Correct answer: A. Amyloidosis involving the small intestine 
 
Rationale  
This patient has a protein-losing enteropathy as indicated by his diarrhea, peripheral edema, and positive stool alpha-1 antitrypsin test. Multiple diseases, particularly in their later stages, can be associated with a protein-losing enteropathy including primary intestinal lymphangectasia, Crohn's disease of the small intestine, small intestinal bacterial overgrowth (SIBO), and amyloidosis of the small intestine (A). Celiac disease (B) is not associated with protein-losing enteropathy. While Crohn's disease can be associated with protein-losing enteropathy, ulcerative colitis (C) is not usually associated with it. Small bowel dysmotility (D) does not impact absorption or secretion unless associated with SIBO, making this a wrong answer.

Correct answer: A. Amyloidosis involving the small intestine 
 
Rationale  
This patient has a protein-losing enteropathy as indicated by his diarrhea, peripheral edema, and positive stool alpha-1 antitrypsin test. Multiple diseases, particularly in their later stages, can be associated with a protein-losing enteropathy including primary intestinal lymphangectasia, Crohn's disease of the small intestine, small intestinal bacterial overgrowth (SIBO), and amyloidosis of the small intestine (A). Celiac disease (B) is not associated with protein-losing enteropathy. While Crohn's disease can be associated with protein-losing enteropathy, ulcerative colitis (C) is not usually associated with it. Small bowel dysmotility (D) does not impact absorption or secretion unless associated with SIBO, making this a wrong answer.

Correct answer: A. Amyloidosis involving the small intestine 
 
Rationale  
This patient has a protein-losing enteropathy as indicated by his diarrhea, peripheral edema, and positive stool alpha-1 antitrypsin test. Multiple diseases, particularly in their later stages, can be associated with a protein-losing enteropathy including primary intestinal lymphangectasia, Crohn's disease of the small intestine, small intestinal bacterial overgrowth (SIBO), and amyloidosis of the small intestine (A). Celiac disease (B) is not associated with protein-losing enteropathy. While Crohn's disease can be associated with protein-losing enteropathy, ulcerative colitis (C) is not usually associated with it. Small bowel dysmotility (D) does not impact absorption or secretion unless associated with SIBO, making this a wrong answer.

In her month-long memoir, A Really Good Day: How Microdosing Made a Mega Difference in My Mood, My Marriage, and My Life (Knopf, 2017), author Ayelet Waldman turns herself into a one-woman experiment.

Over a single month she takes one-tenth of a recreational dose of LSD every third day. She plots her emotions, her productivity, and her pain along the way. Ms. Waldman obtains the LSD in a single vial, enough for 10 doses, from a researcher, who is retiring. What she’s looking for, she tells the reader, is a really good day – something that has been elusive in her turbulent life.

Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins in Baltimore. Dr. Miller has no conflicts of interest.

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

In her month-long memoir, A Really Good Day: How Microdosing Made a Mega Difference in My Mood, My Marriage, and My Life (Knopf, 2017), author Ayelet Waldman turns herself into a one-woman experiment.

Over a single month she takes one-tenth of a recreational dose of LSD every third day. She plots her emotions, her productivity, and her pain along the way. Ms. Waldman obtains the LSD in a single vial, enough for 10 doses, from a researcher, who is retiring. What she’s looking for, she tells the reader, is a really good day – something that has been elusive in her turbulent life.

Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins in Baltimore. Dr. Miller has no conflicts of interest.

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

In her month-long memoir, A Really Good Day: How Microdosing Made a Mega Difference in My Mood, My Marriage, and My Life (Knopf, 2017), author Ayelet Waldman turns herself into a one-woman experiment.

Over a single month she takes one-tenth of a recreational dose of LSD every third day. She plots her emotions, her productivity, and her pain along the way. Ms. Waldman obtains the LSD in a single vial, enough for 10 doses, from a researcher, who is retiring. What she’s looking for, she tells the reader, is a really good day – something that has been elusive in her turbulent life.

Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins in Baltimore. Dr. Miller has no conflicts of interest.

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

A panel of experts that advises the FDA narrowly voted to reject a new drug intended to treat amyotrophic lateral scelrosis (ALS). Six of 10 members of the FDA Peripheral and Central Nervous System Drugs Advisory Committee decided there is not enough evidence to support approval of the drug from Amylyx Pharmaceuticals. The evidence from a single phase 2 trial is insufficient, the panel said.

The fate of the drug, known as AMX0035, and the panel’s vote, has been closely watched as new treatments for this devastating disease are greatly needed. Committee members said they were moved by passionate testimony from patients, caregivers, and others. But, they believe the evidence does not meet the required standard for FDA approval.

“We were asked to look for substantial evidence of persuasiveness and robustness, and I think this one trial doesn’t quite meet that bar and was problematic,” said Kenneth Fischbeck, MD, investigator with the National Institute of Neurological Disorders and Stroke. “It would be a disservice to patients and their families to move ahead and approve a treatment that is of uncertain benefit,” said Dr. Fischbeck.

The committee’s vote is not binding. While the FDA often follows its advisors’ decisions, the agency last year approved a controversial new drug for Alzheimer’s disease after a similar advisory committee voted against it.
 

Phase 3 study in the works

This new ALS drug was shown to slow the decline caused by ALS, sometimes known as Lou Gehrig’s disease, Jamie Timmons, MD, head of scientific communications at Amylyx Pharmaceuticals, said. The study found the drug slowed decline by 25%, compared with patients taking a placebo. That change is considered clinically meaningful.

This is the first time a treatment has shown a benefit on both function and survival in ALS, the two key measures in a relentlessly progressive, fatal disease, said Joshua Cohen, co-CEO and co-founder of Amylyx.

During the meeting, patients with ALS said they were willing to accept greater risk for the possibility of having even a little more time with their loved ones and argued that the drug contains two compounds that are already available. They pleaded for the FDA to exercise its regulatory flexibility in approving this experimental drug.

However, the FDA panel raised a number of issues with the trial. These concerns included the study’s small sample size and no survival benefit at 24 weeks.

Many panel members said they hope an ongoing phase III trial will be more definitive because it’s so much larger. The results of that trial are expected by early 2024.

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

A panel of experts that advises the FDA narrowly voted to reject a new drug intended to treat amyotrophic lateral scelrosis (ALS). Six of 10 members of the FDA Peripheral and Central Nervous System Drugs Advisory Committee decided there is not enough evidence to support approval of the drug from Amylyx Pharmaceuticals. The evidence from a single phase 2 trial is insufficient, the panel said.

The fate of the drug, known as AMX0035, and the panel’s vote, has been closely watched as new treatments for this devastating disease are greatly needed. Committee members said they were moved by passionate testimony from patients, caregivers, and others. But, they believe the evidence does not meet the required standard for FDA approval.

“We were asked to look for substantial evidence of persuasiveness and robustness, and I think this one trial doesn’t quite meet that bar and was problematic,” said Kenneth Fischbeck, MD, investigator with the National Institute of Neurological Disorders and Stroke. “It would be a disservice to patients and their families to move ahead and approve a treatment that is of uncertain benefit,” said Dr. Fischbeck.

The committee’s vote is not binding. While the FDA often follows its advisors’ decisions, the agency last year approved a controversial new drug for Alzheimer’s disease after a similar advisory committee voted against it.
 

Phase 3 study in the works

This new ALS drug was shown to slow the decline caused by ALS, sometimes known as Lou Gehrig’s disease, Jamie Timmons, MD, head of scientific communications at Amylyx Pharmaceuticals, said. The study found the drug slowed decline by 25%, compared with patients taking a placebo. That change is considered clinically meaningful.

This is the first time a treatment has shown a benefit on both function and survival in ALS, the two key measures in a relentlessly progressive, fatal disease, said Joshua Cohen, co-CEO and co-founder of Amylyx.

During the meeting, patients with ALS said they were willing to accept greater risk for the possibility of having even a little more time with their loved ones and argued that the drug contains two compounds that are already available. They pleaded for the FDA to exercise its regulatory flexibility in approving this experimental drug.

However, the FDA panel raised a number of issues with the trial. These concerns included the study’s small sample size and no survival benefit at 24 weeks.

Many panel members said they hope an ongoing phase III trial will be more definitive because it’s so much larger. The results of that trial are expected by early 2024.

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

A panel of experts that advises the FDA narrowly voted to reject a new drug intended to treat amyotrophic lateral scelrosis (ALS). Six of 10 members of the FDA Peripheral and Central Nervous System Drugs Advisory Committee decided there is not enough evidence to support approval of the drug from Amylyx Pharmaceuticals. The evidence from a single phase 2 trial is insufficient, the panel said.

The fate of the drug, known as AMX0035, and the panel’s vote, has been closely watched as new treatments for this devastating disease are greatly needed. Committee members said they were moved by passionate testimony from patients, caregivers, and others. But, they believe the evidence does not meet the required standard for FDA approval.

“We were asked to look for substantial evidence of persuasiveness and robustness, and I think this one trial doesn’t quite meet that bar and was problematic,” said Kenneth Fischbeck, MD, investigator with the National Institute of Neurological Disorders and Stroke. “It would be a disservice to patients and their families to move ahead and approve a treatment that is of uncertain benefit,” said Dr. Fischbeck.

The committee’s vote is not binding. While the FDA often follows its advisors’ decisions, the agency last year approved a controversial new drug for Alzheimer’s disease after a similar advisory committee voted against it.
 

Phase 3 study in the works

This new ALS drug was shown to slow the decline caused by ALS, sometimes known as Lou Gehrig’s disease, Jamie Timmons, MD, head of scientific communications at Amylyx Pharmaceuticals, said. The study found the drug slowed decline by 25%, compared with patients taking a placebo. That change is considered clinically meaningful.

This is the first time a treatment has shown a benefit on both function and survival in ALS, the two key measures in a relentlessly progressive, fatal disease, said Joshua Cohen, co-CEO and co-founder of Amylyx.

During the meeting, patients with ALS said they were willing to accept greater risk for the possibility of having even a little more time with their loved ones and argued that the drug contains two compounds that are already available. They pleaded for the FDA to exercise its regulatory flexibility in approving this experimental drug.

However, the FDA panel raised a number of issues with the trial. These concerns included the study’s small sample size and no survival benefit at 24 weeks.

Many panel members said they hope an ongoing phase III trial will be more definitive because it’s so much larger. The results of that trial are expected by early 2024.

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

Only a small number of pediatric hematologist oncologists and even fewer of our adult counterparts feel comfortable evaluating and treating vascular anomalies. 

While admittedly rare, these conditions are still common enough that clinicians in many disciplines encounter them. Hematologist/oncologists are most likely to see vascular malformations, which often present as mass lesions. Complications of these disorders occur across the hematology-oncology spectrum and include clots, pulmonary emboli, cancer predisposition, and an array of functional and psychosocial disorders. 

Vascular anomalies are broadly categorized as vascular tumors or malformations. The tumors include hemangiomas, locally aggressive lesions, and true cancers. Malformations can be isolated disorders of one or more blood vessel types (veins, arteries, capillaries or lymphatics), or they can be one part of syndromic disorders. Lymphedema also falls under the heading of vascular anomalies. To make the terminology less confusing, in 2018 the International Society for the Study of Vascular Anomalies refined its classification scheme.

Vascular malformations are thought to be congenital. Although some are obvious at birth, others aren’t apparent until adulthood. In most cases, they grow with a child and may do so disproportionately at puberty and with pregnancies. The fact that vascular malformations persist into adulthood is one reason why their care should be integral to medical hematology-oncology. 

Although the cause of a vascular malformation is not always known, a wide range of genetic mutations thought to be pathogenic have been reported. These mutations are usually somatic (only within the involved tissues, not in the blood or germ cells and therefore, not heritable) and tend to cluster in the VEGF-PIK3CA and RAS-MAP signaling pathways. 

These genes and pathways will be familiar to any oncologist who cares for patients with solid tumors, notably breast cancer or melanoma. However, unlike the clonal expansion seen in cancers, most vascular malformations will express pathogenic mutations in less than 20% of vascular endothelium within a malformation. 

Since 2008, medical management has been limited to sirolimus (rapamycin), a mammalian target of rapamycin inhibitor, which can be effective even when mTOR mutations aren’t apparent. In a seminal phase 2 trial of 57 patients with complex vascular anomalies who were aged 0-29 years, 47 patients had a partial response, 3 patients had stable disease, and 7 patients had progressive disease. None had complete responses. These data highlight the need for more effective treatments.

Recently, vascular anomalists have begun to repurpose drugs from adult oncology that specifically target pathogenic mutations. Some studies underway include Novartis’ international Alpelisib (Piqray) clinical trial for adults and children with PIK3CA-related overgrowth syndromes (NCT04589650) and Merck’s follow-up study of the AKT inhibitor miransertib for PROS and Proteus syndrome. Doses tend to be lower than those used to treat cancers. To date, these have been generally well-tolerated, with sometimes striking but preliminary evidence of efficacy. 

During the past 2 years, symposia on vascular anomalies at the annual meeting of the American Society of Hematology have launched what we are hoping is just the start of a broader discussion. In 2020, Fran Blei, MD, chaired Vascular Anomalies 101: Case-Based Discussion on the Diagnosis, Treatment and Lifelong Care of These Patients, and in 2021, Adrienne Hammill, MD, PhD, and Dr. Raj Kasthuri, MBBS, MD, chaired a more specialized symposium: Hereditary Hemorrhagic Telangiectasia (HHT): A Practical Guide to Management. 

As awareness of vascular anomalies grows and research on effective treatments continues, a new focus on this natural offshoot of hematology and oncology offers adult and pediatric specialists in our field a fertile area for career development.

Dr. Blatt is in the division of pediatric hematology oncology at the University of North Carolina at Chapel Hill. She disclosed no relevant financial relationships.

Only a small number of pediatric hematologist oncologists and even fewer of our adult counterparts feel comfortable evaluating and treating vascular anomalies. 

While admittedly rare, these conditions are still common enough that clinicians in many disciplines encounter them. Hematologist/oncologists are most likely to see vascular malformations, which often present as mass lesions. Complications of these disorders occur across the hematology-oncology spectrum and include clots, pulmonary emboli, cancer predisposition, and an array of functional and psychosocial disorders. 

Vascular anomalies are broadly categorized as vascular tumors or malformations. The tumors include hemangiomas, locally aggressive lesions, and true cancers. Malformations can be isolated disorders of one or more blood vessel types (veins, arteries, capillaries or lymphatics), or they can be one part of syndromic disorders. Lymphedema also falls under the heading of vascular anomalies. To make the terminology less confusing, in 2018 the International Society for the Study of Vascular Anomalies refined its classification scheme.

Vascular malformations are thought to be congenital. Although some are obvious at birth, others aren’t apparent until adulthood. In most cases, they grow with a child and may do so disproportionately at puberty and with pregnancies. The fact that vascular malformations persist into adulthood is one reason why their care should be integral to medical hematology-oncology. 

Although the cause of a vascular malformation is not always known, a wide range of genetic mutations thought to be pathogenic have been reported. These mutations are usually somatic (only within the involved tissues, not in the blood or germ cells and therefore, not heritable) and tend to cluster in the VEGF-PIK3CA and RAS-MAP signaling pathways. 

These genes and pathways will be familiar to any oncologist who cares for patients with solid tumors, notably breast cancer or melanoma. However, unlike the clonal expansion seen in cancers, most vascular malformations will express pathogenic mutations in less than 20% of vascular endothelium within a malformation. 

Since 2008, medical management has been limited to sirolimus (rapamycin), a mammalian target of rapamycin inhibitor, which can be effective even when mTOR mutations aren’t apparent. In a seminal phase 2 trial of 57 patients with complex vascular anomalies who were aged 0-29 years, 47 patients had a partial response, 3 patients had stable disease, and 7 patients had progressive disease. None had complete responses. These data highlight the need for more effective treatments.

Recently, vascular anomalists have begun to repurpose drugs from adult oncology that specifically target pathogenic mutations. Some studies underway include Novartis’ international Alpelisib (Piqray) clinical trial for adults and children with PIK3CA-related overgrowth syndromes (NCT04589650) and Merck’s follow-up study of the AKT inhibitor miransertib for PROS and Proteus syndrome. Doses tend to be lower than those used to treat cancers. To date, these have been generally well-tolerated, with sometimes striking but preliminary evidence of efficacy. 

During the past 2 years, symposia on vascular anomalies at the annual meeting of the American Society of Hematology have launched what we are hoping is just the start of a broader discussion. In 2020, Fran Blei, MD, chaired Vascular Anomalies 101: Case-Based Discussion on the Diagnosis, Treatment and Lifelong Care of These Patients, and in 2021, Adrienne Hammill, MD, PhD, and Dr. Raj Kasthuri, MBBS, MD, chaired a more specialized symposium: Hereditary Hemorrhagic Telangiectasia (HHT): A Practical Guide to Management. 

As awareness of vascular anomalies grows and research on effective treatments continues, a new focus on this natural offshoot of hematology and oncology offers adult and pediatric specialists in our field a fertile area for career development.

Dr. Blatt is in the division of pediatric hematology oncology at the University of North Carolina at Chapel Hill. She disclosed no relevant financial relationships.

Only a small number of pediatric hematologist oncologists and even fewer of our adult counterparts feel comfortable evaluating and treating vascular anomalies. 

While admittedly rare, these conditions are still common enough that clinicians in many disciplines encounter them. Hematologist/oncologists are most likely to see vascular malformations, which often present as mass lesions. Complications of these disorders occur across the hematology-oncology spectrum and include clots, pulmonary emboli, cancer predisposition, and an array of functional and psychosocial disorders. 

Vascular anomalies are broadly categorized as vascular tumors or malformations. The tumors include hemangiomas, locally aggressive lesions, and true cancers. Malformations can be isolated disorders of one or more blood vessel types (veins, arteries, capillaries or lymphatics), or they can be one part of syndromic disorders. Lymphedema also falls under the heading of vascular anomalies. To make the terminology less confusing, in 2018 the International Society for the Study of Vascular Anomalies refined its classification scheme.

Vascular malformations are thought to be congenital. Although some are obvious at birth, others aren’t apparent until adulthood. In most cases, they grow with a child and may do so disproportionately at puberty and with pregnancies. The fact that vascular malformations persist into adulthood is one reason why their care should be integral to medical hematology-oncology. 

Although the cause of a vascular malformation is not always known, a wide range of genetic mutations thought to be pathogenic have been reported. These mutations are usually somatic (only within the involved tissues, not in the blood or germ cells and therefore, not heritable) and tend to cluster in the VEGF-PIK3CA and RAS-MAP signaling pathways. 

These genes and pathways will be familiar to any oncologist who cares for patients with solid tumors, notably breast cancer or melanoma. However, unlike the clonal expansion seen in cancers, most vascular malformations will express pathogenic mutations in less than 20% of vascular endothelium within a malformation. 

Since 2008, medical management has been limited to sirolimus (rapamycin), a mammalian target of rapamycin inhibitor, which can be effective even when mTOR mutations aren’t apparent. In a seminal phase 2 trial of 57 patients with complex vascular anomalies who were aged 0-29 years, 47 patients had a partial response, 3 patients had stable disease, and 7 patients had progressive disease. None had complete responses. These data highlight the need for more effective treatments.

Recently, vascular anomalists have begun to repurpose drugs from adult oncology that specifically target pathogenic mutations. Some studies underway include Novartis’ international Alpelisib (Piqray) clinical trial for adults and children with PIK3CA-related overgrowth syndromes (NCT04589650) and Merck’s follow-up study of the AKT inhibitor miransertib for PROS and Proteus syndrome. Doses tend to be lower than those used to treat cancers. To date, these have been generally well-tolerated, with sometimes striking but preliminary evidence of efficacy. 

During the past 2 years, symposia on vascular anomalies at the annual meeting of the American Society of Hematology have launched what we are hoping is just the start of a broader discussion. In 2020, Fran Blei, MD, chaired Vascular Anomalies 101: Case-Based Discussion on the Diagnosis, Treatment and Lifelong Care of These Patients, and in 2021, Adrienne Hammill, MD, PhD, and Dr. Raj Kasthuri, MBBS, MD, chaired a more specialized symposium: Hereditary Hemorrhagic Telangiectasia (HHT): A Practical Guide to Management. 

As awareness of vascular anomalies grows and research on effective treatments continues, a new focus on this natural offshoot of hematology and oncology offers adult and pediatric specialists in our field a fertile area for career development.

Dr. Blatt is in the division of pediatric hematology oncology at the University of North Carolina at Chapel Hill. She disclosed no relevant financial relationships.

Over the last several years, payer policies that dictate and restrict treatments for patients with inflammatory bowel diseases (IBD) have proliferated. The implementation of new coverage restrictions, expansion of services and procedures requiring prior authorization (PA), and dosing and access restriction to covered drugs, and the requirement of repeated treatment reviews including nonmedical switching for stable patients are widespread. The AGA administered a member needs assessment survey in December 2021 to determine the extent to which these policies harm patients and overburden gastroenterologists and their staff.

Survey findings

Most of the 100 surveyed members reported facing administrative burdens that prevented timely access to patient care. Utilization management practices such as PA, step therapy, and nonmedical switching and dosing restrictions create critical barriers to high quality GI care for patients with chronic conditions and jeopardize the physician-patient relationship. At a time when physicians have faced unprecedented challenges because of the public health emergency from the COVID-19 pandemic, these burdens also contribute to increasing physician burnout.

Prior authorization: Among AGA members, 96% of members said that PA is burdensome, with 61% indicating that it is significantly burdensome. Almost 99% of members indicated that PA has a negative impact on patients’ access to clinically appropriate treatments; 89% reported that the burden associated with PA has increased over the last 5 years in their practice.

Step therapy: Among members, 87% described the impact step therapy has on their practice as burdensome. Almost 90% of members said step therapy negatively impacted patients’ access to clinically appropriate treatments. Almost 90% of members felt that there was an overall negative impact on patient clinical outcomes for those patients who were required to follow a step therapy protocol.

An increasing number of insurance companies are restricting effective biologic therapy to Food and Drug Administration–labeled doses, in direct conflict with current established best practices. It is most concerning that many patients who had been stable on optimized dosing are suddenly notified that they will no longer be able to receive the dose or treatment frequency prescribed by their physician. The concept of optimizing drug therapy based on disease activity and therapeutic drug monitoring is well established, and artificial restrictions to FDA-labeled doses force unnecessary drug deescalation. This transparent effort to reduce costs lacks evidence for safety. Our sickest patients often require higher doses for induction in order to respond, given drug losses, yet some payers refuse to cover the doses these patients require. This new payer-centered effort prioritizes cost containment over the judgment of the treating physician. It causes direct patient harm risking efficacy or loss of response, and subsequent irreversible disease-related complications.
 

Medicare drug costs

Medicare patients receiving self-injectable or oral medications are not eligible for co-pay assistance programs through pharmaceutical companies because of federal rules. For non-Medicare patients, these programs reduce the co-pay costs to as low as $5 per month. Medicare patients are able to receive infusions like infliximab and vedolizumab at no cost. However, any self-injectable or oral agent can carry a co-pay of over $1,000. Other than for patients meeting income-based eligibility requirements (e.g., below the poverty line), these treatments become prohibitively expensive. Thousands of patients have had to discontinue their self-injectable and/or oral medications because of this cost or have been denied access to the therapy altogether because of cost.

Need for change

These recent changes in insurance policies have resulted in increased harm to our patients with IBD rather than improving the safety or quality of their care. These changes create barriers to disease treatment and have not improved quality of care, patient outcomes, or quality of life. The AGA and other societies have published multiple guidelines and literature on the management of patients with IBD that should serve as the foundation for insurers’ medication coverage policies. Additionally, insurance companies should seek input from panels of IBD experts when developing their medication coverage policies to ensure they are patient oriented and facilitate high-quality IBD care.

The following are opportunities for insurers to improve the IBD drug approval process:

• Simplify the appeal process.
• Guarantee rapid response/turnaround to appeal processes to avoid additional delays in care.
• Incorporate experienced expert review by a gastroenterologist.
• Ensure coverage of drug and disease monitoring.
• Integrate expert input in policy development.

Conclusion

Effective patient care in IBD, as well as in other chronic gastrointestinal diseases, requires a collaborative approach to maximize clinical outcomes. It is an exciting time in our field, with rapidly expanding therapeutic options to treat IBD that have the potential to modify the disease course and prevent long-term complications for patients. However, optimizing the use of these treatments to achieve disease remission is challenging and requires the ability to individualize the timely choice of medications at the right dose for each patient to capture and monitor response. The ability to provide individualized, data driven care is essential to improving the quality of life of our patients, as well as to reducing health care spending over time.

Achieving high-value care is a goal that benefits everyone involved in the health care system. Policies that interfere with the timely treatment of sick patients with the right therapies, optimized to achieve disease remission, hurt the very patients that our health care system exists to serve. We cannot stand by while impediments to treatment result in harm to our patients and worsen clinical outcomes. Collaboratively developing aligned incentives can lead us to patient-centered policies that fulfill a shared purpose to optimize the health of people with chronic digestive diseases.

The authors reported having no relevant conflicts of interest.

Dr. Feuerstein is with the Center for Inflammatory Bowel Disease at Beth Israel Deaconess Medical Center and is an associate professor of medicine Harvard Medical School, both in Boston. Dr. Sofia is an assistant professor of medicine with the division of gastroenterology and hepatology at Oregon Health and Science University, Portland. Dr. Guha is a professor of medicine at the division of gastroenterology, hepatology and nutrition and is codirector of the Center for Interventional Gastroenterology at UTHealth (iGUT) at UT Health Science Center, Houston. Dr. Streett is a clinical professor of medicine, gastroenterology, and hepatology and director of the IBD Education and Advanced IBD Fellowship at Stanford (Calif.) Medicine.

Over the last several years, payer policies that dictate and restrict treatments for patients with inflammatory bowel diseases (IBD) have proliferated. The implementation of new coverage restrictions, expansion of services and procedures requiring prior authorization (PA), and dosing and access restriction to covered drugs, and the requirement of repeated treatment reviews including nonmedical switching for stable patients are widespread. The AGA administered a member needs assessment survey in December 2021 to determine the extent to which these policies harm patients and overburden gastroenterologists and their staff.

Survey findings

Most of the 100 surveyed members reported facing administrative burdens that prevented timely access to patient care. Utilization management practices such as PA, step therapy, and nonmedical switching and dosing restrictions create critical barriers to high quality GI care for patients with chronic conditions and jeopardize the physician-patient relationship. At a time when physicians have faced unprecedented challenges because of the public health emergency from the COVID-19 pandemic, these burdens also contribute to increasing physician burnout.

Prior authorization: Among AGA members, 96% of members said that PA is burdensome, with 61% indicating that it is significantly burdensome. Almost 99% of members indicated that PA has a negative impact on patients’ access to clinically appropriate treatments; 89% reported that the burden associated with PA has increased over the last 5 years in their practice.

Step therapy: Among members, 87% described the impact step therapy has on their practice as burdensome. Almost 90% of members said step therapy negatively impacted patients’ access to clinically appropriate treatments. Almost 90% of members felt that there was an overall negative impact on patient clinical outcomes for those patients who were required to follow a step therapy protocol.

An increasing number of insurance companies are restricting effective biologic therapy to Food and Drug Administration–labeled doses, in direct conflict with current established best practices. It is most concerning that many patients who had been stable on optimized dosing are suddenly notified that they will no longer be able to receive the dose or treatment frequency prescribed by their physician. The concept of optimizing drug therapy based on disease activity and therapeutic drug monitoring is well established, and artificial restrictions to FDA-labeled doses force unnecessary drug deescalation. This transparent effort to reduce costs lacks evidence for safety. Our sickest patients often require higher doses for induction in order to respond, given drug losses, yet some payers refuse to cover the doses these patients require. This new payer-centered effort prioritizes cost containment over the judgment of the treating physician. It causes direct patient harm risking efficacy or loss of response, and subsequent irreversible disease-related complications.
 

Medicare drug costs

Medicare patients receiving self-injectable or oral medications are not eligible for co-pay assistance programs through pharmaceutical companies because of federal rules. For non-Medicare patients, these programs reduce the co-pay costs to as low as $5 per month. Medicare patients are able to receive infusions like infliximab and vedolizumab at no cost. However, any self-injectable or oral agent can carry a co-pay of over $1,000. Other than for patients meeting income-based eligibility requirements (e.g., below the poverty line), these treatments become prohibitively expensive. Thousands of patients have had to discontinue their self-injectable and/or oral medications because of this cost or have been denied access to the therapy altogether because of cost.

Need for change

These recent changes in insurance policies have resulted in increased harm to our patients with IBD rather than improving the safety or quality of their care. These changes create barriers to disease treatment and have not improved quality of care, patient outcomes, or quality of life. The AGA and other societies have published multiple guidelines and literature on the management of patients with IBD that should serve as the foundation for insurers’ medication coverage policies. Additionally, insurance companies should seek input from panels of IBD experts when developing their medication coverage policies to ensure they are patient oriented and facilitate high-quality IBD care.

The following are opportunities for insurers to improve the IBD drug approval process:

• Simplify the appeal process.
• Guarantee rapid response/turnaround to appeal processes to avoid additional delays in care.
• Incorporate experienced expert review by a gastroenterologist.
• Ensure coverage of drug and disease monitoring.
• Integrate expert input in policy development.

Conclusion

Effective patient care in IBD, as well as in other chronic gastrointestinal diseases, requires a collaborative approach to maximize clinical outcomes. It is an exciting time in our field, with rapidly expanding therapeutic options to treat IBD that have the potential to modify the disease course and prevent long-term complications for patients. However, optimizing the use of these treatments to achieve disease remission is challenging and requires the ability to individualize the timely choice of medications at the right dose for each patient to capture and monitor response. The ability to provide individualized, data driven care is essential to improving the quality of life of our patients, as well as to reducing health care spending over time.

Achieving high-value care is a goal that benefits everyone involved in the health care system. Policies that interfere with the timely treatment of sick patients with the right therapies, optimized to achieve disease remission, hurt the very patients that our health care system exists to serve. We cannot stand by while impediments to treatment result in harm to our patients and worsen clinical outcomes. Collaboratively developing aligned incentives can lead us to patient-centered policies that fulfill a shared purpose to optimize the health of people with chronic digestive diseases.

The authors reported having no relevant conflicts of interest.

Dr. Feuerstein is with the Center for Inflammatory Bowel Disease at Beth Israel Deaconess Medical Center and is an associate professor of medicine Harvard Medical School, both in Boston. Dr. Sofia is an assistant professor of medicine with the division of gastroenterology and hepatology at Oregon Health and Science University, Portland. Dr. Guha is a professor of medicine at the division of gastroenterology, hepatology and nutrition and is codirector of the Center for Interventional Gastroenterology at UTHealth (iGUT) at UT Health Science Center, Houston. Dr. Streett is a clinical professor of medicine, gastroenterology, and hepatology and director of the IBD Education and Advanced IBD Fellowship at Stanford (Calif.) Medicine.

Over the last several years, payer policies that dictate and restrict treatments for patients with inflammatory bowel diseases (IBD) have proliferated. The implementation of new coverage restrictions, expansion of services and procedures requiring prior authorization (PA), and dosing and access restriction to covered drugs, and the requirement of repeated treatment reviews including nonmedical switching for stable patients are widespread. The AGA administered a member needs assessment survey in December 2021 to determine the extent to which these policies harm patients and overburden gastroenterologists and their staff.

Survey findings

Most of the 100 surveyed members reported facing administrative burdens that prevented timely access to patient care. Utilization management practices such as PA, step therapy, and nonmedical switching and dosing restrictions create critical barriers to high quality GI care for patients with chronic conditions and jeopardize the physician-patient relationship. At a time when physicians have faced unprecedented challenges because of the public health emergency from the COVID-19 pandemic, these burdens also contribute to increasing physician burnout.

Prior authorization: Among AGA members, 96% of members said that PA is burdensome, with 61% indicating that it is significantly burdensome. Almost 99% of members indicated that PA has a negative impact on patients’ access to clinically appropriate treatments; 89% reported that the burden associated with PA has increased over the last 5 years in their practice.

Step therapy: Among members, 87% described the impact step therapy has on their practice as burdensome. Almost 90% of members said step therapy negatively impacted patients’ access to clinically appropriate treatments. Almost 90% of members felt that there was an overall negative impact on patient clinical outcomes for those patients who were required to follow a step therapy protocol.

An increasing number of insurance companies are restricting effective biologic therapy to Food and Drug Administration–labeled doses, in direct conflict with current established best practices. It is most concerning that many patients who had been stable on optimized dosing are suddenly notified that they will no longer be able to receive the dose or treatment frequency prescribed by their physician. The concept of optimizing drug therapy based on disease activity and therapeutic drug monitoring is well established, and artificial restrictions to FDA-labeled doses force unnecessary drug deescalation. This transparent effort to reduce costs lacks evidence for safety. Our sickest patients often require higher doses for induction in order to respond, given drug losses, yet some payers refuse to cover the doses these patients require. This new payer-centered effort prioritizes cost containment over the judgment of the treating physician. It causes direct patient harm risking efficacy or loss of response, and subsequent irreversible disease-related complications.
 

Medicare drug costs

Medicare patients receiving self-injectable or oral medications are not eligible for co-pay assistance programs through pharmaceutical companies because of federal rules. For non-Medicare patients, these programs reduce the co-pay costs to as low as $5 per month. Medicare patients are able to receive infusions like infliximab and vedolizumab at no cost. However, any self-injectable or oral agent can carry a co-pay of over $1,000. Other than for patients meeting income-based eligibility requirements (e.g., below the poverty line), these treatments become prohibitively expensive. Thousands of patients have had to discontinue their self-injectable and/or oral medications because of this cost or have been denied access to the therapy altogether because of cost.

Need for change

These recent changes in insurance policies have resulted in increased harm to our patients with IBD rather than improving the safety or quality of their care. These changes create barriers to disease treatment and have not improved quality of care, patient outcomes, or quality of life. The AGA and other societies have published multiple guidelines and literature on the management of patients with IBD that should serve as the foundation for insurers’ medication coverage policies. Additionally, insurance companies should seek input from panels of IBD experts when developing their medication coverage policies to ensure they are patient oriented and facilitate high-quality IBD care.

The following are opportunities for insurers to improve the IBD drug approval process:

• Simplify the appeal process.
• Guarantee rapid response/turnaround to appeal processes to avoid additional delays in care.
• Incorporate experienced expert review by a gastroenterologist.
• Ensure coverage of drug and disease monitoring.
• Integrate expert input in policy development.

Conclusion

Effective patient care in IBD, as well as in other chronic gastrointestinal diseases, requires a collaborative approach to maximize clinical outcomes. It is an exciting time in our field, with rapidly expanding therapeutic options to treat IBD that have the potential to modify the disease course and prevent long-term complications for patients. However, optimizing the use of these treatments to achieve disease remission is challenging and requires the ability to individualize the timely choice of medications at the right dose for each patient to capture and monitor response. The ability to provide individualized, data driven care is essential to improving the quality of life of our patients, as well as to reducing health care spending over time.

Achieving high-value care is a goal that benefits everyone involved in the health care system. Policies that interfere with the timely treatment of sick patients with the right therapies, optimized to achieve disease remission, hurt the very patients that our health care system exists to serve. We cannot stand by while impediments to treatment result in harm to our patients and worsen clinical outcomes. Collaboratively developing aligned incentives can lead us to patient-centered policies that fulfill a shared purpose to optimize the health of people with chronic digestive diseases.

The authors reported having no relevant conflicts of interest.

Dr. Feuerstein is with the Center for Inflammatory Bowel Disease at Beth Israel Deaconess Medical Center and is an associate professor of medicine Harvard Medical School, both in Boston. Dr. Sofia is an assistant professor of medicine with the division of gastroenterology and hepatology at Oregon Health and Science University, Portland. Dr. Guha is a professor of medicine at the division of gastroenterology, hepatology and nutrition and is codirector of the Center for Interventional Gastroenterology at UTHealth (iGUT) at UT Health Science Center, Houston. Dr. Streett is a clinical professor of medicine, gastroenterology, and hepatology and director of the IBD Education and Advanced IBD Fellowship at Stanford (Calif.) Medicine.

BOSTON – Dupilumab, a human monoclonal IgG4 antibody, was an effective treatment for prurigo nodularis (PN), improving itching and skin lesions after 12 and 24 weeks of treatment, in a phase 3 trial presented at the American Academy of Dermatology 2022 Annual Meeting.

There are currently no Food and Drug Administration–approved systemic therapies for PN. Although several treatments for the disease are used off label for the condition, such as ultraviolet light therapy and immunosuppressive agents, moderate to severe PN is usually difficult to control, noted Gil Yosipovitch, MD, director of the Miami Itch Center at the University of Miami Miller School of Medicine, Florida. He led the research and presented the findings at the conference.

“Many dermatologists feel very uncomfortable dealing with these patients because they suffer from chronicity, they are miserable, and previously, the drugs didn’t work well,” Dr. Yosipovitch told this news organization. The results from this trial “are very promising,” he said. “It opens a new field of treatment for itchy conditions.”

The trial, named LIBERTY-PN PRIME2, enrolled patients aged 18-80 who had been living with PN for at least 3 months. Patients had at least 20 lesions at baseline as well as severe itch, defined as a score of 7 or greater on the Worst Itch Numerical Rating Scale (WI-NRS). The scale ranges from 0 (no itch) to 10 (worst itch imaginable). Participants also had a history of treatment failure with medium to super-potent topical corticosteroids (TCSs), or treatment with TCSs was not medically advisable for them.

The randomized, double-blinded study enrolled 160 adults with PN. Of those, 78 were assigned to the treatment arm and received a 600-mg loading dose of dupilumab, administered subcutaneously, followed by 300-mg doses every 2 weeks for 24 weeks; 82 patients were allocated to receive placebo.

During the study, 25 patients in the placebo arm discontinued treatment. In the treatment arm, one patient was not treated and two discontinued treatment due to lack of efficacy.

The primary endpoint of the study was a reduction of at least 4 points on the WI-NRS at 12 weeks. Secondary endpoints included at least a 4-point WI-NRS reduction at 24 weeks and clear to nearly clear skin, defined as having a score of 0 or 1 on the Investigator’s Global Assessment PN-Stage (IGN PN-S). The scale ranges from 0 (clear) to 4 (severe).

At 12 weeks, 37.2% of patients given dupilumab reported a reduction of at least 4 points in WI-NRS, compared with 22.0% of patients given placebo (P = .0216). By 24 weeks, 57.7% of adults who received dupilumab achieved a greater than or equal to 4-point reduction in WI-NRS, compared with 19.5% of those who received placebo (P < .0001). Additionally, 44.9% of participants in the treatment arm achieved a score of 0 or 1 on the IGA PN-S, compared with 15.9% of those in the placebo arm (P < .0001).

Forty-four participants who received dupilumab (57.1%) and 42 participants who received placebo (51.2%) reported at least one treatment-emergent adverse event (TEAE) during the study, though none of these events were serious. The most common TEAE in the study was headache, occurring in five patients taking placebo and four patients receiving dupilumab. In the dupilumab group, there were five cases of herpes virus infection, four non-herpes skin infections, and three cases of conjunctivitis. In the placebo group, seven non-herpes skin infections were reported.

Sanofi and Regeneron, who jointly developed dupilumab, plan to file for regulatory approval for dupilumab for PN “around the world” in the first half of this year, according to a press release.

“It’s great news and a step in the right direction,” Sarina Elmariah, MD, PhD, a dermatologist at Massachusetts General Hospital and instructor of dermatology at Harvard Medical School, both in Boston, told this news organization. She was not involved with the research.

“We’re finally starting to shed light on this condition and its pathogenesis,” she said. She noted that other potential therapeutics for PN are also in development. “It’s reflective of the fact that we are making strides in this area.”

Sanofi and Regeneron Pharmaceuticals sponsored the LIBERTY-PN PRIME2 trial. Dr. Yosipovitch has reported financial relationships with Bellus Health, Eli Lilly, Galderma, GSK, Kiniksa Pharmaceuticals, LEO Pharma, Novartis, Pfizer, Regeneron, Sanofi, and Trevi Therapeutics. Dr. Elmariah is on the advisory boards of Sanofi, Galderma, and Trevi Therapeutics.

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

BOSTON – Dupilumab, a human monoclonal IgG4 antibody, was an effective treatment for prurigo nodularis (PN), improving itching and skin lesions after 12 and 24 weeks of treatment, in a phase 3 trial presented at the American Academy of Dermatology 2022 Annual Meeting.

There are currently no Food and Drug Administration–approved systemic therapies for PN. Although several treatments for the disease are used off label for the condition, such as ultraviolet light therapy and immunosuppressive agents, moderate to severe PN is usually difficult to control, noted Gil Yosipovitch, MD, director of the Miami Itch Center at the University of Miami Miller School of Medicine, Florida. He led the research and presented the findings at the conference.

“Many dermatologists feel very uncomfortable dealing with these patients because they suffer from chronicity, they are miserable, and previously, the drugs didn’t work well,” Dr. Yosipovitch told this news organization. The results from this trial “are very promising,” he said. “It opens a new field of treatment for itchy conditions.”

The trial, named LIBERTY-PN PRIME2, enrolled patients aged 18-80 who had been living with PN for at least 3 months. Patients had at least 20 lesions at baseline as well as severe itch, defined as a score of 7 or greater on the Worst Itch Numerical Rating Scale (WI-NRS). The scale ranges from 0 (no itch) to 10 (worst itch imaginable). Participants also had a history of treatment failure with medium to super-potent topical corticosteroids (TCSs), or treatment with TCSs was not medically advisable for them.

The randomized, double-blinded study enrolled 160 adults with PN. Of those, 78 were assigned to the treatment arm and received a 600-mg loading dose of dupilumab, administered subcutaneously, followed by 300-mg doses every 2 weeks for 24 weeks; 82 patients were allocated to receive placebo.

During the study, 25 patients in the placebo arm discontinued treatment. In the treatment arm, one patient was not treated and two discontinued treatment due to lack of efficacy.

The primary endpoint of the study was a reduction of at least 4 points on the WI-NRS at 12 weeks. Secondary endpoints included at least a 4-point WI-NRS reduction at 24 weeks and clear to nearly clear skin, defined as having a score of 0 or 1 on the Investigator’s Global Assessment PN-Stage (IGN PN-S). The scale ranges from 0 (clear) to 4 (severe).

At 12 weeks, 37.2% of patients given dupilumab reported a reduction of at least 4 points in WI-NRS, compared with 22.0% of patients given placebo (P = .0216). By 24 weeks, 57.7% of adults who received dupilumab achieved a greater than or equal to 4-point reduction in WI-NRS, compared with 19.5% of those who received placebo (P < .0001). Additionally, 44.9% of participants in the treatment arm achieved a score of 0 or 1 on the IGA PN-S, compared with 15.9% of those in the placebo arm (P < .0001).

Forty-four participants who received dupilumab (57.1%) and 42 participants who received placebo (51.2%) reported at least one treatment-emergent adverse event (TEAE) during the study, though none of these events were serious. The most common TEAE in the study was headache, occurring in five patients taking placebo and four patients receiving dupilumab. In the dupilumab group, there were five cases of herpes virus infection, four non-herpes skin infections, and three cases of conjunctivitis. In the placebo group, seven non-herpes skin infections were reported.

Sanofi and Regeneron, who jointly developed dupilumab, plan to file for regulatory approval for dupilumab for PN “around the world” in the first half of this year, according to a press release.

“It’s great news and a step in the right direction,” Sarina Elmariah, MD, PhD, a dermatologist at Massachusetts General Hospital and instructor of dermatology at Harvard Medical School, both in Boston, told this news organization. She was not involved with the research.

“We’re finally starting to shed light on this condition and its pathogenesis,” she said. She noted that other potential therapeutics for PN are also in development. “It’s reflective of the fact that we are making strides in this area.”

Sanofi and Regeneron Pharmaceuticals sponsored the LIBERTY-PN PRIME2 trial. Dr. Yosipovitch has reported financial relationships with Bellus Health, Eli Lilly, Galderma, GSK, Kiniksa Pharmaceuticals, LEO Pharma, Novartis, Pfizer, Regeneron, Sanofi, and Trevi Therapeutics. Dr. Elmariah is on the advisory boards of Sanofi, Galderma, and Trevi Therapeutics.

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

BOSTON – Dupilumab, a human monoclonal IgG4 antibody, was an effective treatment for prurigo nodularis (PN), improving itching and skin lesions after 12 and 24 weeks of treatment, in a phase 3 trial presented at the American Academy of Dermatology 2022 Annual Meeting.

There are currently no Food and Drug Administration–approved systemic therapies for PN. Although several treatments for the disease are used off label for the condition, such as ultraviolet light therapy and immunosuppressive agents, moderate to severe PN is usually difficult to control, noted Gil Yosipovitch, MD, director of the Miami Itch Center at the University of Miami Miller School of Medicine, Florida. He led the research and presented the findings at the conference.

“Many dermatologists feel very uncomfortable dealing with these patients because they suffer from chronicity, they are miserable, and previously, the drugs didn’t work well,” Dr. Yosipovitch told this news organization. The results from this trial “are very promising,” he said. “It opens a new field of treatment for itchy conditions.”

The trial, named LIBERTY-PN PRIME2, enrolled patients aged 18-80 who had been living with PN for at least 3 months. Patients had at least 20 lesions at baseline as well as severe itch, defined as a score of 7 or greater on the Worst Itch Numerical Rating Scale (WI-NRS). The scale ranges from 0 (no itch) to 10 (worst itch imaginable). Participants also had a history of treatment failure with medium to super-potent topical corticosteroids (TCSs), or treatment with TCSs was not medically advisable for them.

The randomized, double-blinded study enrolled 160 adults with PN. Of those, 78 were assigned to the treatment arm and received a 600-mg loading dose of dupilumab, administered subcutaneously, followed by 300-mg doses every 2 weeks for 24 weeks; 82 patients were allocated to receive placebo.

During the study, 25 patients in the placebo arm discontinued treatment. In the treatment arm, one patient was not treated and two discontinued treatment due to lack of efficacy.

The primary endpoint of the study was a reduction of at least 4 points on the WI-NRS at 12 weeks. Secondary endpoints included at least a 4-point WI-NRS reduction at 24 weeks and clear to nearly clear skin, defined as having a score of 0 or 1 on the Investigator’s Global Assessment PN-Stage (IGN PN-S). The scale ranges from 0 (clear) to 4 (severe).

At 12 weeks, 37.2% of patients given dupilumab reported a reduction of at least 4 points in WI-NRS, compared with 22.0% of patients given placebo (P = .0216). By 24 weeks, 57.7% of adults who received dupilumab achieved a greater than or equal to 4-point reduction in WI-NRS, compared with 19.5% of those who received placebo (P < .0001). Additionally, 44.9% of participants in the treatment arm achieved a score of 0 or 1 on the IGA PN-S, compared with 15.9% of those in the placebo arm (P < .0001).

Forty-four participants who received dupilumab (57.1%) and 42 participants who received placebo (51.2%) reported at least one treatment-emergent adverse event (TEAE) during the study, though none of these events were serious. The most common TEAE in the study was headache, occurring in five patients taking placebo and four patients receiving dupilumab. In the dupilumab group, there were five cases of herpes virus infection, four non-herpes skin infections, and three cases of conjunctivitis. In the placebo group, seven non-herpes skin infections were reported.

Sanofi and Regeneron, who jointly developed dupilumab, plan to file for regulatory approval for dupilumab for PN “around the world” in the first half of this year, according to a press release.

“It’s great news and a step in the right direction,” Sarina Elmariah, MD, PhD, a dermatologist at Massachusetts General Hospital and instructor of dermatology at Harvard Medical School, both in Boston, told this news organization. She was not involved with the research.

“We’re finally starting to shed light on this condition and its pathogenesis,” she said. She noted that other potential therapeutics for PN are also in development. “It’s reflective of the fact that we are making strides in this area.”

Sanofi and Regeneron Pharmaceuticals sponsored the LIBERTY-PN PRIME2 trial. Dr. Yosipovitch has reported financial relationships with Bellus Health, Eli Lilly, Galderma, GSK, Kiniksa Pharmaceuticals, LEO Pharma, Novartis, Pfizer, Regeneron, Sanofi, and Trevi Therapeutics. Dr. Elmariah is on the advisory boards of Sanofi, Galderma, and Trevi Therapeutics.

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

BOSTON – Requests for a medical waiver to avoid a second COVID-19 vaccine dose or a booster after cutaneous reactions to the first dose are not justified on the basis of risk, according to an analysis of several large sets of data presented at the annual meeting of the American Academy of Dermatology.

According to the data, “there are no serious adverse consequences from these cutaneous reactions,” said Esther Freeman, MD, PhD, director of Global Health Dermatology, Massachusetts General Hospital, Boston.

This is important because the risk of vaccine hesitancy goes up dramatically in patients who experience reactions to the first vaccine dose, according to follow-up of more than 50,000 employees vaccinated in the Mass General Brigham Healthcare System (MGBHS). According to Dr. Freeman, there was almost a fourfold increase in the rate of second-dose refusals for those with cutaneous reactions and a more than fourfold increase in those who developed angioedema.

Before the data were available, skin reactions were a source of concern among dermatologists and others involved in monitoring vaccine-related adverse events. Injection site reactions (ISRs) are associated with essentially every injectable vaccine, so these were expected, but a small proportion of patients developed large red plaques in the injection arm 7-8 days after the inoculation.

“These delayed reactions caused a lot of initial panic,” said Dr. Freeman, who counted herself among those alarmed about what the reactions might signify. “Was this cellulitis? Would the next dose cause anaphylaxis? We were concerned.”

This concern dissipated with the availability of more data. In a global registry that has so far captured more than 1,000 cutaneous reactions from 52 participating countries, it appears that about 2% of patients have a cutaneous reaction other than an ISR after the first dose. All resolve with minimal skin care or no treatment.

After the second dose, the proportion is lower. If there is a reaction, it typically occurs earlier and resolves more quickly.

“What we have learned is that fewer than half of patients who had a reaction to the first dose have a reaction to the second, and those who did have a reaction had a milder course,” said Dr. Freeman.

These data are “incredibly reassuring” on many levels, she explained. In addition, it allows clinicians to confidently explain to patients that there are no serious sequelae from the rashes, whether immediate or delayed, from the available COVID-19 vaccines.

“Every skin reaction I have seen is something we can treat through,” she added, noting that most reactions resolve with little or no supportive care. Following skin reactions, particularly the delayed lesions, it is not uncommon for patients to refuse a second shot. Some request a medical waiver to avoid further vaccine exposure. According to Dr. Freeman, this is unwarranted.

“I have granted exactly zero waivers,” she said. She explains to patients that these reactions have not been predictive of serious events, such as anaphylaxis. Although the trigger of the hypersensitivity reaction remains unknown, there is no evidence of serious consequences.

Delayed skin reactions are more commonly associated with the Moderna than the Pfizer vaccine. One notable difference between these vaccines is the greater content of mRNA in the Moderna formulation, but Freeman said that this is only one potential hypothesis for higher frequency of reactions to this version of the vaccine.

Patients with a history of allergic disease are more likely to develop a reaction but not significantly more likely to have a reaction that is more difficult to manage, according to Kimberly G. Blumenthal, MD, quality and safety officer for allergy, and codirector of the clinical epidemiology program in the division of rheumatology, allergy, and immunology at Mass General.

Massachusetts General Hospital

Anaphylaxis has been associated with COVD-19 vaccines just as it has with essentially every injectable vaccine, Dr. Blumenthal said during the same session. But the risk is very low, and it stays low even among those with a history of severe hypersensitivity reactions in the past.

Among the data collected from more than 52,000 vaccinated MGBHS employees, 0.9% had a history of severe allergic reaction to a prior vaccine. Of these, 11.6% had an allergic reaction to the COVID-19 vaccine. This was more than twice the 4.6% rate of allergic reactions among employees without a history of allergic reactions, but serious consequences were rare in both groups.

Of those with a reaction to the first dose, all but 2.4% took a subsequent dose. Again, serious reactions were exceedingly rare. These serious reactions did include anaphylaxis and hospitalization in 3% of patients, but there were no fatalities and all resolved.

The absence of serious sequelae from a reaction to a COVID-19 vaccine must be considered within the context of the benefit, which includes protection from death and hospitalization from the virus, according to Dr. Blumenthal. Citing the evidence that first-shot reactions are a source of vaccine hesitancy, she agreed that it is important to educate patients about relative risks.

“Even in our own cohort of MGBHS employees, we have people, including those who had been provaccine in the past, become hesitant,” commented Dr. Blumenthal, who said there are data from the Kaiser Permanente System showing similar vaccine reluctance following a first-shot reaction.

After more than 500 million doses of the Moderna and Pfizer vaccines had been administered worldwide, there was not a single reported death from anaphylaxis. Although Dr. Blumenthal said that an unconfirmed death of this type had been recently reported, she emphasized that this single death, if valid, is dwarfed by the lives saved with vaccination.

Asked about her strategy for counseling patients with vaccine hesitancy, Dr. Freeman said the body of safety data is large and compelling. There is overwhelming evidence of a favorable benefit-to-risk ratio overall and among those with a first-shot reaction.

“I can reassure them on the basis of the data,” Dr. Freeman said in an interview. “Less than half will have a reaction to the second shot and even if they do have a reaction, it is likely to be less severe.”

Although the main message is that vaccination is potentially lifesaving and far outweighs any risks, Freeman specifically gives this message to those hesitant to take a second shot after a first-shot reaction: “I can get you through it.”

Dr. Freeman encouraged health care professionals to report cases of COVID-19 vaccine–related dermatologic side effects to the American Academy of Dermatology / International League of Dermatologic Societies COVID-19 dermatology registry. Dermatologic manifestations of COVID-19 can also be reported to the registry.

Dr. Freeman disclosed receiving grants/research funding from the International League of Dermatologic Societies and from the National Institutes of Health. Dr. Blumenthal disclosed no relevant financial relationships.

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

BOSTON – Requests for a medical waiver to avoid a second COVID-19 vaccine dose or a booster after cutaneous reactions to the first dose are not justified on the basis of risk, according to an analysis of several large sets of data presented at the annual meeting of the American Academy of Dermatology.

According to the data, “there are no serious adverse consequences from these cutaneous reactions,” said Esther Freeman, MD, PhD, director of Global Health Dermatology, Massachusetts General Hospital, Boston.

This is important because the risk of vaccine hesitancy goes up dramatically in patients who experience reactions to the first vaccine dose, according to follow-up of more than 50,000 employees vaccinated in the Mass General Brigham Healthcare System (MGBHS). According to Dr. Freeman, there was almost a fourfold increase in the rate of second-dose refusals for those with cutaneous reactions and a more than fourfold increase in those who developed angioedema.

Before the data were available, skin reactions were a source of concern among dermatologists and others involved in monitoring vaccine-related adverse events. Injection site reactions (ISRs) are associated with essentially every injectable vaccine, so these were expected, but a small proportion of patients developed large red plaques in the injection arm 7-8 days after the inoculation.

“These delayed reactions caused a lot of initial panic,” said Dr. Freeman, who counted herself among those alarmed about what the reactions might signify. “Was this cellulitis? Would the next dose cause anaphylaxis? We were concerned.”

This concern dissipated with the availability of more data. In a global registry that has so far captured more than 1,000 cutaneous reactions from 52 participating countries, it appears that about 2% of patients have a cutaneous reaction other than an ISR after the first dose. All resolve with minimal skin care or no treatment.

After the second dose, the proportion is lower. If there is a reaction, it typically occurs earlier and resolves more quickly.

“What we have learned is that fewer than half of patients who had a reaction to the first dose have a reaction to the second, and those who did have a reaction had a milder course,” said Dr. Freeman.

These data are “incredibly reassuring” on many levels, she explained. In addition, it allows clinicians to confidently explain to patients that there are no serious sequelae from the rashes, whether immediate or delayed, from the available COVID-19 vaccines.

“Every skin reaction I have seen is something we can treat through,” she added, noting that most reactions resolve with little or no supportive care. Following skin reactions, particularly the delayed lesions, it is not uncommon for patients to refuse a second shot. Some request a medical waiver to avoid further vaccine exposure. According to Dr. Freeman, this is unwarranted.

“I have granted exactly zero waivers,” she said. She explains to patients that these reactions have not been predictive of serious events, such as anaphylaxis. Although the trigger of the hypersensitivity reaction remains unknown, there is no evidence of serious consequences.

Delayed skin reactions are more commonly associated with the Moderna than the Pfizer vaccine. One notable difference between these vaccines is the greater content of mRNA in the Moderna formulation, but Freeman said that this is only one potential hypothesis for higher frequency of reactions to this version of the vaccine.

Patients with a history of allergic disease are more likely to develop a reaction but not significantly more likely to have a reaction that is more difficult to manage, according to Kimberly G. Blumenthal, MD, quality and safety officer for allergy, and codirector of the clinical epidemiology program in the division of rheumatology, allergy, and immunology at Mass General.

Massachusetts General Hospital

Anaphylaxis has been associated with COVD-19 vaccines just as it has with essentially every injectable vaccine, Dr. Blumenthal said during the same session. But the risk is very low, and it stays low even among those with a history of severe hypersensitivity reactions in the past.

Among the data collected from more than 52,000 vaccinated MGBHS employees, 0.9% had a history of severe allergic reaction to a prior vaccine. Of these, 11.6% had an allergic reaction to the COVID-19 vaccine. This was more than twice the 4.6% rate of allergic reactions among employees without a history of allergic reactions, but serious consequences were rare in both groups.

Of those with a reaction to the first dose, all but 2.4% took a subsequent dose. Again, serious reactions were exceedingly rare. These serious reactions did include anaphylaxis and hospitalization in 3% of patients, but there were no fatalities and all resolved.

The absence of serious sequelae from a reaction to a COVID-19 vaccine must be considered within the context of the benefit, which includes protection from death and hospitalization from the virus, according to Dr. Blumenthal. Citing the evidence that first-shot reactions are a source of vaccine hesitancy, she agreed that it is important to educate patients about relative risks.

“Even in our own cohort of MGBHS employees, we have people, including those who had been provaccine in the past, become hesitant,” commented Dr. Blumenthal, who said there are data from the Kaiser Permanente System showing similar vaccine reluctance following a first-shot reaction.

After more than 500 million doses of the Moderna and Pfizer vaccines had been administered worldwide, there was not a single reported death from anaphylaxis. Although Dr. Blumenthal said that an unconfirmed death of this type had been recently reported, she emphasized that this single death, if valid, is dwarfed by the lives saved with vaccination.

Asked about her strategy for counseling patients with vaccine hesitancy, Dr. Freeman said the body of safety data is large and compelling. There is overwhelming evidence of a favorable benefit-to-risk ratio overall and among those with a first-shot reaction.

“I can reassure them on the basis of the data,” Dr. Freeman said in an interview. “Less than half will have a reaction to the second shot and even if they do have a reaction, it is likely to be less severe.”

Although the main message is that vaccination is potentially lifesaving and far outweighs any risks, Freeman specifically gives this message to those hesitant to take a second shot after a first-shot reaction: “I can get you through it.”

Dr. Freeman encouraged health care professionals to report cases of COVID-19 vaccine–related dermatologic side effects to the American Academy of Dermatology / International League of Dermatologic Societies COVID-19 dermatology registry. Dermatologic manifestations of COVID-19 can also be reported to the registry.

Dr. Freeman disclosed receiving grants/research funding from the International League of Dermatologic Societies and from the National Institutes of Health. Dr. Blumenthal disclosed no relevant financial relationships.

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

BOSTON – Requests for a medical waiver to avoid a second COVID-19 vaccine dose or a booster after cutaneous reactions to the first dose are not justified on the basis of risk, according to an analysis of several large sets of data presented at the annual meeting of the American Academy of Dermatology.

According to the data, “there are no serious adverse consequences from these cutaneous reactions,” said Esther Freeman, MD, PhD, director of Global Health Dermatology, Massachusetts General Hospital, Boston.

This is important because the risk of vaccine hesitancy goes up dramatically in patients who experience reactions to the first vaccine dose, according to follow-up of more than 50,000 employees vaccinated in the Mass General Brigham Healthcare System (MGBHS). According to Dr. Freeman, there was almost a fourfold increase in the rate of second-dose refusals for those with cutaneous reactions and a more than fourfold increase in those who developed angioedema.

Before the data were available, skin reactions were a source of concern among dermatologists and others involved in monitoring vaccine-related adverse events. Injection site reactions (ISRs) are associated with essentially every injectable vaccine, so these were expected, but a small proportion of patients developed large red plaques in the injection arm 7-8 days after the inoculation.

“These delayed reactions caused a lot of initial panic,” said Dr. Freeman, who counted herself among those alarmed about what the reactions might signify. “Was this cellulitis? Would the next dose cause anaphylaxis? We were concerned.”

This concern dissipated with the availability of more data. In a global registry that has so far captured more than 1,000 cutaneous reactions from 52 participating countries, it appears that about 2% of patients have a cutaneous reaction other than an ISR after the first dose. All resolve with minimal skin care or no treatment.

After the second dose, the proportion is lower. If there is a reaction, it typically occurs earlier and resolves more quickly.

“What we have learned is that fewer than half of patients who had a reaction to the first dose have a reaction to the second, and those who did have a reaction had a milder course,” said Dr. Freeman.

These data are “incredibly reassuring” on many levels, she explained. In addition, it allows clinicians to confidently explain to patients that there are no serious sequelae from the rashes, whether immediate or delayed, from the available COVID-19 vaccines.

“Every skin reaction I have seen is something we can treat through,” she added, noting that most reactions resolve with little or no supportive care. Following skin reactions, particularly the delayed lesions, it is not uncommon for patients to refuse a second shot. Some request a medical waiver to avoid further vaccine exposure. According to Dr. Freeman, this is unwarranted.

“I have granted exactly zero waivers,” she said. She explains to patients that these reactions have not been predictive of serious events, such as anaphylaxis. Although the trigger of the hypersensitivity reaction remains unknown, there is no evidence of serious consequences.

Delayed skin reactions are more commonly associated with the Moderna than the Pfizer vaccine. One notable difference between these vaccines is the greater content of mRNA in the Moderna formulation, but Freeman said that this is only one potential hypothesis for higher frequency of reactions to this version of the vaccine.

Patients with a history of allergic disease are more likely to develop a reaction but not significantly more likely to have a reaction that is more difficult to manage, according to Kimberly G. Blumenthal, MD, quality and safety officer for allergy, and codirector of the clinical epidemiology program in the division of rheumatology, allergy, and immunology at Mass General.

Massachusetts General Hospital

Anaphylaxis has been associated with COVD-19 vaccines just as it has with essentially every injectable vaccine, Dr. Blumenthal said during the same session. But the risk is very low, and it stays low even among those with a history of severe hypersensitivity reactions in the past.

Among the data collected from more than 52,000 vaccinated MGBHS employees, 0.9% had a history of severe allergic reaction to a prior vaccine. Of these, 11.6% had an allergic reaction to the COVID-19 vaccine. This was more than twice the 4.6% rate of allergic reactions among employees without a history of allergic reactions, but serious consequences were rare in both groups.

Of those with a reaction to the first dose, all but 2.4% took a subsequent dose. Again, serious reactions were exceedingly rare. These serious reactions did include anaphylaxis and hospitalization in 3% of patients, but there were no fatalities and all resolved.

The absence of serious sequelae from a reaction to a COVID-19 vaccine must be considered within the context of the benefit, which includes protection from death and hospitalization from the virus, according to Dr. Blumenthal. Citing the evidence that first-shot reactions are a source of vaccine hesitancy, she agreed that it is important to educate patients about relative risks.

“Even in our own cohort of MGBHS employees, we have people, including those who had been provaccine in the past, become hesitant,” commented Dr. Blumenthal, who said there are data from the Kaiser Permanente System showing similar vaccine reluctance following a first-shot reaction.

After more than 500 million doses of the Moderna and Pfizer vaccines had been administered worldwide, there was not a single reported death from anaphylaxis. Although Dr. Blumenthal said that an unconfirmed death of this type had been recently reported, she emphasized that this single death, if valid, is dwarfed by the lives saved with vaccination.

Asked about her strategy for counseling patients with vaccine hesitancy, Dr. Freeman said the body of safety data is large and compelling. There is overwhelming evidence of a favorable benefit-to-risk ratio overall and among those with a first-shot reaction.

“I can reassure them on the basis of the data,” Dr. Freeman said in an interview. “Less than half will have a reaction to the second shot and even if they do have a reaction, it is likely to be less severe.”

Although the main message is that vaccination is potentially lifesaving and far outweighs any risks, Freeman specifically gives this message to those hesitant to take a second shot after a first-shot reaction: “I can get you through it.”

Dr. Freeman encouraged health care professionals to report cases of COVID-19 vaccine–related dermatologic side effects to the American Academy of Dermatology / International League of Dermatologic Societies COVID-19 dermatology registry. Dermatologic manifestations of COVID-19 can also be reported to the registry.

Dr. Freeman disclosed receiving grants/research funding from the International League of Dermatologic Societies and from the National Institutes of Health. Dr. Blumenthal disclosed no relevant financial relationships.

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

When an individual develops a terminal illness, those closest to them often start to grieve long before the person dies. Although a common syndrome, it often goes unrecognized and unaddressed.

A new review proposes a way of defining this specific type of grief in the hope that better, more precise descriptive categories will inform therapeutic interventions to help those facing a life-changing loss.

It is “vital” to reduce pre-death grief, inasmuch as numerous studies show that it can result in higher rates of prolonged grief disorder, lead author Jonathan Singer, PhD, visiting assistant professor of clinical psychology, Texas Tech University, Lubbock, told this news organization.

Texas Tech University

‘Typical’ versus ‘impairing’ grief

“Most deaths worldwide are attributed to a chronic or life-limiting Illness,” the authors write. The experience of grief before the loss of a family member “has been studied frequently, but there have been conceptualization issues, which is problematic, as it hinders the potential advancement of the field in differentiating typical grief from more impairing grief before the death,” Dr. Singer said. “Further complicating the picture is the sheer number of terms used to describe grief before death.”

Dr. Singer said that when he started conducting research in this field, he “realized someone had to combine the articles that have been published in order to create definitions that will advance the field, so risk and protective factors could be identified and interventions could be tested.”

For the current study, the investigators searched six databases to find research that “evaluated family members’ or friends’ grief related to an individual currently living with a life-limiting illness.” They excluded studies that evaluated grief after death.

Of 9,568 records reviewed, the researchers selected 134 full-text articles that met inclusion criteria. Most studies (57.46%) were quantitative; 23.88% were qualitative, and 17.91% used mixed methods. Most studies were retrospective, although 14.93% were prospective, and 3% included both prospective and retrospective analyses.

Most participants reported that the family member/friend was diagnosed either with “late-stage dementia” or “advanced cancer.” The majority (58%) were adult children of the individual with the illness, followed by spouses/partners (28.1%) and other relatives/friends (13.9%) in studies that reported the relationship to the participant and the person with the illness.

Various scales were used in the studies to measure grief, particularly the Marwit-Meuser-Caregiver Grief Inventory (n = 28), the Anticipatory Grief Scale (n = 18), and the Prolonged Grief–12 (n = 13).
 

A new name

Owing to the large number of articles included in the review, the researchers limited the analysis to those in which a given term was used in ≥ 1 articles.

The researchers found 18 different terms used by family members/friends of individuals with life-limiting illness to describe grief, including AG (used in the most studies, n = 54); pre-death grief (n = 18), grief (n = 12), pre-loss grief (n = 6), caregiver grief (n = 5), and anticipatory mourning (n = 4). These 18 terms were associated with greater than or equal to 30 different definitions across all of the various studies.

“Definitions of these terms differed drastically,” and many studies used the term AG without defining it.

Nineteen studies used multiple terms within a single article, and the terms were “used interchangeably, with the same definition applied,” the researchers report.

For example, one study defined AG as “the process associated with grieving the eventual loss of a family member in advance of their inevitable death,” while another defined AG as “a series of losses based on a loved one’s progression of cognitive and physical decline.”

On the basis of this analysis, the researchers chose the term “pre-death grief,” which encompasses IRG and AG.

Dr. Singer explained that IRG is “present-oriented” and involves the “longing and yearning for the family member to be as they were before the illness.” AG is “future oriented” and is defined as “family members’ grief experience while the person with the life-limiting illness is alive but that is focused on feared or anticipated losses that will occur after the person’s death.”

The study was intended “to advance the field and provide the knowledge and definitions in order to create and test an evidence-based intervention,” Dr. Singer said.

He pointed to interventions (for example: behavioral activation, meaning-centered grief therapy) that could be tested to reduce pre-death grief or specific interventions that focus on addressing IRG or AG. “For example, cognitive behavior therapy might be used to challenge worry about life without the person, which would be classified as AG.”

Dr. Singer feels it is “vital” to reduce pre-death grief, insofar as numerous studies have shown that high rates of pre-death grief “result in higher rates of prolonged grief disorder.”
 

‘Paradoxical reality’

Francesca Falzarano, PhD, a postdoctoral associate in medicine, Weill Cornell Medicine, New York, called the article a “timely piece drawing much-needed attention to an all-too-often overlooked experience lived by those affected by terminal illnesses.”

Dr. Falzarano, who was not involved in the review, said that “from her own experience” as both a caregiver and behavioral scientist conducting research in this area, the concept of pre-death grief is a paradoxical reality – “how do we grieve someone we haven’t lost yet?”

The experience of pre-death grief is “quite distinct from grief after bereavement” because there is no end date. Rather, the person “cycles back and forth between preparing themselves for an impending death while also attending to whatever is happening in the current moment.” It’s also “unique in that both patients and caregivers individually and collectively grieve losses over the course of the illness,” she noted.

“We as researchers absolutely need to focus our attention on achieving consensus on an appropriate definition for pre-death grief that adequately encompasses its complexity and multidimensionality,” she said.

The authors and Dr. Falzarano report no relevant financial relationships.

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

When an individual develops a terminal illness, those closest to them often start to grieve long before the person dies. Although a common syndrome, it often goes unrecognized and unaddressed.

A new review proposes a way of defining this specific type of grief in the hope that better, more precise descriptive categories will inform therapeutic interventions to help those facing a life-changing loss.

It is “vital” to reduce pre-death grief, inasmuch as numerous studies show that it can result in higher rates of prolonged grief disorder, lead author Jonathan Singer, PhD, visiting assistant professor of clinical psychology, Texas Tech University, Lubbock, told this news organization.

Texas Tech University

‘Typical’ versus ‘impairing’ grief

“Most deaths worldwide are attributed to a chronic or life-limiting Illness,” the authors write. The experience of grief before the loss of a family member “has been studied frequently, but there have been conceptualization issues, which is problematic, as it hinders the potential advancement of the field in differentiating typical grief from more impairing grief before the death,” Dr. Singer said. “Further complicating the picture is the sheer number of terms used to describe grief before death.”

Dr. Singer said that when he started conducting research in this field, he “realized someone had to combine the articles that have been published in order to create definitions that will advance the field, so risk and protective factors could be identified and interventions could be tested.”

For the current study, the investigators searched six databases to find research that “evaluated family members’ or friends’ grief related to an individual currently living with a life-limiting illness.” They excluded studies that evaluated grief after death.

Of 9,568 records reviewed, the researchers selected 134 full-text articles that met inclusion criteria. Most studies (57.46%) were quantitative; 23.88% were qualitative, and 17.91% used mixed methods. Most studies were retrospective, although 14.93% were prospective, and 3% included both prospective and retrospective analyses.

Most participants reported that the family member/friend was diagnosed either with “late-stage dementia” or “advanced cancer.” The majority (58%) were adult children of the individual with the illness, followed by spouses/partners (28.1%) and other relatives/friends (13.9%) in studies that reported the relationship to the participant and the person with the illness.

Various scales were used in the studies to measure grief, particularly the Marwit-Meuser-Caregiver Grief Inventory (n = 28), the Anticipatory Grief Scale (n = 18), and the Prolonged Grief–12 (n = 13).
 

A new name

Owing to the large number of articles included in the review, the researchers limited the analysis to those in which a given term was used in ≥ 1 articles.

The researchers found 18 different terms used by family members/friends of individuals with life-limiting illness to describe grief, including AG (used in the most studies, n = 54); pre-death grief (n = 18), grief (n = 12), pre-loss grief (n = 6), caregiver grief (n = 5), and anticipatory mourning (n = 4). These 18 terms were associated with greater than or equal to 30 different definitions across all of the various studies.

“Definitions of these terms differed drastically,” and many studies used the term AG without defining it.

Nineteen studies used multiple terms within a single article, and the terms were “used interchangeably, with the same definition applied,” the researchers report.

For example, one study defined AG as “the process associated with grieving the eventual loss of a family member in advance of their inevitable death,” while another defined AG as “a series of losses based on a loved one’s progression of cognitive and physical decline.”

On the basis of this analysis, the researchers chose the term “pre-death grief,” which encompasses IRG and AG.

Dr. Singer explained that IRG is “present-oriented” and involves the “longing and yearning for the family member to be as they were before the illness.” AG is “future oriented” and is defined as “family members’ grief experience while the person with the life-limiting illness is alive but that is focused on feared or anticipated losses that will occur after the person’s death.”

The study was intended “to advance the field and provide the knowledge and definitions in order to create and test an evidence-based intervention,” Dr. Singer said.

He pointed to interventions (for example: behavioral activation, meaning-centered grief therapy) that could be tested to reduce pre-death grief or specific interventions that focus on addressing IRG or AG. “For example, cognitive behavior therapy might be used to challenge worry about life without the person, which would be classified as AG.”

Dr. Singer feels it is “vital” to reduce pre-death grief, insofar as numerous studies have shown that high rates of pre-death grief “result in higher rates of prolonged grief disorder.”
 

‘Paradoxical reality’

Francesca Falzarano, PhD, a postdoctoral associate in medicine, Weill Cornell Medicine, New York, called the article a “timely piece drawing much-needed attention to an all-too-often overlooked experience lived by those affected by terminal illnesses.”

Dr. Falzarano, who was not involved in the review, said that “from her own experience” as both a caregiver and behavioral scientist conducting research in this area, the concept of pre-death grief is a paradoxical reality – “how do we grieve someone we haven’t lost yet?”

The experience of pre-death grief is “quite distinct from grief after bereavement” because there is no end date. Rather, the person “cycles back and forth between preparing themselves for an impending death while also attending to whatever is happening in the current moment.” It’s also “unique in that both patients and caregivers individually and collectively grieve losses over the course of the illness,” she noted.

“We as researchers absolutely need to focus our attention on achieving consensus on an appropriate definition for pre-death grief that adequately encompasses its complexity and multidimensionality,” she said.

The authors and Dr. Falzarano report no relevant financial relationships.

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

When an individual develops a terminal illness, those closest to them often start to grieve long before the person dies. Although a common syndrome, it often goes unrecognized and unaddressed.

A new review proposes a way of defining this specific type of grief in the hope that better, more precise descriptive categories will inform therapeutic interventions to help those facing a life-changing loss.

It is “vital” to reduce pre-death grief, inasmuch as numerous studies show that it can result in higher rates of prolonged grief disorder, lead author Jonathan Singer, PhD, visiting assistant professor of clinical psychology, Texas Tech University, Lubbock, told this news organization.

Texas Tech University

‘Typical’ versus ‘impairing’ grief

“Most deaths worldwide are attributed to a chronic or life-limiting Illness,” the authors write. The experience of grief before the loss of a family member “has been studied frequently, but there have been conceptualization issues, which is problematic, as it hinders the potential advancement of the field in differentiating typical grief from more impairing grief before the death,” Dr. Singer said. “Further complicating the picture is the sheer number of terms used to describe grief before death.”

Dr. Singer said that when he started conducting research in this field, he “realized someone had to combine the articles that have been published in order to create definitions that will advance the field, so risk and protective factors could be identified and interventions could be tested.”

For the current study, the investigators searched six databases to find research that “evaluated family members’ or friends’ grief related to an individual currently living with a life-limiting illness.” They excluded studies that evaluated grief after death.

Of 9,568 records reviewed, the researchers selected 134 full-text articles that met inclusion criteria. Most studies (57.46%) were quantitative; 23.88% were qualitative, and 17.91% used mixed methods. Most studies were retrospective, although 14.93% were prospective, and 3% included both prospective and retrospective analyses.

Most participants reported that the family member/friend was diagnosed either with “late-stage dementia” or “advanced cancer.” The majority (58%) were adult children of the individual with the illness, followed by spouses/partners (28.1%) and other relatives/friends (13.9%) in studies that reported the relationship to the participant and the person with the illness.

Various scales were used in the studies to measure grief, particularly the Marwit-Meuser-Caregiver Grief Inventory (n = 28), the Anticipatory Grief Scale (n = 18), and the Prolonged Grief–12 (n = 13).
 

A new name

Owing to the large number of articles included in the review, the researchers limited the analysis to those in which a given term was used in ≥ 1 articles.

The researchers found 18 different terms used by family members/friends of individuals with life-limiting illness to describe grief, including AG (used in the most studies, n = 54); pre-death grief (n = 18), grief (n = 12), pre-loss grief (n = 6), caregiver grief (n = 5), and anticipatory mourning (n = 4). These 18 terms were associated with greater than or equal to 30 different definitions across all of the various studies.

“Definitions of these terms differed drastically,” and many studies used the term AG without defining it.

Nineteen studies used multiple terms within a single article, and the terms were “used interchangeably, with the same definition applied,” the researchers report.

For example, one study defined AG as “the process associated with grieving the eventual loss of a family member in advance of their inevitable death,” while another defined AG as “a series of losses based on a loved one’s progression of cognitive and physical decline.”

On the basis of this analysis, the researchers chose the term “pre-death grief,” which encompasses IRG and AG.

Dr. Singer explained that IRG is “present-oriented” and involves the “longing and yearning for the family member to be as they were before the illness.” AG is “future oriented” and is defined as “family members’ grief experience while the person with the life-limiting illness is alive but that is focused on feared or anticipated losses that will occur after the person’s death.”

The study was intended “to advance the field and provide the knowledge and definitions in order to create and test an evidence-based intervention,” Dr. Singer said.

He pointed to interventions (for example: behavioral activation, meaning-centered grief therapy) that could be tested to reduce pre-death grief or specific interventions that focus on addressing IRG or AG. “For example, cognitive behavior therapy might be used to challenge worry about life without the person, which would be classified as AG.”

Dr. Singer feels it is “vital” to reduce pre-death grief, insofar as numerous studies have shown that high rates of pre-death grief “result in higher rates of prolonged grief disorder.”
 

‘Paradoxical reality’

Francesca Falzarano, PhD, a postdoctoral associate in medicine, Weill Cornell Medicine, New York, called the article a “timely piece drawing much-needed attention to an all-too-often overlooked experience lived by those affected by terminal illnesses.”

Dr. Falzarano, who was not involved in the review, said that “from her own experience” as both a caregiver and behavioral scientist conducting research in this area, the concept of pre-death grief is a paradoxical reality – “how do we grieve someone we haven’t lost yet?”

The experience of pre-death grief is “quite distinct from grief after bereavement” because there is no end date. Rather, the person “cycles back and forth between preparing themselves for an impending death while also attending to whatever is happening in the current moment.” It’s also “unique in that both patients and caregivers individually and collectively grieve losses over the course of the illness,” she noted.

“We as researchers absolutely need to focus our attention on achieving consensus on an appropriate definition for pre-death grief that adequately encompasses its complexity and multidimensionality,” she said.

The authors and Dr. Falzarano report no relevant financial relationships.

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

There is a link between cannabis exposure during pregnancy and higher fasting glucose levels and adiposity in the offspring in early childhood, a new study suggests.

Research looking at the effect of prenatal exposure to cannabis on offspring is growing. It is known to affect childhood cognition and behavior; however, there is little work to date on how it affects metabolic outcomes, said lead author Brianna F. Moore, PhD.

“Officially, the American Academy of Obstetricians and Gynecologists recommends that women do not use cannabis during pregnancy or while breastfeeding to limit the effects on offspring. There’s really a lot we don’t know, but researchers across the country are starting to look into this more, and there are signs that it isn’t great for the offspring,” Dr. Moore, assistant professor at the Colorado School of Public Health in Aurora, said in an interview.

And she noted that while some women turn to cannabis to manage the challenging symptoms of pregnancy, “Clinicians should encourage pregnant women to refrain from using cannabis; it is best for these pregnant women to talk to their physicians about alternative ways of managing these symptoms.”

The findings were published online March 31 in the Journal of Clinical Endocrinology & Metabolism.
 

Study of mother and 5-year-old child pairs

The researchers assessed 103 sets of mothers and children from the Healthy Start study. At 27 weeks of gestation, the investigators assessed 12 metabolites of cannabis/cannabinoids in urine samples. Results from these samples were used to categorize fetal exposure to cannabis as either not exposed or exposed. They found that about 15% of the mothers had traceable amounts of cannabinoids, suggesting fetal cannabis exposure.

At follow-up, the study team assessed fat-free mass and fat mass using air displacement plethysmography among the offspring around age 5. They used generalized linear models to approximate the relationship between fetal exposure to cannabis with metabolic measures such as insulin, glucose, and homeostatic model assessment of insulin resistance (HOMA-IR), and adiposity measures such as body mass index, fat-free mass, fat mass, adiposity, and BMI z-scores.

The findings showed that, compared with nonexposed offspring, exposed offspring had greater:

• Fasting glucose (5.6 mg/dL; 95% confidence interval [CI], 0.8-10.3).
• Fat-free mass (1.2 kg; 95% CI, 0.4-2.0).
• Fat mass (1.0 kg; 95% CI, 0.3-1.7).
• Adiposity (2.6%; 95% CI, 0.1-5.2).

“This finding may suggest that fetal exposure to cannabis contributes to higher fasting glucose levels via a direct effect on the pancreatic β-cells. However, we cannot draw conclusions about β-cell response to glucose because we did not perform oral glucose tolerance tests,” the study authors wrote.

Notably, however, there was no relationship between BMI z-scores, BMI, or HOMA-IR and fasting insulin, the study team found.

Study limitations include the small sample size and lack of self-report data on cannabis use to differentiate between direct use and exposure to cannabis, Dr. Moore acknowledged.

Given the small sample size, the researchers were unable to look at dose-response, which future studies will focus on, Dr. Moore noted. Future efforts will also focus on comparing the effects of tetrahydrocannabinol (THC) and cannabidiol (CBD), Dr. Moore added.

“This is a relatively new field, so there’s still work to be done. This is just one study, and we need to study this more in other cohorts to confirm our findings,” she concluded.

Dr. Moore has reported no relevant financial relationships.

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

There is a link between cannabis exposure during pregnancy and higher fasting glucose levels and adiposity in the offspring in early childhood, a new study suggests.

Research looking at the effect of prenatal exposure to cannabis on offspring is growing. It is known to affect childhood cognition and behavior; however, there is little work to date on how it affects metabolic outcomes, said lead author Brianna F. Moore, PhD.

“Officially, the American Academy of Obstetricians and Gynecologists recommends that women do not use cannabis during pregnancy or while breastfeeding to limit the effects on offspring. There’s really a lot we don’t know, but researchers across the country are starting to look into this more, and there are signs that it isn’t great for the offspring,” Dr. Moore, assistant professor at the Colorado School of Public Health in Aurora, said in an interview.

And she noted that while some women turn to cannabis to manage the challenging symptoms of pregnancy, “Clinicians should encourage pregnant women to refrain from using cannabis; it is best for these pregnant women to talk to their physicians about alternative ways of managing these symptoms.”

The findings were published online March 31 in the Journal of Clinical Endocrinology & Metabolism.
 

Study of mother and 5-year-old child pairs

The researchers assessed 103 sets of mothers and children from the Healthy Start study. At 27 weeks of gestation, the investigators assessed 12 metabolites of cannabis/cannabinoids in urine samples. Results from these samples were used to categorize fetal exposure to cannabis as either not exposed or exposed. They found that about 15% of the mothers had traceable amounts of cannabinoids, suggesting fetal cannabis exposure.

At follow-up, the study team assessed fat-free mass and fat mass using air displacement plethysmography among the offspring around age 5. They used generalized linear models to approximate the relationship between fetal exposure to cannabis with metabolic measures such as insulin, glucose, and homeostatic model assessment of insulin resistance (HOMA-IR), and adiposity measures such as body mass index, fat-free mass, fat mass, adiposity, and BMI z-scores.

The findings showed that, compared with nonexposed offspring, exposed offspring had greater:

• Fasting glucose (5.6 mg/dL; 95% confidence interval [CI], 0.8-10.3).
• Fat-free mass (1.2 kg; 95% CI, 0.4-2.0).
• Fat mass (1.0 kg; 95% CI, 0.3-1.7).
• Adiposity (2.6%; 95% CI, 0.1-5.2).

“This finding may suggest that fetal exposure to cannabis contributes to higher fasting glucose levels via a direct effect on the pancreatic β-cells. However, we cannot draw conclusions about β-cell response to glucose because we did not perform oral glucose tolerance tests,” the study authors wrote.

Notably, however, there was no relationship between BMI z-scores, BMI, or HOMA-IR and fasting insulin, the study team found.

Study limitations include the small sample size and lack of self-report data on cannabis use to differentiate between direct use and exposure to cannabis, Dr. Moore acknowledged.

Given the small sample size, the researchers were unable to look at dose-response, which future studies will focus on, Dr. Moore noted. Future efforts will also focus on comparing the effects of tetrahydrocannabinol (THC) and cannabidiol (CBD), Dr. Moore added.

“This is a relatively new field, so there’s still work to be done. This is just one study, and we need to study this more in other cohorts to confirm our findings,” she concluded.

Dr. Moore has reported no relevant financial relationships.

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

There is a link between cannabis exposure during pregnancy and higher fasting glucose levels and adiposity in the offspring in early childhood, a new study suggests.

Research looking at the effect of prenatal exposure to cannabis on offspring is growing. It is known to affect childhood cognition and behavior; however, there is little work to date on how it affects metabolic outcomes, said lead author Brianna F. Moore, PhD.

“Officially, the American Academy of Obstetricians and Gynecologists recommends that women do not use cannabis during pregnancy or while breastfeeding to limit the effects on offspring. There’s really a lot we don’t know, but researchers across the country are starting to look into this more, and there are signs that it isn’t great for the offspring,” Dr. Moore, assistant professor at the Colorado School of Public Health in Aurora, said in an interview.

And she noted that while some women turn to cannabis to manage the challenging symptoms of pregnancy, “Clinicians should encourage pregnant women to refrain from using cannabis; it is best for these pregnant women to talk to their physicians about alternative ways of managing these symptoms.”

The findings were published online March 31 in the Journal of Clinical Endocrinology & Metabolism.
 

Study of mother and 5-year-old child pairs

The researchers assessed 103 sets of mothers and children from the Healthy Start study. At 27 weeks of gestation, the investigators assessed 12 metabolites of cannabis/cannabinoids in urine samples. Results from these samples were used to categorize fetal exposure to cannabis as either not exposed or exposed. They found that about 15% of the mothers had traceable amounts of cannabinoids, suggesting fetal cannabis exposure.

At follow-up, the study team assessed fat-free mass and fat mass using air displacement plethysmography among the offspring around age 5. They used generalized linear models to approximate the relationship between fetal exposure to cannabis with metabolic measures such as insulin, glucose, and homeostatic model assessment of insulin resistance (HOMA-IR), and adiposity measures such as body mass index, fat-free mass, fat mass, adiposity, and BMI z-scores.

The findings showed that, compared with nonexposed offspring, exposed offspring had greater:

• Fasting glucose (5.6 mg/dL; 95% confidence interval [CI], 0.8-10.3).
• Fat-free mass (1.2 kg; 95% CI, 0.4-2.0).
• Fat mass (1.0 kg; 95% CI, 0.3-1.7).
• Adiposity (2.6%; 95% CI, 0.1-5.2).

“This finding may suggest that fetal exposure to cannabis contributes to higher fasting glucose levels via a direct effect on the pancreatic β-cells. However, we cannot draw conclusions about β-cell response to glucose because we did not perform oral glucose tolerance tests,” the study authors wrote.

Notably, however, there was no relationship between BMI z-scores, BMI, or HOMA-IR and fasting insulin, the study team found.

Study limitations include the small sample size and lack of self-report data on cannabis use to differentiate between direct use and exposure to cannabis, Dr. Moore acknowledged.

Given the small sample size, the researchers were unable to look at dose-response, which future studies will focus on, Dr. Moore noted. Future efforts will also focus on comparing the effects of tetrahydrocannabinol (THC) and cannabidiol (CBD), Dr. Moore added.

“This is a relatively new field, so there’s still work to be done. This is just one study, and we need to study this more in other cohorts to confirm our findings,” she concluded.

Dr. Moore has reported no relevant financial relationships.

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

A new score to gauge histologic remission in ulcerative colitis (UC), based simply on the presence or absence of neutrophils, is effective and easier to use than other indices, according to authors of a study published online in Gut.
 

Researchers, led by Xianyong Gui, MD, a surgical pathologist at the University of Washington, Seattle, developed the index, called the Paddington International Virtual Chromoendoscopy Score (PICaSSO) Histologic Remission Index (PHRI). They wrote that, when the index was plugged into an artificial intelligence (AI) model, the algorithm accurately determined histologic remission.

“Our preliminary AI algorithm differentiated active from quiescent UC with 78% sensitivity, 91.7% specificity, and 86% accuracy,” the authors noted.

Histologic remission has been previously proposed as a treatment target for UC and many indices have been developed to score disease activity, but they haven’t been widely used because of their complexity, the authors wrote. They believe this index can be applied easily and efficiently in clinical practice. “Since a pathologist needs only to identify neutrophils, which is a part of routine in reading biopsy slides as clinical histopathological evaluation, one can have the PHRI score immediately without making additional effort and spending extra time. Thus, the PHRI score can also be easily included into the pathology reports.”

The researchers found that the index correlates strongly with endoscopic activity and predicts UC clinical outcomes, including hospitalization, colectomy, and initiation or changes in treatment caused by UC flare-up.

Dr. Gui’s team developed the index using 614 biopsies from 307 patients with UC from 11 centers in Europe and North America who were prospectively enrolled in the PICaSSO study.

The index was a collaboration between pathologists and endoscopists who wanted a histologic score that would align with the endoscopic score and go beyond endoscopic evaluation. It eliminates consideration of ulceration/erosion, often a factor in other indices because variability can be high without contributing much to accuracy.
 

Keen interest in histologic remission

David T. Rubin, MD, chief of gastroenterology, hepatology and nutrition and the codirector of the Digestive Diseases Center at the University of Chicago, noted continued interest in whether histologic findings (biopsies) of the mucosa are a clinically important and reachable treatment goal with UC.

“It’s important to acknowledge that it is not yet a target of treatment, in part because of a variety of challenges and unknowns related to it,” he said.

The current study addresses a major barrier to incorporation of histology in the clinical management of patients with UC: individual interpretation. “Development of this simplified novel scoring approach with artificial intelligence could be a major step forward. We are hopeful that this type of AI approach will eliminate some of the barriers to use of histology as a marker of treatment control. It is of interest to note that this novel score correlated to the endoscopic appearance, but didn’t necessarily demonstrate superiority to it. This is important, since we have hypothesized that histology may provide more information about outcomes than endoscopy alone,” Dr. Rubin said.

He added that PHRI will need broader validation and incorporation into meaningful interventions before it can be incorporated into clinical practice, but that “this type of technological innovation is what the field needs in order to move forward.”

The authors and Dr. Rubin declared no relevant financial conflicts. Two coauthors are funded by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham in the United Kingdom.

A new score to gauge histologic remission in ulcerative colitis (UC), based simply on the presence or absence of neutrophils, is effective and easier to use than other indices, according to authors of a study published online in Gut.
 

Researchers, led by Xianyong Gui, MD, a surgical pathologist at the University of Washington, Seattle, developed the index, called the Paddington International Virtual Chromoendoscopy Score (PICaSSO) Histologic Remission Index (PHRI). They wrote that, when the index was plugged into an artificial intelligence (AI) model, the algorithm accurately determined histologic remission.

“Our preliminary AI algorithm differentiated active from quiescent UC with 78% sensitivity, 91.7% specificity, and 86% accuracy,” the authors noted.

Histologic remission has been previously proposed as a treatment target for UC and many indices have been developed to score disease activity, but they haven’t been widely used because of their complexity, the authors wrote. They believe this index can be applied easily and efficiently in clinical practice. “Since a pathologist needs only to identify neutrophils, which is a part of routine in reading biopsy slides as clinical histopathological evaluation, one can have the PHRI score immediately without making additional effort and spending extra time. Thus, the PHRI score can also be easily included into the pathology reports.”

The researchers found that the index correlates strongly with endoscopic activity and predicts UC clinical outcomes, including hospitalization, colectomy, and initiation or changes in treatment caused by UC flare-up.

Dr. Gui’s team developed the index using 614 biopsies from 307 patients with UC from 11 centers in Europe and North America who were prospectively enrolled in the PICaSSO study.

The index was a collaboration between pathologists and endoscopists who wanted a histologic score that would align with the endoscopic score and go beyond endoscopic evaluation. It eliminates consideration of ulceration/erosion, often a factor in other indices because variability can be high without contributing much to accuracy.
 

Keen interest in histologic remission

David T. Rubin, MD, chief of gastroenterology, hepatology and nutrition and the codirector of the Digestive Diseases Center at the University of Chicago, noted continued interest in whether histologic findings (biopsies) of the mucosa are a clinically important and reachable treatment goal with UC.

“It’s important to acknowledge that it is not yet a target of treatment, in part because of a variety of challenges and unknowns related to it,” he said.

The current study addresses a major barrier to incorporation of histology in the clinical management of patients with UC: individual interpretation. “Development of this simplified novel scoring approach with artificial intelligence could be a major step forward. We are hopeful that this type of AI approach will eliminate some of the barriers to use of histology as a marker of treatment control. It is of interest to note that this novel score correlated to the endoscopic appearance, but didn’t necessarily demonstrate superiority to it. This is important, since we have hypothesized that histology may provide more information about outcomes than endoscopy alone,” Dr. Rubin said.

He added that PHRI will need broader validation and incorporation into meaningful interventions before it can be incorporated into clinical practice, but that “this type of technological innovation is what the field needs in order to move forward.”

The authors and Dr. Rubin declared no relevant financial conflicts. Two coauthors are funded by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham in the United Kingdom.

A new score to gauge histologic remission in ulcerative colitis (UC), based simply on the presence or absence of neutrophils, is effective and easier to use than other indices, according to authors of a study published online in Gut.
 

Researchers, led by Xianyong Gui, MD, a surgical pathologist at the University of Washington, Seattle, developed the index, called the Paddington International Virtual Chromoendoscopy Score (PICaSSO) Histologic Remission Index (PHRI). They wrote that, when the index was plugged into an artificial intelligence (AI) model, the algorithm accurately determined histologic remission.

“Our preliminary AI algorithm differentiated active from quiescent UC with 78% sensitivity, 91.7% specificity, and 86% accuracy,” the authors noted.

Histologic remission has been previously proposed as a treatment target for UC and many indices have been developed to score disease activity, but they haven’t been widely used because of their complexity, the authors wrote. They believe this index can be applied easily and efficiently in clinical practice. “Since a pathologist needs only to identify neutrophils, which is a part of routine in reading biopsy slides as clinical histopathological evaluation, one can have the PHRI score immediately without making additional effort and spending extra time. Thus, the PHRI score can also be easily included into the pathology reports.”

The researchers found that the index correlates strongly with endoscopic activity and predicts UC clinical outcomes, including hospitalization, colectomy, and initiation or changes in treatment caused by UC flare-up.

Dr. Gui’s team developed the index using 614 biopsies from 307 patients with UC from 11 centers in Europe and North America who were prospectively enrolled in the PICaSSO study.

The index was a collaboration between pathologists and endoscopists who wanted a histologic score that would align with the endoscopic score and go beyond endoscopic evaluation. It eliminates consideration of ulceration/erosion, often a factor in other indices because variability can be high without contributing much to accuracy.
 

Keen interest in histologic remission

David T. Rubin, MD, chief of gastroenterology, hepatology and nutrition and the codirector of the Digestive Diseases Center at the University of Chicago, noted continued interest in whether histologic findings (biopsies) of the mucosa are a clinically important and reachable treatment goal with UC.

“It’s important to acknowledge that it is not yet a target of treatment, in part because of a variety of challenges and unknowns related to it,” he said.

The current study addresses a major barrier to incorporation of histology in the clinical management of patients with UC: individual interpretation. “Development of this simplified novel scoring approach with artificial intelligence could be a major step forward. We are hopeful that this type of AI approach will eliminate some of the barriers to use of histology as a marker of treatment control. It is of interest to note that this novel score correlated to the endoscopic appearance, but didn’t necessarily demonstrate superiority to it. This is important, since we have hypothesized that histology may provide more information about outcomes than endoscopy alone,” Dr. Rubin said.

He added that PHRI will need broader validation and incorporation into meaningful interventions before it can be incorporated into clinical practice, but that “this type of technological innovation is what the field needs in order to move forward.”

The authors and Dr. Rubin declared no relevant financial conflicts. Two coauthors are funded by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham in the United Kingdom.