Rurioctocog alfa pegol prophylaxis was linked to fewer bleeding episodes in people with hemophilia A when it targeted higher levels of factor VIII (FVIII) troughs, according to a report published in Blood (2021;137[13]:1818-27).

Earlier studies demonstrated that the treatment effectively prevented bleeds with an acceptable safety profile in people with hemophilia A. The current prospective, randomized, open label PROPEL trial compared safety and efficacy of two target FVIII troughs in this population. Targeting 1%-3% and 8%-12% FVIII troughs was efficacious, with fewer bleeds in the latter arm and acceptable safety across both, according to Robert Klamroth, MD, of Vivantes Klinikum Friedrichshain, Berlin, and colleagues.

The PROPEL trial (NCT02585960) population comprised 155 patients with hepatitis A, aged 12-65 years, with severe disease and an annualized bleeding rate of at least 2 during the 12 months before enrollment in the study. All had previous FVIII treatment. Patients were randomized to 12 months’ pharmacokinetic rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1%-3% (reference arm) or 8%-12%.

The primary endpoint was absence of bleeds during the second 6-month period. A total of 95 patients completed the protocol.
 

Promising results

In the 1%-3% and 8%-12% arms, the proportions of patients who completed the protocol and had no bleeds were 40% and 67% respectively (P = .015). Serious adverse events occurred in 7 of 115 (6%) patients, including one treatment-related event in the 8%-12% arm. There were no deaths, serious thrombotic events, or adverse event-related discontinuations.

“Targeting 8% to 12% FVIII troughs resulted in a higher proportion of [patients] with no bleeds than prophylaxis that targeted 1% to 3% FVIII troughs. These results support the hypothesis that an elevated FVIII trough can benefit [patients]without changing the safety profile,” the researchers reported. Personalized treatment in this patient population should be considered, they added.
 

Problems remain

In an invited commentary, Christine L. Kempton, MD, of Emory University, Atlanta, pointed out that the study did not answer the question of what trough level is best, and that the target trough level may be up to a patient’s individual clinician to decide. “Many participants (42%) treated with the target trough level of 1% to 3% had no bleeding events during the study period, but some (38%) continued to have bleeding events despite higher target trough levels,” Dr. Kempton wrote. She added that, beyond this concern, the presence of subclinical bleeding is difficult to study and quantify, but its presence is supported in the literature by magnetic resonance imaging that demonstrated joint damage despite a lack of clinically evident bleeding.

“Thus, targeting zero clinical bleeding events does not mean that all joint disease, dysfunction, and pain will be eliminated. This reality underscores the need for better, not just more convenient, therapies,” she concluded.

The authors reported numerous relationships with a variety of pharmaceutical companies including grants, honoraria, and participation in speakers bureaus. Dr. Kempton reported honoraria from Takeda, Spark, Octapharma, and Pfizer, and research grants from Novo Nordisk.

[email protected]

Rurioctocog alfa pegol prophylaxis was linked to fewer bleeding episodes in people with hemophilia A when it targeted higher levels of factor VIII (FVIII) troughs, according to a report published in Blood (2021;137[13]:1818-27).

Earlier studies demonstrated that the treatment effectively prevented bleeds with an acceptable safety profile in people with hemophilia A. The current prospective, randomized, open label PROPEL trial compared safety and efficacy of two target FVIII troughs in this population. Targeting 1%-3% and 8%-12% FVIII troughs was efficacious, with fewer bleeds in the latter arm and acceptable safety across both, according to Robert Klamroth, MD, of Vivantes Klinikum Friedrichshain, Berlin, and colleagues.

The PROPEL trial (NCT02585960) population comprised 155 patients with hepatitis A, aged 12-65 years, with severe disease and an annualized bleeding rate of at least 2 during the 12 months before enrollment in the study. All had previous FVIII treatment. Patients were randomized to 12 months’ pharmacokinetic rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1%-3% (reference arm) or 8%-12%.

The primary endpoint was absence of bleeds during the second 6-month period. A total of 95 patients completed the protocol.
 

Promising results

In the 1%-3% and 8%-12% arms, the proportions of patients who completed the protocol and had no bleeds were 40% and 67% respectively (P = .015). Serious adverse events occurred in 7 of 115 (6%) patients, including one treatment-related event in the 8%-12% arm. There were no deaths, serious thrombotic events, or adverse event-related discontinuations.

“Targeting 8% to 12% FVIII troughs resulted in a higher proportion of [patients] with no bleeds than prophylaxis that targeted 1% to 3% FVIII troughs. These results support the hypothesis that an elevated FVIII trough can benefit [patients]without changing the safety profile,” the researchers reported. Personalized treatment in this patient population should be considered, they added.
 

Problems remain

In an invited commentary, Christine L. Kempton, MD, of Emory University, Atlanta, pointed out that the study did not answer the question of what trough level is best, and that the target trough level may be up to a patient’s individual clinician to decide. “Many participants (42%) treated with the target trough level of 1% to 3% had no bleeding events during the study period, but some (38%) continued to have bleeding events despite higher target trough levels,” Dr. Kempton wrote. She added that, beyond this concern, the presence of subclinical bleeding is difficult to study and quantify, but its presence is supported in the literature by magnetic resonance imaging that demonstrated joint damage despite a lack of clinically evident bleeding.

“Thus, targeting zero clinical bleeding events does not mean that all joint disease, dysfunction, and pain will be eliminated. This reality underscores the need for better, not just more convenient, therapies,” she concluded.

The authors reported numerous relationships with a variety of pharmaceutical companies including grants, honoraria, and participation in speakers bureaus. Dr. Kempton reported honoraria from Takeda, Spark, Octapharma, and Pfizer, and research grants from Novo Nordisk.

[email protected]

Rurioctocog alfa pegol prophylaxis was linked to fewer bleeding episodes in people with hemophilia A when it targeted higher levels of factor VIII (FVIII) troughs, according to a report published in Blood (2021;137[13]:1818-27).

Earlier studies demonstrated that the treatment effectively prevented bleeds with an acceptable safety profile in people with hemophilia A. The current prospective, randomized, open label PROPEL trial compared safety and efficacy of two target FVIII troughs in this population. Targeting 1%-3% and 8%-12% FVIII troughs was efficacious, with fewer bleeds in the latter arm and acceptable safety across both, according to Robert Klamroth, MD, of Vivantes Klinikum Friedrichshain, Berlin, and colleagues.

The PROPEL trial (NCT02585960) population comprised 155 patients with hepatitis A, aged 12-65 years, with severe disease and an annualized bleeding rate of at least 2 during the 12 months before enrollment in the study. All had previous FVIII treatment. Patients were randomized to 12 months’ pharmacokinetic rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1%-3% (reference arm) or 8%-12%.

The primary endpoint was absence of bleeds during the second 6-month period. A total of 95 patients completed the protocol.
 

Promising results

In the 1%-3% and 8%-12% arms, the proportions of patients who completed the protocol and had no bleeds were 40% and 67% respectively (P = .015). Serious adverse events occurred in 7 of 115 (6%) patients, including one treatment-related event in the 8%-12% arm. There were no deaths, serious thrombotic events, or adverse event-related discontinuations.

“Targeting 8% to 12% FVIII troughs resulted in a higher proportion of [patients] with no bleeds than prophylaxis that targeted 1% to 3% FVIII troughs. These results support the hypothesis that an elevated FVIII trough can benefit [patients]without changing the safety profile,” the researchers reported. Personalized treatment in this patient population should be considered, they added.
 

Problems remain

In an invited commentary, Christine L. Kempton, MD, of Emory University, Atlanta, pointed out that the study did not answer the question of what trough level is best, and that the target trough level may be up to a patient’s individual clinician to decide. “Many participants (42%) treated with the target trough level of 1% to 3% had no bleeding events during the study period, but some (38%) continued to have bleeding events despite higher target trough levels,” Dr. Kempton wrote. She added that, beyond this concern, the presence of subclinical bleeding is difficult to study and quantify, but its presence is supported in the literature by magnetic resonance imaging that demonstrated joint damage despite a lack of clinically evident bleeding.

“Thus, targeting zero clinical bleeding events does not mean that all joint disease, dysfunction, and pain will be eliminated. This reality underscores the need for better, not just more convenient, therapies,” she concluded.

The authors reported numerous relationships with a variety of pharmaceutical companies including grants, honoraria, and participation in speakers bureaus. Dr. Kempton reported honoraria from Takeda, Spark, Octapharma, and Pfizer, and research grants from Novo Nordisk.

[email protected]

The COVID-19 pandemic has been difficult for all hospitalists, especially those who are parents of young children. For hospitalist moms who are also immigrants working on temporary H1-B visas, this stress is exacerbated. Though each story is unique, the underlying themes are the same: Worries over visa renewals, the immigration process, family members back home, and the risk of illness, job loss, and deportation.

Supporting the family

Like all health care workers, Prasanna Palabindela, MD, a hospitalist at Jennie Stuart Health in Hopkinsville, Ky., has been worried about bringing COVID-19 home to her family, especially in the beginning. Her in-laws had just arrived from India for a visit in March 2020 when the pandemic began, everything was shut down, and her in-laws were forced to settle in for an unexpected months-long stay.

Along with her elderly in-laws, who also have chronic conditions, Dr. Palabindela had two small children to worry about – a then-5-month-old daughter and a 5-year-old son. “I was more worried about them than me,” she said. “I used to take showers before coming home and just do all precautions as much as I can. I’m glad that I did not bring COVID, so far, to the family.”

Once she could safely send her in-laws back to India, Dr. Palabindela began searching for a nanny. Daycare was out of the question because she didn’t want her children to be exposed to illness. After a long search, she found a nanny who could also help her son with virtual school. “It’s expensive, but still, my family and my family’s health is my priority,” she said.

Working on visas has caused multiple issues for Dr. Palabindela and her husband. After living in different states because of their jobs, her husband joined her in West Virginia for her residency and found a job there. When Dr. Palabindela took her current position, her husband had to quit his job in West Virginia and move with her to Kentucky for them to stay together. Unfortunately, he couldn’t find a good fit for work in Kentucky, so the couple decided to put him on her visa so they wouldn’t have to live apart.

Now Dr. Palabindela is the family’s sole breadwinner. “That means if something happens to me, I always worry what’s going to happen with my family because legally, my husband cannot work. Technically, everyone is deported back to home,” she said. Not being able to work is hard for her husband too. “It’s just so much stress in the family because he worked for 11 years,” said Dr. Palabindela.

Through all the upheavals, Dr. Palabindela has had support from all sides. Her husband has been the biggest source. “He’s my backbone. Every time, he supported me in each and every aspect,” she said. Her parents and her brothers check in on her constantly to make sure she’s staying safe. Even the chief at her hospital has played a significant role, going to bat for his physicians to ensure their safety.

Dr. Palabindela credits everyone who works with COVID-19 patients as heroes. “The nurses, the physicians, the housekeeping, respiratory therapist, speech therapist, physical therapy ... everybody has a role. Everybody is a hero,” she said. “Whoever is wearing a mask is a hero, too, because they are contributing to this community.”
 

Advocating for immigration reform

A lack of transparency and information in the beginning of the pandemic significantly contributed to anxiety, said Anuradha Amara, MD, MBBS, a hospitalist in Wilmington, Del. She felt that what was on the news and what was actually going on in the hospitals were quite different. Colleagues were getting sick, there wasn’t enough personal protective equipment, and planning went out the window. “It’s like a meteor hitting a place and then we start dealing with the aftermath, but we weren’t ready before,” Dr. Amara said. “We didn’t have a plan for a pandemic.”

Then there was the concern of either her or her husband, a cardiologist, getting sick and potentially losing their jobs and immigration status. “How am I going to go back to my country if I had to? What will happen to my family if I die? If I go on the ventilator? Those are the insecurities we found additional to the pandemic challenges we had,” Dr. Amara said.

Not being able to go see their family in India or have them come visit was difficult – “it was pretty bad up there,” said Dr. Amara. Fortunately, her family members in India remained safe, but there’s a very real uneasiness about returning should an emergency arise. “Should I go back and then take the risk of losing my job and losing my position and my kids are here, they’re going to school here. How do you decide that?” she asked.

One of the worst effects of her visa restrictions was not being able to help in New York when hospitals were so short-staffed, and the morgues were overflowing. “New York is 3 hours away from where I live, but I was in chains. I couldn’t help them because of these visa restrictions,” Dr. Amara said. During the emergency, the state allowed physicians from other states to practice without being licensed in New York, but immigrant physicians were not included. “Even if we wanted to, we couldn’t volunteer,” said Dr. Amara. “I have family in New York, and I was really worried. Out of compassion I wanted to help, but I couldn’t do anything.”

Before the pandemic, Dr. Amara joined in advocacy efforts for immigrant physicians through Physicians for American Healthcare Access (PAHA). “In uncertain times, like COVID, it gets worse that you’re challenged with everything on top of your health, your family, and you have to be worried about deportation,” she said. “We need to strengthen legislation. Nobody should suffer with immigration processes during an active pandemic or otherwise.”

In the United States, 28% of physicians are immigrants. Dr. Amara pointed out that these physicians go through years of expensive training with extensive background checks at every level, yet they’re classified as second preference (EB-2) workers. She believes that physicians as a group should be excluded from this category and allowed to automatically become citizens after 5 years of living in the United States and working in an underserved area.

There have been an estimated 15,000 unused green cards since 2005. And if Congress went back to 1992, there could be more than 220,000 previously unused green cards recaptured. These unused green cards are the basis behind bills H.R.2255 and S.1024, the Healthcare Workforce Resiliency Act, which has been championed by SHM and PAHA. “It will allow the frontline physicians, 15,000 of them, and 25,000 nurses, to obtain their permanent residency,” said Dr. Amara. “These are people who already applied for their permanent residencies and they’re still waiting.”

SHM has consistently advocated for the Act since it was first introduced, written multiple letters on the issue, and supported it both on and off Capitol Hill. The society says the legislation would be an “important first step toward addressing a critical shortage” in the U.S. health care system by “recognizing the vital role immigrant physicians and nurses are playing in the fight against COVID-19.”

Currently, SHM has a live action alert open for the reintroduced bill, and encourages members to contact their legislators and urge them to support the reintroduction of the Act by cosponsoring and working to pass the legislation

Dr. Amara encourages physicians to start engaging in advocacy efforts early. Though she didn’t begin participating until late in her career, she said being aware of and part of policies that affect medicine is important. If more physicians get involved, “there are so many things we can take care of,” said Dr. Amara. “The medical profession doesn’t have to be so difficult and so busy. There are ways we can make it better and I believe that. And obviously I’ll continue to work and advocate for the entire medical profession, their problems, their health and well-being, to prevent burnout.”
 

Making time for positivity and self-care

Sandhya Tagaram, MD, a hospitalist at UMass Memorial Medical Center in Worcester, Mass., and her husband, also a hospitalist physician, had only ever read about pandemics in books. They certainly never expected to be in the middle of one. “That was a totally different level of anxiety to work as frontline physicians with two kids under 5 years and families away back home in India,” she said.

UMass Memorial Medical Center

Dr. Tagaram and her husband work opposite shifts so that one of them is always home with their two young children. “Our schedules became more challenging when the pandemic started. Between both of our schedules and with minimal childcare facilities, we managed to strike a decent work-family balance, although we experience less vacation time together. We are fortunate to have an understanding work group,” said Dr. Tagaram.

Even before COVID-19, Dr. Tagaram found working on the temporary work visa challenging. “I think the pandemic has exposed the layer of uncertainty associated with it,” she said. “It’s incredibly stressful to imagine any minor turbulence that could alter our family and work lives. As a frontline physician mom, I take pride in raising my kids and taking care of my patients. We want to serve our communities and at the same time secure our families.”

Not being able to visit family back home and travel is exceedingly difficult. Dr. Tagaram said it would be helpful if there was a separate permanent residence pathway for physicians because they play a critical role in public health and they have been an integral part of the COVID-19 pandemic response team. A separate pathway could help keep their families secure and enable them to give their best to their communities.

Amid all the anxiety, Dr. Tagaram said she and her husband realized they could not keep living with so much pressure. As parents and as physicians, they did not want their stress to leak out and affect their ability and commitment to care for their children or their patients. They decided they needed to figure out how to be positive and constructive.

“We try some daily fun activities with the kids after returning home from work,” said Dr. Tagaram. They also formed a bubble group with two other physician families so the children could interact safely. She said that it’s critical that physicians take time for themselves. “We have to cultivate a serious hobby that helps to rejuvenate and calm our busy minds,” said Dr. Tagaram.

She makes time every day to exercise and to read at least a few pages from a good book. She is also learning Carnatic music along with one of her daughters. And every month since March 2020, she has journaled about her work and what she learned so her daughters can read it someday. “These things keep me jazzed up,” she said.

The pandemic has highlighted the fact that we are all part of one global community. “Although we hail from different backgrounds, we learned that we do have some common goals of being kind and supportive to each other and to give back to our communities. Hopefully we will continue this spirit,” said Dr. Tagaram. As a physician mother, “I feel it’s a privilege and honor to take care of my family and my community.”
 

Soldiering on in the COVID-19 war

The uncertainty everyone felt at the beginning of the pandemic was “very, very scary,” said Mamtha Balla, MD, MPH, a hospitalist and clinical assistant professor in northwest Ohio. “Initially, I was so involved in it and I felt like it was like a war, a COVID-19 war, and we are soldiers in that and trying to protect and do whatever we can.”

She and her husband, a geriatrician also working on an H-1B visa, have worked hard not to bring the virus home to their 2-year-old daughter. Going into 2021, the past 2 years have been “the most hectic and emotionally draining – and physically exhausting – years of my life,” said Dr. Balla.

The COVID-19 vaccine has helped reduce some pressure, but Dr. Balla is still concerned about the high risk to health care workers and the new COVID-19 strains coming out. “We are really not sure what we are dealing with and how the COVID will calm,” she said. “It is pretty challenging being a health care worker because not only are you responsible for your patients at the end of the day, but you are also responsible for your families.”

Initially in the United States from India on a student visa in 2008, Dr. Balla was placed on an H-1B visa when she started her residency. It was during this time that her mother was diagnosed with cancer and went through surgeries and chemotherapy. “She was pretty ill,” recalled Dr. Balla.

Despite the situation, Dr. Balla was afraid to go stay with her mother in case her visa application was rejected, and she couldn’t complete her third year of education. “I opted not to go to India at that time because I did not want to take a chance,” Dr. Balla said. “I have tears in my eyes because those are not easy moments, to withhold from seeing your parents, or to be in any other emergency where you cannot travel. That especially puts us at a higher risk emotionally and physically.”

She has not seen her parents in 2½ years. Between the very real possibility of not being able to get her visa stamp and the unpredictability of how other countries are dealing with COVID-19, Dr. Balla feels it is impossible to even think of going to visit. “Even if I go, what if something happens where my visa gets stuck, or the visa office is not open?” she said. If she could not get back to the United States as planned, she would have patients left behind here.

Recently, Dr. Balla did travel to India and her passport stamp did not come on time, so her husband had to come back to the United States by himself. She had to wait for her stamp for a couple more weeks before she could leave and, in the meantime, had to make arrangements at her hospital. “It is so much trauma,” she said.

There’s also the worry she has about getting sick or disabled and not being able to work anymore, resulting in deportation. “Is that what we are doing for people who are working like soldiers? Are we really treating them the correct way?” Dr. Balla asked.

Dr. Balla considers all health care workers to be soldiers in the COVID-19 war. As such, she believes the government should step up to make sure they are supporting and helping these immigrant physician-soldiers who are so necessary. She applauds France’s recent decision to grant citizenship to its frontline immigrant health care workers and feels that the same should be done in the United States. She filed her green card application in 2012, but she is nowhere close to getting it. (The backlog for employment-based green cards is more than 900,000 now.)

As people putting their own and their family’s lives at risk to care for patients with COVID-19, Dr. Balla and her husband have talked about moving to another country or even back to India. “I am a taxpayer; I am a good human being working for the community and for the job. This is my 13th year here. If I am not eligible [for citizenship] still, then I am not sure what else I have to do to prove myself,” she said. “I am owning United States citizens as my people, so please own us and help us out in this difficult scenario.”

The COVID-19 pandemic has been difficult for all hospitalists, especially those who are parents of young children. For hospitalist moms who are also immigrants working on temporary H1-B visas, this stress is exacerbated. Though each story is unique, the underlying themes are the same: Worries over visa renewals, the immigration process, family members back home, and the risk of illness, job loss, and deportation.

Supporting the family

Like all health care workers, Prasanna Palabindela, MD, a hospitalist at Jennie Stuart Health in Hopkinsville, Ky., has been worried about bringing COVID-19 home to her family, especially in the beginning. Her in-laws had just arrived from India for a visit in March 2020 when the pandemic began, everything was shut down, and her in-laws were forced to settle in for an unexpected months-long stay.

Along with her elderly in-laws, who also have chronic conditions, Dr. Palabindela had two small children to worry about – a then-5-month-old daughter and a 5-year-old son. “I was more worried about them than me,” she said. “I used to take showers before coming home and just do all precautions as much as I can. I’m glad that I did not bring COVID, so far, to the family.”

Once she could safely send her in-laws back to India, Dr. Palabindela began searching for a nanny. Daycare was out of the question because she didn’t want her children to be exposed to illness. After a long search, she found a nanny who could also help her son with virtual school. “It’s expensive, but still, my family and my family’s health is my priority,” she said.

Working on visas has caused multiple issues for Dr. Palabindela and her husband. After living in different states because of their jobs, her husband joined her in West Virginia for her residency and found a job there. When Dr. Palabindela took her current position, her husband had to quit his job in West Virginia and move with her to Kentucky for them to stay together. Unfortunately, he couldn’t find a good fit for work in Kentucky, so the couple decided to put him on her visa so they wouldn’t have to live apart.

Now Dr. Palabindela is the family’s sole breadwinner. “That means if something happens to me, I always worry what’s going to happen with my family because legally, my husband cannot work. Technically, everyone is deported back to home,” she said. Not being able to work is hard for her husband too. “It’s just so much stress in the family because he worked for 11 years,” said Dr. Palabindela.

Through all the upheavals, Dr. Palabindela has had support from all sides. Her husband has been the biggest source. “He’s my backbone. Every time, he supported me in each and every aspect,” she said. Her parents and her brothers check in on her constantly to make sure she’s staying safe. Even the chief at her hospital has played a significant role, going to bat for his physicians to ensure their safety.

Dr. Palabindela credits everyone who works with COVID-19 patients as heroes. “The nurses, the physicians, the housekeeping, respiratory therapist, speech therapist, physical therapy ... everybody has a role. Everybody is a hero,” she said. “Whoever is wearing a mask is a hero, too, because they are contributing to this community.”
 

Advocating for immigration reform

A lack of transparency and information in the beginning of the pandemic significantly contributed to anxiety, said Anuradha Amara, MD, MBBS, a hospitalist in Wilmington, Del. She felt that what was on the news and what was actually going on in the hospitals were quite different. Colleagues were getting sick, there wasn’t enough personal protective equipment, and planning went out the window. “It’s like a meteor hitting a place and then we start dealing with the aftermath, but we weren’t ready before,” Dr. Amara said. “We didn’t have a plan for a pandemic.”

Then there was the concern of either her or her husband, a cardiologist, getting sick and potentially losing their jobs and immigration status. “How am I going to go back to my country if I had to? What will happen to my family if I die? If I go on the ventilator? Those are the insecurities we found additional to the pandemic challenges we had,” Dr. Amara said.

Not being able to go see their family in India or have them come visit was difficult – “it was pretty bad up there,” said Dr. Amara. Fortunately, her family members in India remained safe, but there’s a very real uneasiness about returning should an emergency arise. “Should I go back and then take the risk of losing my job and losing my position and my kids are here, they’re going to school here. How do you decide that?” she asked.

One of the worst effects of her visa restrictions was not being able to help in New York when hospitals were so short-staffed, and the morgues were overflowing. “New York is 3 hours away from where I live, but I was in chains. I couldn’t help them because of these visa restrictions,” Dr. Amara said. During the emergency, the state allowed physicians from other states to practice without being licensed in New York, but immigrant physicians were not included. “Even if we wanted to, we couldn’t volunteer,” said Dr. Amara. “I have family in New York, and I was really worried. Out of compassion I wanted to help, but I couldn’t do anything.”

Before the pandemic, Dr. Amara joined in advocacy efforts for immigrant physicians through Physicians for American Healthcare Access (PAHA). “In uncertain times, like COVID, it gets worse that you’re challenged with everything on top of your health, your family, and you have to be worried about deportation,” she said. “We need to strengthen legislation. Nobody should suffer with immigration processes during an active pandemic or otherwise.”

In the United States, 28% of physicians are immigrants. Dr. Amara pointed out that these physicians go through years of expensive training with extensive background checks at every level, yet they’re classified as second preference (EB-2) workers. She believes that physicians as a group should be excluded from this category and allowed to automatically become citizens after 5 years of living in the United States and working in an underserved area.

There have been an estimated 15,000 unused green cards since 2005. And if Congress went back to 1992, there could be more than 220,000 previously unused green cards recaptured. These unused green cards are the basis behind bills H.R.2255 and S.1024, the Healthcare Workforce Resiliency Act, which has been championed by SHM and PAHA. “It will allow the frontline physicians, 15,000 of them, and 25,000 nurses, to obtain their permanent residency,” said Dr. Amara. “These are people who already applied for their permanent residencies and they’re still waiting.”

SHM has consistently advocated for the Act since it was first introduced, written multiple letters on the issue, and supported it both on and off Capitol Hill. The society says the legislation would be an “important first step toward addressing a critical shortage” in the U.S. health care system by “recognizing the vital role immigrant physicians and nurses are playing in the fight against COVID-19.”

Currently, SHM has a live action alert open for the reintroduced bill, and encourages members to contact their legislators and urge them to support the reintroduction of the Act by cosponsoring and working to pass the legislation

Dr. Amara encourages physicians to start engaging in advocacy efforts early. Though she didn’t begin participating until late in her career, she said being aware of and part of policies that affect medicine is important. If more physicians get involved, “there are so many things we can take care of,” said Dr. Amara. “The medical profession doesn’t have to be so difficult and so busy. There are ways we can make it better and I believe that. And obviously I’ll continue to work and advocate for the entire medical profession, their problems, their health and well-being, to prevent burnout.”
 

Making time for positivity and self-care

Sandhya Tagaram, MD, a hospitalist at UMass Memorial Medical Center in Worcester, Mass., and her husband, also a hospitalist physician, had only ever read about pandemics in books. They certainly never expected to be in the middle of one. “That was a totally different level of anxiety to work as frontline physicians with two kids under 5 years and families away back home in India,” she said.

UMass Memorial Medical Center

Dr. Tagaram and her husband work opposite shifts so that one of them is always home with their two young children. “Our schedules became more challenging when the pandemic started. Between both of our schedules and with minimal childcare facilities, we managed to strike a decent work-family balance, although we experience less vacation time together. We are fortunate to have an understanding work group,” said Dr. Tagaram.

Even before COVID-19, Dr. Tagaram found working on the temporary work visa challenging. “I think the pandemic has exposed the layer of uncertainty associated with it,” she said. “It’s incredibly stressful to imagine any minor turbulence that could alter our family and work lives. As a frontline physician mom, I take pride in raising my kids and taking care of my patients. We want to serve our communities and at the same time secure our families.”

Not being able to visit family back home and travel is exceedingly difficult. Dr. Tagaram said it would be helpful if there was a separate permanent residence pathway for physicians because they play a critical role in public health and they have been an integral part of the COVID-19 pandemic response team. A separate pathway could help keep their families secure and enable them to give their best to their communities.

Amid all the anxiety, Dr. Tagaram said she and her husband realized they could not keep living with so much pressure. As parents and as physicians, they did not want their stress to leak out and affect their ability and commitment to care for their children or their patients. They decided they needed to figure out how to be positive and constructive.

“We try some daily fun activities with the kids after returning home from work,” said Dr. Tagaram. They also formed a bubble group with two other physician families so the children could interact safely. She said that it’s critical that physicians take time for themselves. “We have to cultivate a serious hobby that helps to rejuvenate and calm our busy minds,” said Dr. Tagaram.

She makes time every day to exercise and to read at least a few pages from a good book. She is also learning Carnatic music along with one of her daughters. And every month since March 2020, she has journaled about her work and what she learned so her daughters can read it someday. “These things keep me jazzed up,” she said.

The pandemic has highlighted the fact that we are all part of one global community. “Although we hail from different backgrounds, we learned that we do have some common goals of being kind and supportive to each other and to give back to our communities. Hopefully we will continue this spirit,” said Dr. Tagaram. As a physician mother, “I feel it’s a privilege and honor to take care of my family and my community.”
 

Soldiering on in the COVID-19 war

The uncertainty everyone felt at the beginning of the pandemic was “very, very scary,” said Mamtha Balla, MD, MPH, a hospitalist and clinical assistant professor in northwest Ohio. “Initially, I was so involved in it and I felt like it was like a war, a COVID-19 war, and we are soldiers in that and trying to protect and do whatever we can.”

She and her husband, a geriatrician also working on an H-1B visa, have worked hard not to bring the virus home to their 2-year-old daughter. Going into 2021, the past 2 years have been “the most hectic and emotionally draining – and physically exhausting – years of my life,” said Dr. Balla.

The COVID-19 vaccine has helped reduce some pressure, but Dr. Balla is still concerned about the high risk to health care workers and the new COVID-19 strains coming out. “We are really not sure what we are dealing with and how the COVID will calm,” she said. “It is pretty challenging being a health care worker because not only are you responsible for your patients at the end of the day, but you are also responsible for your families.”

Initially in the United States from India on a student visa in 2008, Dr. Balla was placed on an H-1B visa when she started her residency. It was during this time that her mother was diagnosed with cancer and went through surgeries and chemotherapy. “She was pretty ill,” recalled Dr. Balla.

Despite the situation, Dr. Balla was afraid to go stay with her mother in case her visa application was rejected, and she couldn’t complete her third year of education. “I opted not to go to India at that time because I did not want to take a chance,” Dr. Balla said. “I have tears in my eyes because those are not easy moments, to withhold from seeing your parents, or to be in any other emergency where you cannot travel. That especially puts us at a higher risk emotionally and physically.”

She has not seen her parents in 2½ years. Between the very real possibility of not being able to get her visa stamp and the unpredictability of how other countries are dealing with COVID-19, Dr. Balla feels it is impossible to even think of going to visit. “Even if I go, what if something happens where my visa gets stuck, or the visa office is not open?” she said. If she could not get back to the United States as planned, she would have patients left behind here.

Recently, Dr. Balla did travel to India and her passport stamp did not come on time, so her husband had to come back to the United States by himself. She had to wait for her stamp for a couple more weeks before she could leave and, in the meantime, had to make arrangements at her hospital. “It is so much trauma,” she said.

There’s also the worry she has about getting sick or disabled and not being able to work anymore, resulting in deportation. “Is that what we are doing for people who are working like soldiers? Are we really treating them the correct way?” Dr. Balla asked.

Dr. Balla considers all health care workers to be soldiers in the COVID-19 war. As such, she believes the government should step up to make sure they are supporting and helping these immigrant physician-soldiers who are so necessary. She applauds France’s recent decision to grant citizenship to its frontline immigrant health care workers and feels that the same should be done in the United States. She filed her green card application in 2012, but she is nowhere close to getting it. (The backlog for employment-based green cards is more than 900,000 now.)

As people putting their own and their family’s lives at risk to care for patients with COVID-19, Dr. Balla and her husband have talked about moving to another country or even back to India. “I am a taxpayer; I am a good human being working for the community and for the job. This is my 13th year here. If I am not eligible [for citizenship] still, then I am not sure what else I have to do to prove myself,” she said. “I am owning United States citizens as my people, so please own us and help us out in this difficult scenario.”

The COVID-19 pandemic has been difficult for all hospitalists, especially those who are parents of young children. For hospitalist moms who are also immigrants working on temporary H1-B visas, this stress is exacerbated. Though each story is unique, the underlying themes are the same: Worries over visa renewals, the immigration process, family members back home, and the risk of illness, job loss, and deportation.

Supporting the family

Like all health care workers, Prasanna Palabindela, MD, a hospitalist at Jennie Stuart Health in Hopkinsville, Ky., has been worried about bringing COVID-19 home to her family, especially in the beginning. Her in-laws had just arrived from India for a visit in March 2020 when the pandemic began, everything was shut down, and her in-laws were forced to settle in for an unexpected months-long stay.

Along with her elderly in-laws, who also have chronic conditions, Dr. Palabindela had two small children to worry about – a then-5-month-old daughter and a 5-year-old son. “I was more worried about them than me,” she said. “I used to take showers before coming home and just do all precautions as much as I can. I’m glad that I did not bring COVID, so far, to the family.”

Once she could safely send her in-laws back to India, Dr. Palabindela began searching for a nanny. Daycare was out of the question because she didn’t want her children to be exposed to illness. After a long search, she found a nanny who could also help her son with virtual school. “It’s expensive, but still, my family and my family’s health is my priority,” she said.

Working on visas has caused multiple issues for Dr. Palabindela and her husband. After living in different states because of their jobs, her husband joined her in West Virginia for her residency and found a job there. When Dr. Palabindela took her current position, her husband had to quit his job in West Virginia and move with her to Kentucky for them to stay together. Unfortunately, he couldn’t find a good fit for work in Kentucky, so the couple decided to put him on her visa so they wouldn’t have to live apart.

Now Dr. Palabindela is the family’s sole breadwinner. “That means if something happens to me, I always worry what’s going to happen with my family because legally, my husband cannot work. Technically, everyone is deported back to home,” she said. Not being able to work is hard for her husband too. “It’s just so much stress in the family because he worked for 11 years,” said Dr. Palabindela.

Through all the upheavals, Dr. Palabindela has had support from all sides. Her husband has been the biggest source. “He’s my backbone. Every time, he supported me in each and every aspect,” she said. Her parents and her brothers check in on her constantly to make sure she’s staying safe. Even the chief at her hospital has played a significant role, going to bat for his physicians to ensure their safety.

Dr. Palabindela credits everyone who works with COVID-19 patients as heroes. “The nurses, the physicians, the housekeeping, respiratory therapist, speech therapist, physical therapy ... everybody has a role. Everybody is a hero,” she said. “Whoever is wearing a mask is a hero, too, because they are contributing to this community.”
 

Advocating for immigration reform

A lack of transparency and information in the beginning of the pandemic significantly contributed to anxiety, said Anuradha Amara, MD, MBBS, a hospitalist in Wilmington, Del. She felt that what was on the news and what was actually going on in the hospitals were quite different. Colleagues were getting sick, there wasn’t enough personal protective equipment, and planning went out the window. “It’s like a meteor hitting a place and then we start dealing with the aftermath, but we weren’t ready before,” Dr. Amara said. “We didn’t have a plan for a pandemic.”

Then there was the concern of either her or her husband, a cardiologist, getting sick and potentially losing their jobs and immigration status. “How am I going to go back to my country if I had to? What will happen to my family if I die? If I go on the ventilator? Those are the insecurities we found additional to the pandemic challenges we had,” Dr. Amara said.

Not being able to go see their family in India or have them come visit was difficult – “it was pretty bad up there,” said Dr. Amara. Fortunately, her family members in India remained safe, but there’s a very real uneasiness about returning should an emergency arise. “Should I go back and then take the risk of losing my job and losing my position and my kids are here, they’re going to school here. How do you decide that?” she asked.

One of the worst effects of her visa restrictions was not being able to help in New York when hospitals were so short-staffed, and the morgues were overflowing. “New York is 3 hours away from where I live, but I was in chains. I couldn’t help them because of these visa restrictions,” Dr. Amara said. During the emergency, the state allowed physicians from other states to practice without being licensed in New York, but immigrant physicians were not included. “Even if we wanted to, we couldn’t volunteer,” said Dr. Amara. “I have family in New York, and I was really worried. Out of compassion I wanted to help, but I couldn’t do anything.”

Before the pandemic, Dr. Amara joined in advocacy efforts for immigrant physicians through Physicians for American Healthcare Access (PAHA). “In uncertain times, like COVID, it gets worse that you’re challenged with everything on top of your health, your family, and you have to be worried about deportation,” she said. “We need to strengthen legislation. Nobody should suffer with immigration processes during an active pandemic or otherwise.”

In the United States, 28% of physicians are immigrants. Dr. Amara pointed out that these physicians go through years of expensive training with extensive background checks at every level, yet they’re classified as second preference (EB-2) workers. She believes that physicians as a group should be excluded from this category and allowed to automatically become citizens after 5 years of living in the United States and working in an underserved area.

There have been an estimated 15,000 unused green cards since 2005. And if Congress went back to 1992, there could be more than 220,000 previously unused green cards recaptured. These unused green cards are the basis behind bills H.R.2255 and S.1024, the Healthcare Workforce Resiliency Act, which has been championed by SHM and PAHA. “It will allow the frontline physicians, 15,000 of them, and 25,000 nurses, to obtain their permanent residency,” said Dr. Amara. “These are people who already applied for their permanent residencies and they’re still waiting.”

SHM has consistently advocated for the Act since it was first introduced, written multiple letters on the issue, and supported it both on and off Capitol Hill. The society says the legislation would be an “important first step toward addressing a critical shortage” in the U.S. health care system by “recognizing the vital role immigrant physicians and nurses are playing in the fight against COVID-19.”

Currently, SHM has a live action alert open for the reintroduced bill, and encourages members to contact their legislators and urge them to support the reintroduction of the Act by cosponsoring and working to pass the legislation

Dr. Amara encourages physicians to start engaging in advocacy efforts early. Though she didn’t begin participating until late in her career, she said being aware of and part of policies that affect medicine is important. If more physicians get involved, “there are so many things we can take care of,” said Dr. Amara. “The medical profession doesn’t have to be so difficult and so busy. There are ways we can make it better and I believe that. And obviously I’ll continue to work and advocate for the entire medical profession, their problems, their health and well-being, to prevent burnout.”
 

Making time for positivity and self-care

Sandhya Tagaram, MD, a hospitalist at UMass Memorial Medical Center in Worcester, Mass., and her husband, also a hospitalist physician, had only ever read about pandemics in books. They certainly never expected to be in the middle of one. “That was a totally different level of anxiety to work as frontline physicians with two kids under 5 years and families away back home in India,” she said.

UMass Memorial Medical Center

Dr. Tagaram and her husband work opposite shifts so that one of them is always home with their two young children. “Our schedules became more challenging when the pandemic started. Between both of our schedules and with minimal childcare facilities, we managed to strike a decent work-family balance, although we experience less vacation time together. We are fortunate to have an understanding work group,” said Dr. Tagaram.

Even before COVID-19, Dr. Tagaram found working on the temporary work visa challenging. “I think the pandemic has exposed the layer of uncertainty associated with it,” she said. “It’s incredibly stressful to imagine any minor turbulence that could alter our family and work lives. As a frontline physician mom, I take pride in raising my kids and taking care of my patients. We want to serve our communities and at the same time secure our families.”

Not being able to visit family back home and travel is exceedingly difficult. Dr. Tagaram said it would be helpful if there was a separate permanent residence pathway for physicians because they play a critical role in public health and they have been an integral part of the COVID-19 pandemic response team. A separate pathway could help keep their families secure and enable them to give their best to their communities.

Amid all the anxiety, Dr. Tagaram said she and her husband realized they could not keep living with so much pressure. As parents and as physicians, they did not want their stress to leak out and affect their ability and commitment to care for their children or their patients. They decided they needed to figure out how to be positive and constructive.

“We try some daily fun activities with the kids after returning home from work,” said Dr. Tagaram. They also formed a bubble group with two other physician families so the children could interact safely. She said that it’s critical that physicians take time for themselves. “We have to cultivate a serious hobby that helps to rejuvenate and calm our busy minds,” said Dr. Tagaram.

She makes time every day to exercise and to read at least a few pages from a good book. She is also learning Carnatic music along with one of her daughters. And every month since March 2020, she has journaled about her work and what she learned so her daughters can read it someday. “These things keep me jazzed up,” she said.

The pandemic has highlighted the fact that we are all part of one global community. “Although we hail from different backgrounds, we learned that we do have some common goals of being kind and supportive to each other and to give back to our communities. Hopefully we will continue this spirit,” said Dr. Tagaram. As a physician mother, “I feel it’s a privilege and honor to take care of my family and my community.”
 

Soldiering on in the COVID-19 war

The uncertainty everyone felt at the beginning of the pandemic was “very, very scary,” said Mamtha Balla, MD, MPH, a hospitalist and clinical assistant professor in northwest Ohio. “Initially, I was so involved in it and I felt like it was like a war, a COVID-19 war, and we are soldiers in that and trying to protect and do whatever we can.”

She and her husband, a geriatrician also working on an H-1B visa, have worked hard not to bring the virus home to their 2-year-old daughter. Going into 2021, the past 2 years have been “the most hectic and emotionally draining – and physically exhausting – years of my life,” said Dr. Balla.

The COVID-19 vaccine has helped reduce some pressure, but Dr. Balla is still concerned about the high risk to health care workers and the new COVID-19 strains coming out. “We are really not sure what we are dealing with and how the COVID will calm,” she said. “It is pretty challenging being a health care worker because not only are you responsible for your patients at the end of the day, but you are also responsible for your families.”

Initially in the United States from India on a student visa in 2008, Dr. Balla was placed on an H-1B visa when she started her residency. It was during this time that her mother was diagnosed with cancer and went through surgeries and chemotherapy. “She was pretty ill,” recalled Dr. Balla.

Despite the situation, Dr. Balla was afraid to go stay with her mother in case her visa application was rejected, and she couldn’t complete her third year of education. “I opted not to go to India at that time because I did not want to take a chance,” Dr. Balla said. “I have tears in my eyes because those are not easy moments, to withhold from seeing your parents, or to be in any other emergency where you cannot travel. That especially puts us at a higher risk emotionally and physically.”

She has not seen her parents in 2½ years. Between the very real possibility of not being able to get her visa stamp and the unpredictability of how other countries are dealing with COVID-19, Dr. Balla feels it is impossible to even think of going to visit. “Even if I go, what if something happens where my visa gets stuck, or the visa office is not open?” she said. If she could not get back to the United States as planned, she would have patients left behind here.

Recently, Dr. Balla did travel to India and her passport stamp did not come on time, so her husband had to come back to the United States by himself. She had to wait for her stamp for a couple more weeks before she could leave and, in the meantime, had to make arrangements at her hospital. “It is so much trauma,” she said.

There’s also the worry she has about getting sick or disabled and not being able to work anymore, resulting in deportation. “Is that what we are doing for people who are working like soldiers? Are we really treating them the correct way?” Dr. Balla asked.

Dr. Balla considers all health care workers to be soldiers in the COVID-19 war. As such, she believes the government should step up to make sure they are supporting and helping these immigrant physician-soldiers who are so necessary. She applauds France’s recent decision to grant citizenship to its frontline immigrant health care workers and feels that the same should be done in the United States. She filed her green card application in 2012, but she is nowhere close to getting it. (The backlog for employment-based green cards is more than 900,000 now.)

As people putting their own and their family’s lives at risk to care for patients with COVID-19, Dr. Balla and her husband have talked about moving to another country or even back to India. “I am a taxpayer; I am a good human being working for the community and for the job. This is my 13th year here. If I am not eligible [for citizenship] still, then I am not sure what else I have to do to prove myself,” she said. “I am owning United States citizens as my people, so please own us and help us out in this difficult scenario.”

The American Association of Clinical Endocrinology (AACE) has issued its first-ever official guidelines addressing the use of advanced technologies in the management of people with diabetes.

They were presented on May 28 at the annual scientific & clinical congress of the American Association of Clinical Endocrinologists and simultaneously published in Endocrine Practice.

Previous AACE guidance on the clinical use of insulin pumps and CGM over the past decade has been published in the form of consensus or position statements rather than official evidence-based guidelines, task force cochair George Grunberger, MD, of the Grunberger Diabetes Institute, Bloomfield Hills, Mich., explained.

“There’s never really been, until now, hardcore evidence, [with] peer-reviewed, quality trials published in the literature to go after the evidence that is required for guidelines. ... This is not an opinion piece or position statement.”

The problem with that strict approach to “guidelines” is how quickly the diabetes technology field is evolving, he acknowledged. “It’s frustrating because we know what’s [coming up], but we can’t put it in a guideline because it hasn’t been published yet.”

In an AACE podcast, Dr. Grunberger said the guidelines will likely become a “living” document, along the lines of the American Diabetes Association’s annual Standards of Care, as “any cutoff date is arbitrary. More and more papers will be published on these technologies. ... This is certainly not a static field.”

In the meantime, task force cochair and author Jennifer Sherr, MD, PhD, a pediatric endocrinologist, said she hopes the guidelines will help to reduce insurance company barriers to use of the currently available technologies.

“I am very hopeful that these guidelines will also encourage payers to change their stance. And I think that we as a community can continue to advocate and inform them of these guidelines so they can appropriately change their coverage practices,” added Dr. Sherr, of Yale University, New Haven, Conn.
 

Recommendations address CGM, pumps, and connected systems

In the guidelines, CGM is “strongly recommended for all persons with diabetes treated with intensive insulin therapy, defined as three or more injections of insulin per day or the use of an insulin pump.” For those with diabetes who use CGM, “priority metrics” include a “time in range” of greater than 70% from 14 days of active use. Targets for mean glucose should be individualized, with glycemic variability 36% or lower.

Further specific CGM target metrics are given for people with type 1 diabetes, older/high risk individuals, and for pregnant women. The recommendations align with those issued in a 2019 joint consensus statement on CGM time-in-range endorsed by several organizations, including AACE.    

In response to an audience question about whether AACE is advising that time-in-range replace A1c for glycemia assessment, Dr. Sherr responded: “I think currently we’re not in a position where we can completely replace A1c with time in range. However, I’m hopeful that in future years we’ll see further data gathered ... to allow for that recommendation to occur.”

For now, she said, “What we really want to hone in on in the guidelines is that time-in-range and use of CGM truly allow clinicians to better understand how to optimize care for their persons with diabetes. It gives us a better picture. It’s not just a number of whether we’re hitting target. It tells us whether we need to attack time above range or time below range. So we really think it’s critical for clinical care.”

The document also provides specifics about real-time versus intermittently scanned CGM and use of diagnostic/professional CGM.

The “insulin delivery technologies” section covers use of connected pens, insulin pumps without CGM, insulin pumps with separate CGM, and the more advanced combined insulin pump-CGM systems including those with low-glucose suspend, predictive low-glucose suspend, and hybrid closed-loops (sometimes called the artificial pancreas).

In general, these automated insulin delivery systems (artificial pancreas), “are strongly recommended for all persons with [type 1 diabetes], since their use has been shown to increase time in range, especially in the overnight period, without causing an increased risk of hypoglycemia,” Dr. Sherr observed.
 

Other tech topics: Apps, telemedicine, and safety

The new guidelines say that “clinically validated” smartphone apps should be recommended to help teach or reinforce diabetes self-management skills and provide support and encouragement for healthy behaviors around food and exercise.

Dr. Grunberger pointed out: “As we know, there are tons of apps out there, and patients are using them. The problem is that very few of them have actually been validated in clinical trials in published peer-reviewed [journals].”

He recommended a joint statement on diabetes apps from the American Diabetes Association and the European Association for the Study of Diabetes that was initially discussed at the 2019 EASD meeting, as reported by this news organization, and subsequently published in January 2020 in Diabetes Care and Diabetologia.

“Telemedicine, including periodic phone calls, smartphone-web interactions ... by health care professionals ... is strongly recommended to treat persons with diabetes, provide diabetes education, remotely monitor glucose and/or insulin data to indicate the need for therapy adjustments, and improve diabetes-related outcomes/control with better engagement,” the document says.

Safety concerns addressed include the issue of certain medications interfering with CGM [readings] ... including acetaminophen, high-dose vitamin C, and hydroxyurea, as well as cautions about what to do in the event of device malfunction and assessing that the patient is sufficiently trained in proper device use. Criteria for insulin pump discontinuation are also given.
 

Implementation: Who will be prescribing? ‘This is not for amateurs’

A final section on implementation recommends that “initiation and use of diabetes technology should be implemented by health care professionals who are trained, committed, and experienced to prescribe and direct the use of these tools. Clinicians should have the infrastructure to support the needs of persons with diabetes using the technology.”

Dr. Grunberger commented: “I think the key is going to be who should be doing this? What is the role of a clinical endocrinologist in the future? What is our responsibility, [since] we don’t have the manpower and womanpower to take care of all these people as these technologies advance? It’s our responsibility to provide these hopefully valued recommendations as a resource for those who want to know more about it.”

However, he noted, “This is not for amateurs. If you want to actually use this in your practice, you need the infrastructure, the expertise, the training, the dedication, and the energy to be there for the patients all the time ... This clinical practice guideline is a foundation.”

Dr. Sherr added: “To me, it’s really thinking about ... changing our mindset from who is an appropriate candidate to who can benefit and how vast a group that entails ... I’m hopeful that we will see more technology use through continued conversations with our patients with diabetes, and hopefully through more clinicians being excited to be part of this revolution.”

Dr. Grunberger has reported being on speakers bureaus for Eli Lilly, Novo Nordisk, and Abbott. Dr. Sherr has reported being a consultant and speaker for Lilly and Medtronic Diabetes, a consultant for Insulet and Sanofi, and on advisory boards for Bigfoot Biomedical, Cecelia Health, Insulet, JDRF T1D fund, and Medtronic.

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

The American Association of Clinical Endocrinology (AACE) has issued its first-ever official guidelines addressing the use of advanced technologies in the management of people with diabetes.

They were presented on May 28 at the annual scientific & clinical congress of the American Association of Clinical Endocrinologists and simultaneously published in Endocrine Practice.

Previous AACE guidance on the clinical use of insulin pumps and CGM over the past decade has been published in the form of consensus or position statements rather than official evidence-based guidelines, task force cochair George Grunberger, MD, of the Grunberger Diabetes Institute, Bloomfield Hills, Mich., explained.

“There’s never really been, until now, hardcore evidence, [with] peer-reviewed, quality trials published in the literature to go after the evidence that is required for guidelines. ... This is not an opinion piece or position statement.”

The problem with that strict approach to “guidelines” is how quickly the diabetes technology field is evolving, he acknowledged. “It’s frustrating because we know what’s [coming up], but we can’t put it in a guideline because it hasn’t been published yet.”

In an AACE podcast, Dr. Grunberger said the guidelines will likely become a “living” document, along the lines of the American Diabetes Association’s annual Standards of Care, as “any cutoff date is arbitrary. More and more papers will be published on these technologies. ... This is certainly not a static field.”

In the meantime, task force cochair and author Jennifer Sherr, MD, PhD, a pediatric endocrinologist, said she hopes the guidelines will help to reduce insurance company barriers to use of the currently available technologies.

“I am very hopeful that these guidelines will also encourage payers to change their stance. And I think that we as a community can continue to advocate and inform them of these guidelines so they can appropriately change their coverage practices,” added Dr. Sherr, of Yale University, New Haven, Conn.
 

Recommendations address CGM, pumps, and connected systems

In the guidelines, CGM is “strongly recommended for all persons with diabetes treated with intensive insulin therapy, defined as three or more injections of insulin per day or the use of an insulin pump.” For those with diabetes who use CGM, “priority metrics” include a “time in range” of greater than 70% from 14 days of active use. Targets for mean glucose should be individualized, with glycemic variability 36% or lower.

Further specific CGM target metrics are given for people with type 1 diabetes, older/high risk individuals, and for pregnant women. The recommendations align with those issued in a 2019 joint consensus statement on CGM time-in-range endorsed by several organizations, including AACE.    

In response to an audience question about whether AACE is advising that time-in-range replace A1c for glycemia assessment, Dr. Sherr responded: “I think currently we’re not in a position where we can completely replace A1c with time in range. However, I’m hopeful that in future years we’ll see further data gathered ... to allow for that recommendation to occur.”

For now, she said, “What we really want to hone in on in the guidelines is that time-in-range and use of CGM truly allow clinicians to better understand how to optimize care for their persons with diabetes. It gives us a better picture. It’s not just a number of whether we’re hitting target. It tells us whether we need to attack time above range or time below range. So we really think it’s critical for clinical care.”

The document also provides specifics about real-time versus intermittently scanned CGM and use of diagnostic/professional CGM.

The “insulin delivery technologies” section covers use of connected pens, insulin pumps without CGM, insulin pumps with separate CGM, and the more advanced combined insulin pump-CGM systems including those with low-glucose suspend, predictive low-glucose suspend, and hybrid closed-loops (sometimes called the artificial pancreas).

In general, these automated insulin delivery systems (artificial pancreas), “are strongly recommended for all persons with [type 1 diabetes], since their use has been shown to increase time in range, especially in the overnight period, without causing an increased risk of hypoglycemia,” Dr. Sherr observed.
 

Other tech topics: Apps, telemedicine, and safety

The new guidelines say that “clinically validated” smartphone apps should be recommended to help teach or reinforce diabetes self-management skills and provide support and encouragement for healthy behaviors around food and exercise.

Dr. Grunberger pointed out: “As we know, there are tons of apps out there, and patients are using them. The problem is that very few of them have actually been validated in clinical trials in published peer-reviewed [journals].”

He recommended a joint statement on diabetes apps from the American Diabetes Association and the European Association for the Study of Diabetes that was initially discussed at the 2019 EASD meeting, as reported by this news organization, and subsequently published in January 2020 in Diabetes Care and Diabetologia.

“Telemedicine, including periodic phone calls, smartphone-web interactions ... by health care professionals ... is strongly recommended to treat persons with diabetes, provide diabetes education, remotely monitor glucose and/or insulin data to indicate the need for therapy adjustments, and improve diabetes-related outcomes/control with better engagement,” the document says.

Safety concerns addressed include the issue of certain medications interfering with CGM [readings] ... including acetaminophen, high-dose vitamin C, and hydroxyurea, as well as cautions about what to do in the event of device malfunction and assessing that the patient is sufficiently trained in proper device use. Criteria for insulin pump discontinuation are also given.
 

Implementation: Who will be prescribing? ‘This is not for amateurs’

A final section on implementation recommends that “initiation and use of diabetes technology should be implemented by health care professionals who are trained, committed, and experienced to prescribe and direct the use of these tools. Clinicians should have the infrastructure to support the needs of persons with diabetes using the technology.”

Dr. Grunberger commented: “I think the key is going to be who should be doing this? What is the role of a clinical endocrinologist in the future? What is our responsibility, [since] we don’t have the manpower and womanpower to take care of all these people as these technologies advance? It’s our responsibility to provide these hopefully valued recommendations as a resource for those who want to know more about it.”

However, he noted, “This is not for amateurs. If you want to actually use this in your practice, you need the infrastructure, the expertise, the training, the dedication, and the energy to be there for the patients all the time ... This clinical practice guideline is a foundation.”

Dr. Sherr added: “To me, it’s really thinking about ... changing our mindset from who is an appropriate candidate to who can benefit and how vast a group that entails ... I’m hopeful that we will see more technology use through continued conversations with our patients with diabetes, and hopefully through more clinicians being excited to be part of this revolution.”

Dr. Grunberger has reported being on speakers bureaus for Eli Lilly, Novo Nordisk, and Abbott. Dr. Sherr has reported being a consultant and speaker for Lilly and Medtronic Diabetes, a consultant for Insulet and Sanofi, and on advisory boards for Bigfoot Biomedical, Cecelia Health, Insulet, JDRF T1D fund, and Medtronic.

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

The American Association of Clinical Endocrinology (AACE) has issued its first-ever official guidelines addressing the use of advanced technologies in the management of people with diabetes.

They were presented on May 28 at the annual scientific & clinical congress of the American Association of Clinical Endocrinologists and simultaneously published in Endocrine Practice.

Previous AACE guidance on the clinical use of insulin pumps and CGM over the past decade has been published in the form of consensus or position statements rather than official evidence-based guidelines, task force cochair George Grunberger, MD, of the Grunberger Diabetes Institute, Bloomfield Hills, Mich., explained.

“There’s never really been, until now, hardcore evidence, [with] peer-reviewed, quality trials published in the literature to go after the evidence that is required for guidelines. ... This is not an opinion piece or position statement.”

The problem with that strict approach to “guidelines” is how quickly the diabetes technology field is evolving, he acknowledged. “It’s frustrating because we know what’s [coming up], but we can’t put it in a guideline because it hasn’t been published yet.”

In an AACE podcast, Dr. Grunberger said the guidelines will likely become a “living” document, along the lines of the American Diabetes Association’s annual Standards of Care, as “any cutoff date is arbitrary. More and more papers will be published on these technologies. ... This is certainly not a static field.”

In the meantime, task force cochair and author Jennifer Sherr, MD, PhD, a pediatric endocrinologist, said she hopes the guidelines will help to reduce insurance company barriers to use of the currently available technologies.

“I am very hopeful that these guidelines will also encourage payers to change their stance. And I think that we as a community can continue to advocate and inform them of these guidelines so they can appropriately change their coverage practices,” added Dr. Sherr, of Yale University, New Haven, Conn.
 

Recommendations address CGM, pumps, and connected systems

In the guidelines, CGM is “strongly recommended for all persons with diabetes treated with intensive insulin therapy, defined as three or more injections of insulin per day or the use of an insulin pump.” For those with diabetes who use CGM, “priority metrics” include a “time in range” of greater than 70% from 14 days of active use. Targets for mean glucose should be individualized, with glycemic variability 36% or lower.

Further specific CGM target metrics are given for people with type 1 diabetes, older/high risk individuals, and for pregnant women. The recommendations align with those issued in a 2019 joint consensus statement on CGM time-in-range endorsed by several organizations, including AACE.    

In response to an audience question about whether AACE is advising that time-in-range replace A1c for glycemia assessment, Dr. Sherr responded: “I think currently we’re not in a position where we can completely replace A1c with time in range. However, I’m hopeful that in future years we’ll see further data gathered ... to allow for that recommendation to occur.”

For now, she said, “What we really want to hone in on in the guidelines is that time-in-range and use of CGM truly allow clinicians to better understand how to optimize care for their persons with diabetes. It gives us a better picture. It’s not just a number of whether we’re hitting target. It tells us whether we need to attack time above range or time below range. So we really think it’s critical for clinical care.”

The document also provides specifics about real-time versus intermittently scanned CGM and use of diagnostic/professional CGM.

The “insulin delivery technologies” section covers use of connected pens, insulin pumps without CGM, insulin pumps with separate CGM, and the more advanced combined insulin pump-CGM systems including those with low-glucose suspend, predictive low-glucose suspend, and hybrid closed-loops (sometimes called the artificial pancreas).

In general, these automated insulin delivery systems (artificial pancreas), “are strongly recommended for all persons with [type 1 diabetes], since their use has been shown to increase time in range, especially in the overnight period, without causing an increased risk of hypoglycemia,” Dr. Sherr observed.
 

Other tech topics: Apps, telemedicine, and safety

The new guidelines say that “clinically validated” smartphone apps should be recommended to help teach or reinforce diabetes self-management skills and provide support and encouragement for healthy behaviors around food and exercise.

Dr. Grunberger pointed out: “As we know, there are tons of apps out there, and patients are using them. The problem is that very few of them have actually been validated in clinical trials in published peer-reviewed [journals].”

He recommended a joint statement on diabetes apps from the American Diabetes Association and the European Association for the Study of Diabetes that was initially discussed at the 2019 EASD meeting, as reported by this news organization, and subsequently published in January 2020 in Diabetes Care and Diabetologia.

“Telemedicine, including periodic phone calls, smartphone-web interactions ... by health care professionals ... is strongly recommended to treat persons with diabetes, provide diabetes education, remotely monitor glucose and/or insulin data to indicate the need for therapy adjustments, and improve diabetes-related outcomes/control with better engagement,” the document says.

Safety concerns addressed include the issue of certain medications interfering with CGM [readings] ... including acetaminophen, high-dose vitamin C, and hydroxyurea, as well as cautions about what to do in the event of device malfunction and assessing that the patient is sufficiently trained in proper device use. Criteria for insulin pump discontinuation are also given.
 

Implementation: Who will be prescribing? ‘This is not for amateurs’

A final section on implementation recommends that “initiation and use of diabetes technology should be implemented by health care professionals who are trained, committed, and experienced to prescribe and direct the use of these tools. Clinicians should have the infrastructure to support the needs of persons with diabetes using the technology.”

Dr. Grunberger commented: “I think the key is going to be who should be doing this? What is the role of a clinical endocrinologist in the future? What is our responsibility, [since] we don’t have the manpower and womanpower to take care of all these people as these technologies advance? It’s our responsibility to provide these hopefully valued recommendations as a resource for those who want to know more about it.”

However, he noted, “This is not for amateurs. If you want to actually use this in your practice, you need the infrastructure, the expertise, the training, the dedication, and the energy to be there for the patients all the time ... This clinical practice guideline is a foundation.”

Dr. Sherr added: “To me, it’s really thinking about ... changing our mindset from who is an appropriate candidate to who can benefit and how vast a group that entails ... I’m hopeful that we will see more technology use through continued conversations with our patients with diabetes, and hopefully through more clinicians being excited to be part of this revolution.”

Dr. Grunberger has reported being on speakers bureaus for Eli Lilly, Novo Nordisk, and Abbott. Dr. Sherr has reported being a consultant and speaker for Lilly and Medtronic Diabetes, a consultant for Insulet and Sanofi, and on advisory boards for Bigfoot Biomedical, Cecelia Health, Insulet, JDRF T1D fund, and Medtronic.

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

Valisure, an online pharmacy known for testing every batch of medication it sells, announced that it has petitioned the Food and Drug Administration to recall 40 batches of sunscreens and after-sun products they say tested for high levels of the chemical benzene.

The company tested 294 batches from 69 companies and found benzene in 27% – many in major national brands like Neutrogena and Banana Boat. Some batches contained as much as three times the emergency FDA limit of 2 parts per million.

Long-term exposure to benzene is known to cause cancer in humans.

“This is especially concerning with sunscreen because multiple FDA studies have shown that sunscreen ingredients absorb through the skin and end up in the blood at high levels,” said David Light, CEO of Valisure.

The FDA is seeking more information about the potential risks from common sunscreen ingredients.

“There is not a safe level of benzene that can exist in sunscreen products,” Christopher Bunick, MD, PhD, associate professor of dermatology at Yale University, New Haven, Conn., said in Valisure’s FDA petition. “The total mass of sunscreen required to cover and protect the human body, in single daily application or repeated applications daily, means that even benzene at 0.1 ppm in a sunscreen could expose people to excessively high nanogram amounts of benzene.”

Valisure’s testing previously led to FDA recalls of heartburn medications and hand sanitizers.
 

Examining sunscreen’s environmental impact

Chemicals in sunscreen may be harmful to other forms of life, too. For years, scientists have been examining whether certain chemicals in sunscreen could be causing damage to marine life, in particular the world’s coral reefs. Specific ingredients, including oxybenzone, benzophenone-1, benzophenone-8, OD-PABA, 4-methylbenzylidene camphor, 3-benzylidene camphor, nano-titanium dioxide, nano-zinc oxide, octinoxate, and octocrylene, have been identified as potential risks.

Earlier this year, the National Academies of Sciences, Engineering, and Medicine created a committee to review the existing science about the potential environmental hazards. Over the next 2 years, they’ll also consider the public health implications if people stopped using sunscreen.

Valisure’s announcement included this message: “It is important to note that not all sunscreen products contain benzene and that uncontaminated products are available, should continue to be used, and are important for protecting against potentially harmful solar radiation.”

Using sunscreen with SPF 15 every day can lower risk of squamous cell carcinoma by around 40% and melanoma by 50%. The American Academy of Dermatology recommends a broad-spectrum, water-resistant sunscreen with an SPF of 30 or higher.

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

Valisure, an online pharmacy known for testing every batch of medication it sells, announced that it has petitioned the Food and Drug Administration to recall 40 batches of sunscreens and after-sun products they say tested for high levels of the chemical benzene.

The company tested 294 batches from 69 companies and found benzene in 27% – many in major national brands like Neutrogena and Banana Boat. Some batches contained as much as three times the emergency FDA limit of 2 parts per million.

Long-term exposure to benzene is known to cause cancer in humans.

“This is especially concerning with sunscreen because multiple FDA studies have shown that sunscreen ingredients absorb through the skin and end up in the blood at high levels,” said David Light, CEO of Valisure.

The FDA is seeking more information about the potential risks from common sunscreen ingredients.

“There is not a safe level of benzene that can exist in sunscreen products,” Christopher Bunick, MD, PhD, associate professor of dermatology at Yale University, New Haven, Conn., said in Valisure’s FDA petition. “The total mass of sunscreen required to cover and protect the human body, in single daily application or repeated applications daily, means that even benzene at 0.1 ppm in a sunscreen could expose people to excessively high nanogram amounts of benzene.”

Valisure’s testing previously led to FDA recalls of heartburn medications and hand sanitizers.
 

Examining sunscreen’s environmental impact

Chemicals in sunscreen may be harmful to other forms of life, too. For years, scientists have been examining whether certain chemicals in sunscreen could be causing damage to marine life, in particular the world’s coral reefs. Specific ingredients, including oxybenzone, benzophenone-1, benzophenone-8, OD-PABA, 4-methylbenzylidene camphor, 3-benzylidene camphor, nano-titanium dioxide, nano-zinc oxide, octinoxate, and octocrylene, have been identified as potential risks.

Earlier this year, the National Academies of Sciences, Engineering, and Medicine created a committee to review the existing science about the potential environmental hazards. Over the next 2 years, they’ll also consider the public health implications if people stopped using sunscreen.

Valisure’s announcement included this message: “It is important to note that not all sunscreen products contain benzene and that uncontaminated products are available, should continue to be used, and are important for protecting against potentially harmful solar radiation.”

Using sunscreen with SPF 15 every day can lower risk of squamous cell carcinoma by around 40% and melanoma by 50%. The American Academy of Dermatology recommends a broad-spectrum, water-resistant sunscreen with an SPF of 30 or higher.

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

Valisure, an online pharmacy known for testing every batch of medication it sells, announced that it has petitioned the Food and Drug Administration to recall 40 batches of sunscreens and after-sun products they say tested for high levels of the chemical benzene.

The company tested 294 batches from 69 companies and found benzene in 27% – many in major national brands like Neutrogena and Banana Boat. Some batches contained as much as three times the emergency FDA limit of 2 parts per million.

Long-term exposure to benzene is known to cause cancer in humans.

“This is especially concerning with sunscreen because multiple FDA studies have shown that sunscreen ingredients absorb through the skin and end up in the blood at high levels,” said David Light, CEO of Valisure.

The FDA is seeking more information about the potential risks from common sunscreen ingredients.

“There is not a safe level of benzene that can exist in sunscreen products,” Christopher Bunick, MD, PhD, associate professor of dermatology at Yale University, New Haven, Conn., said in Valisure’s FDA petition. “The total mass of sunscreen required to cover and protect the human body, in single daily application or repeated applications daily, means that even benzene at 0.1 ppm in a sunscreen could expose people to excessively high nanogram amounts of benzene.”

Valisure’s testing previously led to FDA recalls of heartburn medications and hand sanitizers.
 

Examining sunscreen’s environmental impact

Chemicals in sunscreen may be harmful to other forms of life, too. For years, scientists have been examining whether certain chemicals in sunscreen could be causing damage to marine life, in particular the world’s coral reefs. Specific ingredients, including oxybenzone, benzophenone-1, benzophenone-8, OD-PABA, 4-methylbenzylidene camphor, 3-benzylidene camphor, nano-titanium dioxide, nano-zinc oxide, octinoxate, and octocrylene, have been identified as potential risks.

Earlier this year, the National Academies of Sciences, Engineering, and Medicine created a committee to review the existing science about the potential environmental hazards. Over the next 2 years, they’ll also consider the public health implications if people stopped using sunscreen.

Valisure’s announcement included this message: “It is important to note that not all sunscreen products contain benzene and that uncontaminated products are available, should continue to be used, and are important for protecting against potentially harmful solar radiation.”

Using sunscreen with SPF 15 every day can lower risk of squamous cell carcinoma by around 40% and melanoma by 50%. The American Academy of Dermatology recommends a broad-spectrum, water-resistant sunscreen with an SPF of 30 or higher.

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

A subcutaneous dose of the second-generation glycoprotein IIb/IIIa inhibitor RUC-4 achieved rapid dose-dependent platelet inhibition in patients with ST-segment elevation MI (STEMI) undergoing stenting in the CEL-02 study.

Platelet inhibition occurred within 15 minutes among the 27 patients, and wore off rapidly, with almost 50% of platelet function recovered within 122 minutes.

The drug was well tolerated, with no thrombocytopenia in the first 72 hours after administration, one injection-site reaction, and two major bleeds likely caused by catheter-based trauma to the proximal radial artery, reported Jurrien ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands.

The results were reported during the annual meeting of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR 2021) and published simultaneously in EuroIntervention.

Dr. ten Berg noted that there is a need for drugs like RUC-4 in the early treatment of STEMI because oral P2Y12 inhibitors have a “seriously delayed” onset by about 2-4 hours. Prehospital use of the glycoprotein inhibitor (GPI) tirofiban was shown to improve reperfusion and late outcomes in the ON-TIME 2 trial, but GPIs require continuous intravenous administration and are associated with thrombocytopenia.

“Since RUC-4 is unique among small-molecule GPI in not inducing the receptor to undergo a major conformational change that has been implicated in the development of thrombocytopenia, it is possible that RUC-4 may be associated with fewer episodes of thrombocytopenia than current GPI,” the authors wrote.

RUC-4, also called zalunfiban, can be delivered with a single subcutaneous dose and, in a phase 1 study, demonstrated platelet inhibition within 15 minutes and was well tolerated up to a dose of 0.075 mg/kg among healthy volunteers and patients with stable coronary artery disease on aspirin.

In the CEL-02 study, 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before primary percutaneous coronary intervention (PCI) in escalating doses of 0.075 mg/kg, 0.090 mg/kg, and 0.110 mg/kg. Patients were given standard treatment in the ambulance, which included aspirin (93%), ticagrelor (93%), and unfractionated heparin (96%). The activated clotting time was less than 200 seconds in 92% of patients who received additional heparin during cardiac catheterization.

The patients’ mean age was 62 years, 26% were women, and 96% were White. Pharmacodynamic data were available for 24 patients.

The average platelet inhibition 15 minutes after the injection was 77.5%, 87.5%, and 91.7%, respectively, for the three escalating doses (P = .002 for trend).

The primary endpoint of at least 77% inhibition of the iso-TRAP channel – which corresponds to 80% inhibition of light transmission aggregometry stimulated by 20 mcM adenosine diphosphate within 15 minutes – was achieved in three of eight patients at the lowest dose and in seven of eight patients at the middle and highest doses.

“Single-dose subcutaneous RUC-4 induces a fast, potent dose-dependent response of platelet inhibition in patients with STEMI presenting for primary PCI,” Dr. ten Berg concluded. “It is therefore promising for prehospital platelet inhibition in STEMI patients, and the results support further research on clinical benefit.”

The double-blind, randomized phase 2b CELEBRATE trial is underway, evaluating 1,668 STEMI patients treated with a 0.110 mg/kg or 0.130 mg/kg dose of RUC-4 or placebo in the ambulance. The coprimary outcomes are restoration of coronary artery blood flow and resolution of ST-segment deviation post-PCI/angiography. Primary completion is set for March 2023.

MDedge News

Marco Valgimigli, MD, who was not involved in the study, said in an interview that RUC-4 has “some theoretical advantages, compared with conventional IIb/IIIa inhibitors, namely the absence of thrombocytopenia which is, however, relatively rare, especially with tirofiban or eptifibatide.”

The subcutaneous approach may also offer an advantage. Yet, if the administration of RUC-4 is “to happen in the ambulance – a setting where an IV line is usually established – whether the subcutaneous versus IV administration of the treatment proves to be advantageous remains to be seen,” said Dr. Valgimigli, from Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland.

“We would need to see the results of large randomized trials embracing this treatment option before a clinical decision can be made, especially considering that IIb/IIa inhibitors in the ambulance have been tested in the past but ultimately abandoned,” he said.

Limitations of the study are its open-label design, the fact that iso-TRAP channel assay data were not reported by the VeryifyNow instrument and had to be calculated from the raw data, and the fact that the timing of the RUC-4 injection immediately before PCI does not fully resemble the expected use of RUC-4 in clinical practice, where RUC-4 would be administered at the same time as the aspirin, ticagrelor, and heparin, and about an hour before PCI, ten Berg and colleagues wrote.

CeleCor Therapeutics sponsored the study and provided study materials. Dr. ten Berg reported receiving lecture or consultancy fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, AccuMetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Ferrer, and Idorsia, and institutional research grants from ZonMw and AstraZeneca. Coauthor Barry S. Coller is an inventor of RUC-4 and a founder, equity holder, and consultant to CeleCor. He also receives royalties from Centocor/Janssen and the VerifyNow assays. Dr. Valgimigli has received grants from Abbott, Terumo, Medicure, and AstraZeneca, and personal fees from Abbott, Chiesi, Bayer, Daiichi Sankyo, Amgen, Terumo, Alvimedica, AstraZeneca, Biosensors, and Idorsia.

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

A subcutaneous dose of the second-generation glycoprotein IIb/IIIa inhibitor RUC-4 achieved rapid dose-dependent platelet inhibition in patients with ST-segment elevation MI (STEMI) undergoing stenting in the CEL-02 study.

Platelet inhibition occurred within 15 minutes among the 27 patients, and wore off rapidly, with almost 50% of platelet function recovered within 122 minutes.

The drug was well tolerated, with no thrombocytopenia in the first 72 hours after administration, one injection-site reaction, and two major bleeds likely caused by catheter-based trauma to the proximal radial artery, reported Jurrien ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands.

The results were reported during the annual meeting of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR 2021) and published simultaneously in EuroIntervention.

Dr. ten Berg noted that there is a need for drugs like RUC-4 in the early treatment of STEMI because oral P2Y12 inhibitors have a “seriously delayed” onset by about 2-4 hours. Prehospital use of the glycoprotein inhibitor (GPI) tirofiban was shown to improve reperfusion and late outcomes in the ON-TIME 2 trial, but GPIs require continuous intravenous administration and are associated with thrombocytopenia.

“Since RUC-4 is unique among small-molecule GPI in not inducing the receptor to undergo a major conformational change that has been implicated in the development of thrombocytopenia, it is possible that RUC-4 may be associated with fewer episodes of thrombocytopenia than current GPI,” the authors wrote.

RUC-4, also called zalunfiban, can be delivered with a single subcutaneous dose and, in a phase 1 study, demonstrated platelet inhibition within 15 minutes and was well tolerated up to a dose of 0.075 mg/kg among healthy volunteers and patients with stable coronary artery disease on aspirin.

In the CEL-02 study, 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before primary percutaneous coronary intervention (PCI) in escalating doses of 0.075 mg/kg, 0.090 mg/kg, and 0.110 mg/kg. Patients were given standard treatment in the ambulance, which included aspirin (93%), ticagrelor (93%), and unfractionated heparin (96%). The activated clotting time was less than 200 seconds in 92% of patients who received additional heparin during cardiac catheterization.

The patients’ mean age was 62 years, 26% were women, and 96% were White. Pharmacodynamic data were available for 24 patients.

The average platelet inhibition 15 minutes after the injection was 77.5%, 87.5%, and 91.7%, respectively, for the three escalating doses (P = .002 for trend).

The primary endpoint of at least 77% inhibition of the iso-TRAP channel – which corresponds to 80% inhibition of light transmission aggregometry stimulated by 20 mcM adenosine diphosphate within 15 minutes – was achieved in three of eight patients at the lowest dose and in seven of eight patients at the middle and highest doses.

“Single-dose subcutaneous RUC-4 induces a fast, potent dose-dependent response of platelet inhibition in patients with STEMI presenting for primary PCI,” Dr. ten Berg concluded. “It is therefore promising for prehospital platelet inhibition in STEMI patients, and the results support further research on clinical benefit.”

The double-blind, randomized phase 2b CELEBRATE trial is underway, evaluating 1,668 STEMI patients treated with a 0.110 mg/kg or 0.130 mg/kg dose of RUC-4 or placebo in the ambulance. The coprimary outcomes are restoration of coronary artery blood flow and resolution of ST-segment deviation post-PCI/angiography. Primary completion is set for March 2023.

MDedge News

Marco Valgimigli, MD, who was not involved in the study, said in an interview that RUC-4 has “some theoretical advantages, compared with conventional IIb/IIIa inhibitors, namely the absence of thrombocytopenia which is, however, relatively rare, especially with tirofiban or eptifibatide.”

The subcutaneous approach may also offer an advantage. Yet, if the administration of RUC-4 is “to happen in the ambulance – a setting where an IV line is usually established – whether the subcutaneous versus IV administration of the treatment proves to be advantageous remains to be seen,” said Dr. Valgimigli, from Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland.

“We would need to see the results of large randomized trials embracing this treatment option before a clinical decision can be made, especially considering that IIb/IIa inhibitors in the ambulance have been tested in the past but ultimately abandoned,” he said.

Limitations of the study are its open-label design, the fact that iso-TRAP channel assay data were not reported by the VeryifyNow instrument and had to be calculated from the raw data, and the fact that the timing of the RUC-4 injection immediately before PCI does not fully resemble the expected use of RUC-4 in clinical practice, where RUC-4 would be administered at the same time as the aspirin, ticagrelor, and heparin, and about an hour before PCI, ten Berg and colleagues wrote.

CeleCor Therapeutics sponsored the study and provided study materials. Dr. ten Berg reported receiving lecture or consultancy fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, AccuMetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Ferrer, and Idorsia, and institutional research grants from ZonMw and AstraZeneca. Coauthor Barry S. Coller is an inventor of RUC-4 and a founder, equity holder, and consultant to CeleCor. He also receives royalties from Centocor/Janssen and the VerifyNow assays. Dr. Valgimigli has received grants from Abbott, Terumo, Medicure, and AstraZeneca, and personal fees from Abbott, Chiesi, Bayer, Daiichi Sankyo, Amgen, Terumo, Alvimedica, AstraZeneca, Biosensors, and Idorsia.

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

A subcutaneous dose of the second-generation glycoprotein IIb/IIIa inhibitor RUC-4 achieved rapid dose-dependent platelet inhibition in patients with ST-segment elevation MI (STEMI) undergoing stenting in the CEL-02 study.

Platelet inhibition occurred within 15 minutes among the 27 patients, and wore off rapidly, with almost 50% of platelet function recovered within 122 minutes.

The drug was well tolerated, with no thrombocytopenia in the first 72 hours after administration, one injection-site reaction, and two major bleeds likely caused by catheter-based trauma to the proximal radial artery, reported Jurrien ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands.

The results were reported during the annual meeting of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR 2021) and published simultaneously in EuroIntervention.

Dr. ten Berg noted that there is a need for drugs like RUC-4 in the early treatment of STEMI because oral P2Y12 inhibitors have a “seriously delayed” onset by about 2-4 hours. Prehospital use of the glycoprotein inhibitor (GPI) tirofiban was shown to improve reperfusion and late outcomes in the ON-TIME 2 trial, but GPIs require continuous intravenous administration and are associated with thrombocytopenia.

“Since RUC-4 is unique among small-molecule GPI in not inducing the receptor to undergo a major conformational change that has been implicated in the development of thrombocytopenia, it is possible that RUC-4 may be associated with fewer episodes of thrombocytopenia than current GPI,” the authors wrote.

RUC-4, also called zalunfiban, can be delivered with a single subcutaneous dose and, in a phase 1 study, demonstrated platelet inhibition within 15 minutes and was well tolerated up to a dose of 0.075 mg/kg among healthy volunteers and patients with stable coronary artery disease on aspirin.

In the CEL-02 study, 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before primary percutaneous coronary intervention (PCI) in escalating doses of 0.075 mg/kg, 0.090 mg/kg, and 0.110 mg/kg. Patients were given standard treatment in the ambulance, which included aspirin (93%), ticagrelor (93%), and unfractionated heparin (96%). The activated clotting time was less than 200 seconds in 92% of patients who received additional heparin during cardiac catheterization.

The patients’ mean age was 62 years, 26% were women, and 96% were White. Pharmacodynamic data were available for 24 patients.

The average platelet inhibition 15 minutes after the injection was 77.5%, 87.5%, and 91.7%, respectively, for the three escalating doses (P = .002 for trend).

The primary endpoint of at least 77% inhibition of the iso-TRAP channel – which corresponds to 80% inhibition of light transmission aggregometry stimulated by 20 mcM adenosine diphosphate within 15 minutes – was achieved in three of eight patients at the lowest dose and in seven of eight patients at the middle and highest doses.

“Single-dose subcutaneous RUC-4 induces a fast, potent dose-dependent response of platelet inhibition in patients with STEMI presenting for primary PCI,” Dr. ten Berg concluded. “It is therefore promising for prehospital platelet inhibition in STEMI patients, and the results support further research on clinical benefit.”

The double-blind, randomized phase 2b CELEBRATE trial is underway, evaluating 1,668 STEMI patients treated with a 0.110 mg/kg or 0.130 mg/kg dose of RUC-4 or placebo in the ambulance. The coprimary outcomes are restoration of coronary artery blood flow and resolution of ST-segment deviation post-PCI/angiography. Primary completion is set for March 2023.

MDedge News

Marco Valgimigli, MD, who was not involved in the study, said in an interview that RUC-4 has “some theoretical advantages, compared with conventional IIb/IIIa inhibitors, namely the absence of thrombocytopenia which is, however, relatively rare, especially with tirofiban or eptifibatide.”

The subcutaneous approach may also offer an advantage. Yet, if the administration of RUC-4 is “to happen in the ambulance – a setting where an IV line is usually established – whether the subcutaneous versus IV administration of the treatment proves to be advantageous remains to be seen,” said Dr. Valgimigli, from Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland.

“We would need to see the results of large randomized trials embracing this treatment option before a clinical decision can be made, especially considering that IIb/IIa inhibitors in the ambulance have been tested in the past but ultimately abandoned,” he said.

Limitations of the study are its open-label design, the fact that iso-TRAP channel assay data were not reported by the VeryifyNow instrument and had to be calculated from the raw data, and the fact that the timing of the RUC-4 injection immediately before PCI does not fully resemble the expected use of RUC-4 in clinical practice, where RUC-4 would be administered at the same time as the aspirin, ticagrelor, and heparin, and about an hour before PCI, ten Berg and colleagues wrote.

CeleCor Therapeutics sponsored the study and provided study materials. Dr. ten Berg reported receiving lecture or consultancy fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, AccuMetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Ferrer, and Idorsia, and institutional research grants from ZonMw and AstraZeneca. Coauthor Barry S. Coller is an inventor of RUC-4 and a founder, equity holder, and consultant to CeleCor. He also receives royalties from Centocor/Janssen and the VerifyNow assays. Dr. Valgimigli has received grants from Abbott, Terumo, Medicure, and AstraZeneca, and personal fees from Abbott, Chiesi, Bayer, Daiichi Sankyo, Amgen, Terumo, Alvimedica, AstraZeneca, Biosensors, and Idorsia.

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

After taking it on the chin for previously reporting Bayesian estimates, actual 2-year data from the EVOLUT Low Risk trial confirm that transcatheter aortic valve replacement (TAVR) is noninferior to surgery for the primary endpoint of death or disabling stroke.

Among 1,414 as-treated patients, Kaplan-Meier rates for all-cause death or disabling stroke at 24 months were 4.3% with TAVR and 6.3% with surgery (P = .084).

There was also no difference in the individual components of all-cause death (3.5% vs. 4.4%; log-rank P = .366) and disabling stroke (1.5% vs. 2.7%; log-rank P = .119).

Recent low-risk TAVR studies have raised questions about whether there’s a possible catch-up for surgery between 12 and 24 months, given the early mortality benefit from the less-invasive transcatheter procedure, prompting a landmark analysis, John K. Forrest, MD, said during the virtual presentation at the 2021 Congress of European Association of Percutaneous Cardiovascular Interventions, EuroPCR 2021.

“Between 1 and 2 years, there was no convergence of the Kaplan-Meier curves for death or disabling stroke,” with an incidence of 1.9% for the TAVR group and 2.1% for the surgery group (log-rank P = .742), said Dr. Forrest, of Yale University, New Haven, Conn. “The lines were almost superimposed upon each other.”

Session moderator Bernard Prendergast, MD, observed that the Bayesian analysis, which was reported in 2019 and used 12-month follow-up to predict 2-year outcomes, generated questions and criticism over whether this was an appropriate method, compared with traditional Kaplan-Meier analysis. “Indeed, some people accused the investigators of gaming it with this form of statistical analysis.”

To act as a “fact checker,” Dr. Prendergast called in Christopher Cook, MRC, from the PCR Clinical Research Group and Imperial College London. The key methodologic question, Dr. Cook said, is whether Bayesian methods accurately predict actual clinical outcomes in this randomized clinical trial. “The simple answer to this for me, is yes.”

He pointed out that the Kaplan-Meier data for the primary outcome at 2 years were, in fact, numerically better than Bayesian estimates of 5.3% in the TAVR group and 6.7% in the surgery group.

“This validates the use of the original Bayesian methods to estimate patient outcomes in low-risk TAVI patients and, indeed, it may act as an example of where Bayesian methods can be safely applied in order to fast track potentially transformative procedures and technologies to our patients,” Dr. Cook said.

The rate of disabling stroke with TAVR was 1.5% in the new analysis, up from 1.1% in the Bayesian analysis, and 2.7% with surgery, down from 3.5% in the Bayesian analysis.

All-cause mortality, also noted earlier, was 3.5% with TAVR and 4.4% with surgery, whereas the Bayesian estimate was 4.5% for each group.

Dr. Prendergast of St. Thomas’ Hospital, London, said the actual 2-year data are reassuring regarding the statistical tools used and supplement those recently reported from low-risk patients in PARTNER 3.

But, he asked, “what does this mean for practice, what does it mean for guidelines, and how long do we need to wait until we are comfortable and reassured that we can apply TAVI in younger and low-risk patients with a durable outcome?”

Dr. Forrest said that clinicians can be reassured that these patients “are doing very well” but that long-term follow-up is critical.

“We need to be realistic here. We’re really going to be interested in 5- and 10-year outcomes and potentially even thereafter,” he said. “What happens to these valves when they eventually fail? Are superior hemodynamics going to give us longer valve durability in some way or are there going to be other unforeseen things that come up 10 years out? We don’t know those answers.”

TAVR with a supra-annular, self-expanding valve (CoreValve , Evolut R, or Evolut PRO) had superior hemodynamics in the new 2-year analysis with lower aortic valve gradients (9.0 vs. 11.7 mm Hg) and larger valve areas (2.2 vs. 2.0 cm²).

Prosthesis-patient mismatch also favored TAVR, with moderate or severe mismatch occurring in 7.2% and 2.1%, respectively, compared with 19.1% and 4.9%, respectively, with surgery. “We know that this has an impact on long-term outcomes, so it’s important to note that significant difference here,” Dr. Forrest said.

The chink in TAVR’s armor remains paravalvular leak, particularly mild leak, which was significantly higher at 26.6%, compared with only 2.6% with surgery. Moderate to severe leaks were seen in 1.7% and 0.4%, respectively, reflecting the improvement in TAVR with new iterations, he said.

Surgery was also superior to TAVR with regard to the need for permanent pacemaker implantation (7.9% vs. 21.1%). This compares with Bayesian estimates of 6.7% and 23.0%, respectively.

Rates of myocardial infarction remained constant in the two analyses for the TAVR (2.2%) and surgery (1.6%) groups, whereas heart failure hospitalizations improved slightly, from 5.4% versus 7.9%, respectively, in the Bayesian analysis to 5.3% versus 7.1%, respectively, in the new analysis.

Fellow discussant Marie-Claude Morice, MD, Institute Hospitalier Jacques Cartier, Massy, France, highlighted several meta-analyses in different risk patients showing “a lot of good news,” including decreased stroke and mortality rates and the combined outcome clearly favoring TAVR.

“The remaining question is the longevity of the valve, but with 5 years’ follow-up we have for comparison [in high-risk patients], it is the same,” she said. “What this illustrates is that the tidal wave of TAVR is continuing, and we can look optimistically to the future. Is it the nonsymptomatic patients?”

Medtronic funded the study. Dr. Forrest reported grant support from, serving on the advisory board, and proctoring for Edwards Lifesciences and Medtronic. Dr. Prendergast has received grants from Edwards Lifesciences; and speaker/consultancy fees from Abbott, Anteris, and Edwards.

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

After taking it on the chin for previously reporting Bayesian estimates, actual 2-year data from the EVOLUT Low Risk trial confirm that transcatheter aortic valve replacement (TAVR) is noninferior to surgery for the primary endpoint of death or disabling stroke.

Among 1,414 as-treated patients, Kaplan-Meier rates for all-cause death or disabling stroke at 24 months were 4.3% with TAVR and 6.3% with surgery (P = .084).

There was also no difference in the individual components of all-cause death (3.5% vs. 4.4%; log-rank P = .366) and disabling stroke (1.5% vs. 2.7%; log-rank P = .119).

Recent low-risk TAVR studies have raised questions about whether there’s a possible catch-up for surgery between 12 and 24 months, given the early mortality benefit from the less-invasive transcatheter procedure, prompting a landmark analysis, John K. Forrest, MD, said during the virtual presentation at the 2021 Congress of European Association of Percutaneous Cardiovascular Interventions, EuroPCR 2021.

“Between 1 and 2 years, there was no convergence of the Kaplan-Meier curves for death or disabling stroke,” with an incidence of 1.9% for the TAVR group and 2.1% for the surgery group (log-rank P = .742), said Dr. Forrest, of Yale University, New Haven, Conn. “The lines were almost superimposed upon each other.”

Session moderator Bernard Prendergast, MD, observed that the Bayesian analysis, which was reported in 2019 and used 12-month follow-up to predict 2-year outcomes, generated questions and criticism over whether this was an appropriate method, compared with traditional Kaplan-Meier analysis. “Indeed, some people accused the investigators of gaming it with this form of statistical analysis.”

To act as a “fact checker,” Dr. Prendergast called in Christopher Cook, MRC, from the PCR Clinical Research Group and Imperial College London. The key methodologic question, Dr. Cook said, is whether Bayesian methods accurately predict actual clinical outcomes in this randomized clinical trial. “The simple answer to this for me, is yes.”

He pointed out that the Kaplan-Meier data for the primary outcome at 2 years were, in fact, numerically better than Bayesian estimates of 5.3% in the TAVR group and 6.7% in the surgery group.

“This validates the use of the original Bayesian methods to estimate patient outcomes in low-risk TAVI patients and, indeed, it may act as an example of where Bayesian methods can be safely applied in order to fast track potentially transformative procedures and technologies to our patients,” Dr. Cook said.

The rate of disabling stroke with TAVR was 1.5% in the new analysis, up from 1.1% in the Bayesian analysis, and 2.7% with surgery, down from 3.5% in the Bayesian analysis.

All-cause mortality, also noted earlier, was 3.5% with TAVR and 4.4% with surgery, whereas the Bayesian estimate was 4.5% for each group.

Dr. Prendergast of St. Thomas’ Hospital, London, said the actual 2-year data are reassuring regarding the statistical tools used and supplement those recently reported from low-risk patients in PARTNER 3.

But, he asked, “what does this mean for practice, what does it mean for guidelines, and how long do we need to wait until we are comfortable and reassured that we can apply TAVI in younger and low-risk patients with a durable outcome?”

Dr. Forrest said that clinicians can be reassured that these patients “are doing very well” but that long-term follow-up is critical.

“We need to be realistic here. We’re really going to be interested in 5- and 10-year outcomes and potentially even thereafter,” he said. “What happens to these valves when they eventually fail? Are superior hemodynamics going to give us longer valve durability in some way or are there going to be other unforeseen things that come up 10 years out? We don’t know those answers.”

TAVR with a supra-annular, self-expanding valve (CoreValve , Evolut R, or Evolut PRO) had superior hemodynamics in the new 2-year analysis with lower aortic valve gradients (9.0 vs. 11.7 mm Hg) and larger valve areas (2.2 vs. 2.0 cm²).

Prosthesis-patient mismatch also favored TAVR, with moderate or severe mismatch occurring in 7.2% and 2.1%, respectively, compared with 19.1% and 4.9%, respectively, with surgery. “We know that this has an impact on long-term outcomes, so it’s important to note that significant difference here,” Dr. Forrest said.

The chink in TAVR’s armor remains paravalvular leak, particularly mild leak, which was significantly higher at 26.6%, compared with only 2.6% with surgery. Moderate to severe leaks were seen in 1.7% and 0.4%, respectively, reflecting the improvement in TAVR with new iterations, he said.

Surgery was also superior to TAVR with regard to the need for permanent pacemaker implantation (7.9% vs. 21.1%). This compares with Bayesian estimates of 6.7% and 23.0%, respectively.

Rates of myocardial infarction remained constant in the two analyses for the TAVR (2.2%) and surgery (1.6%) groups, whereas heart failure hospitalizations improved slightly, from 5.4% versus 7.9%, respectively, in the Bayesian analysis to 5.3% versus 7.1%, respectively, in the new analysis.

Fellow discussant Marie-Claude Morice, MD, Institute Hospitalier Jacques Cartier, Massy, France, highlighted several meta-analyses in different risk patients showing “a lot of good news,” including decreased stroke and mortality rates and the combined outcome clearly favoring TAVR.

“The remaining question is the longevity of the valve, but with 5 years’ follow-up we have for comparison [in high-risk patients], it is the same,” she said. “What this illustrates is that the tidal wave of TAVR is continuing, and we can look optimistically to the future. Is it the nonsymptomatic patients?”

Medtronic funded the study. Dr. Forrest reported grant support from, serving on the advisory board, and proctoring for Edwards Lifesciences and Medtronic. Dr. Prendergast has received grants from Edwards Lifesciences; and speaker/consultancy fees from Abbott, Anteris, and Edwards.

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

After taking it on the chin for previously reporting Bayesian estimates, actual 2-year data from the EVOLUT Low Risk trial confirm that transcatheter aortic valve replacement (TAVR) is noninferior to surgery for the primary endpoint of death or disabling stroke.

Among 1,414 as-treated patients, Kaplan-Meier rates for all-cause death or disabling stroke at 24 months were 4.3% with TAVR and 6.3% with surgery (P = .084).

There was also no difference in the individual components of all-cause death (3.5% vs. 4.4%; log-rank P = .366) and disabling stroke (1.5% vs. 2.7%; log-rank P = .119).

Recent low-risk TAVR studies have raised questions about whether there’s a possible catch-up for surgery between 12 and 24 months, given the early mortality benefit from the less-invasive transcatheter procedure, prompting a landmark analysis, John K. Forrest, MD, said during the virtual presentation at the 2021 Congress of European Association of Percutaneous Cardiovascular Interventions, EuroPCR 2021.

“Between 1 and 2 years, there was no convergence of the Kaplan-Meier curves for death or disabling stroke,” with an incidence of 1.9% for the TAVR group and 2.1% for the surgery group (log-rank P = .742), said Dr. Forrest, of Yale University, New Haven, Conn. “The lines were almost superimposed upon each other.”

Session moderator Bernard Prendergast, MD, observed that the Bayesian analysis, which was reported in 2019 and used 12-month follow-up to predict 2-year outcomes, generated questions and criticism over whether this was an appropriate method, compared with traditional Kaplan-Meier analysis. “Indeed, some people accused the investigators of gaming it with this form of statistical analysis.”

To act as a “fact checker,” Dr. Prendergast called in Christopher Cook, MRC, from the PCR Clinical Research Group and Imperial College London. The key methodologic question, Dr. Cook said, is whether Bayesian methods accurately predict actual clinical outcomes in this randomized clinical trial. “The simple answer to this for me, is yes.”

He pointed out that the Kaplan-Meier data for the primary outcome at 2 years were, in fact, numerically better than Bayesian estimates of 5.3% in the TAVR group and 6.7% in the surgery group.

“This validates the use of the original Bayesian methods to estimate patient outcomes in low-risk TAVI patients and, indeed, it may act as an example of where Bayesian methods can be safely applied in order to fast track potentially transformative procedures and technologies to our patients,” Dr. Cook said.

The rate of disabling stroke with TAVR was 1.5% in the new analysis, up from 1.1% in the Bayesian analysis, and 2.7% with surgery, down from 3.5% in the Bayesian analysis.

All-cause mortality, also noted earlier, was 3.5% with TAVR and 4.4% with surgery, whereas the Bayesian estimate was 4.5% for each group.

Dr. Prendergast of St. Thomas’ Hospital, London, said the actual 2-year data are reassuring regarding the statistical tools used and supplement those recently reported from low-risk patients in PARTNER 3.

But, he asked, “what does this mean for practice, what does it mean for guidelines, and how long do we need to wait until we are comfortable and reassured that we can apply TAVI in younger and low-risk patients with a durable outcome?”

Dr. Forrest said that clinicians can be reassured that these patients “are doing very well” but that long-term follow-up is critical.

“We need to be realistic here. We’re really going to be interested in 5- and 10-year outcomes and potentially even thereafter,” he said. “What happens to these valves when they eventually fail? Are superior hemodynamics going to give us longer valve durability in some way or are there going to be other unforeseen things that come up 10 years out? We don’t know those answers.”

TAVR with a supra-annular, self-expanding valve (CoreValve , Evolut R, or Evolut PRO) had superior hemodynamics in the new 2-year analysis with lower aortic valve gradients (9.0 vs. 11.7 mm Hg) and larger valve areas (2.2 vs. 2.0 cm²).

Prosthesis-patient mismatch also favored TAVR, with moderate or severe mismatch occurring in 7.2% and 2.1%, respectively, compared with 19.1% and 4.9%, respectively, with surgery. “We know that this has an impact on long-term outcomes, so it’s important to note that significant difference here,” Dr. Forrest said.

The chink in TAVR’s armor remains paravalvular leak, particularly mild leak, which was significantly higher at 26.6%, compared with only 2.6% with surgery. Moderate to severe leaks were seen in 1.7% and 0.4%, respectively, reflecting the improvement in TAVR with new iterations, he said.

Surgery was also superior to TAVR with regard to the need for permanent pacemaker implantation (7.9% vs. 21.1%). This compares with Bayesian estimates of 6.7% and 23.0%, respectively.

Rates of myocardial infarction remained constant in the two analyses for the TAVR (2.2%) and surgery (1.6%) groups, whereas heart failure hospitalizations improved slightly, from 5.4% versus 7.9%, respectively, in the Bayesian analysis to 5.3% versus 7.1%, respectively, in the new analysis.

Fellow discussant Marie-Claude Morice, MD, Institute Hospitalier Jacques Cartier, Massy, France, highlighted several meta-analyses in different risk patients showing “a lot of good news,” including decreased stroke and mortality rates and the combined outcome clearly favoring TAVR.

“The remaining question is the longevity of the valve, but with 5 years’ follow-up we have for comparison [in high-risk patients], it is the same,” she said. “What this illustrates is that the tidal wave of TAVR is continuing, and we can look optimistically to the future. Is it the nonsymptomatic patients?”

Medtronic funded the study. Dr. Forrest reported grant support from, serving on the advisory board, and proctoring for Edwards Lifesciences and Medtronic. Dr. Prendergast has received grants from Edwards Lifesciences; and speaker/consultancy fees from Abbott, Anteris, and Edwards.

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

Burnout is seldom the result of a single factor. It is more often a tragic case of death by a thousand cuts: a balky user-unfriendly electronic medical record system, administrative pressure to see more patients and the resulting frustration of not being able to provide the care you feel they deserve, an overemphasis on documentation or you won’t get paid, the dark cloud of malpractice always overhead, and of course the difficult balance between family responsibilities and work. It often boils down to feeling that there aren’t enough hours in the day to get everything done and still have time to recharge your physical and psychological batteries.

A recent report in the Harvard Business School newsletter, Working Knowledge (“Commuting Hurts Productivity and Your Best Talent Suffers Most.” Lane Lambert. 2021 Mar 30) describes an interesting study by Andy Wu, assistant professor of business administration, in which he discovered that, for every 10 kilometers of commuting distance, there was a decrease in the productivity of high-tech inventors as measured by the number of patents registered by their companies. The quality of their inventions declined even more (7%) for each additional 10 kilometers of commute.

You might question the relevance of these findings with your work in an outpatient clinic, but a conscientious physician is also an inventor and a creator. Every patient, even those with what sounds like a routine complaint, presents a novel collection of management challenges. The best physicians treat their profession as an art and must be invent solutions on the fly.

There is abundant evidence that commuting also can have a negative effect on the physical and mental health of workers. (“The astonishing human potential wasted on commutes.” The Washington Post .Christopher Ingraham. 2016 Feb 25). Watching my father walk into the house after an hour-long train ride out of the city and listening to him grumble created an image that influenced every decision I made about where my wife and I would live and work.

Did I benefit from the luxury of growing up in a small suburban community? Of course I did and I shall be forever grateful for the sacrifice my father made to allow that to happen. But, I promised myself that, while I would make sacrifices for my family, a long or unpleasant commute was not going to be on that list. For a few years I tolerated a 10- to 12-minute car commute (three stoplights) but asked to dissolve the partnership because even that 9-mile ride was too much for me and instead spent the bulk of my 40-year career a 10-minute bike ride from my office and the two hospitals. It meant we didn’t have a view of the ocean or a gentleman’s farm but we had an extra hour together as a family and I arrived at work and at home happy.

The pandemic has been a wake-up call for many of the fortunate folks who have found that they can work from home, eliminating what may have been a time-gobbling commute that was creating more stress than they may have realized. Even if telemedicine continues to maintain some postpandemic presence, I suspect that most physicians will continue to be faced with the challenge of traveling to an office or hospital.

If work is losing some of its luster and/or you are arriving home grumpy from a long day in the office, it is easy to blame an insensitive office administrator or the clunky electronic medical record system ... they deserve it. But, it may be the journey and not just the destination that is the contributing to the problem. I realize that rethinking the decision about where one lives can be painful and the options may be limited. However, I hope that at least some of you can rethink the role your journey is playing in your life.

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

Burnout is seldom the result of a single factor. It is more often a tragic case of death by a thousand cuts: a balky user-unfriendly electronic medical record system, administrative pressure to see more patients and the resulting frustration of not being able to provide the care you feel they deserve, an overemphasis on documentation or you won’t get paid, the dark cloud of malpractice always overhead, and of course the difficult balance between family responsibilities and work. It often boils down to feeling that there aren’t enough hours in the day to get everything done and still have time to recharge your physical and psychological batteries.

A recent report in the Harvard Business School newsletter, Working Knowledge (“Commuting Hurts Productivity and Your Best Talent Suffers Most.” Lane Lambert. 2021 Mar 30) describes an interesting study by Andy Wu, assistant professor of business administration, in which he discovered that, for every 10 kilometers of commuting distance, there was a decrease in the productivity of high-tech inventors as measured by the number of patents registered by their companies. The quality of their inventions declined even more (7%) for each additional 10 kilometers of commute.

You might question the relevance of these findings with your work in an outpatient clinic, but a conscientious physician is also an inventor and a creator. Every patient, even those with what sounds like a routine complaint, presents a novel collection of management challenges. The best physicians treat their profession as an art and must be invent solutions on the fly.

There is abundant evidence that commuting also can have a negative effect on the physical and mental health of workers. (“The astonishing human potential wasted on commutes.” The Washington Post .Christopher Ingraham. 2016 Feb 25). Watching my father walk into the house after an hour-long train ride out of the city and listening to him grumble created an image that influenced every decision I made about where my wife and I would live and work.

Did I benefit from the luxury of growing up in a small suburban community? Of course I did and I shall be forever grateful for the sacrifice my father made to allow that to happen. But, I promised myself that, while I would make sacrifices for my family, a long or unpleasant commute was not going to be on that list. For a few years I tolerated a 10- to 12-minute car commute (three stoplights) but asked to dissolve the partnership because even that 9-mile ride was too much for me and instead spent the bulk of my 40-year career a 10-minute bike ride from my office and the two hospitals. It meant we didn’t have a view of the ocean or a gentleman’s farm but we had an extra hour together as a family and I arrived at work and at home happy.

The pandemic has been a wake-up call for many of the fortunate folks who have found that they can work from home, eliminating what may have been a time-gobbling commute that was creating more stress than they may have realized. Even if telemedicine continues to maintain some postpandemic presence, I suspect that most physicians will continue to be faced with the challenge of traveling to an office or hospital.

If work is losing some of its luster and/or you are arriving home grumpy from a long day in the office, it is easy to blame an insensitive office administrator or the clunky electronic medical record system ... they deserve it. But, it may be the journey and not just the destination that is the contributing to the problem. I realize that rethinking the decision about where one lives can be painful and the options may be limited. However, I hope that at least some of you can rethink the role your journey is playing in your life.

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

Burnout is seldom the result of a single factor. It is more often a tragic case of death by a thousand cuts: a balky user-unfriendly electronic medical record system, administrative pressure to see more patients and the resulting frustration of not being able to provide the care you feel they deserve, an overemphasis on documentation or you won’t get paid, the dark cloud of malpractice always overhead, and of course the difficult balance between family responsibilities and work. It often boils down to feeling that there aren’t enough hours in the day to get everything done and still have time to recharge your physical and psychological batteries.

A recent report in the Harvard Business School newsletter, Working Knowledge (“Commuting Hurts Productivity and Your Best Talent Suffers Most.” Lane Lambert. 2021 Mar 30) describes an interesting study by Andy Wu, assistant professor of business administration, in which he discovered that, for every 10 kilometers of commuting distance, there was a decrease in the productivity of high-tech inventors as measured by the number of patents registered by their companies. The quality of their inventions declined even more (7%) for each additional 10 kilometers of commute.

You might question the relevance of these findings with your work in an outpatient clinic, but a conscientious physician is also an inventor and a creator. Every patient, even those with what sounds like a routine complaint, presents a novel collection of management challenges. The best physicians treat their profession as an art and must be invent solutions on the fly.

There is abundant evidence that commuting also can have a negative effect on the physical and mental health of workers. (“The astonishing human potential wasted on commutes.” The Washington Post .Christopher Ingraham. 2016 Feb 25). Watching my father walk into the house after an hour-long train ride out of the city and listening to him grumble created an image that influenced every decision I made about where my wife and I would live and work.

Did I benefit from the luxury of growing up in a small suburban community? Of course I did and I shall be forever grateful for the sacrifice my father made to allow that to happen. But, I promised myself that, while I would make sacrifices for my family, a long or unpleasant commute was not going to be on that list. For a few years I tolerated a 10- to 12-minute car commute (three stoplights) but asked to dissolve the partnership because even that 9-mile ride was too much for me and instead spent the bulk of my 40-year career a 10-minute bike ride from my office and the two hospitals. It meant we didn’t have a view of the ocean or a gentleman’s farm but we had an extra hour together as a family and I arrived at work and at home happy.

The pandemic has been a wake-up call for many of the fortunate folks who have found that they can work from home, eliminating what may have been a time-gobbling commute that was creating more stress than they may have realized. Even if telemedicine continues to maintain some postpandemic presence, I suspect that most physicians will continue to be faced with the challenge of traveling to an office or hospital.

If work is losing some of its luster and/or you are arriving home grumpy from a long day in the office, it is easy to blame an insensitive office administrator or the clunky electronic medical record system ... they deserve it. But, it may be the journey and not just the destination that is the contributing to the problem. I realize that rethinking the decision about where one lives can be painful and the options may be limited. However, I hope that at least some of you can rethink the role your journey is playing in your life.

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

The U.S. Food and Drug Administration has approved a once-daily oral medication, which is a combination of olanzapine and samidorphan (Lybalvi, Alkermes), for the treatment of schizophrenia and bipolar I disorder.

The drug is approved for the treatment of adults with schizophrenia and for adults with bipolar I disorder as a maintenance monotherapy or to treat acute manic or mixed episodes, as either monotherapy or an adjunct to lithium or valproate.

An atypical antipsychotic, the drug is a combination of olanzapine, an established antipsychotic medication, and samidorphan, a new chemical entity.

“Schizophrenia and bipolar I disorder are complex, chronic diseases, and there remains a persistent need for new medications with proven efficacy and safety. Olanzapine, a highly efficacious atypical antipsychotic, is associated with significant side effects, including weight gain that may impact patients’ treatment experiences and limit its use. With the efficacy of olanzapine and evidence of less weight gain in patients with schizophrenia, Lybalvi brings a welcome new addition to our medication arsenal,” René S. Kahn, MD, PhD, Esther and Joseph Klingenstein professor & chair, department of psychiatry and Behavioral Health System at the Icahn School of Medicine at Mount Sinai, New York, said in a company press release.

In a clinical development program, the drug demonstrated antipsychotic efficacy, safety, and tolerability, including significantly less weight gain than olanzapine in patients with schizophrenia in the ENLIGHTEN-2 study.

The FDA approved Lybalvi under the 505(b)(2) regulatory pathway based on data from 27 clinical studies, including 18 studies evaluating Lybalvi and nine studies evaluating samidorphan alone and the FDA’s findings of the safety and effectiveness of olanzapine in the treatment of bipolar I disorder and schizophrenia. Data suggest that olanzapine-associated weight gain is disease independent, the company reports.

“People living with schizophrenia or bipolar I disorder must evaluate both efficacy and tolerability when making treatment decisions,” Paul Gionfriddo, president and CEO of Mental Health America, said in the same company press release. “We are grateful that companies like Alkermes are driven to continue developing new treatment options in psychiatry that seek to address unmet needs of our community, and we applaud the FDA for considering the experiences of individuals living with these conditions.” 

Alkermes expects to make Lybalvi available for patients in the fourth quarter of 2021.

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

The U.S. Food and Drug Administration has approved a once-daily oral medication, which is a combination of olanzapine and samidorphan (Lybalvi, Alkermes), for the treatment of schizophrenia and bipolar I disorder.

The drug is approved for the treatment of adults with schizophrenia and for adults with bipolar I disorder as a maintenance monotherapy or to treat acute manic or mixed episodes, as either monotherapy or an adjunct to lithium or valproate.

An atypical antipsychotic, the drug is a combination of olanzapine, an established antipsychotic medication, and samidorphan, a new chemical entity.

“Schizophrenia and bipolar I disorder are complex, chronic diseases, and there remains a persistent need for new medications with proven efficacy and safety. Olanzapine, a highly efficacious atypical antipsychotic, is associated with significant side effects, including weight gain that may impact patients’ treatment experiences and limit its use. With the efficacy of olanzapine and evidence of less weight gain in patients with schizophrenia, Lybalvi brings a welcome new addition to our medication arsenal,” René S. Kahn, MD, PhD, Esther and Joseph Klingenstein professor & chair, department of psychiatry and Behavioral Health System at the Icahn School of Medicine at Mount Sinai, New York, said in a company press release.

In a clinical development program, the drug demonstrated antipsychotic efficacy, safety, and tolerability, including significantly less weight gain than olanzapine in patients with schizophrenia in the ENLIGHTEN-2 study.

The FDA approved Lybalvi under the 505(b)(2) regulatory pathway based on data from 27 clinical studies, including 18 studies evaluating Lybalvi and nine studies evaluating samidorphan alone and the FDA’s findings of the safety and effectiveness of olanzapine in the treatment of bipolar I disorder and schizophrenia. Data suggest that olanzapine-associated weight gain is disease independent, the company reports.

“People living with schizophrenia or bipolar I disorder must evaluate both efficacy and tolerability when making treatment decisions,” Paul Gionfriddo, president and CEO of Mental Health America, said in the same company press release. “We are grateful that companies like Alkermes are driven to continue developing new treatment options in psychiatry that seek to address unmet needs of our community, and we applaud the FDA for considering the experiences of individuals living with these conditions.” 

Alkermes expects to make Lybalvi available for patients in the fourth quarter of 2021.

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

The U.S. Food and Drug Administration has approved a once-daily oral medication, which is a combination of olanzapine and samidorphan (Lybalvi, Alkermes), for the treatment of schizophrenia and bipolar I disorder.

The drug is approved for the treatment of adults with schizophrenia and for adults with bipolar I disorder as a maintenance monotherapy or to treat acute manic or mixed episodes, as either monotherapy or an adjunct to lithium or valproate.

An atypical antipsychotic, the drug is a combination of olanzapine, an established antipsychotic medication, and samidorphan, a new chemical entity.

“Schizophrenia and bipolar I disorder are complex, chronic diseases, and there remains a persistent need for new medications with proven efficacy and safety. Olanzapine, a highly efficacious atypical antipsychotic, is associated with significant side effects, including weight gain that may impact patients’ treatment experiences and limit its use. With the efficacy of olanzapine and evidence of less weight gain in patients with schizophrenia, Lybalvi brings a welcome new addition to our medication arsenal,” René S. Kahn, MD, PhD, Esther and Joseph Klingenstein professor & chair, department of psychiatry and Behavioral Health System at the Icahn School of Medicine at Mount Sinai, New York, said in a company press release.

In a clinical development program, the drug demonstrated antipsychotic efficacy, safety, and tolerability, including significantly less weight gain than olanzapine in patients with schizophrenia in the ENLIGHTEN-2 study.

The FDA approved Lybalvi under the 505(b)(2) regulatory pathway based on data from 27 clinical studies, including 18 studies evaluating Lybalvi and nine studies evaluating samidorphan alone and the FDA’s findings of the safety and effectiveness of olanzapine in the treatment of bipolar I disorder and schizophrenia. Data suggest that olanzapine-associated weight gain is disease independent, the company reports.

“People living with schizophrenia or bipolar I disorder must evaluate both efficacy and tolerability when making treatment decisions,” Paul Gionfriddo, president and CEO of Mental Health America, said in the same company press release. “We are grateful that companies like Alkermes are driven to continue developing new treatment options in psychiatry that seek to address unmet needs of our community, and we applaud the FDA for considering the experiences of individuals living with these conditions.” 

Alkermes expects to make Lybalvi available for patients in the fourth quarter of 2021.

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

Mike died last week.

He was a long-retired doc, in his mid-90s. One of my favorite patients to just chat with about nothing in particular. I learned more from him about restoring old grandfather clocks than I ever dreamed I’d know.

After receiving the sad news, I sat down, as I often do, to write a letter to his family. After 23 years I have a pretty standard idea of what I want to say, but it still always takes some thought.

Sealing the envelopes on these letters always seems to be more than just paperwork. There’s a symbolism to it, that I’m closing out my relationship, sometimes of 10-20 years, with the person involved.

Some patients become friends after a time. It’s a matter of chemistry. I don’t socialize with them outside my office, but still enjoy seeing them and talking about nonmedical stuff in the space around clinical questions and answers. They’re the ones it’s hardest to say goodbye to.

I’ll miss my 2-3 visits a year with Mike. We swapped medical war stories, family anecdotes, and the occasional tip about clock restoration that I’ll probably never use (but who knows, he didn’t start until after he retired).

Closing the envelope comes with the realization that I won’t be seeing him again. I don’t go to patient funerals, as I believe those are for families and close friends, and so writing the letter is the closest I’ll get to saying goodbye.

Medicine, and how we practice, is focused on what we do for the patient – which is what it should be.

But lost in the shuffle sometimes is realizing what the patient does for us. That’s also important, but harder to quantify. And sometimes we don’t realize it until we seal the envelope.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Mike died last week.

He was a long-retired doc, in his mid-90s. One of my favorite patients to just chat with about nothing in particular. I learned more from him about restoring old grandfather clocks than I ever dreamed I’d know.

After receiving the sad news, I sat down, as I often do, to write a letter to his family. After 23 years I have a pretty standard idea of what I want to say, but it still always takes some thought.

Sealing the envelopes on these letters always seems to be more than just paperwork. There’s a symbolism to it, that I’m closing out my relationship, sometimes of 10-20 years, with the person involved.

Some patients become friends after a time. It’s a matter of chemistry. I don’t socialize with them outside my office, but still enjoy seeing them and talking about nonmedical stuff in the space around clinical questions and answers. They’re the ones it’s hardest to say goodbye to.

I’ll miss my 2-3 visits a year with Mike. We swapped medical war stories, family anecdotes, and the occasional tip about clock restoration that I’ll probably never use (but who knows, he didn’t start until after he retired).

Closing the envelope comes with the realization that I won’t be seeing him again. I don’t go to patient funerals, as I believe those are for families and close friends, and so writing the letter is the closest I’ll get to saying goodbye.

Medicine, and how we practice, is focused on what we do for the patient – which is what it should be.

But lost in the shuffle sometimes is realizing what the patient does for us. That’s also important, but harder to quantify. And sometimes we don’t realize it until we seal the envelope.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Mike died last week.

He was a long-retired doc, in his mid-90s. One of my favorite patients to just chat with about nothing in particular. I learned more from him about restoring old grandfather clocks than I ever dreamed I’d know.

After receiving the sad news, I sat down, as I often do, to write a letter to his family. After 23 years I have a pretty standard idea of what I want to say, but it still always takes some thought.

Sealing the envelopes on these letters always seems to be more than just paperwork. There’s a symbolism to it, that I’m closing out my relationship, sometimes of 10-20 years, with the person involved.

Some patients become friends after a time. It’s a matter of chemistry. I don’t socialize with them outside my office, but still enjoy seeing them and talking about nonmedical stuff in the space around clinical questions and answers. They’re the ones it’s hardest to say goodbye to.

I’ll miss my 2-3 visits a year with Mike. We swapped medical war stories, family anecdotes, and the occasional tip about clock restoration that I’ll probably never use (but who knows, he didn’t start until after he retired).

Closing the envelope comes with the realization that I won’t be seeing him again. I don’t go to patient funerals, as I believe those are for families and close friends, and so writing the letter is the closest I’ll get to saying goodbye.

Medicine, and how we practice, is focused on what we do for the patient – which is what it should be.

But lost in the shuffle sometimes is realizing what the patient does for us. That’s also important, but harder to quantify. And sometimes we don’t realize it until we seal the envelope.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

In the periurban slum of Lusaka, Zambia, asymptomatic pertussis infections were common among both mothers and infants, a surprising finding since asymptomatic infections are assumed to be rare in infants. The findings suggested that pertussis should be considered in cases of chronic cough, and that current standards of treating pertussis infections in low-resource settings may need to be reexamined.

The results come from testing of 1,320 infant-mother pairs who were first enrolled at a public health clinic, then followed over at least four visits. The researchers tracked pertussis infection using quantitative PCR (qPCR) on nasopharyngeal swabs. Over the course of the study, 8.9% tested positive, although only one infant developed clinical pertussis during the study.

The study was presented by Christian Gunning, a postdoctoral researcher at the University of Georgia, at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. The group also included researchers at Boston University and the University of Zambia, where PCR tests were conducted.

“That was amazing,” said session moderator Vana Spoulou, MD, PhD, professor of pediatric infectious diseases at National and Kapodistrian University of Athens, who is associated with Aghia Sofia Children’s Hospital of Athens. She noted that the study found that many physicians misdiagnosed coughs, believing them to be caused by another agent. “It was very interesting that there was so much pertussis spreading around in that community, and that nobody knew that it was around,” said Dr. Spoulou.

It’s important that physicians provide appropriate treatment, since ampicillin, which is typically prescribed for childhood upper respiratory illnesses, is believed to be ineffective against pertussis, while macrolides are effective and can prevent transmission.

Dr. Spoulou also noted that Zambia uses a whole cell vaccine, which is contraindicated in pregnant women because of potential side effects. “The good thing, despite that there was [a lot of] infection, there were no deaths, which means that maybe because the mother was infected, maybe some antibodies of the mother had passed to the child and could help the child to develop milder symptoms. So these are the pros and cons of natural infection,” said Dr. Spoulou.

The study took place in 2015, and participants were seen at the Chawama Public Health Clinic from about age 1 week to 4 months (with a target of seven clinic visits). Researchers recorded respiratory symptoms and antibiotics use at each visit, and collected a nasopharyngeal swab that was tested retrospectively using qPCR for Bordetella pertussis.

Real-time PCR analysis of the samples yields the CT value, which represents the number of amplification cycles that the PCR test must complete before Bordetella pertussis is detectable. The fewer the cycles (and the lower the CT value), the more infectious particles must have been present in the sample. For pertussis testing, a value below 35 is considered a clinically positive result. Tests that come back with higher CT values are increasingly likely to be false positives.

The researchers plotted a value called evidence for infection (EFI), which combined a range of CT values with the number of positive tests over the seven clinic visits to group patients into none, weak, or strong EFI. Among infants with no symptoms, 77% were in the no EFI category, 16% were in the weak category, and 7% were in the strong EFI group. Of infants with minimal respiratory symptoms, 18% were in the strong group, and 20% with moderate to severe symptoms were in the strong EFI group. Among mothers, 13% with no symptoms were in the strong group. 19% in the minimal symptom group were categorized as strong EFI, as were 11% in the moderate to severe symptom group.

The study used a full range of CT, not just positive test results (for pertussis, CT ≤ 35). Beyond contributing to composite measures such as EFI, CT values can serve as leading indicators of infectious disease outbreaks in a population, according to Dr. Gunning. That’s because weaker qPCR signals (CT > 35) can provide additional information within a large sample population. Higher CT values are successively more prone to false positives, but that’s less important for disease surveillance where sensitivity is of the highest importance. The false positive “noise” tends to cancel out over time. “It may be the case that you don’t make that call (correctly) 100% of the time for 100% of the people, but if you get it right in 80 out of 100 people, that’s sufficient to say we see this pathogen circulating in the population,” said Dr. Gunning.

The study was funded by the National Institute of Allergy and Infectious Diseases. Dr. Gunning and Dr. Spoulou have no relevant financial disclosures.

In the periurban slum of Lusaka, Zambia, asymptomatic pertussis infections were common among both mothers and infants, a surprising finding since asymptomatic infections are assumed to be rare in infants. The findings suggested that pertussis should be considered in cases of chronic cough, and that current standards of treating pertussis infections in low-resource settings may need to be reexamined.

The results come from testing of 1,320 infant-mother pairs who were first enrolled at a public health clinic, then followed over at least four visits. The researchers tracked pertussis infection using quantitative PCR (qPCR) on nasopharyngeal swabs. Over the course of the study, 8.9% tested positive, although only one infant developed clinical pertussis during the study.

The study was presented by Christian Gunning, a postdoctoral researcher at the University of Georgia, at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. The group also included researchers at Boston University and the University of Zambia, where PCR tests were conducted.

“That was amazing,” said session moderator Vana Spoulou, MD, PhD, professor of pediatric infectious diseases at National and Kapodistrian University of Athens, who is associated with Aghia Sofia Children’s Hospital of Athens. She noted that the study found that many physicians misdiagnosed coughs, believing them to be caused by another agent. “It was very interesting that there was so much pertussis spreading around in that community, and that nobody knew that it was around,” said Dr. Spoulou.

It’s important that physicians provide appropriate treatment, since ampicillin, which is typically prescribed for childhood upper respiratory illnesses, is believed to be ineffective against pertussis, while macrolides are effective and can prevent transmission.

Dr. Spoulou also noted that Zambia uses a whole cell vaccine, which is contraindicated in pregnant women because of potential side effects. “The good thing, despite that there was [a lot of] infection, there were no deaths, which means that maybe because the mother was infected, maybe some antibodies of the mother had passed to the child and could help the child to develop milder symptoms. So these are the pros and cons of natural infection,” said Dr. Spoulou.

The study took place in 2015, and participants were seen at the Chawama Public Health Clinic from about age 1 week to 4 months (with a target of seven clinic visits). Researchers recorded respiratory symptoms and antibiotics use at each visit, and collected a nasopharyngeal swab that was tested retrospectively using qPCR for Bordetella pertussis.

Real-time PCR analysis of the samples yields the CT value, which represents the number of amplification cycles that the PCR test must complete before Bordetella pertussis is detectable. The fewer the cycles (and the lower the CT value), the more infectious particles must have been present in the sample. For pertussis testing, a value below 35 is considered a clinically positive result. Tests that come back with higher CT values are increasingly likely to be false positives.

The researchers plotted a value called evidence for infection (EFI), which combined a range of CT values with the number of positive tests over the seven clinic visits to group patients into none, weak, or strong EFI. Among infants with no symptoms, 77% were in the no EFI category, 16% were in the weak category, and 7% were in the strong EFI group. Of infants with minimal respiratory symptoms, 18% were in the strong group, and 20% with moderate to severe symptoms were in the strong EFI group. Among mothers, 13% with no symptoms were in the strong group. 19% in the minimal symptom group were categorized as strong EFI, as were 11% in the moderate to severe symptom group.

The study used a full range of CT, not just positive test results (for pertussis, CT ≤ 35). Beyond contributing to composite measures such as EFI, CT values can serve as leading indicators of infectious disease outbreaks in a population, according to Dr. Gunning. That’s because weaker qPCR signals (CT > 35) can provide additional information within a large sample population. Higher CT values are successively more prone to false positives, but that’s less important for disease surveillance where sensitivity is of the highest importance. The false positive “noise” tends to cancel out over time. “It may be the case that you don’t make that call (correctly) 100% of the time for 100% of the people, but if you get it right in 80 out of 100 people, that’s sufficient to say we see this pathogen circulating in the population,” said Dr. Gunning.

The study was funded by the National Institute of Allergy and Infectious Diseases. Dr. Gunning and Dr. Spoulou have no relevant financial disclosures.

In the periurban slum of Lusaka, Zambia, asymptomatic pertussis infections were common among both mothers and infants, a surprising finding since asymptomatic infections are assumed to be rare in infants. The findings suggested that pertussis should be considered in cases of chronic cough, and that current standards of treating pertussis infections in low-resource settings may need to be reexamined.

The results come from testing of 1,320 infant-mother pairs who were first enrolled at a public health clinic, then followed over at least four visits. The researchers tracked pertussis infection using quantitative PCR (qPCR) on nasopharyngeal swabs. Over the course of the study, 8.9% tested positive, although only one infant developed clinical pertussis during the study.

The study was presented by Christian Gunning, a postdoctoral researcher at the University of Georgia, at the annual meeting of the European Society for Paediatric Infectious Diseases, held virtually this year. The group also included researchers at Boston University and the University of Zambia, where PCR tests were conducted.

“That was amazing,” said session moderator Vana Spoulou, MD, PhD, professor of pediatric infectious diseases at National and Kapodistrian University of Athens, who is associated with Aghia Sofia Children’s Hospital of Athens. She noted that the study found that many physicians misdiagnosed coughs, believing them to be caused by another agent. “It was very interesting that there was so much pertussis spreading around in that community, and that nobody knew that it was around,” said Dr. Spoulou.

It’s important that physicians provide appropriate treatment, since ampicillin, which is typically prescribed for childhood upper respiratory illnesses, is believed to be ineffective against pertussis, while macrolides are effective and can prevent transmission.

Dr. Spoulou also noted that Zambia uses a whole cell vaccine, which is contraindicated in pregnant women because of potential side effects. “The good thing, despite that there was [a lot of] infection, there were no deaths, which means that maybe because the mother was infected, maybe some antibodies of the mother had passed to the child and could help the child to develop milder symptoms. So these are the pros and cons of natural infection,” said Dr. Spoulou.

The study took place in 2015, and participants were seen at the Chawama Public Health Clinic from about age 1 week to 4 months (with a target of seven clinic visits). Researchers recorded respiratory symptoms and antibiotics use at each visit, and collected a nasopharyngeal swab that was tested retrospectively using qPCR for Bordetella pertussis.

Real-time PCR analysis of the samples yields the CT value, which represents the number of amplification cycles that the PCR test must complete before Bordetella pertussis is detectable. The fewer the cycles (and the lower the CT value), the more infectious particles must have been present in the sample. For pertussis testing, a value below 35 is considered a clinically positive result. Tests that come back with higher CT values are increasingly likely to be false positives.

The researchers plotted a value called evidence for infection (EFI), which combined a range of CT values with the number of positive tests over the seven clinic visits to group patients into none, weak, or strong EFI. Among infants with no symptoms, 77% were in the no EFI category, 16% were in the weak category, and 7% were in the strong EFI group. Of infants with minimal respiratory symptoms, 18% were in the strong group, and 20% with moderate to severe symptoms were in the strong EFI group. Among mothers, 13% with no symptoms were in the strong group. 19% in the minimal symptom group were categorized as strong EFI, as were 11% in the moderate to severe symptom group.

The study used a full range of CT, not just positive test results (for pertussis, CT ≤ 35). Beyond contributing to composite measures such as EFI, CT values can serve as leading indicators of infectious disease outbreaks in a population, according to Dr. Gunning. That’s because weaker qPCR signals (CT > 35) can provide additional information within a large sample population. Higher CT values are successively more prone to false positives, but that’s less important for disease surveillance where sensitivity is of the highest importance. The false positive “noise” tends to cancel out over time. “It may be the case that you don’t make that call (correctly) 100% of the time for 100% of the people, but if you get it right in 80 out of 100 people, that’s sufficient to say we see this pathogen circulating in the population,” said Dr. Gunning.

The study was funded by the National Institute of Allergy and Infectious Diseases. Dr. Gunning and Dr. Spoulou have no relevant financial disclosures.