It was supper time in the Whittier, California, home of Air Force veteran Danyelle Clark-Gutierrez, and eagerly awaiting a bowl of kibble and canned dog food was Lisa, a 3-year-old yellow Labrador retriever.

Her nails clicking on the kitchen floor as she danced about, Lisa looked more like an exuberant puppy than the highly trained service animal that helps Clark-Gutierrez manage the symptoms of post-traumatic stress disorder.

“Having her now, it’s like I can go anywhere,” Clark-Gutierrez said. “And, yes, if somebody did come at me, I’d have warning — I could run.”

A growing body of research into PTSD and service animals paved the way for President Joe Biden to sign into law the Puppies Assisting Wounded Servicemembers (PAWS) for Veterans Therapy Act. The legislation, enacted in August, requires the Department of Veterans Affairs to open its service dog referral program to veterans with PTSD and to launch a five-year pilot program in which veterans with PTSD train service dogs for other veterans.

Clark-Gutierrez, 33, is among the 25 percent of female veterans who have reported experiencing military sexual trauma while serving in the U.S. armed services.

Military sexual trauma, combat violence and brain injuries are some of the experiences that increase the risk that service members will develop PTSD. Symptoms include flashbacks to the traumatic event, severe anxiety, nightmares and hypervigilance — all normal reactions to experiencing or witnessing violence, according to psychologists. Someone receives a PTSD diagnosis when symptoms worsen or remain for months or years.

That’s what Clark-Gutierrez said happened to her after ongoing sexual harassment by a fellow airman escalated to a physical attack about a decade ago. A lawyer with three children, she said that to feel safe leaving her home she needed her husband by her side. After diagnosing Clark-Gutierrez with PTSD, doctors at VA hospitals prescribed a cascade of medications for her. At one point, Clark-Gutierrez said, her prescriptions added up to more than a dozen pills a day.

“I had medication, and then I had medication for the two or three side effects for each medication,” she said. “And every time they gave me a new med, they had to give me three more. I just couldn’t do it anymore. I was just getting so tired. So we started looking at other therapies.”

And that’s how she got her service dog, Lisa. Clark-Gutierrez’s husband, also an Air Force veteran, discovered the nonprofit group K9s for Warriors, which rescues dogs — many from kill shelters — and trains them to be service animals for veterans with PTSD. Lisa is one of about 700 dogs the group has paired with veterans dealing with symptoms caused by traumatic experiences.

“Now with Lisa we take bike rides, we go down to the park, we go to Home Depot,” said Clark-Gutierrez. “I go grocery shopping — normal-people things that I get to do that I didn’t get to do before Lisa.”

That comes as no surprise to Maggie O’Haire, an associate professor of human-animal interaction at Purdue University. Her research suggests that while service dogs aren’t necessarily a cure for PTSD, they do ease its symptoms. Among her published studies is one showing that veterans partnered with these dogs experience less anger and anxiety and get better sleep than those without a service dog. Another of her studies suggests that service dogs lower cortisol levels in veterans who have been traumatized.

“We actually saw patterns of that stress hormone that were more similar to healthy adults who don’t have post-traumatic stress disorder,” O’Haire said.

A congressionally mandated VA study that focuses on service dogs’ impact on veterans with PTSD and was published this year suggests that those partnered with the animals experience less suicidal ideation and more improvement to their symptoms than those without them.

Until now, the federal dog referral program — which relies on nonprofit service dog organizations to pay for the dogs and to provide them to veterans for free — required that participating veterans have a physical mobility issue, such as a lost limb, paralysis or blindness. Veterans like Clark-Gutierrez who have PTSD but no physical disability were on their own in arranging for a service dog.

The pilot program created by the new federal law will give veterans with PTSD the chance to train mental health service dogs for other veterans. It’s modeled on a program at the VA hospital in Palo Alto, California, and will be offered at five VA medical centers nationwide in partnership with accredited service dog training organizations.

“This bill is really about therapeutic, on-the-job training, or ‘training the trainer,’” said Adam Webb, a spokesperson for Sen. Thom Tillis (R-N.C.), who introduced the legislation in the Senate. “We don’t anticipate VA will start prescribing PTSD service dogs, but the data we generate from this pilot program will likely be useful in making that case in the future.”

The Congressional Budget Office estimates the pilot program will cost the VA about $19 million. The law stops short of requiring the VA to pay for the dogs. Instead, the agency will partner with accredited service dog organizations that use private money to cover the cost of adopting, training and pairing the dogs with veterans.

Still, the law represents a welcome about-face in VA policy, said Rory Diamond, CEO of K9s for Warriors.

“For the last 10 years, the VA has essentially told us that they don’t recognize service dogs as helping a veteran with post-traumatic stress,” Diamond said.

PTSD service dogs are often confused with emotional support dogs, Diamond said. The latter provide companionship and are not trained to support someone with a disability. PTSD service dogs cost about $25,000 to adopt and train, he said.

Diamond explained that the command “cover” means “the dog will sit next to the warrior, look behind them and alert them if someone comes up from behind.” The command “block” means the dog will “stand perpendicular and give them some space from whatever’s in front of them.”

Retired Army Master Sgt. David Crenshaw of Kearny, New Jersey, said his service dog, Doc, has changed his life.

“We teach in the military to have a battle buddy,” Crenshaw said. “And these service animals act as a battle buddy.”

A few months ago, Crenshaw experienced this firsthand. He had generally avoided large gatherings because persistent hypervigilance is one symptom of his combat-caused PTSD. But this summer, Doc, a pointer and Labrador mix, helped Crenshaw navigate the crowds at Disney World — a significant first for Crenshaw and his family of five.

“I was not agitated. I was not anxious. I was not upset,” said Crenshaw, 39. “It was truly, truly amazing and so much so that I didn’t even have to even stop to think about it in the moment. It just happened naturally.”

Thanks to Doc, Crenshaw said, he no longer takes PTSD drugs or self-medicates with alcohol. Clark-Gutierrez said Lisa, too, has helped her quit using alcohol and stop taking VA-prescribed medications for panic attacks, nightmares and periods of disassociation.

The dogs actually save the VA money over time, Diamond said. “Our warriors are far less likely to be on expensive prescription drugs, are far less likely to use other VA services and far more likely to go to school or go to work. So it’s a win-win-win across the board.”

It was supper time in the Whittier, California, home of Air Force veteran Danyelle Clark-Gutierrez, and eagerly awaiting a bowl of kibble and canned dog food was Lisa, a 3-year-old yellow Labrador retriever.

Her nails clicking on the kitchen floor as she danced about, Lisa looked more like an exuberant puppy than the highly trained service animal that helps Clark-Gutierrez manage the symptoms of post-traumatic stress disorder.

“Having her now, it’s like I can go anywhere,” Clark-Gutierrez said. “And, yes, if somebody did come at me, I’d have warning — I could run.”

A growing body of research into PTSD and service animals paved the way for President Joe Biden to sign into law the Puppies Assisting Wounded Servicemembers (PAWS) for Veterans Therapy Act. The legislation, enacted in August, requires the Department of Veterans Affairs to open its service dog referral program to veterans with PTSD and to launch a five-year pilot program in which veterans with PTSD train service dogs for other veterans.

Clark-Gutierrez, 33, is among the 25 percent of female veterans who have reported experiencing military sexual trauma while serving in the U.S. armed services.

Military sexual trauma, combat violence and brain injuries are some of the experiences that increase the risk that service members will develop PTSD. Symptoms include flashbacks to the traumatic event, severe anxiety, nightmares and hypervigilance — all normal reactions to experiencing or witnessing violence, according to psychologists. Someone receives a PTSD diagnosis when symptoms worsen or remain for months or years.

That’s what Clark-Gutierrez said happened to her after ongoing sexual harassment by a fellow airman escalated to a physical attack about a decade ago. A lawyer with three children, she said that to feel safe leaving her home she needed her husband by her side. After diagnosing Clark-Gutierrez with PTSD, doctors at VA hospitals prescribed a cascade of medications for her. At one point, Clark-Gutierrez said, her prescriptions added up to more than a dozen pills a day.

“I had medication, and then I had medication for the two or three side effects for each medication,” she said. “And every time they gave me a new med, they had to give me three more. I just couldn’t do it anymore. I was just getting so tired. So we started looking at other therapies.”

And that’s how she got her service dog, Lisa. Clark-Gutierrez’s husband, also an Air Force veteran, discovered the nonprofit group K9s for Warriors, which rescues dogs — many from kill shelters — and trains them to be service animals for veterans with PTSD. Lisa is one of about 700 dogs the group has paired with veterans dealing with symptoms caused by traumatic experiences.

“Now with Lisa we take bike rides, we go down to the park, we go to Home Depot,” said Clark-Gutierrez. “I go grocery shopping — normal-people things that I get to do that I didn’t get to do before Lisa.”

That comes as no surprise to Maggie O’Haire, an associate professor of human-animal interaction at Purdue University. Her research suggests that while service dogs aren’t necessarily a cure for PTSD, they do ease its symptoms. Among her published studies is one showing that veterans partnered with these dogs experience less anger and anxiety and get better sleep than those without a service dog. Another of her studies suggests that service dogs lower cortisol levels in veterans who have been traumatized.

“We actually saw patterns of that stress hormone that were more similar to healthy adults who don’t have post-traumatic stress disorder,” O’Haire said.

A congressionally mandated VA study that focuses on service dogs’ impact on veterans with PTSD and was published this year suggests that those partnered with the animals experience less suicidal ideation and more improvement to their symptoms than those without them.

Until now, the federal dog referral program — which relies on nonprofit service dog organizations to pay for the dogs and to provide them to veterans for free — required that participating veterans have a physical mobility issue, such as a lost limb, paralysis or blindness. Veterans like Clark-Gutierrez who have PTSD but no physical disability were on their own in arranging for a service dog.

The pilot program created by the new federal law will give veterans with PTSD the chance to train mental health service dogs for other veterans. It’s modeled on a program at the VA hospital in Palo Alto, California, and will be offered at five VA medical centers nationwide in partnership with accredited service dog training organizations.

“This bill is really about therapeutic, on-the-job training, or ‘training the trainer,’” said Adam Webb, a spokesperson for Sen. Thom Tillis (R-N.C.), who introduced the legislation in the Senate. “We don’t anticipate VA will start prescribing PTSD service dogs, but the data we generate from this pilot program will likely be useful in making that case in the future.”

The Congressional Budget Office estimates the pilot program will cost the VA about $19 million. The law stops short of requiring the VA to pay for the dogs. Instead, the agency will partner with accredited service dog organizations that use private money to cover the cost of adopting, training and pairing the dogs with veterans.

Still, the law represents a welcome about-face in VA policy, said Rory Diamond, CEO of K9s for Warriors.

“For the last 10 years, the VA has essentially told us that they don’t recognize service dogs as helping a veteran with post-traumatic stress,” Diamond said.

PTSD service dogs are often confused with emotional support dogs, Diamond said. The latter provide companionship and are not trained to support someone with a disability. PTSD service dogs cost about $25,000 to adopt and train, he said.

Diamond explained that the command “cover” means “the dog will sit next to the warrior, look behind them and alert them if someone comes up from behind.” The command “block” means the dog will “stand perpendicular and give them some space from whatever’s in front of them.”

Retired Army Master Sgt. David Crenshaw of Kearny, New Jersey, said his service dog, Doc, has changed his life.

“We teach in the military to have a battle buddy,” Crenshaw said. “And these service animals act as a battle buddy.”

A few months ago, Crenshaw experienced this firsthand. He had generally avoided large gatherings because persistent hypervigilance is one symptom of his combat-caused PTSD. But this summer, Doc, a pointer and Labrador mix, helped Crenshaw navigate the crowds at Disney World — a significant first for Crenshaw and his family of five.

“I was not agitated. I was not anxious. I was not upset,” said Crenshaw, 39. “It was truly, truly amazing and so much so that I didn’t even have to even stop to think about it in the moment. It just happened naturally.”

Thanks to Doc, Crenshaw said, he no longer takes PTSD drugs or self-medicates with alcohol. Clark-Gutierrez said Lisa, too, has helped her quit using alcohol and stop taking VA-prescribed medications for panic attacks, nightmares and periods of disassociation.

The dogs actually save the VA money over time, Diamond said. “Our warriors are far less likely to be on expensive prescription drugs, are far less likely to use other VA services and far more likely to go to school or go to work. So it’s a win-win-win across the board.”

It was supper time in the Whittier, California, home of Air Force veteran Danyelle Clark-Gutierrez, and eagerly awaiting a bowl of kibble and canned dog food was Lisa, a 3-year-old yellow Labrador retriever.

Her nails clicking on the kitchen floor as she danced about, Lisa looked more like an exuberant puppy than the highly trained service animal that helps Clark-Gutierrez manage the symptoms of post-traumatic stress disorder.

“Having her now, it’s like I can go anywhere,” Clark-Gutierrez said. “And, yes, if somebody did come at me, I’d have warning — I could run.”

A growing body of research into PTSD and service animals paved the way for President Joe Biden to sign into law the Puppies Assisting Wounded Servicemembers (PAWS) for Veterans Therapy Act. The legislation, enacted in August, requires the Department of Veterans Affairs to open its service dog referral program to veterans with PTSD and to launch a five-year pilot program in which veterans with PTSD train service dogs for other veterans.

Clark-Gutierrez, 33, is among the 25 percent of female veterans who have reported experiencing military sexual trauma while serving in the U.S. armed services.

Military sexual trauma, combat violence and brain injuries are some of the experiences that increase the risk that service members will develop PTSD. Symptoms include flashbacks to the traumatic event, severe anxiety, nightmares and hypervigilance — all normal reactions to experiencing or witnessing violence, according to psychologists. Someone receives a PTSD diagnosis when symptoms worsen or remain for months or years.

That’s what Clark-Gutierrez said happened to her after ongoing sexual harassment by a fellow airman escalated to a physical attack about a decade ago. A lawyer with three children, she said that to feel safe leaving her home she needed her husband by her side. After diagnosing Clark-Gutierrez with PTSD, doctors at VA hospitals prescribed a cascade of medications for her. At one point, Clark-Gutierrez said, her prescriptions added up to more than a dozen pills a day.

“I had medication, and then I had medication for the two or three side effects for each medication,” she said. “And every time they gave me a new med, they had to give me three more. I just couldn’t do it anymore. I was just getting so tired. So we started looking at other therapies.”

And that’s how she got her service dog, Lisa. Clark-Gutierrez’s husband, also an Air Force veteran, discovered the nonprofit group K9s for Warriors, which rescues dogs — many from kill shelters — and trains them to be service animals for veterans with PTSD. Lisa is one of about 700 dogs the group has paired with veterans dealing with symptoms caused by traumatic experiences.

“Now with Lisa we take bike rides, we go down to the park, we go to Home Depot,” said Clark-Gutierrez. “I go grocery shopping — normal-people things that I get to do that I didn’t get to do before Lisa.”

That comes as no surprise to Maggie O’Haire, an associate professor of human-animal interaction at Purdue University. Her research suggests that while service dogs aren’t necessarily a cure for PTSD, they do ease its symptoms. Among her published studies is one showing that veterans partnered with these dogs experience less anger and anxiety and get better sleep than those without a service dog. Another of her studies suggests that service dogs lower cortisol levels in veterans who have been traumatized.

“We actually saw patterns of that stress hormone that were more similar to healthy adults who don’t have post-traumatic stress disorder,” O’Haire said.

A congressionally mandated VA study that focuses on service dogs’ impact on veterans with PTSD and was published this year suggests that those partnered with the animals experience less suicidal ideation and more improvement to their symptoms than those without them.

Until now, the federal dog referral program — which relies on nonprofit service dog organizations to pay for the dogs and to provide them to veterans for free — required that participating veterans have a physical mobility issue, such as a lost limb, paralysis or blindness. Veterans like Clark-Gutierrez who have PTSD but no physical disability were on their own in arranging for a service dog.

The pilot program created by the new federal law will give veterans with PTSD the chance to train mental health service dogs for other veterans. It’s modeled on a program at the VA hospital in Palo Alto, California, and will be offered at five VA medical centers nationwide in partnership with accredited service dog training organizations.

“This bill is really about therapeutic, on-the-job training, or ‘training the trainer,’” said Adam Webb, a spokesperson for Sen. Thom Tillis (R-N.C.), who introduced the legislation in the Senate. “We don’t anticipate VA will start prescribing PTSD service dogs, but the data we generate from this pilot program will likely be useful in making that case in the future.”

The Congressional Budget Office estimates the pilot program will cost the VA about $19 million. The law stops short of requiring the VA to pay for the dogs. Instead, the agency will partner with accredited service dog organizations that use private money to cover the cost of adopting, training and pairing the dogs with veterans.

Still, the law represents a welcome about-face in VA policy, said Rory Diamond, CEO of K9s for Warriors.

“For the last 10 years, the VA has essentially told us that they don’t recognize service dogs as helping a veteran with post-traumatic stress,” Diamond said.

PTSD service dogs are often confused with emotional support dogs, Diamond said. The latter provide companionship and are not trained to support someone with a disability. PTSD service dogs cost about $25,000 to adopt and train, he said.

Diamond explained that the command “cover” means “the dog will sit next to the warrior, look behind them and alert them if someone comes up from behind.” The command “block” means the dog will “stand perpendicular and give them some space from whatever’s in front of them.”

Retired Army Master Sgt. David Crenshaw of Kearny, New Jersey, said his service dog, Doc, has changed his life.

“We teach in the military to have a battle buddy,” Crenshaw said. “And these service animals act as a battle buddy.”

A few months ago, Crenshaw experienced this firsthand. He had generally avoided large gatherings because persistent hypervigilance is one symptom of his combat-caused PTSD. But this summer, Doc, a pointer and Labrador mix, helped Crenshaw navigate the crowds at Disney World — a significant first for Crenshaw and his family of five.

“I was not agitated. I was not anxious. I was not upset,” said Crenshaw, 39. “It was truly, truly amazing and so much so that I didn’t even have to even stop to think about it in the moment. It just happened naturally.”

Thanks to Doc, Crenshaw said, he no longer takes PTSD drugs or self-medicates with alcohol. Clark-Gutierrez said Lisa, too, has helped her quit using alcohol and stop taking VA-prescribed medications for panic attacks, nightmares and periods of disassociation.

The dogs actually save the VA money over time, Diamond said. “Our warriors are far less likely to be on expensive prescription drugs, are far less likely to use other VA services and far more likely to go to school or go to work. So it’s a win-win-win across the board.”

The diagnosis is squamous cell carcinoma. A central or hilar mass is most likely to be a squamous cell carcinoma or a small cell tumor and less commonly an adenocarcinoma. Histologically, when there is lack of cohesion among the epithelial cells due to malignant changes, the cells get arranged in a concentric manner. The fate of a squamous cell is to form keratin, so these cells lay down keratin in a concentric manner and then appear as keratin pearls. 

This patient's tumor is found to have programmed cell death–ligand 1 ≥ 1% and has no actionable molecular markers. The patient has a performance status score of 1. In a patient with advanced or metastatic squamous cell carcinoma with a performance status score of 1, the National Comprehensive Cancer Network recommends pembrolizumab/carboplatin/paclitaxel or pembrolizumab/carboplatin/albumin-bound paclitaxel as preferred regimens. The pembrolizumab component is based on the results of the KEYNOTE-407 trial. In patients with previously untreated metastatic, squamous non-small cell lung cancer, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.

Maurie Markman, MD, President, Department of Medical Oncology, Cancer Treatment Centers of America.

Maurie Markman, MD, has disclosed the following relevant financial relationships:

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Merck
Serve(d) as a speaker or a member of a speakers bureau for: AstraZeneca; Novis; Glaxo Smith Kline
Received research grant from: AstraZeneca; Novis; GSK; Merck

The diagnosis is squamous cell carcinoma. A central or hilar mass is most likely to be a squamous cell carcinoma or a small cell tumor and less commonly an adenocarcinoma. Histologically, when there is lack of cohesion among the epithelial cells due to malignant changes, the cells get arranged in a concentric manner. The fate of a squamous cell is to form keratin, so these cells lay down keratin in a concentric manner and then appear as keratin pearls. 

This patient's tumor is found to have programmed cell death–ligand 1 ≥ 1% and has no actionable molecular markers. The patient has a performance status score of 1. In a patient with advanced or metastatic squamous cell carcinoma with a performance status score of 1, the National Comprehensive Cancer Network recommends pembrolizumab/carboplatin/paclitaxel or pembrolizumab/carboplatin/albumin-bound paclitaxel as preferred regimens. The pembrolizumab component is based on the results of the KEYNOTE-407 trial. In patients with previously untreated metastatic, squamous non-small cell lung cancer, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.

Maurie Markman, MD, President, Department of Medical Oncology, Cancer Treatment Centers of America.

Maurie Markman, MD, has disclosed the following relevant financial relationships:

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Merck
Serve(d) as a speaker or a member of a speakers bureau for: AstraZeneca; Novis; Glaxo Smith Kline
Received research grant from: AstraZeneca; Novis; GSK; Merck

The diagnosis is squamous cell carcinoma. A central or hilar mass is most likely to be a squamous cell carcinoma or a small cell tumor and less commonly an adenocarcinoma. Histologically, when there is lack of cohesion among the epithelial cells due to malignant changes, the cells get arranged in a concentric manner. The fate of a squamous cell is to form keratin, so these cells lay down keratin in a concentric manner and then appear as keratin pearls. 

This patient's tumor is found to have programmed cell death–ligand 1 ≥ 1% and has no actionable molecular markers. The patient has a performance status score of 1. In a patient with advanced or metastatic squamous cell carcinoma with a performance status score of 1, the National Comprehensive Cancer Network recommends pembrolizumab/carboplatin/paclitaxel or pembrolizumab/carboplatin/albumin-bound paclitaxel as preferred regimens. The pembrolizumab component is based on the results of the KEYNOTE-407 trial. In patients with previously untreated metastatic, squamous non-small cell lung cancer, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.

Maurie Markman, MD, President, Department of Medical Oncology, Cancer Treatment Centers of America.

Maurie Markman, MD, has disclosed the following relevant financial relationships:

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Merck
Serve(d) as a speaker or a member of a speakers bureau for: AstraZeneca; Novis; Glaxo Smith Kline
Received research grant from: AstraZeneca; Novis; GSK; Merck

Dr. April Lockley’s commentary marks the final special article Family Practice News is publishing to celebrate its 50th Anniversary. While this is the last piece in a series, my intention is for it to read more like the opening of a new book on family medicine, rather than an ending to a story about the specialty.

April Lockley, DO, represents a new generation of family physicians who began their careers in the 21st century, and she is hopeful that the experiences of practicing family medicine and being the patient of a family physician will change in several ways.

Among her desires for the future, is to be able to write a prescription for a medication or physical therapy to a patient who is able “to fill the prescription without having to worry about the financial implications of paying for it,” she writes. She also hopes “patients can seek out care without the fear of discrimination or racism through an increasingly diverse work force.”

In her article, Dr. Lockley both expresses how she wants family medicine to change and what she already finds satisfying about being a family physician.

I hope you enjoyed reading about the professional journeys of Dr. Lockley and other family physicians who have written commentaries or interviewed for articles in Family Practice News’ 50th Anniversary series this year.

To revisit any of these articles, go to the 50th Anniversary bucket on mdedge.com/familymedicine.

Thank you for continuing to read Family Practice News, and I hope to celebrate more milestones with you in the future.

klennon@mdedge.com

Dr. April Lockley’s commentary marks the final special article Family Practice News is publishing to celebrate its 50th Anniversary. While this is the last piece in a series, my intention is for it to read more like the opening of a new book on family medicine, rather than an ending to a story about the specialty.

April Lockley, DO, represents a new generation of family physicians who began their careers in the 21st century, and she is hopeful that the experiences of practicing family medicine and being the patient of a family physician will change in several ways.

Among her desires for the future, is to be able to write a prescription for a medication or physical therapy to a patient who is able “to fill the prescription without having to worry about the financial implications of paying for it,” she writes. She also hopes “patients can seek out care without the fear of discrimination or racism through an increasingly diverse work force.”

In her article, Dr. Lockley both expresses how she wants family medicine to change and what she already finds satisfying about being a family physician.

I hope you enjoyed reading about the professional journeys of Dr. Lockley and other family physicians who have written commentaries or interviewed for articles in Family Practice News’ 50th Anniversary series this year.

To revisit any of these articles, go to the 50th Anniversary bucket on mdedge.com/familymedicine.

Thank you for continuing to read Family Practice News, and I hope to celebrate more milestones with you in the future.

klennon@mdedge.com

Dr. April Lockley’s commentary marks the final special article Family Practice News is publishing to celebrate its 50th Anniversary. While this is the last piece in a series, my intention is for it to read more like the opening of a new book on family medicine, rather than an ending to a story about the specialty.

April Lockley, DO, represents a new generation of family physicians who began their careers in the 21st century, and she is hopeful that the experiences of practicing family medicine and being the patient of a family physician will change in several ways.

Among her desires for the future, is to be able to write a prescription for a medication or physical therapy to a patient who is able “to fill the prescription without having to worry about the financial implications of paying for it,” she writes. She also hopes “patients can seek out care without the fear of discrimination or racism through an increasingly diverse work force.”

In her article, Dr. Lockley both expresses how she wants family medicine to change and what she already finds satisfying about being a family physician.

I hope you enjoyed reading about the professional journeys of Dr. Lockley and other family physicians who have written commentaries or interviewed for articles in Family Practice News’ 50th Anniversary series this year.

To revisit any of these articles, go to the 50th Anniversary bucket on mdedge.com/familymedicine.

Thank you for continuing to read Family Practice News, and I hope to celebrate more milestones with you in the future.

klennon@mdedge.com

Background: There are extensive publications regarding preoperative risk assessment and optimization of risk management. This article is a review of current aggregate data from various meta-analyses and observational studies. It explores a systematic approach to preoperative risk assessment.

Dr. Young is a hospitalist at Northwestern Memorial Hospital and instructor of medicine, Feinberg School of Medicine, both in Chicago.

Background: There are extensive publications regarding preoperative risk assessment and optimization of risk management. This article is a review of current aggregate data from various meta-analyses and observational studies. It explores a systematic approach to preoperative risk assessment.

Dr. Young is a hospitalist at Northwestern Memorial Hospital and instructor of medicine, Feinberg School of Medicine, both in Chicago.

Background: There are extensive publications regarding preoperative risk assessment and optimization of risk management. This article is a review of current aggregate data from various meta-analyses and observational studies. It explores a systematic approach to preoperative risk assessment.

Dr. Young is a hospitalist at Northwestern Memorial Hospital and instructor of medicine, Feinberg School of Medicine, both in Chicago.

While laboratory studies move forward at full speed, the clinical use of stem cells—undifferentiated cells that can develop into many different types of specialized cells—remains controversial. Presently, only unadulterated stem cells are allowed to be used in patients, and only on an experimental and investigational basis. Stem cells that have been expanded, modified, or enhanced outside of the body are not allowed to be used for clinical application in the United States at this time. In June 2021, the FDA strengthened the language of stem cell regulation, further limiting their clinical application (see https://www.fda.gov/vaccines-blood-biologics/consumers-biologics/important-patient-and-consumer-information-about-regenerative-medicine-therapies). Yet some applications, such as treatment of lymphoma or restorative knee injections, are covered by some health insurance plans, and the acceptance of stem cell treatment is growing.

In this article, I describe the basics of stem cells, and explore the potential therapeutic use of stem cells for treating various mental illnesses.

Stem cells: A primer

Human embryonic stem cells were initially investigated for their healing properties. However, the need to harvest these cells from embryos drew much criticism, and many found the process to be ethically and religiously unacceptable. This was resolved by the Nobel prize–winning discovery that adult somatic cells can be reprogrammed into cells with embryonic stem cell properties by introducing specific transcription factors. These cells have been termed “induced pluripotent stem cells” (iPSCs).¹ The use of adult stem cells and stem cells from the umbilical cords of healthy newborns has allowed for wider acceptance of stem cell research and treatment.

Stem cells may be collected from the patient himself or herself; these are autologous stem cells. They may also be harvested from healthy newborn waste, such as the umbilical cord blood and wall; these are allogenic stem cells. Autologous stem cells are present in almost any tissue but are usually collected from the patient’s adipose tissue or from bone marrow. Understandably, younger stem cells possess higher healing properties. Stem cells may be mesenchymal, producing primarily connective and nervous tissue, or hematopoietic, influencing the immune system and blood cell production, though there is a considerable overlap in the function of these types of cells.

Adult somatic stem cells may be turned into stem cells (iPSCs) and then become any tissue, including neurons. This ability of stem cells to physically regenerate the CNS is directly relevant to psychiatry.

In addition to neurogenesis, stem cell transplants can assist in immune and vascular restoration as well as in suppressing inflammation. The ability of stem cells to replace mutated genes may be useful for addressing inheritable neuropsychiatric conditions.

Both autoimmune and inflammatory mechanisms play an important role in most psychiatric illnesses. The more we learn, the more it is clear that brain function is profoundly dependent on more than just its structure, and that structure depends on more than blood supply. Stem cells influence the vascular, nutritional, functional, inflammatory, and immune environment of the brain, potentially assisting in cognitive and emotional rehabilitation.

Stem cells operate in 2 fundamental ways: via direct cell-to-cell interaction, and via the production and release of growth, immune-regulating, and anti-inflammatory factors. Such factors are produced within the cells and then released in the extracellular environment as a content of exosomes. The route of administration is important in the delivery of the stem cells to the target tissue. Unlike their direct introduction into a joint, muscle, or intervertebral disk, injection of stem cells into the brain is more complicated and not routinely feasible. Intrathecal injections may bring stem cells into the CNS, but cerebrospinal fluid does not easily carry stem cells into the brain, and certainly cannot deliver them to an identified target within the brain. Existing technology can allow stem cells to be packaged in such a way that they can penetrate the blood-brain barrier, but this requires stem cell modification, which presently is not permitted in clinical practice in the United States. Alternatively, there is a way to weaken the blood-brain barrier to allow stem cells to travel through the “opened doors,” so to speak, but this allows everything to have access to the CNS, which may be unsafe. IV administration is technologically easy, and it grants stem cells the environment to multiply and produce extracellular factors that can cross the blood-brain barrier, while large cells cannot.

Continue to: Stem cells as a treatment for mental illness...

Stem cells as a treatment for mental illness

Based on our understanding of the function of stem cells, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions can be influenced by stem cell treatment. Here I review the potential therapeutic role of stem cells in the treatment of several psychiatric disorders.

Alzheimer’s dementia

Alzheimer’s dementia (AD) is a progressive neurodegenerative pathology based on neuronal and synaptic loss. Repopulation and regeneration of depleted neuronal circuitry by exogenous stem cells may be a rational therapeutic strategy.² The regeneration of lost neurons has the potential to restore cognitive function. Multiple growth factors that regulate neurogenesis are abundant during child development but dramatically decline with age. The introduction of stem cells—especially those derived from newborn waste—seem to promote recovery from neuro­degenerative disease or injury.³

There currently is no cure for AD. Cellular therapy promises new advances in treatment.⁴ Neurogenesis occurs not only during fetal development but in the adult brain. Neural stem cells reside in the adult CNS of all mammals.⁵ They are intimately involved in continuous restoration, but age just like the rest of the animal tissue, providing ever-decreasing restorative potential.

The number of studies of stem cells in AD has increased since the early 2000 s,^6,7 and research continues to demonstrate robust CNS neurogenesis. In a 2020 study, Zappa Villar et al⁸ evaluated stem cells as a treatment for rats in which an AD model was induced by the intracerebroventricular injection of streptozotocin (STZ). The STZ-treated rats displayed poor performance in all behavioral tests. Stem cell therapy increased exploratory behavior, decreased anxiety, and improved spatial memory and marble-burying behavior; the latter was representative of daily life activities. Importantly, stem cell therapy ameliorated and restored hippocampal atrophy and some presynaptic protein levels in the rats with AD.⁸ Animal models cannot be automatically applied to humans, but they shine a light on the areas that need further exploration.

In humans, elevated cortisol levels during aging predict hippocampal atrophy and memory deficits,⁹ and this deficiency may be positively influenced by stem cell treatment.

Schizophrenia

Recent research indicates that schizophrenia may begin with abnormal neurogenesis from neural stem cells inside the embryo, and that this process may be particularly vulnerable to numerous genetic and/or environmental disturbances of early brain development.¹⁰ Because neurogenesis is not confined to the womb but is a protracted process that continues into postnatal life, adolescence and beyond, influencing this process may be a way to add to the schizophrenia treatment armamentarium.¹⁰ Sacco et al¹¹ described links between the alteration of intrauterine and adult neurogenesis and the causes of neuropsychiatric disorders, including schizophrenia. Immune and inflammatory mechanisms are important in the etiology of schizophrenia. By their core function, stem cells address both mechanisms, and may directly modulate this devastating disease.

In addition to clinical hopes, advances in research tools hold the promise of new discoveries. With the advent of iPSC technology, it is possible to generate live neurons in vitro from somatic tissue of patients with schizophrenia. Despite its many limitations, this revolutionary technology has already helped to advance our understanding of schizophrenia.¹¹

Bipolar disorder

Many of the fundamental neurobiological mechanisms of schizophrenia are mirrored in bipolar disorder.¹² Though we are not ready to bring stem cells into the day-to-day treatment of this condition, several groups are starting to apply iPSC technology to the study of bipolar disorder.¹³

Neurodevelopmental factors—particularly pathways related to nervous system development, cell migration, extracellular matrix, methylation, and calcium signaling—have been identified in large gene expression studies as altered in bipolar disorder.¹⁴ Stem cell technology opens doorways to reverse engineering of human neuro­degenerative disease.¹⁵

Continue to: Autism spectrum disorders...

The exact mechanisms of action of MSCs to restore function in patients with ASDs are largely unknown, but proposed mechanisms include:

• synthesizing and releasing anti-inflammatory cytokines and survival-promoting growth factors
• integrating into the existing neural and synaptic network
• restoring plasticity.¹⁸

In a study of transplantation of human cord blood cells and umbilical cord–derived MSCs for patients with ASDs, Bradstreet et al¹⁹ found a statistically significant difference on scores for domains of speech, sociability, sensory, and overall health, as well as reductions in the total scores, in those who received transplants compared to their pretreatment values.

In another study of stem cell therapy for ASDs, Lv et al²⁰ demonstrated the safety and efficacy of combined transplantation of human cord blood cells and umbilical cord–derived MSCs in treating children with ASDs. The transplantations included 4 stem cell IV infusions and intrathecal injections once a week. Statistically significant differences were shown at 24 weeks post-treatment. Although this nonrandomized, open-label, single-center Phase I/II trial cannot be relied on for any definitive conclusions, it suggests an important area of investigation.²⁰

The vascular aspects of ASDs’ pathogenesis should not be overlooked. For example, specific temporal lobe areas associated with facial recognition, social interaction, and language comprehension have been demonstrated to be hypoperfused in children with ASDs, but not in controls. The degree of hypoperfusion and resulting hypoxia correlates with the severity of ASD symptoms. The damage causing hypoperfusion of temporal areas was associated with the onset of autism-like disorders. Damage of the amygdala, hippocampus, or other temporal structures induces permanent or transient autistic-like characteristics, such as unexpressive faces, little eye contact, and motor stereotypes. Clinically, temporal lobe damage by viral and other means has been implicated in the development of ASD in children and adults. Hypoperfusion may contribute to defects, not only by inducing hypoxia, but also by allowing for abnormal metabolite or neurotransmitter accumulation. This is one of the reasons glutamate toxicity has been implicated in ASD. The augmentation of perfusion through stimulation of angiogenesis by stem cells should allow for metabolite clearance and restoration of functionality. Vargas et al²¹ compared brain autopsy samples from 11 children with ASDs to those of 7 age-matched controls. They demonstrated an active neuroinflammatory process in the cerebral cortex, white matter, and cerebellum of patients with ASDs, both by immunohistochemistry and morphology.²¹

Multiple studies have confirmed that the systemic administration of cord blood cells is sufficient to induce neuroregeneration.^22,23 Angiogenesis has been experimentally demonstrated in peripheral artery disease, myocardial ischemia, and stroke, and has direct implications on brain repair.²⁴ Immune dysregulation^25,26 and immune modulation²⁷ also are addressed by stem cell treatment, which provides a promising avenue for battling ASDs.

Like attention-deficit/hyperactivity disorder and obsessive-compulsive disorder, ASDs are neurodevelopmental conditions. Advances based on the use of stem cells hold great promise for understanding, diagnosing and, possibly, treating these psychiatric disorders.^28,29

Depression

Neuropsychiatric disorders arise from deviations from the regular differentiation process of the CNS, leading to altered neuronal connectivity. Relatively subtle abnormalities in the size and number of cells in the prefrontal cortex and basal ganglia have been observed in patients with depressive disorder and Tourette syndrome.³⁰ Fibroblast-derived iPSCs generate serotonergic neurons through the exposure of the cells to growth factors and modulators of signaling pathways. If these serotonergic neurons are made from the patients’ own cells, they can be used to screen for new therapeutics and elucidate the unknown mechanisms through which current medications may function.³¹ This development could lead to the discovery of new medication targets and new insights into the molecular biology of depression.³²

Deficiencies of brain-derived neurotrophic factor (BDNF) have a role in depression, anxiety, and other neuropsychiatric illnesses. The acute behavioral effects of selective serotonin reuptake inhibitors and tricyclic antidepressants seem to require BDNF signaling, which suggests that BDNF holds great potential as a therapeutic agent. Cell therapies focused on correcting BDNF deficiencies in mice have had some success.³³

Dysregulation of GABAergic neurons has also been implicated in depression and anxiety. Patients with major depressive disorder have reduced gamma aminobutyric acid (GABA) receptors in the parahippocampal and lateral temporal lobes.³⁴

Ultimately, the development of differentiation protocols for serotonergic and GABAergic neuronal populations will pave the way for examining the role of these populations in the pathogenesis of depression and anxiety, and may eventually open the door for cell-based therapies in humans.³⁵

Studies have demonstrated a reduction in the density of pyramidal and nonpyramidal neurons in the anterior cingulate cortex of patients with schizophrenia and bipolar disorder,³⁶ glial reduction in the subgenual prefrontal cortex in mood disorders,³⁷ and morphometric evidence for neuronal and glial prefrontal cell pathology in major depressive disorder.³⁸ The potential for stem cells to repair such pathology may be of clinical benefit to many patients.

Aside from their other suggested clinical uses, iPSCs may be utilized in new pathways for research on the biology and pharmacology of major depressive disorder.³⁹

Continue to: Obsessive-compulsive disorder...

Obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is often characterized by excessive behaviors related to cleanliness, including grooming, which is represented across most animal species. In mice, behaviors such as compulsive grooming and hair removal—similar to behaviors in humans with OCD or trichotillomania—are associated with a specific mutation. Chen et al⁴⁰ reported that the transplantation of bone marrow stem cells into mice with this mutation (bone marrow–derived microglia specifically home to the brain) rescues their pathological phenotype by repairing native neurons.

The autoimmune, inflammatory, and neurodegenerative changes that are prevalent in OCD may be remedied by stem cell treatment in a fashion described throughout this article.

Other conditions

The Box^41-50 describes a possible role for stem cells in the treatment or prevention of several types of substance use disorders.

Box

Chronic pain is a neuropsychiatric condition that involves the immune system, inflammation, vascularization, trophic changes, and other aspects of the CNS function in addition to peripheral factors and somatic pain generators. Treatment of painful conditions with the aid of stem cells represents a large and ever-developing field that lies outside of the scope of this article.⁵¹

Experimental, but promising

It is not easy to accept revolutionary new approaches in medicine. Endless research and due diligence are needed to prove a concept and then to work out specific applications, safeguards, and limitations for any novel treatments. The stem cell terrain is poorly explored, and one needs to be careful when venturing there. Presently, the FDA appropriately sees treatment with stem cells as experimental and investigational, particularly in the mental health arena. Stem cells are not approved for treatment of any specific condition. At the same time, research and clinical practice suggest stem cell treatment may someday play a more prominent role in health care. Undoubtedly, psychiatry will eventually benefit from the knowledge and application of stem cell research and practice.

Related Resources

• De Los Angeles A, Fernando MB, Hall NAL, et al. Induced pluripotent stem cells in psychiatry: an overview and critical perspective. Biol Psychiatry. 2021;90(6):362-372.
• Heider J, Vogel S, Volkmer H, et al. Human iPSC-derived glia as a tool for neuropsychiatric research and drug development. Int J Mol Sci. 2021;22(19):10254.

Drug Brand Name

Streptozotocin • Zanosar

Bottom Line

Treatment with stem cell transplantation is experimental and not approved for any medical or psychiatric illness. However, based on our growing understanding of the function of stem cells, and preliminary research conducted mainly in animals, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions might be beneficially influenced by stem cell treatment.

While laboratory studies move forward at full speed, the clinical use of stem cells—undifferentiated cells that can develop into many different types of specialized cells—remains controversial. Presently, only unadulterated stem cells are allowed to be used in patients, and only on an experimental and investigational basis. Stem cells that have been expanded, modified, or enhanced outside of the body are not allowed to be used for clinical application in the United States at this time. In June 2021, the FDA strengthened the language of stem cell regulation, further limiting their clinical application (see https://www.fda.gov/vaccines-blood-biologics/consumers-biologics/important-patient-and-consumer-information-about-regenerative-medicine-therapies). Yet some applications, such as treatment of lymphoma or restorative knee injections, are covered by some health insurance plans, and the acceptance of stem cell treatment is growing.

In this article, I describe the basics of stem cells, and explore the potential therapeutic use of stem cells for treating various mental illnesses.

Stem cells: A primer

Human embryonic stem cells were initially investigated for their healing properties. However, the need to harvest these cells from embryos drew much criticism, and many found the process to be ethically and religiously unacceptable. This was resolved by the Nobel prize–winning discovery that adult somatic cells can be reprogrammed into cells with embryonic stem cell properties by introducing specific transcription factors. These cells have been termed “induced pluripotent stem cells” (iPSCs).¹ The use of adult stem cells and stem cells from the umbilical cords of healthy newborns has allowed for wider acceptance of stem cell research and treatment.

Stem cells may be collected from the patient himself or herself; these are autologous stem cells. They may also be harvested from healthy newborn waste, such as the umbilical cord blood and wall; these are allogenic stem cells. Autologous stem cells are present in almost any tissue but are usually collected from the patient’s adipose tissue or from bone marrow. Understandably, younger stem cells possess higher healing properties. Stem cells may be mesenchymal, producing primarily connective and nervous tissue, or hematopoietic, influencing the immune system and blood cell production, though there is a considerable overlap in the function of these types of cells.

Adult somatic stem cells may be turned into stem cells (iPSCs) and then become any tissue, including neurons. This ability of stem cells to physically regenerate the CNS is directly relevant to psychiatry.

In addition to neurogenesis, stem cell transplants can assist in immune and vascular restoration as well as in suppressing inflammation. The ability of stem cells to replace mutated genes may be useful for addressing inheritable neuropsychiatric conditions.

Both autoimmune and inflammatory mechanisms play an important role in most psychiatric illnesses. The more we learn, the more it is clear that brain function is profoundly dependent on more than just its structure, and that structure depends on more than blood supply. Stem cells influence the vascular, nutritional, functional, inflammatory, and immune environment of the brain, potentially assisting in cognitive and emotional rehabilitation.

Stem cells operate in 2 fundamental ways: via direct cell-to-cell interaction, and via the production and release of growth, immune-regulating, and anti-inflammatory factors. Such factors are produced within the cells and then released in the extracellular environment as a content of exosomes. The route of administration is important in the delivery of the stem cells to the target tissue. Unlike their direct introduction into a joint, muscle, or intervertebral disk, injection of stem cells into the brain is more complicated and not routinely feasible. Intrathecal injections may bring stem cells into the CNS, but cerebrospinal fluid does not easily carry stem cells into the brain, and certainly cannot deliver them to an identified target within the brain. Existing technology can allow stem cells to be packaged in such a way that they can penetrate the blood-brain barrier, but this requires stem cell modification, which presently is not permitted in clinical practice in the United States. Alternatively, there is a way to weaken the blood-brain barrier to allow stem cells to travel through the “opened doors,” so to speak, but this allows everything to have access to the CNS, which may be unsafe. IV administration is technologically easy, and it grants stem cells the environment to multiply and produce extracellular factors that can cross the blood-brain barrier, while large cells cannot.

Continue to: Stem cells as a treatment for mental illness...

Stem cells as a treatment for mental illness

Based on our understanding of the function of stem cells, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions can be influenced by stem cell treatment. Here I review the potential therapeutic role of stem cells in the treatment of several psychiatric disorders.

Alzheimer’s dementia

Alzheimer’s dementia (AD) is a progressive neurodegenerative pathology based on neuronal and synaptic loss. Repopulation and regeneration of depleted neuronal circuitry by exogenous stem cells may be a rational therapeutic strategy.² The regeneration of lost neurons has the potential to restore cognitive function. Multiple growth factors that regulate neurogenesis are abundant during child development but dramatically decline with age. The introduction of stem cells—especially those derived from newborn waste—seem to promote recovery from neuro­degenerative disease or injury.³

There currently is no cure for AD. Cellular therapy promises new advances in treatment.⁴ Neurogenesis occurs not only during fetal development but in the adult brain. Neural stem cells reside in the adult CNS of all mammals.⁵ They are intimately involved in continuous restoration, but age just like the rest of the animal tissue, providing ever-decreasing restorative potential.

The number of studies of stem cells in AD has increased since the early 2000 s,^6,7 and research continues to demonstrate robust CNS neurogenesis. In a 2020 study, Zappa Villar et al⁸ evaluated stem cells as a treatment for rats in which an AD model was induced by the intracerebroventricular injection of streptozotocin (STZ). The STZ-treated rats displayed poor performance in all behavioral tests. Stem cell therapy increased exploratory behavior, decreased anxiety, and improved spatial memory and marble-burying behavior; the latter was representative of daily life activities. Importantly, stem cell therapy ameliorated and restored hippocampal atrophy and some presynaptic protein levels in the rats with AD.⁸ Animal models cannot be automatically applied to humans, but they shine a light on the areas that need further exploration.

In humans, elevated cortisol levels during aging predict hippocampal atrophy and memory deficits,⁹ and this deficiency may be positively influenced by stem cell treatment.

Schizophrenia

Recent research indicates that schizophrenia may begin with abnormal neurogenesis from neural stem cells inside the embryo, and that this process may be particularly vulnerable to numerous genetic and/or environmental disturbances of early brain development.¹⁰ Because neurogenesis is not confined to the womb but is a protracted process that continues into postnatal life, adolescence and beyond, influencing this process may be a way to add to the schizophrenia treatment armamentarium.¹⁰ Sacco et al¹¹ described links between the alteration of intrauterine and adult neurogenesis and the causes of neuropsychiatric disorders, including schizophrenia. Immune and inflammatory mechanisms are important in the etiology of schizophrenia. By their core function, stem cells address both mechanisms, and may directly modulate this devastating disease.

In addition to clinical hopes, advances in research tools hold the promise of new discoveries. With the advent of iPSC technology, it is possible to generate live neurons in vitro from somatic tissue of patients with schizophrenia. Despite its many limitations, this revolutionary technology has already helped to advance our understanding of schizophrenia.¹¹

Bipolar disorder

Many of the fundamental neurobiological mechanisms of schizophrenia are mirrored in bipolar disorder.¹² Though we are not ready to bring stem cells into the day-to-day treatment of this condition, several groups are starting to apply iPSC technology to the study of bipolar disorder.¹³

Neurodevelopmental factors—particularly pathways related to nervous system development, cell migration, extracellular matrix, methylation, and calcium signaling—have been identified in large gene expression studies as altered in bipolar disorder.¹⁴ Stem cell technology opens doorways to reverse engineering of human neuro­degenerative disease.¹⁵

Continue to: Autism spectrum disorders...

The exact mechanisms of action of MSCs to restore function in patients with ASDs are largely unknown, but proposed mechanisms include:

• synthesizing and releasing anti-inflammatory cytokines and survival-promoting growth factors
• integrating into the existing neural and synaptic network
• restoring plasticity.¹⁸

In a study of transplantation of human cord blood cells and umbilical cord–derived MSCs for patients with ASDs, Bradstreet et al¹⁹ found a statistically significant difference on scores for domains of speech, sociability, sensory, and overall health, as well as reductions in the total scores, in those who received transplants compared to their pretreatment values.

In another study of stem cell therapy for ASDs, Lv et al²⁰ demonstrated the safety and efficacy of combined transplantation of human cord blood cells and umbilical cord–derived MSCs in treating children with ASDs. The transplantations included 4 stem cell IV infusions and intrathecal injections once a week. Statistically significant differences were shown at 24 weeks post-treatment. Although this nonrandomized, open-label, single-center Phase I/II trial cannot be relied on for any definitive conclusions, it suggests an important area of investigation.²⁰

The vascular aspects of ASDs’ pathogenesis should not be overlooked. For example, specific temporal lobe areas associated with facial recognition, social interaction, and language comprehension have been demonstrated to be hypoperfused in children with ASDs, but not in controls. The degree of hypoperfusion and resulting hypoxia correlates with the severity of ASD symptoms. The damage causing hypoperfusion of temporal areas was associated with the onset of autism-like disorders. Damage of the amygdala, hippocampus, or other temporal structures induces permanent or transient autistic-like characteristics, such as unexpressive faces, little eye contact, and motor stereotypes. Clinically, temporal lobe damage by viral and other means has been implicated in the development of ASD in children and adults. Hypoperfusion may contribute to defects, not only by inducing hypoxia, but also by allowing for abnormal metabolite or neurotransmitter accumulation. This is one of the reasons glutamate toxicity has been implicated in ASD. The augmentation of perfusion through stimulation of angiogenesis by stem cells should allow for metabolite clearance and restoration of functionality. Vargas et al²¹ compared brain autopsy samples from 11 children with ASDs to those of 7 age-matched controls. They demonstrated an active neuroinflammatory process in the cerebral cortex, white matter, and cerebellum of patients with ASDs, both by immunohistochemistry and morphology.²¹

Multiple studies have confirmed that the systemic administration of cord blood cells is sufficient to induce neuroregeneration.^22,23 Angiogenesis has been experimentally demonstrated in peripheral artery disease, myocardial ischemia, and stroke, and has direct implications on brain repair.²⁴ Immune dysregulation^25,26 and immune modulation²⁷ also are addressed by stem cell treatment, which provides a promising avenue for battling ASDs.

Like attention-deficit/hyperactivity disorder and obsessive-compulsive disorder, ASDs are neurodevelopmental conditions. Advances based on the use of stem cells hold great promise for understanding, diagnosing and, possibly, treating these psychiatric disorders.^28,29

Depression

Neuropsychiatric disorders arise from deviations from the regular differentiation process of the CNS, leading to altered neuronal connectivity. Relatively subtle abnormalities in the size and number of cells in the prefrontal cortex and basal ganglia have been observed in patients with depressive disorder and Tourette syndrome.³⁰ Fibroblast-derived iPSCs generate serotonergic neurons through the exposure of the cells to growth factors and modulators of signaling pathways. If these serotonergic neurons are made from the patients’ own cells, they can be used to screen for new therapeutics and elucidate the unknown mechanisms through which current medications may function.³¹ This development could lead to the discovery of new medication targets and new insights into the molecular biology of depression.³²

Deficiencies of brain-derived neurotrophic factor (BDNF) have a role in depression, anxiety, and other neuropsychiatric illnesses. The acute behavioral effects of selective serotonin reuptake inhibitors and tricyclic antidepressants seem to require BDNF signaling, which suggests that BDNF holds great potential as a therapeutic agent. Cell therapies focused on correcting BDNF deficiencies in mice have had some success.³³

Dysregulation of GABAergic neurons has also been implicated in depression and anxiety. Patients with major depressive disorder have reduced gamma aminobutyric acid (GABA) receptors in the parahippocampal and lateral temporal lobes.³⁴

Ultimately, the development of differentiation protocols for serotonergic and GABAergic neuronal populations will pave the way for examining the role of these populations in the pathogenesis of depression and anxiety, and may eventually open the door for cell-based therapies in humans.³⁵

Studies have demonstrated a reduction in the density of pyramidal and nonpyramidal neurons in the anterior cingulate cortex of patients with schizophrenia and bipolar disorder,³⁶ glial reduction in the subgenual prefrontal cortex in mood disorders,³⁷ and morphometric evidence for neuronal and glial prefrontal cell pathology in major depressive disorder.³⁸ The potential for stem cells to repair such pathology may be of clinical benefit to many patients.

Aside from their other suggested clinical uses, iPSCs may be utilized in new pathways for research on the biology and pharmacology of major depressive disorder.³⁹

Continue to: Obsessive-compulsive disorder...

Obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is often characterized by excessive behaviors related to cleanliness, including grooming, which is represented across most animal species. In mice, behaviors such as compulsive grooming and hair removal—similar to behaviors in humans with OCD or trichotillomania—are associated with a specific mutation. Chen et al⁴⁰ reported that the transplantation of bone marrow stem cells into mice with this mutation (bone marrow–derived microglia specifically home to the brain) rescues their pathological phenotype by repairing native neurons.

The autoimmune, inflammatory, and neurodegenerative changes that are prevalent in OCD may be remedied by stem cell treatment in a fashion described throughout this article.

Other conditions

The Box^41-50 describes a possible role for stem cells in the treatment or prevention of several types of substance use disorders.

Box

Chronic pain is a neuropsychiatric condition that involves the immune system, inflammation, vascularization, trophic changes, and other aspects of the CNS function in addition to peripheral factors and somatic pain generators. Treatment of painful conditions with the aid of stem cells represents a large and ever-developing field that lies outside of the scope of this article.⁵¹

Experimental, but promising

It is not easy to accept revolutionary new approaches in medicine. Endless research and due diligence are needed to prove a concept and then to work out specific applications, safeguards, and limitations for any novel treatments. The stem cell terrain is poorly explored, and one needs to be careful when venturing there. Presently, the FDA appropriately sees treatment with stem cells as experimental and investigational, particularly in the mental health arena. Stem cells are not approved for treatment of any specific condition. At the same time, research and clinical practice suggest stem cell treatment may someday play a more prominent role in health care. Undoubtedly, psychiatry will eventually benefit from the knowledge and application of stem cell research and practice.

Related Resources

• De Los Angeles A, Fernando MB, Hall NAL, et al. Induced pluripotent stem cells in psychiatry: an overview and critical perspective. Biol Psychiatry. 2021;90(6):362-372.
• Heider J, Vogel S, Volkmer H, et al. Human iPSC-derived glia as a tool for neuropsychiatric research and drug development. Int J Mol Sci. 2021;22(19):10254.

Drug Brand Name

Streptozotocin • Zanosar

Bottom Line

Treatment with stem cell transplantation is experimental and not approved for any medical or psychiatric illness. However, based on our growing understanding of the function of stem cells, and preliminary research conducted mainly in animals, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions might be beneficially influenced by stem cell treatment.

While laboratory studies move forward at full speed, the clinical use of stem cells—undifferentiated cells that can develop into many different types of specialized cells—remains controversial. Presently, only unadulterated stem cells are allowed to be used in patients, and only on an experimental and investigational basis. Stem cells that have been expanded, modified, or enhanced outside of the body are not allowed to be used for clinical application in the United States at this time. In June 2021, the FDA strengthened the language of stem cell regulation, further limiting their clinical application (see https://www.fda.gov/vaccines-blood-biologics/consumers-biologics/important-patient-and-consumer-information-about-regenerative-medicine-therapies). Yet some applications, such as treatment of lymphoma or restorative knee injections, are covered by some health insurance plans, and the acceptance of stem cell treatment is growing.

In this article, I describe the basics of stem cells, and explore the potential therapeutic use of stem cells for treating various mental illnesses.

Stem cells: A primer

Human embryonic stem cells were initially investigated for their healing properties. However, the need to harvest these cells from embryos drew much criticism, and many found the process to be ethically and religiously unacceptable. This was resolved by the Nobel prize–winning discovery that adult somatic cells can be reprogrammed into cells with embryonic stem cell properties by introducing specific transcription factors. These cells have been termed “induced pluripotent stem cells” (iPSCs).¹ The use of adult stem cells and stem cells from the umbilical cords of healthy newborns has allowed for wider acceptance of stem cell research and treatment.

Stem cells may be collected from the patient himself or herself; these are autologous stem cells. They may also be harvested from healthy newborn waste, such as the umbilical cord blood and wall; these are allogenic stem cells. Autologous stem cells are present in almost any tissue but are usually collected from the patient’s adipose tissue or from bone marrow. Understandably, younger stem cells possess higher healing properties. Stem cells may be mesenchymal, producing primarily connective and nervous tissue, or hematopoietic, influencing the immune system and blood cell production, though there is a considerable overlap in the function of these types of cells.

Adult somatic stem cells may be turned into stem cells (iPSCs) and then become any tissue, including neurons. This ability of stem cells to physically regenerate the CNS is directly relevant to psychiatry.

In addition to neurogenesis, stem cell transplants can assist in immune and vascular restoration as well as in suppressing inflammation. The ability of stem cells to replace mutated genes may be useful for addressing inheritable neuropsychiatric conditions.

Both autoimmune and inflammatory mechanisms play an important role in most psychiatric illnesses. The more we learn, the more it is clear that brain function is profoundly dependent on more than just its structure, and that structure depends on more than blood supply. Stem cells influence the vascular, nutritional, functional, inflammatory, and immune environment of the brain, potentially assisting in cognitive and emotional rehabilitation.

Stem cells operate in 2 fundamental ways: via direct cell-to-cell interaction, and via the production and release of growth, immune-regulating, and anti-inflammatory factors. Such factors are produced within the cells and then released in the extracellular environment as a content of exosomes. The route of administration is important in the delivery of the stem cells to the target tissue. Unlike their direct introduction into a joint, muscle, or intervertebral disk, injection of stem cells into the brain is more complicated and not routinely feasible. Intrathecal injections may bring stem cells into the CNS, but cerebrospinal fluid does not easily carry stem cells into the brain, and certainly cannot deliver them to an identified target within the brain. Existing technology can allow stem cells to be packaged in such a way that they can penetrate the blood-brain barrier, but this requires stem cell modification, which presently is not permitted in clinical practice in the United States. Alternatively, there is a way to weaken the blood-brain barrier to allow stem cells to travel through the “opened doors,” so to speak, but this allows everything to have access to the CNS, which may be unsafe. IV administration is technologically easy, and it grants stem cells the environment to multiply and produce extracellular factors that can cross the blood-brain barrier, while large cells cannot.

Continue to: Stem cells as a treatment for mental illness...

Stem cells as a treatment for mental illness

Based on our understanding of the function of stem cells, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions can be influenced by stem cell treatment. Here I review the potential therapeutic role of stem cells in the treatment of several psychiatric disorders.

Alzheimer’s dementia

Alzheimer’s dementia (AD) is a progressive neurodegenerative pathology based on neuronal and synaptic loss. Repopulation and regeneration of depleted neuronal circuitry by exogenous stem cells may be a rational therapeutic strategy.² The regeneration of lost neurons has the potential to restore cognitive function. Multiple growth factors that regulate neurogenesis are abundant during child development but dramatically decline with age. The introduction of stem cells—especially those derived from newborn waste—seem to promote recovery from neuro­degenerative disease or injury.³

There currently is no cure for AD. Cellular therapy promises new advances in treatment.⁴ Neurogenesis occurs not only during fetal development but in the adult brain. Neural stem cells reside in the adult CNS of all mammals.⁵ They are intimately involved in continuous restoration, but age just like the rest of the animal tissue, providing ever-decreasing restorative potential.

The number of studies of stem cells in AD has increased since the early 2000 s,^6,7 and research continues to demonstrate robust CNS neurogenesis. In a 2020 study, Zappa Villar et al⁸ evaluated stem cells as a treatment for rats in which an AD model was induced by the intracerebroventricular injection of streptozotocin (STZ). The STZ-treated rats displayed poor performance in all behavioral tests. Stem cell therapy increased exploratory behavior, decreased anxiety, and improved spatial memory and marble-burying behavior; the latter was representative of daily life activities. Importantly, stem cell therapy ameliorated and restored hippocampal atrophy and some presynaptic protein levels in the rats with AD.⁸ Animal models cannot be automatically applied to humans, but they shine a light on the areas that need further exploration.

In humans, elevated cortisol levels during aging predict hippocampal atrophy and memory deficits,⁹ and this deficiency may be positively influenced by stem cell treatment.

Schizophrenia

Recent research indicates that schizophrenia may begin with abnormal neurogenesis from neural stem cells inside the embryo, and that this process may be particularly vulnerable to numerous genetic and/or environmental disturbances of early brain development.¹⁰ Because neurogenesis is not confined to the womb but is a protracted process that continues into postnatal life, adolescence and beyond, influencing this process may be a way to add to the schizophrenia treatment armamentarium.¹⁰ Sacco et al¹¹ described links between the alteration of intrauterine and adult neurogenesis and the causes of neuropsychiatric disorders, including schizophrenia. Immune and inflammatory mechanisms are important in the etiology of schizophrenia. By their core function, stem cells address both mechanisms, and may directly modulate this devastating disease.

In addition to clinical hopes, advances in research tools hold the promise of new discoveries. With the advent of iPSC technology, it is possible to generate live neurons in vitro from somatic tissue of patients with schizophrenia. Despite its many limitations, this revolutionary technology has already helped to advance our understanding of schizophrenia.¹¹

Bipolar disorder

Many of the fundamental neurobiological mechanisms of schizophrenia are mirrored in bipolar disorder.¹² Though we are not ready to bring stem cells into the day-to-day treatment of this condition, several groups are starting to apply iPSC technology to the study of bipolar disorder.¹³

Neurodevelopmental factors—particularly pathways related to nervous system development, cell migration, extracellular matrix, methylation, and calcium signaling—have been identified in large gene expression studies as altered in bipolar disorder.¹⁴ Stem cell technology opens doorways to reverse engineering of human neuro­degenerative disease.¹⁵

Continue to: Autism spectrum disorders...

The exact mechanisms of action of MSCs to restore function in patients with ASDs are largely unknown, but proposed mechanisms include:

• synthesizing and releasing anti-inflammatory cytokines and survival-promoting growth factors
• integrating into the existing neural and synaptic network
• restoring plasticity.¹⁸

In a study of transplantation of human cord blood cells and umbilical cord–derived MSCs for patients with ASDs, Bradstreet et al¹⁹ found a statistically significant difference on scores for domains of speech, sociability, sensory, and overall health, as well as reductions in the total scores, in those who received transplants compared to their pretreatment values.

In another study of stem cell therapy for ASDs, Lv et al²⁰ demonstrated the safety and efficacy of combined transplantation of human cord blood cells and umbilical cord–derived MSCs in treating children with ASDs. The transplantations included 4 stem cell IV infusions and intrathecal injections once a week. Statistically significant differences were shown at 24 weeks post-treatment. Although this nonrandomized, open-label, single-center Phase I/II trial cannot be relied on for any definitive conclusions, it suggests an important area of investigation.²⁰

The vascular aspects of ASDs’ pathogenesis should not be overlooked. For example, specific temporal lobe areas associated with facial recognition, social interaction, and language comprehension have been demonstrated to be hypoperfused in children with ASDs, but not in controls. The degree of hypoperfusion and resulting hypoxia correlates with the severity of ASD symptoms. The damage causing hypoperfusion of temporal areas was associated with the onset of autism-like disorders. Damage of the amygdala, hippocampus, or other temporal structures induces permanent or transient autistic-like characteristics, such as unexpressive faces, little eye contact, and motor stereotypes. Clinically, temporal lobe damage by viral and other means has been implicated in the development of ASD in children and adults. Hypoperfusion may contribute to defects, not only by inducing hypoxia, but also by allowing for abnormal metabolite or neurotransmitter accumulation. This is one of the reasons glutamate toxicity has been implicated in ASD. The augmentation of perfusion through stimulation of angiogenesis by stem cells should allow for metabolite clearance and restoration of functionality. Vargas et al²¹ compared brain autopsy samples from 11 children with ASDs to those of 7 age-matched controls. They demonstrated an active neuroinflammatory process in the cerebral cortex, white matter, and cerebellum of patients with ASDs, both by immunohistochemistry and morphology.²¹

Multiple studies have confirmed that the systemic administration of cord blood cells is sufficient to induce neuroregeneration.^22,23 Angiogenesis has been experimentally demonstrated in peripheral artery disease, myocardial ischemia, and stroke, and has direct implications on brain repair.²⁴ Immune dysregulation^25,26 and immune modulation²⁷ also are addressed by stem cell treatment, which provides a promising avenue for battling ASDs.

Like attention-deficit/hyperactivity disorder and obsessive-compulsive disorder, ASDs are neurodevelopmental conditions. Advances based on the use of stem cells hold great promise for understanding, diagnosing and, possibly, treating these psychiatric disorders.^28,29

Depression

Neuropsychiatric disorders arise from deviations from the regular differentiation process of the CNS, leading to altered neuronal connectivity. Relatively subtle abnormalities in the size and number of cells in the prefrontal cortex and basal ganglia have been observed in patients with depressive disorder and Tourette syndrome.³⁰ Fibroblast-derived iPSCs generate serotonergic neurons through the exposure of the cells to growth factors and modulators of signaling pathways. If these serotonergic neurons are made from the patients’ own cells, they can be used to screen for new therapeutics and elucidate the unknown mechanisms through which current medications may function.³¹ This development could lead to the discovery of new medication targets and new insights into the molecular biology of depression.³²

Deficiencies of brain-derived neurotrophic factor (BDNF) have a role in depression, anxiety, and other neuropsychiatric illnesses. The acute behavioral effects of selective serotonin reuptake inhibitors and tricyclic antidepressants seem to require BDNF signaling, which suggests that BDNF holds great potential as a therapeutic agent. Cell therapies focused on correcting BDNF deficiencies in mice have had some success.³³

Dysregulation of GABAergic neurons has also been implicated in depression and anxiety. Patients with major depressive disorder have reduced gamma aminobutyric acid (GABA) receptors in the parahippocampal and lateral temporal lobes.³⁴

Ultimately, the development of differentiation protocols for serotonergic and GABAergic neuronal populations will pave the way for examining the role of these populations in the pathogenesis of depression and anxiety, and may eventually open the door for cell-based therapies in humans.³⁵

Studies have demonstrated a reduction in the density of pyramidal and nonpyramidal neurons in the anterior cingulate cortex of patients with schizophrenia and bipolar disorder,³⁶ glial reduction in the subgenual prefrontal cortex in mood disorders,³⁷ and morphometric evidence for neuronal and glial prefrontal cell pathology in major depressive disorder.³⁸ The potential for stem cells to repair such pathology may be of clinical benefit to many patients.

Aside from their other suggested clinical uses, iPSCs may be utilized in new pathways for research on the biology and pharmacology of major depressive disorder.³⁹

Continue to: Obsessive-compulsive disorder...

Obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is often characterized by excessive behaviors related to cleanliness, including grooming, which is represented across most animal species. In mice, behaviors such as compulsive grooming and hair removal—similar to behaviors in humans with OCD or trichotillomania—are associated with a specific mutation. Chen et al⁴⁰ reported that the transplantation of bone marrow stem cells into mice with this mutation (bone marrow–derived microglia specifically home to the brain) rescues their pathological phenotype by repairing native neurons.

The autoimmune, inflammatory, and neurodegenerative changes that are prevalent in OCD may be remedied by stem cell treatment in a fashion described throughout this article.

Other conditions

The Box^41-50 describes a possible role for stem cells in the treatment or prevention of several types of substance use disorders.

Box

Chronic pain is a neuropsychiatric condition that involves the immune system, inflammation, vascularization, trophic changes, and other aspects of the CNS function in addition to peripheral factors and somatic pain generators. Treatment of painful conditions with the aid of stem cells represents a large and ever-developing field that lies outside of the scope of this article.⁵¹

Experimental, but promising

It is not easy to accept revolutionary new approaches in medicine. Endless research and due diligence are needed to prove a concept and then to work out specific applications, safeguards, and limitations for any novel treatments. The stem cell terrain is poorly explored, and one needs to be careful when venturing there. Presently, the FDA appropriately sees treatment with stem cells as experimental and investigational, particularly in the mental health arena. Stem cells are not approved for treatment of any specific condition. At the same time, research and clinical practice suggest stem cell treatment may someday play a more prominent role in health care. Undoubtedly, psychiatry will eventually benefit from the knowledge and application of stem cell research and practice.

Related Resources

• De Los Angeles A, Fernando MB, Hall NAL, et al. Induced pluripotent stem cells in psychiatry: an overview and critical perspective. Biol Psychiatry. 2021;90(6):362-372.
• Heider J, Vogel S, Volkmer H, et al. Human iPSC-derived glia as a tool for neuropsychiatric research and drug development. Int J Mol Sci. 2021;22(19):10254.

Drug Brand Name

Streptozotocin • Zanosar

Bottom Line

Treatment with stem cell transplantation is experimental and not approved for any medical or psychiatric illness. However, based on our growing understanding of the function of stem cells, and preliminary research conducted mainly in animals, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions might be beneficially influenced by stem cell treatment.

The investigational PCSK9 inhibitor that Merck showcased recently would be more than a “me-too” drug if it ultimately wins approval, despite competition from several approved agents that slash elevated cholesterol levels by targeting the same protein.

BananaStock/thinkstockphotos.com

In fact, it would be something of a breakthrough. The new agent under study – now called MK-0616 – comes in pill form, in contrast to the three currently available PCSK9-lowering drugs that must be given in injections separated by weeks to months.

The drug faces an uncertain road to regulatory review and any approval, but MK-0616 at least seems to be starting out in the right direction.

In two phase 1 studies with a total of 100 participants, plasma PCSK9 levels plunged more than 90% after a single dose of the drug; and low-density-lipoprotein cholesterol (LDL-C) levels dropped about 65% when MK-0616 was given daily for 2 weeks on a background of statin therapy.

Moreover, “MK-0616 was generally well tolerated at up to and including single doses of 300 milligrams,” the maximum tested in the studies, Douglas G. Johns, PhD, reported at the virtual American Heart Association scientific sessions.

The collective results from the oral agent’s earliest human experience are “definitely encouraging” and support MK-0616 as a potential LDL-lowering agent that would be more convenient and arguably more accessible to patients compared to current injectable PCSK9 inhibitors, proposed Dr. Johns, clinical director of translational medicine for Merck in Kenilworth, N.J.

Available PCSK9-targeting agents include alirocumab (Praluent, Sanofi/Regeneron), Food and Drug Administration–approved in July 2015, and evolocumab (Repatha, Amgen), approved by the agency the following month. Both are monoclonal antibodies with neutralizing specificity for the PCSK9 protein; whereas the third such agent, inclisiran (Leqvio, Novartis) is a small-molecule interfering-RNA that suppresses PCSK9 synthesis. Inclisiran is approved in the European Union but its case to the FDA was turned down in 2020.

Dr. Johns said MK-0616 is a cyclic peptide that is “about one-hundredth the size of a monoclonal antibody, but we’re able to achieve monoclonal antibody-like potency and selectivity with this much smaller footprint.”

Added to statin therapy, the current PCSK9-targeting agents reduce LDL-C by an additional one-half or more, and the two antibody-based agents “also decrease atherosclerotic cardiovascular events. They are, however, expensive and not always available, requiring insurance or other approval,” observed Anne C. Goldberg, MD, as invited discussant after Dr. Johns’ presentation.

“They require every 2- to 4-week injections. They’re generally reserved for secondary prevention, and sometimes primary prevention as in familial hypercholesterolemia,” said Dr. Goldberg, of Washington University, St. Louis. Inclisiran, she noted, requires injections every 6 months and has yet to show its mettle in cardiovascular outcomes trials.

“Certainly, an oral form would be easier to use,” she said. “This would be particularly helpful in patients averse to injections,” especially, perhaps, in children. “Children with familial hypercholesterolemia could benefit with greater cholesterol lowering and might be better off with a pill than an injection.” That would be good reason to emphasize the enrollment of children in the drug’s upcoming clinical trials, Dr. Goldberg said.

But cost could potentially become restrictive for MK-0616 as well, should it ever be approved. “If it’s priced too high, then are you really going to see the increased use?” she posed. “Certainly, there’s a high bar for therapies that are add-on to statins in terms of cost effectiveness.”

In the first of the two trials, 60 predominantly White male participants aged 50 or younger were randomly assigned to receive a single dose of MK-0616, at different levels ranging from 10 mg to 300 mg, or placebo. They subsequently crossed over to a different group for a second round of dosing. Both times, three participants took the drug for every one who received placebo.

Participants who took the active drug, regardless of dosage, showed greater than 90% reductions in circulating PCSK9 levels compared to baseline. Six participants discontinued the study before its completion.

In the second trial, 40 White adults aged 65 or younger (mean, 58), including 13 women, with LDL-C of 60 mg/dL to 160 mg/dL (mean, 87 mg/dL) on statin therapy for at least 3 months were randomly assigned 3-to-1 to add-on MK-0616, either 10 mg or 20 mg daily, or placebo for 14 days.

LDL-C levels fell an average of about 65% over the 2 weeks among those taking the active drug; they declined less than 5% for those who took placebo.

There were no deaths or serious adverse events in either trial, Dr. Johns reported. On the other hand, pharmacokinetics studies showed that exposure to the drug fell by “about 50%-60%” when dosing was preceded by food intake within the previous 30 minutes. “However, if a meal is consumed 30 minutes after the dose, this food effect is much, much less prominent, almost negligible.”

These preliminary results show the drug is “orally bioavailable and exerts a clinically meaningful effect,” Dr. Johns said. “However, there’s definitely more to be done. And we are planning the next phase of clinical development, a phase 2 trial, sometime next year.”

The research was funded by Merck. Dr. Johns disclosed employment with and equity ownership in Merck, as did all the study’s coauthors. Dr. Goldberg disclosed holding research contracts through her institution with Regeneron/Sanofi-Aventis, Amarin, Amgen, Pfizer, IONIS/Akcea, Regeneron, Novartis, Arrowroot Pharmaceuticals, and the FH Foundation; and consulting for Novartis, Akcea, Regeneron, and Esperion.

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

The investigational PCSK9 inhibitor that Merck showcased recently would be more than a “me-too” drug if it ultimately wins approval, despite competition from several approved agents that slash elevated cholesterol levels by targeting the same protein.

BananaStock/thinkstockphotos.com

In fact, it would be something of a breakthrough. The new agent under study – now called MK-0616 – comes in pill form, in contrast to the three currently available PCSK9-lowering drugs that must be given in injections separated by weeks to months.

The drug faces an uncertain road to regulatory review and any approval, but MK-0616 at least seems to be starting out in the right direction.

In two phase 1 studies with a total of 100 participants, plasma PCSK9 levels plunged more than 90% after a single dose of the drug; and low-density-lipoprotein cholesterol (LDL-C) levels dropped about 65% when MK-0616 was given daily for 2 weeks on a background of statin therapy.

Moreover, “MK-0616 was generally well tolerated at up to and including single doses of 300 milligrams,” the maximum tested in the studies, Douglas G. Johns, PhD, reported at the virtual American Heart Association scientific sessions.

The collective results from the oral agent’s earliest human experience are “definitely encouraging” and support MK-0616 as a potential LDL-lowering agent that would be more convenient and arguably more accessible to patients compared to current injectable PCSK9 inhibitors, proposed Dr. Johns, clinical director of translational medicine for Merck in Kenilworth, N.J.

Available PCSK9-targeting agents include alirocumab (Praluent, Sanofi/Regeneron), Food and Drug Administration–approved in July 2015, and evolocumab (Repatha, Amgen), approved by the agency the following month. Both are monoclonal antibodies with neutralizing specificity for the PCSK9 protein; whereas the third such agent, inclisiran (Leqvio, Novartis) is a small-molecule interfering-RNA that suppresses PCSK9 synthesis. Inclisiran is approved in the European Union but its case to the FDA was turned down in 2020.

Dr. Johns said MK-0616 is a cyclic peptide that is “about one-hundredth the size of a monoclonal antibody, but we’re able to achieve monoclonal antibody-like potency and selectivity with this much smaller footprint.”

Added to statin therapy, the current PCSK9-targeting agents reduce LDL-C by an additional one-half or more, and the two antibody-based agents “also decrease atherosclerotic cardiovascular events. They are, however, expensive and not always available, requiring insurance or other approval,” observed Anne C. Goldberg, MD, as invited discussant after Dr. Johns’ presentation.

“They require every 2- to 4-week injections. They’re generally reserved for secondary prevention, and sometimes primary prevention as in familial hypercholesterolemia,” said Dr. Goldberg, of Washington University, St. Louis. Inclisiran, she noted, requires injections every 6 months and has yet to show its mettle in cardiovascular outcomes trials.

“Certainly, an oral form would be easier to use,” she said. “This would be particularly helpful in patients averse to injections,” especially, perhaps, in children. “Children with familial hypercholesterolemia could benefit with greater cholesterol lowering and might be better off with a pill than an injection.” That would be good reason to emphasize the enrollment of children in the drug’s upcoming clinical trials, Dr. Goldberg said.

But cost could potentially become restrictive for MK-0616 as well, should it ever be approved. “If it’s priced too high, then are you really going to see the increased use?” she posed. “Certainly, there’s a high bar for therapies that are add-on to statins in terms of cost effectiveness.”

In the first of the two trials, 60 predominantly White male participants aged 50 or younger were randomly assigned to receive a single dose of MK-0616, at different levels ranging from 10 mg to 300 mg, or placebo. They subsequently crossed over to a different group for a second round of dosing. Both times, three participants took the drug for every one who received placebo.

Participants who took the active drug, regardless of dosage, showed greater than 90% reductions in circulating PCSK9 levels compared to baseline. Six participants discontinued the study before its completion.

In the second trial, 40 White adults aged 65 or younger (mean, 58), including 13 women, with LDL-C of 60 mg/dL to 160 mg/dL (mean, 87 mg/dL) on statin therapy for at least 3 months were randomly assigned 3-to-1 to add-on MK-0616, either 10 mg or 20 mg daily, or placebo for 14 days.

LDL-C levels fell an average of about 65% over the 2 weeks among those taking the active drug; they declined less than 5% for those who took placebo.

There were no deaths or serious adverse events in either trial, Dr. Johns reported. On the other hand, pharmacokinetics studies showed that exposure to the drug fell by “about 50%-60%” when dosing was preceded by food intake within the previous 30 minutes. “However, if a meal is consumed 30 minutes after the dose, this food effect is much, much less prominent, almost negligible.”

These preliminary results show the drug is “orally bioavailable and exerts a clinically meaningful effect,” Dr. Johns said. “However, there’s definitely more to be done. And we are planning the next phase of clinical development, a phase 2 trial, sometime next year.”

The research was funded by Merck. Dr. Johns disclosed employment with and equity ownership in Merck, as did all the study’s coauthors. Dr. Goldberg disclosed holding research contracts through her institution with Regeneron/Sanofi-Aventis, Amarin, Amgen, Pfizer, IONIS/Akcea, Regeneron, Novartis, Arrowroot Pharmaceuticals, and the FH Foundation; and consulting for Novartis, Akcea, Regeneron, and Esperion.

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

The investigational PCSK9 inhibitor that Merck showcased recently would be more than a “me-too” drug if it ultimately wins approval, despite competition from several approved agents that slash elevated cholesterol levels by targeting the same protein.

BananaStock/thinkstockphotos.com

In fact, it would be something of a breakthrough. The new agent under study – now called MK-0616 – comes in pill form, in contrast to the three currently available PCSK9-lowering drugs that must be given in injections separated by weeks to months.

The drug faces an uncertain road to regulatory review and any approval, but MK-0616 at least seems to be starting out in the right direction.

In two phase 1 studies with a total of 100 participants, plasma PCSK9 levels plunged more than 90% after a single dose of the drug; and low-density-lipoprotein cholesterol (LDL-C) levels dropped about 65% when MK-0616 was given daily for 2 weeks on a background of statin therapy.

Moreover, “MK-0616 was generally well tolerated at up to and including single doses of 300 milligrams,” the maximum tested in the studies, Douglas G. Johns, PhD, reported at the virtual American Heart Association scientific sessions.

The collective results from the oral agent’s earliest human experience are “definitely encouraging” and support MK-0616 as a potential LDL-lowering agent that would be more convenient and arguably more accessible to patients compared to current injectable PCSK9 inhibitors, proposed Dr. Johns, clinical director of translational medicine for Merck in Kenilworth, N.J.

Available PCSK9-targeting agents include alirocumab (Praluent, Sanofi/Regeneron), Food and Drug Administration–approved in July 2015, and evolocumab (Repatha, Amgen), approved by the agency the following month. Both are monoclonal antibodies with neutralizing specificity for the PCSK9 protein; whereas the third such agent, inclisiran (Leqvio, Novartis) is a small-molecule interfering-RNA that suppresses PCSK9 synthesis. Inclisiran is approved in the European Union but its case to the FDA was turned down in 2020.

Dr. Johns said MK-0616 is a cyclic peptide that is “about one-hundredth the size of a monoclonal antibody, but we’re able to achieve monoclonal antibody-like potency and selectivity with this much smaller footprint.”

Added to statin therapy, the current PCSK9-targeting agents reduce LDL-C by an additional one-half or more, and the two antibody-based agents “also decrease atherosclerotic cardiovascular events. They are, however, expensive and not always available, requiring insurance or other approval,” observed Anne C. Goldberg, MD, as invited discussant after Dr. Johns’ presentation.

“They require every 2- to 4-week injections. They’re generally reserved for secondary prevention, and sometimes primary prevention as in familial hypercholesterolemia,” said Dr. Goldberg, of Washington University, St. Louis. Inclisiran, she noted, requires injections every 6 months and has yet to show its mettle in cardiovascular outcomes trials.

“Certainly, an oral form would be easier to use,” she said. “This would be particularly helpful in patients averse to injections,” especially, perhaps, in children. “Children with familial hypercholesterolemia could benefit with greater cholesterol lowering and might be better off with a pill than an injection.” That would be good reason to emphasize the enrollment of children in the drug’s upcoming clinical trials, Dr. Goldberg said.

But cost could potentially become restrictive for MK-0616 as well, should it ever be approved. “If it’s priced too high, then are you really going to see the increased use?” she posed. “Certainly, there’s a high bar for therapies that are add-on to statins in terms of cost effectiveness.”

In the first of the two trials, 60 predominantly White male participants aged 50 or younger were randomly assigned to receive a single dose of MK-0616, at different levels ranging from 10 mg to 300 mg, or placebo. They subsequently crossed over to a different group for a second round of dosing. Both times, three participants took the drug for every one who received placebo.

Participants who took the active drug, regardless of dosage, showed greater than 90% reductions in circulating PCSK9 levels compared to baseline. Six participants discontinued the study before its completion.

In the second trial, 40 White adults aged 65 or younger (mean, 58), including 13 women, with LDL-C of 60 mg/dL to 160 mg/dL (mean, 87 mg/dL) on statin therapy for at least 3 months were randomly assigned 3-to-1 to add-on MK-0616, either 10 mg or 20 mg daily, or placebo for 14 days.

LDL-C levels fell an average of about 65% over the 2 weeks among those taking the active drug; they declined less than 5% for those who took placebo.

There were no deaths or serious adverse events in either trial, Dr. Johns reported. On the other hand, pharmacokinetics studies showed that exposure to the drug fell by “about 50%-60%” when dosing was preceded by food intake within the previous 30 minutes. “However, if a meal is consumed 30 minutes after the dose, this food effect is much, much less prominent, almost negligible.”

These preliminary results show the drug is “orally bioavailable and exerts a clinically meaningful effect,” Dr. Johns said. “However, there’s definitely more to be done. And we are planning the next phase of clinical development, a phase 2 trial, sometime next year.”

The research was funded by Merck. Dr. Johns disclosed employment with and equity ownership in Merck, as did all the study’s coauthors. Dr. Goldberg disclosed holding research contracts through her institution with Regeneron/Sanofi-Aventis, Amarin, Amgen, Pfizer, IONIS/Akcea, Regeneron, Novartis, Arrowroot Pharmaceuticals, and the FH Foundation; and consulting for Novartis, Akcea, Regeneron, and Esperion.

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

A “virtual” liver transplant center servicing Vermont and New Hampshire has improved access to liver transplant listing among patients in rural areas of the region, according to a new analysis.

The virtual center was established in 2016 at Dartmouth Hitchcock Medical Center, and it allows patients to receive pre–liver transplant evaluations, testing, and care and posttransplant follow-up there rather than at the liver transplant center that conducts the surgery. The center includes two hepatologists, two associate care providers, and a nurse liver transplant coordinator at DHMC, and led to increased transplant listing in the vicinity, according to Margaret Liu, MD, who presented the study at the virtual annual meeting of the American Association for the Study of Liver Diseases.

“The initiation of this Virtual Liver Transplant Center has been able to provide patients with the ability to get a full liver transplant workup and evaluation at a center near their home rather than the often time-consuming and costly process of potentially multiple trips to a liver transplant center up to 250 miles away for a full transplant evaluation,” said Dr. Liu in an interview. Dr. Liu is an internal medicine resident at Dartmouth Hitchcock Medical Center.

“Our results did show that the initiation of a virtual liver transplant center correlated with an increased and sustained liver transplant listing rate within 60 miles of Dartmouth over that particular study period. Conversely there was no significant change in the listing rate of New Hampshire zip codes that were within 60 miles of the nearest transplant center during the same study period,” said Dr. Liu.

The center receives referrals of patients who are potential candidates for liver transplant listing from practices throughout New Hampshire and Vermont, or from their own center. Their specialists conduct full testing, including a full liver transplant workup that includes evaluation of the patient’s general health and social factors, prior to sending the patient to the actual liver transplant center for their evaluation and transplant surgery. “We essentially do all of the pre–liver transplant workup, a formal liver transplant evaluation, and then the whole packet gets sent to an actual liver transplant center to expedite the process of getting listed for liver transplant. We’re able to streamline the process, so they get everything done here at a hospital near their home. If that requires multiple trips, it’s a lot more doable for the patients,” said Dr. Liu.

The researchers defined urban areas as having more than 50,000 people per square mile and within 30 miles of the nearest hospital, and rural as fewer than 10,000 and more than 60 miles from the nearest hospital. They used the Scientific Registry of Transplant Recipients to determine the number of liver transplant listings per zip code.

Between 2015 and 2019, the frequency of liver transplant listings per 10,000 people remained nearly unchanged in the metropolitan area of southern New Hampshire, ranging from around 0.36 to 0.75. In the rural area within 60 miles of DHMC, the frequency increased from about 0.7 per 10,000 in 2015 to about 1.4 in 2016 and 0.9 in 2017. There was an increase to nearly 3 in 10,000 in 2018, and the frequency was just over 2 in 2019.

The model has the potential to be used in other areas, according to Dr. Liu. “This could potentially be implemented in other rural areas that do not have a transplant center or don’t have a formal liver transplant evaluation process,” said Dr. Liu.

While other centers may have taken on some aspects of liver transplant evaluation and posttransplant care, the Virtual Liver Transplant Center is unique in that a great deal of effort has gone into covering all of a patient’s needs for the liver transplant evaluation. “It’s really the formalization that, from what I have researched, has not been done before,” said Dr. Liu.

The model addresses transplant-listing disparity, as well as improves patient quality of life through reduction in travel, according to Mayur Brahmania, MD, of Western University, London, Ont., who moderated the session. “They’ve proven that they can get more of their patients listed over the study period, which I think is amazing. The next step, I think, would be about whether getting them onto the transplant list actually made a difference in terms of outcome – looking at their wait list mortality, looking at how many of these patients actually got a liver transplantation. That’s the ultimate outcome,” said Dr. Brahmania.

He also noted the challenge of setting up a virtual center. “You have to have allied health staff – addiction counselors, physical therapists, dietitians, social workers. You need to have the appropriate ancillary services like cardiac testing, pulmonary function testing. It’s quite an endeavor, and if the program isn’t too enthusiastic or doesn’t have a local champion, it’s really hard to get something like this started off. So kudos to them for taking on this challenge and getting this up and running over the last 5 years,” said Dr. Brahmania.

Dr. Liu and Dr. Brahmania have no relevant financial disclosures.

AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project.

A “virtual” liver transplant center servicing Vermont and New Hampshire has improved access to liver transplant listing among patients in rural areas of the region, according to a new analysis.

The virtual center was established in 2016 at Dartmouth Hitchcock Medical Center, and it allows patients to receive pre–liver transplant evaluations, testing, and care and posttransplant follow-up there rather than at the liver transplant center that conducts the surgery. The center includes two hepatologists, two associate care providers, and a nurse liver transplant coordinator at DHMC, and led to increased transplant listing in the vicinity, according to Margaret Liu, MD, who presented the study at the virtual annual meeting of the American Association for the Study of Liver Diseases.

“The initiation of this Virtual Liver Transplant Center has been able to provide patients with the ability to get a full liver transplant workup and evaluation at a center near their home rather than the often time-consuming and costly process of potentially multiple trips to a liver transplant center up to 250 miles away for a full transplant evaluation,” said Dr. Liu in an interview. Dr. Liu is an internal medicine resident at Dartmouth Hitchcock Medical Center.

“Our results did show that the initiation of a virtual liver transplant center correlated with an increased and sustained liver transplant listing rate within 60 miles of Dartmouth over that particular study period. Conversely there was no significant change in the listing rate of New Hampshire zip codes that were within 60 miles of the nearest transplant center during the same study period,” said Dr. Liu.

The center receives referrals of patients who are potential candidates for liver transplant listing from practices throughout New Hampshire and Vermont, or from their own center. Their specialists conduct full testing, including a full liver transplant workup that includes evaluation of the patient’s general health and social factors, prior to sending the patient to the actual liver transplant center for their evaluation and transplant surgery. “We essentially do all of the pre–liver transplant workup, a formal liver transplant evaluation, and then the whole packet gets sent to an actual liver transplant center to expedite the process of getting listed for liver transplant. We’re able to streamline the process, so they get everything done here at a hospital near their home. If that requires multiple trips, it’s a lot more doable for the patients,” said Dr. Liu.

The researchers defined urban areas as having more than 50,000 people per square mile and within 30 miles of the nearest hospital, and rural as fewer than 10,000 and more than 60 miles from the nearest hospital. They used the Scientific Registry of Transplant Recipients to determine the number of liver transplant listings per zip code.

Between 2015 and 2019, the frequency of liver transplant listings per 10,000 people remained nearly unchanged in the metropolitan area of southern New Hampshire, ranging from around 0.36 to 0.75. In the rural area within 60 miles of DHMC, the frequency increased from about 0.7 per 10,000 in 2015 to about 1.4 in 2016 and 0.9 in 2017. There was an increase to nearly 3 in 10,000 in 2018, and the frequency was just over 2 in 2019.

The model has the potential to be used in other areas, according to Dr. Liu. “This could potentially be implemented in other rural areas that do not have a transplant center or don’t have a formal liver transplant evaluation process,” said Dr. Liu.

While other centers may have taken on some aspects of liver transplant evaluation and posttransplant care, the Virtual Liver Transplant Center is unique in that a great deal of effort has gone into covering all of a patient’s needs for the liver transplant evaluation. “It’s really the formalization that, from what I have researched, has not been done before,” said Dr. Liu.

The model addresses transplant-listing disparity, as well as improves patient quality of life through reduction in travel, according to Mayur Brahmania, MD, of Western University, London, Ont., who moderated the session. “They’ve proven that they can get more of their patients listed over the study period, which I think is amazing. The next step, I think, would be about whether getting them onto the transplant list actually made a difference in terms of outcome – looking at their wait list mortality, looking at how many of these patients actually got a liver transplantation. That’s the ultimate outcome,” said Dr. Brahmania.

He also noted the challenge of setting up a virtual center. “You have to have allied health staff – addiction counselors, physical therapists, dietitians, social workers. You need to have the appropriate ancillary services like cardiac testing, pulmonary function testing. It’s quite an endeavor, and if the program isn’t too enthusiastic or doesn’t have a local champion, it’s really hard to get something like this started off. So kudos to them for taking on this challenge and getting this up and running over the last 5 years,” said Dr. Brahmania.

Dr. Liu and Dr. Brahmania have no relevant financial disclosures.

AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project.

A “virtual” liver transplant center servicing Vermont and New Hampshire has improved access to liver transplant listing among patients in rural areas of the region, according to a new analysis.

The virtual center was established in 2016 at Dartmouth Hitchcock Medical Center, and it allows patients to receive pre–liver transplant evaluations, testing, and care and posttransplant follow-up there rather than at the liver transplant center that conducts the surgery. The center includes two hepatologists, two associate care providers, and a nurse liver transplant coordinator at DHMC, and led to increased transplant listing in the vicinity, according to Margaret Liu, MD, who presented the study at the virtual annual meeting of the American Association for the Study of Liver Diseases.

“The initiation of this Virtual Liver Transplant Center has been able to provide patients with the ability to get a full liver transplant workup and evaluation at a center near their home rather than the often time-consuming and costly process of potentially multiple trips to a liver transplant center up to 250 miles away for a full transplant evaluation,” said Dr. Liu in an interview. Dr. Liu is an internal medicine resident at Dartmouth Hitchcock Medical Center.

“Our results did show that the initiation of a virtual liver transplant center correlated with an increased and sustained liver transplant listing rate within 60 miles of Dartmouth over that particular study period. Conversely there was no significant change in the listing rate of New Hampshire zip codes that were within 60 miles of the nearest transplant center during the same study period,” said Dr. Liu.

The center receives referrals of patients who are potential candidates for liver transplant listing from practices throughout New Hampshire and Vermont, or from their own center. Their specialists conduct full testing, including a full liver transplant workup that includes evaluation of the patient’s general health and social factors, prior to sending the patient to the actual liver transplant center for their evaluation and transplant surgery. “We essentially do all of the pre–liver transplant workup, a formal liver transplant evaluation, and then the whole packet gets sent to an actual liver transplant center to expedite the process of getting listed for liver transplant. We’re able to streamline the process, so they get everything done here at a hospital near their home. If that requires multiple trips, it’s a lot more doable for the patients,” said Dr. Liu.

The researchers defined urban areas as having more than 50,000 people per square mile and within 30 miles of the nearest hospital, and rural as fewer than 10,000 and more than 60 miles from the nearest hospital. They used the Scientific Registry of Transplant Recipients to determine the number of liver transplant listings per zip code.

Between 2015 and 2019, the frequency of liver transplant listings per 10,000 people remained nearly unchanged in the metropolitan area of southern New Hampshire, ranging from around 0.36 to 0.75. In the rural area within 60 miles of DHMC, the frequency increased from about 0.7 per 10,000 in 2015 to about 1.4 in 2016 and 0.9 in 2017. There was an increase to nearly 3 in 10,000 in 2018, and the frequency was just over 2 in 2019.

The model has the potential to be used in other areas, according to Dr. Liu. “This could potentially be implemented in other rural areas that do not have a transplant center or don’t have a formal liver transplant evaluation process,” said Dr. Liu.

While other centers may have taken on some aspects of liver transplant evaluation and posttransplant care, the Virtual Liver Transplant Center is unique in that a great deal of effort has gone into covering all of a patient’s needs for the liver transplant evaluation. “It’s really the formalization that, from what I have researched, has not been done before,” said Dr. Liu.

The model addresses transplant-listing disparity, as well as improves patient quality of life through reduction in travel, according to Mayur Brahmania, MD, of Western University, London, Ont., who moderated the session. “They’ve proven that they can get more of their patients listed over the study period, which I think is amazing. The next step, I think, would be about whether getting them onto the transplant list actually made a difference in terms of outcome – looking at their wait list mortality, looking at how many of these patients actually got a liver transplantation. That’s the ultimate outcome,” said Dr. Brahmania.

He also noted the challenge of setting up a virtual center. “You have to have allied health staff – addiction counselors, physical therapists, dietitians, social workers. You need to have the appropriate ancillary services like cardiac testing, pulmonary function testing. It’s quite an endeavor, and if the program isn’t too enthusiastic or doesn’t have a local champion, it’s really hard to get something like this started off. So kudos to them for taking on this challenge and getting this up and running over the last 5 years,” said Dr. Brahmania.

Dr. Liu and Dr. Brahmania have no relevant financial disclosures.

AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project.

What is the most ominous manifestation of congenital parvovirus infection, and what is the cause of this abnormality?

Continue to the answer...

Hydrops fetalis is the most ominous complication of congenital parvovirus infection. The virus crosses the placenta and attacks red cell progenitor cells, resulting in an aplastic anemia. In addition, the virus may cause myocarditis that, in turn, may result in cardiac failure in the fetus.

What is the most ominous manifestation of congenital parvovirus infection, and what is the cause of this abnormality?

Continue to the answer...

Hydrops fetalis is the most ominous complication of congenital parvovirus infection. The virus crosses the placenta and attacks red cell progenitor cells, resulting in an aplastic anemia. In addition, the virus may cause myocarditis that, in turn, may result in cardiac failure in the fetus.

What is the most ominous manifestation of congenital parvovirus infection, and what is the cause of this abnormality?

Continue to the answer...

Hydrops fetalis is the most ominous complication of congenital parvovirus infection. The virus crosses the placenta and attacks red cell progenitor cells, resulting in an aplastic anemia. In addition, the virus may cause myocarditis that, in turn, may result in cardiac failure in the fetus.

What are the major complications of pyelonephritis in pregnancy?

Continue to the answer...

Pyelonephritis is an important cause of preterm labor, sepsis, and adult respiratory distress syndrome. Most cases of pyelonephritis develop as a result of an untreated or inadequately treated lower urinary tract infection.

What are the major complications of pyelonephritis in pregnancy?

Continue to the answer...

Pyelonephritis is an important cause of preterm labor, sepsis, and adult respiratory distress syndrome. Most cases of pyelonephritis develop as a result of an untreated or inadequately treated lower urinary tract infection.

What are the major complications of pyelonephritis in pregnancy?

Continue to the answer...

Pyelonephritis is an important cause of preterm labor, sepsis, and adult respiratory distress syndrome. Most cases of pyelonephritis develop as a result of an untreated or inadequately treated lower urinary tract infection.

The U.S. Food and Drug Administration has approved pafolacianine (Cytalux), an imaging drug indicated for use in adult patients with ovarian cancer undergoing surgery.

The new drug “is designed to improve the ability to locate additional ovarian cancerous tissue that is normally difficult to detect during surgery,” according to the agency.

Pafolacianine, administered via intravenous injection prior to surgery, is the first FDA-approved tumor-targeted fluorescent agent for ovarian cancer.

In a press statement, drug inventor Philip Low, PhD, of Purdue University in West Lafayette, Ind., said the agent causes ovarian cancer lesions to “light up like stars against a night sky.”

Improving detection of ovarian cancer lesions is critical given that ovarian cancer is one of the “deadliest of all female reproductive system cancers,” according to the American Cancer Society. The organization estimates that there will be more than 21,000 new cases and more than 13,000 deaths in 2021.

Currently, surgeons use preoperative imaging as well as visual inspection of tumors under normal light and examination by touch to identify ovarian cancer lesions.

Pafolacianine offers a new tool to enhance surgeons’ ability “to identify deadly ovarian tumors that may otherwise go undetected,” Alex Gorovets, MD, deputy director of the office of specialty medicine in the FDA’s Center for Drug Evaluation and Research, said in a press statement.

Ovarian cancer often causes the body to overproduce the folate receptor protein in cell membranes. Pafolacianine, employed with a near-infrared fluorescence imaging system cleared by the FDA for use alongside the drug, binds to and illuminates these proteins under fluorescent light, “boosting surgeons’ ability to identify the cancerous tissue,” the agency in a statement.

The safety and effectiveness of pafolacianine was evaluated in a randomized, multi-center, open-label study of women diagnosed with ovarian cancer or with high clinical suspicion of ovarian cancer. Of the 134 women undergoing surgery who received a dose of pafolacianine and were evaluated under both normal and fluorescent light, 26.9% had at least one cancerous lesion detected that was not observed by standard visual or tactile inspection.

The most common side effects of pafolacianine were infusion-related reactions, including nausea, vomiting, abdominal pain, flushing, dyspepsia, chest discomfort, itching, and hypersensitivity.

Pafolacianine may cause fetal harm when administered to a pregnant woman. The use of folate, folic acid, or folate-containing supplements should be avoided within 48 hours before administration of pafolacianine. 

The FDA also cautioned about the possible risk of image interpretation errors, including false negatives and false positives, with the use of the new drug and near-infrared fluorescence imaging system.

The FDA previously granted pafolacianine orphan-drug, priority, and fast track designations.

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

The U.S. Food and Drug Administration has approved pafolacianine (Cytalux), an imaging drug indicated for use in adult patients with ovarian cancer undergoing surgery.

The new drug “is designed to improve the ability to locate additional ovarian cancerous tissue that is normally difficult to detect during surgery,” according to the agency.

Pafolacianine, administered via intravenous injection prior to surgery, is the first FDA-approved tumor-targeted fluorescent agent for ovarian cancer.

In a press statement, drug inventor Philip Low, PhD, of Purdue University in West Lafayette, Ind., said the agent causes ovarian cancer lesions to “light up like stars against a night sky.”

Improving detection of ovarian cancer lesions is critical given that ovarian cancer is one of the “deadliest of all female reproductive system cancers,” according to the American Cancer Society. The organization estimates that there will be more than 21,000 new cases and more than 13,000 deaths in 2021.

Currently, surgeons use preoperative imaging as well as visual inspection of tumors under normal light and examination by touch to identify ovarian cancer lesions.

Pafolacianine offers a new tool to enhance surgeons’ ability “to identify deadly ovarian tumors that may otherwise go undetected,” Alex Gorovets, MD, deputy director of the office of specialty medicine in the FDA’s Center for Drug Evaluation and Research, said in a press statement.

Ovarian cancer often causes the body to overproduce the folate receptor protein in cell membranes. Pafolacianine, employed with a near-infrared fluorescence imaging system cleared by the FDA for use alongside the drug, binds to and illuminates these proteins under fluorescent light, “boosting surgeons’ ability to identify the cancerous tissue,” the agency in a statement.

The safety and effectiveness of pafolacianine was evaluated in a randomized, multi-center, open-label study of women diagnosed with ovarian cancer or with high clinical suspicion of ovarian cancer. Of the 134 women undergoing surgery who received a dose of pafolacianine and were evaluated under both normal and fluorescent light, 26.9% had at least one cancerous lesion detected that was not observed by standard visual or tactile inspection.

The most common side effects of pafolacianine were infusion-related reactions, including nausea, vomiting, abdominal pain, flushing, dyspepsia, chest discomfort, itching, and hypersensitivity.

Pafolacianine may cause fetal harm when administered to a pregnant woman. The use of folate, folic acid, or folate-containing supplements should be avoided within 48 hours before administration of pafolacianine. 

The FDA also cautioned about the possible risk of image interpretation errors, including false negatives and false positives, with the use of the new drug and near-infrared fluorescence imaging system.

The FDA previously granted pafolacianine orphan-drug, priority, and fast track designations.

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

The U.S. Food and Drug Administration has approved pafolacianine (Cytalux), an imaging drug indicated for use in adult patients with ovarian cancer undergoing surgery.

The new drug “is designed to improve the ability to locate additional ovarian cancerous tissue that is normally difficult to detect during surgery,” according to the agency.

Pafolacianine, administered via intravenous injection prior to surgery, is the first FDA-approved tumor-targeted fluorescent agent for ovarian cancer.

In a press statement, drug inventor Philip Low, PhD, of Purdue University in West Lafayette, Ind., said the agent causes ovarian cancer lesions to “light up like stars against a night sky.”

Improving detection of ovarian cancer lesions is critical given that ovarian cancer is one of the “deadliest of all female reproductive system cancers,” according to the American Cancer Society. The organization estimates that there will be more than 21,000 new cases and more than 13,000 deaths in 2021.

Currently, surgeons use preoperative imaging as well as visual inspection of tumors under normal light and examination by touch to identify ovarian cancer lesions.

Pafolacianine offers a new tool to enhance surgeons’ ability “to identify deadly ovarian tumors that may otherwise go undetected,” Alex Gorovets, MD, deputy director of the office of specialty medicine in the FDA’s Center for Drug Evaluation and Research, said in a press statement.

Ovarian cancer often causes the body to overproduce the folate receptor protein in cell membranes. Pafolacianine, employed with a near-infrared fluorescence imaging system cleared by the FDA for use alongside the drug, binds to and illuminates these proteins under fluorescent light, “boosting surgeons’ ability to identify the cancerous tissue,” the agency in a statement.

The safety and effectiveness of pafolacianine was evaluated in a randomized, multi-center, open-label study of women diagnosed with ovarian cancer or with high clinical suspicion of ovarian cancer. Of the 134 women undergoing surgery who received a dose of pafolacianine and were evaluated under both normal and fluorescent light, 26.9% had at least one cancerous lesion detected that was not observed by standard visual or tactile inspection.

The most common side effects of pafolacianine were infusion-related reactions, including nausea, vomiting, abdominal pain, flushing, dyspepsia, chest discomfort, itching, and hypersensitivity.

Pafolacianine may cause fetal harm when administered to a pregnant woman. The use of folate, folic acid, or folate-containing supplements should be avoided within 48 hours before administration of pafolacianine. 

The FDA also cautioned about the possible risk of image interpretation errors, including false negatives and false positives, with the use of the new drug and near-infrared fluorescence imaging system.

The FDA previously granted pafolacianine orphan-drug, priority, and fast track designations.

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