023 Apr 27;16(5):655.
9. Kantikosum K et al. Clin Cosmet Investig Dermatol. 2019 Feb 19;12:151-161.
10. Jayamani J et al. Int J Biol Macromol. 2018 Feb;107(Pt A):175-185.
Introducing: A New Way to Get Teens Mental Health Care
Lauren Opladen remembers the agonizing wait all too well.
At age 17, struggling with paralyzing depression after losing her brother to suicide and her father to amyotrophic lateral sclerosis, her teacher suggested she seek help.
So, she did. But she had to spend 3 days inside an emergency department at the University of Rochester Medical Center in Rochester, New York, where the Comprehensive Psychiatric Emergency Program (CPEP) provides immediate care for youth and adults experiencing psychiatric emergencies.
“We were sleeping on a couch just waiting for all these services, when that’s precious time wasted,” Ms. Opladen said.
Ms. Opladen made it through that dark period, and 5 years later, she is a registered nurse at the same hospital. Every day she walks past a new facility she wishes had existed during her troubled teenage years: An urgent care center for children and adolescents experiencing mental health crises.
Brighter Days Pediatric Mental Health Urgent Care Center, Rochester, New York, opened in July as a walk-in clinic offering rapid assessment, crisis intervention, and short-term stabilization, provides referrals to counseling or psychiatric care. Children and adolescents at immediate risk of harming themselves or others, or who need inpatient care, are sent to CPEP or another emergency department in the area.
Similar walk-in facilities linking youth to longer-term services are popping up in nearly a dozen states, including New York, Ohio, Massachusetts, and Wisconsin. The emerging model of care may offer a crucial bridge between traditional outpatient services and emergency room (ER) visits for some young people experiencing mental health crises.
“We’ve seen a significant increase in the number of children and adolescents presenting to emergency departments with mental health concerns,” said Michael A. Scharf, MD, chief of the Division of Child and Adolescent Psychiatry at the University of Rochester Medical Center, who oversees operations at Brighter Days. “These urgent care centers provide a more appropriate setting for many of these cases, offering specialized care without the often overwhelming environment of an ER.”
The urgency of addressing youth behavioral health has become increasingly apparent. The most recent data from the US Centers for Disease Control and Prevention showed that over a 6-month period in 2020, during the early months of the COVID-19 pandemic, visits to the emergency department for mental health problems spiked 24% among children aged 5-11 years and 31% among 12-17-year-olds compared with the same period in 2019. Between March 2021 and February 2022, such emergency visits rose by 22% for teen girls, while falling by 15% for boys ages 5-12 years and 9% for older boys. Most visits occur during the school year.
But staffing shortages and limited physical space are taxing the capacity of the healthcare system to screen, diagnose, and manage these patients, according to a 2023 report published in Pediatrics.
Urgent Care: A Misnomer?
Some in the mental health community said the label “urgent” in these centers’ titles is misleading. Brighter Days and similar facilities do not conduct involuntary holds, administer medication, or handle serious cases like psychotic episodes.
David Mathison, MD, senior vice president of clinic operations at PM Pediatrics, a chain of pediatric urgent care clinics in Maryland, said patients and their families may mistakenly believe the centers will address mental health problems quickly.
“It’s really not urgent behavioral health. It’s really just another access point to get behavioral health,” Dr. Mathison said. “Crises in pediatrics are so much more complex” than physical injuries or acute infections, which are the bread and butter of urgent care centers.
“An urgent care center almost implies you’re going to come in for a solution to a simple problem, and it’s going to be done relatively quickly on demand, and it’s just not what the behavioral health centers do,” he said.
Dr. Mathison, who also serves on the executive committee for the section on urgent care at the American Academy of Pediatrics, likened the centers to in-person versions of crisis center hotlines, which offer virtual counseling and talk therapy and may refer individuals to specialists who can provide clinical care over the long term.
Instead, Brighter Days and other centers provide crisis de-escalation for individuals experiencing an exacerbation of a diagnosed mental illness, such a manic episode from bipolar disorder.
“Most places aren’t just going to change their therapy without either contacting their psychiatrist or having psychiatrists on staff,” Dr. Mathison said.
Other challenges at Brighter Days and similar centers include staffing with appropriately trained mental health professionals, given the nationwide shortage of child and adolescent psychiatrists, Dr. Scharf said.
The number of child and adolescent psychiatrists per 100,000 children varies significantly across states. Nationally, the average stands at 14 psychiatrists per 100,000 children, but ranges from as low as 4 to 65, according to the American Academy of Child & Adolescent Psychiatry.
For now, Dr. Scharf said, patients who visit Brighter Days are billed as if they are having a routine pediatric office visit as opposed to a pricier trip to the emergency department. And the center accepts all individuals, regardless of their insurance status.
Ms. Opladen said the urgent care center represents a significant improvement over her experience at the emergency department’s psychiatric triage.
“I saw how awful it was and just the environment,” she said. “The first thing I thought was, what do I need to do to get out of here?”
She said the pediatric mental health urgent care centers are “the complete opposite.” Like Brighter Days, these centers are designed to look more like a pediatrician’s office, with bright welcoming colors and games and toys.
“It’s separated from everything else. There’s a welcome, relaxed space,” she said. “The welcoming feel is just a whole different environment, and that’s really how it should be.”
A version of this article first appeared on Medscape.com.
Lauren Opladen remembers the agonizing wait all too well.
At age 17, struggling with paralyzing depression after losing her brother to suicide and her father to amyotrophic lateral sclerosis, her teacher suggested she seek help.
So, she did. But she had to spend 3 days inside an emergency department at the University of Rochester Medical Center in Rochester, New York, where the Comprehensive Psychiatric Emergency Program (CPEP) provides immediate care for youth and adults experiencing psychiatric emergencies.
“We were sleeping on a couch just waiting for all these services, when that’s precious time wasted,” Ms. Opladen said.
Ms. Opladen made it through that dark period, and 5 years later, she is a registered nurse at the same hospital. Every day she walks past a new facility she wishes had existed during her troubled teenage years: An urgent care center for children and adolescents experiencing mental health crises.
Brighter Days Pediatric Mental Health Urgent Care Center, Rochester, New York, opened in July as a walk-in clinic offering rapid assessment, crisis intervention, and short-term stabilization, provides referrals to counseling or psychiatric care. Children and adolescents at immediate risk of harming themselves or others, or who need inpatient care, are sent to CPEP or another emergency department in the area.
Similar walk-in facilities linking youth to longer-term services are popping up in nearly a dozen states, including New York, Ohio, Massachusetts, and Wisconsin. The emerging model of care may offer a crucial bridge between traditional outpatient services and emergency room (ER) visits for some young people experiencing mental health crises.
“We’ve seen a significant increase in the number of children and adolescents presenting to emergency departments with mental health concerns,” said Michael A. Scharf, MD, chief of the Division of Child and Adolescent Psychiatry at the University of Rochester Medical Center, who oversees operations at Brighter Days. “These urgent care centers provide a more appropriate setting for many of these cases, offering specialized care without the often overwhelming environment of an ER.”
The urgency of addressing youth behavioral health has become increasingly apparent. The most recent data from the US Centers for Disease Control and Prevention showed that over a 6-month period in 2020, during the early months of the COVID-19 pandemic, visits to the emergency department for mental health problems spiked 24% among children aged 5-11 years and 31% among 12-17-year-olds compared with the same period in 2019. Between March 2021 and February 2022, such emergency visits rose by 22% for teen girls, while falling by 15% for boys ages 5-12 years and 9% for older boys. Most visits occur during the school year.
But staffing shortages and limited physical space are taxing the capacity of the healthcare system to screen, diagnose, and manage these patients, according to a 2023 report published in Pediatrics.
Urgent Care: A Misnomer?
Some in the mental health community said the label “urgent” in these centers’ titles is misleading. Brighter Days and similar facilities do not conduct involuntary holds, administer medication, or handle serious cases like psychotic episodes.
David Mathison, MD, senior vice president of clinic operations at PM Pediatrics, a chain of pediatric urgent care clinics in Maryland, said patients and their families may mistakenly believe the centers will address mental health problems quickly.
“It’s really not urgent behavioral health. It’s really just another access point to get behavioral health,” Dr. Mathison said. “Crises in pediatrics are so much more complex” than physical injuries or acute infections, which are the bread and butter of urgent care centers.
“An urgent care center almost implies you’re going to come in for a solution to a simple problem, and it’s going to be done relatively quickly on demand, and it’s just not what the behavioral health centers do,” he said.
Dr. Mathison, who also serves on the executive committee for the section on urgent care at the American Academy of Pediatrics, likened the centers to in-person versions of crisis center hotlines, which offer virtual counseling and talk therapy and may refer individuals to specialists who can provide clinical care over the long term.
Instead, Brighter Days and other centers provide crisis de-escalation for individuals experiencing an exacerbation of a diagnosed mental illness, such a manic episode from bipolar disorder.
“Most places aren’t just going to change their therapy without either contacting their psychiatrist or having psychiatrists on staff,” Dr. Mathison said.
Other challenges at Brighter Days and similar centers include staffing with appropriately trained mental health professionals, given the nationwide shortage of child and adolescent psychiatrists, Dr. Scharf said.
The number of child and adolescent psychiatrists per 100,000 children varies significantly across states. Nationally, the average stands at 14 psychiatrists per 100,000 children, but ranges from as low as 4 to 65, according to the American Academy of Child & Adolescent Psychiatry.
For now, Dr. Scharf said, patients who visit Brighter Days are billed as if they are having a routine pediatric office visit as opposed to a pricier trip to the emergency department. And the center accepts all individuals, regardless of their insurance status.
Ms. Opladen said the urgent care center represents a significant improvement over her experience at the emergency department’s psychiatric triage.
“I saw how awful it was and just the environment,” she said. “The first thing I thought was, what do I need to do to get out of here?”
She said the pediatric mental health urgent care centers are “the complete opposite.” Like Brighter Days, these centers are designed to look more like a pediatrician’s office, with bright welcoming colors and games and toys.
“It’s separated from everything else. There’s a welcome, relaxed space,” she said. “The welcoming feel is just a whole different environment, and that’s really how it should be.”
A version of this article first appeared on Medscape.com.
Lauren Opladen remembers the agonizing wait all too well.
At age 17, struggling with paralyzing depression after losing her brother to suicide and her father to amyotrophic lateral sclerosis, her teacher suggested she seek help.
So, she did. But she had to spend 3 days inside an emergency department at the University of Rochester Medical Center in Rochester, New York, where the Comprehensive Psychiatric Emergency Program (CPEP) provides immediate care for youth and adults experiencing psychiatric emergencies.
“We were sleeping on a couch just waiting for all these services, when that’s precious time wasted,” Ms. Opladen said.
Ms. Opladen made it through that dark period, and 5 years later, she is a registered nurse at the same hospital. Every day she walks past a new facility she wishes had existed during her troubled teenage years: An urgent care center for children and adolescents experiencing mental health crises.
Brighter Days Pediatric Mental Health Urgent Care Center, Rochester, New York, opened in July as a walk-in clinic offering rapid assessment, crisis intervention, and short-term stabilization, provides referrals to counseling or psychiatric care. Children and adolescents at immediate risk of harming themselves or others, or who need inpatient care, are sent to CPEP or another emergency department in the area.
Similar walk-in facilities linking youth to longer-term services are popping up in nearly a dozen states, including New York, Ohio, Massachusetts, and Wisconsin. The emerging model of care may offer a crucial bridge between traditional outpatient services and emergency room (ER) visits for some young people experiencing mental health crises.
“We’ve seen a significant increase in the number of children and adolescents presenting to emergency departments with mental health concerns,” said Michael A. Scharf, MD, chief of the Division of Child and Adolescent Psychiatry at the University of Rochester Medical Center, who oversees operations at Brighter Days. “These urgent care centers provide a more appropriate setting for many of these cases, offering specialized care without the often overwhelming environment of an ER.”
The urgency of addressing youth behavioral health has become increasingly apparent. The most recent data from the US Centers for Disease Control and Prevention showed that over a 6-month period in 2020, during the early months of the COVID-19 pandemic, visits to the emergency department for mental health problems spiked 24% among children aged 5-11 years and 31% among 12-17-year-olds compared with the same period in 2019. Between March 2021 and February 2022, such emergency visits rose by 22% for teen girls, while falling by 15% for boys ages 5-12 years and 9% for older boys. Most visits occur during the school year.
But staffing shortages and limited physical space are taxing the capacity of the healthcare system to screen, diagnose, and manage these patients, according to a 2023 report published in Pediatrics.
Urgent Care: A Misnomer?
Some in the mental health community said the label “urgent” in these centers’ titles is misleading. Brighter Days and similar facilities do not conduct involuntary holds, administer medication, or handle serious cases like psychotic episodes.
David Mathison, MD, senior vice president of clinic operations at PM Pediatrics, a chain of pediatric urgent care clinics in Maryland, said patients and their families may mistakenly believe the centers will address mental health problems quickly.
“It’s really not urgent behavioral health. It’s really just another access point to get behavioral health,” Dr. Mathison said. “Crises in pediatrics are so much more complex” than physical injuries or acute infections, which are the bread and butter of urgent care centers.
“An urgent care center almost implies you’re going to come in for a solution to a simple problem, and it’s going to be done relatively quickly on demand, and it’s just not what the behavioral health centers do,” he said.
Dr. Mathison, who also serves on the executive committee for the section on urgent care at the American Academy of Pediatrics, likened the centers to in-person versions of crisis center hotlines, which offer virtual counseling and talk therapy and may refer individuals to specialists who can provide clinical care over the long term.
Instead, Brighter Days and other centers provide crisis de-escalation for individuals experiencing an exacerbation of a diagnosed mental illness, such a manic episode from bipolar disorder.
“Most places aren’t just going to change their therapy without either contacting their psychiatrist or having psychiatrists on staff,” Dr. Mathison said.
Other challenges at Brighter Days and similar centers include staffing with appropriately trained mental health professionals, given the nationwide shortage of child and adolescent psychiatrists, Dr. Scharf said.
The number of child and adolescent psychiatrists per 100,000 children varies significantly across states. Nationally, the average stands at 14 psychiatrists per 100,000 children, but ranges from as low as 4 to 65, according to the American Academy of Child & Adolescent Psychiatry.
For now, Dr. Scharf said, patients who visit Brighter Days are billed as if they are having a routine pediatric office visit as opposed to a pricier trip to the emergency department. And the center accepts all individuals, regardless of their insurance status.
Ms. Opladen said the urgent care center represents a significant improvement over her experience at the emergency department’s psychiatric triage.
“I saw how awful it was and just the environment,” she said. “The first thing I thought was, what do I need to do to get out of here?”
She said the pediatric mental health urgent care centers are “the complete opposite.” Like Brighter Days, these centers are designed to look more like a pediatrician’s office, with bright welcoming colors and games and toys.
“It’s separated from everything else. There’s a welcome, relaxed space,” she said. “The welcoming feel is just a whole different environment, and that’s really how it should be.”
A version of this article first appeared on Medscape.com.
Two Diets Linked to Improved Cognition, Slowed Brain Aging
An intermittent fasting (IF) diet and a standard healthy living (HL) diet focused on healthy foods both lead to weight loss, reduced insulin resistance (IR), and slowed brain aging in older overweight adults with IR, new research showed. However, neither diet has an effect on Alzheimer’s disease (AD) biomarkers.
Although investigators found both diets were beneficial, some outcomes were more robust with the IF diet.
“The study provides a blueprint for assessing brain effects of dietary interventions and motivates further research on intermittent fasting and continuous diets for brain health optimization,” wrote the investigators, led by Dimitrios Kapogiannis, MD, chief, human neuroscience section, National Institute on Aging, and adjunct associate professor of neurology, the Johns Hopkins University School of Medicine.
The findings were published online in Cell Metabolism.
Cognitive Outcomes
The prevalence of IR — reduced cellular sensitivity to insulin that’s a hallmark of type 2 diabetes — increases with age and obesity, adding to an increased risk for accelerated brain aging as well as AD and related dementias (ADRD) in older adults who have overweight.
Studies reported healthy diets promote overall health, but it’s unclear whether, and to what extent, they improve brain health beyond general health enhancement.
Researchers used multiple brain and cognitive measures to assess dietary effects on brain health, including peripherally harvested neuron-derived extracellular vesicles (NDEVs) to probe neuronal insulin signaling; MRI to investigate the pace of brain aging; magnetic resonance spectroscopy (MRS) to measure brain glucose, metabolites, and neurotransmitters; and NDEVs and cerebrospinal fluid to derive biomarkers for AD/ADRD.
The study included 40 cognitively intact overweight participants with IR, mean age 63.2 years, 60% women, and 62.5% White. Their mean body weight was 97.1 kg and mean body mass index (BMI) was 34.4.
Participants were randomly assigned to 8 weeks of an IF diet or a HL diet that emphasizes fruits, vegetables, whole grains, lean proteins, and low-fat dairy and limits added sugars, saturated fats, and sodium.
The IF diet involved following the HL diet for 5 days per week and restricting calories to a quarter of the recommended daily intake for 2 consecutive days.
Both diets reduced neuronal IR and had comparable effects in improving insulin signaling biomarkers in NDEVs, reducing brain glucose on MRS, and improving blood biomarkers of carbohydrate and lipid metabolism.
Using MRI, researchers also assessed brain age, an indication of whether the brain appears older or younger than an individual’s chronological age. There was a decrease of 2.63 years with the IF diet (P = .05) and 2.42 years with the HL diet (P < .001) in the anterior cingulate and ventromedial prefrontal cortex.
Both diets improved executive function and memory, with those following the IF diet benefiting more in strategic planning, switching between two cognitively demanding tasks, cued recall, and other areas.
Hypothesis-Generating Research
AD biomarkers including amyloid beta 42 (Aß42), Aß40, and plasma phosphorylated-tau181 did not change with either diet, a finding that investigators speculated may be due to the short duration of the study. Light-chain neurofilaments increased across groups with no differences between the diets.
In other findings, BMI decreased by 1.41 with the IF diet and by 0.80 with the HL diet, and a similar pattern was observed for weight. Waist circumference decreased in both groups with no significant differences between diets.
An exploratory analysis showed executive function improved with the IF diet but not with the HL diet in women, whereas it improved with both diets in men. BMI and apolipoprotein E and SLC16A7 genotypes also modulated diet effects.
Both diets were well tolerated. The most frequent adverse events were gastrointestinal and occurred only with the IF diet.
The authors noted the findings are preliminary and results are hypothesis generating. Study limitations included the study’s short duration and its power to detect anything other than large to moderate effect size changes and differences between the diets. Researchers also didn’t acquire data on dietary intake, so lapses in adherence can’t be excluded. However, the large decreases in BMI, weight, and waist circumference with both diets indicated high adherence.
The study was supported by the National Institutes of Health’s National Institute on Aging. The authors reported no competing interests.
A version of this article first appeared on Medscape.com.
An intermittent fasting (IF) diet and a standard healthy living (HL) diet focused on healthy foods both lead to weight loss, reduced insulin resistance (IR), and slowed brain aging in older overweight adults with IR, new research showed. However, neither diet has an effect on Alzheimer’s disease (AD) biomarkers.
Although investigators found both diets were beneficial, some outcomes were more robust with the IF diet.
“The study provides a blueprint for assessing brain effects of dietary interventions and motivates further research on intermittent fasting and continuous diets for brain health optimization,” wrote the investigators, led by Dimitrios Kapogiannis, MD, chief, human neuroscience section, National Institute on Aging, and adjunct associate professor of neurology, the Johns Hopkins University School of Medicine.
The findings were published online in Cell Metabolism.
Cognitive Outcomes
The prevalence of IR — reduced cellular sensitivity to insulin that’s a hallmark of type 2 diabetes — increases with age and obesity, adding to an increased risk for accelerated brain aging as well as AD and related dementias (ADRD) in older adults who have overweight.
Studies reported healthy diets promote overall health, but it’s unclear whether, and to what extent, they improve brain health beyond general health enhancement.
Researchers used multiple brain and cognitive measures to assess dietary effects on brain health, including peripherally harvested neuron-derived extracellular vesicles (NDEVs) to probe neuronal insulin signaling; MRI to investigate the pace of brain aging; magnetic resonance spectroscopy (MRS) to measure brain glucose, metabolites, and neurotransmitters; and NDEVs and cerebrospinal fluid to derive biomarkers for AD/ADRD.
The study included 40 cognitively intact overweight participants with IR, mean age 63.2 years, 60% women, and 62.5% White. Their mean body weight was 97.1 kg and mean body mass index (BMI) was 34.4.
Participants were randomly assigned to 8 weeks of an IF diet or a HL diet that emphasizes fruits, vegetables, whole grains, lean proteins, and low-fat dairy and limits added sugars, saturated fats, and sodium.
The IF diet involved following the HL diet for 5 days per week and restricting calories to a quarter of the recommended daily intake for 2 consecutive days.
Both diets reduced neuronal IR and had comparable effects in improving insulin signaling biomarkers in NDEVs, reducing brain glucose on MRS, and improving blood biomarkers of carbohydrate and lipid metabolism.
Using MRI, researchers also assessed brain age, an indication of whether the brain appears older or younger than an individual’s chronological age. There was a decrease of 2.63 years with the IF diet (P = .05) and 2.42 years with the HL diet (P < .001) in the anterior cingulate and ventromedial prefrontal cortex.
Both diets improved executive function and memory, with those following the IF diet benefiting more in strategic planning, switching between two cognitively demanding tasks, cued recall, and other areas.
Hypothesis-Generating Research
AD biomarkers including amyloid beta 42 (Aß42), Aß40, and plasma phosphorylated-tau181 did not change with either diet, a finding that investigators speculated may be due to the short duration of the study. Light-chain neurofilaments increased across groups with no differences between the diets.
In other findings, BMI decreased by 1.41 with the IF diet and by 0.80 with the HL diet, and a similar pattern was observed for weight. Waist circumference decreased in both groups with no significant differences between diets.
An exploratory analysis showed executive function improved with the IF diet but not with the HL diet in women, whereas it improved with both diets in men. BMI and apolipoprotein E and SLC16A7 genotypes also modulated diet effects.
Both diets were well tolerated. The most frequent adverse events were gastrointestinal and occurred only with the IF diet.
The authors noted the findings are preliminary and results are hypothesis generating. Study limitations included the study’s short duration and its power to detect anything other than large to moderate effect size changes and differences between the diets. Researchers also didn’t acquire data on dietary intake, so lapses in adherence can’t be excluded. However, the large decreases in BMI, weight, and waist circumference with both diets indicated high adherence.
The study was supported by the National Institutes of Health’s National Institute on Aging. The authors reported no competing interests.
A version of this article first appeared on Medscape.com.
An intermittent fasting (IF) diet and a standard healthy living (HL) diet focused on healthy foods both lead to weight loss, reduced insulin resistance (IR), and slowed brain aging in older overweight adults with IR, new research showed. However, neither diet has an effect on Alzheimer’s disease (AD) biomarkers.
Although investigators found both diets were beneficial, some outcomes were more robust with the IF diet.
“The study provides a blueprint for assessing brain effects of dietary interventions and motivates further research on intermittent fasting and continuous diets for brain health optimization,” wrote the investigators, led by Dimitrios Kapogiannis, MD, chief, human neuroscience section, National Institute on Aging, and adjunct associate professor of neurology, the Johns Hopkins University School of Medicine.
The findings were published online in Cell Metabolism.
Cognitive Outcomes
The prevalence of IR — reduced cellular sensitivity to insulin that’s a hallmark of type 2 diabetes — increases with age and obesity, adding to an increased risk for accelerated brain aging as well as AD and related dementias (ADRD) in older adults who have overweight.
Studies reported healthy diets promote overall health, but it’s unclear whether, and to what extent, they improve brain health beyond general health enhancement.
Researchers used multiple brain and cognitive measures to assess dietary effects on brain health, including peripherally harvested neuron-derived extracellular vesicles (NDEVs) to probe neuronal insulin signaling; MRI to investigate the pace of brain aging; magnetic resonance spectroscopy (MRS) to measure brain glucose, metabolites, and neurotransmitters; and NDEVs and cerebrospinal fluid to derive biomarkers for AD/ADRD.
The study included 40 cognitively intact overweight participants with IR, mean age 63.2 years, 60% women, and 62.5% White. Their mean body weight was 97.1 kg and mean body mass index (BMI) was 34.4.
Participants were randomly assigned to 8 weeks of an IF diet or a HL diet that emphasizes fruits, vegetables, whole grains, lean proteins, and low-fat dairy and limits added sugars, saturated fats, and sodium.
The IF diet involved following the HL diet for 5 days per week and restricting calories to a quarter of the recommended daily intake for 2 consecutive days.
Both diets reduced neuronal IR and had comparable effects in improving insulin signaling biomarkers in NDEVs, reducing brain glucose on MRS, and improving blood biomarkers of carbohydrate and lipid metabolism.
Using MRI, researchers also assessed brain age, an indication of whether the brain appears older or younger than an individual’s chronological age. There was a decrease of 2.63 years with the IF diet (P = .05) and 2.42 years with the HL diet (P < .001) in the anterior cingulate and ventromedial prefrontal cortex.
Both diets improved executive function and memory, with those following the IF diet benefiting more in strategic planning, switching between two cognitively demanding tasks, cued recall, and other areas.
Hypothesis-Generating Research
AD biomarkers including amyloid beta 42 (Aß42), Aß40, and plasma phosphorylated-tau181 did not change with either diet, a finding that investigators speculated may be due to the short duration of the study. Light-chain neurofilaments increased across groups with no differences between the diets.
In other findings, BMI decreased by 1.41 with the IF diet and by 0.80 with the HL diet, and a similar pattern was observed for weight. Waist circumference decreased in both groups with no significant differences between diets.
An exploratory analysis showed executive function improved with the IF diet but not with the HL diet in women, whereas it improved with both diets in men. BMI and apolipoprotein E and SLC16A7 genotypes also modulated diet effects.
Both diets were well tolerated. The most frequent adverse events were gastrointestinal and occurred only with the IF diet.
The authors noted the findings are preliminary and results are hypothesis generating. Study limitations included the study’s short duration and its power to detect anything other than large to moderate effect size changes and differences between the diets. Researchers also didn’t acquire data on dietary intake, so lapses in adherence can’t be excluded. However, the large decreases in BMI, weight, and waist circumference with both diets indicated high adherence.
The study was supported by the National Institutes of Health’s National Institute on Aging. The authors reported no competing interests.
A version of this article first appeared on Medscape.com.
FROM CELL METABOLISM
Twice-Yearly PrEP Gives ‘Huge’ 100% Protection
Twice-yearly injections are 100% effective in preventing new infections, according to the final results from the PURPOSE 1 trial of lenacapavir.
For weeks, the HIV community has been talking about this highly anticipated clinical trial and whether the strong — and to many, surprising — interim results would hold at final presentation at the International AIDS Conference 2024 in Munich, Germany.
Presenting the results, Linda-Gail Bekker, MD, director of the Desmond Tutu HIV Center at the University of Cape Town, South Africa, reported zero new infections in those who got the shots in the study of about 5000 young women. In the group given daily oral preexposure prophylaxis (PrEP), roughly 2% contracted HIV from infected partners.
“A twice-yearly PrEP choice could overcome some of the adherence and persistence challenges and contribute critically to our quest to reduce HIV infection in women around the world,” Dr. Bekker said about the results, which were published simultaneously in The New England Journal of Medicine.
PURPOSE 1 confirmed that lenacapavir is a “breakthrough” for HIV prevention, said International AIDS Society president Sharon Lewin, PhD, MBBS. It has “huge public health potential,” said Dr. Lewin, the AIDS 2024 conference cochair and director of the Peter Doherty Institute for Infection and Immunity at the University of Melbourne in Australia.
Lenacapavir is a novel, first-in-class multistage HIV-1 capsid inhibitor with a long half-life, which enables the twice-yearly dosing.
PURPOSE 1 enrolled women aged 15-25 years who were at risk for HIV in South Africa and Uganda, with a primary endpoint of HIV infection. Because of the previously announced interim results, which showed the injection was preventing infections, study sponsor Gilead Sciences discontinued the randomized phase of the trial and shifted to an open-label design for lenacapavir.
“One hundred percent efficacy is more that we could ever have hoped for a potential prevention efficacy,” said Christoph Spinner, MD, MBA, an infectious disease specialist at the University Hospital of the Technical University of Munich and AIDS 2024 conference cochair.
Dr. Spinner added that while this is the first study of lenacapavir for PrEP, it’s also the first to explore outcomes of emtricitabine-tenofovir in cisgender women.
Strong Adherence Rates
The twice-yearly injection demonstrated adherence rates above 90% in the trial for both the 6- and 12-month injection intervals.
“Adherence was 91.5% at week 26 and 92.8% at week 52,” Dr. Bekker reported.
The trial compared three PrEP options including the lenacapavir injection to once-daily oral emtricitabine 200 mg and tenofovir-alafenamide 25 mg (F/TAF) and once-daily emtricitabine 200 mg and tenofovir–disoproxil fumarate 300 mg (F/TDF).
“Most participants in both the F/TAF and F/TDF groups had low adherence, and this declined over time,” Dr. Bekker reported. At 52 weeks, the vast majority of patients on both oral therapies had low adherence with dosing, defined at less than two doses a week.
Dr. Bekker called the adherence to the oral agents in this trial “disappointing.”
Findings from the trial underscore the challenges of adherence to a daily oral medication, Rochelle Walensky, MD, and Lindsey Baden, MD, from the Harvard Kennedy School of Government and Harvard Business School in Cambridge, Massachusetts, wrote in an editorial accompanying the published results.
With almost 92% attendance for the twice-yearly lenacapavir injections, the “well-done,” large, randomized, controlled trial “exemplifies not only that women can dependably adhere to this administration schedule, but also that levels of an HIV-1 capsid inhibitor can remain high enough over a period of 6 months to reliably prevent infection,” they added.
Another key focus of the presentation was adverse events. The rate of adverse events grade 3 or more in the lenacapavir arm was 4.1%, Bekker said, which is slightly lower than the rates in the oral arms. The rates of serious adverse events were 2.8% for lenacapavir, 4% for F/TAF and 3.3% for F/TDF.
Injection Site Reactions
Injection site reactions occurred in 68% of the lenacapavir group, including 63% with subcutaneous nodules.
The injection can form “a drug depot which may be palpable as a nodule,” Dr. Bekker said. In the placebo group, 34% of patients had injection-site reactions and 16% had nodules. Nearly all injection-site reactions were grade 1 or 2, she said. “Higher grade injection-site reactions were rare and not serious and occurred in a similar percentage in lenacapavir and placebo,” she said.
Overall, more than 25,000 injections of lenacapavir have been given, Dr. Bekker said, and four patients discontinued treatment because of injection-site reactions. “Reporting of injection-site reactions, including nodules, decreased with subsequent doses,” she said.
Contraception was not a requirement for enrollment in the study, Dr. Bekker pointed out, and pregnancy outcomes across the treatment arms were similar to the general population.
First in a Series of Trials
This is the first in a series of PURPOSE trials, Bekker reported. The phase 3 PURPOSE 2 trial, enrolling 3000 gay men, transgender women, transgender men and gender nonbinary people who have sex with male partners, is the second pivotal trial now underway.
Three other smaller trials are in the clinic in the United States and Europe.
PURPOSE 1 participants will continue to access lenacapavir until the product is available in South Africa and Uganda, Dr. Bekker said. Trial sponsor Gilead Sciences is also developing a direct licensing program to expedite generic access to the drug in high-incidence, resource-limited countries, she said.
Dr. Walensky and Dr. Baden report that lenacapavir currently costs about $43,000 annually in the United States. “But the results of the PURPOSE 1 trial have now created a moral imperative to make lenacapavir broadly accessible and affordable as PrEP” to people who were enrolled, as well as all those who are similarly eligible and could benefit.
So now we have a PrEP product with high efficacy, they added. “That is great news for science but not (yet) great for women.”
Given the high pregnancy rate among participants in the PURPOSE 1 trial, Dr. Walensky and Dr. Baden point out the assessment of lenacapavir safety is a priority. They are also interested in learning more about drug resistance with this new option.
“I f approved and delivered — rapidly, affordably, and equitably — to those who need or want it, this long-acting tool could help accelerate global progress in HIV prevention,” Dr. Lewin said.
Now, she added, “we eagerly await results from PURPOSE 2.”
A version of this article first appeared on Medscape.com.
Twice-yearly injections are 100% effective in preventing new infections, according to the final results from the PURPOSE 1 trial of lenacapavir.
For weeks, the HIV community has been talking about this highly anticipated clinical trial and whether the strong — and to many, surprising — interim results would hold at final presentation at the International AIDS Conference 2024 in Munich, Germany.
Presenting the results, Linda-Gail Bekker, MD, director of the Desmond Tutu HIV Center at the University of Cape Town, South Africa, reported zero new infections in those who got the shots in the study of about 5000 young women. In the group given daily oral preexposure prophylaxis (PrEP), roughly 2% contracted HIV from infected partners.
“A twice-yearly PrEP choice could overcome some of the adherence and persistence challenges and contribute critically to our quest to reduce HIV infection in women around the world,” Dr. Bekker said about the results, which were published simultaneously in The New England Journal of Medicine.
PURPOSE 1 confirmed that lenacapavir is a “breakthrough” for HIV prevention, said International AIDS Society president Sharon Lewin, PhD, MBBS. It has “huge public health potential,” said Dr. Lewin, the AIDS 2024 conference cochair and director of the Peter Doherty Institute for Infection and Immunity at the University of Melbourne in Australia.
Lenacapavir is a novel, first-in-class multistage HIV-1 capsid inhibitor with a long half-life, which enables the twice-yearly dosing.
PURPOSE 1 enrolled women aged 15-25 years who were at risk for HIV in South Africa and Uganda, with a primary endpoint of HIV infection. Because of the previously announced interim results, which showed the injection was preventing infections, study sponsor Gilead Sciences discontinued the randomized phase of the trial and shifted to an open-label design for lenacapavir.
“One hundred percent efficacy is more that we could ever have hoped for a potential prevention efficacy,” said Christoph Spinner, MD, MBA, an infectious disease specialist at the University Hospital of the Technical University of Munich and AIDS 2024 conference cochair.
Dr. Spinner added that while this is the first study of lenacapavir for PrEP, it’s also the first to explore outcomes of emtricitabine-tenofovir in cisgender women.
Strong Adherence Rates
The twice-yearly injection demonstrated adherence rates above 90% in the trial for both the 6- and 12-month injection intervals.
“Adherence was 91.5% at week 26 and 92.8% at week 52,” Dr. Bekker reported.
The trial compared three PrEP options including the lenacapavir injection to once-daily oral emtricitabine 200 mg and tenofovir-alafenamide 25 mg (F/TAF) and once-daily emtricitabine 200 mg and tenofovir–disoproxil fumarate 300 mg (F/TDF).
“Most participants in both the F/TAF and F/TDF groups had low adherence, and this declined over time,” Dr. Bekker reported. At 52 weeks, the vast majority of patients on both oral therapies had low adherence with dosing, defined at less than two doses a week.
Dr. Bekker called the adherence to the oral agents in this trial “disappointing.”
Findings from the trial underscore the challenges of adherence to a daily oral medication, Rochelle Walensky, MD, and Lindsey Baden, MD, from the Harvard Kennedy School of Government and Harvard Business School in Cambridge, Massachusetts, wrote in an editorial accompanying the published results.
With almost 92% attendance for the twice-yearly lenacapavir injections, the “well-done,” large, randomized, controlled trial “exemplifies not only that women can dependably adhere to this administration schedule, but also that levels of an HIV-1 capsid inhibitor can remain high enough over a period of 6 months to reliably prevent infection,” they added.
Another key focus of the presentation was adverse events. The rate of adverse events grade 3 or more in the lenacapavir arm was 4.1%, Bekker said, which is slightly lower than the rates in the oral arms. The rates of serious adverse events were 2.8% for lenacapavir, 4% for F/TAF and 3.3% for F/TDF.
Injection Site Reactions
Injection site reactions occurred in 68% of the lenacapavir group, including 63% with subcutaneous nodules.
The injection can form “a drug depot which may be palpable as a nodule,” Dr. Bekker said. In the placebo group, 34% of patients had injection-site reactions and 16% had nodules. Nearly all injection-site reactions were grade 1 or 2, she said. “Higher grade injection-site reactions were rare and not serious and occurred in a similar percentage in lenacapavir and placebo,” she said.
Overall, more than 25,000 injections of lenacapavir have been given, Dr. Bekker said, and four patients discontinued treatment because of injection-site reactions. “Reporting of injection-site reactions, including nodules, decreased with subsequent doses,” she said.
Contraception was not a requirement for enrollment in the study, Dr. Bekker pointed out, and pregnancy outcomes across the treatment arms were similar to the general population.
First in a Series of Trials
This is the first in a series of PURPOSE trials, Bekker reported. The phase 3 PURPOSE 2 trial, enrolling 3000 gay men, transgender women, transgender men and gender nonbinary people who have sex with male partners, is the second pivotal trial now underway.
Three other smaller trials are in the clinic in the United States and Europe.
PURPOSE 1 participants will continue to access lenacapavir until the product is available in South Africa and Uganda, Dr. Bekker said. Trial sponsor Gilead Sciences is also developing a direct licensing program to expedite generic access to the drug in high-incidence, resource-limited countries, she said.
Dr. Walensky and Dr. Baden report that lenacapavir currently costs about $43,000 annually in the United States. “But the results of the PURPOSE 1 trial have now created a moral imperative to make lenacapavir broadly accessible and affordable as PrEP” to people who were enrolled, as well as all those who are similarly eligible and could benefit.
So now we have a PrEP product with high efficacy, they added. “That is great news for science but not (yet) great for women.”
Given the high pregnancy rate among participants in the PURPOSE 1 trial, Dr. Walensky and Dr. Baden point out the assessment of lenacapavir safety is a priority. They are also interested in learning more about drug resistance with this new option.
“I f approved and delivered — rapidly, affordably, and equitably — to those who need or want it, this long-acting tool could help accelerate global progress in HIV prevention,” Dr. Lewin said.
Now, she added, “we eagerly await results from PURPOSE 2.”
A version of this article first appeared on Medscape.com.
Twice-yearly injections are 100% effective in preventing new infections, according to the final results from the PURPOSE 1 trial of lenacapavir.
For weeks, the HIV community has been talking about this highly anticipated clinical trial and whether the strong — and to many, surprising — interim results would hold at final presentation at the International AIDS Conference 2024 in Munich, Germany.
Presenting the results, Linda-Gail Bekker, MD, director of the Desmond Tutu HIV Center at the University of Cape Town, South Africa, reported zero new infections in those who got the shots in the study of about 5000 young women. In the group given daily oral preexposure prophylaxis (PrEP), roughly 2% contracted HIV from infected partners.
“A twice-yearly PrEP choice could overcome some of the adherence and persistence challenges and contribute critically to our quest to reduce HIV infection in women around the world,” Dr. Bekker said about the results, which were published simultaneously in The New England Journal of Medicine.
PURPOSE 1 confirmed that lenacapavir is a “breakthrough” for HIV prevention, said International AIDS Society president Sharon Lewin, PhD, MBBS. It has “huge public health potential,” said Dr. Lewin, the AIDS 2024 conference cochair and director of the Peter Doherty Institute for Infection and Immunity at the University of Melbourne in Australia.
Lenacapavir is a novel, first-in-class multistage HIV-1 capsid inhibitor with a long half-life, which enables the twice-yearly dosing.
PURPOSE 1 enrolled women aged 15-25 years who were at risk for HIV in South Africa and Uganda, with a primary endpoint of HIV infection. Because of the previously announced interim results, which showed the injection was preventing infections, study sponsor Gilead Sciences discontinued the randomized phase of the trial and shifted to an open-label design for lenacapavir.
“One hundred percent efficacy is more that we could ever have hoped for a potential prevention efficacy,” said Christoph Spinner, MD, MBA, an infectious disease specialist at the University Hospital of the Technical University of Munich and AIDS 2024 conference cochair.
Dr. Spinner added that while this is the first study of lenacapavir for PrEP, it’s also the first to explore outcomes of emtricitabine-tenofovir in cisgender women.
Strong Adherence Rates
The twice-yearly injection demonstrated adherence rates above 90% in the trial for both the 6- and 12-month injection intervals.
“Adherence was 91.5% at week 26 and 92.8% at week 52,” Dr. Bekker reported.
The trial compared three PrEP options including the lenacapavir injection to once-daily oral emtricitabine 200 mg and tenofovir-alafenamide 25 mg (F/TAF) and once-daily emtricitabine 200 mg and tenofovir–disoproxil fumarate 300 mg (F/TDF).
“Most participants in both the F/TAF and F/TDF groups had low adherence, and this declined over time,” Dr. Bekker reported. At 52 weeks, the vast majority of patients on both oral therapies had low adherence with dosing, defined at less than two doses a week.
Dr. Bekker called the adherence to the oral agents in this trial “disappointing.”
Findings from the trial underscore the challenges of adherence to a daily oral medication, Rochelle Walensky, MD, and Lindsey Baden, MD, from the Harvard Kennedy School of Government and Harvard Business School in Cambridge, Massachusetts, wrote in an editorial accompanying the published results.
With almost 92% attendance for the twice-yearly lenacapavir injections, the “well-done,” large, randomized, controlled trial “exemplifies not only that women can dependably adhere to this administration schedule, but also that levels of an HIV-1 capsid inhibitor can remain high enough over a period of 6 months to reliably prevent infection,” they added.
Another key focus of the presentation was adverse events. The rate of adverse events grade 3 or more in the lenacapavir arm was 4.1%, Bekker said, which is slightly lower than the rates in the oral arms. The rates of serious adverse events were 2.8% for lenacapavir, 4% for F/TAF and 3.3% for F/TDF.
Injection Site Reactions
Injection site reactions occurred in 68% of the lenacapavir group, including 63% with subcutaneous nodules.
The injection can form “a drug depot which may be palpable as a nodule,” Dr. Bekker said. In the placebo group, 34% of patients had injection-site reactions and 16% had nodules. Nearly all injection-site reactions were grade 1 or 2, she said. “Higher grade injection-site reactions were rare and not serious and occurred in a similar percentage in lenacapavir and placebo,” she said.
Overall, more than 25,000 injections of lenacapavir have been given, Dr. Bekker said, and four patients discontinued treatment because of injection-site reactions. “Reporting of injection-site reactions, including nodules, decreased with subsequent doses,” she said.
Contraception was not a requirement for enrollment in the study, Dr. Bekker pointed out, and pregnancy outcomes across the treatment arms were similar to the general population.
First in a Series of Trials
This is the first in a series of PURPOSE trials, Bekker reported. The phase 3 PURPOSE 2 trial, enrolling 3000 gay men, transgender women, transgender men and gender nonbinary people who have sex with male partners, is the second pivotal trial now underway.
Three other smaller trials are in the clinic in the United States and Europe.
PURPOSE 1 participants will continue to access lenacapavir until the product is available in South Africa and Uganda, Dr. Bekker said. Trial sponsor Gilead Sciences is also developing a direct licensing program to expedite generic access to the drug in high-incidence, resource-limited countries, she said.
Dr. Walensky and Dr. Baden report that lenacapavir currently costs about $43,000 annually in the United States. “But the results of the PURPOSE 1 trial have now created a moral imperative to make lenacapavir broadly accessible and affordable as PrEP” to people who were enrolled, as well as all those who are similarly eligible and could benefit.
So now we have a PrEP product with high efficacy, they added. “That is great news for science but not (yet) great for women.”
Given the high pregnancy rate among participants in the PURPOSE 1 trial, Dr. Walensky and Dr. Baden point out the assessment of lenacapavir safety is a priority. They are also interested in learning more about drug resistance with this new option.
“I f approved and delivered — rapidly, affordably, and equitably — to those who need or want it, this long-acting tool could help accelerate global progress in HIV prevention,” Dr. Lewin said.
Now, she added, “we eagerly await results from PURPOSE 2.”
A version of this article first appeared on Medscape.com.
FROM AIDS 2024