As of January 10, 2021, a reported 4,041,396 first doses of Moderna’s COVID-19 vaccine had been administered in the US. Reports of 1,266 (0.03%) adverse effects (AEs) after receipt of the vaccine were submitted to the Vaccine Adverse Event Reporting System (VAERS), according to researchers from the Centers for Disease Control and Prevention (CDC) COVID-19 Response Team and Food and Drug Administration in a Morbidity and Mortality Weekly Report early release.

The researchers screened VAERS reports that described suspected severe allergic reactions and anaphylaxis and collected information from medical records and outreach to healthcare facilities, providers, and recipients. They identified 108 reports for further review as possible severe allergic reaction, including anaphylaxis, a rare vaccination reaction. Ten cases were determined to be anaphylaxis—or a rate of 2.5 cases per million vaccine doses administered. Nine of the cases were people with a documented history of allergies or allergic reactions; 5 had a history of anaphylaxis.

The median interval from vaccine receipt to symptom onset was 7.5 minutes. Eight people had follow-up information available; all had recovered or were discharged. Of the case reports that were determined not to be anaphylaxis, 47 were assessed as nonanaphylactic allergic reactions and 47 were considered nonallergic adverse events. Four cases lacked enough information to be determined.

Based on those preliminary findings, it appears anaphylaxis is rare after the Moderna vaccination, but the researchers note that comparisons with other non–COVID-19 vaccines are constrained due to the limited information available this early in the vaccination program. They did cite an analysis of the Pfizer-BioNTech COVID-19 vaccine, also an mRNA vaccine, which estimated an initial rate of 11.1 cases per million doses after the first shot.

The researchers found a “strong female predominance” of anaphylaxis for both vaccines. All 10 anaphylaxis cases reported with the Moderna vaccine were in women. However, during the analytic period, 61% of first doses were given to women, vs 36% to men. Similarly, two thirds of first doses of the Pfizer-BioNTech vaccine were administered to women, and women were more affected.

Postvaccine COVID-19 Infections

But patients shouldn’t be too hasty to assume that symptoms after the vaccination are vaccine related, researchers at Israel’s Sheba Medical Center warn. The mere availability of a vaccine may lead to a certain laxity of precautions and a consequent rise in COVID-19 cases. “Thus, almost every physical complaint after vaccination poses a true diagnostic dilemma,” they point out, “as to whether an adverse reaction or a new COVID-19 infection is the cause.”

They studied 4,081 healthcare workers given the Pfizer-BioNTech vaccine. Of the vaccinated healthcare workers, 22 (0.54%) later had laboratory-confirmed COVID-19. Thirteen were tested because they had symptoms, usually an influenza-like illness that included fever, chills, cough, headache, myalgia, and sore throat. The median time between the first dose of vaccine and first symptoms was 3.5 days (one HCW had symptoms before immunization).

The vaccine, BNT162b2, is not likely to protect against clinical disease during the first days after receipt of the first dose, the researchers say. Efficacy was 52% a week after the first dose and positive COVID-19 cases were described among vaccinees even early after the second dose.

Clinicians should have a high level of suspicion of reported symptoms, the researchers advise, and avoid dismissing complaints as vaccine related until true infection is ruled out and the vaccine recipient is tested.

As of January 10, 2021, a reported 4,041,396 first doses of Moderna’s COVID-19 vaccine had been administered in the US. Reports of 1,266 (0.03%) adverse effects (AEs) after receipt of the vaccine were submitted to the Vaccine Adverse Event Reporting System (VAERS), according to researchers from the Centers for Disease Control and Prevention (CDC) COVID-19 Response Team and Food and Drug Administration in a Morbidity and Mortality Weekly Report early release.

The researchers screened VAERS reports that described suspected severe allergic reactions and anaphylaxis and collected information from medical records and outreach to healthcare facilities, providers, and recipients. They identified 108 reports for further review as possible severe allergic reaction, including anaphylaxis, a rare vaccination reaction. Ten cases were determined to be anaphylaxis—or a rate of 2.5 cases per million vaccine doses administered. Nine of the cases were people with a documented history of allergies or allergic reactions; 5 had a history of anaphylaxis.

The median interval from vaccine receipt to symptom onset was 7.5 minutes. Eight people had follow-up information available; all had recovered or were discharged. Of the case reports that were determined not to be anaphylaxis, 47 were assessed as nonanaphylactic allergic reactions and 47 were considered nonallergic adverse events. Four cases lacked enough information to be determined.

Based on those preliminary findings, it appears anaphylaxis is rare after the Moderna vaccination, but the researchers note that comparisons with other non–COVID-19 vaccines are constrained due to the limited information available this early in the vaccination program. They did cite an analysis of the Pfizer-BioNTech COVID-19 vaccine, also an mRNA vaccine, which estimated an initial rate of 11.1 cases per million doses after the first shot.

The researchers found a “strong female predominance” of anaphylaxis for both vaccines. All 10 anaphylaxis cases reported with the Moderna vaccine were in women. However, during the analytic period, 61% of first doses were given to women, vs 36% to men. Similarly, two thirds of first doses of the Pfizer-BioNTech vaccine were administered to women, and women were more affected.

Postvaccine COVID-19 Infections

But patients shouldn’t be too hasty to assume that symptoms after the vaccination are vaccine related, researchers at Israel’s Sheba Medical Center warn. The mere availability of a vaccine may lead to a certain laxity of precautions and a consequent rise in COVID-19 cases. “Thus, almost every physical complaint after vaccination poses a true diagnostic dilemma,” they point out, “as to whether an adverse reaction or a new COVID-19 infection is the cause.”

They studied 4,081 healthcare workers given the Pfizer-BioNTech vaccine. Of the vaccinated healthcare workers, 22 (0.54%) later had laboratory-confirmed COVID-19. Thirteen were tested because they had symptoms, usually an influenza-like illness that included fever, chills, cough, headache, myalgia, and sore throat. The median time between the first dose of vaccine and first symptoms was 3.5 days (one HCW had symptoms before immunization).

The vaccine, BNT162b2, is not likely to protect against clinical disease during the first days after receipt of the first dose, the researchers say. Efficacy was 52% a week after the first dose and positive COVID-19 cases were described among vaccinees even early after the second dose.

Clinicians should have a high level of suspicion of reported symptoms, the researchers advise, and avoid dismissing complaints as vaccine related until true infection is ruled out and the vaccine recipient is tested.

As of January 10, 2021, a reported 4,041,396 first doses of Moderna’s COVID-19 vaccine had been administered in the US. Reports of 1,266 (0.03%) adverse effects (AEs) after receipt of the vaccine were submitted to the Vaccine Adverse Event Reporting System (VAERS), according to researchers from the Centers for Disease Control and Prevention (CDC) COVID-19 Response Team and Food and Drug Administration in a Morbidity and Mortality Weekly Report early release.

The researchers screened VAERS reports that described suspected severe allergic reactions and anaphylaxis and collected information from medical records and outreach to healthcare facilities, providers, and recipients. They identified 108 reports for further review as possible severe allergic reaction, including anaphylaxis, a rare vaccination reaction. Ten cases were determined to be anaphylaxis—or a rate of 2.5 cases per million vaccine doses administered. Nine of the cases were people with a documented history of allergies or allergic reactions; 5 had a history of anaphylaxis.

The median interval from vaccine receipt to symptom onset was 7.5 minutes. Eight people had follow-up information available; all had recovered or were discharged. Of the case reports that were determined not to be anaphylaxis, 47 were assessed as nonanaphylactic allergic reactions and 47 were considered nonallergic adverse events. Four cases lacked enough information to be determined.

Based on those preliminary findings, it appears anaphylaxis is rare after the Moderna vaccination, but the researchers note that comparisons with other non–COVID-19 vaccines are constrained due to the limited information available this early in the vaccination program. They did cite an analysis of the Pfizer-BioNTech COVID-19 vaccine, also an mRNA vaccine, which estimated an initial rate of 11.1 cases per million doses after the first shot.

The researchers found a “strong female predominance” of anaphylaxis for both vaccines. All 10 anaphylaxis cases reported with the Moderna vaccine were in women. However, during the analytic period, 61% of first doses were given to women, vs 36% to men. Similarly, two thirds of first doses of the Pfizer-BioNTech vaccine were administered to women, and women were more affected.

Postvaccine COVID-19 Infections

But patients shouldn’t be too hasty to assume that symptoms after the vaccination are vaccine related, researchers at Israel’s Sheba Medical Center warn. The mere availability of a vaccine may lead to a certain laxity of precautions and a consequent rise in COVID-19 cases. “Thus, almost every physical complaint after vaccination poses a true diagnostic dilemma,” they point out, “as to whether an adverse reaction or a new COVID-19 infection is the cause.”

They studied 4,081 healthcare workers given the Pfizer-BioNTech vaccine. Of the vaccinated healthcare workers, 22 (0.54%) later had laboratory-confirmed COVID-19. Thirteen were tested because they had symptoms, usually an influenza-like illness that included fever, chills, cough, headache, myalgia, and sore throat. The median time between the first dose of vaccine and first symptoms was 3.5 days (one HCW had symptoms before immunization).

The vaccine, BNT162b2, is not likely to protect against clinical disease during the first days after receipt of the first dose, the researchers say. Efficacy was 52% a week after the first dose and positive COVID-19 cases were described among vaccinees even early after the second dose.

Clinicians should have a high level of suspicion of reported symptoms, the researchers advise, and avoid dismissing complaints as vaccine related until true infection is ruled out and the vaccine recipient is tested.

COVID-19 did not discriminate when it came to the impact it imposed on our hospitalist community. As the nomenclature moves away from the negative connotations of ‘burnout’ to ‘wellbeing,’ the pandemic has taught us something important about being intentional about our personal health: we must secure our own oxygen masks before helping others.

In February 2020, the Society of Hospital Medicine’s Wellbeing Taskforce efforts quickly changed focus from addressing general wellbeing, to wellbeing during COVID-19. Our Taskforce was commissioned by SHM’s Board with a new charge: Address immediate and ongoing needs of well-being and resiliency support for hospitalists during the COVID-19 pandemic. In this essay, I will discuss how our SHM Wellbeing Taskforce approached the overall topic of wellbeing for hospitalists during the COVID-19 pandemic, including some of our Taskforce group experiences.

The Taskforce started with a framework to aide in cultivating open and authentic conversations within hospital medicine groups. Creating spaces for honest sharing around how providers are doing is a crucial first step to reducing stigma, building mutual support within a group, and elevating issues of wellbeing to the level where structural change can take place. The Taskforce established two objectives for normalizing and mitigating stressors we face as hospitalists during the COVID-19 pandemic:

• Provide a framework for hospitalists to take their own emotional pulse
• Provide an approach to reduce stigma of hospitalists who are suffering from pandemic stress

While a more typical approach to fix stress and burnout is using formal institutional interventions, we used the value and insight provided by SHM’s 7 Drivers of Burnout in Hospital Medicine to help guide the creation of SHM resources in addressing the severe emotional strain being felt across the country by hospitalists. The 7 Drivers support the idea that the social role peers and hospital leaders can make a crucial difference in mitigating stress and burnout. Two examples of social support come to mind from the Wellbeing Taskforce experience:

• Participate in your meetings. One example comes from a member of our group who had underestimated the “healing power” that our group meetings had provided to his psyche. The simple act of participating in our Taskforce meeting and being in the presence of our group had provided such a positive impact that he was better able to face the “death and misery” in his unit with a smile on his face.
• Share what is stressful. The second example of social support comes from an hour of Zoom-based facilitation meetings between the SHM’s Wellbeing Taskforce members and Chapter Leaders in late October. During our Taskforce debrief after the meeting, we came to realize the enormous burden of grief our peers were carrying as one hospitalist had lost a group colleague the previous week due to suicide. Our member who led this meeting was moved – as were we – at how this had impacted his small team, and he was reminded he was not alone.

To form meaningful relationships that foster support, there needs to be a space where people can safely come together at times that initially might feel awkward. After taking steps toward your peers, these conversations can become normalized and contribute to meaningful relationships, providing the opportunity for healthy exchanges on vulnerable topics like emotional and psychological wellbeing. A printable guide for this specific purpose (“HM COVID-19 Check-In Guide for Self and Peers”) was designed to help hospitalists move into safe and supportive conversations with each other. While it is difficult to place a value on the importance these types of conversations have on individual wellbeing, it is known that the quality of a positive work environment where people feel supported can moderate stress, morale, and depression. In other words, hospitalist groups can positively contribute to their social environment during stressful times by sharing meaningful and difficult experiences with one another.

Second, the Taskforce created a social media campaign to provide a public social space for sharing hospitalists’ COVID-19 experiences. We believed that sharing collective experiences with the theme of #YouAreNotAlone and a complementary social media campaign, SHM Cares, on SHM’s social media channels, would further connect the national hospitalist community and provide a different communication pathway to decrease a sense of isolation. This idea came from the second social support idea mentioned earlier to share what is stressful with others in a safe space. We understood that some hospitalists would be more comfortable sharing publicly their comments, photos, and videos in achieving a sense of hospitalist unity.

Using our shared experiences, we identified three pillars for the final structure of the HM COVID-19 Check-In Guide for Self and Peers:

• Pillar 1. Recognize your issues. Recall our oxygen mask metaphor and this is what we mean by recognizing symptoms of new stressors (e.g., sleeplessness, irritability, forgetfulness).
• Pillar 2. Know what to say. A simple open-ended question about how the other person is working through the pandemic is an easy way to start a connection. We learned from a mental health perspective that it is unlikely that you could say anything to make a situation worse by offering a listening ear.
• Pillar 3. Check in with others. Listen to others without trying to fix the person or the situation. When appropriate, offer humorous reflections without diminishing the problem. Be a partner and commit to check in regularly with the other person.

Cultivating human connections outside of your immediate peer group can be valuable and offer additional perspective to stressful situations. For instance, one of my roles as a hospitalist administrator has been offering support by regularly listening as my physicians ‘talk out’ their day confidentially for as long as they needed. Offering open conversation in a safe and confidential way can have a healing effect. As one of my former hospitalists used to say, if issues are not addressed, they will “ooze out somewhere else.”

The HM COVID-19 Check-In Guide for Self and Peers and the SHM Cares social media campaign was the result of the Taskforce’s collective observations to help others normalize the feeling that ‘it’s OK not to be OK.’ Using the pandemic as context, the 7 Drivers of Hospitalist Burnout reminded us that the increased burnout issues we face will require continued attention past the pandemic. The value in cultivating human connections has never been more important. The SHM Wellbeing Taskforce is committed to provide continued resources. Checking in with others and listening to peers are all part of a personal wellbeing and resilience strategy. On behalf of the SHM Wellbeing Taskforce, we hope the information in this article will highlight the importance of continued attention to personal wellbeing during and after the pandemic.

Dr. Robinson received her PhD in organizational learning, performance and change from Colorado State University in 2019. Her dissertation topic was exploring hospitalist burnout, engagement, and social support. She is administrative director of inpatient medicine at St. Mary’s Medical Center in Grand Junction, Colo., a part of SCL Health. She has volunteered in numerous SHM committees, and currently serves on the SHM Wellbeing Taskforce.

COVID-19 did not discriminate when it came to the impact it imposed on our hospitalist community. As the nomenclature moves away from the negative connotations of ‘burnout’ to ‘wellbeing,’ the pandemic has taught us something important about being intentional about our personal health: we must secure our own oxygen masks before helping others.

In February 2020, the Society of Hospital Medicine’s Wellbeing Taskforce efforts quickly changed focus from addressing general wellbeing, to wellbeing during COVID-19. Our Taskforce was commissioned by SHM’s Board with a new charge: Address immediate and ongoing needs of well-being and resiliency support for hospitalists during the COVID-19 pandemic. In this essay, I will discuss how our SHM Wellbeing Taskforce approached the overall topic of wellbeing for hospitalists during the COVID-19 pandemic, including some of our Taskforce group experiences.

The Taskforce started with a framework to aide in cultivating open and authentic conversations within hospital medicine groups. Creating spaces for honest sharing around how providers are doing is a crucial first step to reducing stigma, building mutual support within a group, and elevating issues of wellbeing to the level where structural change can take place. The Taskforce established two objectives for normalizing and mitigating stressors we face as hospitalists during the COVID-19 pandemic:

• Provide a framework for hospitalists to take their own emotional pulse
• Provide an approach to reduce stigma of hospitalists who are suffering from pandemic stress

While a more typical approach to fix stress and burnout is using formal institutional interventions, we used the value and insight provided by SHM’s 7 Drivers of Burnout in Hospital Medicine to help guide the creation of SHM resources in addressing the severe emotional strain being felt across the country by hospitalists. The 7 Drivers support the idea that the social role peers and hospital leaders can make a crucial difference in mitigating stress and burnout. Two examples of social support come to mind from the Wellbeing Taskforce experience:

• Participate in your meetings. One example comes from a member of our group who had underestimated the “healing power” that our group meetings had provided to his psyche. The simple act of participating in our Taskforce meeting and being in the presence of our group had provided such a positive impact that he was better able to face the “death and misery” in his unit with a smile on his face.
• Share what is stressful. The second example of social support comes from an hour of Zoom-based facilitation meetings between the SHM’s Wellbeing Taskforce members and Chapter Leaders in late October. During our Taskforce debrief after the meeting, we came to realize the enormous burden of grief our peers were carrying as one hospitalist had lost a group colleague the previous week due to suicide. Our member who led this meeting was moved – as were we – at how this had impacted his small team, and he was reminded he was not alone.

To form meaningful relationships that foster support, there needs to be a space where people can safely come together at times that initially might feel awkward. After taking steps toward your peers, these conversations can become normalized and contribute to meaningful relationships, providing the opportunity for healthy exchanges on vulnerable topics like emotional and psychological wellbeing. A printable guide for this specific purpose (“HM COVID-19 Check-In Guide for Self and Peers”) was designed to help hospitalists move into safe and supportive conversations with each other. While it is difficult to place a value on the importance these types of conversations have on individual wellbeing, it is known that the quality of a positive work environment where people feel supported can moderate stress, morale, and depression. In other words, hospitalist groups can positively contribute to their social environment during stressful times by sharing meaningful and difficult experiences with one another.

Second, the Taskforce created a social media campaign to provide a public social space for sharing hospitalists’ COVID-19 experiences. We believed that sharing collective experiences with the theme of #YouAreNotAlone and a complementary social media campaign, SHM Cares, on SHM’s social media channels, would further connect the national hospitalist community and provide a different communication pathway to decrease a sense of isolation. This idea came from the second social support idea mentioned earlier to share what is stressful with others in a safe space. We understood that some hospitalists would be more comfortable sharing publicly their comments, photos, and videos in achieving a sense of hospitalist unity.

Using our shared experiences, we identified three pillars for the final structure of the HM COVID-19 Check-In Guide for Self and Peers:

• Pillar 1. Recognize your issues. Recall our oxygen mask metaphor and this is what we mean by recognizing symptoms of new stressors (e.g., sleeplessness, irritability, forgetfulness).
• Pillar 2. Know what to say. A simple open-ended question about how the other person is working through the pandemic is an easy way to start a connection. We learned from a mental health perspective that it is unlikely that you could say anything to make a situation worse by offering a listening ear.
• Pillar 3. Check in with others. Listen to others without trying to fix the person or the situation. When appropriate, offer humorous reflections without diminishing the problem. Be a partner and commit to check in regularly with the other person.

Cultivating human connections outside of your immediate peer group can be valuable and offer additional perspective to stressful situations. For instance, one of my roles as a hospitalist administrator has been offering support by regularly listening as my physicians ‘talk out’ their day confidentially for as long as they needed. Offering open conversation in a safe and confidential way can have a healing effect. As one of my former hospitalists used to say, if issues are not addressed, they will “ooze out somewhere else.”

The HM COVID-19 Check-In Guide for Self and Peers and the SHM Cares social media campaign was the result of the Taskforce’s collective observations to help others normalize the feeling that ‘it’s OK not to be OK.’ Using the pandemic as context, the 7 Drivers of Hospitalist Burnout reminded us that the increased burnout issues we face will require continued attention past the pandemic. The value in cultivating human connections has never been more important. The SHM Wellbeing Taskforce is committed to provide continued resources. Checking in with others and listening to peers are all part of a personal wellbeing and resilience strategy. On behalf of the SHM Wellbeing Taskforce, we hope the information in this article will highlight the importance of continued attention to personal wellbeing during and after the pandemic.

Dr. Robinson received her PhD in organizational learning, performance and change from Colorado State University in 2019. Her dissertation topic was exploring hospitalist burnout, engagement, and social support. She is administrative director of inpatient medicine at St. Mary’s Medical Center in Grand Junction, Colo., a part of SCL Health. She has volunteered in numerous SHM committees, and currently serves on the SHM Wellbeing Taskforce.

COVID-19 did not discriminate when it came to the impact it imposed on our hospitalist community. As the nomenclature moves away from the negative connotations of ‘burnout’ to ‘wellbeing,’ the pandemic has taught us something important about being intentional about our personal health: we must secure our own oxygen masks before helping others.

In February 2020, the Society of Hospital Medicine’s Wellbeing Taskforce efforts quickly changed focus from addressing general wellbeing, to wellbeing during COVID-19. Our Taskforce was commissioned by SHM’s Board with a new charge: Address immediate and ongoing needs of well-being and resiliency support for hospitalists during the COVID-19 pandemic. In this essay, I will discuss how our SHM Wellbeing Taskforce approached the overall topic of wellbeing for hospitalists during the COVID-19 pandemic, including some of our Taskforce group experiences.

The Taskforce started with a framework to aide in cultivating open and authentic conversations within hospital medicine groups. Creating spaces for honest sharing around how providers are doing is a crucial first step to reducing stigma, building mutual support within a group, and elevating issues of wellbeing to the level where structural change can take place. The Taskforce established two objectives for normalizing and mitigating stressors we face as hospitalists during the COVID-19 pandemic:

• Provide a framework for hospitalists to take their own emotional pulse
• Provide an approach to reduce stigma of hospitalists who are suffering from pandemic stress

While a more typical approach to fix stress and burnout is using formal institutional interventions, we used the value and insight provided by SHM’s 7 Drivers of Burnout in Hospital Medicine to help guide the creation of SHM resources in addressing the severe emotional strain being felt across the country by hospitalists. The 7 Drivers support the idea that the social role peers and hospital leaders can make a crucial difference in mitigating stress and burnout. Two examples of social support come to mind from the Wellbeing Taskforce experience:

• Participate in your meetings. One example comes from a member of our group who had underestimated the “healing power” that our group meetings had provided to his psyche. The simple act of participating in our Taskforce meeting and being in the presence of our group had provided such a positive impact that he was better able to face the “death and misery” in his unit with a smile on his face.
• Share what is stressful. The second example of social support comes from an hour of Zoom-based facilitation meetings between the SHM’s Wellbeing Taskforce members and Chapter Leaders in late October. During our Taskforce debrief after the meeting, we came to realize the enormous burden of grief our peers were carrying as one hospitalist had lost a group colleague the previous week due to suicide. Our member who led this meeting was moved – as were we – at how this had impacted his small team, and he was reminded he was not alone.

To form meaningful relationships that foster support, there needs to be a space where people can safely come together at times that initially might feel awkward. After taking steps toward your peers, these conversations can become normalized and contribute to meaningful relationships, providing the opportunity for healthy exchanges on vulnerable topics like emotional and psychological wellbeing. A printable guide for this specific purpose (“HM COVID-19 Check-In Guide for Self and Peers”) was designed to help hospitalists move into safe and supportive conversations with each other. While it is difficult to place a value on the importance these types of conversations have on individual wellbeing, it is known that the quality of a positive work environment where people feel supported can moderate stress, morale, and depression. In other words, hospitalist groups can positively contribute to their social environment during stressful times by sharing meaningful and difficult experiences with one another.

Second, the Taskforce created a social media campaign to provide a public social space for sharing hospitalists’ COVID-19 experiences. We believed that sharing collective experiences with the theme of #YouAreNotAlone and a complementary social media campaign, SHM Cares, on SHM’s social media channels, would further connect the national hospitalist community and provide a different communication pathway to decrease a sense of isolation. This idea came from the second social support idea mentioned earlier to share what is stressful with others in a safe space. We understood that some hospitalists would be more comfortable sharing publicly their comments, photos, and videos in achieving a sense of hospitalist unity.

Using our shared experiences, we identified three pillars for the final structure of the HM COVID-19 Check-In Guide for Self and Peers:

• Pillar 1. Recognize your issues. Recall our oxygen mask metaphor and this is what we mean by recognizing symptoms of new stressors (e.g., sleeplessness, irritability, forgetfulness).
• Pillar 2. Know what to say. A simple open-ended question about how the other person is working through the pandemic is an easy way to start a connection. We learned from a mental health perspective that it is unlikely that you could say anything to make a situation worse by offering a listening ear.
• Pillar 3. Check in with others. Listen to others without trying to fix the person or the situation. When appropriate, offer humorous reflections without diminishing the problem. Be a partner and commit to check in regularly with the other person.

Cultivating human connections outside of your immediate peer group can be valuable and offer additional perspective to stressful situations. For instance, one of my roles as a hospitalist administrator has been offering support by regularly listening as my physicians ‘talk out’ their day confidentially for as long as they needed. Offering open conversation in a safe and confidential way can have a healing effect. As one of my former hospitalists used to say, if issues are not addressed, they will “ooze out somewhere else.”

The HM COVID-19 Check-In Guide for Self and Peers and the SHM Cares social media campaign was the result of the Taskforce’s collective observations to help others normalize the feeling that ‘it’s OK not to be OK.’ Using the pandemic as context, the 7 Drivers of Hospitalist Burnout reminded us that the increased burnout issues we face will require continued attention past the pandemic. The value in cultivating human connections has never been more important. The SHM Wellbeing Taskforce is committed to provide continued resources. Checking in with others and listening to peers are all part of a personal wellbeing and resilience strategy. On behalf of the SHM Wellbeing Taskforce, we hope the information in this article will highlight the importance of continued attention to personal wellbeing during and after the pandemic.

Dr. Robinson received her PhD in organizational learning, performance and change from Colorado State University in 2019. Her dissertation topic was exploring hospitalist burnout, engagement, and social support. She is administrative director of inpatient medicine at St. Mary’s Medical Center in Grand Junction, Colo., a part of SCL Health. She has volunteered in numerous SHM committees, and currently serves on the SHM Wellbeing Taskforce.

Monoclonal antibodies (mAbs) to treat COVID-19 are in ample supply, but scant evidence on their effectiveness, paltry reimbursement, and a lack of a planned infrastructure to administer them has led to major underutilization of these potentially useful therapies, according to a new report from The National Academies of Sciences, Engineering, and Medicine.

The 35-page report described missed opportunities to work with states and hospitals to establish trust with clinicians and patients and to set up an infusion infrastructure to funnel patients to sites. Though the therapies still need more study, they should be an option for the right patient at the right time, said the National Academies experts in their report, Rapid Expert Consultation on Allocating COVID-19 Monoclonal Antibody Therapies and Other Novel Therapeutics.

“No potentially eligible patient should be left uninformed, and no eligible patient should be denied access, if there are doses available and the patient and doctor agree it is a reasonable course,” they concluded. The report also noted that underuse, and in particular underuse by members of vulnerable and underserved communities “raises concerns about exacerbating already dramatic health disparities.”

The federal government has spent $375 million on Eli Lilly’s bamlanivimab and $450 million on Regeneron’s casirivimab plus imdevimab cocktail, and agreed last month to spend as much as $2.6 billion more on up to 1.25 million additional doses.

Some 785,000 doses of the two therapeutics have been produced and about a half million have been distributed to states. But about three quarters have gone unused. The U.S. Department of Health & Human Services has launched an online treatment locater to try to spur interest in the therapies.

But the federal government hasn’t addressed some of the basic barriers to use of the monoclonals, said the National Academies experts.

“Lack of awareness, interest, and confidence in COVID-19 mAb therapies among patients and providers are major issues,” they said in the report. Patients who have tested positive might not want to travel to an infusion site, while others might not have access to health care or only seek such treatments when it’s too late. Some who are eligible might not have the time, resources, or transportation to go to a site and sit through a 2-hour treatment.

In addition, “the supply and availability of infusion centers and personnel was identified as a greater constraint than the supply of COVID-19 mAbs,” said the report.
 

Cost a big impediment

While the federal government has covered the cost of the therapies, hospitals and patients inevitably incur related costs.

“The fragmented payment system in the United States has not provided adequate support to cover the spectrum of costs associated with COVID-19 mAb therapies,” said the report. That is compounded by chronic underfunding and restrictions on federally qualified health centers for community health, the report said.

Patients may have to pay for testing, office visits, follow-up appointments, transportation to and from the infusion site, and potentially a copay for the administration of the drug.

While Medicare pays hospitals $309 per infusion, that might not be enough, especially if a hospital or other site had to build out a new infusion center, the report shows. For clinicians, the administrative payment under Medicare Part B does “not cover the total practice cost to furnish infusion services, resulting in a substantial cost-reimbursement disparity,” the report states.

In addition, there are no specific codes for observing patients during the 2-hour procedure.

“The established Medicare payment rate for furnishing COVID-19 mAb therapies does not cover the cost associated with coordinating care for those patients, nor does it justify the risk and opportunity costs associated with investing in infrastructure modifications to safely integrate COVID-19 patients into existing facilities or building temporary infusion capacity,” the report concluded.
 

More data needed

The U.S. Food and Drug Administration issued emergency-use authorizations (EUAs) for the two monoclonal therapies based on phase 2 trial data, and that leaves a lot of uncertainty, noted the National Academies.

In trials, both therapies reduced COVID-19-related hospitalizations and emergency room visits within 28 days after treatment among patients at high risk of progression, compared with those who received placebo.

But clinicians aren’t certain about who should use the monoclonals, said the report. The underuse has in turn led to trouble collecting data – either through ongoing trials or in starting new trials.

The National Academies recommended allocating the monoclonal antibodies in a way that would give rise to better data collection to inform clinicians. Payers could support the development of a core data platform or registry, or Medicare could develop pilot trials, said the report.

Lilly and UnitedHealth Group are collaborating on a study in high-risk Medicare patients, according to Reuters. Patients who test positive will be given bamlanivimab at home.

“Building infusion capacity and developing the evidence base about the impact of COVID-19 mAbs on clinical outcomes other than hospitalization, including mortality, are the most promising strategies for increasing effective utilization moving forward,” stated the National Academies report.

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

Monoclonal antibodies (mAbs) to treat COVID-19 are in ample supply, but scant evidence on their effectiveness, paltry reimbursement, and a lack of a planned infrastructure to administer them has led to major underutilization of these potentially useful therapies, according to a new report from The National Academies of Sciences, Engineering, and Medicine.

The 35-page report described missed opportunities to work with states and hospitals to establish trust with clinicians and patients and to set up an infusion infrastructure to funnel patients to sites. Though the therapies still need more study, they should be an option for the right patient at the right time, said the National Academies experts in their report, Rapid Expert Consultation on Allocating COVID-19 Monoclonal Antibody Therapies and Other Novel Therapeutics.

“No potentially eligible patient should be left uninformed, and no eligible patient should be denied access, if there are doses available and the patient and doctor agree it is a reasonable course,” they concluded. The report also noted that underuse, and in particular underuse by members of vulnerable and underserved communities “raises concerns about exacerbating already dramatic health disparities.”

The federal government has spent $375 million on Eli Lilly’s bamlanivimab and $450 million on Regeneron’s casirivimab plus imdevimab cocktail, and agreed last month to spend as much as $2.6 billion more on up to 1.25 million additional doses.

Some 785,000 doses of the two therapeutics have been produced and about a half million have been distributed to states. But about three quarters have gone unused. The U.S. Department of Health & Human Services has launched an online treatment locater to try to spur interest in the therapies.

But the federal government hasn’t addressed some of the basic barriers to use of the monoclonals, said the National Academies experts.

“Lack of awareness, interest, and confidence in COVID-19 mAb therapies among patients and providers are major issues,” they said in the report. Patients who have tested positive might not want to travel to an infusion site, while others might not have access to health care or only seek such treatments when it’s too late. Some who are eligible might not have the time, resources, or transportation to go to a site and sit through a 2-hour treatment.

In addition, “the supply and availability of infusion centers and personnel was identified as a greater constraint than the supply of COVID-19 mAbs,” said the report.
 

Cost a big impediment

While the federal government has covered the cost of the therapies, hospitals and patients inevitably incur related costs.

“The fragmented payment system in the United States has not provided adequate support to cover the spectrum of costs associated with COVID-19 mAb therapies,” said the report. That is compounded by chronic underfunding and restrictions on federally qualified health centers for community health, the report said.

Patients may have to pay for testing, office visits, follow-up appointments, transportation to and from the infusion site, and potentially a copay for the administration of the drug.

While Medicare pays hospitals $309 per infusion, that might not be enough, especially if a hospital or other site had to build out a new infusion center, the report shows. For clinicians, the administrative payment under Medicare Part B does “not cover the total practice cost to furnish infusion services, resulting in a substantial cost-reimbursement disparity,” the report states.

In addition, there are no specific codes for observing patients during the 2-hour procedure.

“The established Medicare payment rate for furnishing COVID-19 mAb therapies does not cover the cost associated with coordinating care for those patients, nor does it justify the risk and opportunity costs associated with investing in infrastructure modifications to safely integrate COVID-19 patients into existing facilities or building temporary infusion capacity,” the report concluded.
 

More data needed

The U.S. Food and Drug Administration issued emergency-use authorizations (EUAs) for the two monoclonal therapies based on phase 2 trial data, and that leaves a lot of uncertainty, noted the National Academies.

In trials, both therapies reduced COVID-19-related hospitalizations and emergency room visits within 28 days after treatment among patients at high risk of progression, compared with those who received placebo.

But clinicians aren’t certain about who should use the monoclonals, said the report. The underuse has in turn led to trouble collecting data – either through ongoing trials or in starting new trials.

The National Academies recommended allocating the monoclonal antibodies in a way that would give rise to better data collection to inform clinicians. Payers could support the development of a core data platform or registry, or Medicare could develop pilot trials, said the report.

Lilly and UnitedHealth Group are collaborating on a study in high-risk Medicare patients, according to Reuters. Patients who test positive will be given bamlanivimab at home.

“Building infusion capacity and developing the evidence base about the impact of COVID-19 mAbs on clinical outcomes other than hospitalization, including mortality, are the most promising strategies for increasing effective utilization moving forward,” stated the National Academies report.

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

Monoclonal antibodies (mAbs) to treat COVID-19 are in ample supply, but scant evidence on their effectiveness, paltry reimbursement, and a lack of a planned infrastructure to administer them has led to major underutilization of these potentially useful therapies, according to a new report from The National Academies of Sciences, Engineering, and Medicine.

The 35-page report described missed opportunities to work with states and hospitals to establish trust with clinicians and patients and to set up an infusion infrastructure to funnel patients to sites. Though the therapies still need more study, they should be an option for the right patient at the right time, said the National Academies experts in their report, Rapid Expert Consultation on Allocating COVID-19 Monoclonal Antibody Therapies and Other Novel Therapeutics.

“No potentially eligible patient should be left uninformed, and no eligible patient should be denied access, if there are doses available and the patient and doctor agree it is a reasonable course,” they concluded. The report also noted that underuse, and in particular underuse by members of vulnerable and underserved communities “raises concerns about exacerbating already dramatic health disparities.”

The federal government has spent $375 million on Eli Lilly’s bamlanivimab and $450 million on Regeneron’s casirivimab plus imdevimab cocktail, and agreed last month to spend as much as $2.6 billion more on up to 1.25 million additional doses.

Some 785,000 doses of the two therapeutics have been produced and about a half million have been distributed to states. But about three quarters have gone unused. The U.S. Department of Health & Human Services has launched an online treatment locater to try to spur interest in the therapies.

But the federal government hasn’t addressed some of the basic barriers to use of the monoclonals, said the National Academies experts.

“Lack of awareness, interest, and confidence in COVID-19 mAb therapies among patients and providers are major issues,” they said in the report. Patients who have tested positive might not want to travel to an infusion site, while others might not have access to health care or only seek such treatments when it’s too late. Some who are eligible might not have the time, resources, or transportation to go to a site and sit through a 2-hour treatment.

In addition, “the supply and availability of infusion centers and personnel was identified as a greater constraint than the supply of COVID-19 mAbs,” said the report.
 

Cost a big impediment

While the federal government has covered the cost of the therapies, hospitals and patients inevitably incur related costs.

“The fragmented payment system in the United States has not provided adequate support to cover the spectrum of costs associated with COVID-19 mAb therapies,” said the report. That is compounded by chronic underfunding and restrictions on federally qualified health centers for community health, the report said.

Patients may have to pay for testing, office visits, follow-up appointments, transportation to and from the infusion site, and potentially a copay for the administration of the drug.

While Medicare pays hospitals $309 per infusion, that might not be enough, especially if a hospital or other site had to build out a new infusion center, the report shows. For clinicians, the administrative payment under Medicare Part B does “not cover the total practice cost to furnish infusion services, resulting in a substantial cost-reimbursement disparity,” the report states.

In addition, there are no specific codes for observing patients during the 2-hour procedure.

“The established Medicare payment rate for furnishing COVID-19 mAb therapies does not cover the cost associated with coordinating care for those patients, nor does it justify the risk and opportunity costs associated with investing in infrastructure modifications to safely integrate COVID-19 patients into existing facilities or building temporary infusion capacity,” the report concluded.
 

More data needed

The U.S. Food and Drug Administration issued emergency-use authorizations (EUAs) for the two monoclonal therapies based on phase 2 trial data, and that leaves a lot of uncertainty, noted the National Academies.

In trials, both therapies reduced COVID-19-related hospitalizations and emergency room visits within 28 days after treatment among patients at high risk of progression, compared with those who received placebo.

But clinicians aren’t certain about who should use the monoclonals, said the report. The underuse has in turn led to trouble collecting data – either through ongoing trials or in starting new trials.

The National Academies recommended allocating the monoclonal antibodies in a way that would give rise to better data collection to inform clinicians. Payers could support the development of a core data platform or registry, or Medicare could develop pilot trials, said the report.

Lilly and UnitedHealth Group are collaborating on a study in high-risk Medicare patients, according to Reuters. Patients who test positive will be given bamlanivimab at home.

“Building infusion capacity and developing the evidence base about the impact of COVID-19 mAbs on clinical outcomes other than hospitalization, including mortality, are the most promising strategies for increasing effective utilization moving forward,” stated the National Academies report.

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

Among critically ill patients pulseless after planned withdrawal of life-sustaining therapies, cardiac activity restarted in 14% of cases, research shows.

Reassuringly, most resumption of heart activity happened in the first 1-2 minutes and most lasted 1 or 2 seconds.

“The reason we wanted to look at death determination specifically is we know that the stories persist about people coming back to life following death, and that’s not just in the public, it’s in the medical community as well,” lead author Sonny Dhanani, MD, of Children’s Hospital of Eastern Ontario, Ottawa, said in an interview.

“We thought that if we provided scientific evidence of whether this happened or not, we might dispel some myths and misunderstanding, which would hopefully promote organ donation.”

About 70% of organ donations occur after brain death, but an increasing number follow circulatory determination of death, he noted. Most protocols recommend 5 minutes of apnea and pulselessness by arterial catheter monitor before declaring death. But practices vary from 10 minutes in some European countries to 75 seconds in infant heart donors at one Colorado hospital.

Reports of patients recovering 10 minutes after pulselessness have raised concerns about the Lazarus phenomenon, or autoresuscitation, but are based in patients after cardiopulmonary resuscitation was terminated.

The present study, known as Death Prediction and Physiology after Removal of Therapy (DePParRT), enrolled patients at 20 intensive care sites in Canada, the Czech Republic, and the Netherlands, only if surrogate decision-makers agreed on withdrawal of life-sustaining measures without CPR and imminent death was anticipated.

As reported Jan. 28 in the New England Journal of Medicine, physicians observed resumption of circulation or cardiac activity prospectively in 1% of 631 patients based on bedside ECG, arterial pressure catheter monitors, palpated arterial pulse, breaths, or physical movements.

A retrospective review of data from 480 patients with complete ECG and arterial waveforms and at least 5 minutes of continuous waveform monitoring after pulselessness showed resumption of cardiac activity in 14% of patients.

The longest period of pulselessness before the heart showed signs of activity again was 4 minutes and 20 seconds. “So that was a reassuring number, because that’s within our 5-minute window that we currently use,” Dr. Dhanani said.

Importantly, “nobody woke up, nobody ended up being resuscitated, and all of these individuals died. And I think that’s going to be very helpful in this context,” he added.

In all, there were 77 cessations and resumptions in 67 of the 480 patients. The median duration of resumed cardiac activity was 3.9 seconds but, notably, ranged from 1 second to 13 minutes and 14 seconds.

“Though surprising, I think maybe not unreasonable,” observed Dr. Dhanani. “The heart is a very robust organ, and we maybe should anticipate these things happening, where at the end of life the heart may restart for minutes.”

In this situation, it’s important to wait the 13 minutes for the heart to stop again and then “wait another 5 minutes to make sure it doesn’t restart before determining death,” he said. “I think that’s where this study is going to now inform policy makers and guidelines, especially in the context of donations.”

The findings will be taken as strong support for the 5-minute window, said Robert Truog, MD, director of the Harvard Medical School Center for Bioethics and the Frances Glessner Lee Professor of Medical Ethics, Anaesthesia, and Pediatrics, Boston.

“I think it’s a safe point, I think people will refer to it, and it will be used to support the 5-minute window, and that’s probably reasonable,” he told this news organization. “Certainly, if it’s read in Europe it will cut the time from 10 minutes to 5 minutes, and that’s a good thing because 10 minutes is a very long time to wait.”

He noted that the 5-minute window provides reasonable assurance to the public and, with new technologies, permits most organs to be usable for donation after cardiac death. That said, there’s nothing magical about the number.

“In some ways I see this paper as providing interesting data but not actually providing an answer, because from the patient’s perspective and from the recipient’s perspective, waiting until the heart has made its last squeeze may not be the most relevant ethical question,” Dr. Truog said. “It may be, once we know this patient is not going to have return of cardiorespiratory function, is not going to wake up, that’s the point at which we ought to focus on organ preservation and organ retrieval, and that can be much sooner than 5 minutes.”

Dr. Dhanani and colleagues note that the generalizability of the results might be limited because patients without arterial pressure catheters were excluded, and 24% of enrolled patients could not be included in the retrospective waveform analysis owing to incomplete data.

“Our study definition of cardiac activity used an arbitrary threshold of pulse pressure (less than 5 mm Hg) that does not imply meaningful circulation,” they add. “This conservative consensus definition may have been partially responsible for the ostensibly high incidence (14%) of transient resumptions of cardiac activity identified through waveform adjudication.”

The study was supported by the Canadian Institutes for Health Research as part of the Canadian Donation and Transplantation Research Program, CHEO Research Institute, and Karel Pavlík Foundation. Dr. Dhanani has consulted for Canadian Blood Services. Dr. Truog reports no relevant conflicts of interest.

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

Among critically ill patients pulseless after planned withdrawal of life-sustaining therapies, cardiac activity restarted in 14% of cases, research shows.

Reassuringly, most resumption of heart activity happened in the first 1-2 minutes and most lasted 1 or 2 seconds.

“The reason we wanted to look at death determination specifically is we know that the stories persist about people coming back to life following death, and that’s not just in the public, it’s in the medical community as well,” lead author Sonny Dhanani, MD, of Children’s Hospital of Eastern Ontario, Ottawa, said in an interview.

“We thought that if we provided scientific evidence of whether this happened or not, we might dispel some myths and misunderstanding, which would hopefully promote organ donation.”

About 70% of organ donations occur after brain death, but an increasing number follow circulatory determination of death, he noted. Most protocols recommend 5 minutes of apnea and pulselessness by arterial catheter monitor before declaring death. But practices vary from 10 minutes in some European countries to 75 seconds in infant heart donors at one Colorado hospital.

Reports of patients recovering 10 minutes after pulselessness have raised concerns about the Lazarus phenomenon, or autoresuscitation, but are based in patients after cardiopulmonary resuscitation was terminated.

The present study, known as Death Prediction and Physiology after Removal of Therapy (DePParRT), enrolled patients at 20 intensive care sites in Canada, the Czech Republic, and the Netherlands, only if surrogate decision-makers agreed on withdrawal of life-sustaining measures without CPR and imminent death was anticipated.

As reported Jan. 28 in the New England Journal of Medicine, physicians observed resumption of circulation or cardiac activity prospectively in 1% of 631 patients based on bedside ECG, arterial pressure catheter monitors, palpated arterial pulse, breaths, or physical movements.

A retrospective review of data from 480 patients with complete ECG and arterial waveforms and at least 5 minutes of continuous waveform monitoring after pulselessness showed resumption of cardiac activity in 14% of patients.

The longest period of pulselessness before the heart showed signs of activity again was 4 minutes and 20 seconds. “So that was a reassuring number, because that’s within our 5-minute window that we currently use,” Dr. Dhanani said.

Importantly, “nobody woke up, nobody ended up being resuscitated, and all of these individuals died. And I think that’s going to be very helpful in this context,” he added.

In all, there were 77 cessations and resumptions in 67 of the 480 patients. The median duration of resumed cardiac activity was 3.9 seconds but, notably, ranged from 1 second to 13 minutes and 14 seconds.

“Though surprising, I think maybe not unreasonable,” observed Dr. Dhanani. “The heart is a very robust organ, and we maybe should anticipate these things happening, where at the end of life the heart may restart for minutes.”

In this situation, it’s important to wait the 13 minutes for the heart to stop again and then “wait another 5 minutes to make sure it doesn’t restart before determining death,” he said. “I think that’s where this study is going to now inform policy makers and guidelines, especially in the context of donations.”

The findings will be taken as strong support for the 5-minute window, said Robert Truog, MD, director of the Harvard Medical School Center for Bioethics and the Frances Glessner Lee Professor of Medical Ethics, Anaesthesia, and Pediatrics, Boston.

“I think it’s a safe point, I think people will refer to it, and it will be used to support the 5-minute window, and that’s probably reasonable,” he told this news organization. “Certainly, if it’s read in Europe it will cut the time from 10 minutes to 5 minutes, and that’s a good thing because 10 minutes is a very long time to wait.”

He noted that the 5-minute window provides reasonable assurance to the public and, with new technologies, permits most organs to be usable for donation after cardiac death. That said, there’s nothing magical about the number.

“In some ways I see this paper as providing interesting data but not actually providing an answer, because from the patient’s perspective and from the recipient’s perspective, waiting until the heart has made its last squeeze may not be the most relevant ethical question,” Dr. Truog said. “It may be, once we know this patient is not going to have return of cardiorespiratory function, is not going to wake up, that’s the point at which we ought to focus on organ preservation and organ retrieval, and that can be much sooner than 5 minutes.”

Dr. Dhanani and colleagues note that the generalizability of the results might be limited because patients without arterial pressure catheters were excluded, and 24% of enrolled patients could not be included in the retrospective waveform analysis owing to incomplete data.

“Our study definition of cardiac activity used an arbitrary threshold of pulse pressure (less than 5 mm Hg) that does not imply meaningful circulation,” they add. “This conservative consensus definition may have been partially responsible for the ostensibly high incidence (14%) of transient resumptions of cardiac activity identified through waveform adjudication.”

The study was supported by the Canadian Institutes for Health Research as part of the Canadian Donation and Transplantation Research Program, CHEO Research Institute, and Karel Pavlík Foundation. Dr. Dhanani has consulted for Canadian Blood Services. Dr. Truog reports no relevant conflicts of interest.

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

Among critically ill patients pulseless after planned withdrawal of life-sustaining therapies, cardiac activity restarted in 14% of cases, research shows.

Reassuringly, most resumption of heart activity happened in the first 1-2 minutes and most lasted 1 or 2 seconds.

“The reason we wanted to look at death determination specifically is we know that the stories persist about people coming back to life following death, and that’s not just in the public, it’s in the medical community as well,” lead author Sonny Dhanani, MD, of Children’s Hospital of Eastern Ontario, Ottawa, said in an interview.

“We thought that if we provided scientific evidence of whether this happened or not, we might dispel some myths and misunderstanding, which would hopefully promote organ donation.”

About 70% of organ donations occur after brain death, but an increasing number follow circulatory determination of death, he noted. Most protocols recommend 5 minutes of apnea and pulselessness by arterial catheter monitor before declaring death. But practices vary from 10 minutes in some European countries to 75 seconds in infant heart donors at one Colorado hospital.

Reports of patients recovering 10 minutes after pulselessness have raised concerns about the Lazarus phenomenon, or autoresuscitation, but are based in patients after cardiopulmonary resuscitation was terminated.

The present study, known as Death Prediction and Physiology after Removal of Therapy (DePParRT), enrolled patients at 20 intensive care sites in Canada, the Czech Republic, and the Netherlands, only if surrogate decision-makers agreed on withdrawal of life-sustaining measures without CPR and imminent death was anticipated.

As reported Jan. 28 in the New England Journal of Medicine, physicians observed resumption of circulation or cardiac activity prospectively in 1% of 631 patients based on bedside ECG, arterial pressure catheter monitors, palpated arterial pulse, breaths, or physical movements.

A retrospective review of data from 480 patients with complete ECG and arterial waveforms and at least 5 minutes of continuous waveform monitoring after pulselessness showed resumption of cardiac activity in 14% of patients.

The longest period of pulselessness before the heart showed signs of activity again was 4 minutes and 20 seconds. “So that was a reassuring number, because that’s within our 5-minute window that we currently use,” Dr. Dhanani said.

Importantly, “nobody woke up, nobody ended up being resuscitated, and all of these individuals died. And I think that’s going to be very helpful in this context,” he added.

In all, there were 77 cessations and resumptions in 67 of the 480 patients. The median duration of resumed cardiac activity was 3.9 seconds but, notably, ranged from 1 second to 13 minutes and 14 seconds.

“Though surprising, I think maybe not unreasonable,” observed Dr. Dhanani. “The heart is a very robust organ, and we maybe should anticipate these things happening, where at the end of life the heart may restart for minutes.”

In this situation, it’s important to wait the 13 minutes for the heart to stop again and then “wait another 5 minutes to make sure it doesn’t restart before determining death,” he said. “I think that’s where this study is going to now inform policy makers and guidelines, especially in the context of donations.”

The findings will be taken as strong support for the 5-minute window, said Robert Truog, MD, director of the Harvard Medical School Center for Bioethics and the Frances Glessner Lee Professor of Medical Ethics, Anaesthesia, and Pediatrics, Boston.

“I think it’s a safe point, I think people will refer to it, and it will be used to support the 5-minute window, and that’s probably reasonable,” he told this news organization. “Certainly, if it’s read in Europe it will cut the time from 10 minutes to 5 minutes, and that’s a good thing because 10 minutes is a very long time to wait.”

He noted that the 5-minute window provides reasonable assurance to the public and, with new technologies, permits most organs to be usable for donation after cardiac death. That said, there’s nothing magical about the number.

“In some ways I see this paper as providing interesting data but not actually providing an answer, because from the patient’s perspective and from the recipient’s perspective, waiting until the heart has made its last squeeze may not be the most relevant ethical question,” Dr. Truog said. “It may be, once we know this patient is not going to have return of cardiorespiratory function, is not going to wake up, that’s the point at which we ought to focus on organ preservation and organ retrieval, and that can be much sooner than 5 minutes.”

Dr. Dhanani and colleagues note that the generalizability of the results might be limited because patients without arterial pressure catheters were excluded, and 24% of enrolled patients could not be included in the retrospective waveform analysis owing to incomplete data.

“Our study definition of cardiac activity used an arbitrary threshold of pulse pressure (less than 5 mm Hg) that does not imply meaningful circulation,” they add. “This conservative consensus definition may have been partially responsible for the ostensibly high incidence (14%) of transient resumptions of cardiac activity identified through waveform adjudication.”

The study was supported by the Canadian Institutes for Health Research as part of the Canadian Donation and Transplantation Research Program, CHEO Research Institute, and Karel Pavlík Foundation. Dr. Dhanani has consulted for Canadian Blood Services. Dr. Truog reports no relevant conflicts of interest.

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

A levonorgestrel 52-mg intrauterine device is noninferior to a copper IUD for emergency contraception, according to randomized trial results published online in the New England Journal of Medicine.

Although the trial didn’t directly compare emergency oral contraception to the hormonal IUD, the authors speculated, on the basis of prior findings, that the levonorgestrel IUD is more effective than oral emergency contraceptive pills. In addition, there is no delay in providing ongoing contraception as there is when ulipristal acetate is used for emergency contraception.

Prior research has found that copper IUDs are a highly effective method of emergency contraception, but studies of the use of other IUDs as emergency contraception have been lacking.

To examine whether the levonorgestrel IUD is noninferior to the copper IUD as emergency contraception after unprotected sexual intercourse during the previous 5 days, David K. Turok, MD, MPH, associate professor of obstetrics and gynecology at the University of Utah Health, Salt Lake City, and colleagues conducted a trial at six Planned Parenthood health centers in Utah.

Researchers enrolled patients between August 2016 and December 2019. Trial sites purchased levonorgestrel 52-mg IUDs (Liletta) and copper T380A IUDs (ParaGard) for the study. The companies that distribute the IUDs were not involved in the trial.

Pregnancy rates were 1 of 317 participants (0.3%) among those who received the levonorgestrel IUD, and 0 of 321 (0%) among those who received the copper IUD. The difference between the two arms was well within the prespecified noninferiority margin of 2.5%.

Adverse event rates were generally similar between the two groups, with 5.2% of participants in the levonorgestrel IUD group seeking medical care in the month after IUD placement, compared with 4.9% in the copper IUD group.
 

A welcome option

The study “benefits women by allowing us to introduce a new option into the method mix of emergency contraception,” commented Wing Kay Fok, MD, a clinical assistant professor of obstetrics and gynecology at Weill Cornell Medicine, New York.

Specialists in family planning had followed preliminary data from this study and were anticipating the final results. Clinicians who are comfortable placing a copper IUD for emergency contraception are likely to be comfortable placing a levonorgestrel 52-mg IUD, given these data, Dr. Fok said.

“This is definitely – from what we can tell – a more effective method than the pill,” she said.

Gabriela Aguilar, MD, MPH, fellow and clinical instructor in the department of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn., said she is reassured by the data and is prepared to offer the 52-mg levonorgestrel IUD as emergency contraception.

The trial is “an important clinical study that has the ability to significantly change clinical practice,” Dr. Aguilar said. She credited the University of Utah and Planned Parenthood for their roles in it.

“Anytime that there are more options, ideally, that means that access is also increased,” Dr. Aguilar said.

Many patients will still prefer oral emergency contraceptive pills, she said. “But for those who are interested in an IUD ... for the immediate and ongoing birth control after that, now they have the two options instead of just the one IUD option.”
 

One pregnancy

The trial included women aged 18-35 years who requested emergency contraception after unprotected sexual intercourse within the previous 5 days. Other inclusion criteria were that participants had a desire to initiate use of an IUD; a desire to prevent pregnancy for at least 1 year; a negative result on urine pregnancy testing; a history of regular menstrual cycles; and a known date of the last menstrual period. The investigators did not exclude individuals who had unprotected sexual intercourse more than 5 days before IUD placement.

Participants were unaware of their assigned intervention. The nurse practitioners and certified nurse midwives who performed the IUD insertions were aware of the IUD type.

The primary outcome was pregnancy, as determined by a positive result on urine pregnancy testing 1 month after IUD insertion or by a review of survey and health record data.

One pregnancy “occurred in a participant who reported a single episode of unprotected sexual intercourse 48 hours before IUD placement,” the study authors wrote. “Pregnancy dating by an ultrasound examination at 10 weeks was consistent with conception occurring as a result of an emergency contraception failure. The pregnancy ended in a spontaneous abortion at 10 weeks with the IUD still in place.”

“We hope that providers can begin to deliver this method to everyone who wants and needs it and that people considering both emergency contraception and an ongoing method of birth control know that they now have the option of a hormonal IUD in addition to the nonhormonal, copper IUD,” Dr. Turok said in a news release from Planned Parenthood.

The study used a hormonal IUD manufactured by Liletta; Mirena also manufactures a levonorgestrel 52-mg IUD. The results of the study would apply to Mirena’s product too, according to Planned Parenthood.

“There are various IUDs on the market that are at lower doses, and so those IUDs may not demonstrate similar results,” Dr. Aguilar said.

The research was supported by the National Institutes of Health and the University of Utah. Dr. Turok is the director of surgical services for Planned Parenthood Association of Utah; the trial was conducted at PPAU centers, but Dr. Turok does not work at the sites where the study was conducted. Dr. Turok has consulted for Sebela Pharmaceuticals as the principal investigator for two phase 3 studies that assessed novel IUDs. Dr. Turok and one coauthor received grant support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Fok and Dr. Aguilar disclosed no relevant financial relationships.

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

A levonorgestrel 52-mg intrauterine device is noninferior to a copper IUD for emergency contraception, according to randomized trial results published online in the New England Journal of Medicine.

Although the trial didn’t directly compare emergency oral contraception to the hormonal IUD, the authors speculated, on the basis of prior findings, that the levonorgestrel IUD is more effective than oral emergency contraceptive pills. In addition, there is no delay in providing ongoing contraception as there is when ulipristal acetate is used for emergency contraception.

Prior research has found that copper IUDs are a highly effective method of emergency contraception, but studies of the use of other IUDs as emergency contraception have been lacking.

To examine whether the levonorgestrel IUD is noninferior to the copper IUD as emergency contraception after unprotected sexual intercourse during the previous 5 days, David K. Turok, MD, MPH, associate professor of obstetrics and gynecology at the University of Utah Health, Salt Lake City, and colleagues conducted a trial at six Planned Parenthood health centers in Utah.

Researchers enrolled patients between August 2016 and December 2019. Trial sites purchased levonorgestrel 52-mg IUDs (Liletta) and copper T380A IUDs (ParaGard) for the study. The companies that distribute the IUDs were not involved in the trial.

Pregnancy rates were 1 of 317 participants (0.3%) among those who received the levonorgestrel IUD, and 0 of 321 (0%) among those who received the copper IUD. The difference between the two arms was well within the prespecified noninferiority margin of 2.5%.

Adverse event rates were generally similar between the two groups, with 5.2% of participants in the levonorgestrel IUD group seeking medical care in the month after IUD placement, compared with 4.9% in the copper IUD group.
 

A welcome option

The study “benefits women by allowing us to introduce a new option into the method mix of emergency contraception,” commented Wing Kay Fok, MD, a clinical assistant professor of obstetrics and gynecology at Weill Cornell Medicine, New York.

Specialists in family planning had followed preliminary data from this study and were anticipating the final results. Clinicians who are comfortable placing a copper IUD for emergency contraception are likely to be comfortable placing a levonorgestrel 52-mg IUD, given these data, Dr. Fok said.

“This is definitely – from what we can tell – a more effective method than the pill,” she said.

Gabriela Aguilar, MD, MPH, fellow and clinical instructor in the department of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn., said she is reassured by the data and is prepared to offer the 52-mg levonorgestrel IUD as emergency contraception.

The trial is “an important clinical study that has the ability to significantly change clinical practice,” Dr. Aguilar said. She credited the University of Utah and Planned Parenthood for their roles in it.

“Anytime that there are more options, ideally, that means that access is also increased,” Dr. Aguilar said.

Many patients will still prefer oral emergency contraceptive pills, she said. “But for those who are interested in an IUD ... for the immediate and ongoing birth control after that, now they have the two options instead of just the one IUD option.”
 

One pregnancy

The trial included women aged 18-35 years who requested emergency contraception after unprotected sexual intercourse within the previous 5 days. Other inclusion criteria were that participants had a desire to initiate use of an IUD; a desire to prevent pregnancy for at least 1 year; a negative result on urine pregnancy testing; a history of regular menstrual cycles; and a known date of the last menstrual period. The investigators did not exclude individuals who had unprotected sexual intercourse more than 5 days before IUD placement.

Participants were unaware of their assigned intervention. The nurse practitioners and certified nurse midwives who performed the IUD insertions were aware of the IUD type.

The primary outcome was pregnancy, as determined by a positive result on urine pregnancy testing 1 month after IUD insertion or by a review of survey and health record data.

One pregnancy “occurred in a participant who reported a single episode of unprotected sexual intercourse 48 hours before IUD placement,” the study authors wrote. “Pregnancy dating by an ultrasound examination at 10 weeks was consistent with conception occurring as a result of an emergency contraception failure. The pregnancy ended in a spontaneous abortion at 10 weeks with the IUD still in place.”

“We hope that providers can begin to deliver this method to everyone who wants and needs it and that people considering both emergency contraception and an ongoing method of birth control know that they now have the option of a hormonal IUD in addition to the nonhormonal, copper IUD,” Dr. Turok said in a news release from Planned Parenthood.

The study used a hormonal IUD manufactured by Liletta; Mirena also manufactures a levonorgestrel 52-mg IUD. The results of the study would apply to Mirena’s product too, according to Planned Parenthood.

“There are various IUDs on the market that are at lower doses, and so those IUDs may not demonstrate similar results,” Dr. Aguilar said.

The research was supported by the National Institutes of Health and the University of Utah. Dr. Turok is the director of surgical services for Planned Parenthood Association of Utah; the trial was conducted at PPAU centers, but Dr. Turok does not work at the sites where the study was conducted. Dr. Turok has consulted for Sebela Pharmaceuticals as the principal investigator for two phase 3 studies that assessed novel IUDs. Dr. Turok and one coauthor received grant support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Fok and Dr. Aguilar disclosed no relevant financial relationships.

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

A levonorgestrel 52-mg intrauterine device is noninferior to a copper IUD for emergency contraception, according to randomized trial results published online in the New England Journal of Medicine.

Although the trial didn’t directly compare emergency oral contraception to the hormonal IUD, the authors speculated, on the basis of prior findings, that the levonorgestrel IUD is more effective than oral emergency contraceptive pills. In addition, there is no delay in providing ongoing contraception as there is when ulipristal acetate is used for emergency contraception.

Prior research has found that copper IUDs are a highly effective method of emergency contraception, but studies of the use of other IUDs as emergency contraception have been lacking.

To examine whether the levonorgestrel IUD is noninferior to the copper IUD as emergency contraception after unprotected sexual intercourse during the previous 5 days, David K. Turok, MD, MPH, associate professor of obstetrics and gynecology at the University of Utah Health, Salt Lake City, and colleagues conducted a trial at six Planned Parenthood health centers in Utah.

Researchers enrolled patients between August 2016 and December 2019. Trial sites purchased levonorgestrel 52-mg IUDs (Liletta) and copper T380A IUDs (ParaGard) for the study. The companies that distribute the IUDs were not involved in the trial.

Pregnancy rates were 1 of 317 participants (0.3%) among those who received the levonorgestrel IUD, and 0 of 321 (0%) among those who received the copper IUD. The difference between the two arms was well within the prespecified noninferiority margin of 2.5%.

Adverse event rates were generally similar between the two groups, with 5.2% of participants in the levonorgestrel IUD group seeking medical care in the month after IUD placement, compared with 4.9% in the copper IUD group.
 

A welcome option

The study “benefits women by allowing us to introduce a new option into the method mix of emergency contraception,” commented Wing Kay Fok, MD, a clinical assistant professor of obstetrics and gynecology at Weill Cornell Medicine, New York.

Specialists in family planning had followed preliminary data from this study and were anticipating the final results. Clinicians who are comfortable placing a copper IUD for emergency contraception are likely to be comfortable placing a levonorgestrel 52-mg IUD, given these data, Dr. Fok said.

“This is definitely – from what we can tell – a more effective method than the pill,” she said.

Gabriela Aguilar, MD, MPH, fellow and clinical instructor in the department of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn., said she is reassured by the data and is prepared to offer the 52-mg levonorgestrel IUD as emergency contraception.

The trial is “an important clinical study that has the ability to significantly change clinical practice,” Dr. Aguilar said. She credited the University of Utah and Planned Parenthood for their roles in it.

“Anytime that there are more options, ideally, that means that access is also increased,” Dr. Aguilar said.

Many patients will still prefer oral emergency contraceptive pills, she said. “But for those who are interested in an IUD ... for the immediate and ongoing birth control after that, now they have the two options instead of just the one IUD option.”
 

One pregnancy

The trial included women aged 18-35 years who requested emergency contraception after unprotected sexual intercourse within the previous 5 days. Other inclusion criteria were that participants had a desire to initiate use of an IUD; a desire to prevent pregnancy for at least 1 year; a negative result on urine pregnancy testing; a history of regular menstrual cycles; and a known date of the last menstrual period. The investigators did not exclude individuals who had unprotected sexual intercourse more than 5 days before IUD placement.

Participants were unaware of their assigned intervention. The nurse practitioners and certified nurse midwives who performed the IUD insertions were aware of the IUD type.

The primary outcome was pregnancy, as determined by a positive result on urine pregnancy testing 1 month after IUD insertion or by a review of survey and health record data.

One pregnancy “occurred in a participant who reported a single episode of unprotected sexual intercourse 48 hours before IUD placement,” the study authors wrote. “Pregnancy dating by an ultrasound examination at 10 weeks was consistent with conception occurring as a result of an emergency contraception failure. The pregnancy ended in a spontaneous abortion at 10 weeks with the IUD still in place.”

“We hope that providers can begin to deliver this method to everyone who wants and needs it and that people considering both emergency contraception and an ongoing method of birth control know that they now have the option of a hormonal IUD in addition to the nonhormonal, copper IUD,” Dr. Turok said in a news release from Planned Parenthood.

The study used a hormonal IUD manufactured by Liletta; Mirena also manufactures a levonorgestrel 52-mg IUD. The results of the study would apply to Mirena’s product too, according to Planned Parenthood.

“There are various IUDs on the market that are at lower doses, and so those IUDs may not demonstrate similar results,” Dr. Aguilar said.

The research was supported by the National Institutes of Health and the University of Utah. Dr. Turok is the director of surgical services for Planned Parenthood Association of Utah; the trial was conducted at PPAU centers, but Dr. Turok does not work at the sites where the study was conducted. Dr. Turok has consulted for Sebela Pharmaceuticals as the principal investigator for two phase 3 studies that assessed novel IUDs. Dr. Turok and one coauthor received grant support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Fok and Dr. Aguilar disclosed no relevant financial relationships.

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

A psychiatrist known for her expertise in gun violence prevention is alleging that the editor of a medical journal plagiarized her work and published it under his name after she withdrew her paper from the journal.

Amy Barnhorst, MD, vice chair for community mental health at the University of California, Davis, is still waiting for the Journal of Health Service Psychology, published by Springer, to take action on what she says is blatant copying of an article she and colleague Rocco Pallin, MPH, wrote in response to an invitation from the managing editor, Gary VandenBos, PhD.

Out of frustration and sheer disbelief, Dr. Barnhorst, who is also director of the BulletPoints Project, said she took to Twitter to share her experience.

“I reached a new academic milestone last week when I read a published journal article about firearm suicide and realized it was my and my colleague’s writing! Except that the authors on the paper were these two other guys we don’t know,” Dr. Barnhorst tweeted. Barnhorst did not name the journal or its editor.

“I wasn’t mad so much as befuddled,” she said in an interview. She also wondered if other people had experienced anything similar.

The tweet thread was retweeted 7,800 times and liked by almost 40,000 people.

“I got so many messages and emails and comments from people saying, ‘This [also] happened to me,’ ” Barnhorst said.

In documents shared with this news organization, it appears that large portions of the VandenBos paper were either copied verbatim or only slightly altered from Dr. Barnhorst’s original draft.

The published paper also listed a coauthor, Michael O. Miller, a retired judge who trained as a psychologist, and who has largely written about juvenile delinquency.

Dr. Barnhorst said she became aware of the VandenBos paper when he notified her that it had been posted to the journal’s website. According to Dr. Barnhorst, he said: “Thought you two might be interested to see what we came up with.” When she viewed the article in full, she said she was speechless.

“It was really stunning,” said Dr. Barnhorst, noting that the bibliography, structure, vignette, and other elements were either similar or the same.

As soon as she saw the abstract, she said she became suspicious. Even the case vignette was extremely similar.

In the VandenBos paper, the case was Scott, a white 52-year-old divorced veteran struggling over the relatively recent death of his exwife. Dr. Barnhorst and Ms. Pallin’s vignette was about Robert, a white 55-year-old widower and veteran. In both papers, the patient had problems with alcohol.

Initially, she said, she and Ms. Pallin “were trying to rationalize it or justify it or make excuses for him because it just seemed so out there.” However, the women soon concluded that they were plagiarized.

Dr. Barnhorst said she emailed the journal’s editor-in-chief, Morgan Sammons, PhD, who is also the CEO of the National Register of Health Service Psychologists.

Initially, Dr. Sammons offered her and her colleague coauthorship on the paper, which she rejected. In a subsequent phone call, Dr. Sammons said he would investigate.
 

Publisher investigating

According to Dr. Barnhorst, Dr. Sammons later said he would retract the paper, but only after suggesting that she not go to “external parties” with her concerns. It was at that point that she emailed Springer.

“My colleague and I believe the evidence of plagiarism is plain and anticipate that you will so conclude,” she wrote in her email to the publishing company. “We are requesting that Springer take prompt remedial action in accordance with prevailing industry standards and your policy on publishing integrity.”

Dr. Barnhorst also told the company she and Ms. Pallin could not submit their original paper for publication elsewhere until Springer made a determination on the plagiarism allegation.

A Springer spokesperson told this news organization that the company is “extremely concerned” and “committed to fully investigating the concerns raised in line with COPE [Committee on Publication Ethics] guidelines, as a matter of urgency.”

On Feb. 1, Springer added an editor’s note to the paper, which has not been taken down or officially retracted. The note said: “Concerns have been raised with this article and are being investigated. Further editorial action will be taken as appropriate once the investigation into the concerns is complete and all parties have been given an opportunity to respond in full.”

The Springer spokesperson said the company was investigating and would “take further action as appropriate once our investigation is complete.”

Neither Dr. Sammons nor Dr. VandenBos responded to requests for comment.

Dr. Barnhorst has consulted her university’s general counsel but has not taken any legal action and is not currently exploring any, she said in an interview. “It’s not a tough question whether or not this was plagiarism. We just want this article pulled down and retracted.”

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

A psychiatrist known for her expertise in gun violence prevention is alleging that the editor of a medical journal plagiarized her work and published it under his name after she withdrew her paper from the journal.

Amy Barnhorst, MD, vice chair for community mental health at the University of California, Davis, is still waiting for the Journal of Health Service Psychology, published by Springer, to take action on what she says is blatant copying of an article she and colleague Rocco Pallin, MPH, wrote in response to an invitation from the managing editor, Gary VandenBos, PhD.

Out of frustration and sheer disbelief, Dr. Barnhorst, who is also director of the BulletPoints Project, said she took to Twitter to share her experience.

“I reached a new academic milestone last week when I read a published journal article about firearm suicide and realized it was my and my colleague’s writing! Except that the authors on the paper were these two other guys we don’t know,” Dr. Barnhorst tweeted. Barnhorst did not name the journal or its editor.

“I wasn’t mad so much as befuddled,” she said in an interview. She also wondered if other people had experienced anything similar.

The tweet thread was retweeted 7,800 times and liked by almost 40,000 people.

“I got so many messages and emails and comments from people saying, ‘This [also] happened to me,’ ” Barnhorst said.

In documents shared with this news organization, it appears that large portions of the VandenBos paper were either copied verbatim or only slightly altered from Dr. Barnhorst’s original draft.

The published paper also listed a coauthor, Michael O. Miller, a retired judge who trained as a psychologist, and who has largely written about juvenile delinquency.

Dr. Barnhorst said she became aware of the VandenBos paper when he notified her that it had been posted to the journal’s website. According to Dr. Barnhorst, he said: “Thought you two might be interested to see what we came up with.” When she viewed the article in full, she said she was speechless.

“It was really stunning,” said Dr. Barnhorst, noting that the bibliography, structure, vignette, and other elements were either similar or the same.

As soon as she saw the abstract, she said she became suspicious. Even the case vignette was extremely similar.

In the VandenBos paper, the case was Scott, a white 52-year-old divorced veteran struggling over the relatively recent death of his exwife. Dr. Barnhorst and Ms. Pallin’s vignette was about Robert, a white 55-year-old widower and veteran. In both papers, the patient had problems with alcohol.

Initially, she said, she and Ms. Pallin “were trying to rationalize it or justify it or make excuses for him because it just seemed so out there.” However, the women soon concluded that they were plagiarized.

Dr. Barnhorst said she emailed the journal’s editor-in-chief, Morgan Sammons, PhD, who is also the CEO of the National Register of Health Service Psychologists.

Initially, Dr. Sammons offered her and her colleague coauthorship on the paper, which she rejected. In a subsequent phone call, Dr. Sammons said he would investigate.
 

Publisher investigating

According to Dr. Barnhorst, Dr. Sammons later said he would retract the paper, but only after suggesting that she not go to “external parties” with her concerns. It was at that point that she emailed Springer.

“My colleague and I believe the evidence of plagiarism is plain and anticipate that you will so conclude,” she wrote in her email to the publishing company. “We are requesting that Springer take prompt remedial action in accordance with prevailing industry standards and your policy on publishing integrity.”

Dr. Barnhorst also told the company she and Ms. Pallin could not submit their original paper for publication elsewhere until Springer made a determination on the plagiarism allegation.

A Springer spokesperson told this news organization that the company is “extremely concerned” and “committed to fully investigating the concerns raised in line with COPE [Committee on Publication Ethics] guidelines, as a matter of urgency.”

On Feb. 1, Springer added an editor’s note to the paper, which has not been taken down or officially retracted. The note said: “Concerns have been raised with this article and are being investigated. Further editorial action will be taken as appropriate once the investigation into the concerns is complete and all parties have been given an opportunity to respond in full.”

The Springer spokesperson said the company was investigating and would “take further action as appropriate once our investigation is complete.”

Neither Dr. Sammons nor Dr. VandenBos responded to requests for comment.

Dr. Barnhorst has consulted her university’s general counsel but has not taken any legal action and is not currently exploring any, she said in an interview. “It’s not a tough question whether or not this was plagiarism. We just want this article pulled down and retracted.”

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

A psychiatrist known for her expertise in gun violence prevention is alleging that the editor of a medical journal plagiarized her work and published it under his name after she withdrew her paper from the journal.

Amy Barnhorst, MD, vice chair for community mental health at the University of California, Davis, is still waiting for the Journal of Health Service Psychology, published by Springer, to take action on what she says is blatant copying of an article she and colleague Rocco Pallin, MPH, wrote in response to an invitation from the managing editor, Gary VandenBos, PhD.

Out of frustration and sheer disbelief, Dr. Barnhorst, who is also director of the BulletPoints Project, said she took to Twitter to share her experience.

“I reached a new academic milestone last week when I read a published journal article about firearm suicide and realized it was my and my colleague’s writing! Except that the authors on the paper were these two other guys we don’t know,” Dr. Barnhorst tweeted. Barnhorst did not name the journal or its editor.

“I wasn’t mad so much as befuddled,” she said in an interview. She also wondered if other people had experienced anything similar.

The tweet thread was retweeted 7,800 times and liked by almost 40,000 people.

“I got so many messages and emails and comments from people saying, ‘This [also] happened to me,’ ” Barnhorst said.

In documents shared with this news organization, it appears that large portions of the VandenBos paper were either copied verbatim or only slightly altered from Dr. Barnhorst’s original draft.

The published paper also listed a coauthor, Michael O. Miller, a retired judge who trained as a psychologist, and who has largely written about juvenile delinquency.

Dr. Barnhorst said she became aware of the VandenBos paper when he notified her that it had been posted to the journal’s website. According to Dr. Barnhorst, he said: “Thought you two might be interested to see what we came up with.” When she viewed the article in full, she said she was speechless.

“It was really stunning,” said Dr. Barnhorst, noting that the bibliography, structure, vignette, and other elements were either similar or the same.

As soon as she saw the abstract, she said she became suspicious. Even the case vignette was extremely similar.

In the VandenBos paper, the case was Scott, a white 52-year-old divorced veteran struggling over the relatively recent death of his exwife. Dr. Barnhorst and Ms. Pallin’s vignette was about Robert, a white 55-year-old widower and veteran. In both papers, the patient had problems with alcohol.

Initially, she said, she and Ms. Pallin “were trying to rationalize it or justify it or make excuses for him because it just seemed so out there.” However, the women soon concluded that they were plagiarized.

Dr. Barnhorst said she emailed the journal’s editor-in-chief, Morgan Sammons, PhD, who is also the CEO of the National Register of Health Service Psychologists.

Initially, Dr. Sammons offered her and her colleague coauthorship on the paper, which she rejected. In a subsequent phone call, Dr. Sammons said he would investigate.
 

Publisher investigating

According to Dr. Barnhorst, Dr. Sammons later said he would retract the paper, but only after suggesting that she not go to “external parties” with her concerns. It was at that point that she emailed Springer.

“My colleague and I believe the evidence of plagiarism is plain and anticipate that you will so conclude,” she wrote in her email to the publishing company. “We are requesting that Springer take prompt remedial action in accordance with prevailing industry standards and your policy on publishing integrity.”

Dr. Barnhorst also told the company she and Ms. Pallin could not submit their original paper for publication elsewhere until Springer made a determination on the plagiarism allegation.

A Springer spokesperson told this news organization that the company is “extremely concerned” and “committed to fully investigating the concerns raised in line with COPE [Committee on Publication Ethics] guidelines, as a matter of urgency.”

On Feb. 1, Springer added an editor’s note to the paper, which has not been taken down or officially retracted. The note said: “Concerns have been raised with this article and are being investigated. Further editorial action will be taken as appropriate once the investigation into the concerns is complete and all parties have been given an opportunity to respond in full.”

The Springer spokesperson said the company was investigating and would “take further action as appropriate once our investigation is complete.”

Neither Dr. Sammons nor Dr. VandenBos responded to requests for comment.

Dr. Barnhorst has consulted her university’s general counsel but has not taken any legal action and is not currently exploring any, she said in an interview. “It’s not a tough question whether or not this was plagiarism. We just want this article pulled down and retracted.”

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

Background: Early antibiotic administration reduces mortality in patients with severe sepsis. Administering antibiotics before blood cultures could potentially decrease time to treatment and improve outcomes, but the diagnostic yield of blood cultures drawn shortly after antibiotics is unknown.

There were several study limitations including: lack of sequential recruitment, lower than expected proportion of bacteremic patients, and variation in blood culture collection. Despite this, the magnitude of the findings are convincing and support current practice.

Bottom line: Continue to obtain blood cultures before antibiotics.

Citation: Cheng MP et al. Blood culture results before and after antimicrobial administration in patients with severe manifestations of sepsis. Ann Intern Med. 2019 Oct 15;171(8):547-54.

Dr. Waner is clinical instructor of medicine, hospital medicine, at the Rocky Mountain Veterans Affairs Regional Medical Center, Aurora, Colo.

Background: Early antibiotic administration reduces mortality in patients with severe sepsis. Administering antibiotics before blood cultures could potentially decrease time to treatment and improve outcomes, but the diagnostic yield of blood cultures drawn shortly after antibiotics is unknown.

There were several study limitations including: lack of sequential recruitment, lower than expected proportion of bacteremic patients, and variation in blood culture collection. Despite this, the magnitude of the findings are convincing and support current practice.

Bottom line: Continue to obtain blood cultures before antibiotics.

Citation: Cheng MP et al. Blood culture results before and after antimicrobial administration in patients with severe manifestations of sepsis. Ann Intern Med. 2019 Oct 15;171(8):547-54.

Dr. Waner is clinical instructor of medicine, hospital medicine, at the Rocky Mountain Veterans Affairs Regional Medical Center, Aurora, Colo.

Background: Early antibiotic administration reduces mortality in patients with severe sepsis. Administering antibiotics before blood cultures could potentially decrease time to treatment and improve outcomes, but the diagnostic yield of blood cultures drawn shortly after antibiotics is unknown.

There were several study limitations including: lack of sequential recruitment, lower than expected proportion of bacteremic patients, and variation in blood culture collection. Despite this, the magnitude of the findings are convincing and support current practice.

Bottom line: Continue to obtain blood cultures before antibiotics.

Citation: Cheng MP et al. Blood culture results before and after antimicrobial administration in patients with severe manifestations of sepsis. Ann Intern Med. 2019 Oct 15;171(8):547-54.

Dr. Waner is clinical instructor of medicine, hospital medicine, at the Rocky Mountain Veterans Affairs Regional Medical Center, Aurora, Colo.

Offering a combination of colonoscopy and fecal immunochemical testing (FIT), either in sequence or by choice, may significantly increase participation in colorectal cancer (CRC) screening, according to a prospective study involving more than 12,000 individuals in Poland.

Still, greater participation did not lead to significantly higher rates of advanced disease detection, reported lead author Nastazja Dagny Pilonis, MD, of the Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, and colleagues in Gastroenterology.

According to the investigators, screening programs that offer colonoscopy and FIT are more effective than those that offer colonoscopy alone, but an optimal combination protocol has yet to be established, and some parts of the world still rely upon a single diagnostic method.

“In Europe, CRC screening programs often implement only one screening modality: colonoscopy, sigmoidoscopy, or stool testing, depending on the health care provider,” the investigators wrote in Gastroenterology. They noted, however, that national guidelines in the United States recommend strategies that include more than one screening method. “‘One-size-fits-all’ approaches to CRC screening do not result in satisfactory participation” because of behavioral, cultural, and socioeconomic variation among individuals.

To improve understanding of the best ways to improve participation, the investigators conducted a prospective randomized trial, PICCOLINO, via the Polish Colonoscopy Screening Program. In total, 12,485 eligible individuals aged between 55 and 64 years received postal invitations to participate in CRC screening. Individuals were randomized in a 1:1:1 ratio into one of three mailing protocols, each of which involved an initial invitation, and, if needed, a second invitation that offered the following:

• Control group: colonoscopy, with nonresponders receiving the same invitation again
• Sequential group: colonoscopy, with nonresponders or refusers receiving a second invitation that offered FIT
• Choice group: choice between colonoscopy or FIT, with nonresponders receiving the same invitation again

The primary outcome was participation in screening within 18 weeks of enrollment. The secondary outcome was diagnostic yield for either advanced adenoma or CRC.

Out of the three groups, the control group had the lowest participation rate, at 17.5%, compared with 25.8% for the sequential group and 26.5% for the choice group. Multivariable logistic regression showed that individuals in the sequential and choice groups had 64% and 70% higher rates of participation, respectively. Across all groups, age of 60 years or older predicted 12% higher likelihood of participation; in contrast, location more than 40 kilometers from a testing center was associated with an 18% decrease in participation, compared with individuals who lived less than 20 kilometers away.

While the control and sequential groups had similar rates of colonoscopy participation, at 17.5% and 15.9%, respectively (P = .788), this rate was significantly lower, at 8.5%, in the choice group (P = .001). Conversely, the sequential group had a significantly lower rate of FITs than the choice group, at 9.9% versus 17.9%, respectively (P = .001). Among participants with a positive FIT, diagnostic work-up colonoscopies were performed in 70.0% of those in the sequential group and 73.3% in the choice group, “despite active call-recall efforts.”

Across all invited individuals, advanced disease detection rates were similar across groups, at 1.1% for both the control and the sequential group and 1.2% for the choice group. Among those who were actually screened, the control group had a slightly higher diagnostic yield for advanced neoplasia, at 6.5%, compared with 4.2% in the sequential group and 4.4% in the choice group; however, these differences were not statistically significant. In contrast, significantly more adenomas of any kind were detected in the control and sequential groups (5.6% for both) than the choice group (3.9%) (P < .001).

“Although the strategies which included FIT showed higher participation rates than the strategy of offering colonoscopy alone, these strategies did not result in increased detection rates of advanced neoplasia in the intention to screen analysis,” the investigators wrote. “An absolute increase in participation rates of 8%-10% seems insufficient to translate into higher advanced neoplasia detection at the population level.”

Dr. Pilonis and colleagues also suggested that the relatively low rate of diagnostic colonoscopy after positive FIT contributed to the suboptimal diagnostic yield.

“These rates are unsatisfactory taking into account significant call-recall efforts, but are within the range reported in other studies,” they wrote.

They also wrote that their study compared participation and detection between one-time colonoscopy and one-time screening strategies combining colonoscopy and FIT. In acknowledging this, they noted that these approaches have different screening intervals and uptake over time: “FIT has been shown to achieve higher participation rates than colonoscopy for one time screening, but its uptake over several rounds may not be superior to one time colonoscopy.” Furthermore, detection rates of the sequential or choice strategies for advanced disease may rise over time with further implementation, so the one-time screening may not be sufficient to reveal what could become significant differences.

The study was funded by the Polish Ministry of Health, the Polish Foundation of Gastroenterology, and the Centre of Postgraduate Medical Education in Warsaw. FITs, materials, and reagents were provided by Eiken Chemical. The investigators disclosed relationships with Boston Scientific, AbbVie, Olympus, and others.

Offering a combination of colonoscopy and fecal immunochemical testing (FIT), either in sequence or by choice, may significantly increase participation in colorectal cancer (CRC) screening, according to a prospective study involving more than 12,000 individuals in Poland.

Still, greater participation did not lead to significantly higher rates of advanced disease detection, reported lead author Nastazja Dagny Pilonis, MD, of the Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, and colleagues in Gastroenterology.

According to the investigators, screening programs that offer colonoscopy and FIT are more effective than those that offer colonoscopy alone, but an optimal combination protocol has yet to be established, and some parts of the world still rely upon a single diagnostic method.

“In Europe, CRC screening programs often implement only one screening modality: colonoscopy, sigmoidoscopy, or stool testing, depending on the health care provider,” the investigators wrote in Gastroenterology. They noted, however, that national guidelines in the United States recommend strategies that include more than one screening method. “‘One-size-fits-all’ approaches to CRC screening do not result in satisfactory participation” because of behavioral, cultural, and socioeconomic variation among individuals.

To improve understanding of the best ways to improve participation, the investigators conducted a prospective randomized trial, PICCOLINO, via the Polish Colonoscopy Screening Program. In total, 12,485 eligible individuals aged between 55 and 64 years received postal invitations to participate in CRC screening. Individuals were randomized in a 1:1:1 ratio into one of three mailing protocols, each of which involved an initial invitation, and, if needed, a second invitation that offered the following:

• Control group: colonoscopy, with nonresponders receiving the same invitation again
• Sequential group: colonoscopy, with nonresponders or refusers receiving a second invitation that offered FIT
• Choice group: choice between colonoscopy or FIT, with nonresponders receiving the same invitation again

The primary outcome was participation in screening within 18 weeks of enrollment. The secondary outcome was diagnostic yield for either advanced adenoma or CRC.

Out of the three groups, the control group had the lowest participation rate, at 17.5%, compared with 25.8% for the sequential group and 26.5% for the choice group. Multivariable logistic regression showed that individuals in the sequential and choice groups had 64% and 70% higher rates of participation, respectively. Across all groups, age of 60 years or older predicted 12% higher likelihood of participation; in contrast, location more than 40 kilometers from a testing center was associated with an 18% decrease in participation, compared with individuals who lived less than 20 kilometers away.

While the control and sequential groups had similar rates of colonoscopy participation, at 17.5% and 15.9%, respectively (P = .788), this rate was significantly lower, at 8.5%, in the choice group (P = .001). Conversely, the sequential group had a significantly lower rate of FITs than the choice group, at 9.9% versus 17.9%, respectively (P = .001). Among participants with a positive FIT, diagnostic work-up colonoscopies were performed in 70.0% of those in the sequential group and 73.3% in the choice group, “despite active call-recall efforts.”

Across all invited individuals, advanced disease detection rates were similar across groups, at 1.1% for both the control and the sequential group and 1.2% for the choice group. Among those who were actually screened, the control group had a slightly higher diagnostic yield for advanced neoplasia, at 6.5%, compared with 4.2% in the sequential group and 4.4% in the choice group; however, these differences were not statistically significant. In contrast, significantly more adenomas of any kind were detected in the control and sequential groups (5.6% for both) than the choice group (3.9%) (P < .001).

“Although the strategies which included FIT showed higher participation rates than the strategy of offering colonoscopy alone, these strategies did not result in increased detection rates of advanced neoplasia in the intention to screen analysis,” the investigators wrote. “An absolute increase in participation rates of 8%-10% seems insufficient to translate into higher advanced neoplasia detection at the population level.”

Dr. Pilonis and colleagues also suggested that the relatively low rate of diagnostic colonoscopy after positive FIT contributed to the suboptimal diagnostic yield.

“These rates are unsatisfactory taking into account significant call-recall efforts, but are within the range reported in other studies,” they wrote.

They also wrote that their study compared participation and detection between one-time colonoscopy and one-time screening strategies combining colonoscopy and FIT. In acknowledging this, they noted that these approaches have different screening intervals and uptake over time: “FIT has been shown to achieve higher participation rates than colonoscopy for one time screening, but its uptake over several rounds may not be superior to one time colonoscopy.” Furthermore, detection rates of the sequential or choice strategies for advanced disease may rise over time with further implementation, so the one-time screening may not be sufficient to reveal what could become significant differences.

The study was funded by the Polish Ministry of Health, the Polish Foundation of Gastroenterology, and the Centre of Postgraduate Medical Education in Warsaw. FITs, materials, and reagents were provided by Eiken Chemical. The investigators disclosed relationships with Boston Scientific, AbbVie, Olympus, and others.

Offering a combination of colonoscopy and fecal immunochemical testing (FIT), either in sequence or by choice, may significantly increase participation in colorectal cancer (CRC) screening, according to a prospective study involving more than 12,000 individuals in Poland.

Still, greater participation did not lead to significantly higher rates of advanced disease detection, reported lead author Nastazja Dagny Pilonis, MD, of the Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, and colleagues in Gastroenterology.

According to the investigators, screening programs that offer colonoscopy and FIT are more effective than those that offer colonoscopy alone, but an optimal combination protocol has yet to be established, and some parts of the world still rely upon a single diagnostic method.

“In Europe, CRC screening programs often implement only one screening modality: colonoscopy, sigmoidoscopy, or stool testing, depending on the health care provider,” the investigators wrote in Gastroenterology. They noted, however, that national guidelines in the United States recommend strategies that include more than one screening method. “‘One-size-fits-all’ approaches to CRC screening do not result in satisfactory participation” because of behavioral, cultural, and socioeconomic variation among individuals.

To improve understanding of the best ways to improve participation, the investigators conducted a prospective randomized trial, PICCOLINO, via the Polish Colonoscopy Screening Program. In total, 12,485 eligible individuals aged between 55 and 64 years received postal invitations to participate in CRC screening. Individuals were randomized in a 1:1:1 ratio into one of three mailing protocols, each of which involved an initial invitation, and, if needed, a second invitation that offered the following:

• Control group: colonoscopy, with nonresponders receiving the same invitation again
• Sequential group: colonoscopy, with nonresponders or refusers receiving a second invitation that offered FIT
• Choice group: choice between colonoscopy or FIT, with nonresponders receiving the same invitation again

The primary outcome was participation in screening within 18 weeks of enrollment. The secondary outcome was diagnostic yield for either advanced adenoma or CRC.

Out of the three groups, the control group had the lowest participation rate, at 17.5%, compared with 25.8% for the sequential group and 26.5% for the choice group. Multivariable logistic regression showed that individuals in the sequential and choice groups had 64% and 70% higher rates of participation, respectively. Across all groups, age of 60 years or older predicted 12% higher likelihood of participation; in contrast, location more than 40 kilometers from a testing center was associated with an 18% decrease in participation, compared with individuals who lived less than 20 kilometers away.

While the control and sequential groups had similar rates of colonoscopy participation, at 17.5% and 15.9%, respectively (P = .788), this rate was significantly lower, at 8.5%, in the choice group (P = .001). Conversely, the sequential group had a significantly lower rate of FITs than the choice group, at 9.9% versus 17.9%, respectively (P = .001). Among participants with a positive FIT, diagnostic work-up colonoscopies were performed in 70.0% of those in the sequential group and 73.3% in the choice group, “despite active call-recall efforts.”

Across all invited individuals, advanced disease detection rates were similar across groups, at 1.1% for both the control and the sequential group and 1.2% for the choice group. Among those who were actually screened, the control group had a slightly higher diagnostic yield for advanced neoplasia, at 6.5%, compared with 4.2% in the sequential group and 4.4% in the choice group; however, these differences were not statistically significant. In contrast, significantly more adenomas of any kind were detected in the control and sequential groups (5.6% for both) than the choice group (3.9%) (P < .001).

“Although the strategies which included FIT showed higher participation rates than the strategy of offering colonoscopy alone, these strategies did not result in increased detection rates of advanced neoplasia in the intention to screen analysis,” the investigators wrote. “An absolute increase in participation rates of 8%-10% seems insufficient to translate into higher advanced neoplasia detection at the population level.”

Dr. Pilonis and colleagues also suggested that the relatively low rate of diagnostic colonoscopy after positive FIT contributed to the suboptimal diagnostic yield.

“These rates are unsatisfactory taking into account significant call-recall efforts, but are within the range reported in other studies,” they wrote.

They also wrote that their study compared participation and detection between one-time colonoscopy and one-time screening strategies combining colonoscopy and FIT. In acknowledging this, they noted that these approaches have different screening intervals and uptake over time: “FIT has been shown to achieve higher participation rates than colonoscopy for one time screening, but its uptake over several rounds may not be superior to one time colonoscopy.” Furthermore, detection rates of the sequential or choice strategies for advanced disease may rise over time with further implementation, so the one-time screening may not be sufficient to reveal what could become significant differences.

The study was funded by the Polish Ministry of Health, the Polish Foundation of Gastroenterology, and the Centre of Postgraduate Medical Education in Warsaw. FITs, materials, and reagents were provided by Eiken Chemical. The investigators disclosed relationships with Boston Scientific, AbbVie, Olympus, and others.

People with rheumatic and musculoskeletal diseases (RMDs) who contract the SARS-CoV-2 virus appear more likely to die from COVID-19 if their rheumatologic condition is not being well controlled at the time of their infection.

New data from the COVID-19 Global Rheumatology Alliance (GRA) physician registry reported in Annals of the Rheumatic Diseases have found that the odds of dying from COVID-19 were 87% higher in individuals recorded as having moderate to high disease activity versus those reported to be in remission or having low disease activity.

“I think this really highlights the importance of continuing to appropriately, and actively, treat our patients, and the importance of controlling their disease,” Pedro Machado, MD, PhD, said in an interview. Dr. Machado, an associate professor in rheumatology and muscle diseases at University College London and a consultant rheumatologist at several U.K. hospitals, has been involved in the GRA physician registry from the start, and sits on the GRA steering committee.

Alongside higher disease activity, several other important factors were found to be associated with increased odds of dying from COVID-19 – older age, male gender, and the presence of one or more comorbidities, such as hypertension combined with cardiovascular disease or chronic lung disease.

These demographic and disease-based factors have been linked to an increased risk for COVID-19–related hospitalization before, both in people with RMDs and in the general population, but the latest GRA physician registry data now take that a step further, and link them also to an increased risk for death, together with several other factors more specific to RMDs.
 

Logging COVID-19 rheumatologic cases

Since the start of the global pandemic, the potential effects that SARS-CoV-2 infection might have on people with RMDs in particular has concerned the rheumatology community. The main worries being that, either because of the underlying RMD itself or to its treatment, there may be immunoregulatory deficits or other risk factors that would make individuals more susceptible to not only infection but also to developing more severe COVID-19 than the general population.

These concerns led to the rapid formation of the GRA and the COVID-19 GRA physician registry in March 2020 to collect and analyze data on adults with rheumatic disease and confirmed or presumptive COVID-19. Entries into the registry are made by or under the direction of rheumatologists, and this is a voluntary process.

“This population cannot ever be entirely representative of the population of patients with rheumatic diseases,” Dr. Machado acknowledged. There will be selection and other biases that affect the reported data. That said, it’s the largest database of reported COVID-19 cases in adult rheumatology patients across the world, with more than 9,000 cases so far included from multiple registries, including those based in Europe and North and South America. Data from one of these – the French RMD cohort – have also recently been published in Annals of the Rheumatic Diseases, showing much the same findings but on a national level.

Hospitalization was the focus of a previous report because “you need large sample sizes” to look at endpoints that occur less frequently. When the first analysis was done, there were around 600 cases from 40 countries in the registry with sufficient data that could be used. Now, with a greater number of recorded cases, factors influencing the risk for death could be examined.

Death rate and risk factors found

Data on 3,729 COVID-19 cases in people with RMDs were included in the current analysis, all recorded in the first few months of the registry being open and up until July 1, 2020. In all, 390 (10.5%) of people died. While this is “clearly higher” than reported in the general population in most countries, the analysis was not designed to calculate a precise estimate.

“It should not be taken as an estimate of the overall death rate among patients with rheumatic diseases and COVID-19,” Dr. Machado and coauthors have been keen to point out.

“Age is always the biggest risk factor,” Dr. Machado explained. “There’s always a gradient: the older the patient, the worse the outcome.”

Indeed, there was a threefold increased risk for death among those aged 66-75 years versus those who were 65 years or younger (odds ratio, 3.00), and a sixfold increased risk for patients older than 75, compared with the younger age group (OR, 6.18).

Having both hypertension and cardiovascular disease was associated with an OR of 1.89, and coexisting chronic lung disease also significantly increased the chances of dying from COVID-19 (OR, 1.68).

Being of male sex was associated with a 46% increased risk for death from COVID-19 versus being of female sex.

The risk for COVID-19 death also rose with the use of corticosteroids. Compared with no steroid use, there was a 69% increased risk for with death at doses of 10 mg or more prednisolone equivalent per day.

“The finding about moderate to high doses of steroids being associated with a worse outcome is consistent with the first report; it was the same for hospitalization,” Dr. Machado observed.

The general consensus on steroid use in the COVID-19 setting is that they should be continued as needed, but at the lowest possible dose, as outlined in provisional recommendations set out by the recently renamed European Alliance of Associations for Rheumatology.

The GRA physician registry findings provide further support for this, suggesting that disease control should be optimized with disease-modifying antirheumatic drugs, ideally without increasing the dose of steroids.

Surprise over sulfasalazine risk

“Taking all medications into account – such as methotrexate, leflunomide, hydroxychloroquine, [tumor necrosis factor] blockers, interleukin-6 blockers, and [Janus kinase] inhibitors – it is quite reassuring because we did not see an association with worse outcome with those drugs overall,” Dr. Machado said.

However, treatment with rituximab (OR, 4.0), sulfasalazine (OR, 3.6), and immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, mycophenolate, or tacrolimus (OR, 2.2), were associated with higher odds of dying from COVID-19 when compared with treatment with methotrexate alone.

The findings for rituximab and immunosuppressant use were perhaps not unexpected, but the possible association between sulfasalazine and COVID-19 death was “a bit intriguing,” Dr. Machado observed. “Sulfasalazine is believed to have low immunosuppressive effect.”

This warrants further investigation, but there are likely a range of confounding factors at play. One could be that people considered to be at higher risk may have been more often prescribed sulfasalazine because it was thought to be less immunosuppressive. Another might be because people taking sulfasalazine were more likely to be smokers, and they were also not advised to protect themselves from exposure to the virus (shielding) during the first wave of the pandemic, at least not in the United Kingdom.
 

Rituximab caution and vaccination

“Rituximab is a concern,” Dr. Machado acknowledged. “It is a concern that rheumatologists are now aware of and they are addressing, but then it’s a concern for a very specific subgroup of patients.”

While rheumatologists are, and will continue to prescribe it, there will be even more careful consideration over when, in whom, and how to use it during, and possibly even after, the pandemic.

“COVID is here to stay, it will become endemic, and it’s going to be part of our lives like the flu virus is,” Dr. Machado predicted.

Then there is the issue on vaccinating people against COVID-19, should those on rituximab still receive it? The answer is a yes, but, as with other vaccinations it’s all about the timing of when the vaccination is given.

Societies such as the British Society for Rheumatology have already begun to include guidance on this, recommending one of the available COVID-19 vaccines is given at least a month before the next or first dose of rituximab is due. As rituximab is given every few months, with doses sometimes spaced as much as 9 months or even a year apart, this should not be too much of a problem, but it is “better to have the vaccine first,” Dr. Machado said.
 

Has COVID-19 care improved in RMDs?

In separate research published in The Lancet Rheumatology, April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and associates found that the risks of severe COVID-19 outcomes have improved over time, although they still “remain substantial.”

Dr. Jorge and colleagues looked at temporal trends in COVID-19 outcomes in patients with RMDs over the course of the first 6 months of the pandemic in 2020, using data from a large, multicenter, electronic health record network (TriNetX).

They formed two patient cohorts – a late (diagnosed from April 20 to July 20) and an early (diagnosed from January 20 to April 20) cohort – to see if outcomes had improved and discovered lower relative risks among patients in the late cohort for hospitalization (0.67), admission to the ICU (0.56), mechanical ventilation (0.39), acute kidney injury (0.66), renal replacement (0.53), and death (0.39).

“These results are encouraging,” but it’s difficult to match these different populations of patients, Dr. Machado said. “There are always factors that you cannot match for” and were not included in the U.S. analysis.

While there are important caveats in how the analysis was performed and thus in interpreting these data, they do “suggest that one of the reasons why outcomes have improved is because we have become better at treating these patients,” Dr. Machado added.

“Our treatment has improved, and our capacity to treat the complications has improved. We understand better how the disease behaves – we know that they can have thromboembolic complications that we can manage, and we are now able to manage ventilation issues better.”

Moreover, Dr. Machado said that, not only were clinicians more aware of what they should or should not do, there were treatments that were being used routinely or in some cases based on recent clinical trial results. “I think we are indeed treating these patients better.”

The COVID-19 GRA physician registry is financially supported by the American College of Rheumatology and EULAR. Dr. Machado had no relevant conflicts of interest.

People with rheumatic and musculoskeletal diseases (RMDs) who contract the SARS-CoV-2 virus appear more likely to die from COVID-19 if their rheumatologic condition is not being well controlled at the time of their infection.

New data from the COVID-19 Global Rheumatology Alliance (GRA) physician registry reported in Annals of the Rheumatic Diseases have found that the odds of dying from COVID-19 were 87% higher in individuals recorded as having moderate to high disease activity versus those reported to be in remission or having low disease activity.

“I think this really highlights the importance of continuing to appropriately, and actively, treat our patients, and the importance of controlling their disease,” Pedro Machado, MD, PhD, said in an interview. Dr. Machado, an associate professor in rheumatology and muscle diseases at University College London and a consultant rheumatologist at several U.K. hospitals, has been involved in the GRA physician registry from the start, and sits on the GRA steering committee.

Alongside higher disease activity, several other important factors were found to be associated with increased odds of dying from COVID-19 – older age, male gender, and the presence of one or more comorbidities, such as hypertension combined with cardiovascular disease or chronic lung disease.

These demographic and disease-based factors have been linked to an increased risk for COVID-19–related hospitalization before, both in people with RMDs and in the general population, but the latest GRA physician registry data now take that a step further, and link them also to an increased risk for death, together with several other factors more specific to RMDs.
 

Logging COVID-19 rheumatologic cases

Since the start of the global pandemic, the potential effects that SARS-CoV-2 infection might have on people with RMDs in particular has concerned the rheumatology community. The main worries being that, either because of the underlying RMD itself or to its treatment, there may be immunoregulatory deficits or other risk factors that would make individuals more susceptible to not only infection but also to developing more severe COVID-19 than the general population.

These concerns led to the rapid formation of the GRA and the COVID-19 GRA physician registry in March 2020 to collect and analyze data on adults with rheumatic disease and confirmed or presumptive COVID-19. Entries into the registry are made by or under the direction of rheumatologists, and this is a voluntary process.

“This population cannot ever be entirely representative of the population of patients with rheumatic diseases,” Dr. Machado acknowledged. There will be selection and other biases that affect the reported data. That said, it’s the largest database of reported COVID-19 cases in adult rheumatology patients across the world, with more than 9,000 cases so far included from multiple registries, including those based in Europe and North and South America. Data from one of these – the French RMD cohort – have also recently been published in Annals of the Rheumatic Diseases, showing much the same findings but on a national level.

Hospitalization was the focus of a previous report because “you need large sample sizes” to look at endpoints that occur less frequently. When the first analysis was done, there were around 600 cases from 40 countries in the registry with sufficient data that could be used. Now, with a greater number of recorded cases, factors influencing the risk for death could be examined.

Death rate and risk factors found

Data on 3,729 COVID-19 cases in people with RMDs were included in the current analysis, all recorded in the first few months of the registry being open and up until July 1, 2020. In all, 390 (10.5%) of people died. While this is “clearly higher” than reported in the general population in most countries, the analysis was not designed to calculate a precise estimate.

“It should not be taken as an estimate of the overall death rate among patients with rheumatic diseases and COVID-19,” Dr. Machado and coauthors have been keen to point out.

“Age is always the biggest risk factor,” Dr. Machado explained. “There’s always a gradient: the older the patient, the worse the outcome.”

Indeed, there was a threefold increased risk for death among those aged 66-75 years versus those who were 65 years or younger (odds ratio, 3.00), and a sixfold increased risk for patients older than 75, compared with the younger age group (OR, 6.18).

Having both hypertension and cardiovascular disease was associated with an OR of 1.89, and coexisting chronic lung disease also significantly increased the chances of dying from COVID-19 (OR, 1.68).

Being of male sex was associated with a 46% increased risk for death from COVID-19 versus being of female sex.

The risk for COVID-19 death also rose with the use of corticosteroids. Compared with no steroid use, there was a 69% increased risk for with death at doses of 10 mg or more prednisolone equivalent per day.

“The finding about moderate to high doses of steroids being associated with a worse outcome is consistent with the first report; it was the same for hospitalization,” Dr. Machado observed.

The general consensus on steroid use in the COVID-19 setting is that they should be continued as needed, but at the lowest possible dose, as outlined in provisional recommendations set out by the recently renamed European Alliance of Associations for Rheumatology.

The GRA physician registry findings provide further support for this, suggesting that disease control should be optimized with disease-modifying antirheumatic drugs, ideally without increasing the dose of steroids.

Surprise over sulfasalazine risk

“Taking all medications into account – such as methotrexate, leflunomide, hydroxychloroquine, [tumor necrosis factor] blockers, interleukin-6 blockers, and [Janus kinase] inhibitors – it is quite reassuring because we did not see an association with worse outcome with those drugs overall,” Dr. Machado said.

However, treatment with rituximab (OR, 4.0), sulfasalazine (OR, 3.6), and immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, mycophenolate, or tacrolimus (OR, 2.2), were associated with higher odds of dying from COVID-19 when compared with treatment with methotrexate alone.

The findings for rituximab and immunosuppressant use were perhaps not unexpected, but the possible association between sulfasalazine and COVID-19 death was “a bit intriguing,” Dr. Machado observed. “Sulfasalazine is believed to have low immunosuppressive effect.”

This warrants further investigation, but there are likely a range of confounding factors at play. One could be that people considered to be at higher risk may have been more often prescribed sulfasalazine because it was thought to be less immunosuppressive. Another might be because people taking sulfasalazine were more likely to be smokers, and they were also not advised to protect themselves from exposure to the virus (shielding) during the first wave of the pandemic, at least not in the United Kingdom.
 

Rituximab caution and vaccination

“Rituximab is a concern,” Dr. Machado acknowledged. “It is a concern that rheumatologists are now aware of and they are addressing, but then it’s a concern for a very specific subgroup of patients.”

While rheumatologists are, and will continue to prescribe it, there will be even more careful consideration over when, in whom, and how to use it during, and possibly even after, the pandemic.

“COVID is here to stay, it will become endemic, and it’s going to be part of our lives like the flu virus is,” Dr. Machado predicted.

Then there is the issue on vaccinating people against COVID-19, should those on rituximab still receive it? The answer is a yes, but, as with other vaccinations it’s all about the timing of when the vaccination is given.

Societies such as the British Society for Rheumatology have already begun to include guidance on this, recommending one of the available COVID-19 vaccines is given at least a month before the next or first dose of rituximab is due. As rituximab is given every few months, with doses sometimes spaced as much as 9 months or even a year apart, this should not be too much of a problem, but it is “better to have the vaccine first,” Dr. Machado said.
 

Has COVID-19 care improved in RMDs?

In separate research published in The Lancet Rheumatology, April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and associates found that the risks of severe COVID-19 outcomes have improved over time, although they still “remain substantial.”

Dr. Jorge and colleagues looked at temporal trends in COVID-19 outcomes in patients with RMDs over the course of the first 6 months of the pandemic in 2020, using data from a large, multicenter, electronic health record network (TriNetX).

They formed two patient cohorts – a late (diagnosed from April 20 to July 20) and an early (diagnosed from January 20 to April 20) cohort – to see if outcomes had improved and discovered lower relative risks among patients in the late cohort for hospitalization (0.67), admission to the ICU (0.56), mechanical ventilation (0.39), acute kidney injury (0.66), renal replacement (0.53), and death (0.39).

“These results are encouraging,” but it’s difficult to match these different populations of patients, Dr. Machado said. “There are always factors that you cannot match for” and were not included in the U.S. analysis.

While there are important caveats in how the analysis was performed and thus in interpreting these data, they do “suggest that one of the reasons why outcomes have improved is because we have become better at treating these patients,” Dr. Machado added.

“Our treatment has improved, and our capacity to treat the complications has improved. We understand better how the disease behaves – we know that they can have thromboembolic complications that we can manage, and we are now able to manage ventilation issues better.”

Moreover, Dr. Machado said that, not only were clinicians more aware of what they should or should not do, there were treatments that were being used routinely or in some cases based on recent clinical trial results. “I think we are indeed treating these patients better.”

The COVID-19 GRA physician registry is financially supported by the American College of Rheumatology and EULAR. Dr. Machado had no relevant conflicts of interest.

People with rheumatic and musculoskeletal diseases (RMDs) who contract the SARS-CoV-2 virus appear more likely to die from COVID-19 if their rheumatologic condition is not being well controlled at the time of their infection.

New data from the COVID-19 Global Rheumatology Alliance (GRA) physician registry reported in Annals of the Rheumatic Diseases have found that the odds of dying from COVID-19 were 87% higher in individuals recorded as having moderate to high disease activity versus those reported to be in remission or having low disease activity.

“I think this really highlights the importance of continuing to appropriately, and actively, treat our patients, and the importance of controlling their disease,” Pedro Machado, MD, PhD, said in an interview. Dr. Machado, an associate professor in rheumatology and muscle diseases at University College London and a consultant rheumatologist at several U.K. hospitals, has been involved in the GRA physician registry from the start, and sits on the GRA steering committee.

Alongside higher disease activity, several other important factors were found to be associated with increased odds of dying from COVID-19 – older age, male gender, and the presence of one or more comorbidities, such as hypertension combined with cardiovascular disease or chronic lung disease.

These demographic and disease-based factors have been linked to an increased risk for COVID-19–related hospitalization before, both in people with RMDs and in the general population, but the latest GRA physician registry data now take that a step further, and link them also to an increased risk for death, together with several other factors more specific to RMDs.
 

Logging COVID-19 rheumatologic cases

Since the start of the global pandemic, the potential effects that SARS-CoV-2 infection might have on people with RMDs in particular has concerned the rheumatology community. The main worries being that, either because of the underlying RMD itself or to its treatment, there may be immunoregulatory deficits or other risk factors that would make individuals more susceptible to not only infection but also to developing more severe COVID-19 than the general population.

These concerns led to the rapid formation of the GRA and the COVID-19 GRA physician registry in March 2020 to collect and analyze data on adults with rheumatic disease and confirmed or presumptive COVID-19. Entries into the registry are made by or under the direction of rheumatologists, and this is a voluntary process.

“This population cannot ever be entirely representative of the population of patients with rheumatic diseases,” Dr. Machado acknowledged. There will be selection and other biases that affect the reported data. That said, it’s the largest database of reported COVID-19 cases in adult rheumatology patients across the world, with more than 9,000 cases so far included from multiple registries, including those based in Europe and North and South America. Data from one of these – the French RMD cohort – have also recently been published in Annals of the Rheumatic Diseases, showing much the same findings but on a national level.

Hospitalization was the focus of a previous report because “you need large sample sizes” to look at endpoints that occur less frequently. When the first analysis was done, there were around 600 cases from 40 countries in the registry with sufficient data that could be used. Now, with a greater number of recorded cases, factors influencing the risk for death could be examined.

Death rate and risk factors found

Data on 3,729 COVID-19 cases in people with RMDs were included in the current analysis, all recorded in the first few months of the registry being open and up until July 1, 2020. In all, 390 (10.5%) of people died. While this is “clearly higher” than reported in the general population in most countries, the analysis was not designed to calculate a precise estimate.

“It should not be taken as an estimate of the overall death rate among patients with rheumatic diseases and COVID-19,” Dr. Machado and coauthors have been keen to point out.

“Age is always the biggest risk factor,” Dr. Machado explained. “There’s always a gradient: the older the patient, the worse the outcome.”

Indeed, there was a threefold increased risk for death among those aged 66-75 years versus those who were 65 years or younger (odds ratio, 3.00), and a sixfold increased risk for patients older than 75, compared with the younger age group (OR, 6.18).

Having both hypertension and cardiovascular disease was associated with an OR of 1.89, and coexisting chronic lung disease also significantly increased the chances of dying from COVID-19 (OR, 1.68).

Being of male sex was associated with a 46% increased risk for death from COVID-19 versus being of female sex.

The risk for COVID-19 death also rose with the use of corticosteroids. Compared with no steroid use, there was a 69% increased risk for with death at doses of 10 mg or more prednisolone equivalent per day.

“The finding about moderate to high doses of steroids being associated with a worse outcome is consistent with the first report; it was the same for hospitalization,” Dr. Machado observed.

The general consensus on steroid use in the COVID-19 setting is that they should be continued as needed, but at the lowest possible dose, as outlined in provisional recommendations set out by the recently renamed European Alliance of Associations for Rheumatology.

The GRA physician registry findings provide further support for this, suggesting that disease control should be optimized with disease-modifying antirheumatic drugs, ideally without increasing the dose of steroids.

Surprise over sulfasalazine risk

“Taking all medications into account – such as methotrexate, leflunomide, hydroxychloroquine, [tumor necrosis factor] blockers, interleukin-6 blockers, and [Janus kinase] inhibitors – it is quite reassuring because we did not see an association with worse outcome with those drugs overall,” Dr. Machado said.

However, treatment with rituximab (OR, 4.0), sulfasalazine (OR, 3.6), and immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, mycophenolate, or tacrolimus (OR, 2.2), were associated with higher odds of dying from COVID-19 when compared with treatment with methotrexate alone.

The findings for rituximab and immunosuppressant use were perhaps not unexpected, but the possible association between sulfasalazine and COVID-19 death was “a bit intriguing,” Dr. Machado observed. “Sulfasalazine is believed to have low immunosuppressive effect.”

This warrants further investigation, but there are likely a range of confounding factors at play. One could be that people considered to be at higher risk may have been more often prescribed sulfasalazine because it was thought to be less immunosuppressive. Another might be because people taking sulfasalazine were more likely to be smokers, and they were also not advised to protect themselves from exposure to the virus (shielding) during the first wave of the pandemic, at least not in the United Kingdom.
 

Rituximab caution and vaccination

“Rituximab is a concern,” Dr. Machado acknowledged. “It is a concern that rheumatologists are now aware of and they are addressing, but then it’s a concern for a very specific subgroup of patients.”

While rheumatologists are, and will continue to prescribe it, there will be even more careful consideration over when, in whom, and how to use it during, and possibly even after, the pandemic.

“COVID is here to stay, it will become endemic, and it’s going to be part of our lives like the flu virus is,” Dr. Machado predicted.

Then there is the issue on vaccinating people against COVID-19, should those on rituximab still receive it? The answer is a yes, but, as with other vaccinations it’s all about the timing of when the vaccination is given.

Societies such as the British Society for Rheumatology have already begun to include guidance on this, recommending one of the available COVID-19 vaccines is given at least a month before the next or first dose of rituximab is due. As rituximab is given every few months, with doses sometimes spaced as much as 9 months or even a year apart, this should not be too much of a problem, but it is “better to have the vaccine first,” Dr. Machado said.
 

Has COVID-19 care improved in RMDs?

In separate research published in The Lancet Rheumatology, April Jorge, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, and associates found that the risks of severe COVID-19 outcomes have improved over time, although they still “remain substantial.”

Dr. Jorge and colleagues looked at temporal trends in COVID-19 outcomes in patients with RMDs over the course of the first 6 months of the pandemic in 2020, using data from a large, multicenter, electronic health record network (TriNetX).

They formed two patient cohorts – a late (diagnosed from April 20 to July 20) and an early (diagnosed from January 20 to April 20) cohort – to see if outcomes had improved and discovered lower relative risks among patients in the late cohort for hospitalization (0.67), admission to the ICU (0.56), mechanical ventilation (0.39), acute kidney injury (0.66), renal replacement (0.53), and death (0.39).

“These results are encouraging,” but it’s difficult to match these different populations of patients, Dr. Machado said. “There are always factors that you cannot match for” and were not included in the U.S. analysis.

While there are important caveats in how the analysis was performed and thus in interpreting these data, they do “suggest that one of the reasons why outcomes have improved is because we have become better at treating these patients,” Dr. Machado added.

“Our treatment has improved, and our capacity to treat the complications has improved. We understand better how the disease behaves – we know that they can have thromboembolic complications that we can manage, and we are now able to manage ventilation issues better.”

Moreover, Dr. Machado said that, not only were clinicians more aware of what they should or should not do, there were treatments that were being used routinely or in some cases based on recent clinical trial results. “I think we are indeed treating these patients better.”

The COVID-19 GRA physician registry is financially supported by the American College of Rheumatology and EULAR. Dr. Machado had no relevant conflicts of interest.

Nanoparticle encapsulation may enable targeting of aberrant glucose metabolism in hepatocellular carcinoma (HCC), potentially amplifying the effects of existing therapies and overcoming resistance mechanisms, according to investigators.

In a preclinical trial involving cell lines, xenograft tumors, and mouse models, encapsulated 2-deoxy-D-glucose (2DG) nanoparticles enhanced the antineoplastic effects of sorafenib and checkpoint inhibitors and suppressed anti-programmed cell death protein 1 (PD1)–resistant tumors, reported lead author Kyo Sasaki, PhD, of Kyushu University in Fukuoka, Japan, and colleagues.

As a glycolysis inhibitor, 2DG acts against the Warburg effect, a cancer immune-resistance mechanism “in which a substantial amount of pyruvate is reduced to lactic acid instead of being directed into mitochondria,” the investigators wrote. Their report is in Cellular and Molecular Gastroenterology and Hepatology.

But this isn’t new information, and Dr. Sasaki and colleagues weren’t the first to address the Warburg effect with 2DG; two clinical trials reported signs of efficacy in patients with solid tumors, one in 2010 and the other in 2013.

“However, 2DG does not seem to have a significant effect on tumor growth at a dose that does not induce serious adverse effects,” wrote Dr. Sasaki and colleagues. “These results suggest a need to develop an efficient drug delivery system for 2DG.”

The investigators turned to nanoparticles, which accumulate in tumor tissue more than healthy tissue, thereby limiting off-target toxicity. Specifically, they encapsulated 2DG in nanoparticles of poly(lactic-co-glycolic acid) (PLGA), a Food and Drug Administration–approved biodegradable polymer.

After characterizing the physical properties of the encapsulated 2DG nanoparticles (2DG-PLGA-NPs), and observing tumor localization in nude mice with xenograft liver tumors, the investigators assessed cytotoxic effects.

Treatment resulted in “significant growth reduction” of not only xenograft liver tumors, but also xenograft renal, colon, and pancreatic tumors, “indicating the potential antitumor effects of this method against various tumors.” Furthermore, mice treated with encapsulated 2DG nanoparticles had significantly less weight loss compared with those receiving conventional 2DG, suggesting a reduction in 2DG-related adverse effects.

Additional experiments involving two immunocompetent mouse models with multiple large liver tumors added data to support to the relative efficacy of encapsulated versus nonencapsulated 2DG. Both mouse models had significant reductions in liver tumors when treated with 2DG-PLGA-NPs; in contrast, treatment with 2DG alone reduced tumor number in only one of the two mouse models and to a lesser degree than treatment with 2DG nanoparticles.

Further in vivo and ex vivo testing revealed that encapsulated 2DG nanoparticles exerted their cytotoxic effects via endoplasmic reticulum stress, oxidative stress, and inactivation of mTOR. Simultaneously, treatment was associated with CD8+ T-cell migration into tumor tissue via increased glucose uptake and IFN-gamma production in CD8+ T cells, reduced lactate production in tumors, and increased production of CXCL9/CXCL10/CXCL11 in both the tumors and CD8+ T cells.

According to the investigators, these findings suggested that 2DG-PLGA-NPs might upregulate PD-1 positive T cells in tumors, thereby enhancing the effects of a checkpoint inhibitor. Indeed, when syngeneic mice with anti-PD-1–resistant tumors were treated with encapsulated 2DG nanoparticles, the investigators observed significant reductions in tumor growth, compared with treatment using an isotype control, PLGA alone, or an anti-PD-1 antibody. And in nude mice with xenograft tumors, combination therapy with 2DG-PLGA-NPs and sorafenib significantly reduced tumor growth, compared with no treatment, 2DG, PLGA, or PLGA with sorafenib.

“2DG-PLGA-NPs amplified the antitumor effect of anti-PD1 or sorafenib, and showed an antitumor effect against anti-PD1–resistant tumors,” the investigators wrote.

Dr. Sasaki and colleagues also noted that encapsulated 2DG nanoparticles did not accumulate in nontumorous cirrhotic hepatocytes, which suggests that treatment would be safe for patients with chronic liver diseases.

“Another practical concern is the extent to which 2DG is effectively taken up by HCC cells,” the investigators wrote.

PET showed that the hepatic accumulation rate of F-2-fluoro-2-deoxyglucose (F-FDG), a radioactive tracer of 2DG, was 50% in well-differentiated HCC, and “much higher” in sorafenib-resistant HCC cells and poorly and moderately differentiated HCC cells.

“Thus, 2DG-PLGA-NPs are expected to be good therapeutic agent candidates for patients with advanced HCC,” the investigators concluded.

The investigators disclosed no conflicts of interest. Some authors received grants from the Japan Society for the Promotion of Science.

Nanoparticle encapsulation may enable targeting of aberrant glucose metabolism in hepatocellular carcinoma (HCC), potentially amplifying the effects of existing therapies and overcoming resistance mechanisms, according to investigators.

In a preclinical trial involving cell lines, xenograft tumors, and mouse models, encapsulated 2-deoxy-D-glucose (2DG) nanoparticles enhanced the antineoplastic effects of sorafenib and checkpoint inhibitors and suppressed anti-programmed cell death protein 1 (PD1)–resistant tumors, reported lead author Kyo Sasaki, PhD, of Kyushu University in Fukuoka, Japan, and colleagues.

As a glycolysis inhibitor, 2DG acts against the Warburg effect, a cancer immune-resistance mechanism “in which a substantial amount of pyruvate is reduced to lactic acid instead of being directed into mitochondria,” the investigators wrote. Their report is in Cellular and Molecular Gastroenterology and Hepatology.

But this isn’t new information, and Dr. Sasaki and colleagues weren’t the first to address the Warburg effect with 2DG; two clinical trials reported signs of efficacy in patients with solid tumors, one in 2010 and the other in 2013.

“However, 2DG does not seem to have a significant effect on tumor growth at a dose that does not induce serious adverse effects,” wrote Dr. Sasaki and colleagues. “These results suggest a need to develop an efficient drug delivery system for 2DG.”

The investigators turned to nanoparticles, which accumulate in tumor tissue more than healthy tissue, thereby limiting off-target toxicity. Specifically, they encapsulated 2DG in nanoparticles of poly(lactic-co-glycolic acid) (PLGA), a Food and Drug Administration–approved biodegradable polymer.

After characterizing the physical properties of the encapsulated 2DG nanoparticles (2DG-PLGA-NPs), and observing tumor localization in nude mice with xenograft liver tumors, the investigators assessed cytotoxic effects.

Treatment resulted in “significant growth reduction” of not only xenograft liver tumors, but also xenograft renal, colon, and pancreatic tumors, “indicating the potential antitumor effects of this method against various tumors.” Furthermore, mice treated with encapsulated 2DG nanoparticles had significantly less weight loss compared with those receiving conventional 2DG, suggesting a reduction in 2DG-related adverse effects.

Additional experiments involving two immunocompetent mouse models with multiple large liver tumors added data to support to the relative efficacy of encapsulated versus nonencapsulated 2DG. Both mouse models had significant reductions in liver tumors when treated with 2DG-PLGA-NPs; in contrast, treatment with 2DG alone reduced tumor number in only one of the two mouse models and to a lesser degree than treatment with 2DG nanoparticles.

Further in vivo and ex vivo testing revealed that encapsulated 2DG nanoparticles exerted their cytotoxic effects via endoplasmic reticulum stress, oxidative stress, and inactivation of mTOR. Simultaneously, treatment was associated with CD8+ T-cell migration into tumor tissue via increased glucose uptake and IFN-gamma production in CD8+ T cells, reduced lactate production in tumors, and increased production of CXCL9/CXCL10/CXCL11 in both the tumors and CD8+ T cells.

According to the investigators, these findings suggested that 2DG-PLGA-NPs might upregulate PD-1 positive T cells in tumors, thereby enhancing the effects of a checkpoint inhibitor. Indeed, when syngeneic mice with anti-PD-1–resistant tumors were treated with encapsulated 2DG nanoparticles, the investigators observed significant reductions in tumor growth, compared with treatment using an isotype control, PLGA alone, or an anti-PD-1 antibody. And in nude mice with xenograft tumors, combination therapy with 2DG-PLGA-NPs and sorafenib significantly reduced tumor growth, compared with no treatment, 2DG, PLGA, or PLGA with sorafenib.

“2DG-PLGA-NPs amplified the antitumor effect of anti-PD1 or sorafenib, and showed an antitumor effect against anti-PD1–resistant tumors,” the investigators wrote.

Dr. Sasaki and colleagues also noted that encapsulated 2DG nanoparticles did not accumulate in nontumorous cirrhotic hepatocytes, which suggests that treatment would be safe for patients with chronic liver diseases.

“Another practical concern is the extent to which 2DG is effectively taken up by HCC cells,” the investigators wrote.

PET showed that the hepatic accumulation rate of F-2-fluoro-2-deoxyglucose (F-FDG), a radioactive tracer of 2DG, was 50% in well-differentiated HCC, and “much higher” in sorafenib-resistant HCC cells and poorly and moderately differentiated HCC cells.

“Thus, 2DG-PLGA-NPs are expected to be good therapeutic agent candidates for patients with advanced HCC,” the investigators concluded.

The investigators disclosed no conflicts of interest. Some authors received grants from the Japan Society for the Promotion of Science.

Nanoparticle encapsulation may enable targeting of aberrant glucose metabolism in hepatocellular carcinoma (HCC), potentially amplifying the effects of existing therapies and overcoming resistance mechanisms, according to investigators.

In a preclinical trial involving cell lines, xenograft tumors, and mouse models, encapsulated 2-deoxy-D-glucose (2DG) nanoparticles enhanced the antineoplastic effects of sorafenib and checkpoint inhibitors and suppressed anti-programmed cell death protein 1 (PD1)–resistant tumors, reported lead author Kyo Sasaki, PhD, of Kyushu University in Fukuoka, Japan, and colleagues.

As a glycolysis inhibitor, 2DG acts against the Warburg effect, a cancer immune-resistance mechanism “in which a substantial amount of pyruvate is reduced to lactic acid instead of being directed into mitochondria,” the investigators wrote. Their report is in Cellular and Molecular Gastroenterology and Hepatology.

But this isn’t new information, and Dr. Sasaki and colleagues weren’t the first to address the Warburg effect with 2DG; two clinical trials reported signs of efficacy in patients with solid tumors, one in 2010 and the other in 2013.

“However, 2DG does not seem to have a significant effect on tumor growth at a dose that does not induce serious adverse effects,” wrote Dr. Sasaki and colleagues. “These results suggest a need to develop an efficient drug delivery system for 2DG.”

The investigators turned to nanoparticles, which accumulate in tumor tissue more than healthy tissue, thereby limiting off-target toxicity. Specifically, they encapsulated 2DG in nanoparticles of poly(lactic-co-glycolic acid) (PLGA), a Food and Drug Administration–approved biodegradable polymer.

After characterizing the physical properties of the encapsulated 2DG nanoparticles (2DG-PLGA-NPs), and observing tumor localization in nude mice with xenograft liver tumors, the investigators assessed cytotoxic effects.

Treatment resulted in “significant growth reduction” of not only xenograft liver tumors, but also xenograft renal, colon, and pancreatic tumors, “indicating the potential antitumor effects of this method against various tumors.” Furthermore, mice treated with encapsulated 2DG nanoparticles had significantly less weight loss compared with those receiving conventional 2DG, suggesting a reduction in 2DG-related adverse effects.

Additional experiments involving two immunocompetent mouse models with multiple large liver tumors added data to support to the relative efficacy of encapsulated versus nonencapsulated 2DG. Both mouse models had significant reductions in liver tumors when treated with 2DG-PLGA-NPs; in contrast, treatment with 2DG alone reduced tumor number in only one of the two mouse models and to a lesser degree than treatment with 2DG nanoparticles.

Further in vivo and ex vivo testing revealed that encapsulated 2DG nanoparticles exerted their cytotoxic effects via endoplasmic reticulum stress, oxidative stress, and inactivation of mTOR. Simultaneously, treatment was associated with CD8+ T-cell migration into tumor tissue via increased glucose uptake and IFN-gamma production in CD8+ T cells, reduced lactate production in tumors, and increased production of CXCL9/CXCL10/CXCL11 in both the tumors and CD8+ T cells.

According to the investigators, these findings suggested that 2DG-PLGA-NPs might upregulate PD-1 positive T cells in tumors, thereby enhancing the effects of a checkpoint inhibitor. Indeed, when syngeneic mice with anti-PD-1–resistant tumors were treated with encapsulated 2DG nanoparticles, the investigators observed significant reductions in tumor growth, compared with treatment using an isotype control, PLGA alone, or an anti-PD-1 antibody. And in nude mice with xenograft tumors, combination therapy with 2DG-PLGA-NPs and sorafenib significantly reduced tumor growth, compared with no treatment, 2DG, PLGA, or PLGA with sorafenib.

“2DG-PLGA-NPs amplified the antitumor effect of anti-PD1 or sorafenib, and showed an antitumor effect against anti-PD1–resistant tumors,” the investigators wrote.

Dr. Sasaki and colleagues also noted that encapsulated 2DG nanoparticles did not accumulate in nontumorous cirrhotic hepatocytes, which suggests that treatment would be safe for patients with chronic liver diseases.

“Another practical concern is the extent to which 2DG is effectively taken up by HCC cells,” the investigators wrote.

PET showed that the hepatic accumulation rate of F-2-fluoro-2-deoxyglucose (F-FDG), a radioactive tracer of 2DG, was 50% in well-differentiated HCC, and “much higher” in sorafenib-resistant HCC cells and poorly and moderately differentiated HCC cells.

“Thus, 2DG-PLGA-NPs are expected to be good therapeutic agent candidates for patients with advanced HCC,” the investigators concluded.

The investigators disclosed no conflicts of interest. Some authors received grants from the Japan Society for the Promotion of Science.