Telepsychiatry appointments (eg, video conferencing) initially replaced face-to-face outpatient encounters during the first phase of the COVID-19 pandemic. However, as offices reopened for in-person appointments, many patients still prefer “virtual” appointments. Telepsychiatry allows for easier delivery of mental health services, including psychotherapy, and may become the new normal.

Although therapy conducted via video conferencing allows you to connect with patients at a safe distance, it alters the basic conditions under which therapy occurs, such as being in the same room.¹ While focusing on preserving the verbal elements of communication, you might inadvertently forget the nonverbal elements, which at times might render your words ineffective.¹ The main elements of nonverbal communication are facial expression, gaze, posture, gesture, and proxemics (ie, how much space you take up, and your distance from others).² The following tips can help you preserve the nonverbal elements of communication when conducting telepsychiatry sessions.

Reduce gaze error. Gaze error is the deviation from direct eye contact that occurs during video conferencing. It results from the distance between the image of the person on your screen and the camera above it.¹ Gaze error can muddy intended cues and communicate unintended cues.² Examples of gaze errors include downcast eyes (the most common gaze error), sideways gaze, or gazing over the person’s head.² These errors can communicate social deference, evasion, insincerity, or even boredom.² To lessen gaze error, move the patient’s image as close as possible to your camera.¹ In addition, avoid looking at yourself on the screen; some video conferencing platforms allow users to hide their self-view.

Create distance and incorporate upper body language. In the office, sitting very close to your patient and staring directly at their face for an hour would be awkward and intrusive.¹ Doing so online is no different. While you may be tempted to move close to the screen to compensate for feeling distant or having difficulty hearing or seeing your patient, you should back away from the camera. Doing so will help both parties feel less self-conscious, more at ease, and more focused on the session.¹ Backing up from the camera will allow patients to see your upper body language (eg, hand gestures, posture) as well as your facial expressions.¹ Empathy improves when patients can see your upper-body cues.² Keep in mind that the angle of your camera is just as important as the distance. For example, if your camera is positioned so that it is looking up toward your eyes, patients may perceive that you are looking down at them.¹ This problem can be remedied by stacking books under the monitor to raise the camera.

Be aware of your facial expressions, posture, gestures, and proxemics. Ensure that your face does not go slack when you are listening to patients talk.³ Just as you would do in person, a slight head tilt and occasional head nod lets patients know that you are engaged and actively listening.³ Maintain an open body posture by keeping your feet firmly on the ground and putting your hands on the table in front of you.³ Lean in when patients share intimate information, just as you would in person. Avoid hunching over the laptop/keyboard because this could make you seem tired or tense.³ Pay attention to your arm and hand movements so that you do not exaggerate them.

Maintain office professionalism. The office setting conveys a therapeutic formality that can get lost online.¹ As tempting as it may be to conduct online sessions in pajamas or sweatpants, continue to dress as if you were in the office. Be mindful of your backdrop, set all cell phones to silent, turn off your email alerts, and lock the room.^1,3 Stick to the clock as you would in the office, and encourage patients to do the same.

Minor technological improvements—such as headphones with a built-in microphone, a high-definition camera, a larger monitor, or a faster internet connection—might be needed to improve your nonverbal communication during telepsychiatry sessions.¹ Although this is not an exhaustive list, these tips can serve as a starting point to ensure effective communication while you are physically distanced from your patients.

Telepsychiatry appointments (eg, video conferencing) initially replaced face-to-face outpatient encounters during the first phase of the COVID-19 pandemic. However, as offices reopened for in-person appointments, many patients still prefer “virtual” appointments. Telepsychiatry allows for easier delivery of mental health services, including psychotherapy, and may become the new normal.

Although therapy conducted via video conferencing allows you to connect with patients at a safe distance, it alters the basic conditions under which therapy occurs, such as being in the same room.¹ While focusing on preserving the verbal elements of communication, you might inadvertently forget the nonverbal elements, which at times might render your words ineffective.¹ The main elements of nonverbal communication are facial expression, gaze, posture, gesture, and proxemics (ie, how much space you take up, and your distance from others).² The following tips can help you preserve the nonverbal elements of communication when conducting telepsychiatry sessions.

Reduce gaze error. Gaze error is the deviation from direct eye contact that occurs during video conferencing. It results from the distance between the image of the person on your screen and the camera above it.¹ Gaze error can muddy intended cues and communicate unintended cues.² Examples of gaze errors include downcast eyes (the most common gaze error), sideways gaze, or gazing over the person’s head.² These errors can communicate social deference, evasion, insincerity, or even boredom.² To lessen gaze error, move the patient’s image as close as possible to your camera.¹ In addition, avoid looking at yourself on the screen; some video conferencing platforms allow users to hide their self-view.

Create distance and incorporate upper body language. In the office, sitting very close to your patient and staring directly at their face for an hour would be awkward and intrusive.¹ Doing so online is no different. While you may be tempted to move close to the screen to compensate for feeling distant or having difficulty hearing or seeing your patient, you should back away from the camera. Doing so will help both parties feel less self-conscious, more at ease, and more focused on the session.¹ Backing up from the camera will allow patients to see your upper body language (eg, hand gestures, posture) as well as your facial expressions.¹ Empathy improves when patients can see your upper-body cues.² Keep in mind that the angle of your camera is just as important as the distance. For example, if your camera is positioned so that it is looking up toward your eyes, patients may perceive that you are looking down at them.¹ This problem can be remedied by stacking books under the monitor to raise the camera.

Be aware of your facial expressions, posture, gestures, and proxemics. Ensure that your face does not go slack when you are listening to patients talk.³ Just as you would do in person, a slight head tilt and occasional head nod lets patients know that you are engaged and actively listening.³ Maintain an open body posture by keeping your feet firmly on the ground and putting your hands on the table in front of you.³ Lean in when patients share intimate information, just as you would in person. Avoid hunching over the laptop/keyboard because this could make you seem tired or tense.³ Pay attention to your arm and hand movements so that you do not exaggerate them.

Maintain office professionalism. The office setting conveys a therapeutic formality that can get lost online.¹ As tempting as it may be to conduct online sessions in pajamas or sweatpants, continue to dress as if you were in the office. Be mindful of your backdrop, set all cell phones to silent, turn off your email alerts, and lock the room.^1,3 Stick to the clock as you would in the office, and encourage patients to do the same.

Minor technological improvements—such as headphones with a built-in microphone, a high-definition camera, a larger monitor, or a faster internet connection—might be needed to improve your nonverbal communication during telepsychiatry sessions.¹ Although this is not an exhaustive list, these tips can serve as a starting point to ensure effective communication while you are physically distanced from your patients.

Telepsychiatry appointments (eg, video conferencing) initially replaced face-to-face outpatient encounters during the first phase of the COVID-19 pandemic. However, as offices reopened for in-person appointments, many patients still prefer “virtual” appointments. Telepsychiatry allows for easier delivery of mental health services, including psychotherapy, and may become the new normal.

Although therapy conducted via video conferencing allows you to connect with patients at a safe distance, it alters the basic conditions under which therapy occurs, such as being in the same room.¹ While focusing on preserving the verbal elements of communication, you might inadvertently forget the nonverbal elements, which at times might render your words ineffective.¹ The main elements of nonverbal communication are facial expression, gaze, posture, gesture, and proxemics (ie, how much space you take up, and your distance from others).² The following tips can help you preserve the nonverbal elements of communication when conducting telepsychiatry sessions.

Reduce gaze error. Gaze error is the deviation from direct eye contact that occurs during video conferencing. It results from the distance between the image of the person on your screen and the camera above it.¹ Gaze error can muddy intended cues and communicate unintended cues.² Examples of gaze errors include downcast eyes (the most common gaze error), sideways gaze, or gazing over the person’s head.² These errors can communicate social deference, evasion, insincerity, or even boredom.² To lessen gaze error, move the patient’s image as close as possible to your camera.¹ In addition, avoid looking at yourself on the screen; some video conferencing platforms allow users to hide their self-view.

Create distance and incorporate upper body language. In the office, sitting very close to your patient and staring directly at their face for an hour would be awkward and intrusive.¹ Doing so online is no different. While you may be tempted to move close to the screen to compensate for feeling distant or having difficulty hearing or seeing your patient, you should back away from the camera. Doing so will help both parties feel less self-conscious, more at ease, and more focused on the session.¹ Backing up from the camera will allow patients to see your upper body language (eg, hand gestures, posture) as well as your facial expressions.¹ Empathy improves when patients can see your upper-body cues.² Keep in mind that the angle of your camera is just as important as the distance. For example, if your camera is positioned so that it is looking up toward your eyes, patients may perceive that you are looking down at them.¹ This problem can be remedied by stacking books under the monitor to raise the camera.

Be aware of your facial expressions, posture, gestures, and proxemics. Ensure that your face does not go slack when you are listening to patients talk.³ Just as you would do in person, a slight head tilt and occasional head nod lets patients know that you are engaged and actively listening.³ Maintain an open body posture by keeping your feet firmly on the ground and putting your hands on the table in front of you.³ Lean in when patients share intimate information, just as you would in person. Avoid hunching over the laptop/keyboard because this could make you seem tired or tense.³ Pay attention to your arm and hand movements so that you do not exaggerate them.

Maintain office professionalism. The office setting conveys a therapeutic formality that can get lost online.¹ As tempting as it may be to conduct online sessions in pajamas or sweatpants, continue to dress as if you were in the office. Be mindful of your backdrop, set all cell phones to silent, turn off your email alerts, and lock the room.^1,3 Stick to the clock as you would in the office, and encourage patients to do the same.

Minor technological improvements—such as headphones with a built-in microphone, a high-definition camera, a larger monitor, or a faster internet connection—might be needed to improve your nonverbal communication during telepsychiatry sessions.¹ Although this is not an exhaustive list, these tips can serve as a starting point to ensure effective communication while you are physically distanced from your patients.

The peak age of onset of schizophrenia coincides with the peak childbearing age of 25 to 35 years.¹ So it would not be unusual for your patient with schizophrenia to tell you she is trying to get pregnant, or thinks she might be pregnant. In these situations, you must carefully weigh the risks to the mother (eg, relapse, complications) and to the fetus (eg, possible miscarriage, teratogenesis) when deciding whether to continue or change her treatment regimen. When faced with making these decisions, keep the following factors in mind.

1. Most importantly: Do not make knee-jerk changes. Do not suddenly stop medications. Proceed in a thoughtful and measured way.

2. Discuss the risks with your patient. There is no such thing as a risk-free decision. There are potential risks from untreated psychosis as well as from medications. Mothers with untreated psychosis have an increased risk of suicide and violence, as well as poor self-care. Schizophrenia may be associated with an increased risk of poor birth outcomes, including preterm delivery, low birthweight, and neonatal complications.² Avoid making absolute statements about specific medications during pregnancy; there needs to be an individualized risk-benefit discussion for each patient, and for each medication.

3. Involve the patient’s partner and family in treatment planning if possible. The patient’s family can be important in promoting mental health during pregnancy and the postpartum. Educating the family as well as the patient regarding medications and the risks of untreated mental illness can go a long way toward compliance.

4. Do not rely on what pregnancy category a medication was. There are multiple dimensions to evaluate when considering the use of an antipsychotic agent during pregnancy. Does it increase the risk of miscarriage? Malformations? Preterm birth? Perinatal toxicity? Behavioral teratogenesis (neurodevelopmental sequelae)? Looking for a simple summary or single letter grade minimizes the understanding of the specific outcome of concern in the specific mother. Instead, look at the Pregnancy section under Use in Specific Populations on the medication’s package insert (prescribing information), consult a web site such as MotherToBaby (mothertobaby.org/healthcare-professionals/), and/or search for the latest research on PubMed.

5. Collaborate with the patient’s obstetrician or family medicine physician. Make sure that you are on the same page regarding treating the patient’s psychosis. Other clinicians often will agree with your treatment plan because they understand the risks of untreated psychosis compared with other risks the patient is facing. However, if you don’t communicate with your patient’s other health care professionals, she might receive mixed messages.

6. As for medication choice, pregnancy is the most important time to conduct a careful medication history to inform your choice of medication. Was Medication X ineffective, or did the patient not pick it up from the pharmacy? Did she really have a trial of 3 months, or did she only take it for a week before she decided to stop?

Continue to: Determine which medication has worked for the patient in the past

7. Determine which medication has worked for the patient in the past. If Medication Y worked before she was pregnant, it is likely to still work during pregnancy. If it is a relatively safe option, it may be the best choice.

8. Avoid multiple medication exposures wherever possible. If a patient is taking Medication Z, it is working, and she tells you she is 3 months pregnant, it is often better to continue it (assuming it is a relatively safe medication) than to switch to Medication A, which has slightly better “safety data.” By switching to a different antipsychotic, you would be exposing the fetus to a second agent that may not even work for the mother.

9. Focus on treating the patient’s present symptoms. Medication doses may need to change due to pregnancy-related changes in symptoms, drug distribution, and/or metabolism.

10. Remain vigilant for other risks. Keep in mind that pregnant women with psychosis often face risks other than psychiatric medications and psychosis. Comorbidities such as substance use disorders, obesity, and poor prenatal care must also be addressed.³

11. Follow your patient more closely during pregnancy. Pregnancy is an uncertain time for any new mother. Be sure to have an open line of communication with the patient, and be responsive to her concerns.

Continue to: Provide psychoeducation about the postpartum period

12. Provide psychoeducation about the postpartum period. Pregnancy is the time to educate your patient about the importance of sleep, warning signs of exacerbation of psychosis, and breastfeeding safety.

13. Be proactive with future female pa­tients of childbearing age, regardless of whether they tell you they are sexually active. Women with psychosis have higher rates of unplanned pregnancy.^3,4 When initiating treatment of psychosis in a woman of childbearing age, rather than treating her with the newest available medication that does not yet have safety data in pregnancy, it is best to start with a medication already known to be relatively safe in pregnancy. This way, if she were to become pregnant, your treatment plan would already be safe and appropriate.

14. Consult a reproductive psychiatrist if needed.

The peak age of onset of schizophrenia coincides with the peak childbearing age of 25 to 35 years.¹ So it would not be unusual for your patient with schizophrenia to tell you she is trying to get pregnant, or thinks she might be pregnant. In these situations, you must carefully weigh the risks to the mother (eg, relapse, complications) and to the fetus (eg, possible miscarriage, teratogenesis) when deciding whether to continue or change her treatment regimen. When faced with making these decisions, keep the following factors in mind.

1. Most importantly: Do not make knee-jerk changes. Do not suddenly stop medications. Proceed in a thoughtful and measured way.

2. Discuss the risks with your patient. There is no such thing as a risk-free decision. There are potential risks from untreated psychosis as well as from medications. Mothers with untreated psychosis have an increased risk of suicide and violence, as well as poor self-care. Schizophrenia may be associated with an increased risk of poor birth outcomes, including preterm delivery, low birthweight, and neonatal complications.² Avoid making absolute statements about specific medications during pregnancy; there needs to be an individualized risk-benefit discussion for each patient, and for each medication.

3. Involve the patient’s partner and family in treatment planning if possible. The patient’s family can be important in promoting mental health during pregnancy and the postpartum. Educating the family as well as the patient regarding medications and the risks of untreated mental illness can go a long way toward compliance.

4. Do not rely on what pregnancy category a medication was. There are multiple dimensions to evaluate when considering the use of an antipsychotic agent during pregnancy. Does it increase the risk of miscarriage? Malformations? Preterm birth? Perinatal toxicity? Behavioral teratogenesis (neurodevelopmental sequelae)? Looking for a simple summary or single letter grade minimizes the understanding of the specific outcome of concern in the specific mother. Instead, look at the Pregnancy section under Use in Specific Populations on the medication’s package insert (prescribing information), consult a web site such as MotherToBaby (mothertobaby.org/healthcare-professionals/), and/or search for the latest research on PubMed.

5. Collaborate with the patient’s obstetrician or family medicine physician. Make sure that you are on the same page regarding treating the patient’s psychosis. Other clinicians often will agree with your treatment plan because they understand the risks of untreated psychosis compared with other risks the patient is facing. However, if you don’t communicate with your patient’s other health care professionals, she might receive mixed messages.

6. As for medication choice, pregnancy is the most important time to conduct a careful medication history to inform your choice of medication. Was Medication X ineffective, or did the patient not pick it up from the pharmacy? Did she really have a trial of 3 months, or did she only take it for a week before she decided to stop?

Continue to: Determine which medication has worked for the patient in the past

7. Determine which medication has worked for the patient in the past. If Medication Y worked before she was pregnant, it is likely to still work during pregnancy. If it is a relatively safe option, it may be the best choice.

8. Avoid multiple medication exposures wherever possible. If a patient is taking Medication Z, it is working, and she tells you she is 3 months pregnant, it is often better to continue it (assuming it is a relatively safe medication) than to switch to Medication A, which has slightly better “safety data.” By switching to a different antipsychotic, you would be exposing the fetus to a second agent that may not even work for the mother.

9. Focus on treating the patient’s present symptoms. Medication doses may need to change due to pregnancy-related changes in symptoms, drug distribution, and/or metabolism.

10. Remain vigilant for other risks. Keep in mind that pregnant women with psychosis often face risks other than psychiatric medications and psychosis. Comorbidities such as substance use disorders, obesity, and poor prenatal care must also be addressed.³

11. Follow your patient more closely during pregnancy. Pregnancy is an uncertain time for any new mother. Be sure to have an open line of communication with the patient, and be responsive to her concerns.

Continue to: Provide psychoeducation about the postpartum period

12. Provide psychoeducation about the postpartum period. Pregnancy is the time to educate your patient about the importance of sleep, warning signs of exacerbation of psychosis, and breastfeeding safety.

13. Be proactive with future female pa­tients of childbearing age, regardless of whether they tell you they are sexually active. Women with psychosis have higher rates of unplanned pregnancy.^3,4 When initiating treatment of psychosis in a woman of childbearing age, rather than treating her with the newest available medication that does not yet have safety data in pregnancy, it is best to start with a medication already known to be relatively safe in pregnancy. This way, if she were to become pregnant, your treatment plan would already be safe and appropriate.

14. Consult a reproductive psychiatrist if needed.

The peak age of onset of schizophrenia coincides with the peak childbearing age of 25 to 35 years.¹ So it would not be unusual for your patient with schizophrenia to tell you she is trying to get pregnant, or thinks she might be pregnant. In these situations, you must carefully weigh the risks to the mother (eg, relapse, complications) and to the fetus (eg, possible miscarriage, teratogenesis) when deciding whether to continue or change her treatment regimen. When faced with making these decisions, keep the following factors in mind.

1. Most importantly: Do not make knee-jerk changes. Do not suddenly stop medications. Proceed in a thoughtful and measured way.

2. Discuss the risks with your patient. There is no such thing as a risk-free decision. There are potential risks from untreated psychosis as well as from medications. Mothers with untreated psychosis have an increased risk of suicide and violence, as well as poor self-care. Schizophrenia may be associated with an increased risk of poor birth outcomes, including preterm delivery, low birthweight, and neonatal complications.² Avoid making absolute statements about specific medications during pregnancy; there needs to be an individualized risk-benefit discussion for each patient, and for each medication.

3. Involve the patient’s partner and family in treatment planning if possible. The patient’s family can be important in promoting mental health during pregnancy and the postpartum. Educating the family as well as the patient regarding medications and the risks of untreated mental illness can go a long way toward compliance.

4. Do not rely on what pregnancy category a medication was. There are multiple dimensions to evaluate when considering the use of an antipsychotic agent during pregnancy. Does it increase the risk of miscarriage? Malformations? Preterm birth? Perinatal toxicity? Behavioral teratogenesis (neurodevelopmental sequelae)? Looking for a simple summary or single letter grade minimizes the understanding of the specific outcome of concern in the specific mother. Instead, look at the Pregnancy section under Use in Specific Populations on the medication’s package insert (prescribing information), consult a web site such as MotherToBaby (mothertobaby.org/healthcare-professionals/), and/or search for the latest research on PubMed.

5. Collaborate with the patient’s obstetrician or family medicine physician. Make sure that you are on the same page regarding treating the patient’s psychosis. Other clinicians often will agree with your treatment plan because they understand the risks of untreated psychosis compared with other risks the patient is facing. However, if you don’t communicate with your patient’s other health care professionals, she might receive mixed messages.

6. As for medication choice, pregnancy is the most important time to conduct a careful medication history to inform your choice of medication. Was Medication X ineffective, or did the patient not pick it up from the pharmacy? Did she really have a trial of 3 months, or did she only take it for a week before she decided to stop?

Continue to: Determine which medication has worked for the patient in the past

7. Determine which medication has worked for the patient in the past. If Medication Y worked before she was pregnant, it is likely to still work during pregnancy. If it is a relatively safe option, it may be the best choice.

8. Avoid multiple medication exposures wherever possible. If a patient is taking Medication Z, it is working, and she tells you she is 3 months pregnant, it is often better to continue it (assuming it is a relatively safe medication) than to switch to Medication A, which has slightly better “safety data.” By switching to a different antipsychotic, you would be exposing the fetus to a second agent that may not even work for the mother.

9. Focus on treating the patient’s present symptoms. Medication doses may need to change due to pregnancy-related changes in symptoms, drug distribution, and/or metabolism.

10. Remain vigilant for other risks. Keep in mind that pregnant women with psychosis often face risks other than psychiatric medications and psychosis. Comorbidities such as substance use disorders, obesity, and poor prenatal care must also be addressed.³

11. Follow your patient more closely during pregnancy. Pregnancy is an uncertain time for any new mother. Be sure to have an open line of communication with the patient, and be responsive to her concerns.

Continue to: Provide psychoeducation about the postpartum period

12. Provide psychoeducation about the postpartum period. Pregnancy is the time to educate your patient about the importance of sleep, warning signs of exacerbation of psychosis, and breastfeeding safety.

13. Be proactive with future female pa­tients of childbearing age, regardless of whether they tell you they are sexually active. Women with psychosis have higher rates of unplanned pregnancy.^3,4 When initiating treatment of psychosis in a woman of childbearing age, rather than treating her with the newest available medication that does not yet have safety data in pregnancy, it is best to start with a medication already known to be relatively safe in pregnancy. This way, if she were to become pregnant, your treatment plan would already be safe and appropriate.

14. Consult a reproductive psychiatrist if needed.

Since receiving FDA approval in March 2019, intranasal esketamine—the S-enantiomer of ketamine—has become a valuable treatment option for adults with treatment-resistant depression (TRD), owing to its limited adverse effects profile, rapid onset, and potential for significant improvement in depressive symptoms. In August 2020, the FDA expanded esketamine’s indication to include treatment of depressive symptoms in adults with acute suicidal ideation or behavior, thus providing psychiatrists with an additional option for improving the care of their most seriously ill patients. In this article, we review 4 factors to consider before recommending esketamine.

1. Confirm that the patient’s depression qualifies as treatment-resistant. A patient is considered to have TRD if they have long-standing depression that meets DSM-5 criteria for major depressive disorder, and have not adequately responded to at least 2 antidepressant trials of adequate dose and duration.

2. Confirm that the patient’s suicidal ideation and/or suicidal behavior does not require acute hospitalization. The time between the onset of suicidal ideation and a suicide attempt typically is short, which highlights the need to intervene quickly in these patients.¹ Being able to provide a treatment that works quickly and effectively may be lifesaving. However, to receive esketamine, patients must be enrolled in the Risk Evaluation Mitigation Strategy (REMS) patient registry through a certified treatment center, and prior authorization from insurance generally is required. These steps take time, so patients at high or imminent risk for suicide may initially require psychiatric hospitalization before they are able to begin esketamine treatment. Parsing out whether the suicidal ideation is chronic or acute can help clinicians assess current dangerousness and determine if esketamine treatment might be appropriate. If a patient with chronic suicidal ideation is stable for outpatient treatment with close monitoring, esketamine might provide an effective treatment option for treating both depression and suicidality. Esketamine’s rapid effect may be an integral part of the treatment for a suicidal patient by bridging the gap caused by the delayed onset of action in typical antidepressants.²

3. Identify a local certified treatment center. Use the online database at www.spravato.com/find-a-center to locate a nearby certified esketamine treatment center. Choosing a center that you can collaborate with regularly is important to determine if the treatment is effective, to provide updates on the treatment course, and to consider tailoring of ongoing treatment.

4. Ensure the patient is also treated with an oral antidepressant. Esketamine should be administered in conjunction with an oral antidepressant. As such, patients must be willing and able to tolerate treatment with a medication that can be construed as an antidepressant while undergoing esketamine treatment. A long-term maintenance trial found that patients with TRD who experienced remission or response after esketamine treatment had a delayed relapse of symptoms when they continued esketamine in addition to an oral antidepressant.³

Considering its rapid onset of action and low adverse effects profile with manageable tolerability, esketamine adjunctive to an oral antidepressant is a reasonable option to consider for patients with TRD, including those with suicidality.

Since receiving FDA approval in March 2019, intranasal esketamine—the S-enantiomer of ketamine—has become a valuable treatment option for adults with treatment-resistant depression (TRD), owing to its limited adverse effects profile, rapid onset, and potential for significant improvement in depressive symptoms. In August 2020, the FDA expanded esketamine’s indication to include treatment of depressive symptoms in adults with acute suicidal ideation or behavior, thus providing psychiatrists with an additional option for improving the care of their most seriously ill patients. In this article, we review 4 factors to consider before recommending esketamine.

1. Confirm that the patient’s depression qualifies as treatment-resistant. A patient is considered to have TRD if they have long-standing depression that meets DSM-5 criteria for major depressive disorder, and have not adequately responded to at least 2 antidepressant trials of adequate dose and duration.

2. Confirm that the patient’s suicidal ideation and/or suicidal behavior does not require acute hospitalization. The time between the onset of suicidal ideation and a suicide attempt typically is short, which highlights the need to intervene quickly in these patients.¹ Being able to provide a treatment that works quickly and effectively may be lifesaving. However, to receive esketamine, patients must be enrolled in the Risk Evaluation Mitigation Strategy (REMS) patient registry through a certified treatment center, and prior authorization from insurance generally is required. These steps take time, so patients at high or imminent risk for suicide may initially require psychiatric hospitalization before they are able to begin esketamine treatment. Parsing out whether the suicidal ideation is chronic or acute can help clinicians assess current dangerousness and determine if esketamine treatment might be appropriate. If a patient with chronic suicidal ideation is stable for outpatient treatment with close monitoring, esketamine might provide an effective treatment option for treating both depression and suicidality. Esketamine’s rapid effect may be an integral part of the treatment for a suicidal patient by bridging the gap caused by the delayed onset of action in typical antidepressants.²

3. Identify a local certified treatment center. Use the online database at www.spravato.com/find-a-center to locate a nearby certified esketamine treatment center. Choosing a center that you can collaborate with regularly is important to determine if the treatment is effective, to provide updates on the treatment course, and to consider tailoring of ongoing treatment.

4. Ensure the patient is also treated with an oral antidepressant. Esketamine should be administered in conjunction with an oral antidepressant. As such, patients must be willing and able to tolerate treatment with a medication that can be construed as an antidepressant while undergoing esketamine treatment. A long-term maintenance trial found that patients with TRD who experienced remission or response after esketamine treatment had a delayed relapse of symptoms when they continued esketamine in addition to an oral antidepressant.³

Considering its rapid onset of action and low adverse effects profile with manageable tolerability, esketamine adjunctive to an oral antidepressant is a reasonable option to consider for patients with TRD, including those with suicidality.

Since receiving FDA approval in March 2019, intranasal esketamine—the S-enantiomer of ketamine—has become a valuable treatment option for adults with treatment-resistant depression (TRD), owing to its limited adverse effects profile, rapid onset, and potential for significant improvement in depressive symptoms. In August 2020, the FDA expanded esketamine’s indication to include treatment of depressive symptoms in adults with acute suicidal ideation or behavior, thus providing psychiatrists with an additional option for improving the care of their most seriously ill patients. In this article, we review 4 factors to consider before recommending esketamine.

1. Confirm that the patient’s depression qualifies as treatment-resistant. A patient is considered to have TRD if they have long-standing depression that meets DSM-5 criteria for major depressive disorder, and have not adequately responded to at least 2 antidepressant trials of adequate dose and duration.

2. Confirm that the patient’s suicidal ideation and/or suicidal behavior does not require acute hospitalization. The time between the onset of suicidal ideation and a suicide attempt typically is short, which highlights the need to intervene quickly in these patients.¹ Being able to provide a treatment that works quickly and effectively may be lifesaving. However, to receive esketamine, patients must be enrolled in the Risk Evaluation Mitigation Strategy (REMS) patient registry through a certified treatment center, and prior authorization from insurance generally is required. These steps take time, so patients at high or imminent risk for suicide may initially require psychiatric hospitalization before they are able to begin esketamine treatment. Parsing out whether the suicidal ideation is chronic or acute can help clinicians assess current dangerousness and determine if esketamine treatment might be appropriate. If a patient with chronic suicidal ideation is stable for outpatient treatment with close monitoring, esketamine might provide an effective treatment option for treating both depression and suicidality. Esketamine’s rapid effect may be an integral part of the treatment for a suicidal patient by bridging the gap caused by the delayed onset of action in typical antidepressants.²

3. Identify a local certified treatment center. Use the online database at www.spravato.com/find-a-center to locate a nearby certified esketamine treatment center. Choosing a center that you can collaborate with regularly is important to determine if the treatment is effective, to provide updates on the treatment course, and to consider tailoring of ongoing treatment.

4. Ensure the patient is also treated with an oral antidepressant. Esketamine should be administered in conjunction with an oral antidepressant. As such, patients must be willing and able to tolerate treatment with a medication that can be construed as an antidepressant while undergoing esketamine treatment. A long-term maintenance trial found that patients with TRD who experienced remission or response after esketamine treatment had a delayed relapse of symptoms when they continued esketamine in addition to an oral antidepressant.³

Considering its rapid onset of action and low adverse effects profile with manageable tolerability, esketamine adjunctive to an oral antidepressant is a reasonable option to consider for patients with TRD, including those with suicidality.

Dear colleagues and friends,

The Perspectives series continues! There are few issues in our discipline that are as challenging, and controversial, as liver transplant prioritization. The Model for End-Stage Liver Disease (MELD) has been the mainstay for organ allocation for nearly 2 decades, and there has been vigorous debate as to whether it should remain so. In this issue, Dr. Jasmohan Bajaj and Dr. Julie Heimbach discuss the strengths and limitations of MELD and provide a vision of upcoming developments. As always, I welcome your feedback and suggestions for future topics at [email protected].

Charles J. Kahi, MD, MS, AGAF, is professor of medicine at Indiana University, Indianapolis. He is an associate editor for GI & Hepatology News.
 

Yes, it’s time for an update

BY JASMOHAN S. BAJAJ, MD, AGAF

Since February 2002, the U.S.-based liver transplant system has adopted the MELD score for transplant priority. Initially developed to predict outcomes after transjugular intrahepatic porto-systemic shunt, it was modified to exclude etiology for the purpose of listing patients.¹

There were several advantages with MELD including objectivity, ease of calculation using a website, and over time, a burgeoning experience nationwide that extended even beyond transplant. Moreover, it focused on “sickest-first,” did away with the extremely “manipulable” waiting list, and left off hepatic encephalopathy (HE) and ascites severity.¹ However, even earlier on, there were concerns regarding not capturing hepatocellular cancer (HCC) and some complications of cirrhosis that required exceptions. The points awarded to all these exceptions also changed with time, with lower priority and reincorporation of the waiting list time for HCC. Over time, the addition of serum sodium led it to be converted to “MELD-Na,” which now remains the primary method for transplant listing priority.

But the population with cirrhosis that existed 20 years ago has shifted radically. Patients with cirrhosis currently tend to either be much older with more comorbid conditions that predispose them to chronic kidney disease and cerebrovascular and cardiovascular compromise or be younger with an earlier presentation of alcohol-associated hepatitis. Moreover, the widespread availability of hepatitis C virus (HCV) eradication has changed the landscape and stopped the progression of cirrhosis organically by virtually removing that etiology. This is relevant because a recent United Network for Organ Sharing (UNOS) analysis showed that the concordance between MELD score and 90-day mortality was the lowest in the rapidly increasing population with alcohol-related and nonalcoholic fatty liver disease etiologies, but conversely, this concordance was the highest in the population with hepatitis C–related cirrhosis.² These demographic shifts in age and changes in etiology likely lessen the predictive power of the current MELD score iteration.

There is also increasing evidence that MELD is “stuck in the middle.” This means that both patients at low MELD score and those with organ failures may be underserved with respect to transplant listing with the current MELD score iteration.

Among patients with a MELD score disproportionately lower than their complications of cirrhosis several studies demonstrate the improvement in prognostication with addition of covert HE, history of overt HE, frailty, and sarcopenia indices. These are independently prognostic variables that affect daily function, affect patient-reported outcomes, and can influence readmissions. The burden of impending falls, readmissions, infections, and overall ill health is not captured even though relatively objective methods such as cognitive tests and documented admissions for overt HE can be utilized.³ This relative mistrust in including HE and covariables likely harkens back to a dramatic reduction in grade III/IV HE severity seen the year after MELD introduction, when compared with the year before, during which that designation was added to the listing priority.⁴ However, objective additions to the MELD score that capture the distress of patients and their families with multiple readmissions for HE worsened by sarcopenia are desperately needed (see table).

Jasmohan S. Bajaj, MD, AGAF, is with the division of gastroenterology, hepatology, and nutrition at Virginia Commonwealth University, Richmond, and Richmond VA Medical Center. He has no conflicts of interest.

References

1. Kamath PS and Kim WR. Hepatology. 2007;45:797-805.

2. Godfrey EL et al. Am J Transplant. 2019;19:3299-307.

3. Acharya C and Bajaj JS. Liver Transpl. 2021 May 21. doi:10.1002/lt.26099.

4. Bajaj JS and Saeian K. Dig Dis Sci 2005;50:753-6.

5. Artru F and Samuel D. JHEP Rep 2019 May;1(1):53-65.

6. Bernardi M et al. J Hepatol 2010 Dec 9;54:1297-306.
 

Maybe, but take it slow

BY JULIE K. HEIMBACH, MD

Even though 2020 was another record year for organ donation in the United States, a truly remarkable feat considering the profound impact of COVID-19 on health care as well as the population at large, there remains a critical shortage of available liver allografts.1 Last year in the U.S., of the approximately 13,000 patients waiting for a liver transplant, just under 9,000 patients underwent liver transplantation from a deceased or a living donor, while 2,345 either died waiting on the list or were removed for being too sick, and the rest remained waiting.¹ In a perfect system, we would transplant every wait-listed patient at a time that would provide them the greatest benefit with the least amount of distress. However, because of the shortage of available organs for transplantation, an allocation system to rank wait-listed candidates is required. Because organ transplantation relies on the incredible altruism of individuals and their family members who make this ultimate gift on their behalf, it is crucial both for donor families and for waiting recipients that organ allocation be transparent, as fair and equitable as possible, and compliant with federal law, which is currently determined by the “Final Rule” that states that organ allocation be based in order of urgency.²

Since February 2002, U.S. liver allocation policy has been based on MELD.³ Prior to that time, liver allocation was based in part on the Child-Turcot-Pugh classification of liver disease, which included subjective components (ascites and encephalopathy) that are difficult to measure, as well as increased priority based on admission to the intensive care unit, also subjective and open to interpretation or abuse. Most crucially, the system defaulted to length of waiting time with large numbers of patients in the same category, which led to higher death rates for patients whose disease progressed more quickly or who were referred very late in their disease course.

MELD relies on a simple set of laboratory values that are easily obtained at any clinical lab and are already being routinely monitored as part of standard care for patients with end-stage liver disease.³ MELD initially required just three variables (bilirubin, creatinine, INR) and was updated to include just four variables with the adoption of MELD-Na in 2016, which added sodium levels. The MELD- and MELD-Na–based approach is a highly reliable, accurate way to rank patients who are most at risk of death in the next 3 months, with a C statistic of approximately 0.83-0.84.3,4 Perhaps the greatest testament to the strength of MELD is that, following the adoption of MELD-based liver allocation, MELD has gradually been adopted as the system of liver allocation by most countries around the world.

With the adoption of MELD and subsequently MELD-Na, which prioritize deceased donor liver allografts to the sickest patients first and is therefore compliant with the Final Rule, outcomes for patients waiting for liver transplant have steadily improved.^3,4 In addition, MELD has provided an easily obtainable, objective measure to guide decisions about timing of liver transplant, especially in the setting of potential living donor liver transplantation. MELD is also predictive of outcome for patients undergoing nontransplant elective and emergent surgical procedures, and because of the ease in calculating the score, it allows for an objective comparison of patients with cirrhosis across a variety of clinical and research settings.

The MELD system has many additional strengths, though perhaps the most important is that it is adaptable. While the MELD score accurately predicts death from chronic liver disease, the MELD score is not able to predict mortality or risk of wait-list dropout due to disease progression from certain complications of chronic liver disease such as the development of HCC or hepatopulmonary syndrome, in which access to timely transplantation has been proven to be beneficial. This has required an adaption to the system whereby candidates with conditions, such as HCC, that meet specific criteria receive an assigned MELD score, rather than a calculated score. Determining which patients should qualify for MELD exceptions, as well as what the assigned priority score should be, has required careful analysis and ongoing revision. An additional issue for MELD, which was identified more than a decade ago and is overdue for adjustment, is the disparity in access to transplant for women who continue to experience a lower transplant rate (14.4% according to the most recent analysis) and approximately 8.6% higher death rate than men with the same MELD score.⁵ This is due, in part, to the use of creatinine in the MELD equation, which as a by-product of muscle metabolism, underestimates the degree of renal dysfunction in women and thus underestimates their risk of wait-list mortality.⁵ A potential modification to the MELD-Na score that corrects for this sex-based disparity is currently being studied by the OPTN Liver-Intestine committee, which is further evidence of the strength and adaptability of a MELD-based allocation system.

While it is tempting to conclude that a system that requires on-going monitoring and revision is best discarded in favor of a new model such as an artificial intelligence–based solution, policy development requires a tremendous amount of time for consensus-building, as well as effort to ensure that unexpected negative effects are not created. Whereas a novel system could be identified and determined to be superior down the road, the amount of effort and expense that would be needed to build consensus around such a new model should not be underestimated. Considering the challenges to health care and the population at large that are already occurring as we emerge from the COVID pandemic, as well as the short-term need to monitor the impact from the recent adoption of the acuity circle model which went live in February 2020 and allocates according to MELD but over a broader geographic area based on a circle around the donor hospital, building consensus around incremental changes to a MELD-based allocation system likely represents the best option in our continued quest for the optimal liver allocation system.
 

Julie K. Heimbach, MD, is a transplant surgeon and the surgical director of liver transplantation at Mayo Clinic in Rochester, Minn. She has no conflicts to report.

References

1. Organ Procurement and Transplantation Network data. Available at https://optn.transplant.hrsa.gov/data/view-data-reports/national-data. Accessed May 1, 2021.

2. Organ Procurement and Transplantation Network. Final rule. Available at https://optn.transplant.hrsa.gov/governance/about-the-optn/final-rule. Accessed May 1, 2021.

3. Wiesner R et al; United Network for Organ Sharing Liver Disease Severity Score Committee. Gastroenterology. 2003 Jan;124(1):91-6.

4. Nagai S et al. Gastroenterology. 2018 Nov;155(5):1451-62.e3.

5. Locke JE et al. JAMA Surg. 2020 Jul 1;155(7):e201129.

Dear colleagues and friends,

The Perspectives series continues! There are few issues in our discipline that are as challenging, and controversial, as liver transplant prioritization. The Model for End-Stage Liver Disease (MELD) has been the mainstay for organ allocation for nearly 2 decades, and there has been vigorous debate as to whether it should remain so. In this issue, Dr. Jasmohan Bajaj and Dr. Julie Heimbach discuss the strengths and limitations of MELD and provide a vision of upcoming developments. As always, I welcome your feedback and suggestions for future topics at [email protected].

Charles J. Kahi, MD, MS, AGAF, is professor of medicine at Indiana University, Indianapolis. He is an associate editor for GI & Hepatology News.
 

Yes, it’s time for an update

BY JASMOHAN S. BAJAJ, MD, AGAF

Since February 2002, the U.S.-based liver transplant system has adopted the MELD score for transplant priority. Initially developed to predict outcomes after transjugular intrahepatic porto-systemic shunt, it was modified to exclude etiology for the purpose of listing patients.¹

There were several advantages with MELD including objectivity, ease of calculation using a website, and over time, a burgeoning experience nationwide that extended even beyond transplant. Moreover, it focused on “sickest-first,” did away with the extremely “manipulable” waiting list, and left off hepatic encephalopathy (HE) and ascites severity.¹ However, even earlier on, there were concerns regarding not capturing hepatocellular cancer (HCC) and some complications of cirrhosis that required exceptions. The points awarded to all these exceptions also changed with time, with lower priority and reincorporation of the waiting list time for HCC. Over time, the addition of serum sodium led it to be converted to “MELD-Na,” which now remains the primary method for transplant listing priority.

But the population with cirrhosis that existed 20 years ago has shifted radically. Patients with cirrhosis currently tend to either be much older with more comorbid conditions that predispose them to chronic kidney disease and cerebrovascular and cardiovascular compromise or be younger with an earlier presentation of alcohol-associated hepatitis. Moreover, the widespread availability of hepatitis C virus (HCV) eradication has changed the landscape and stopped the progression of cirrhosis organically by virtually removing that etiology. This is relevant because a recent United Network for Organ Sharing (UNOS) analysis showed that the concordance between MELD score and 90-day mortality was the lowest in the rapidly increasing population with alcohol-related and nonalcoholic fatty liver disease etiologies, but conversely, this concordance was the highest in the population with hepatitis C–related cirrhosis.² These demographic shifts in age and changes in etiology likely lessen the predictive power of the current MELD score iteration.

There is also increasing evidence that MELD is “stuck in the middle.” This means that both patients at low MELD score and those with organ failures may be underserved with respect to transplant listing with the current MELD score iteration.

Among patients with a MELD score disproportionately lower than their complications of cirrhosis several studies demonstrate the improvement in prognostication with addition of covert HE, history of overt HE, frailty, and sarcopenia indices. These are independently prognostic variables that affect daily function, affect patient-reported outcomes, and can influence readmissions. The burden of impending falls, readmissions, infections, and overall ill health is not captured even though relatively objective methods such as cognitive tests and documented admissions for overt HE can be utilized.³ This relative mistrust in including HE and covariables likely harkens back to a dramatic reduction in grade III/IV HE severity seen the year after MELD introduction, when compared with the year before, during which that designation was added to the listing priority.⁴ However, objective additions to the MELD score that capture the distress of patients and their families with multiple readmissions for HE worsened by sarcopenia are desperately needed (see table).

Jasmohan S. Bajaj, MD, AGAF, is with the division of gastroenterology, hepatology, and nutrition at Virginia Commonwealth University, Richmond, and Richmond VA Medical Center. He has no conflicts of interest.

References

1. Kamath PS and Kim WR. Hepatology. 2007;45:797-805.

2. Godfrey EL et al. Am J Transplant. 2019;19:3299-307.

3. Acharya C and Bajaj JS. Liver Transpl. 2021 May 21. doi:10.1002/lt.26099.

4. Bajaj JS and Saeian K. Dig Dis Sci 2005;50:753-6.

5. Artru F and Samuel D. JHEP Rep 2019 May;1(1):53-65.

6. Bernardi M et al. J Hepatol 2010 Dec 9;54:1297-306.
 

Maybe, but take it slow

BY JULIE K. HEIMBACH, MD

Even though 2020 was another record year for organ donation in the United States, a truly remarkable feat considering the profound impact of COVID-19 on health care as well as the population at large, there remains a critical shortage of available liver allografts.1 Last year in the U.S., of the approximately 13,000 patients waiting for a liver transplant, just under 9,000 patients underwent liver transplantation from a deceased or a living donor, while 2,345 either died waiting on the list or were removed for being too sick, and the rest remained waiting.¹ In a perfect system, we would transplant every wait-listed patient at a time that would provide them the greatest benefit with the least amount of distress. However, because of the shortage of available organs for transplantation, an allocation system to rank wait-listed candidates is required. Because organ transplantation relies on the incredible altruism of individuals and their family members who make this ultimate gift on their behalf, it is crucial both for donor families and for waiting recipients that organ allocation be transparent, as fair and equitable as possible, and compliant with federal law, which is currently determined by the “Final Rule” that states that organ allocation be based in order of urgency.²

Since February 2002, U.S. liver allocation policy has been based on MELD.³ Prior to that time, liver allocation was based in part on the Child-Turcot-Pugh classification of liver disease, which included subjective components (ascites and encephalopathy) that are difficult to measure, as well as increased priority based on admission to the intensive care unit, also subjective and open to interpretation or abuse. Most crucially, the system defaulted to length of waiting time with large numbers of patients in the same category, which led to higher death rates for patients whose disease progressed more quickly or who were referred very late in their disease course.

MELD relies on a simple set of laboratory values that are easily obtained at any clinical lab and are already being routinely monitored as part of standard care for patients with end-stage liver disease.³ MELD initially required just three variables (bilirubin, creatinine, INR) and was updated to include just four variables with the adoption of MELD-Na in 2016, which added sodium levels. The MELD- and MELD-Na–based approach is a highly reliable, accurate way to rank patients who are most at risk of death in the next 3 months, with a C statistic of approximately 0.83-0.84.3,4 Perhaps the greatest testament to the strength of MELD is that, following the adoption of MELD-based liver allocation, MELD has gradually been adopted as the system of liver allocation by most countries around the world.

With the adoption of MELD and subsequently MELD-Na, which prioritize deceased donor liver allografts to the sickest patients first and is therefore compliant with the Final Rule, outcomes for patients waiting for liver transplant have steadily improved.^3,4 In addition, MELD has provided an easily obtainable, objective measure to guide decisions about timing of liver transplant, especially in the setting of potential living donor liver transplantation. MELD is also predictive of outcome for patients undergoing nontransplant elective and emergent surgical procedures, and because of the ease in calculating the score, it allows for an objective comparison of patients with cirrhosis across a variety of clinical and research settings.

The MELD system has many additional strengths, though perhaps the most important is that it is adaptable. While the MELD score accurately predicts death from chronic liver disease, the MELD score is not able to predict mortality or risk of wait-list dropout due to disease progression from certain complications of chronic liver disease such as the development of HCC or hepatopulmonary syndrome, in which access to timely transplantation has been proven to be beneficial. This has required an adaption to the system whereby candidates with conditions, such as HCC, that meet specific criteria receive an assigned MELD score, rather than a calculated score. Determining which patients should qualify for MELD exceptions, as well as what the assigned priority score should be, has required careful analysis and ongoing revision. An additional issue for MELD, which was identified more than a decade ago and is overdue for adjustment, is the disparity in access to transplant for women who continue to experience a lower transplant rate (14.4% according to the most recent analysis) and approximately 8.6% higher death rate than men with the same MELD score.⁵ This is due, in part, to the use of creatinine in the MELD equation, which as a by-product of muscle metabolism, underestimates the degree of renal dysfunction in women and thus underestimates their risk of wait-list mortality.⁵ A potential modification to the MELD-Na score that corrects for this sex-based disparity is currently being studied by the OPTN Liver-Intestine committee, which is further evidence of the strength and adaptability of a MELD-based allocation system.

While it is tempting to conclude that a system that requires on-going monitoring and revision is best discarded in favor of a new model such as an artificial intelligence–based solution, policy development requires a tremendous amount of time for consensus-building, as well as effort to ensure that unexpected negative effects are not created. Whereas a novel system could be identified and determined to be superior down the road, the amount of effort and expense that would be needed to build consensus around such a new model should not be underestimated. Considering the challenges to health care and the population at large that are already occurring as we emerge from the COVID pandemic, as well as the short-term need to monitor the impact from the recent adoption of the acuity circle model which went live in February 2020 and allocates according to MELD but over a broader geographic area based on a circle around the donor hospital, building consensus around incremental changes to a MELD-based allocation system likely represents the best option in our continued quest for the optimal liver allocation system.
 

Julie K. Heimbach, MD, is a transplant surgeon and the surgical director of liver transplantation at Mayo Clinic in Rochester, Minn. She has no conflicts to report.

References

1. Organ Procurement and Transplantation Network data. Available at https://optn.transplant.hrsa.gov/data/view-data-reports/national-data. Accessed May 1, 2021.

2. Organ Procurement and Transplantation Network. Final rule. Available at https://optn.transplant.hrsa.gov/governance/about-the-optn/final-rule. Accessed May 1, 2021.

3. Wiesner R et al; United Network for Organ Sharing Liver Disease Severity Score Committee. Gastroenterology. 2003 Jan;124(1):91-6.

4. Nagai S et al. Gastroenterology. 2018 Nov;155(5):1451-62.e3.

5. Locke JE et al. JAMA Surg. 2020 Jul 1;155(7):e201129.

Dear colleagues and friends,

The Perspectives series continues! There are few issues in our discipline that are as challenging, and controversial, as liver transplant prioritization. The Model for End-Stage Liver Disease (MELD) has been the mainstay for organ allocation for nearly 2 decades, and there has been vigorous debate as to whether it should remain so. In this issue, Dr. Jasmohan Bajaj and Dr. Julie Heimbach discuss the strengths and limitations of MELD and provide a vision of upcoming developments. As always, I welcome your feedback and suggestions for future topics at [email protected].

Charles J. Kahi, MD, MS, AGAF, is professor of medicine at Indiana University, Indianapolis. He is an associate editor for GI & Hepatology News.
 

Yes, it’s time for an update

BY JASMOHAN S. BAJAJ, MD, AGAF

Since February 2002, the U.S.-based liver transplant system has adopted the MELD score for transplant priority. Initially developed to predict outcomes after transjugular intrahepatic porto-systemic shunt, it was modified to exclude etiology for the purpose of listing patients.¹

There were several advantages with MELD including objectivity, ease of calculation using a website, and over time, a burgeoning experience nationwide that extended even beyond transplant. Moreover, it focused on “sickest-first,” did away with the extremely “manipulable” waiting list, and left off hepatic encephalopathy (HE) and ascites severity.¹ However, even earlier on, there were concerns regarding not capturing hepatocellular cancer (HCC) and some complications of cirrhosis that required exceptions. The points awarded to all these exceptions also changed with time, with lower priority and reincorporation of the waiting list time for HCC. Over time, the addition of serum sodium led it to be converted to “MELD-Na,” which now remains the primary method for transplant listing priority.

But the population with cirrhosis that existed 20 years ago has shifted radically. Patients with cirrhosis currently tend to either be much older with more comorbid conditions that predispose them to chronic kidney disease and cerebrovascular and cardiovascular compromise or be younger with an earlier presentation of alcohol-associated hepatitis. Moreover, the widespread availability of hepatitis C virus (HCV) eradication has changed the landscape and stopped the progression of cirrhosis organically by virtually removing that etiology. This is relevant because a recent United Network for Organ Sharing (UNOS) analysis showed that the concordance between MELD score and 90-day mortality was the lowest in the rapidly increasing population with alcohol-related and nonalcoholic fatty liver disease etiologies, but conversely, this concordance was the highest in the population with hepatitis C–related cirrhosis.² These demographic shifts in age and changes in etiology likely lessen the predictive power of the current MELD score iteration.

There is also increasing evidence that MELD is “stuck in the middle.” This means that both patients at low MELD score and those with organ failures may be underserved with respect to transplant listing with the current MELD score iteration.

Among patients with a MELD score disproportionately lower than their complications of cirrhosis several studies demonstrate the improvement in prognostication with addition of covert HE, history of overt HE, frailty, and sarcopenia indices. These are independently prognostic variables that affect daily function, affect patient-reported outcomes, and can influence readmissions. The burden of impending falls, readmissions, infections, and overall ill health is not captured even though relatively objective methods such as cognitive tests and documented admissions for overt HE can be utilized.³ This relative mistrust in including HE and covariables likely harkens back to a dramatic reduction in grade III/IV HE severity seen the year after MELD introduction, when compared with the year before, during which that designation was added to the listing priority.⁴ However, objective additions to the MELD score that capture the distress of patients and their families with multiple readmissions for HE worsened by sarcopenia are desperately needed (see table).

Jasmohan S. Bajaj, MD, AGAF, is with the division of gastroenterology, hepatology, and nutrition at Virginia Commonwealth University, Richmond, and Richmond VA Medical Center. He has no conflicts of interest.

References

1. Kamath PS and Kim WR. Hepatology. 2007;45:797-805.

2. Godfrey EL et al. Am J Transplant. 2019;19:3299-307.

3. Acharya C and Bajaj JS. Liver Transpl. 2021 May 21. doi:10.1002/lt.26099.

4. Bajaj JS and Saeian K. Dig Dis Sci 2005;50:753-6.

5. Artru F and Samuel D. JHEP Rep 2019 May;1(1):53-65.

6. Bernardi M et al. J Hepatol 2010 Dec 9;54:1297-306.
 

Maybe, but take it slow

BY JULIE K. HEIMBACH, MD

Even though 2020 was another record year for organ donation in the United States, a truly remarkable feat considering the profound impact of COVID-19 on health care as well as the population at large, there remains a critical shortage of available liver allografts.1 Last year in the U.S., of the approximately 13,000 patients waiting for a liver transplant, just under 9,000 patients underwent liver transplantation from a deceased or a living donor, while 2,345 either died waiting on the list or were removed for being too sick, and the rest remained waiting.¹ In a perfect system, we would transplant every wait-listed patient at a time that would provide them the greatest benefit with the least amount of distress. However, because of the shortage of available organs for transplantation, an allocation system to rank wait-listed candidates is required. Because organ transplantation relies on the incredible altruism of individuals and their family members who make this ultimate gift on their behalf, it is crucial both for donor families and for waiting recipients that organ allocation be transparent, as fair and equitable as possible, and compliant with federal law, which is currently determined by the “Final Rule” that states that organ allocation be based in order of urgency.²

Since February 2002, U.S. liver allocation policy has been based on MELD.³ Prior to that time, liver allocation was based in part on the Child-Turcot-Pugh classification of liver disease, which included subjective components (ascites and encephalopathy) that are difficult to measure, as well as increased priority based on admission to the intensive care unit, also subjective and open to interpretation or abuse. Most crucially, the system defaulted to length of waiting time with large numbers of patients in the same category, which led to higher death rates for patients whose disease progressed more quickly or who were referred very late in their disease course.

MELD relies on a simple set of laboratory values that are easily obtained at any clinical lab and are already being routinely monitored as part of standard care for patients with end-stage liver disease.³ MELD initially required just three variables (bilirubin, creatinine, INR) and was updated to include just four variables with the adoption of MELD-Na in 2016, which added sodium levels. The MELD- and MELD-Na–based approach is a highly reliable, accurate way to rank patients who are most at risk of death in the next 3 months, with a C statistic of approximately 0.83-0.84.3,4 Perhaps the greatest testament to the strength of MELD is that, following the adoption of MELD-based liver allocation, MELD has gradually been adopted as the system of liver allocation by most countries around the world.

With the adoption of MELD and subsequently MELD-Na, which prioritize deceased donor liver allografts to the sickest patients first and is therefore compliant with the Final Rule, outcomes for patients waiting for liver transplant have steadily improved.^3,4 In addition, MELD has provided an easily obtainable, objective measure to guide decisions about timing of liver transplant, especially in the setting of potential living donor liver transplantation. MELD is also predictive of outcome for patients undergoing nontransplant elective and emergent surgical procedures, and because of the ease in calculating the score, it allows for an objective comparison of patients with cirrhosis across a variety of clinical and research settings.

The MELD system has many additional strengths, though perhaps the most important is that it is adaptable. While the MELD score accurately predicts death from chronic liver disease, the MELD score is not able to predict mortality or risk of wait-list dropout due to disease progression from certain complications of chronic liver disease such as the development of HCC or hepatopulmonary syndrome, in which access to timely transplantation has been proven to be beneficial. This has required an adaption to the system whereby candidates with conditions, such as HCC, that meet specific criteria receive an assigned MELD score, rather than a calculated score. Determining which patients should qualify for MELD exceptions, as well as what the assigned priority score should be, has required careful analysis and ongoing revision. An additional issue for MELD, which was identified more than a decade ago and is overdue for adjustment, is the disparity in access to transplant for women who continue to experience a lower transplant rate (14.4% according to the most recent analysis) and approximately 8.6% higher death rate than men with the same MELD score.⁵ This is due, in part, to the use of creatinine in the MELD equation, which as a by-product of muscle metabolism, underestimates the degree of renal dysfunction in women and thus underestimates their risk of wait-list mortality.⁵ A potential modification to the MELD-Na score that corrects for this sex-based disparity is currently being studied by the OPTN Liver-Intestine committee, which is further evidence of the strength and adaptability of a MELD-based allocation system.

While it is tempting to conclude that a system that requires on-going monitoring and revision is best discarded in favor of a new model such as an artificial intelligence–based solution, policy development requires a tremendous amount of time for consensus-building, as well as effort to ensure that unexpected negative effects are not created. Whereas a novel system could be identified and determined to be superior down the road, the amount of effort and expense that would be needed to build consensus around such a new model should not be underestimated. Considering the challenges to health care and the population at large that are already occurring as we emerge from the COVID pandemic, as well as the short-term need to monitor the impact from the recent adoption of the acuity circle model which went live in February 2020 and allocates according to MELD but over a broader geographic area based on a circle around the donor hospital, building consensus around incremental changes to a MELD-based allocation system likely represents the best option in our continued quest for the optimal liver allocation system.
 

Julie K. Heimbach, MD, is a transplant surgeon and the surgical director of liver transplantation at Mayo Clinic in Rochester, Minn. She has no conflicts to report.

References

1. Organ Procurement and Transplantation Network data. Available at https://optn.transplant.hrsa.gov/data/view-data-reports/national-data. Accessed May 1, 2021.

2. Organ Procurement and Transplantation Network. Final rule. Available at https://optn.transplant.hrsa.gov/governance/about-the-optn/final-rule. Accessed May 1, 2021.

3. Wiesner R et al; United Network for Organ Sharing Liver Disease Severity Score Committee. Gastroenterology. 2003 Jan;124(1):91-6.

4. Nagai S et al. Gastroenterology. 2018 Nov;155(5):1451-62.e3.

5. Locke JE et al. JAMA Surg. 2020 Jul 1;155(7):e201129.

In last month’s Gastroenterology,  Vijay H. Shah, MD, and colleagues share a commentary on the esteemed career of this year’s Julius Friedenwald Medal recipient, Michael Camilleri, MD, of the Mayo Clinic in Rochester, Minnesota. Here are some fun facts about this year’s honoree:

• While growing up in Malta, he was influenced by a combination of his uncle, a kindly family physician, and by watching the shows Dr. Kildare and Marcus Welby, M.D., on a black-and-white television set during his childhood, which led Dr. Camilleri to commit to a career in medicine by the age of 8.
• Dr. Camilleri started his journey at the Mayo Clinic as a research fellow in 1983 conducting fundamental clinical research in GI motility.
• With 660 peer-reviewed original articles and 290 published invited reviews and editorial publications, Dr. Camilleri has redefined the understanding and treatment of disorders covering the entire GI tract from rumination syndrome to pelvic dyssynergia.
• Dr. Camilleri has mentored 79 postdoctoral fellows since he joined the faculty at Mayo Clinic 35 years ago.

Read more about Dr. Camilleri’s life and contribution to the GI community in this Gastroenterology commentary, written by his colleagues and friends, including Dr. Shah and Adil E. Bharucha, MBBS, MD; David A. Katzka, MD; and Gregory J. Gores, MD.

In last month’s Gastroenterology,  Vijay H. Shah, MD, and colleagues share a commentary on the esteemed career of this year’s Julius Friedenwald Medal recipient, Michael Camilleri, MD, of the Mayo Clinic in Rochester, Minnesota. Here are some fun facts about this year’s honoree:

• While growing up in Malta, he was influenced by a combination of his uncle, a kindly family physician, and by watching the shows Dr. Kildare and Marcus Welby, M.D., on a black-and-white television set during his childhood, which led Dr. Camilleri to commit to a career in medicine by the age of 8.
• Dr. Camilleri started his journey at the Mayo Clinic as a research fellow in 1983 conducting fundamental clinical research in GI motility.
• With 660 peer-reviewed original articles and 290 published invited reviews and editorial publications, Dr. Camilleri has redefined the understanding and treatment of disorders covering the entire GI tract from rumination syndrome to pelvic dyssynergia.
• Dr. Camilleri has mentored 79 postdoctoral fellows since he joined the faculty at Mayo Clinic 35 years ago.

Read more about Dr. Camilleri’s life and contribution to the GI community in this Gastroenterology commentary, written by his colleagues and friends, including Dr. Shah and Adil E. Bharucha, MBBS, MD; David A. Katzka, MD; and Gregory J. Gores, MD.

In last month’s Gastroenterology,  Vijay H. Shah, MD, and colleagues share a commentary on the esteemed career of this year’s Julius Friedenwald Medal recipient, Michael Camilleri, MD, of the Mayo Clinic in Rochester, Minnesota. Here are some fun facts about this year’s honoree:

• While growing up in Malta, he was influenced by a combination of his uncle, a kindly family physician, and by watching the shows Dr. Kildare and Marcus Welby, M.D., on a black-and-white television set during his childhood, which led Dr. Camilleri to commit to a career in medicine by the age of 8.
• Dr. Camilleri started his journey at the Mayo Clinic as a research fellow in 1983 conducting fundamental clinical research in GI motility.
• With 660 peer-reviewed original articles and 290 published invited reviews and editorial publications, Dr. Camilleri has redefined the understanding and treatment of disorders covering the entire GI tract from rumination syndrome to pelvic dyssynergia.
• Dr. Camilleri has mentored 79 postdoctoral fellows since he joined the faculty at Mayo Clinic 35 years ago.

Read more about Dr. Camilleri’s life and contribution to the GI community in this Gastroenterology commentary, written by his colleagues and friends, including Dr. Shah and Adil E. Bharucha, MBBS, MD; David A. Katzka, MD; and Gregory J. Gores, MD.

July is typically the month when new students/physicians arrive at academic medical centers, schools, and hospitals to begin the next phase of training. July also marks the beginning of practice for graduating fellows. In the post-COVID world, these settings will have changed dramatically from the past.

Community practices are consolidating rapidly, with many being acquired by private equity firms, hospitals, and health systems. Private equity made its first investment in GI in 2016, when Audax acquired Miami-based Gastro Health. It was announced this past May that Audax sold Gastro Health to Omers (a larger, Canadian PE firm), marking the first PE sale of a practice (second bite) (Newitt P. “Gastro Health sold to private equity company.” Becker’s GI & Endoscopy. 2021 May 19). The financial success of this model has not been lost on any community practice, so expect more such transactions.

Health systems are bouncing back from 2020, with balance sheets that are recovering quickly. But operating margins are still narrow so physician productivity is being pushed and burnout is a hot-button issue. Older workers are retiring at increasing rates, and low-wage workers are often reluctant to return to the workforce. Both trends increase Medicare and Medicaid rolls. As more patients enter government insurance programs, provider reimbursement falls. “Manage to Medicare” (bringing costs down to levels that are sustainable on Medicare rates) has again become a common goal. The historic reaction to these financial pressures has been to push commercial rates higher thru market consolidation and emphasize margin-producing services.

COVID has changed medicine. We will deliver care differently, and health inequities inherent in the current system will not be tolerable. We now can analyze population-level health outcomes by mining data from enormous databases containing both administrative and health records. Imagine the information we could derive by analyzing IBD populations scattered across multiple states, all cared for by 1,000 gastroenterologists working in a mega practice that uses a single electronic medical record. That might break down the town-gown barrier quickly.

John I. Allen, MD, MBA, AGAF
Editor in Chief

July is typically the month when new students/physicians arrive at academic medical centers, schools, and hospitals to begin the next phase of training. July also marks the beginning of practice for graduating fellows. In the post-COVID world, these settings will have changed dramatically from the past.

Community practices are consolidating rapidly, with many being acquired by private equity firms, hospitals, and health systems. Private equity made its first investment in GI in 2016, when Audax acquired Miami-based Gastro Health. It was announced this past May that Audax sold Gastro Health to Omers (a larger, Canadian PE firm), marking the first PE sale of a practice (second bite) (Newitt P. “Gastro Health sold to private equity company.” Becker’s GI & Endoscopy. 2021 May 19). The financial success of this model has not been lost on any community practice, so expect more such transactions.

Health systems are bouncing back from 2020, with balance sheets that are recovering quickly. But operating margins are still narrow so physician productivity is being pushed and burnout is a hot-button issue. Older workers are retiring at increasing rates, and low-wage workers are often reluctant to return to the workforce. Both trends increase Medicare and Medicaid rolls. As more patients enter government insurance programs, provider reimbursement falls. “Manage to Medicare” (bringing costs down to levels that are sustainable on Medicare rates) has again become a common goal. The historic reaction to these financial pressures has been to push commercial rates higher thru market consolidation and emphasize margin-producing services.

COVID has changed medicine. We will deliver care differently, and health inequities inherent in the current system will not be tolerable. We now can analyze population-level health outcomes by mining data from enormous databases containing both administrative and health records. Imagine the information we could derive by analyzing IBD populations scattered across multiple states, all cared for by 1,000 gastroenterologists working in a mega practice that uses a single electronic medical record. That might break down the town-gown barrier quickly.

John I. Allen, MD, MBA, AGAF
Editor in Chief

July is typically the month when new students/physicians arrive at academic medical centers, schools, and hospitals to begin the next phase of training. July also marks the beginning of practice for graduating fellows. In the post-COVID world, these settings will have changed dramatically from the past.

Community practices are consolidating rapidly, with many being acquired by private equity firms, hospitals, and health systems. Private equity made its first investment in GI in 2016, when Audax acquired Miami-based Gastro Health. It was announced this past May that Audax sold Gastro Health to Omers (a larger, Canadian PE firm), marking the first PE sale of a practice (second bite) (Newitt P. “Gastro Health sold to private equity company.” Becker’s GI & Endoscopy. 2021 May 19). The financial success of this model has not been lost on any community practice, so expect more such transactions.

Health systems are bouncing back from 2020, with balance sheets that are recovering quickly. But operating margins are still narrow so physician productivity is being pushed and burnout is a hot-button issue. Older workers are retiring at increasing rates, and low-wage workers are often reluctant to return to the workforce. Both trends increase Medicare and Medicaid rolls. As more patients enter government insurance programs, provider reimbursement falls. “Manage to Medicare” (bringing costs down to levels that are sustainable on Medicare rates) has again become a common goal. The historic reaction to these financial pressures has been to push commercial rates higher thru market consolidation and emphasize margin-producing services.

COVID has changed medicine. We will deliver care differently, and health inequities inherent in the current system will not be tolerable. We now can analyze population-level health outcomes by mining data from enormous databases containing both administrative and health records. Imagine the information we could derive by analyzing IBD populations scattered across multiple states, all cared for by 1,000 gastroenterologists working in a mega practice that uses a single electronic medical record. That might break down the town-gown barrier quickly.

John I. Allen, MD, MBA, AGAF
Editor in Chief

Answer: Erythropoietic protoporphyria.Figure B demonstrated massive cholestasis with brown deposits that represented protoporphyrin precipitates, which plugged the bile ducts and led to a cholestatic pattern of liver injury. Under polarized light, protoporhyrin precipitates produced Maltese crosses (Figure C), which are pathognomonic of erythropoietic protoporphyria (EPP). Porphyria is a rare group of inherited heme biosynthesis disorders. EPP is an uncommon type of porphyria and is secondary to a ferrochelatase (FECH) gene mutation, which results in deficient activity of the mitochondrial enzyme FECH.¹

FECH catalyzes chelation of iron into proptoporphyrin IX to form heme. The inability of protoporphyrins to be transformed into heme inhibits hepatic elimination and results in hepatocyte accumulation of protoporphyrins, leading to protoporphyrin precipitation in bile canaliculi. Painful photosensitivity (Figure A) is the most common manifestation of EPP, beginning in childhood.² Only a small proportion of patients with EPP develop liver dysfunction but the consequences can be severe.² Therefore, therapeutic decisions are based on limited published experience without randomized, controlled data.² One treatment method is to attempt to remove protoporphyrins from the blood via therapeutic plasma exchange.²Our patient underwent one session of therapeutic plasma exchange; however, after this initial course of treatment, the patient’s goals of care changed and she elected to enroll in hospice. Patients with severe liver dysfunction as a result of EPP require consideration of liver transplantation in the setting of fulminant hepatic failure. Liver transplantation does not cure EPP; the graft is at risk for similar EPP-related changes.¹ Only bone marrow transplantation can correct the underlying enzymatic defect in FECH.¹ Although physicians are often taught “common things are common,” this case highlights a rare complication of a rare disease such as porphyria is an often forgotten or missed condition. Vigilance should be kept for other rare conditions, especially ones with curative treatments or fatal consequences. In an era where the role of liver biopsy is often questioned in favor of prediction models or noninvasive testing, we must have a low threshold to safely perform a liver biopsy when the diagnosis is unclear or a patient is deteriorating.

The quiz authors disclosed no conflicts of interest.

References

1. Windon AL et al. Am J Transplant. 2018 Mar;18(3):745-9.

2. Pagano MB et al. J Clin Apher. 2012;27(6):336-41.

Answer: Erythropoietic protoporphyria.Figure B demonstrated massive cholestasis with brown deposits that represented protoporphyrin precipitates, which plugged the bile ducts and led to a cholestatic pattern of liver injury. Under polarized light, protoporhyrin precipitates produced Maltese crosses (Figure C), which are pathognomonic of erythropoietic protoporphyria (EPP). Porphyria is a rare group of inherited heme biosynthesis disorders. EPP is an uncommon type of porphyria and is secondary to a ferrochelatase (FECH) gene mutation, which results in deficient activity of the mitochondrial enzyme FECH.¹

FECH catalyzes chelation of iron into proptoporphyrin IX to form heme. The inability of protoporphyrins to be transformed into heme inhibits hepatic elimination and results in hepatocyte accumulation of protoporphyrins, leading to protoporphyrin precipitation in bile canaliculi. Painful photosensitivity (Figure A) is the most common manifestation of EPP, beginning in childhood.² Only a small proportion of patients with EPP develop liver dysfunction but the consequences can be severe.² Therefore, therapeutic decisions are based on limited published experience without randomized, controlled data.² One treatment method is to attempt to remove protoporphyrins from the blood via therapeutic plasma exchange.²Our patient underwent one session of therapeutic plasma exchange; however, after this initial course of treatment, the patient’s goals of care changed and she elected to enroll in hospice. Patients with severe liver dysfunction as a result of EPP require consideration of liver transplantation in the setting of fulminant hepatic failure. Liver transplantation does not cure EPP; the graft is at risk for similar EPP-related changes.¹ Only bone marrow transplantation can correct the underlying enzymatic defect in FECH.¹ Although physicians are often taught “common things are common,” this case highlights a rare complication of a rare disease such as porphyria is an often forgotten or missed condition. Vigilance should be kept for other rare conditions, especially ones with curative treatments or fatal consequences. In an era where the role of liver biopsy is often questioned in favor of prediction models or noninvasive testing, we must have a low threshold to safely perform a liver biopsy when the diagnosis is unclear or a patient is deteriorating.

The quiz authors disclosed no conflicts of interest.

References

1. Windon AL et al. Am J Transplant. 2018 Mar;18(3):745-9.

2. Pagano MB et al. J Clin Apher. 2012;27(6):336-41.

Answer: Erythropoietic protoporphyria.Figure B demonstrated massive cholestasis with brown deposits that represented protoporphyrin precipitates, which plugged the bile ducts and led to a cholestatic pattern of liver injury. Under polarized light, protoporhyrin precipitates produced Maltese crosses (Figure C), which are pathognomonic of erythropoietic protoporphyria (EPP). Porphyria is a rare group of inherited heme biosynthesis disorders. EPP is an uncommon type of porphyria and is secondary to a ferrochelatase (FECH) gene mutation, which results in deficient activity of the mitochondrial enzyme FECH.¹

FECH catalyzes chelation of iron into proptoporphyrin IX to form heme. The inability of protoporphyrins to be transformed into heme inhibits hepatic elimination and results in hepatocyte accumulation of protoporphyrins, leading to protoporphyrin precipitation in bile canaliculi. Painful photosensitivity (Figure A) is the most common manifestation of EPP, beginning in childhood.² Only a small proportion of patients with EPP develop liver dysfunction but the consequences can be severe.² Therefore, therapeutic decisions are based on limited published experience without randomized, controlled data.² One treatment method is to attempt to remove protoporphyrins from the blood via therapeutic plasma exchange.²Our patient underwent one session of therapeutic plasma exchange; however, after this initial course of treatment, the patient’s goals of care changed and she elected to enroll in hospice. Patients with severe liver dysfunction as a result of EPP require consideration of liver transplantation in the setting of fulminant hepatic failure. Liver transplantation does not cure EPP; the graft is at risk for similar EPP-related changes.¹ Only bone marrow transplantation can correct the underlying enzymatic defect in FECH.¹ Although physicians are often taught “common things are common,” this case highlights a rare complication of a rare disease such as porphyria is an often forgotten or missed condition. Vigilance should be kept for other rare conditions, especially ones with curative treatments or fatal consequences. In an era where the role of liver biopsy is often questioned in favor of prediction models or noninvasive testing, we must have a low threshold to safely perform a liver biopsy when the diagnosis is unclear or a patient is deteriorating.

The quiz authors disclosed no conflicts of interest.

References

1. Windon AL et al. Am J Transplant. 2018 Mar;18(3):745-9.

2. Pagano MB et al. J Clin Apher. 2012;27(6):336-41.

A novel oral inhibitor of transglutaminase 2 appears to block gluten-induced mucosal damage in patients with celiac disease at three different doses, based on proof-of-concept trial data from 132 patients.

“Currently, no drug therapy reliably prevents the effects of dietary gluten or has been approved by regulators to treat celiac disease,” which remains an unmet need in these patients, many of whom struggle with symptoms even when they adhere to a gluten-free diet, wrote Detlef Schuppan, MD, of Johannes Gutenberg University of Mainz (Germany) and colleagues.

Celiac disease is driven in part by the enzyme transglutaminase 2, and a transglutaminase 2 inhibitor known as ZED1227 has been tested safely in phase 1 trials, they reported.

“ZED1227 targets the intestinal mucosa predominantly and thereby mediates protection; thus, it is unaffected by the complexity of the food matrix and is less dependent on the timing of ingestion of gluten-containing food,” the researchers explained.

In a study published in the New England Journal of Medicine, the researchers assessed the safety and efficacy of three dose levels of ZED1227. Adults with controlled celiac disease were randomized to doses of 10 mg (41 patients), 50 mg (41 patients), and 100 mg (41 patients), and 40 patients received a placebo. Of these, 35, 39, 28, and 30 patients, respectively, had sufficient duodenal biopsy samples for analysis.

Patients underwent a daily gluten challenge of 3 g for 6 weeks. At the end of 6 weeks, the primary study endpoint of attenuation of gluten-induced mucosal damage was measured by the ratio of villus height to crypt depth.

Patients in all three treatment groups showed significant attenuation of mucosal damage. The change in the average ratio of villus height to crypt depth compared to placebo in the 10-mg, 50-mg, and 100-mg groups was 0.44, 0.49, and 0.48, respectively, with P values equal to .001 in the 10-mg group and less than .001 in the 50-mg and 100-mg groups.

Adverse events were similar across all treatment groups and the placebo group, with the exception of a rash in three patients in the 100-mg group. A total of 74 patients reported adverse events, and the most common were headache, nausea, diarrhea, vomiting, and abdominal pain. The investigators determined that from 34% to 55% of the adverse events across groups were related to the study drug or placebo.

Two patients developed serious adverse events that were deemed related to the study drug or placebo; one patient in the 50-mg group developed migraine with aura, and one placebo patient developed ventricular extrasystoles. The patients recovered after discontinuing the drug or placebo.

Secondary endpoints included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score. Estimated changes in intraepithelial lymphocyte density, compared with placebo, were –2.7 cells per 100 epithelial cells in the 10-mg group, −4.2 cells per 100 epithelial cells in the 50-mg group, and −9.6 cells per 100 epithelial cells in the 100-mg group. Compared with those of patients taking placebo, the 6-week changes in Celiac Symptom Index scores and Celiac Disease Questionnaire scores suggested slight improvements in symptoms and quality of life for the 100-mg dose.

The study findings were limited by several factors including missing data and loss of several patients to follow-up, as well as the short trial duration and use of controlled gluten ingestion, the researchers noted. Larger studies involving real-world conditions of minor gluten ingestion are needed to support the preliminary signs of safety and efficacy, they said.

Study strengths include high levels of patient adherence to the treatment and the gluten challenge, they said. “Future studies of ZED1227 in more patients are needed to provide additional evidence of the safety and efficacy of the drug, potentially in real-life conditions with minor gluten ingestion,” they concluded.
 

Translating potential into practice

“An absence of mucosal damage is a critical criterion to ensure the long-term health of a patient, and this clinical trial in celiac disease meets this important endpoint,” Bana Jabri, MD, of the University of Chicago, wrote in an accompanying editorial.

The primary endpoint of no mucosal damage is “especially notable because it was achieved under a controlled gluten challenge, albeit with a relatively moderate amount of gluten (a regular diet contains 12 g of gluten daily, whereas the challenge involved 3 g daily) and for a short period of time,” Dr. Jabri said. The reduction of disease-associated symptoms and apparent improvement in quality of life with 100-mg dose added value to the findings, she said.

Future research areas include whether cross-reactive T cells, which were not analyzed in the current study, might “expand and become pathogenic after a long-term gluten challenge,” Dr. Jabri noted.

However, “ZED1227 is the first nondietary treatment that has preliminarily shown the capacity to prevent mucosal damage in persons with celiac disease,” she said.

“Although this trial is very encouraging, whether treatment with ZED1227, and more generally transglutaminase 2 inhibition, in patients with celiac disease will be efficient in real life and during long-term gluten exposure remains to be determined,” Dr. Jabri concluded.
 

Need for data on dosing consistency

“Celiac disease affects up to 2% of the population in many countries, and the main therapy of celiac disease is avoidance of gluten,” Kim Isaacs, MD, of the University of North Carolina, Chapel Hill, said in an interview. “This is challenging due to the ubiquitous nature of gluten in many food products,” she said. “Restrictive eating also affects social interaction which is often focused around food,” she added. “Availability of an oral therapy that is effective to treat celiac in the face of gluten exposure will have a profound impact on patients in terms of liberalization of dietary intake.”

Overall, “the changes in the villus height to crypt depth was similar between all the active treatment groups, whereas there was a dose-dependent reduction in transepithelial lymphocyte density,” Dr. Isaacs noted. “The symptom improvement was greatest in the 100-mg group, suggesting that symptoms may be related to a greater extent to the lymphocyte density than the minimal differences in villus height to crypt depth ratios seen in the active treatment groups,” she said.

Potential barriers to the use of the treatment include cost because “this will need to be a daily long-term therapy,” said Dr. Isaacs. “Compliance is a potential barrier as well,” she said. “This study looks at daily administration of the transglutaminase 2 inhibitor and shows a benefit, but it is not clear whether missing doses of the medication will have a prolonged impact on efficacy,” she emphasized. Consequently, long-term efficacy studies are needed, Dr. Isaacs said. Other research questions to answer include whether patients will become refractory to the beneficial effects over time, the effect of missing doses, and whether patients would lose all the benefits of the therapy if dosing is not consistent, she emphasized.

The study was funded by Dr. Falk Pharma. The researchers, as well as Dr. Jabri and Dr. Isaacs, had no financial conflicts to disclose. Dr. Isaacs is on the editorial advisory board of GI & Hepatology News.

A novel oral inhibitor of transglutaminase 2 appears to block gluten-induced mucosal damage in patients with celiac disease at three different doses, based on proof-of-concept trial data from 132 patients.

“Currently, no drug therapy reliably prevents the effects of dietary gluten or has been approved by regulators to treat celiac disease,” which remains an unmet need in these patients, many of whom struggle with symptoms even when they adhere to a gluten-free diet, wrote Detlef Schuppan, MD, of Johannes Gutenberg University of Mainz (Germany) and colleagues.

Celiac disease is driven in part by the enzyme transglutaminase 2, and a transglutaminase 2 inhibitor known as ZED1227 has been tested safely in phase 1 trials, they reported.

“ZED1227 targets the intestinal mucosa predominantly and thereby mediates protection; thus, it is unaffected by the complexity of the food matrix and is less dependent on the timing of ingestion of gluten-containing food,” the researchers explained.

In a study published in the New England Journal of Medicine, the researchers assessed the safety and efficacy of three dose levels of ZED1227. Adults with controlled celiac disease were randomized to doses of 10 mg (41 patients), 50 mg (41 patients), and 100 mg (41 patients), and 40 patients received a placebo. Of these, 35, 39, 28, and 30 patients, respectively, had sufficient duodenal biopsy samples for analysis.

Patients underwent a daily gluten challenge of 3 g for 6 weeks. At the end of 6 weeks, the primary study endpoint of attenuation of gluten-induced mucosal damage was measured by the ratio of villus height to crypt depth.

Patients in all three treatment groups showed significant attenuation of mucosal damage. The change in the average ratio of villus height to crypt depth compared to placebo in the 10-mg, 50-mg, and 100-mg groups was 0.44, 0.49, and 0.48, respectively, with P values equal to .001 in the 10-mg group and less than .001 in the 50-mg and 100-mg groups.

Adverse events were similar across all treatment groups and the placebo group, with the exception of a rash in three patients in the 100-mg group. A total of 74 patients reported adverse events, and the most common were headache, nausea, diarrhea, vomiting, and abdominal pain. The investigators determined that from 34% to 55% of the adverse events across groups were related to the study drug or placebo.

Two patients developed serious adverse events that were deemed related to the study drug or placebo; one patient in the 50-mg group developed migraine with aura, and one placebo patient developed ventricular extrasystoles. The patients recovered after discontinuing the drug or placebo.

Secondary endpoints included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score. Estimated changes in intraepithelial lymphocyte density, compared with placebo, were –2.7 cells per 100 epithelial cells in the 10-mg group, −4.2 cells per 100 epithelial cells in the 50-mg group, and −9.6 cells per 100 epithelial cells in the 100-mg group. Compared with those of patients taking placebo, the 6-week changes in Celiac Symptom Index scores and Celiac Disease Questionnaire scores suggested slight improvements in symptoms and quality of life for the 100-mg dose.

The study findings were limited by several factors including missing data and loss of several patients to follow-up, as well as the short trial duration and use of controlled gluten ingestion, the researchers noted. Larger studies involving real-world conditions of minor gluten ingestion are needed to support the preliminary signs of safety and efficacy, they said.

Study strengths include high levels of patient adherence to the treatment and the gluten challenge, they said. “Future studies of ZED1227 in more patients are needed to provide additional evidence of the safety and efficacy of the drug, potentially in real-life conditions with minor gluten ingestion,” they concluded.
 

Translating potential into practice

“An absence of mucosal damage is a critical criterion to ensure the long-term health of a patient, and this clinical trial in celiac disease meets this important endpoint,” Bana Jabri, MD, of the University of Chicago, wrote in an accompanying editorial.

The primary endpoint of no mucosal damage is “especially notable because it was achieved under a controlled gluten challenge, albeit with a relatively moderate amount of gluten (a regular diet contains 12 g of gluten daily, whereas the challenge involved 3 g daily) and for a short period of time,” Dr. Jabri said. The reduction of disease-associated symptoms and apparent improvement in quality of life with 100-mg dose added value to the findings, she said.

Future research areas include whether cross-reactive T cells, which were not analyzed in the current study, might “expand and become pathogenic after a long-term gluten challenge,” Dr. Jabri noted.

However, “ZED1227 is the first nondietary treatment that has preliminarily shown the capacity to prevent mucosal damage in persons with celiac disease,” she said.

“Although this trial is very encouraging, whether treatment with ZED1227, and more generally transglutaminase 2 inhibition, in patients with celiac disease will be efficient in real life and during long-term gluten exposure remains to be determined,” Dr. Jabri concluded.
 

Need for data on dosing consistency

“Celiac disease affects up to 2% of the population in many countries, and the main therapy of celiac disease is avoidance of gluten,” Kim Isaacs, MD, of the University of North Carolina, Chapel Hill, said in an interview. “This is challenging due to the ubiquitous nature of gluten in many food products,” she said. “Restrictive eating also affects social interaction which is often focused around food,” she added. “Availability of an oral therapy that is effective to treat celiac in the face of gluten exposure will have a profound impact on patients in terms of liberalization of dietary intake.”

Overall, “the changes in the villus height to crypt depth was similar between all the active treatment groups, whereas there was a dose-dependent reduction in transepithelial lymphocyte density,” Dr. Isaacs noted. “The symptom improvement was greatest in the 100-mg group, suggesting that symptoms may be related to a greater extent to the lymphocyte density than the minimal differences in villus height to crypt depth ratios seen in the active treatment groups,” she said.

Potential barriers to the use of the treatment include cost because “this will need to be a daily long-term therapy,” said Dr. Isaacs. “Compliance is a potential barrier as well,” she said. “This study looks at daily administration of the transglutaminase 2 inhibitor and shows a benefit, but it is not clear whether missing doses of the medication will have a prolonged impact on efficacy,” she emphasized. Consequently, long-term efficacy studies are needed, Dr. Isaacs said. Other research questions to answer include whether patients will become refractory to the beneficial effects over time, the effect of missing doses, and whether patients would lose all the benefits of the therapy if dosing is not consistent, she emphasized.

The study was funded by Dr. Falk Pharma. The researchers, as well as Dr. Jabri and Dr. Isaacs, had no financial conflicts to disclose. Dr. Isaacs is on the editorial advisory board of GI & Hepatology News.

A novel oral inhibitor of transglutaminase 2 appears to block gluten-induced mucosal damage in patients with celiac disease at three different doses, based on proof-of-concept trial data from 132 patients.

“Currently, no drug therapy reliably prevents the effects of dietary gluten or has been approved by regulators to treat celiac disease,” which remains an unmet need in these patients, many of whom struggle with symptoms even when they adhere to a gluten-free diet, wrote Detlef Schuppan, MD, of Johannes Gutenberg University of Mainz (Germany) and colleagues.

Celiac disease is driven in part by the enzyme transglutaminase 2, and a transglutaminase 2 inhibitor known as ZED1227 has been tested safely in phase 1 trials, they reported.

“ZED1227 targets the intestinal mucosa predominantly and thereby mediates protection; thus, it is unaffected by the complexity of the food matrix and is less dependent on the timing of ingestion of gluten-containing food,” the researchers explained.

In a study published in the New England Journal of Medicine, the researchers assessed the safety and efficacy of three dose levels of ZED1227. Adults with controlled celiac disease were randomized to doses of 10 mg (41 patients), 50 mg (41 patients), and 100 mg (41 patients), and 40 patients received a placebo. Of these, 35, 39, 28, and 30 patients, respectively, had sufficient duodenal biopsy samples for analysis.

Patients underwent a daily gluten challenge of 3 g for 6 weeks. At the end of 6 weeks, the primary study endpoint of attenuation of gluten-induced mucosal damage was measured by the ratio of villus height to crypt depth.

Patients in all three treatment groups showed significant attenuation of mucosal damage. The change in the average ratio of villus height to crypt depth compared to placebo in the 10-mg, 50-mg, and 100-mg groups was 0.44, 0.49, and 0.48, respectively, with P values equal to .001 in the 10-mg group and less than .001 in the 50-mg and 100-mg groups.

Adverse events were similar across all treatment groups and the placebo group, with the exception of a rash in three patients in the 100-mg group. A total of 74 patients reported adverse events, and the most common were headache, nausea, diarrhea, vomiting, and abdominal pain. The investigators determined that from 34% to 55% of the adverse events across groups were related to the study drug or placebo.

Two patients developed serious adverse events that were deemed related to the study drug or placebo; one patient in the 50-mg group developed migraine with aura, and one placebo patient developed ventricular extrasystoles. The patients recovered after discontinuing the drug or placebo.

Secondary endpoints included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score. Estimated changes in intraepithelial lymphocyte density, compared with placebo, were –2.7 cells per 100 epithelial cells in the 10-mg group, −4.2 cells per 100 epithelial cells in the 50-mg group, and −9.6 cells per 100 epithelial cells in the 100-mg group. Compared with those of patients taking placebo, the 6-week changes in Celiac Symptom Index scores and Celiac Disease Questionnaire scores suggested slight improvements in symptoms and quality of life for the 100-mg dose.

The study findings were limited by several factors including missing data and loss of several patients to follow-up, as well as the short trial duration and use of controlled gluten ingestion, the researchers noted. Larger studies involving real-world conditions of minor gluten ingestion are needed to support the preliminary signs of safety and efficacy, they said.

Study strengths include high levels of patient adherence to the treatment and the gluten challenge, they said. “Future studies of ZED1227 in more patients are needed to provide additional evidence of the safety and efficacy of the drug, potentially in real-life conditions with minor gluten ingestion,” they concluded.
 

Translating potential into practice

“An absence of mucosal damage is a critical criterion to ensure the long-term health of a patient, and this clinical trial in celiac disease meets this important endpoint,” Bana Jabri, MD, of the University of Chicago, wrote in an accompanying editorial.

The primary endpoint of no mucosal damage is “especially notable because it was achieved under a controlled gluten challenge, albeit with a relatively moderate amount of gluten (a regular diet contains 12 g of gluten daily, whereas the challenge involved 3 g daily) and for a short period of time,” Dr. Jabri said. The reduction of disease-associated symptoms and apparent improvement in quality of life with 100-mg dose added value to the findings, she said.

Future research areas include whether cross-reactive T cells, which were not analyzed in the current study, might “expand and become pathogenic after a long-term gluten challenge,” Dr. Jabri noted.

However, “ZED1227 is the first nondietary treatment that has preliminarily shown the capacity to prevent mucosal damage in persons with celiac disease,” she said.

“Although this trial is very encouraging, whether treatment with ZED1227, and more generally transglutaminase 2 inhibition, in patients with celiac disease will be efficient in real life and during long-term gluten exposure remains to be determined,” Dr. Jabri concluded.
 

Need for data on dosing consistency

“Celiac disease affects up to 2% of the population in many countries, and the main therapy of celiac disease is avoidance of gluten,” Kim Isaacs, MD, of the University of North Carolina, Chapel Hill, said in an interview. “This is challenging due to the ubiquitous nature of gluten in many food products,” she said. “Restrictive eating also affects social interaction which is often focused around food,” she added. “Availability of an oral therapy that is effective to treat celiac in the face of gluten exposure will have a profound impact on patients in terms of liberalization of dietary intake.”

Overall, “the changes in the villus height to crypt depth was similar between all the active treatment groups, whereas there was a dose-dependent reduction in transepithelial lymphocyte density,” Dr. Isaacs noted. “The symptom improvement was greatest in the 100-mg group, suggesting that symptoms may be related to a greater extent to the lymphocyte density than the minimal differences in villus height to crypt depth ratios seen in the active treatment groups,” she said.

Potential barriers to the use of the treatment include cost because “this will need to be a daily long-term therapy,” said Dr. Isaacs. “Compliance is a potential barrier as well,” she said. “This study looks at daily administration of the transglutaminase 2 inhibitor and shows a benefit, but it is not clear whether missing doses of the medication will have a prolonged impact on efficacy,” she emphasized. Consequently, long-term efficacy studies are needed, Dr. Isaacs said. Other research questions to answer include whether patients will become refractory to the beneficial effects over time, the effect of missing doses, and whether patients would lose all the benefits of the therapy if dosing is not consistent, she emphasized.

The study was funded by Dr. Falk Pharma. The researchers, as well as Dr. Jabri and Dr. Isaacs, had no financial conflicts to disclose. Dr. Isaacs is on the editorial advisory board of GI & Hepatology News.

The opioid prescription rates have significantly decreased for children, teens, and younger adults between 2006 and 2018, according to new research.

“What’s important about this new study is that it documented that these improvements were also occurring for children and young adults specifically,” said Kao-Ping Chua, MD, PhD, primary care physician and assistant professor of pediatrics at the University of Michigan, Ann Arbor, who was not involved in the study. “The reason that’s important is that changes in medical practice for adults aren’t always reflected in pediatrics.”

The study, published in JAMA Pediatrics, found that dispensed opioid prescriptions for this population have decreased by 15% annually since 2013. However, the study also examined specific prescribing variables, such as duration of opioid prescription and high-dosage prescriptions. Researchers found reduced rates of high-dosage and long-duration prescriptions for adolescents and younger adults. However, these types of prescription practices increased in children aged 0-5 years.

“I think [the findings are] promising, suggesting that opiate prescribing practices may be improving,” study author Madeline Renny, MD, pediatric emergency medicine doctor at New York University Langone Health, said in an interview. “But we did find that there were increases in the young children for the practice variables, which we didn’t expect. I think that was kind of one of the findings that we were a bit surprised about and want to explore further.”

Previous studies have linked prescription opioid use in children and teens to an increased risk of future opioid misuse. A 2015 study published in Pediatrics found that using prescribed opioids before the 12th grade is associated with a 33% increase in the risk of future opioid misuse by the age of 23. The study also found that for those with a low predicted risk of future opioid misuse, an opioid prescription increases the risk for misuse after high school threefold.

Furthermore, a 2018 study published in JAMA Network Open found that, between 1999 and 2016, the annual estimated mortality rate for all children and adolescents from prescription and illicit opioid use rose 268.2%.

In the new study, Dr. Renny and colleagues examined data from 2006 to 2018 from IQVIA Longitudinal Prescription Data, which captured 74%-92% of U.S. retail outpatient opioid prescriptions dispensed to people up to the age of 24. Researchers also examined prescribing practice variables, which included opioid dispensing rates, average amount of opioid dispensed per prescription, duration of opioid prescription, high-dosage opioid prescription for individuals, and the rate in which extended-release or long-acting opioids are prescribed.

Researchers found that between 2006 and 2018, the total U.S. annual opioid prescriptions dispensed to patients younger than 25 years was highest in 2007 at 15,689,779 prescriptions, and since 2012 has steadily decreased to 6,705,478 in 2018.

“Our study did show that there were declines, but opioids remain readily dispensed,” Dr. Renny said. “And I think it’s good that rates have gone down, but I think opioids are still commonly dispensed to children and adolescents and young adults and all of our age groups.”

Dr. Chua said that the study was important, but when it came to younger children, it didn’t account for the fact that “the underlying population of patients who were getting opioids changed because it’s not the same group of children.”

“Maybe at the beginning there were more surgical patients who are getting shorter duration, lower dosage opioids,” he added. “Now some of those surgical exceptions kind of went away and who’s left in the population of people who get opioids is a sicker population.”

“Who are the 0 to 5-year-olds who are getting opioids now?” Dr. Chua asked. “Well, some of them are going to be cancer or surgical patients. If you think about it, over time their surgeons may be more judicious and they stop prescribing opioids for some things like circumcision or something like that. So that means that who’s left in the population of children who get opiate prescriptions are the cancer patients. Cancer patients’ opioid dosages are going to be higher because they have chronic pain.”

Dr. Chua said it is important to remember that the number of children who are affected by those high-risk prescriptions are lower because the overall number of opioid prescriptions has gone down. He added that the key piece of missing information is the absolute number of prescriptions that were high risk.

Researchers of the current study suggested that, because of the differences between pediatric and adult pain and indications for opioid prescribing, there should be national guidelines on general opioid prescribing for children and adolescents.

Experts did not disclose relevant financial relationships.

The opioid prescription rates have significantly decreased for children, teens, and younger adults between 2006 and 2018, according to new research.

“What’s important about this new study is that it documented that these improvements were also occurring for children and young adults specifically,” said Kao-Ping Chua, MD, PhD, primary care physician and assistant professor of pediatrics at the University of Michigan, Ann Arbor, who was not involved in the study. “The reason that’s important is that changes in medical practice for adults aren’t always reflected in pediatrics.”

The study, published in JAMA Pediatrics, found that dispensed opioid prescriptions for this population have decreased by 15% annually since 2013. However, the study also examined specific prescribing variables, such as duration of opioid prescription and high-dosage prescriptions. Researchers found reduced rates of high-dosage and long-duration prescriptions for adolescents and younger adults. However, these types of prescription practices increased in children aged 0-5 years.

“I think [the findings are] promising, suggesting that opiate prescribing practices may be improving,” study author Madeline Renny, MD, pediatric emergency medicine doctor at New York University Langone Health, said in an interview. “But we did find that there were increases in the young children for the practice variables, which we didn’t expect. I think that was kind of one of the findings that we were a bit surprised about and want to explore further.”

Previous studies have linked prescription opioid use in children and teens to an increased risk of future opioid misuse. A 2015 study published in Pediatrics found that using prescribed opioids before the 12th grade is associated with a 33% increase in the risk of future opioid misuse by the age of 23. The study also found that for those with a low predicted risk of future opioid misuse, an opioid prescription increases the risk for misuse after high school threefold.

Furthermore, a 2018 study published in JAMA Network Open found that, between 1999 and 2016, the annual estimated mortality rate for all children and adolescents from prescription and illicit opioid use rose 268.2%.

In the new study, Dr. Renny and colleagues examined data from 2006 to 2018 from IQVIA Longitudinal Prescription Data, which captured 74%-92% of U.S. retail outpatient opioid prescriptions dispensed to people up to the age of 24. Researchers also examined prescribing practice variables, which included opioid dispensing rates, average amount of opioid dispensed per prescription, duration of opioid prescription, high-dosage opioid prescription for individuals, and the rate in which extended-release or long-acting opioids are prescribed.

Researchers found that between 2006 and 2018, the total U.S. annual opioid prescriptions dispensed to patients younger than 25 years was highest in 2007 at 15,689,779 prescriptions, and since 2012 has steadily decreased to 6,705,478 in 2018.

“Our study did show that there were declines, but opioids remain readily dispensed,” Dr. Renny said. “And I think it’s good that rates have gone down, but I think opioids are still commonly dispensed to children and adolescents and young adults and all of our age groups.”

Dr. Chua said that the study was important, but when it came to younger children, it didn’t account for the fact that “the underlying population of patients who were getting opioids changed because it’s not the same group of children.”

“Maybe at the beginning there were more surgical patients who are getting shorter duration, lower dosage opioids,” he added. “Now some of those surgical exceptions kind of went away and who’s left in the population of people who get opioids is a sicker population.”

“Who are the 0 to 5-year-olds who are getting opioids now?” Dr. Chua asked. “Well, some of them are going to be cancer or surgical patients. If you think about it, over time their surgeons may be more judicious and they stop prescribing opioids for some things like circumcision or something like that. So that means that who’s left in the population of children who get opiate prescriptions are the cancer patients. Cancer patients’ opioid dosages are going to be higher because they have chronic pain.”

Dr. Chua said it is important to remember that the number of children who are affected by those high-risk prescriptions are lower because the overall number of opioid prescriptions has gone down. He added that the key piece of missing information is the absolute number of prescriptions that were high risk.

Researchers of the current study suggested that, because of the differences between pediatric and adult pain and indications for opioid prescribing, there should be national guidelines on general opioid prescribing for children and adolescents.

Experts did not disclose relevant financial relationships.

The opioid prescription rates have significantly decreased for children, teens, and younger adults between 2006 and 2018, according to new research.

“What’s important about this new study is that it documented that these improvements were also occurring for children and young adults specifically,” said Kao-Ping Chua, MD, PhD, primary care physician and assistant professor of pediatrics at the University of Michigan, Ann Arbor, who was not involved in the study. “The reason that’s important is that changes in medical practice for adults aren’t always reflected in pediatrics.”

The study, published in JAMA Pediatrics, found that dispensed opioid prescriptions for this population have decreased by 15% annually since 2013. However, the study also examined specific prescribing variables, such as duration of opioid prescription and high-dosage prescriptions. Researchers found reduced rates of high-dosage and long-duration prescriptions for adolescents and younger adults. However, these types of prescription practices increased in children aged 0-5 years.

“I think [the findings are] promising, suggesting that opiate prescribing practices may be improving,” study author Madeline Renny, MD, pediatric emergency medicine doctor at New York University Langone Health, said in an interview. “But we did find that there were increases in the young children for the practice variables, which we didn’t expect. I think that was kind of one of the findings that we were a bit surprised about and want to explore further.”

Previous studies have linked prescription opioid use in children and teens to an increased risk of future opioid misuse. A 2015 study published in Pediatrics found that using prescribed opioids before the 12th grade is associated with a 33% increase in the risk of future opioid misuse by the age of 23. The study also found that for those with a low predicted risk of future opioid misuse, an opioid prescription increases the risk for misuse after high school threefold.

Furthermore, a 2018 study published in JAMA Network Open found that, between 1999 and 2016, the annual estimated mortality rate for all children and adolescents from prescription and illicit opioid use rose 268.2%.

In the new study, Dr. Renny and colleagues examined data from 2006 to 2018 from IQVIA Longitudinal Prescription Data, which captured 74%-92% of U.S. retail outpatient opioid prescriptions dispensed to people up to the age of 24. Researchers also examined prescribing practice variables, which included opioid dispensing rates, average amount of opioid dispensed per prescription, duration of opioid prescription, high-dosage opioid prescription for individuals, and the rate in which extended-release or long-acting opioids are prescribed.

Researchers found that between 2006 and 2018, the total U.S. annual opioid prescriptions dispensed to patients younger than 25 years was highest in 2007 at 15,689,779 prescriptions, and since 2012 has steadily decreased to 6,705,478 in 2018.

“Our study did show that there were declines, but opioids remain readily dispensed,” Dr. Renny said. “And I think it’s good that rates have gone down, but I think opioids are still commonly dispensed to children and adolescents and young adults and all of our age groups.”

Dr. Chua said that the study was important, but when it came to younger children, it didn’t account for the fact that “the underlying population of patients who were getting opioids changed because it’s not the same group of children.”

“Maybe at the beginning there were more surgical patients who are getting shorter duration, lower dosage opioids,” he added. “Now some of those surgical exceptions kind of went away and who’s left in the population of people who get opioids is a sicker population.”

“Who are the 0 to 5-year-olds who are getting opioids now?” Dr. Chua asked. “Well, some of them are going to be cancer or surgical patients. If you think about it, over time their surgeons may be more judicious and they stop prescribing opioids for some things like circumcision or something like that. So that means that who’s left in the population of children who get opiate prescriptions are the cancer patients. Cancer patients’ opioid dosages are going to be higher because they have chronic pain.”

Dr. Chua said it is important to remember that the number of children who are affected by those high-risk prescriptions are lower because the overall number of opioid prescriptions has gone down. He added that the key piece of missing information is the absolute number of prescriptions that were high risk.

Researchers of the current study suggested that, because of the differences between pediatric and adult pain and indications for opioid prescribing, there should be national guidelines on general opioid prescribing for children and adolescents.

Experts did not disclose relevant financial relationships.

Ignore this pacemaker and it will go away

At some point – and now seems to be that point – we have to say enough is enough. The throwaway culture that produces phones, TVs, and computers that get tossed in the trash because they can’t be repaired has gone too far. That’s right, we’re looking at you, medical science!

This time, it’s a pacemaker that just disappears when it’s no longer needed. Some lazy heart surgeon decided that it was way too much trouble to do another surgery to remove the leads when a temporary pacemaker was no longer needed. You know the type: “It sure would be nice if the pacemaker components were biocompatible and were naturally absorbed by the body over the course of a few weeks and wouldn’t need to be surgically extracted.” Slacker.

Well, get a load of this. Researchers at Northwestern and George Washington universities say that they have come up with a transient pacemaker that “harvests energy from an external, remote antenna using near-field communication protocols – the same technology used in smartphones for electronic payments and in RFID tags.”

Northwestern University/George Washington University

It’s a mask! No, it’s a COVID-19 test!

Mask wearing has gotten more lax as people get vaccinated for COVID-19, but as wearing masks for virus prevention is becoming more normalized in western society, some saw an opportunity to make them work for diagnosis.

Researchers from the Massachusetts Institute of Technology and the Wyss Institute for Biologically Inspired Engineering at Harvard University have found a way to do just that with their wearable freeze-dried cell-free (wFDCF) technology. A single push of a button releases water from a reservoir in the mask that sequentially activates three different freeze-dried biological reactions, which detect the SARS-CoV-2 virus in the wearer’s breath.

Initially meant as a tool for the Zika outbreak in 2015, the team made a quick pivot in May 2020. But this isn’t just some run-of-the-mill, at-home test. The data prove that the wFDCF mask is comparable to polymerase chain reactions tests, the standard in COVID-19 detection. Plus there aren’t any extra factors to deal with, like room or instrument temperature to ensure accuracy. In just 90 minutes, the mask gives results on a readout in a way similar to that of a pregnancy test. Voilà! To have COVID-19 or not to have COVID-19 is an easily answered question.

UerDomwet/PxHere

Finally, an excuse for the all-beer diet

Weight loss is hard work. Extremely hard work, and, as evidenced by the constant inundation and advertisement of quick fixes, crash diets, and expensive gym memberships, there’s not really a solid, 100% solution to the issue. Until now, thanks to a team of doctors from New Zealand, who’ve decided that the best way to combat obesity is to leave you in constant agony.

The DentalSlim Diet Control device is certainly a radical yet comically logical attempt to combat obesity. The creators say that the biggest problem with dieting is compliance, and, well, it’s difficult to eat too much if you can’t actually open your mouth. The metal contraption is mounted onto your teeth and uses magnetic locks to prevent the user from opening their mouths more than 2 mm. That’s less than a tenth of an inch. Which is not a lot. So not a lot that essentially all you can consume is liquid.

University of Otago

Ignore this pacemaker and it will go away

At some point – and now seems to be that point – we have to say enough is enough. The throwaway culture that produces phones, TVs, and computers that get tossed in the trash because they can’t be repaired has gone too far. That’s right, we’re looking at you, medical science!

This time, it’s a pacemaker that just disappears when it’s no longer needed. Some lazy heart surgeon decided that it was way too much trouble to do another surgery to remove the leads when a temporary pacemaker was no longer needed. You know the type: “It sure would be nice if the pacemaker components were biocompatible and were naturally absorbed by the body over the course of a few weeks and wouldn’t need to be surgically extracted.” Slacker.

Well, get a load of this. Researchers at Northwestern and George Washington universities say that they have come up with a transient pacemaker that “harvests energy from an external, remote antenna using near-field communication protocols – the same technology used in smartphones for electronic payments and in RFID tags.”

Northwestern University/George Washington University

It’s a mask! No, it’s a COVID-19 test!

Mask wearing has gotten more lax as people get vaccinated for COVID-19, but as wearing masks for virus prevention is becoming more normalized in western society, some saw an opportunity to make them work for diagnosis.

Researchers from the Massachusetts Institute of Technology and the Wyss Institute for Biologically Inspired Engineering at Harvard University have found a way to do just that with their wearable freeze-dried cell-free (wFDCF) technology. A single push of a button releases water from a reservoir in the mask that sequentially activates three different freeze-dried biological reactions, which detect the SARS-CoV-2 virus in the wearer’s breath.

Initially meant as a tool for the Zika outbreak in 2015, the team made a quick pivot in May 2020. But this isn’t just some run-of-the-mill, at-home test. The data prove that the wFDCF mask is comparable to polymerase chain reactions tests, the standard in COVID-19 detection. Plus there aren’t any extra factors to deal with, like room or instrument temperature to ensure accuracy. In just 90 minutes, the mask gives results on a readout in a way similar to that of a pregnancy test. Voilà! To have COVID-19 or not to have COVID-19 is an easily answered question.

UerDomwet/PxHere

Finally, an excuse for the all-beer diet

Weight loss is hard work. Extremely hard work, and, as evidenced by the constant inundation and advertisement of quick fixes, crash diets, and expensive gym memberships, there’s not really a solid, 100% solution to the issue. Until now, thanks to a team of doctors from New Zealand, who’ve decided that the best way to combat obesity is to leave you in constant agony.

The DentalSlim Diet Control device is certainly a radical yet comically logical attempt to combat obesity. The creators say that the biggest problem with dieting is compliance, and, well, it’s difficult to eat too much if you can’t actually open your mouth. The metal contraption is mounted onto your teeth and uses magnetic locks to prevent the user from opening their mouths more than 2 mm. That’s less than a tenth of an inch. Which is not a lot. So not a lot that essentially all you can consume is liquid.

University of Otago

Ignore this pacemaker and it will go away

At some point – and now seems to be that point – we have to say enough is enough. The throwaway culture that produces phones, TVs, and computers that get tossed in the trash because they can’t be repaired has gone too far. That’s right, we’re looking at you, medical science!

This time, it’s a pacemaker that just disappears when it’s no longer needed. Some lazy heart surgeon decided that it was way too much trouble to do another surgery to remove the leads when a temporary pacemaker was no longer needed. You know the type: “It sure would be nice if the pacemaker components were biocompatible and were naturally absorbed by the body over the course of a few weeks and wouldn’t need to be surgically extracted.” Slacker.

Well, get a load of this. Researchers at Northwestern and George Washington universities say that they have come up with a transient pacemaker that “harvests energy from an external, remote antenna using near-field communication protocols – the same technology used in smartphones for electronic payments and in RFID tags.”

Northwestern University/George Washington University

It’s a mask! No, it’s a COVID-19 test!

Mask wearing has gotten more lax as people get vaccinated for COVID-19, but as wearing masks for virus prevention is becoming more normalized in western society, some saw an opportunity to make them work for diagnosis.

Researchers from the Massachusetts Institute of Technology and the Wyss Institute for Biologically Inspired Engineering at Harvard University have found a way to do just that with their wearable freeze-dried cell-free (wFDCF) technology. A single push of a button releases water from a reservoir in the mask that sequentially activates three different freeze-dried biological reactions, which detect the SARS-CoV-2 virus in the wearer’s breath.

Initially meant as a tool for the Zika outbreak in 2015, the team made a quick pivot in May 2020. But this isn’t just some run-of-the-mill, at-home test. The data prove that the wFDCF mask is comparable to polymerase chain reactions tests, the standard in COVID-19 detection. Plus there aren’t any extra factors to deal with, like room or instrument temperature to ensure accuracy. In just 90 minutes, the mask gives results on a readout in a way similar to that of a pregnancy test. Voilà! To have COVID-19 or not to have COVID-19 is an easily answered question.

UerDomwet/PxHere

Finally, an excuse for the all-beer diet

Weight loss is hard work. Extremely hard work, and, as evidenced by the constant inundation and advertisement of quick fixes, crash diets, and expensive gym memberships, there’s not really a solid, 100% solution to the issue. Until now, thanks to a team of doctors from New Zealand, who’ve decided that the best way to combat obesity is to leave you in constant agony.

The DentalSlim Diet Control device is certainly a radical yet comically logical attempt to combat obesity. The creators say that the biggest problem with dieting is compliance, and, well, it’s difficult to eat too much if you can’t actually open your mouth. The metal contraption is mounted onto your teeth and uses magnetic locks to prevent the user from opening their mouths more than 2 mm. That’s less than a tenth of an inch. Which is not a lot. So not a lot that essentially all you can consume is liquid.

University of Otago