In a pregnant woman who has a life-threatening allergy to penicillin, what is the most appropriate treatment for syphilis?

Continue to the answer...

This patient should be admitted to the hospital and rapidly desensitized to penicillin. She then can be treated with the appropriate dose of penicillin, given her stage of syphilis. Of note, in the future, the patient’s allergy to penicillin will return, despite the brief period of desensitization.

In a pregnant woman who has a life-threatening allergy to penicillin, what is the most appropriate treatment for syphilis?

Continue to the answer...

This patient should be admitted to the hospital and rapidly desensitized to penicillin. She then can be treated with the appropriate dose of penicillin, given her stage of syphilis. Of note, in the future, the patient’s allergy to penicillin will return, despite the brief period of desensitization.

In a pregnant woman who has a life-threatening allergy to penicillin, what is the most appropriate treatment for syphilis?

Continue to the answer...

This patient should be admitted to the hospital and rapidly desensitized to penicillin. She then can be treated with the appropriate dose of penicillin, given her stage of syphilis. Of note, in the future, the patient’s allergy to penicillin will return, despite the brief period of desensitization.

Although it is common to read about patients suing their hospitals, there has been increasing public and political attention given to hospitals suing their patients to collect unpaid hospital bills. KH’s story began with an emergency appendectomy. She did not have health insurance to cover the $14,000 hospital bill. The family was unable to pay the bill, and the nonprofit hospital sued them for that bill, plus some additional expenses (totaling about $17,000), plus interest was accumulating at 9% per year. The hospital won a judgment, and it garnished the husband’s pay (10% of after-taxes pay, in this case) and placed a lien on the family’s home. Years later—because of interest and additional hospital bills—the family had paid $20,000, but still owed $26,000.¹

The extent of the problem

This is neither a hypothetical case nor a rare event. Studies and press reports have noted dozens of examples of hospital collection excesses. One study found that unpaid medical bill lawsuits increased by 37% in Wisconsin between 2001 and 2018, with 5% of hospitals accounting for 25% of the lawsuits.² Another report found almost “31,000 civil cases filed by 139 hospitals in 26 New York counties from 2015 to 2019.”³ Similar to the Wisconsin report, a small number of health care providers accounted for the majority of lawsuits. In another example, one Missouri nonprofit hospital, Heartland (rebranded “Mosaic”), created its own for-profit debt collection agency (Northwest Financial Services), which filed 11,000 lawsuits from 2009 to 2013, resulting in 6,000 wage garnishments.¹ The Wall Street Journal, among others, has reported for years on the difficulties created by lawsuits against patients.⁴ Axios and Johns Hopkins reported that “medical debt comprises 58% of all debt collections in the United States.” And although some collection actions declined early in the pandemic, it did not appear to last.^5,6

Inconsistent collection policies. Collection policies vary greatly from hospital to hospital, with an increasing number of hospitals demanding up-front payments (before services). Many of these health care institutions persuade patients to put medical debt on their credit cards, sometimes as part of an up-front (before service) process.⁷ If using a standard credit card, this comes with a very high interest rate. There are some special health-related credit cards, such as CareCredit, that generally have better interest rates. These cards offer no-interest short-term loans, with significant interest for longer-term loans. Thus, failure to repay the full amount when due means that the “deferred interest” (about 27%) must be paid.⁸ Also any of the problems patients have repaying a credit card (or other loan), of course, are no longer directly related to the hospital. These “indirect collections” still burden patients with medical debt.

Where you go matters. Because there is no common collection policy or practice among hospitals, choosing the wrong hospital may result in a lawsuit. A careful study of lawsuits for medical debt or garnishments related to that debt in 2017 in Virginia showed how being treated at certain hospitals dramatically changed the odds of wage garnishment for unpaid bills.⁹ It revealed that 29,286 hospital lawsuits were filed to collect medical debt—9,232 of which were wage garnishments (the most aggressive form of debt collection). Five hospitals alone accounted for the majority of garnishments in the state. Notably, nonprofit hospitals accounted for 71% of the garnishment cases. On the other hand, about 50% of the hospitals in the study did not file any lawsuits to garnish wages for medical debt.⁹

Why is there so much hospital debt?

One would think the Affordable Care Act (ACA) and other reforms would mean fewer people do not have health insurance—and the problems experienced by the patient in the case above. Indeed, the number of insured has increased in the United States, including through the expansion of Medi­caid. Nonetheless, in 2020, the Census Bureau reported that 28 million people did not have health insurance for any part of the year; that figure would be higher if those who had insurance for only part of the year were included.¹⁰

One reason for medical debt is the very high level of “under” insurance—that is, even with health insurance, copays for significant medical bills exceed what the patient can pay. Nearly half of adults (excluding the elderly) were enrolled in high-deductible health plans (in 2017).¹¹ Among most employment-based plans, deductibles and co-pays have been going up for a decade.¹² Overall, 20% of employer-provided plans had deductibles in excess of $3,000 ($5,000 for families).¹³ Of course, many families do not have anywhere near the resources to pay high deductibles, and that represents likely medical debt. The more modest copays of Medicare (often 20%) can be enough to push some elderly individuals beyond their capacity to pay.

“Out-of-network” care also may result in large hospital charges—and debt. Emergency care, for example, may be sought from the closest provider, even though out of network, and the insurance company may refuse to pay the charges. Another surprise form of billing is when a health care insurance company tentatively approves coverage and then after the patient receives care, determines it was unnecessary. In that case, even in-network charges may be denied, with the patient left to pay all the charges.

Continue to: How medical debt affects patients...

For patients, medical debt places pressure on their financial circumstances. Bankruptcy has a profound financial impact, and approximately two-thirds of bankruptcies are related to medical care costs and debt, including “indirect collection.”¹⁴ Even when the financial effect is not so devastating, it is often substantial, as the above case demonstrated. In a 2018 survey, almost 30% of those with health insurance had medical debts in some form of collection action, and 25% of those individuals said they did not know they owed the money.¹⁵ The same survey found that 20% of respondents had medical debt that adversely affected their credit scores and access to credit.¹⁵

At work, although employers are not supposed to treat employees adversely because of garnishment, some employers may not adhere to that rule. Furthermore, employees may believe or be concerned that the very existence of garnishment may penalize them at their current job or make it difficult to move to a better one.¹⁶

Lastly, patients with medical debt may be reluctant to seek needed medical care. They may be concerned about adding more medical debt or embarrassed or afraid that they would not be welcome at the hospital where they owe money.⁷

Public perception of hospitals

Lawsuits against patients also have a negative effect on hospitals—and it is not limited to the relatively few institutions that file many of these lawsuits each year. Press reports about lawsuits against patients garner great public interest and anger, and this tarnishes the image of heath care facilities in general because many people often do not distinguish the actions of a few institutions.

The sensitivity of health care organizations to bad publicity from debt collection practices was seen in a follow-up study of the previously discussed Virginia data. In the year following this report, there was a 59% decrease in the number of lawsuits filed, including a 66% decrease in garnishments.¹⁷ Eleven hospitals in the state that had been filing debt lawsuits stopped doing so.¹⁷

Medical debt: The obligation of nonprofit hospitals

The response seen in the Virginia follow-up study may also reflect well-founded concern from board members about political consequences and even taxation problems. The majority of hospitals, including those in these studies, are nonprofit institutions with an Internal Revenue Service (IRS) 501(c)(3) “tax-exempt” status. (Note, “nonprofit” does not mean that the organization does not make a profit, but that the profit does not accrue to individuals.) The “nonprofit” status is usually granted by states, but the federal tax-exempt status is granted by the IRS. This status exempts the institutions from paying most federal taxes, and (perhaps most importantly) qualifies donors to receive tax deductions (and similar benefits) for donations made to these hospitals. This important tax treatment is granted based on the theory that their services are so valuable to the public that advancing their work through the tax exemption ultimately benefits the public more than the tax revenue would.

In return for these benefits, the organization has obligations to work in the public interest. For years, hospitals have been criticized for not providing sufficient public benefits (compared, for example, with for-profit hospitals) to justify the tax exemption. That criticism caused the IRS to begin requiring a special Form 990, Schedule H, which is attached to the usual 501(c)(3) informational tax return, “to provide information on the activities and policies of, and community benefit provided by, its hospital facilities and other non-hospital health care facilities.”¹⁸ Part III of Schedule H asks, in part, about bad debt and collection practices.

Then the ACA Section 501(r) enhanced the obligation of nonprofit health facilities to provide charitable care in two ways. First, they must have, and make available, policies to provide free and discounted care; and second, they cannot sue for payment until they make an individualized determination as to whether the patient should have received discounted care or financial assistance.¹⁹

Thus aggressive collection practices (which should include “indirect collection”) invite special scrutiny by local officials and the IRS. In the longer-term, concern that tax-exempt hospitals are not truly operating in the public interest is undoubtedly amplified by these aggressive debt collection practices. How can a hospital claim it is truly operating in the public interest when it sues dozens of modest-income individuals each year?

Regulating medical debt and its collection

The No Surprises Act

In December 2020, Congress adopted the No Surprises Act to address some of the problems of patient debt.²⁰ Among other things, the act protects patients “from receiving surprise medical bills when they receive most emergency services,” or when they are in an in-network hospital but receive services from out-of-network providers (such as anesthesia and radiology).²¹ Several states also have similar legislation, so the federal law specifically states that where state laws are more protective of patients, the state’s higher protections apply, and vice versa. The act took effect on January 1, 2022, though there is an “interim final” regulation that will be subject to change, and there is already litigation over those regulations.²² The real complexity of the rules will arise through the regulations, which are likely to change several times over the next few years. To help with this, the American Medical Association has an extensive toolkit for health care providers.²³

Continue to: Additional regulations...

Additional regulations

Both the federal government and most states are likely to take additional action to reduce hospital debt lawsuits. Some proposals sound simple enough but would have significant complications. For example, governments could prohibit all lawsuits that collect hospital debt.⁷ Such a regulation would mean that paying hospital debts would essentially become optional. Imagine the millionaire who does not want to pay a $25,000 hospital charge; or patients with other debts who would pay those off before the hospital debt. The regulation might have income or asset limits on debt collection lawsuits and the like, but it quickly becomes complicated. Furthermore, to protect themselves, hospitals would undoubtedly become much more aggressive about requiring up-front payments—which would force the debt or prepayment onto credit cards or similar debt obligations that are not subject to the no collection lawsuit rule.

Public reporting. The follow-up study in Virginia¹⁷ suggests that requiring public reporting of the number of cases filed by or on behalf of (directly or indirectly) each hospital may help. Hospitals would, of course, have incentives to make their figures look better, perhaps by selling the debt to an agency that would be able to file suit in its name rather than the hospital’s name. These might be little more than indirect collections. For reporting purposes, any form of transferring debt might be considered filing a lawsuit. The problem, noted earlier, about requiring prepayment or credit cards would also exist.

Get the board involved. A different approach would be to ensure that a hospital’s board of trustees is involved in setting and overseeing debt collection policies. For example, the law might require boards to annually consider and adopt specific debt collection practices—including indirect collection efforts. Boards should already be doing something similar to this, but regulation might be an inexpensive way to ensure it is done—and in a manner consistent with the organization’s values. Another suggestion is to require the board to approve any legal action against specific patients.⁷ By making sure this is not just another item on the consent agenda, the oversight would probably reduce automatic debt collection processes.

Expand IRS reporting requirements for nonprofits. Indeed, for nonprofit hospitals with 501(c)(3) obligations, the Form 990, Schedule H already provides some information about collection actions and uncompensated care, and this is enhanced by the ACA Section 501(r). These could be expanded and perhaps include “indirect” collections. The IRS could “flag” hospitals with high total litigation and similar collection actions, and ask the hospital to provide a detailed explanation for each action and how it was consistent with the obligation to serve the public (thereby justifying the exempt taxation status, an idea proposed by the US Government Accountability Office in 2020).²⁴

Ensure the hospital’s actions reflect their mission and values

Hospitals are created to provide medical care for people and to improve the human condition. Those who lead them should, and generally do, share that purpose. The apparent collection policies that have garnered negative public attention suggest that some of these institutions have lost focus of their ultimate mission and values. The boards and executives of these health care institutions, as well as the medical professionals and attorneys who serve them, should be continuously guided by those values.

Important decisions—including collection and prepayment processes—reflect the values of the institution. Failure to ensure these procedures are in line with the organization’s mission is an embarrassment to all health care facilities, including the majority of hospitals that do not engage in these aggressive collection practices. Not addressing these issues will likely result in political and legal action—blunt and inefficient instruments—to limit what the public sees as wrongdoing. ●

Although it is common to read about patients suing their hospitals, there has been increasing public and political attention given to hospitals suing their patients to collect unpaid hospital bills. KH’s story began with an emergency appendectomy. She did not have health insurance to cover the $14,000 hospital bill. The family was unable to pay the bill, and the nonprofit hospital sued them for that bill, plus some additional expenses (totaling about $17,000), plus interest was accumulating at 9% per year. The hospital won a judgment, and it garnished the husband’s pay (10% of after-taxes pay, in this case) and placed a lien on the family’s home. Years later—because of interest and additional hospital bills—the family had paid $20,000, but still owed $26,000.¹

The extent of the problem

This is neither a hypothetical case nor a rare event. Studies and press reports have noted dozens of examples of hospital collection excesses. One study found that unpaid medical bill lawsuits increased by 37% in Wisconsin between 2001 and 2018, with 5% of hospitals accounting for 25% of the lawsuits.² Another report found almost “31,000 civil cases filed by 139 hospitals in 26 New York counties from 2015 to 2019.”³ Similar to the Wisconsin report, a small number of health care providers accounted for the majority of lawsuits. In another example, one Missouri nonprofit hospital, Heartland (rebranded “Mosaic”), created its own for-profit debt collection agency (Northwest Financial Services), which filed 11,000 lawsuits from 2009 to 2013, resulting in 6,000 wage garnishments.¹ The Wall Street Journal, among others, has reported for years on the difficulties created by lawsuits against patients.⁴ Axios and Johns Hopkins reported that “medical debt comprises 58% of all debt collections in the United States.” And although some collection actions declined early in the pandemic, it did not appear to last.^5,6

Inconsistent collection policies. Collection policies vary greatly from hospital to hospital, with an increasing number of hospitals demanding up-front payments (before services). Many of these health care institutions persuade patients to put medical debt on their credit cards, sometimes as part of an up-front (before service) process.⁷ If using a standard credit card, this comes with a very high interest rate. There are some special health-related credit cards, such as CareCredit, that generally have better interest rates. These cards offer no-interest short-term loans, with significant interest for longer-term loans. Thus, failure to repay the full amount when due means that the “deferred interest” (about 27%) must be paid.⁸ Also any of the problems patients have repaying a credit card (or other loan), of course, are no longer directly related to the hospital. These “indirect collections” still burden patients with medical debt.

Where you go matters. Because there is no common collection policy or practice among hospitals, choosing the wrong hospital may result in a lawsuit. A careful study of lawsuits for medical debt or garnishments related to that debt in 2017 in Virginia showed how being treated at certain hospitals dramatically changed the odds of wage garnishment for unpaid bills.⁹ It revealed that 29,286 hospital lawsuits were filed to collect medical debt—9,232 of which were wage garnishments (the most aggressive form of debt collection). Five hospitals alone accounted for the majority of garnishments in the state. Notably, nonprofit hospitals accounted for 71% of the garnishment cases. On the other hand, about 50% of the hospitals in the study did not file any lawsuits to garnish wages for medical debt.⁹

Why is there so much hospital debt?

One would think the Affordable Care Act (ACA) and other reforms would mean fewer people do not have health insurance—and the problems experienced by the patient in the case above. Indeed, the number of insured has increased in the United States, including through the expansion of Medi­caid. Nonetheless, in 2020, the Census Bureau reported that 28 million people did not have health insurance for any part of the year; that figure would be higher if those who had insurance for only part of the year were included.¹⁰

One reason for medical debt is the very high level of “under” insurance—that is, even with health insurance, copays for significant medical bills exceed what the patient can pay. Nearly half of adults (excluding the elderly) were enrolled in high-deductible health plans (in 2017).¹¹ Among most employment-based plans, deductibles and co-pays have been going up for a decade.¹² Overall, 20% of employer-provided plans had deductibles in excess of $3,000 ($5,000 for families).¹³ Of course, many families do not have anywhere near the resources to pay high deductibles, and that represents likely medical debt. The more modest copays of Medicare (often 20%) can be enough to push some elderly individuals beyond their capacity to pay.

“Out-of-network” care also may result in large hospital charges—and debt. Emergency care, for example, may be sought from the closest provider, even though out of network, and the insurance company may refuse to pay the charges. Another surprise form of billing is when a health care insurance company tentatively approves coverage and then after the patient receives care, determines it was unnecessary. In that case, even in-network charges may be denied, with the patient left to pay all the charges.

Continue to: How medical debt affects patients...

For patients, medical debt places pressure on their financial circumstances. Bankruptcy has a profound financial impact, and approximately two-thirds of bankruptcies are related to medical care costs and debt, including “indirect collection.”¹⁴ Even when the financial effect is not so devastating, it is often substantial, as the above case demonstrated. In a 2018 survey, almost 30% of those with health insurance had medical debts in some form of collection action, and 25% of those individuals said they did not know they owed the money.¹⁵ The same survey found that 20% of respondents had medical debt that adversely affected their credit scores and access to credit.¹⁵

At work, although employers are not supposed to treat employees adversely because of garnishment, some employers may not adhere to that rule. Furthermore, employees may believe or be concerned that the very existence of garnishment may penalize them at their current job or make it difficult to move to a better one.¹⁶

Lastly, patients with medical debt may be reluctant to seek needed medical care. They may be concerned about adding more medical debt or embarrassed or afraid that they would not be welcome at the hospital where they owe money.⁷

Public perception of hospitals

Lawsuits against patients also have a negative effect on hospitals—and it is not limited to the relatively few institutions that file many of these lawsuits each year. Press reports about lawsuits against patients garner great public interest and anger, and this tarnishes the image of heath care facilities in general because many people often do not distinguish the actions of a few institutions.

The sensitivity of health care organizations to bad publicity from debt collection practices was seen in a follow-up study of the previously discussed Virginia data. In the year following this report, there was a 59% decrease in the number of lawsuits filed, including a 66% decrease in garnishments.¹⁷ Eleven hospitals in the state that had been filing debt lawsuits stopped doing so.¹⁷

Medical debt: The obligation of nonprofit hospitals

The response seen in the Virginia follow-up study may also reflect well-founded concern from board members about political consequences and even taxation problems. The majority of hospitals, including those in these studies, are nonprofit institutions with an Internal Revenue Service (IRS) 501(c)(3) “tax-exempt” status. (Note, “nonprofit” does not mean that the organization does not make a profit, but that the profit does not accrue to individuals.) The “nonprofit” status is usually granted by states, but the federal tax-exempt status is granted by the IRS. This status exempts the institutions from paying most federal taxes, and (perhaps most importantly) qualifies donors to receive tax deductions (and similar benefits) for donations made to these hospitals. This important tax treatment is granted based on the theory that their services are so valuable to the public that advancing their work through the tax exemption ultimately benefits the public more than the tax revenue would.

In return for these benefits, the organization has obligations to work in the public interest. For years, hospitals have been criticized for not providing sufficient public benefits (compared, for example, with for-profit hospitals) to justify the tax exemption. That criticism caused the IRS to begin requiring a special Form 990, Schedule H, which is attached to the usual 501(c)(3) informational tax return, “to provide information on the activities and policies of, and community benefit provided by, its hospital facilities and other non-hospital health care facilities.”¹⁸ Part III of Schedule H asks, in part, about bad debt and collection practices.

Then the ACA Section 501(r) enhanced the obligation of nonprofit health facilities to provide charitable care in two ways. First, they must have, and make available, policies to provide free and discounted care; and second, they cannot sue for payment until they make an individualized determination as to whether the patient should have received discounted care or financial assistance.¹⁹

Thus aggressive collection practices (which should include “indirect collection”) invite special scrutiny by local officials and the IRS. In the longer-term, concern that tax-exempt hospitals are not truly operating in the public interest is undoubtedly amplified by these aggressive debt collection practices. How can a hospital claim it is truly operating in the public interest when it sues dozens of modest-income individuals each year?

Regulating medical debt and its collection

The No Surprises Act

In December 2020, Congress adopted the No Surprises Act to address some of the problems of patient debt.²⁰ Among other things, the act protects patients “from receiving surprise medical bills when they receive most emergency services,” or when they are in an in-network hospital but receive services from out-of-network providers (such as anesthesia and radiology).²¹ Several states also have similar legislation, so the federal law specifically states that where state laws are more protective of patients, the state’s higher protections apply, and vice versa. The act took effect on January 1, 2022, though there is an “interim final” regulation that will be subject to change, and there is already litigation over those regulations.²² The real complexity of the rules will arise through the regulations, which are likely to change several times over the next few years. To help with this, the American Medical Association has an extensive toolkit for health care providers.²³

Continue to: Additional regulations...

Additional regulations

Both the federal government and most states are likely to take additional action to reduce hospital debt lawsuits. Some proposals sound simple enough but would have significant complications. For example, governments could prohibit all lawsuits that collect hospital debt.⁷ Such a regulation would mean that paying hospital debts would essentially become optional. Imagine the millionaire who does not want to pay a $25,000 hospital charge; or patients with other debts who would pay those off before the hospital debt. The regulation might have income or asset limits on debt collection lawsuits and the like, but it quickly becomes complicated. Furthermore, to protect themselves, hospitals would undoubtedly become much more aggressive about requiring up-front payments—which would force the debt or prepayment onto credit cards or similar debt obligations that are not subject to the no collection lawsuit rule.

Public reporting. The follow-up study in Virginia¹⁷ suggests that requiring public reporting of the number of cases filed by or on behalf of (directly or indirectly) each hospital may help. Hospitals would, of course, have incentives to make their figures look better, perhaps by selling the debt to an agency that would be able to file suit in its name rather than the hospital’s name. These might be little more than indirect collections. For reporting purposes, any form of transferring debt might be considered filing a lawsuit. The problem, noted earlier, about requiring prepayment or credit cards would also exist.

Get the board involved. A different approach would be to ensure that a hospital’s board of trustees is involved in setting and overseeing debt collection policies. For example, the law might require boards to annually consider and adopt specific debt collection practices—including indirect collection efforts. Boards should already be doing something similar to this, but regulation might be an inexpensive way to ensure it is done—and in a manner consistent with the organization’s values. Another suggestion is to require the board to approve any legal action against specific patients.⁷ By making sure this is not just another item on the consent agenda, the oversight would probably reduce automatic debt collection processes.

Expand IRS reporting requirements for nonprofits. Indeed, for nonprofit hospitals with 501(c)(3) obligations, the Form 990, Schedule H already provides some information about collection actions and uncompensated care, and this is enhanced by the ACA Section 501(r). These could be expanded and perhaps include “indirect” collections. The IRS could “flag” hospitals with high total litigation and similar collection actions, and ask the hospital to provide a detailed explanation for each action and how it was consistent with the obligation to serve the public (thereby justifying the exempt taxation status, an idea proposed by the US Government Accountability Office in 2020).²⁴

Ensure the hospital’s actions reflect their mission and values

Hospitals are created to provide medical care for people and to improve the human condition. Those who lead them should, and generally do, share that purpose. The apparent collection policies that have garnered negative public attention suggest that some of these institutions have lost focus of their ultimate mission and values. The boards and executives of these health care institutions, as well as the medical professionals and attorneys who serve them, should be continuously guided by those values.

Important decisions—including collection and prepayment processes—reflect the values of the institution. Failure to ensure these procedures are in line with the organization’s mission is an embarrassment to all health care facilities, including the majority of hospitals that do not engage in these aggressive collection practices. Not addressing these issues will likely result in political and legal action—blunt and inefficient instruments—to limit what the public sees as wrongdoing. ●

Although it is common to read about patients suing their hospitals, there has been increasing public and political attention given to hospitals suing their patients to collect unpaid hospital bills. KH’s story began with an emergency appendectomy. She did not have health insurance to cover the $14,000 hospital bill. The family was unable to pay the bill, and the nonprofit hospital sued them for that bill, plus some additional expenses (totaling about $17,000), plus interest was accumulating at 9% per year. The hospital won a judgment, and it garnished the husband’s pay (10% of after-taxes pay, in this case) and placed a lien on the family’s home. Years later—because of interest and additional hospital bills—the family had paid $20,000, but still owed $26,000.¹

The extent of the problem

This is neither a hypothetical case nor a rare event. Studies and press reports have noted dozens of examples of hospital collection excesses. One study found that unpaid medical bill lawsuits increased by 37% in Wisconsin between 2001 and 2018, with 5% of hospitals accounting for 25% of the lawsuits.² Another report found almost “31,000 civil cases filed by 139 hospitals in 26 New York counties from 2015 to 2019.”³ Similar to the Wisconsin report, a small number of health care providers accounted for the majority of lawsuits. In another example, one Missouri nonprofit hospital, Heartland (rebranded “Mosaic”), created its own for-profit debt collection agency (Northwest Financial Services), which filed 11,000 lawsuits from 2009 to 2013, resulting in 6,000 wage garnishments.¹ The Wall Street Journal, among others, has reported for years on the difficulties created by lawsuits against patients.⁴ Axios and Johns Hopkins reported that “medical debt comprises 58% of all debt collections in the United States.” And although some collection actions declined early in the pandemic, it did not appear to last.^5,6

Inconsistent collection policies. Collection policies vary greatly from hospital to hospital, with an increasing number of hospitals demanding up-front payments (before services). Many of these health care institutions persuade patients to put medical debt on their credit cards, sometimes as part of an up-front (before service) process.⁷ If using a standard credit card, this comes with a very high interest rate. There are some special health-related credit cards, such as CareCredit, that generally have better interest rates. These cards offer no-interest short-term loans, with significant interest for longer-term loans. Thus, failure to repay the full amount when due means that the “deferred interest” (about 27%) must be paid.⁸ Also any of the problems patients have repaying a credit card (or other loan), of course, are no longer directly related to the hospital. These “indirect collections” still burden patients with medical debt.

Where you go matters. Because there is no common collection policy or practice among hospitals, choosing the wrong hospital may result in a lawsuit. A careful study of lawsuits for medical debt or garnishments related to that debt in 2017 in Virginia showed how being treated at certain hospitals dramatically changed the odds of wage garnishment for unpaid bills.⁹ It revealed that 29,286 hospital lawsuits were filed to collect medical debt—9,232 of which were wage garnishments (the most aggressive form of debt collection). Five hospitals alone accounted for the majority of garnishments in the state. Notably, nonprofit hospitals accounted for 71% of the garnishment cases. On the other hand, about 50% of the hospitals in the study did not file any lawsuits to garnish wages for medical debt.⁹

Why is there so much hospital debt?

One would think the Affordable Care Act (ACA) and other reforms would mean fewer people do not have health insurance—and the problems experienced by the patient in the case above. Indeed, the number of insured has increased in the United States, including through the expansion of Medi­caid. Nonetheless, in 2020, the Census Bureau reported that 28 million people did not have health insurance for any part of the year; that figure would be higher if those who had insurance for only part of the year were included.¹⁰

One reason for medical debt is the very high level of “under” insurance—that is, even with health insurance, copays for significant medical bills exceed what the patient can pay. Nearly half of adults (excluding the elderly) were enrolled in high-deductible health plans (in 2017).¹¹ Among most employment-based plans, deductibles and co-pays have been going up for a decade.¹² Overall, 20% of employer-provided plans had deductibles in excess of $3,000 ($5,000 for families).¹³ Of course, many families do not have anywhere near the resources to pay high deductibles, and that represents likely medical debt. The more modest copays of Medicare (often 20%) can be enough to push some elderly individuals beyond their capacity to pay.

“Out-of-network” care also may result in large hospital charges—and debt. Emergency care, for example, may be sought from the closest provider, even though out of network, and the insurance company may refuse to pay the charges. Another surprise form of billing is when a health care insurance company tentatively approves coverage and then after the patient receives care, determines it was unnecessary. In that case, even in-network charges may be denied, with the patient left to pay all the charges.

Continue to: How medical debt affects patients...

For patients, medical debt places pressure on their financial circumstances. Bankruptcy has a profound financial impact, and approximately two-thirds of bankruptcies are related to medical care costs and debt, including “indirect collection.”¹⁴ Even when the financial effect is not so devastating, it is often substantial, as the above case demonstrated. In a 2018 survey, almost 30% of those with health insurance had medical debts in some form of collection action, and 25% of those individuals said they did not know they owed the money.¹⁵ The same survey found that 20% of respondents had medical debt that adversely affected their credit scores and access to credit.¹⁵

At work, although employers are not supposed to treat employees adversely because of garnishment, some employers may not adhere to that rule. Furthermore, employees may believe or be concerned that the very existence of garnishment may penalize them at their current job or make it difficult to move to a better one.¹⁶

Lastly, patients with medical debt may be reluctant to seek needed medical care. They may be concerned about adding more medical debt or embarrassed or afraid that they would not be welcome at the hospital where they owe money.⁷

Public perception of hospitals

Lawsuits against patients also have a negative effect on hospitals—and it is not limited to the relatively few institutions that file many of these lawsuits each year. Press reports about lawsuits against patients garner great public interest and anger, and this tarnishes the image of heath care facilities in general because many people often do not distinguish the actions of a few institutions.

The sensitivity of health care organizations to bad publicity from debt collection practices was seen in a follow-up study of the previously discussed Virginia data. In the year following this report, there was a 59% decrease in the number of lawsuits filed, including a 66% decrease in garnishments.¹⁷ Eleven hospitals in the state that had been filing debt lawsuits stopped doing so.¹⁷

Medical debt: The obligation of nonprofit hospitals

The response seen in the Virginia follow-up study may also reflect well-founded concern from board members about political consequences and even taxation problems. The majority of hospitals, including those in these studies, are nonprofit institutions with an Internal Revenue Service (IRS) 501(c)(3) “tax-exempt” status. (Note, “nonprofit” does not mean that the organization does not make a profit, but that the profit does not accrue to individuals.) The “nonprofit” status is usually granted by states, but the federal tax-exempt status is granted by the IRS. This status exempts the institutions from paying most federal taxes, and (perhaps most importantly) qualifies donors to receive tax deductions (and similar benefits) for donations made to these hospitals. This important tax treatment is granted based on the theory that their services are so valuable to the public that advancing their work through the tax exemption ultimately benefits the public more than the tax revenue would.

In return for these benefits, the organization has obligations to work in the public interest. For years, hospitals have been criticized for not providing sufficient public benefits (compared, for example, with for-profit hospitals) to justify the tax exemption. That criticism caused the IRS to begin requiring a special Form 990, Schedule H, which is attached to the usual 501(c)(3) informational tax return, “to provide information on the activities and policies of, and community benefit provided by, its hospital facilities and other non-hospital health care facilities.”¹⁸ Part III of Schedule H asks, in part, about bad debt and collection practices.

Then the ACA Section 501(r) enhanced the obligation of nonprofit health facilities to provide charitable care in two ways. First, they must have, and make available, policies to provide free and discounted care; and second, they cannot sue for payment until they make an individualized determination as to whether the patient should have received discounted care or financial assistance.¹⁹

Thus aggressive collection practices (which should include “indirect collection”) invite special scrutiny by local officials and the IRS. In the longer-term, concern that tax-exempt hospitals are not truly operating in the public interest is undoubtedly amplified by these aggressive debt collection practices. How can a hospital claim it is truly operating in the public interest when it sues dozens of modest-income individuals each year?

Regulating medical debt and its collection

The No Surprises Act

In December 2020, Congress adopted the No Surprises Act to address some of the problems of patient debt.²⁰ Among other things, the act protects patients “from receiving surprise medical bills when they receive most emergency services,” or when they are in an in-network hospital but receive services from out-of-network providers (such as anesthesia and radiology).²¹ Several states also have similar legislation, so the federal law specifically states that where state laws are more protective of patients, the state’s higher protections apply, and vice versa. The act took effect on January 1, 2022, though there is an “interim final” regulation that will be subject to change, and there is already litigation over those regulations.²² The real complexity of the rules will arise through the regulations, which are likely to change several times over the next few years. To help with this, the American Medical Association has an extensive toolkit for health care providers.²³

Continue to: Additional regulations...

Additional regulations

Both the federal government and most states are likely to take additional action to reduce hospital debt lawsuits. Some proposals sound simple enough but would have significant complications. For example, governments could prohibit all lawsuits that collect hospital debt.⁷ Such a regulation would mean that paying hospital debts would essentially become optional. Imagine the millionaire who does not want to pay a $25,000 hospital charge; or patients with other debts who would pay those off before the hospital debt. The regulation might have income or asset limits on debt collection lawsuits and the like, but it quickly becomes complicated. Furthermore, to protect themselves, hospitals would undoubtedly become much more aggressive about requiring up-front payments—which would force the debt or prepayment onto credit cards or similar debt obligations that are not subject to the no collection lawsuit rule.

Public reporting. The follow-up study in Virginia¹⁷ suggests that requiring public reporting of the number of cases filed by or on behalf of (directly or indirectly) each hospital may help. Hospitals would, of course, have incentives to make their figures look better, perhaps by selling the debt to an agency that would be able to file suit in its name rather than the hospital’s name. These might be little more than indirect collections. For reporting purposes, any form of transferring debt might be considered filing a lawsuit. The problem, noted earlier, about requiring prepayment or credit cards would also exist.

Get the board involved. A different approach would be to ensure that a hospital’s board of trustees is involved in setting and overseeing debt collection policies. For example, the law might require boards to annually consider and adopt specific debt collection practices—including indirect collection efforts. Boards should already be doing something similar to this, but regulation might be an inexpensive way to ensure it is done—and in a manner consistent with the organization’s values. Another suggestion is to require the board to approve any legal action against specific patients.⁷ By making sure this is not just another item on the consent agenda, the oversight would probably reduce automatic debt collection processes.

Expand IRS reporting requirements for nonprofits. Indeed, for nonprofit hospitals with 501(c)(3) obligations, the Form 990, Schedule H already provides some information about collection actions and uncompensated care, and this is enhanced by the ACA Section 501(r). These could be expanded and perhaps include “indirect” collections. The IRS could “flag” hospitals with high total litigation and similar collection actions, and ask the hospital to provide a detailed explanation for each action and how it was consistent with the obligation to serve the public (thereby justifying the exempt taxation status, an idea proposed by the US Government Accountability Office in 2020).²⁴

Ensure the hospital’s actions reflect their mission and values

Hospitals are created to provide medical care for people and to improve the human condition. Those who lead them should, and generally do, share that purpose. The apparent collection policies that have garnered negative public attention suggest that some of these institutions have lost focus of their ultimate mission and values. The boards and executives of these health care institutions, as well as the medical professionals and attorneys who serve them, should be continuously guided by those values.

Important decisions—including collection and prepayment processes—reflect the values of the institution. Failure to ensure these procedures are in line with the organization’s mission is an embarrassment to all health care facilities, including the majority of hospitals that do not engage in these aggressive collection practices. Not addressing these issues will likely result in political and legal action—blunt and inefficient instruments—to limit what the public sees as wrongdoing. ●

In this question-and-answer article (the third in a series), our objective is to re­inforce for the clinician several practical points of management for common infectious diseases. The principal references for the answers to the questions are 2 textbook chapters written by Dr. Duff.^1,2 Other pertinent references are included in the text.

21. What prophylactic antibiotic should be administered intrapartum to a pregnant woman who is colonized with group B streptococci but who has a mild allergy to penicillin?

In this situation, the drug of choice is intravenous cefazolin, 2 g initially then 1 g every 8 hours until delivery. For patients with a severe allergy to penicillin, the drugs of choice are either clindamycin, 900 mg intravenously every 8 hours (if sensitivity of the organism is confirmed), or vancomycin, 20 mg/kg intravenously every 8 hours (maximum of 2 g per single dose).

22. In a pregnant woman who has a life-threatening allergy to penicillin, what is the most appropriate treatment for syphilis?

This patient should be admitted to the hospital and rapidly desensitized to penicillin. She then can be treated with the appropriate dose of penicillin, given her stage of syphilis. Of note, in the future, the patient’s allergy to penicillin will return, despite the brief period of desensitization.

23. What are the most common organisms that cause chorioamnionitis and puerperal endometritis?

Chorioamnionitis and puerperal endometritis are polymicrobial, mixed aerobic-anaerobic infections. The dominant organisms are anaerobic gram-negative bacilli (Bacteroides and Prevotella species); anaerobic gram-positive cocci (Peptococcus species and Peptostreptococcus species); aerobic gram-negative bacilli (principally, Escherichia coli, Klebsiella pneumoniae, and Proteus species); and aerobic gram-positive cocci (enterococci, staphylococci, and group B streptococci). ●

In this question-and-answer article (the third in a series), our objective is to re­inforce for the clinician several practical points of management for common infectious diseases. The principal references for the answers to the questions are 2 textbook chapters written by Dr. Duff.^1,2 Other pertinent references are included in the text.

21. What prophylactic antibiotic should be administered intrapartum to a pregnant woman who is colonized with group B streptococci but who has a mild allergy to penicillin?

In this situation, the drug of choice is intravenous cefazolin, 2 g initially then 1 g every 8 hours until delivery. For patients with a severe allergy to penicillin, the drugs of choice are either clindamycin, 900 mg intravenously every 8 hours (if sensitivity of the organism is confirmed), or vancomycin, 20 mg/kg intravenously every 8 hours (maximum of 2 g per single dose).

22. In a pregnant woman who has a life-threatening allergy to penicillin, what is the most appropriate treatment for syphilis?

This patient should be admitted to the hospital and rapidly desensitized to penicillin. She then can be treated with the appropriate dose of penicillin, given her stage of syphilis. Of note, in the future, the patient’s allergy to penicillin will return, despite the brief period of desensitization.

23. What are the most common organisms that cause chorioamnionitis and puerperal endometritis?

Chorioamnionitis and puerperal endometritis are polymicrobial, mixed aerobic-anaerobic infections. The dominant organisms are anaerobic gram-negative bacilli (Bacteroides and Prevotella species); anaerobic gram-positive cocci (Peptococcus species and Peptostreptococcus species); aerobic gram-negative bacilli (principally, Escherichia coli, Klebsiella pneumoniae, and Proteus species); and aerobic gram-positive cocci (enterococci, staphylococci, and group B streptococci). ●

In this question-and-answer article (the third in a series), our objective is to re­inforce for the clinician several practical points of management for common infectious diseases. The principal references for the answers to the questions are 2 textbook chapters written by Dr. Duff.^1,2 Other pertinent references are included in the text.

21. What prophylactic antibiotic should be administered intrapartum to a pregnant woman who is colonized with group B streptococci but who has a mild allergy to penicillin?

In this situation, the drug of choice is intravenous cefazolin, 2 g initially then 1 g every 8 hours until delivery. For patients with a severe allergy to penicillin, the drugs of choice are either clindamycin, 900 mg intravenously every 8 hours (if sensitivity of the organism is confirmed), or vancomycin, 20 mg/kg intravenously every 8 hours (maximum of 2 g per single dose).

22. In a pregnant woman who has a life-threatening allergy to penicillin, what is the most appropriate treatment for syphilis?

This patient should be admitted to the hospital and rapidly desensitized to penicillin. She then can be treated with the appropriate dose of penicillin, given her stage of syphilis. Of note, in the future, the patient’s allergy to penicillin will return, despite the brief period of desensitization.

23. What are the most common organisms that cause chorioamnionitis and puerperal endometritis?

Chorioamnionitis and puerperal endometritis are polymicrobial, mixed aerobic-anaerobic infections. The dominant organisms are anaerobic gram-negative bacilli (Bacteroides and Prevotella species); anaerobic gram-positive cocci (Peptococcus species and Peptostreptococcus species); aerobic gram-negative bacilli (principally, Escherichia coli, Klebsiella pneumoniae, and Proteus species); and aerobic gram-positive cocci (enterococci, staphylococci, and group B streptococci). ●

Selective estrogen receptor modulators (SERMs) are unique synthetic compounds that bind to the estrogen receptor and initiate either estrogenic agonistic or antagonistic activity, depending on the confirmational change they produce on binding to the receptor. Many SERMs have come to market, others have not. Unlike estrogens, which regardless of dose or route of administration all carry risks as a boxed warning on the label, referred to as class labeling,¹ various SERMs exert various effects in some tissues (uterus, vagina) while they have apparent class properties in others (bone, breast).²

The first SERM, for all practical purposes, was tamoxifen (although clomiphene citrate is often considered a SERM). Tamoxifen was approved by the US Food and Drug Administration (FDA) in 1978 for the treatment of breast cancer and, subsequently, for breast cancer risk reduction. It became the most widely prescribed anticancer drug worldwide.

Subsequently, when data showed that tamoxifen could produce a small number of endometrial cancers and a larger number of endometrial polyps,^3,4 there was renewed interest in raloxifene. In preclinical animal studies, raloxifene behaved differently than tamoxifen in the uterus. After clinical trials with raloxifene showed uterine safety,⁵ the drug was FDA approved for prevention of osteoporosis in 1997, for treatment of osteoporosis in 1999, and for breast cancer risk reduction in 2009. Most clinicians are familiar with these 2 SERMs, which have been in clinical use for more than 4 and 2 decades, respectively.

Ospemifene: A third-generation SERM and its indications

Hormone deficiency from menopause causes vulvovaginal and urogenital changes as well as a multitude of symptoms and signs, including vulvar and vaginal thinning, loss of rugal folds, diminished elasticity, increased pH, and most notably dyspareunia. The nomenclature that previously described vulvovaginal atrophy (VVA) has been expanded to include genitourinary syndrome of menopause (GSM).⁶ Unfortunately, many health care providers do not ask patients about GSM symptoms, and few women report their symptoms to their clinician.⁷ Furthermore, although low-dose local estrogens applied vaginally have been the mainstay of therapy for VVA/GSM, only 7% of symptomatic women use any pharmacologic agent,⁸ mainly because of fear of estrogens due to the class labeling mentioned above.

Ospemifene, a newer SERM, improved superficial cells and reduced parabasal cells as seen on a maturation index compared with placebo, according to results of multiple phase 3 clinical trials^9,10; it also lowered vaginal pH and improved most bothersome symptoms (original studies were for dyspareunia). As a result, the FDA approved ospemifene for treatment of moderate to severe dyspareunia from VVA of menopause.

Subsequent studies allowed for a broadened indication to include treatment of moderate to severe dryness due to menopause.¹¹ The ospemifene label contains a boxed warning that states, “In the endometrium, [ospemifene] has estrogen agonistic effects.”¹² Although ospemifene is not an estrogen (it’s a SERM), the label goes on to state, “There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.” This statement caused The Medical Letter to initially suggest that patients who receive ospemifene also should receive a progestational agent—a suggestion they later retracted.^13,14

To understand why the ospemifene labeling might be worded in such a way, one must review the data regarding the poorly named entity “weakly proliferative endometrium.” The package labeling combines any proliferative endometrium (“weakly” plus “actively” plus “disordered”) that occurred in the clinical trial. Thus, 86.1 per 1,000 of the ospemifene-treated patients (vs 13.3 per 1,000 of those taking placebo) had any one of the proliferative types. The problem is that “actively proliferative” endometrial glands will have mitotic activity in virtually every nucleus of the gland as well as abundant glandular progression (FIGURE 1), whereas “weakly proliferative” is actually closer to inactive or atrophic endometrium with an occasional mitotic figure in only a few nuclei of each gland (FIGURE 2).

In addition, at 1 year, the incidence of active proliferation with ospemifene was 1%.¹⁵ In examining the uterine safety study for raloxifene, both doses of that agent had an active proliferation incidence of 3% at 1 year.⁵ Furthermore, that study had an estrogen-only arm in which, at end point, the incidence of endometrial proliferation was 39%, and hyperplasia, 23%!⁵ It therefore is evident that, in the endometrium, ospemifene is much more like the SERM raloxifene than it is like estrogen. The American College of Obstetricians and Gynecologists (ACOG) endorsed ospemifene (level A evidence) as a first-line therapy for dyspareunia, noting absent endometrial stimulation.¹⁶

Continue to: Ospemifene effects on breast and bone...

Although ospemifene is approved for treatment of moderate to severe VVA/GSM, it has other SERM effects typical of its class. The label currently states that ospemifene “has not been adequately studied in women with breast cancer; therefore, it should not be used in women with known or suspected breast cancer.”¹² We know that tamoxifen reduced breast cancer 49% in high-risk women in the Breast Cancer Prevention Trial (BCPT).¹⁷ We also know that in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced breast cancer 77% in osteoporotic women,¹⁸ and in the Study of Tamoxifen and Raloxifene (STAR) trial, it performed virtually identically to tamoxifen in breast cancer prevention.¹⁹ Previous studies demonstrated that ospemifene inhibits breast cancer cell growth in in vitro cultures as well as in animal studies²⁰ and inhibits proliferation of human breast tissue epithelial cells,²¹ with breast effects similar to those seen with tamoxifen and raloxifene.

Thus, although one would not choose ospemifene as a primary treatment or risk-reducing agent for a patient with breast cancer, the direction of its activity in breast tissue is indisputable and is likely the reason that in the European Union (unlike in the United States) it is approved to treat dyspareunia from VVA/GSM in women with a prior history of breast cancer.

Virtually all SERMs have estrogen agonistic activity in bone. Bone is a dynamic organ, constantly being laid down and taken away (resorption). Estrogen and SERMs are potent antiresorptives in bone metabolism. Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to that of estradiol and raloxifene.²² Clinical data from 3 phase 1 or 2 clinical trials found that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.²³ Actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, but there is a good correlation between biochemical markers for bone turnover and the occurrence of fracture.²⁴ Once again, women who need treatment for osteoporosis should not be treated primarily with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.

Clinical application

Ospemifene is an oral SERM approved for the treatment of moderate to severe dyspareunia as well as dryness from VVA due to menopause. In addition, it appears one can safely surmise that the direction of ospemifene’s activity in bone and breast is virtually indisputable. The magnitude of that activity, however, is unstudied. Therefore, in selecting an agent to treat women with dyspareunia or vaginal dryness from VVA of menopause, determining any potential add-on benefit for that particular patient in either bone and/or breast is clinically appropriate.

The SERM bazedoxifene

A meta-analysis of 4 randomized, placebo-controlled trials showed that another SERM, bazedoxifene, can significantly decrease the incidence of vertebral fracture in postmenopausal women at follow-up of 3 and 7 years.²⁵ That meta-analysis also confirmed the long-term favorable safety and tolerability of bazedoxifene, with no increase in adverse events, serious adverse events, myocardial infarction, stroke, venous thromboembolic events, or breast carcinoma in patients using bazedoxifene. However, bazedoxifene use did result in an increased incidence of hot flushes and leg cramps across 7 years.²⁵ Bazedoxifene is available in a 20-mg dose for treatment of postmenopausal osteoporosis in Israel and a number of European Union countries.

Continue to: Enter the concept of tissue-selective estrogen complex (TSEC)...

Some postmenopausal women are extremely intolerant of any progestogen added to estrogen therapy to confer endometrial protection in those with a uterus. According to the results of a clinical trial of postmenopausal women, bazedoxifene is the only SERM shown to decrease endometrial thickness compared with placebo.²⁶ This is the basis for thinking that perhaps a SERM like bazedoxifene, instead of a progestogen, could be used to confer endometrial protection.

A further consideration comes out of the evaluation of data derived from the 2 arms of the Women’s Health Initiative (WHI).²⁷ In the arm that combined conjugated estrogen with medroxyprogesterone acetate through 11.3 years, there was a 25% increase in the incidence of invasive breast cancer, which was statistically significant. Contrast that with the arm in hysterectomized women who received only conjugated estrogen (often inaccurately referred to as the “estrogen only” arm of the WHI). In that study arm, the relative risk of invasive breast cancer was reduced 23%, also statistically significant. Thus, the culprit in the breast cancer incidence difference in these 2 arms appears to be the addition of the progestogen medroxyprogesterone acetate.²⁷

Since the progestogen was used only for endometrial protection, could such endometrial protection be provided by a SERM like bazedoxifene? Preclinical trials showed that a combination of bazedoxifene and conjugated estrogen (in various estrogen doses) resulted in uterine wet weight in an ovariectomized rat model that was no different than that with placebo.²⁸

In terms of effects on breast, preclinical models showed that conjugated estrogen use resulted in less mammary duct elongation and end bud proliferation than estradiol by itself, and that the combination of conjugated estrogen and bazedoxifene resulted in mammary duct elongation and end bud proliferation that was similar to that in the ovariectomized animals and considerably less than a combination of estradiol with bazedoxifene.²⁹

Five phase 3 studies known as the SMART (Selective estrogens, Menopause, And Response to Therapy) trials were then conducted. Collectively, these studies examined the frequency and severity of vasomotor symptoms (VMS), BMD, bone turnover markers, lipid profiles, sleep, quality of life, breast density, and endometrial safety with conjugated estrogen/bazedoxifene treatment.³⁰ Based on these trials with more than 7,500 women, in 2013 the FDA approved a compound of conjugated estrogen 0.45 mg and bazedoxifene 20 mg (Duavee in the United States and Duavive outside the United States).

The incidence of endometrial hyperplasia at 12 months was consistently less than 1%, which is the FDA guidance for approval of hormone therapies. The incidence of bleeding or spotting with conjugated estrogen/bazedoxifene (FIGURE 3) in each 4-week interval over 12 months mirror-imaged that of placebo and ranged from 3.9% in the first 4-week interval to 1.7% in the last 4 weeks, compared with conjugated estrogen 0.45 mg/medroxyprogesterone acetate 1.5 mg, which had a 20.8% incidence of bleeding or spotting in the first 4-week interval and was still at an 8.8% incidence in the last 4 weeks.³¹ This is extremely relevant in clinical practice. There was no difference from placebo in breast cancer incidence, breast pain or tenderness, abnormal mammograms, or breast density at month 12.³²

In terms of frequency of VMS, there was a 74% reduction from baseline at 12 weeks compared with placebo (P<.001), as well as a 37% reduction in the VMS severity score (P<.001).³² Statistically significant improvements occurred in lumbar spine and hip BMD (P<.01) for women who were 1 to 5 years since menopause as well as for those who were more than 5 years since menopause.³³

Packaging issue puts TSEC on back order

In May 2020, Pfizer voluntarily recalled its conjugated estrogen/bazedoxifene product after identifying a “flaw in the drug’s foil laminate pouch that introduced oxygen and lowered the dissolution rate of active pharmaceutical ingredient bazedoxifene acetate.”³⁴ The manufacturer then wrote a letter to health care professionals in September 2021 stating, “Duavee continues to be out of stock due to an unexpected and complex packaging issue, resulting in manufacturing delays. This has nothing to do with the safety or quality of the product itself but could affect product stability throughout its shelf life… Given regulatory approval timelines for any new packaging, it is unlikely that Duavee will return to stock in 2022.”³⁵

Other TSECs?

The conjugated estrogen/bazedoxifene combination is the first FDA-approved TSEC. Other attempts have been made to achieve similar results with combined raloxifene and 17β-estradiol.³⁶ That study was meant to be a 52-week treatment trial with either raloxifene 60 mg alone or in combination with 17β-estradiol 1 mg per day to assess effects on VMS and endometrial safety. The study was stopped early because signs of endometrial stimulation were observed in the raloxifene plus estradiol group. Thus, one cannot combine any estrogen with any SERM and assume similar results.

Clinical application

The combination of conjugated estrogen/bazedoxifene is approved for treatment of VMS of menopause as well as prevention of osteoporosis. Although it is not approved for treatment of moderate to severe VVA, in younger women who initiate treatment it should prevent the development of moderate to severe symptoms of VVA.

Finally, this drug should be protective of the breast. Conjugated estrogen has clearly shown a reduction in breast cancer incidence and mortality, and bazedoxifene is a SERM. All SERMs have, as a class effect, been shown to be antiestrogens in breast tissue, and abundant preclinical data point in that direction.

This combination of conjugated estrogen/bazedoxifene, when it is once again clinically available, may well provide a new paradigm of hormone therapy that is progestogen free and has a benefit/risk ratio that tilts toward its benefits.

Potential for wider therapeutic benefits

Newer SERMs like ospemifene, approved for treatment of VVA/GSM, and bazedoxifene/conjugated estrogen combination, approved for treatment of VMS and prevention of bone loss, have other beneficial properties that can and should result in their more widespread use. ●

Selective estrogen receptor modulators (SERMs) are unique synthetic compounds that bind to the estrogen receptor and initiate either estrogenic agonistic or antagonistic activity, depending on the confirmational change they produce on binding to the receptor. Many SERMs have come to market, others have not. Unlike estrogens, which regardless of dose or route of administration all carry risks as a boxed warning on the label, referred to as class labeling,¹ various SERMs exert various effects in some tissues (uterus, vagina) while they have apparent class properties in others (bone, breast).²

The first SERM, for all practical purposes, was tamoxifen (although clomiphene citrate is often considered a SERM). Tamoxifen was approved by the US Food and Drug Administration (FDA) in 1978 for the treatment of breast cancer and, subsequently, for breast cancer risk reduction. It became the most widely prescribed anticancer drug worldwide.

Subsequently, when data showed that tamoxifen could produce a small number of endometrial cancers and a larger number of endometrial polyps,^3,4 there was renewed interest in raloxifene. In preclinical animal studies, raloxifene behaved differently than tamoxifen in the uterus. After clinical trials with raloxifene showed uterine safety,⁵ the drug was FDA approved for prevention of osteoporosis in 1997, for treatment of osteoporosis in 1999, and for breast cancer risk reduction in 2009. Most clinicians are familiar with these 2 SERMs, which have been in clinical use for more than 4 and 2 decades, respectively.

Ospemifene: A third-generation SERM and its indications

Hormone deficiency from menopause causes vulvovaginal and urogenital changes as well as a multitude of symptoms and signs, including vulvar and vaginal thinning, loss of rugal folds, diminished elasticity, increased pH, and most notably dyspareunia. The nomenclature that previously described vulvovaginal atrophy (VVA) has been expanded to include genitourinary syndrome of menopause (GSM).⁶ Unfortunately, many health care providers do not ask patients about GSM symptoms, and few women report their symptoms to their clinician.⁷ Furthermore, although low-dose local estrogens applied vaginally have been the mainstay of therapy for VVA/GSM, only 7% of symptomatic women use any pharmacologic agent,⁸ mainly because of fear of estrogens due to the class labeling mentioned above.

Ospemifene, a newer SERM, improved superficial cells and reduced parabasal cells as seen on a maturation index compared with placebo, according to results of multiple phase 3 clinical trials^9,10; it also lowered vaginal pH and improved most bothersome symptoms (original studies were for dyspareunia). As a result, the FDA approved ospemifene for treatment of moderate to severe dyspareunia from VVA of menopause.

Subsequent studies allowed for a broadened indication to include treatment of moderate to severe dryness due to menopause.¹¹ The ospemifene label contains a boxed warning that states, “In the endometrium, [ospemifene] has estrogen agonistic effects.”¹² Although ospemifene is not an estrogen (it’s a SERM), the label goes on to state, “There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.” This statement caused The Medical Letter to initially suggest that patients who receive ospemifene also should receive a progestational agent—a suggestion they later retracted.^13,14

To understand why the ospemifene labeling might be worded in such a way, one must review the data regarding the poorly named entity “weakly proliferative endometrium.” The package labeling combines any proliferative endometrium (“weakly” plus “actively” plus “disordered”) that occurred in the clinical trial. Thus, 86.1 per 1,000 of the ospemifene-treated patients (vs 13.3 per 1,000 of those taking placebo) had any one of the proliferative types. The problem is that “actively proliferative” endometrial glands will have mitotic activity in virtually every nucleus of the gland as well as abundant glandular progression (FIGURE 1), whereas “weakly proliferative” is actually closer to inactive or atrophic endometrium with an occasional mitotic figure in only a few nuclei of each gland (FIGURE 2).

In addition, at 1 year, the incidence of active proliferation with ospemifene was 1%.¹⁵ In examining the uterine safety study for raloxifene, both doses of that agent had an active proliferation incidence of 3% at 1 year.⁵ Furthermore, that study had an estrogen-only arm in which, at end point, the incidence of endometrial proliferation was 39%, and hyperplasia, 23%!⁵ It therefore is evident that, in the endometrium, ospemifene is much more like the SERM raloxifene than it is like estrogen. The American College of Obstetricians and Gynecologists (ACOG) endorsed ospemifene (level A evidence) as a first-line therapy for dyspareunia, noting absent endometrial stimulation.¹⁶

Continue to: Ospemifene effects on breast and bone...

Although ospemifene is approved for treatment of moderate to severe VVA/GSM, it has other SERM effects typical of its class. The label currently states that ospemifene “has not been adequately studied in women with breast cancer; therefore, it should not be used in women with known or suspected breast cancer.”¹² We know that tamoxifen reduced breast cancer 49% in high-risk women in the Breast Cancer Prevention Trial (BCPT).¹⁷ We also know that in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced breast cancer 77% in osteoporotic women,¹⁸ and in the Study of Tamoxifen and Raloxifene (STAR) trial, it performed virtually identically to tamoxifen in breast cancer prevention.¹⁹ Previous studies demonstrated that ospemifene inhibits breast cancer cell growth in in vitro cultures as well as in animal studies²⁰ and inhibits proliferation of human breast tissue epithelial cells,²¹ with breast effects similar to those seen with tamoxifen and raloxifene.

Thus, although one would not choose ospemifene as a primary treatment or risk-reducing agent for a patient with breast cancer, the direction of its activity in breast tissue is indisputable and is likely the reason that in the European Union (unlike in the United States) it is approved to treat dyspareunia from VVA/GSM in women with a prior history of breast cancer.

Virtually all SERMs have estrogen agonistic activity in bone. Bone is a dynamic organ, constantly being laid down and taken away (resorption). Estrogen and SERMs are potent antiresorptives in bone metabolism. Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to that of estradiol and raloxifene.²² Clinical data from 3 phase 1 or 2 clinical trials found that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.²³ Actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, but there is a good correlation between biochemical markers for bone turnover and the occurrence of fracture.²⁴ Once again, women who need treatment for osteoporosis should not be treated primarily with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.

Clinical application

Ospemifene is an oral SERM approved for the treatment of moderate to severe dyspareunia as well as dryness from VVA due to menopause. In addition, it appears one can safely surmise that the direction of ospemifene’s activity in bone and breast is virtually indisputable. The magnitude of that activity, however, is unstudied. Therefore, in selecting an agent to treat women with dyspareunia or vaginal dryness from VVA of menopause, determining any potential add-on benefit for that particular patient in either bone and/or breast is clinically appropriate.

The SERM bazedoxifene

A meta-analysis of 4 randomized, placebo-controlled trials showed that another SERM, bazedoxifene, can significantly decrease the incidence of vertebral fracture in postmenopausal women at follow-up of 3 and 7 years.²⁵ That meta-analysis also confirmed the long-term favorable safety and tolerability of bazedoxifene, with no increase in adverse events, serious adverse events, myocardial infarction, stroke, venous thromboembolic events, or breast carcinoma in patients using bazedoxifene. However, bazedoxifene use did result in an increased incidence of hot flushes and leg cramps across 7 years.²⁵ Bazedoxifene is available in a 20-mg dose for treatment of postmenopausal osteoporosis in Israel and a number of European Union countries.

Continue to: Enter the concept of tissue-selective estrogen complex (TSEC)...

Some postmenopausal women are extremely intolerant of any progestogen added to estrogen therapy to confer endometrial protection in those with a uterus. According to the results of a clinical trial of postmenopausal women, bazedoxifene is the only SERM shown to decrease endometrial thickness compared with placebo.²⁶ This is the basis for thinking that perhaps a SERM like bazedoxifene, instead of a progestogen, could be used to confer endometrial protection.

A further consideration comes out of the evaluation of data derived from the 2 arms of the Women’s Health Initiative (WHI).²⁷ In the arm that combined conjugated estrogen with medroxyprogesterone acetate through 11.3 years, there was a 25% increase in the incidence of invasive breast cancer, which was statistically significant. Contrast that with the arm in hysterectomized women who received only conjugated estrogen (often inaccurately referred to as the “estrogen only” arm of the WHI). In that study arm, the relative risk of invasive breast cancer was reduced 23%, also statistically significant. Thus, the culprit in the breast cancer incidence difference in these 2 arms appears to be the addition of the progestogen medroxyprogesterone acetate.²⁷

Since the progestogen was used only for endometrial protection, could such endometrial protection be provided by a SERM like bazedoxifene? Preclinical trials showed that a combination of bazedoxifene and conjugated estrogen (in various estrogen doses) resulted in uterine wet weight in an ovariectomized rat model that was no different than that with placebo.²⁸

In terms of effects on breast, preclinical models showed that conjugated estrogen use resulted in less mammary duct elongation and end bud proliferation than estradiol by itself, and that the combination of conjugated estrogen and bazedoxifene resulted in mammary duct elongation and end bud proliferation that was similar to that in the ovariectomized animals and considerably less than a combination of estradiol with bazedoxifene.²⁹

Five phase 3 studies known as the SMART (Selective estrogens, Menopause, And Response to Therapy) trials were then conducted. Collectively, these studies examined the frequency and severity of vasomotor symptoms (VMS), BMD, bone turnover markers, lipid profiles, sleep, quality of life, breast density, and endometrial safety with conjugated estrogen/bazedoxifene treatment.³⁰ Based on these trials with more than 7,500 women, in 2013 the FDA approved a compound of conjugated estrogen 0.45 mg and bazedoxifene 20 mg (Duavee in the United States and Duavive outside the United States).

The incidence of endometrial hyperplasia at 12 months was consistently less than 1%, which is the FDA guidance for approval of hormone therapies. The incidence of bleeding or spotting with conjugated estrogen/bazedoxifene (FIGURE 3) in each 4-week interval over 12 months mirror-imaged that of placebo and ranged from 3.9% in the first 4-week interval to 1.7% in the last 4 weeks, compared with conjugated estrogen 0.45 mg/medroxyprogesterone acetate 1.5 mg, which had a 20.8% incidence of bleeding or spotting in the first 4-week interval and was still at an 8.8% incidence in the last 4 weeks.³¹ This is extremely relevant in clinical practice. There was no difference from placebo in breast cancer incidence, breast pain or tenderness, abnormal mammograms, or breast density at month 12.³²

In terms of frequency of VMS, there was a 74% reduction from baseline at 12 weeks compared with placebo (P<.001), as well as a 37% reduction in the VMS severity score (P<.001).³² Statistically significant improvements occurred in lumbar spine and hip BMD (P<.01) for women who were 1 to 5 years since menopause as well as for those who were more than 5 years since menopause.³³

Packaging issue puts TSEC on back order

In May 2020, Pfizer voluntarily recalled its conjugated estrogen/bazedoxifene product after identifying a “flaw in the drug’s foil laminate pouch that introduced oxygen and lowered the dissolution rate of active pharmaceutical ingredient bazedoxifene acetate.”³⁴ The manufacturer then wrote a letter to health care professionals in September 2021 stating, “Duavee continues to be out of stock due to an unexpected and complex packaging issue, resulting in manufacturing delays. This has nothing to do with the safety or quality of the product itself but could affect product stability throughout its shelf life… Given regulatory approval timelines for any new packaging, it is unlikely that Duavee will return to stock in 2022.”³⁵

Other TSECs?

The conjugated estrogen/bazedoxifene combination is the first FDA-approved TSEC. Other attempts have been made to achieve similar results with combined raloxifene and 17β-estradiol.³⁶ That study was meant to be a 52-week treatment trial with either raloxifene 60 mg alone or in combination with 17β-estradiol 1 mg per day to assess effects on VMS and endometrial safety. The study was stopped early because signs of endometrial stimulation were observed in the raloxifene plus estradiol group. Thus, one cannot combine any estrogen with any SERM and assume similar results.

Clinical application

The combination of conjugated estrogen/bazedoxifene is approved for treatment of VMS of menopause as well as prevention of osteoporosis. Although it is not approved for treatment of moderate to severe VVA, in younger women who initiate treatment it should prevent the development of moderate to severe symptoms of VVA.

Finally, this drug should be protective of the breast. Conjugated estrogen has clearly shown a reduction in breast cancer incidence and mortality, and bazedoxifene is a SERM. All SERMs have, as a class effect, been shown to be antiestrogens in breast tissue, and abundant preclinical data point in that direction.

This combination of conjugated estrogen/bazedoxifene, when it is once again clinically available, may well provide a new paradigm of hormone therapy that is progestogen free and has a benefit/risk ratio that tilts toward its benefits.

Potential for wider therapeutic benefits

Newer SERMs like ospemifene, approved for treatment of VVA/GSM, and bazedoxifene/conjugated estrogen combination, approved for treatment of VMS and prevention of bone loss, have other beneficial properties that can and should result in their more widespread use. ●

Selective estrogen receptor modulators (SERMs) are unique synthetic compounds that bind to the estrogen receptor and initiate either estrogenic agonistic or antagonistic activity, depending on the confirmational change they produce on binding to the receptor. Many SERMs have come to market, others have not. Unlike estrogens, which regardless of dose or route of administration all carry risks as a boxed warning on the label, referred to as class labeling,¹ various SERMs exert various effects in some tissues (uterus, vagina) while they have apparent class properties in others (bone, breast).²

The first SERM, for all practical purposes, was tamoxifen (although clomiphene citrate is often considered a SERM). Tamoxifen was approved by the US Food and Drug Administration (FDA) in 1978 for the treatment of breast cancer and, subsequently, for breast cancer risk reduction. It became the most widely prescribed anticancer drug worldwide.

Subsequently, when data showed that tamoxifen could produce a small number of endometrial cancers and a larger number of endometrial polyps,^3,4 there was renewed interest in raloxifene. In preclinical animal studies, raloxifene behaved differently than tamoxifen in the uterus. After clinical trials with raloxifene showed uterine safety,⁵ the drug was FDA approved for prevention of osteoporosis in 1997, for treatment of osteoporosis in 1999, and for breast cancer risk reduction in 2009. Most clinicians are familiar with these 2 SERMs, which have been in clinical use for more than 4 and 2 decades, respectively.

Ospemifene: A third-generation SERM and its indications

Hormone deficiency from menopause causes vulvovaginal and urogenital changes as well as a multitude of symptoms and signs, including vulvar and vaginal thinning, loss of rugal folds, diminished elasticity, increased pH, and most notably dyspareunia. The nomenclature that previously described vulvovaginal atrophy (VVA) has been expanded to include genitourinary syndrome of menopause (GSM).⁶ Unfortunately, many health care providers do not ask patients about GSM symptoms, and few women report their symptoms to their clinician.⁷ Furthermore, although low-dose local estrogens applied vaginally have been the mainstay of therapy for VVA/GSM, only 7% of symptomatic women use any pharmacologic agent,⁸ mainly because of fear of estrogens due to the class labeling mentioned above.

Ospemifene, a newer SERM, improved superficial cells and reduced parabasal cells as seen on a maturation index compared with placebo, according to results of multiple phase 3 clinical trials^9,10; it also lowered vaginal pH and improved most bothersome symptoms (original studies were for dyspareunia). As a result, the FDA approved ospemifene for treatment of moderate to severe dyspareunia from VVA of menopause.

Subsequent studies allowed for a broadened indication to include treatment of moderate to severe dryness due to menopause.¹¹ The ospemifene label contains a boxed warning that states, “In the endometrium, [ospemifene] has estrogen agonistic effects.”¹² Although ospemifene is not an estrogen (it’s a SERM), the label goes on to state, “There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.” This statement caused The Medical Letter to initially suggest that patients who receive ospemifene also should receive a progestational agent—a suggestion they later retracted.^13,14

To understand why the ospemifene labeling might be worded in such a way, one must review the data regarding the poorly named entity “weakly proliferative endometrium.” The package labeling combines any proliferative endometrium (“weakly” plus “actively” plus “disordered”) that occurred in the clinical trial. Thus, 86.1 per 1,000 of the ospemifene-treated patients (vs 13.3 per 1,000 of those taking placebo) had any one of the proliferative types. The problem is that “actively proliferative” endometrial glands will have mitotic activity in virtually every nucleus of the gland as well as abundant glandular progression (FIGURE 1), whereas “weakly proliferative” is actually closer to inactive or atrophic endometrium with an occasional mitotic figure in only a few nuclei of each gland (FIGURE 2).

In addition, at 1 year, the incidence of active proliferation with ospemifene was 1%.¹⁵ In examining the uterine safety study for raloxifene, both doses of that agent had an active proliferation incidence of 3% at 1 year.⁵ Furthermore, that study had an estrogen-only arm in which, at end point, the incidence of endometrial proliferation was 39%, and hyperplasia, 23%!⁵ It therefore is evident that, in the endometrium, ospemifene is much more like the SERM raloxifene than it is like estrogen. The American College of Obstetricians and Gynecologists (ACOG) endorsed ospemifene (level A evidence) as a first-line therapy for dyspareunia, noting absent endometrial stimulation.¹⁶

Continue to: Ospemifene effects on breast and bone...

Although ospemifene is approved for treatment of moderate to severe VVA/GSM, it has other SERM effects typical of its class. The label currently states that ospemifene “has not been adequately studied in women with breast cancer; therefore, it should not be used in women with known or suspected breast cancer.”¹² We know that tamoxifen reduced breast cancer 49% in high-risk women in the Breast Cancer Prevention Trial (BCPT).¹⁷ We also know that in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced breast cancer 77% in osteoporotic women,¹⁸ and in the Study of Tamoxifen and Raloxifene (STAR) trial, it performed virtually identically to tamoxifen in breast cancer prevention.¹⁹ Previous studies demonstrated that ospemifene inhibits breast cancer cell growth in in vitro cultures as well as in animal studies²⁰ and inhibits proliferation of human breast tissue epithelial cells,²¹ with breast effects similar to those seen with tamoxifen and raloxifene.

Thus, although one would not choose ospemifene as a primary treatment or risk-reducing agent for a patient with breast cancer, the direction of its activity in breast tissue is indisputable and is likely the reason that in the European Union (unlike in the United States) it is approved to treat dyspareunia from VVA/GSM in women with a prior history of breast cancer.

Virtually all SERMs have estrogen agonistic activity in bone. Bone is a dynamic organ, constantly being laid down and taken away (resorption). Estrogen and SERMs are potent antiresorptives in bone metabolism. Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to that of estradiol and raloxifene.²² Clinical data from 3 phase 1 or 2 clinical trials found that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.²³ Actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, but there is a good correlation between biochemical markers for bone turnover and the occurrence of fracture.²⁴ Once again, women who need treatment for osteoporosis should not be treated primarily with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.

Clinical application

Ospemifene is an oral SERM approved for the treatment of moderate to severe dyspareunia as well as dryness from VVA due to menopause. In addition, it appears one can safely surmise that the direction of ospemifene’s activity in bone and breast is virtually indisputable. The magnitude of that activity, however, is unstudied. Therefore, in selecting an agent to treat women with dyspareunia or vaginal dryness from VVA of menopause, determining any potential add-on benefit for that particular patient in either bone and/or breast is clinically appropriate.

The SERM bazedoxifene

A meta-analysis of 4 randomized, placebo-controlled trials showed that another SERM, bazedoxifene, can significantly decrease the incidence of vertebral fracture in postmenopausal women at follow-up of 3 and 7 years.²⁵ That meta-analysis also confirmed the long-term favorable safety and tolerability of bazedoxifene, with no increase in adverse events, serious adverse events, myocardial infarction, stroke, venous thromboembolic events, or breast carcinoma in patients using bazedoxifene. However, bazedoxifene use did result in an increased incidence of hot flushes and leg cramps across 7 years.²⁵ Bazedoxifene is available in a 20-mg dose for treatment of postmenopausal osteoporosis in Israel and a number of European Union countries.

Continue to: Enter the concept of tissue-selective estrogen complex (TSEC)...

Some postmenopausal women are extremely intolerant of any progestogen added to estrogen therapy to confer endometrial protection in those with a uterus. According to the results of a clinical trial of postmenopausal women, bazedoxifene is the only SERM shown to decrease endometrial thickness compared with placebo.²⁶ This is the basis for thinking that perhaps a SERM like bazedoxifene, instead of a progestogen, could be used to confer endometrial protection.

A further consideration comes out of the evaluation of data derived from the 2 arms of the Women’s Health Initiative (WHI).²⁷ In the arm that combined conjugated estrogen with medroxyprogesterone acetate through 11.3 years, there was a 25% increase in the incidence of invasive breast cancer, which was statistically significant. Contrast that with the arm in hysterectomized women who received only conjugated estrogen (often inaccurately referred to as the “estrogen only” arm of the WHI). In that study arm, the relative risk of invasive breast cancer was reduced 23%, also statistically significant. Thus, the culprit in the breast cancer incidence difference in these 2 arms appears to be the addition of the progestogen medroxyprogesterone acetate.²⁷

Since the progestogen was used only for endometrial protection, could such endometrial protection be provided by a SERM like bazedoxifene? Preclinical trials showed that a combination of bazedoxifene and conjugated estrogen (in various estrogen doses) resulted in uterine wet weight in an ovariectomized rat model that was no different than that with placebo.²⁸

In terms of effects on breast, preclinical models showed that conjugated estrogen use resulted in less mammary duct elongation and end bud proliferation than estradiol by itself, and that the combination of conjugated estrogen and bazedoxifene resulted in mammary duct elongation and end bud proliferation that was similar to that in the ovariectomized animals and considerably less than a combination of estradiol with bazedoxifene.²⁹

Five phase 3 studies known as the SMART (Selective estrogens, Menopause, And Response to Therapy) trials were then conducted. Collectively, these studies examined the frequency and severity of vasomotor symptoms (VMS), BMD, bone turnover markers, lipid profiles, sleep, quality of life, breast density, and endometrial safety with conjugated estrogen/bazedoxifene treatment.³⁰ Based on these trials with more than 7,500 women, in 2013 the FDA approved a compound of conjugated estrogen 0.45 mg and bazedoxifene 20 mg (Duavee in the United States and Duavive outside the United States).

The incidence of endometrial hyperplasia at 12 months was consistently less than 1%, which is the FDA guidance for approval of hormone therapies. The incidence of bleeding or spotting with conjugated estrogen/bazedoxifene (FIGURE 3) in each 4-week interval over 12 months mirror-imaged that of placebo and ranged from 3.9% in the first 4-week interval to 1.7% in the last 4 weeks, compared with conjugated estrogen 0.45 mg/medroxyprogesterone acetate 1.5 mg, which had a 20.8% incidence of bleeding or spotting in the first 4-week interval and was still at an 8.8% incidence in the last 4 weeks.³¹ This is extremely relevant in clinical practice. There was no difference from placebo in breast cancer incidence, breast pain or tenderness, abnormal mammograms, or breast density at month 12.³²

In terms of frequency of VMS, there was a 74% reduction from baseline at 12 weeks compared with placebo (P<.001), as well as a 37% reduction in the VMS severity score (P<.001).³² Statistically significant improvements occurred in lumbar spine and hip BMD (P<.01) for women who were 1 to 5 years since menopause as well as for those who were more than 5 years since menopause.³³

Packaging issue puts TSEC on back order

In May 2020, Pfizer voluntarily recalled its conjugated estrogen/bazedoxifene product after identifying a “flaw in the drug’s foil laminate pouch that introduced oxygen and lowered the dissolution rate of active pharmaceutical ingredient bazedoxifene acetate.”³⁴ The manufacturer then wrote a letter to health care professionals in September 2021 stating, “Duavee continues to be out of stock due to an unexpected and complex packaging issue, resulting in manufacturing delays. This has nothing to do with the safety or quality of the product itself but could affect product stability throughout its shelf life… Given regulatory approval timelines for any new packaging, it is unlikely that Duavee will return to stock in 2022.”³⁵

Other TSECs?

The conjugated estrogen/bazedoxifene combination is the first FDA-approved TSEC. Other attempts have been made to achieve similar results with combined raloxifene and 17β-estradiol.³⁶ That study was meant to be a 52-week treatment trial with either raloxifene 60 mg alone or in combination with 17β-estradiol 1 mg per day to assess effects on VMS and endometrial safety. The study was stopped early because signs of endometrial stimulation were observed in the raloxifene plus estradiol group. Thus, one cannot combine any estrogen with any SERM and assume similar results.

Clinical application

The combination of conjugated estrogen/bazedoxifene is approved for treatment of VMS of menopause as well as prevention of osteoporosis. Although it is not approved for treatment of moderate to severe VVA, in younger women who initiate treatment it should prevent the development of moderate to severe symptoms of VVA.

Finally, this drug should be protective of the breast. Conjugated estrogen has clearly shown a reduction in breast cancer incidence and mortality, and bazedoxifene is a SERM. All SERMs have, as a class effect, been shown to be antiestrogens in breast tissue, and abundant preclinical data point in that direction.

This combination of conjugated estrogen/bazedoxifene, when it is once again clinically available, may well provide a new paradigm of hormone therapy that is progestogen free and has a benefit/risk ratio that tilts toward its benefits.

Potential for wider therapeutic benefits

Newer SERMs like ospemifene, approved for treatment of VVA/GSM, and bazedoxifene/conjugated estrogen combination, approved for treatment of VMS and prevention of bone loss, have other beneficial properties that can and should result in their more widespread use. ●

Taglauer ES, Wachman EM, Juttukonda L, et al. Acute severe acute respiratory syndrome coronavirus 2 infection in pregnancy is associated with placental angiotensin-converting enzyme 2 shedding. Am J Pathol. 2022;192:595-603. doi.org/10.1016/j.ajpath.2021.12.011

EXPERT COMMENTARY

Although transmission of SARS-CoV-2 virus from an infected mother to her fetus is rare, placental infection with SARS-CoV-2 can occur and has been observed in association with placental damage and adverse pregnancy outcomes, including stillbirth.¹ Understanding what mechanisms of defense protect the placenta and fetus from direct SARS-CoV-2 infection at the maternal-fetal interface, as well as the factors that might disturb or enhance that protection, is critical to gaining a deeper understanding of the potential impact of maternal COVID-19 on fetal well-being.

Details of the study

In a cohort of 24 pregnant individuals, Taglauer and colleagues investigated levels of placental angiotensin-converting enzyme (ACE)-2, placental ADAM17 (a disintegrin and metalloprotease domain 17) activity, and maternal serum soluble ACE2 in samples obtained at delivery from individuals with a history of second trimester COVID-19 infection, early third trimester COVID-19 infection, and no history of COVID-19 infection.

Results. Maternal COVID-19 infection in the early third trimester of pregnancy resulted in lower ACE2 protein levels in the placenta at delivery, higher ACE2 gene expression, and an increase in ADAM17 activity, compared with infection in the second trimester of pregnancy and compared with noninfected controls.

The authors postulated that increased ADAM17 activity—the enzyme responsible for ACE2 cleavage and shedding—may be responsible for lower ACE2 protein levels. Soluble ACE2 levels in maternal blood at delivery were increased in individuals with third trimester COVID-19 infection, although the source of soluble ACE2 (placental or otherwise) could not be determined with the methods employed. Levels of placental estrogen were no different between groups, which suggests that estrogen is not responsible for the observed differences.

Study strengths and limitations

ACE2 is the main receptor for the SARS-CoV-2 virus and facilitates viral entry into the cell.² Placental villous cells that are in direct contact with maternal blood express the ACE2 protein, rendering them potentially vulnerable to SARS-CoV-2 infection.³ In this study, the authors observed lower placental ACE2 protein in term placentas from recent (early third trimester) but not remote (second trimester) maternal SARS-CoV-2 infection, arguably the result of the observed increase in ADAM17 cleavage activity. Prior studies have shown conflicting results, with equal or higher ACE2 levels noted in the setting of maternal COVID-19 infection, which may be related to differences in COVID-19 disease severity, gestational age of infection, and/or fetal sex in these cohorts.^4-6

The concept that increased placental ACE2 shedding represents a protective defense mechanism that might last weeks beyond the acute infectious period is intriguing, but it requires further study. Observed differences in third but not second trimester COVID-19 infections could indicate either 1) an effect of maternal COVID-19 infection that lasts for several weeks but eventually normalizes over time, in the case of a remote infection; or 2) that second trimester maternal COVID-19 infection does not have the same pronounced effect on ACE2 levels as does third trimester infection. Observational studies of the human placenta are not able to answer this question, as directly sampling the placenta at the time of the exposure (or repeated sampling over time) in ongoing pregnancies is neither practical nor ethical. Further studies using animal or cellular models of SARS-CoV-2 infection in pregnancy may be necessary to fully understand the clinical relevance of these findings.

The study by Taglauer and colleagues provides a compelling argument for exploring how immune defenses at the maternal-fetal interface evolve over time and vary by trimester of exposure. ●

Taglauer ES, Wachman EM, Juttukonda L, et al. Acute severe acute respiratory syndrome coronavirus 2 infection in pregnancy is associated with placental angiotensin-converting enzyme 2 shedding. Am J Pathol. 2022;192:595-603. doi.org/10.1016/j.ajpath.2021.12.011

EXPERT COMMENTARY

Although transmission of SARS-CoV-2 virus from an infected mother to her fetus is rare, placental infection with SARS-CoV-2 can occur and has been observed in association with placental damage and adverse pregnancy outcomes, including stillbirth.¹ Understanding what mechanisms of defense protect the placenta and fetus from direct SARS-CoV-2 infection at the maternal-fetal interface, as well as the factors that might disturb or enhance that protection, is critical to gaining a deeper understanding of the potential impact of maternal COVID-19 on fetal well-being.

Details of the study

In a cohort of 24 pregnant individuals, Taglauer and colleagues investigated levels of placental angiotensin-converting enzyme (ACE)-2, placental ADAM17 (a disintegrin and metalloprotease domain 17) activity, and maternal serum soluble ACE2 in samples obtained at delivery from individuals with a history of second trimester COVID-19 infection, early third trimester COVID-19 infection, and no history of COVID-19 infection.

Results. Maternal COVID-19 infection in the early third trimester of pregnancy resulted in lower ACE2 protein levels in the placenta at delivery, higher ACE2 gene expression, and an increase in ADAM17 activity, compared with infection in the second trimester of pregnancy and compared with noninfected controls.

The authors postulated that increased ADAM17 activity—the enzyme responsible for ACE2 cleavage and shedding—may be responsible for lower ACE2 protein levels. Soluble ACE2 levels in maternal blood at delivery were increased in individuals with third trimester COVID-19 infection, although the source of soluble ACE2 (placental or otherwise) could not be determined with the methods employed. Levels of placental estrogen were no different between groups, which suggests that estrogen is not responsible for the observed differences.

Study strengths and limitations

ACE2 is the main receptor for the SARS-CoV-2 virus and facilitates viral entry into the cell.² Placental villous cells that are in direct contact with maternal blood express the ACE2 protein, rendering them potentially vulnerable to SARS-CoV-2 infection.³ In this study, the authors observed lower placental ACE2 protein in term placentas from recent (early third trimester) but not remote (second trimester) maternal SARS-CoV-2 infection, arguably the result of the observed increase in ADAM17 cleavage activity. Prior studies have shown conflicting results, with equal or higher ACE2 levels noted in the setting of maternal COVID-19 infection, which may be related to differences in COVID-19 disease severity, gestational age of infection, and/or fetal sex in these cohorts.^4-6

The concept that increased placental ACE2 shedding represents a protective defense mechanism that might last weeks beyond the acute infectious period is intriguing, but it requires further study. Observed differences in third but not second trimester COVID-19 infections could indicate either 1) an effect of maternal COVID-19 infection that lasts for several weeks but eventually normalizes over time, in the case of a remote infection; or 2) that second trimester maternal COVID-19 infection does not have the same pronounced effect on ACE2 levels as does third trimester infection. Observational studies of the human placenta are not able to answer this question, as directly sampling the placenta at the time of the exposure (or repeated sampling over time) in ongoing pregnancies is neither practical nor ethical. Further studies using animal or cellular models of SARS-CoV-2 infection in pregnancy may be necessary to fully understand the clinical relevance of these findings.

The study by Taglauer and colleagues provides a compelling argument for exploring how immune defenses at the maternal-fetal interface evolve over time and vary by trimester of exposure. ●

Taglauer ES, Wachman EM, Juttukonda L, et al. Acute severe acute respiratory syndrome coronavirus 2 infection in pregnancy is associated with placental angiotensin-converting enzyme 2 shedding. Am J Pathol. 2022;192:595-603. doi.org/10.1016/j.ajpath.2021.12.011

EXPERT COMMENTARY

Although transmission of SARS-CoV-2 virus from an infected mother to her fetus is rare, placental infection with SARS-CoV-2 can occur and has been observed in association with placental damage and adverse pregnancy outcomes, including stillbirth.¹ Understanding what mechanisms of defense protect the placenta and fetus from direct SARS-CoV-2 infection at the maternal-fetal interface, as well as the factors that might disturb or enhance that protection, is critical to gaining a deeper understanding of the potential impact of maternal COVID-19 on fetal well-being.

Details of the study

In a cohort of 24 pregnant individuals, Taglauer and colleagues investigated levels of placental angiotensin-converting enzyme (ACE)-2, placental ADAM17 (a disintegrin and metalloprotease domain 17) activity, and maternal serum soluble ACE2 in samples obtained at delivery from individuals with a history of second trimester COVID-19 infection, early third trimester COVID-19 infection, and no history of COVID-19 infection.

Results. Maternal COVID-19 infection in the early third trimester of pregnancy resulted in lower ACE2 protein levels in the placenta at delivery, higher ACE2 gene expression, and an increase in ADAM17 activity, compared with infection in the second trimester of pregnancy and compared with noninfected controls.

The authors postulated that increased ADAM17 activity—the enzyme responsible for ACE2 cleavage and shedding—may be responsible for lower ACE2 protein levels. Soluble ACE2 levels in maternal blood at delivery were increased in individuals with third trimester COVID-19 infection, although the source of soluble ACE2 (placental or otherwise) could not be determined with the methods employed. Levels of placental estrogen were no different between groups, which suggests that estrogen is not responsible for the observed differences.

Study strengths and limitations

ACE2 is the main receptor for the SARS-CoV-2 virus and facilitates viral entry into the cell.² Placental villous cells that are in direct contact with maternal blood express the ACE2 protein, rendering them potentially vulnerable to SARS-CoV-2 infection.³ In this study, the authors observed lower placental ACE2 protein in term placentas from recent (early third trimester) but not remote (second trimester) maternal SARS-CoV-2 infection, arguably the result of the observed increase in ADAM17 cleavage activity. Prior studies have shown conflicting results, with equal or higher ACE2 levels noted in the setting of maternal COVID-19 infection, which may be related to differences in COVID-19 disease severity, gestational age of infection, and/or fetal sex in these cohorts.^4-6

The concept that increased placental ACE2 shedding represents a protective defense mechanism that might last weeks beyond the acute infectious period is intriguing, but it requires further study. Observed differences in third but not second trimester COVID-19 infections could indicate either 1) an effect of maternal COVID-19 infection that lasts for several weeks but eventually normalizes over time, in the case of a remote infection; or 2) that second trimester maternal COVID-19 infection does not have the same pronounced effect on ACE2 levels as does third trimester infection. Observational studies of the human placenta are not able to answer this question, as directly sampling the placenta at the time of the exposure (or repeated sampling over time) in ongoing pregnancies is neither practical nor ethical. Further studies using animal or cellular models of SARS-CoV-2 infection in pregnancy may be necessary to fully understand the clinical relevance of these findings.

The study by Taglauer and colleagues provides a compelling argument for exploring how immune defenses at the maternal-fetal interface evolve over time and vary by trimester of exposure. ●

In 2021, state lawmakers introduced a record number of bills that would affect transgender and gender-diverse people. The vast majority were focused on transgender and gender-diverse youth in particular. We’ve seen bills that would take away gender-affirming medical care for minors, ones that would force trans kids to play on sports teams that don’t match their gender identity, and others that would ban trans kids from public facilities like bathrooms that match their gender identities.

These bills aren’t particularly new, but state lawmakers are putting more energy into them than ever. In response, some public figures have started pushing back. Ariana Grande just pledged to match up to 1.5 million dollars in donations to combat anti–trans youth legislative initiatives. However, doctors have been underrepresented in the political discourse.

Sadly, much of the discussion in this area has been driven by wild speculation and emotional rhetoric. It’s rare that we see actual data brought to the table. As clinicians and scientists, we have a responsibility to highlight the data relevant to these legislative debates, and to share them with our representatives. I’m going to break down what we know quantitatively about each of these issues, so that you’ll feel empowered to bring that information to these debates. My hope is that we can move toward evidence-based public policy instead of rhetoric-based public policy, so that we can ensure the best health possible for young people around the country.
 

Bathroom bills

Though they’ve been less of a focus recently, politicians for years have argued that trans people should be forced to use bathrooms and other public facilities that match their sex assigned at birth, not their gender identity. Their central argument is that trans-inclusive public facility policies will result in higher rates of assault. Published peer-review data show this isn’t true. A 2019 study in Sexuality Research and Social Policy examined the impacts of trans-inclusive public facility policies and found they resulted in no increase in assaults among the general (mostly cisgender) population. Another 2019 study in Pediatrics found that trans-inclusive facility policies were associated with lower odds of sexual assault victimization against transgender youth. The myth that trans-inclusive public facilities increase assault risk is simply that: a myth. All existing data indicate that trans-inclusive policies will improve public safety.

Sports bills

One of the hottest debates recently involves whether transgender girls should be allowed to participate in girls’ sports teams. Those in favor of these bills argue that transgender girls have an innate biological sports advantage over cisgender girls, and if allowed to compete in girls’ sports leagues, they will dominate the events, and cisgender girls will no longer win sports titles. The bills feed into longstanding assumptions – those who were assigned male at birth are strong, and those who were assigned female at birth are weak.

But evidence doesn’t show that trans women dominate female sports leagues. It turns out, there are shockingly few transgender athletes competing in sports leagues around the United States, and even fewer winning major titles. When the Associated Press conducted an investigation asking lawmakers introducing such sports bills to name trans athletes in their states, most couldn’t point to a single one. After Utah state legislators passed a trans sports ban, Governor Spencer Cox vetoed it, pointing out that, of 75,000 high school kids participating in sports in Utah, there was only a single transgender girl (the state legislature overrode the veto anyway).

California has explicitly protected the rights of trans athletes to compete on sports teams that match their gender identity since 2013. There’s still an underrepresentation of trans athletes in sports participation and titles. This is likely because the deck is stacked against these young people in so many other ways that are unrelated to testosterone levels. Trans youth suffer from high rates of harassment, discrimination, and subsequent anxiety and depression that make it difficult to compete in and excel in sports.
 

Medical bills

State legislators have introduced bills around the country that would criminalize the provision of gender-affirming medical care for transgender youth. Though such bills are opposed by all major medical organizations (including the American Medical Association, the American Academy of Pediatrics, the American Academy of Child & Adolescent Psychiatry, and the American Psychiatric Association), misinformation continues to spread, and in some instances the bills have become law (though none are currently active due to legal challenges).

Clinicians should be aware that there have been sixteen studies to date, each with unique study designs, that have overall linked gender-affirming medical care for transgender youth to better mental health outcomes. While these interventions do (as with all medications) carry some risks (like delayed bone mineralization with pubertal suppression), the risks must be weighed against potential benefits. Unfortunately, these risks and benefits have not been accurately portrayed in state legislative debates. Politicians have spread a great deal of misinformation about gender-affirming medical care for transgender youth, including false assertions that puberty blockers cause infertility and that most transgender adolescents will grow up to identify as cisgender and regret gender-affirming medical interventions.
 

Minority stress

These bills have direct consequences for pediatric patients. For example, trans-inclusive bathroom policies are associated with lower rates of sexual assault. However, there are also important indirect effects to consider. The gender minority stress framework explains the ways in which stigmatizing national discourse drives higher rates of anxiety, depression, and suicidality among transgender youth. Under this model, so-called “distal factors” like the recent conversations at the national level that marginalize trans young people, are expected to drive higher rates of adverse mental health outcomes. As transgender youth hear high-profile politicians argue that they’re dangerous to their peers in bathrooms and on sports teams, it’s difficult to imagine their mental health would not worsen. Over time, such “distal factors” also lead to “proximal factors” like internalized transphobia in which youth begin to believe the negative things that are said about them. These dangerous processes can have dramatic negative impacts on self-esteem and emotional development. There is strong precedence that public policies have strong indirect mental health effects on LGBTQ youth.

We’ve entered a dangerous era in which politicians are legislating medical care and other aspects of public policy with the potential to hurt the mental health of our young patients. It’s imperative that clinicians and scientists contact their legislators to make sure they are voting for public policy based on data and fact, not misinformation and political rhetoric. The health of American children depends on it.

Dr. Turban (twitter.com/jack_turban) is a chief fellow in child and adolescent psychiatry at Stanford (Calif.) University.

In 2021, state lawmakers introduced a record number of bills that would affect transgender and gender-diverse people. The vast majority were focused on transgender and gender-diverse youth in particular. We’ve seen bills that would take away gender-affirming medical care for minors, ones that would force trans kids to play on sports teams that don’t match their gender identity, and others that would ban trans kids from public facilities like bathrooms that match their gender identities.

These bills aren’t particularly new, but state lawmakers are putting more energy into them than ever. In response, some public figures have started pushing back. Ariana Grande just pledged to match up to 1.5 million dollars in donations to combat anti–trans youth legislative initiatives. However, doctors have been underrepresented in the political discourse.

Sadly, much of the discussion in this area has been driven by wild speculation and emotional rhetoric. It’s rare that we see actual data brought to the table. As clinicians and scientists, we have a responsibility to highlight the data relevant to these legislative debates, and to share them with our representatives. I’m going to break down what we know quantitatively about each of these issues, so that you’ll feel empowered to bring that information to these debates. My hope is that we can move toward evidence-based public policy instead of rhetoric-based public policy, so that we can ensure the best health possible for young people around the country.
 

Bathroom bills

Though they’ve been less of a focus recently, politicians for years have argued that trans people should be forced to use bathrooms and other public facilities that match their sex assigned at birth, not their gender identity. Their central argument is that trans-inclusive public facility policies will result in higher rates of assault. Published peer-review data show this isn’t true. A 2019 study in Sexuality Research and Social Policy examined the impacts of trans-inclusive public facility policies and found they resulted in no increase in assaults among the general (mostly cisgender) population. Another 2019 study in Pediatrics found that trans-inclusive facility policies were associated with lower odds of sexual assault victimization against transgender youth. The myth that trans-inclusive public facilities increase assault risk is simply that: a myth. All existing data indicate that trans-inclusive policies will improve public safety.

Sports bills

One of the hottest debates recently involves whether transgender girls should be allowed to participate in girls’ sports teams. Those in favor of these bills argue that transgender girls have an innate biological sports advantage over cisgender girls, and if allowed to compete in girls’ sports leagues, they will dominate the events, and cisgender girls will no longer win sports titles. The bills feed into longstanding assumptions – those who were assigned male at birth are strong, and those who were assigned female at birth are weak.

But evidence doesn’t show that trans women dominate female sports leagues. It turns out, there are shockingly few transgender athletes competing in sports leagues around the United States, and even fewer winning major titles. When the Associated Press conducted an investigation asking lawmakers introducing such sports bills to name trans athletes in their states, most couldn’t point to a single one. After Utah state legislators passed a trans sports ban, Governor Spencer Cox vetoed it, pointing out that, of 75,000 high school kids participating in sports in Utah, there was only a single transgender girl (the state legislature overrode the veto anyway).

California has explicitly protected the rights of trans athletes to compete on sports teams that match their gender identity since 2013. There’s still an underrepresentation of trans athletes in sports participation and titles. This is likely because the deck is stacked against these young people in so many other ways that are unrelated to testosterone levels. Trans youth suffer from high rates of harassment, discrimination, and subsequent anxiety and depression that make it difficult to compete in and excel in sports.
 

Medical bills

State legislators have introduced bills around the country that would criminalize the provision of gender-affirming medical care for transgender youth. Though such bills are opposed by all major medical organizations (including the American Medical Association, the American Academy of Pediatrics, the American Academy of Child & Adolescent Psychiatry, and the American Psychiatric Association), misinformation continues to spread, and in some instances the bills have become law (though none are currently active due to legal challenges).

Clinicians should be aware that there have been sixteen studies to date, each with unique study designs, that have overall linked gender-affirming medical care for transgender youth to better mental health outcomes. While these interventions do (as with all medications) carry some risks (like delayed bone mineralization with pubertal suppression), the risks must be weighed against potential benefits. Unfortunately, these risks and benefits have not been accurately portrayed in state legislative debates. Politicians have spread a great deal of misinformation about gender-affirming medical care for transgender youth, including false assertions that puberty blockers cause infertility and that most transgender adolescents will grow up to identify as cisgender and regret gender-affirming medical interventions.
 

Minority stress

These bills have direct consequences for pediatric patients. For example, trans-inclusive bathroom policies are associated with lower rates of sexual assault. However, there are also important indirect effects to consider. The gender minority stress framework explains the ways in which stigmatizing national discourse drives higher rates of anxiety, depression, and suicidality among transgender youth. Under this model, so-called “distal factors” like the recent conversations at the national level that marginalize trans young people, are expected to drive higher rates of adverse mental health outcomes. As transgender youth hear high-profile politicians argue that they’re dangerous to their peers in bathrooms and on sports teams, it’s difficult to imagine their mental health would not worsen. Over time, such “distal factors” also lead to “proximal factors” like internalized transphobia in which youth begin to believe the negative things that are said about them. These dangerous processes can have dramatic negative impacts on self-esteem and emotional development. There is strong precedence that public policies have strong indirect mental health effects on LGBTQ youth.

We’ve entered a dangerous era in which politicians are legislating medical care and other aspects of public policy with the potential to hurt the mental health of our young patients. It’s imperative that clinicians and scientists contact their legislators to make sure they are voting for public policy based on data and fact, not misinformation and political rhetoric. The health of American children depends on it.

Dr. Turban (twitter.com/jack_turban) is a chief fellow in child and adolescent psychiatry at Stanford (Calif.) University.

In 2021, state lawmakers introduced a record number of bills that would affect transgender and gender-diverse people. The vast majority were focused on transgender and gender-diverse youth in particular. We’ve seen bills that would take away gender-affirming medical care for minors, ones that would force trans kids to play on sports teams that don’t match their gender identity, and others that would ban trans kids from public facilities like bathrooms that match their gender identities.

These bills aren’t particularly new, but state lawmakers are putting more energy into them than ever. In response, some public figures have started pushing back. Ariana Grande just pledged to match up to 1.5 million dollars in donations to combat anti–trans youth legislative initiatives. However, doctors have been underrepresented in the political discourse.

Sadly, much of the discussion in this area has been driven by wild speculation and emotional rhetoric. It’s rare that we see actual data brought to the table. As clinicians and scientists, we have a responsibility to highlight the data relevant to these legislative debates, and to share them with our representatives. I’m going to break down what we know quantitatively about each of these issues, so that you’ll feel empowered to bring that information to these debates. My hope is that we can move toward evidence-based public policy instead of rhetoric-based public policy, so that we can ensure the best health possible for young people around the country.
 

Bathroom bills

Though they’ve been less of a focus recently, politicians for years have argued that trans people should be forced to use bathrooms and other public facilities that match their sex assigned at birth, not their gender identity. Their central argument is that trans-inclusive public facility policies will result in higher rates of assault. Published peer-review data show this isn’t true. A 2019 study in Sexuality Research and Social Policy examined the impacts of trans-inclusive public facility policies and found they resulted in no increase in assaults among the general (mostly cisgender) population. Another 2019 study in Pediatrics found that trans-inclusive facility policies were associated with lower odds of sexual assault victimization against transgender youth. The myth that trans-inclusive public facilities increase assault risk is simply that: a myth. All existing data indicate that trans-inclusive policies will improve public safety.

Sports bills

One of the hottest debates recently involves whether transgender girls should be allowed to participate in girls’ sports teams. Those in favor of these bills argue that transgender girls have an innate biological sports advantage over cisgender girls, and if allowed to compete in girls’ sports leagues, they will dominate the events, and cisgender girls will no longer win sports titles. The bills feed into longstanding assumptions – those who were assigned male at birth are strong, and those who were assigned female at birth are weak.

But evidence doesn’t show that trans women dominate female sports leagues. It turns out, there are shockingly few transgender athletes competing in sports leagues around the United States, and even fewer winning major titles. When the Associated Press conducted an investigation asking lawmakers introducing such sports bills to name trans athletes in their states, most couldn’t point to a single one. After Utah state legislators passed a trans sports ban, Governor Spencer Cox vetoed it, pointing out that, of 75,000 high school kids participating in sports in Utah, there was only a single transgender girl (the state legislature overrode the veto anyway).

California has explicitly protected the rights of trans athletes to compete on sports teams that match their gender identity since 2013. There’s still an underrepresentation of trans athletes in sports participation and titles. This is likely because the deck is stacked against these young people in so many other ways that are unrelated to testosterone levels. Trans youth suffer from high rates of harassment, discrimination, and subsequent anxiety and depression that make it difficult to compete in and excel in sports.
 

Medical bills

State legislators have introduced bills around the country that would criminalize the provision of gender-affirming medical care for transgender youth. Though such bills are opposed by all major medical organizations (including the American Medical Association, the American Academy of Pediatrics, the American Academy of Child & Adolescent Psychiatry, and the American Psychiatric Association), misinformation continues to spread, and in some instances the bills have become law (though none are currently active due to legal challenges).

Clinicians should be aware that there have been sixteen studies to date, each with unique study designs, that have overall linked gender-affirming medical care for transgender youth to better mental health outcomes. While these interventions do (as with all medications) carry some risks (like delayed bone mineralization with pubertal suppression), the risks must be weighed against potential benefits. Unfortunately, these risks and benefits have not been accurately portrayed in state legislative debates. Politicians have spread a great deal of misinformation about gender-affirming medical care for transgender youth, including false assertions that puberty blockers cause infertility and that most transgender adolescents will grow up to identify as cisgender and regret gender-affirming medical interventions.
 

Minority stress

These bills have direct consequences for pediatric patients. For example, trans-inclusive bathroom policies are associated with lower rates of sexual assault. However, there are also important indirect effects to consider. The gender minority stress framework explains the ways in which stigmatizing national discourse drives higher rates of anxiety, depression, and suicidality among transgender youth. Under this model, so-called “distal factors” like the recent conversations at the national level that marginalize trans young people, are expected to drive higher rates of adverse mental health outcomes. As transgender youth hear high-profile politicians argue that they’re dangerous to their peers in bathrooms and on sports teams, it’s difficult to imagine their mental health would not worsen. Over time, such “distal factors” also lead to “proximal factors” like internalized transphobia in which youth begin to believe the negative things that are said about them. These dangerous processes can have dramatic negative impacts on self-esteem and emotional development. There is strong precedence that public policies have strong indirect mental health effects on LGBTQ youth.

We’ve entered a dangerous era in which politicians are legislating medical care and other aspects of public policy with the potential to hurt the mental health of our young patients. It’s imperative that clinicians and scientists contact their legislators to make sure they are voting for public policy based on data and fact, not misinformation and political rhetoric. The health of American children depends on it.

Dr. Turban (twitter.com/jack_turban) is a chief fellow in child and adolescent psychiatry at Stanford (Calif.) University.

Metacognitive training (MCT) is effective in reducing positive and negative symptoms of schizophrenia, new research suggests.

MCT for psychosis is a brief intervention that “combines psychoeducation, cognitive bias modification, and strategy teaching but does not directly target psychosis symptoms.”

Results from a meta-analysis of 40 studies with more than 1,800 total participants with schizophrenia showed that MCT was associated with reductions in positive symptoms, including auditory hallucinations and delusions, as well as negative symptoms, such as social withdrawal.

Additionally, MCT led to improvement in self-esteem and functioning, and all benefits were maintained up to 1 year post intervention.

“Our study demonstrates the effectiveness and durability of a brief, nonconfrontational intervention in the reduction of serious and debilitating symptoms of schizophrenia,” study investigator Danielle Penney, a doctoral candidate at the University of Montreal, told this news organization.

“Our results were observed in several treatment contexts and suggest that MCT can be successfully delivered by a variety of mental health practitioners [and] provide solid evidence to consider MCT in international treatment guidelines for schizophrenia spectrum disorders,” Ms. Penney said.

The findings were published online  in JAMA Psychiatry.
 

‘Novel contribution’

MCT is a brief intervention consisting of eight to 16 modules that can be delivered in a group setting or on an individual basis. Instead of directly targeting psychotic symptoms, it uses an “indirect approach by promoting awareness of cognitive biases,” the investigators note.

Such biases include maladaptive thinking styles common to psychosis, such as jumping to conclusions, belief inflexibility, and overconfidence in judgments.

It is hypothesized that these biases “contribute to the formation and maintenance of positive symptoms, particularly delusions,” the researchers write.

MCT “aims to plant doubt in delusional beliefs through raising awareness of cognitive biases and aims to raise service engagement by proposing work on this less-confrontational objective first, which is likely to facilitate the therapeutic alliance and more direct work on psychotic symptoms,” they add.

Previous studies of MCT for psychosis yielded inconsistent results. Of the eight previous meta-analyses that analyzed MCT for psychosis, “none investigated the long-term effects of the intervention on directly targeted treatment outcomes,” such as delusions and cognitive biases, Ms. Penney said.

She added that “to our knowledge, no meta-analysis has examined the effectiveness of important indirectly targeted outcomes,” including self-esteem and functioning.

“These important gaps in the literature,” along with a large increase in recently conducted MCT efficacy trials, “provided the motivation for the current study,” said Ms. Penney.

To investigate, the researchers searched 11 databases, beginning with data from 2007, which was when the first report of MCT was published. Studies included participants with schizophrenia spectrum and related psychotic disorders.

Outcomes for the current review and meta-analysis were organized according to a “proximal-distal framework.” Proximal outcomes were those directly targeted by MCT, while distal outcomes were those not directly targeted by MCT but that were associated with improvement in proximal outcomes, either directly or indirectly.

The investigators examined these outcomes quantitatively and qualitatively from preintervention to postintervention and follow-up, “which, to our knowledge, is a novel contribution,” they write.

The review included 43 studies, of which 30 (70%) were randomized controlled trials (RCTs), 11 (25%) were non-RCTs, and two (5%) were quantitative descriptive studies. Of these, 40 reports (n = 1,816 participants) were included in the meta-analysis, and six were included in the narrative review.
 

Transdiagnostic treatment?

Results showed a “small to moderate” effect size (ES) in global proximal outcomes (g = .39; 95% confidence interval, .25-.53; P < .001; 38 reports).

When proximal outcomes were analyzed separately, the largest ES was found for delusions; smaller ES values were found for hallucinations and cognitive biases.

Consistent beneficial effects

Commenting on the study, Philip Harvey, PhD, Leonard M. Miller Professor of Psychiatry and Behavioral Sciences and director of the Division of Psychology, University of Miami Miller School of Medicine, noted that self-awareness and self-assessment are critically important features in patients with serious mental illness.

University of Miami Miller School of Medicine

Impairments in these areas “can actually have a greater impact on everyday functioning than cognitive deficits,” said Dr. Harvey, who is also the editor-in-chief of Schizophrenia Research: Cognition. He was not involved with the current meta-analysis.

He noted that the current results show that “MCT has consistent beneficial effects.”

“This is an intervention that should be considered for most people with serious mental illness, with a specific focus on those with specific types of delusions and more global challenges in self-assessment,” Dr. Harvey concluded.

Funding was provided by the Canada First Research Excellence Fund, awarded through the Healthy Brains, Healthy Lives initiative at McGill University. Ms. Penney reported no relevant financial relationships. Disclosures for the other investigators are listed in the original article. Dr. Harvey reported being a reviewer of the article but that he was not involved in its authorship.

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

Metacognitive training (MCT) is effective in reducing positive and negative symptoms of schizophrenia, new research suggests.

MCT for psychosis is a brief intervention that “combines psychoeducation, cognitive bias modification, and strategy teaching but does not directly target psychosis symptoms.”

Results from a meta-analysis of 40 studies with more than 1,800 total participants with schizophrenia showed that MCT was associated with reductions in positive symptoms, including auditory hallucinations and delusions, as well as negative symptoms, such as social withdrawal.

Additionally, MCT led to improvement in self-esteem and functioning, and all benefits were maintained up to 1 year post intervention.

“Our study demonstrates the effectiveness and durability of a brief, nonconfrontational intervention in the reduction of serious and debilitating symptoms of schizophrenia,” study investigator Danielle Penney, a doctoral candidate at the University of Montreal, told this news organization.

“Our results were observed in several treatment contexts and suggest that MCT can be successfully delivered by a variety of mental health practitioners [and] provide solid evidence to consider MCT in international treatment guidelines for schizophrenia spectrum disorders,” Ms. Penney said.

The findings were published online  in JAMA Psychiatry.
 

‘Novel contribution’

MCT is a brief intervention consisting of eight to 16 modules that can be delivered in a group setting or on an individual basis. Instead of directly targeting psychotic symptoms, it uses an “indirect approach by promoting awareness of cognitive biases,” the investigators note.

Such biases include maladaptive thinking styles common to psychosis, such as jumping to conclusions, belief inflexibility, and overconfidence in judgments.

It is hypothesized that these biases “contribute to the formation and maintenance of positive symptoms, particularly delusions,” the researchers write.

MCT “aims to plant doubt in delusional beliefs through raising awareness of cognitive biases and aims to raise service engagement by proposing work on this less-confrontational objective first, which is likely to facilitate the therapeutic alliance and more direct work on psychotic symptoms,” they add.

Previous studies of MCT for psychosis yielded inconsistent results. Of the eight previous meta-analyses that analyzed MCT for psychosis, “none investigated the long-term effects of the intervention on directly targeted treatment outcomes,” such as delusions and cognitive biases, Ms. Penney said.

She added that “to our knowledge, no meta-analysis has examined the effectiveness of important indirectly targeted outcomes,” including self-esteem and functioning.

“These important gaps in the literature,” along with a large increase in recently conducted MCT efficacy trials, “provided the motivation for the current study,” said Ms. Penney.

To investigate, the researchers searched 11 databases, beginning with data from 2007, which was when the first report of MCT was published. Studies included participants with schizophrenia spectrum and related psychotic disorders.

Outcomes for the current review and meta-analysis were organized according to a “proximal-distal framework.” Proximal outcomes were those directly targeted by MCT, while distal outcomes were those not directly targeted by MCT but that were associated with improvement in proximal outcomes, either directly or indirectly.

The investigators examined these outcomes quantitatively and qualitatively from preintervention to postintervention and follow-up, “which, to our knowledge, is a novel contribution,” they write.

The review included 43 studies, of which 30 (70%) were randomized controlled trials (RCTs), 11 (25%) were non-RCTs, and two (5%) were quantitative descriptive studies. Of these, 40 reports (n = 1,816 participants) were included in the meta-analysis, and six were included in the narrative review.
 

Transdiagnostic treatment?

Results showed a “small to moderate” effect size (ES) in global proximal outcomes (g = .39; 95% confidence interval, .25-.53; P < .001; 38 reports).

When proximal outcomes were analyzed separately, the largest ES was found for delusions; smaller ES values were found for hallucinations and cognitive biases.

Consistent beneficial effects

Commenting on the study, Philip Harvey, PhD, Leonard M. Miller Professor of Psychiatry and Behavioral Sciences and director of the Division of Psychology, University of Miami Miller School of Medicine, noted that self-awareness and self-assessment are critically important features in patients with serious mental illness.

University of Miami Miller School of Medicine

Impairments in these areas “can actually have a greater impact on everyday functioning than cognitive deficits,” said Dr. Harvey, who is also the editor-in-chief of Schizophrenia Research: Cognition. He was not involved with the current meta-analysis.

He noted that the current results show that “MCT has consistent beneficial effects.”

“This is an intervention that should be considered for most people with serious mental illness, with a specific focus on those with specific types of delusions and more global challenges in self-assessment,” Dr. Harvey concluded.

Funding was provided by the Canada First Research Excellence Fund, awarded through the Healthy Brains, Healthy Lives initiative at McGill University. Ms. Penney reported no relevant financial relationships. Disclosures for the other investigators are listed in the original article. Dr. Harvey reported being a reviewer of the article but that he was not involved in its authorship.

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

Metacognitive training (MCT) is effective in reducing positive and negative symptoms of schizophrenia, new research suggests.

MCT for psychosis is a brief intervention that “combines psychoeducation, cognitive bias modification, and strategy teaching but does not directly target psychosis symptoms.”

Results from a meta-analysis of 40 studies with more than 1,800 total participants with schizophrenia showed that MCT was associated with reductions in positive symptoms, including auditory hallucinations and delusions, as well as negative symptoms, such as social withdrawal.

Additionally, MCT led to improvement in self-esteem and functioning, and all benefits were maintained up to 1 year post intervention.

“Our study demonstrates the effectiveness and durability of a brief, nonconfrontational intervention in the reduction of serious and debilitating symptoms of schizophrenia,” study investigator Danielle Penney, a doctoral candidate at the University of Montreal, told this news organization.

“Our results were observed in several treatment contexts and suggest that MCT can be successfully delivered by a variety of mental health practitioners [and] provide solid evidence to consider MCT in international treatment guidelines for schizophrenia spectrum disorders,” Ms. Penney said.

The findings were published online  in JAMA Psychiatry.
 

‘Novel contribution’

MCT is a brief intervention consisting of eight to 16 modules that can be delivered in a group setting or on an individual basis. Instead of directly targeting psychotic symptoms, it uses an “indirect approach by promoting awareness of cognitive biases,” the investigators note.

Such biases include maladaptive thinking styles common to psychosis, such as jumping to conclusions, belief inflexibility, and overconfidence in judgments.

It is hypothesized that these biases “contribute to the formation and maintenance of positive symptoms, particularly delusions,” the researchers write.

MCT “aims to plant doubt in delusional beliefs through raising awareness of cognitive biases and aims to raise service engagement by proposing work on this less-confrontational objective first, which is likely to facilitate the therapeutic alliance and more direct work on psychotic symptoms,” they add.

Previous studies of MCT for psychosis yielded inconsistent results. Of the eight previous meta-analyses that analyzed MCT for psychosis, “none investigated the long-term effects of the intervention on directly targeted treatment outcomes,” such as delusions and cognitive biases, Ms. Penney said.

She added that “to our knowledge, no meta-analysis has examined the effectiveness of important indirectly targeted outcomes,” including self-esteem and functioning.

“These important gaps in the literature,” along with a large increase in recently conducted MCT efficacy trials, “provided the motivation for the current study,” said Ms. Penney.

To investigate, the researchers searched 11 databases, beginning with data from 2007, which was when the first report of MCT was published. Studies included participants with schizophrenia spectrum and related psychotic disorders.

Outcomes for the current review and meta-analysis were organized according to a “proximal-distal framework.” Proximal outcomes were those directly targeted by MCT, while distal outcomes were those not directly targeted by MCT but that were associated with improvement in proximal outcomes, either directly or indirectly.

The investigators examined these outcomes quantitatively and qualitatively from preintervention to postintervention and follow-up, “which, to our knowledge, is a novel contribution,” they write.

The review included 43 studies, of which 30 (70%) were randomized controlled trials (RCTs), 11 (25%) were non-RCTs, and two (5%) were quantitative descriptive studies. Of these, 40 reports (n = 1,816 participants) were included in the meta-analysis, and six were included in the narrative review.
 

Transdiagnostic treatment?

Results showed a “small to moderate” effect size (ES) in global proximal outcomes (g = .39; 95% confidence interval, .25-.53; P < .001; 38 reports).

When proximal outcomes were analyzed separately, the largest ES was found for delusions; smaller ES values were found for hallucinations and cognitive biases.

Consistent beneficial effects

Commenting on the study, Philip Harvey, PhD, Leonard M. Miller Professor of Psychiatry and Behavioral Sciences and director of the Division of Psychology, University of Miami Miller School of Medicine, noted that self-awareness and self-assessment are critically important features in patients with serious mental illness.

University of Miami Miller School of Medicine

Impairments in these areas “can actually have a greater impact on everyday functioning than cognitive deficits,” said Dr. Harvey, who is also the editor-in-chief of Schizophrenia Research: Cognition. He was not involved with the current meta-analysis.

He noted that the current results show that “MCT has consistent beneficial effects.”

“This is an intervention that should be considered for most people with serious mental illness, with a specific focus on those with specific types of delusions and more global challenges in self-assessment,” Dr. Harvey concluded.

Funding was provided by the Canada First Research Excellence Fund, awarded through the Healthy Brains, Healthy Lives initiative at McGill University. Ms. Penney reported no relevant financial relationships. Disclosures for the other investigators are listed in the original article. Dr. Harvey reported being a reviewer of the article but that he was not involved in its authorship.

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

Medical education has seen major changes over the last decade. The allotted time for preclinical education has decreased from 24 months to 18 months or less at most institutions, with an increased focus on content associated with health care delivery and health system science.^1,2 Many schools now include at least some blended learning with online delivery of preclinical education.³ On the other hand, the clinical portion of medical education has remained largely unchanged prior to the COVID-19 pandemic, with the apprenticeship framework allowing the experienced physician to observe, mentor, and pass on practical knowledge so that the apprentice can one day gain independence after demonstrating adequate proficiency.⁴

With respect to dermatology education, skin disorders are in the top 5 reported reasons for visits to primary care⁵; however, a 2009 survey found that only 0.24% to 0.30% of medical schools’ curricula are spent on dermatology.⁶ Moreover, one institution found that fourth-year medical students received an average of 46.6% on a 15-item quiz designed to assess the ability to diagnose and treat common dermatologic conditions, and within that same cohort, 87.6% of students felt that they received inadequate training in dermatology during medical school.⁷

COVID-19 caused an unprecedented paradigm shift when medical schools throughout the country, including our own, canceled clinical rotations at the end of March 2020 to protect students and control the spread of infection. To enable clinical and preclinical learning to continue, institutions around the globe turned to either online learning or participation in telehealth as a substitute for clinical rotations.^8-10 At the Uniformed Services University of the Health Sciences (Bethesda, Maryland), one of the many online clinical courses offered included a distance learning (DL) dermatology course. Herein, we describe the results of a prospective study evaluating short-term information recall and comprehension as well as students’ confidence in their ability to apply course objectives over 3 months of an online DL dermatology course.

Methods

Between April and July 2020, 14 students at the Uniformed Services University of the Health Sciences (Table 1) enrolled in 1 of 3 four-week DL dermatology classes. The students independently completed the Basic Dermatology Curriculum, a set of online modules with demonstrated efficacy from the American Academy of Dermatology, over 4 weeks.¹¹ Additionally, students were instructed to review an hour of clinical dermatology images daily from online dermatology atlases and e-books accessed through our medical school’s virtual library. Optional Free Open Access Meducation resources also were provided. The course syllabus provided the students with clear expectations, links to the resources, and a recommended daily schedule.

An online video conferencing platform was utilized for an orientation session and 4 subsequent weekly 1.5-hour virtual meetings. The weekly DL meetings focused on a discussion of clinical images pertinent to the American Academy of Dermatology modules covered for the week. These interactive analytic sessions were referred to as Clinpic sessions. With instructor guidance, the students learned to describe images, and they provided differential diagnoses, workup, and treatments for various skin diseases. The virtual meetings included supplemental lectures detailing the use of teledermatology and laser therapy in the Military Health System and a journal review on the cutaneous manifestations of COVID-19.

A 40-question, image-based pretest and posttest utilized during clinical rotations evaluated knowledge recall and comprehension. A precourse and postcourse survey using a 5-point Likert scale (1=not confident; 5=extremely confident) assessed students’ confidence levels across course objectives: general knowledge of dermatology, working knowledge of teledermatology, ability to accurately describe skin lesions, generate sound differential diagnoses, and formulate a reasonable treatment plan. Statistical analysis was performed using free online statistical software at statskingdom.com.¹²

Results

All 14 student enrollees completed the precourse and postcourse tests and surveys. Pretest and posttest scores followed a normal distribution and therefore met criteria for utilization of a parametric test. The precourse test average of 67% (range, 40%–90%) improved to 84% postcourse (range, 70%–98%; P<.001; 95% CI, 11-23 by paired t test). Not surprisingly, the 2 students who had completed a dermatology rotation had higher average pretest and posttest scores (pretest, 87%; posttest, 94%). Students’ confidence with the course objectives were mostly at the somewhat confident level on the 5-point Likert scale precourse survey. By the end of the course, student survey responses increased to confident and very confident levels, corresponding to an overall improvement of 1.3 points (P<.001 by paired t test)(Table 2) when the mean of the survey results was aggregated across every question. Instructor evaluation of student performance mirrored student assessments.

The DL dermatology course succeeded in helping the enrolled students attain course objectives and offered a reasonable solution when in-person interaction was restricted. The students in the DL course made notable improvements in their dermatology knowledge and improved their communication, diagnosis, and management skills. Although a blended dermatology curriculum with e-learning combined with clinical experience has been shown to increase knowledge acquisition,^13,14 our results suggest that an online-only program also can increase comprehension as well as students’ confidence in their abilities.

A major challenge for the DL course was the lack of opportunity to perform common dermatology procedures. The addition of a hands-on skin procedure module would have been a great supplement to the course but was not possible due to social distancing guidelines during the COVID-19 pandemic. The small sample size and voluntary enrollment were limitations to this study.

Conclusion

Although the traditional dermatology rotation remains the gold standard for clinical instruction, a well-organized DL teaching environment allowed for a more controlled learning experience with a broader coverage of topics to include potentially greater exposure to rare skin disorders not typically encountered in everyday practice. A DL dermatology course may serve as an enduring curriculum for those who wish to learn dermatology more broadly and are not interested in performing skin procedures or direct patient exposure (eg, those pursuing non–primary care specialties, pathology, or radiology). It also may be attractive to students who have had a prior clinical dermatology rotation and desire a different learning experience with a wide coverage of topics.

Acknowledgments—The authors thank Thomas Darling, MD, PhD (Bethesda, Maryland), for coining the term Clinpic and providing critical feedback throughout the course. The authors also thank Sorana Raiciulescu, MS (Bethesda, Maryland), for assistance with the statistical analysis.

Medical education has seen major changes over the last decade. The allotted time for preclinical education has decreased from 24 months to 18 months or less at most institutions, with an increased focus on content associated with health care delivery and health system science.^1,2 Many schools now include at least some blended learning with online delivery of preclinical education.³ On the other hand, the clinical portion of medical education has remained largely unchanged prior to the COVID-19 pandemic, with the apprenticeship framework allowing the experienced physician to observe, mentor, and pass on practical knowledge so that the apprentice can one day gain independence after demonstrating adequate proficiency.⁴

With respect to dermatology education, skin disorders are in the top 5 reported reasons for visits to primary care⁵; however, a 2009 survey found that only 0.24% to 0.30% of medical schools’ curricula are spent on dermatology.⁶ Moreover, one institution found that fourth-year medical students received an average of 46.6% on a 15-item quiz designed to assess the ability to diagnose and treat common dermatologic conditions, and within that same cohort, 87.6% of students felt that they received inadequate training in dermatology during medical school.⁷

COVID-19 caused an unprecedented paradigm shift when medical schools throughout the country, including our own, canceled clinical rotations at the end of March 2020 to protect students and control the spread of infection. To enable clinical and preclinical learning to continue, institutions around the globe turned to either online learning or participation in telehealth as a substitute for clinical rotations.^8-10 At the Uniformed Services University of the Health Sciences (Bethesda, Maryland), one of the many online clinical courses offered included a distance learning (DL) dermatology course. Herein, we describe the results of a prospective study evaluating short-term information recall and comprehension as well as students’ confidence in their ability to apply course objectives over 3 months of an online DL dermatology course.

Methods

Between April and July 2020, 14 students at the Uniformed Services University of the Health Sciences (Table 1) enrolled in 1 of 3 four-week DL dermatology classes. The students independently completed the Basic Dermatology Curriculum, a set of online modules with demonstrated efficacy from the American Academy of Dermatology, over 4 weeks.¹¹ Additionally, students were instructed to review an hour of clinical dermatology images daily from online dermatology atlases and e-books accessed through our medical school’s virtual library. Optional Free Open Access Meducation resources also were provided. The course syllabus provided the students with clear expectations, links to the resources, and a recommended daily schedule.

An online video conferencing platform was utilized for an orientation session and 4 subsequent weekly 1.5-hour virtual meetings. The weekly DL meetings focused on a discussion of clinical images pertinent to the American Academy of Dermatology modules covered for the week. These interactive analytic sessions were referred to as Clinpic sessions. With instructor guidance, the students learned to describe images, and they provided differential diagnoses, workup, and treatments for various skin diseases. The virtual meetings included supplemental lectures detailing the use of teledermatology and laser therapy in the Military Health System and a journal review on the cutaneous manifestations of COVID-19.

A 40-question, image-based pretest and posttest utilized during clinical rotations evaluated knowledge recall and comprehension. A precourse and postcourse survey using a 5-point Likert scale (1=not confident; 5=extremely confident) assessed students’ confidence levels across course objectives: general knowledge of dermatology, working knowledge of teledermatology, ability to accurately describe skin lesions, generate sound differential diagnoses, and formulate a reasonable treatment plan. Statistical analysis was performed using free online statistical software at statskingdom.com.¹²

Results

All 14 student enrollees completed the precourse and postcourse tests and surveys. Pretest and posttest scores followed a normal distribution and therefore met criteria for utilization of a parametric test. The precourse test average of 67% (range, 40%–90%) improved to 84% postcourse (range, 70%–98%; P<.001; 95% CI, 11-23 by paired t test). Not surprisingly, the 2 students who had completed a dermatology rotation had higher average pretest and posttest scores (pretest, 87%; posttest, 94%). Students’ confidence with the course objectives were mostly at the somewhat confident level on the 5-point Likert scale precourse survey. By the end of the course, student survey responses increased to confident and very confident levels, corresponding to an overall improvement of 1.3 points (P<.001 by paired t test)(Table 2) when the mean of the survey results was aggregated across every question. Instructor evaluation of student performance mirrored student assessments.

The DL dermatology course succeeded in helping the enrolled students attain course objectives and offered a reasonable solution when in-person interaction was restricted. The students in the DL course made notable improvements in their dermatology knowledge and improved their communication, diagnosis, and management skills. Although a blended dermatology curriculum with e-learning combined with clinical experience has been shown to increase knowledge acquisition,^13,14 our results suggest that an online-only program also can increase comprehension as well as students’ confidence in their abilities.

A major challenge for the DL course was the lack of opportunity to perform common dermatology procedures. The addition of a hands-on skin procedure module would have been a great supplement to the course but was not possible due to social distancing guidelines during the COVID-19 pandemic. The small sample size and voluntary enrollment were limitations to this study.

Conclusion

Although the traditional dermatology rotation remains the gold standard for clinical instruction, a well-organized DL teaching environment allowed for a more controlled learning experience with a broader coverage of topics to include potentially greater exposure to rare skin disorders not typically encountered in everyday practice. A DL dermatology course may serve as an enduring curriculum for those who wish to learn dermatology more broadly and are not interested in performing skin procedures or direct patient exposure (eg, those pursuing non–primary care specialties, pathology, or radiology). It also may be attractive to students who have had a prior clinical dermatology rotation and desire a different learning experience with a wide coverage of topics.

Acknowledgments—The authors thank Thomas Darling, MD, PhD (Bethesda, Maryland), for coining the term Clinpic and providing critical feedback throughout the course. The authors also thank Sorana Raiciulescu, MS (Bethesda, Maryland), for assistance with the statistical analysis.

Medical education has seen major changes over the last decade. The allotted time for preclinical education has decreased from 24 months to 18 months or less at most institutions, with an increased focus on content associated with health care delivery and health system science.^1,2 Many schools now include at least some blended learning with online delivery of preclinical education.³ On the other hand, the clinical portion of medical education has remained largely unchanged prior to the COVID-19 pandemic, with the apprenticeship framework allowing the experienced physician to observe, mentor, and pass on practical knowledge so that the apprentice can one day gain independence after demonstrating adequate proficiency.⁴

With respect to dermatology education, skin disorders are in the top 5 reported reasons for visits to primary care⁵; however, a 2009 survey found that only 0.24% to 0.30% of medical schools’ curricula are spent on dermatology.⁶ Moreover, one institution found that fourth-year medical students received an average of 46.6% on a 15-item quiz designed to assess the ability to diagnose and treat common dermatologic conditions, and within that same cohort, 87.6% of students felt that they received inadequate training in dermatology during medical school.⁷

COVID-19 caused an unprecedented paradigm shift when medical schools throughout the country, including our own, canceled clinical rotations at the end of March 2020 to protect students and control the spread of infection. To enable clinical and preclinical learning to continue, institutions around the globe turned to either online learning or participation in telehealth as a substitute for clinical rotations.^8-10 At the Uniformed Services University of the Health Sciences (Bethesda, Maryland), one of the many online clinical courses offered included a distance learning (DL) dermatology course. Herein, we describe the results of a prospective study evaluating short-term information recall and comprehension as well as students’ confidence in their ability to apply course objectives over 3 months of an online DL dermatology course.

Methods

Between April and July 2020, 14 students at the Uniformed Services University of the Health Sciences (Table 1) enrolled in 1 of 3 four-week DL dermatology classes. The students independently completed the Basic Dermatology Curriculum, a set of online modules with demonstrated efficacy from the American Academy of Dermatology, over 4 weeks.¹¹ Additionally, students were instructed to review an hour of clinical dermatology images daily from online dermatology atlases and e-books accessed through our medical school’s virtual library. Optional Free Open Access Meducation resources also were provided. The course syllabus provided the students with clear expectations, links to the resources, and a recommended daily schedule.

An online video conferencing platform was utilized for an orientation session and 4 subsequent weekly 1.5-hour virtual meetings. The weekly DL meetings focused on a discussion of clinical images pertinent to the American Academy of Dermatology modules covered for the week. These interactive analytic sessions were referred to as Clinpic sessions. With instructor guidance, the students learned to describe images, and they provided differential diagnoses, workup, and treatments for various skin diseases. The virtual meetings included supplemental lectures detailing the use of teledermatology and laser therapy in the Military Health System and a journal review on the cutaneous manifestations of COVID-19.

A 40-question, image-based pretest and posttest utilized during clinical rotations evaluated knowledge recall and comprehension. A precourse and postcourse survey using a 5-point Likert scale (1=not confident; 5=extremely confident) assessed students’ confidence levels across course objectives: general knowledge of dermatology, working knowledge of teledermatology, ability to accurately describe skin lesions, generate sound differential diagnoses, and formulate a reasonable treatment plan. Statistical analysis was performed using free online statistical software at statskingdom.com.¹²

Results

All 14 student enrollees completed the precourse and postcourse tests and surveys. Pretest and posttest scores followed a normal distribution and therefore met criteria for utilization of a parametric test. The precourse test average of 67% (range, 40%–90%) improved to 84% postcourse (range, 70%–98%; P<.001; 95% CI, 11-23 by paired t test). Not surprisingly, the 2 students who had completed a dermatology rotation had higher average pretest and posttest scores (pretest, 87%; posttest, 94%). Students’ confidence with the course objectives were mostly at the somewhat confident level on the 5-point Likert scale precourse survey. By the end of the course, student survey responses increased to confident and very confident levels, corresponding to an overall improvement of 1.3 points (P<.001 by paired t test)(Table 2) when the mean of the survey results was aggregated across every question. Instructor evaluation of student performance mirrored student assessments.

The DL dermatology course succeeded in helping the enrolled students attain course objectives and offered a reasonable solution when in-person interaction was restricted. The students in the DL course made notable improvements in their dermatology knowledge and improved their communication, diagnosis, and management skills. Although a blended dermatology curriculum with e-learning combined with clinical experience has been shown to increase knowledge acquisition,^13,14 our results suggest that an online-only program also can increase comprehension as well as students’ confidence in their abilities.

A major challenge for the DL course was the lack of opportunity to perform common dermatology procedures. The addition of a hands-on skin procedure module would have been a great supplement to the course but was not possible due to social distancing guidelines during the COVID-19 pandemic. The small sample size and voluntary enrollment were limitations to this study.

Conclusion

Although the traditional dermatology rotation remains the gold standard for clinical instruction, a well-organized DL teaching environment allowed for a more controlled learning experience with a broader coverage of topics to include potentially greater exposure to rare skin disorders not typically encountered in everyday practice. A DL dermatology course may serve as an enduring curriculum for those who wish to learn dermatology more broadly and are not interested in performing skin procedures or direct patient exposure (eg, those pursuing non–primary care specialties, pathology, or radiology). It also may be attractive to students who have had a prior clinical dermatology rotation and desire a different learning experience with a wide coverage of topics.

Acknowledgments—The authors thank Thomas Darling, MD, PhD (Bethesda, Maryland), for coining the term Clinpic and providing critical feedback throughout the course. The authors also thank Sorana Raiciulescu, MS (Bethesda, Maryland), for assistance with the statistical analysis.

Physically fit children have a greater ability to concentrate and better health-related quality of life (HRQOL), according to a new study.

The findings of the German study involving more than 6,500 kids emphasize the importance of cardiorespiratory health in childhood, and support physical fitness initiatives in schools, according to lead author Katharina Köble, MSc, of the Technical University of Munich (Germany), and colleagues.

“Recent studies show that only a few children meet the recommendations of physical activity,” the investigators wrote in Journal of Clinical Medicine.

While the health benefits of physical activity are clearly documented, Ms. Köble and colleagues noted that typical measures of activity, such as accelerometers or self-reported questionnaires, are suboptimal research tools.

“Physical fitness is a more objective parameter to quantify when evaluating health promotion,” the investigators wrote. “Furthermore, cardiorespiratory fitness as part of physical fitness is more strongly related to risk factors of cardiovascular disease than physical activity.”

According to the investigators, physical fitness has also been linked with better concentration and HRQOL, but never in the same population of children.

The new study aimed to address this knowledge gap by assessing 6,533 healthy children aged 6-10 years, approximately half boys and half girls. Associations between physical fitness, concentration, and HRQOL were evaluated using multiple linear regression analysis in participants aged 9-10 years.

Physical fitness was measured using a series of challenges, including curl-ups (pull-ups with palms facing body), push-ups, standing long jump, handgrip strength measurement, and Progressive Aerobic Cardiovascular Endurance Run (PACER). Performing the multistage shuttle run, PACER, “requires participants to maintain the pace set by an audio signal, which progressively increases the intensity every minute.” Results of the PACER test were used to estimate VO_2max.

Concentration was measured using the d2-R test, “a paper-pencil cancellation test, where subjects have to cross out all ‘d’ letters with two dashes under a time limit.”

HRQOL was evaluated with the KINDL questionnaire, which covers emotional well-being, physical well-being, everyday functioning (school), friends, family, and self-esteem.

Analysis showed that physical fitness improved with age (P < .001), except for VO_2max in girls (P = .129). Concentration also improved with age (P < .001), while HRQOL did not (P = .179).

Among children aged 9-10 years, VO_2max scores were strongly associated with both HRQOL (P < .001) and concentration (P < .001).

“VO_2max was found to be one of the main factors influencing concentration levels and HRQOL dimensions in primary school children,” the investigators wrote. “Physical fitness, especially cardiorespiratory performance, should therefore be promoted more specifically in school settings to support the promotion of an overall healthy lifestyle in children and adolescents.”
 

Findings are having a real-word impact, according to researcher

In an interview, Ms. Köble noted that the findings are already having a real-world impact.

“We continued data assessment in the long-term and specifically adapted prevention programs in school to the needs of the school children we identified in our study,” she said. “Schools are partially offering specific movement and nutrition classes now.”

In addition, Ms. Köble and colleagues plan on educating teachers about the “urgent need for sufficient physical activity.”

“Academic performance should be considered as an additional health factor in future studies, as well as screen time and eating patterns, as all those variables showed interactions with physical fitness and concentration. In a subanalysis, we showed that children with better physical fitness and concentration values were those who usually went to higher education secondary schools,” they wrote.
 

VO_2max did not correlate with BMI

Gregory Weaver, MD, a pediatrician at Cleveland Clinic Children’s, voiced some concerns about the reliability of the findings. He noted that VO_2max did not correlate with body mass index or other measures of physical fitness, and that using the PACER test to estimate VO_2max may have skewed the association between physical fitness and concentration.

“It is quite conceivable that children who can maintain the focus to perform maximally on this test will also do well on other tests of attention/concentration,” Dr. Weaver said. “Most children I know would have a very difficult time performing a physical fitness test which requires them to match a recorded pace that slowly increases overtime. I’m not an expert in the area, but it is my understanding that usually VO_2max tests involve a treadmill which allows investigators to have complete control over pace.”

Dr. Weaver concluded that more work is needed to determine if physical fitness interventions can have a positive impact on HRQOL and concentration.

“I think the authors of this study attempted to ask an important question about the possible association between physical fitness and concentration among school aged children,” Dr. Weaver said in an interview. “But what is even more vital are studies demonstrating that a change in modifiable health factors like nutrition, physical fitness, or the built environment can improve quality of life. I was hoping the authors would show that an improvement in VO_2max over time resulted in an improvement in concentration. Frustratingly, that is not what this article demonstrates.”

The investigators and Dr. Weaver reported no conflicts of interest.

Physically fit children have a greater ability to concentrate and better health-related quality of life (HRQOL), according to a new study.

The findings of the German study involving more than 6,500 kids emphasize the importance of cardiorespiratory health in childhood, and support physical fitness initiatives in schools, according to lead author Katharina Köble, MSc, of the Technical University of Munich (Germany), and colleagues.

“Recent studies show that only a few children meet the recommendations of physical activity,” the investigators wrote in Journal of Clinical Medicine.

While the health benefits of physical activity are clearly documented, Ms. Köble and colleagues noted that typical measures of activity, such as accelerometers or self-reported questionnaires, are suboptimal research tools.

“Physical fitness is a more objective parameter to quantify when evaluating health promotion,” the investigators wrote. “Furthermore, cardiorespiratory fitness as part of physical fitness is more strongly related to risk factors of cardiovascular disease than physical activity.”

According to the investigators, physical fitness has also been linked with better concentration and HRQOL, but never in the same population of children.

The new study aimed to address this knowledge gap by assessing 6,533 healthy children aged 6-10 years, approximately half boys and half girls. Associations between physical fitness, concentration, and HRQOL were evaluated using multiple linear regression analysis in participants aged 9-10 years.

Physical fitness was measured using a series of challenges, including curl-ups (pull-ups with palms facing body), push-ups, standing long jump, handgrip strength measurement, and Progressive Aerobic Cardiovascular Endurance Run (PACER). Performing the multistage shuttle run, PACER, “requires participants to maintain the pace set by an audio signal, which progressively increases the intensity every minute.” Results of the PACER test were used to estimate VO_2max.

Concentration was measured using the d2-R test, “a paper-pencil cancellation test, where subjects have to cross out all ‘d’ letters with two dashes under a time limit.”

HRQOL was evaluated with the KINDL questionnaire, which covers emotional well-being, physical well-being, everyday functioning (school), friends, family, and self-esteem.

Analysis showed that physical fitness improved with age (P < .001), except for VO_2max in girls (P = .129). Concentration also improved with age (P < .001), while HRQOL did not (P = .179).

Among children aged 9-10 years, VO_2max scores were strongly associated with both HRQOL (P < .001) and concentration (P < .001).

“VO_2max was found to be one of the main factors influencing concentration levels and HRQOL dimensions in primary school children,” the investigators wrote. “Physical fitness, especially cardiorespiratory performance, should therefore be promoted more specifically in school settings to support the promotion of an overall healthy lifestyle in children and adolescents.”
 

Findings are having a real-word impact, according to researcher

In an interview, Ms. Köble noted that the findings are already having a real-world impact.

“We continued data assessment in the long-term and specifically adapted prevention programs in school to the needs of the school children we identified in our study,” she said. “Schools are partially offering specific movement and nutrition classes now.”

In addition, Ms. Köble and colleagues plan on educating teachers about the “urgent need for sufficient physical activity.”

“Academic performance should be considered as an additional health factor in future studies, as well as screen time and eating patterns, as all those variables showed interactions with physical fitness and concentration. In a subanalysis, we showed that children with better physical fitness and concentration values were those who usually went to higher education secondary schools,” they wrote.
 

VO_2max did not correlate with BMI

Gregory Weaver, MD, a pediatrician at Cleveland Clinic Children’s, voiced some concerns about the reliability of the findings. He noted that VO_2max did not correlate with body mass index or other measures of physical fitness, and that using the PACER test to estimate VO_2max may have skewed the association between physical fitness and concentration.

“It is quite conceivable that children who can maintain the focus to perform maximally on this test will also do well on other tests of attention/concentration,” Dr. Weaver said. “Most children I know would have a very difficult time performing a physical fitness test which requires them to match a recorded pace that slowly increases overtime. I’m not an expert in the area, but it is my understanding that usually VO_2max tests involve a treadmill which allows investigators to have complete control over pace.”

Dr. Weaver concluded that more work is needed to determine if physical fitness interventions can have a positive impact on HRQOL and concentration.

“I think the authors of this study attempted to ask an important question about the possible association between physical fitness and concentration among school aged children,” Dr. Weaver said in an interview. “But what is even more vital are studies demonstrating that a change in modifiable health factors like nutrition, physical fitness, or the built environment can improve quality of life. I was hoping the authors would show that an improvement in VO_2max over time resulted in an improvement in concentration. Frustratingly, that is not what this article demonstrates.”

The investigators and Dr. Weaver reported no conflicts of interest.

Physically fit children have a greater ability to concentrate and better health-related quality of life (HRQOL), according to a new study.

The findings of the German study involving more than 6,500 kids emphasize the importance of cardiorespiratory health in childhood, and support physical fitness initiatives in schools, according to lead author Katharina Köble, MSc, of the Technical University of Munich (Germany), and colleagues.

“Recent studies show that only a few children meet the recommendations of physical activity,” the investigators wrote in Journal of Clinical Medicine.

While the health benefits of physical activity are clearly documented, Ms. Köble and colleagues noted that typical measures of activity, such as accelerometers or self-reported questionnaires, are suboptimal research tools.

“Physical fitness is a more objective parameter to quantify when evaluating health promotion,” the investigators wrote. “Furthermore, cardiorespiratory fitness as part of physical fitness is more strongly related to risk factors of cardiovascular disease than physical activity.”

According to the investigators, physical fitness has also been linked with better concentration and HRQOL, but never in the same population of children.

The new study aimed to address this knowledge gap by assessing 6,533 healthy children aged 6-10 years, approximately half boys and half girls. Associations between physical fitness, concentration, and HRQOL were evaluated using multiple linear regression analysis in participants aged 9-10 years.

Physical fitness was measured using a series of challenges, including curl-ups (pull-ups with palms facing body), push-ups, standing long jump, handgrip strength measurement, and Progressive Aerobic Cardiovascular Endurance Run (PACER). Performing the multistage shuttle run, PACER, “requires participants to maintain the pace set by an audio signal, which progressively increases the intensity every minute.” Results of the PACER test were used to estimate VO_2max.

Concentration was measured using the d2-R test, “a paper-pencil cancellation test, where subjects have to cross out all ‘d’ letters with two dashes under a time limit.”

HRQOL was evaluated with the KINDL questionnaire, which covers emotional well-being, physical well-being, everyday functioning (school), friends, family, and self-esteem.

Analysis showed that physical fitness improved with age (P < .001), except for VO_2max in girls (P = .129). Concentration also improved with age (P < .001), while HRQOL did not (P = .179).

Among children aged 9-10 years, VO_2max scores were strongly associated with both HRQOL (P < .001) and concentration (P < .001).

“VO_2max was found to be one of the main factors influencing concentration levels and HRQOL dimensions in primary school children,” the investigators wrote. “Physical fitness, especially cardiorespiratory performance, should therefore be promoted more specifically in school settings to support the promotion of an overall healthy lifestyle in children and adolescents.”
 

Findings are having a real-word impact, according to researcher

In an interview, Ms. Köble noted that the findings are already having a real-world impact.

“We continued data assessment in the long-term and specifically adapted prevention programs in school to the needs of the school children we identified in our study,” she said. “Schools are partially offering specific movement and nutrition classes now.”

In addition, Ms. Köble and colleagues plan on educating teachers about the “urgent need for sufficient physical activity.”

“Academic performance should be considered as an additional health factor in future studies, as well as screen time and eating patterns, as all those variables showed interactions with physical fitness and concentration. In a subanalysis, we showed that children with better physical fitness and concentration values were those who usually went to higher education secondary schools,” they wrote.
 

VO_2max did not correlate with BMI

Gregory Weaver, MD, a pediatrician at Cleveland Clinic Children’s, voiced some concerns about the reliability of the findings. He noted that VO_2max did not correlate with body mass index or other measures of physical fitness, and that using the PACER test to estimate VO_2max may have skewed the association between physical fitness and concentration.

“It is quite conceivable that children who can maintain the focus to perform maximally on this test will also do well on other tests of attention/concentration,” Dr. Weaver said. “Most children I know would have a very difficult time performing a physical fitness test which requires them to match a recorded pace that slowly increases overtime. I’m not an expert in the area, but it is my understanding that usually VO_2max tests involve a treadmill which allows investigators to have complete control over pace.”

Dr. Weaver concluded that more work is needed to determine if physical fitness interventions can have a positive impact on HRQOL and concentration.

“I think the authors of this study attempted to ask an important question about the possible association between physical fitness and concentration among school aged children,” Dr. Weaver said in an interview. “But what is even more vital are studies demonstrating that a change in modifiable health factors like nutrition, physical fitness, or the built environment can improve quality of life. I was hoping the authors would show that an improvement in VO_2max over time resulted in an improvement in concentration. Frustratingly, that is not what this article demonstrates.”

The investigators and Dr. Weaver reported no conflicts of interest.

In recent years, patients with advanced lung cancer have benefited from the advent of immune therapies and genotype-directed therapies –both of which have led to improved survival rates. But what will lung cancer look like in 2030?

Pasi A. Janne, MD, PhD, of the Dana-Farber Cancer Institute, Boston, hopes to see improved access to tumor and blood-based genotyping.

Dr. Janne, who serves as director of the Lowe Center for Thoracic Oncology at Dana-Farber, gave a keynote presentation at the 2022 European Lung Cancer Congress, where he highlighted the need to broaden the scope of targeted therapies, make “great drugs work even better,” improve the ability to treat patients based on risk level, and expand the use of targeted therapies in the adjuvant and neoadjuvant setting to make significant progress in the treatment lung cancer treatment in coming years.

Genotyping is underutilized, he said. A 2019 multicenter study reported at the annual meeting of the American Society of Clinical Oncology showed that only 54% of 1,203 patients underwent testing for EGFR mutations, 22% were tested for EGFR, ALK, ROS1, and BRAF mutations, and only 7% were tested for all biomarkers recommended by National Comprehensive Cancer Network guidelines at the time.

That study also showed that only 45% of patients received biomarker-driven treatment, even when driver mutations were detected.

“Immunotherapy was often prescribed instead of targeted therapy, even when molecular results were available,” Dr. Janne said.

Another study, reported at the 2021 ASCO annual meeting, showed some improvement in testing rates, but still, only 37% of patients were tested for all biomarkers as recommended.

Racial disparities in testing have also been observed. Bruno and colleagues found that any next-generation sequencing was performed in 50.1% of White patients, compared with 39.8% of black patients, and NGS prior to first-line therapy was performed in 35.5% and 25.8%, respectively.

The study, also reported at ASCO in 2021, showed that trial participation was observed among 3.9% of White patients and 1.9% of Black patients.

“The studies really highlight the need for increased testing rates and appropriate utilization of testing results to deliver optimal care to our patients with advanced lung cancer. We have a long way to go. To live the promise and appreciate the promise of precision therapy ... we need to be able to offer this testing to all of our patients with lung cancer,” he said.

Dr. Janne reported relationships with numerous pharmaceutical companies, including consulting, research support and stock ownership. He also receives postmarketing royalties from Dana-Farber Cancer Institute–owned intellectual property on EGFR mutations.

In recent years, patients with advanced lung cancer have benefited from the advent of immune therapies and genotype-directed therapies –both of which have led to improved survival rates. But what will lung cancer look like in 2030?

Pasi A. Janne, MD, PhD, of the Dana-Farber Cancer Institute, Boston, hopes to see improved access to tumor and blood-based genotyping.

Dr. Janne, who serves as director of the Lowe Center for Thoracic Oncology at Dana-Farber, gave a keynote presentation at the 2022 European Lung Cancer Congress, where he highlighted the need to broaden the scope of targeted therapies, make “great drugs work even better,” improve the ability to treat patients based on risk level, and expand the use of targeted therapies in the adjuvant and neoadjuvant setting to make significant progress in the treatment lung cancer treatment in coming years.

Genotyping is underutilized, he said. A 2019 multicenter study reported at the annual meeting of the American Society of Clinical Oncology showed that only 54% of 1,203 patients underwent testing for EGFR mutations, 22% were tested for EGFR, ALK, ROS1, and BRAF mutations, and only 7% were tested for all biomarkers recommended by National Comprehensive Cancer Network guidelines at the time.

That study also showed that only 45% of patients received biomarker-driven treatment, even when driver mutations were detected.

“Immunotherapy was often prescribed instead of targeted therapy, even when molecular results were available,” Dr. Janne said.

Another study, reported at the 2021 ASCO annual meeting, showed some improvement in testing rates, but still, only 37% of patients were tested for all biomarkers as recommended.

Racial disparities in testing have also been observed. Bruno and colleagues found that any next-generation sequencing was performed in 50.1% of White patients, compared with 39.8% of black patients, and NGS prior to first-line therapy was performed in 35.5% and 25.8%, respectively.

The study, also reported at ASCO in 2021, showed that trial participation was observed among 3.9% of White patients and 1.9% of Black patients.

“The studies really highlight the need for increased testing rates and appropriate utilization of testing results to deliver optimal care to our patients with advanced lung cancer. We have a long way to go. To live the promise and appreciate the promise of precision therapy ... we need to be able to offer this testing to all of our patients with lung cancer,” he said.

Dr. Janne reported relationships with numerous pharmaceutical companies, including consulting, research support and stock ownership. He also receives postmarketing royalties from Dana-Farber Cancer Institute–owned intellectual property on EGFR mutations.

In recent years, patients with advanced lung cancer have benefited from the advent of immune therapies and genotype-directed therapies –both of which have led to improved survival rates. But what will lung cancer look like in 2030?

Pasi A. Janne, MD, PhD, of the Dana-Farber Cancer Institute, Boston, hopes to see improved access to tumor and blood-based genotyping.

Dr. Janne, who serves as director of the Lowe Center for Thoracic Oncology at Dana-Farber, gave a keynote presentation at the 2022 European Lung Cancer Congress, where he highlighted the need to broaden the scope of targeted therapies, make “great drugs work even better,” improve the ability to treat patients based on risk level, and expand the use of targeted therapies in the adjuvant and neoadjuvant setting to make significant progress in the treatment lung cancer treatment in coming years.

Genotyping is underutilized, he said. A 2019 multicenter study reported at the annual meeting of the American Society of Clinical Oncology showed that only 54% of 1,203 patients underwent testing for EGFR mutations, 22% were tested for EGFR, ALK, ROS1, and BRAF mutations, and only 7% were tested for all biomarkers recommended by National Comprehensive Cancer Network guidelines at the time.

That study also showed that only 45% of patients received biomarker-driven treatment, even when driver mutations were detected.

“Immunotherapy was often prescribed instead of targeted therapy, even when molecular results were available,” Dr. Janne said.

Another study, reported at the 2021 ASCO annual meeting, showed some improvement in testing rates, but still, only 37% of patients were tested for all biomarkers as recommended.

Racial disparities in testing have also been observed. Bruno and colleagues found that any next-generation sequencing was performed in 50.1% of White patients, compared with 39.8% of black patients, and NGS prior to first-line therapy was performed in 35.5% and 25.8%, respectively.

The study, also reported at ASCO in 2021, showed that trial participation was observed among 3.9% of White patients and 1.9% of Black patients.

“The studies really highlight the need for increased testing rates and appropriate utilization of testing results to deliver optimal care to our patients with advanced lung cancer. We have a long way to go. To live the promise and appreciate the promise of precision therapy ... we need to be able to offer this testing to all of our patients with lung cancer,” he said.

Dr. Janne reported relationships with numerous pharmaceutical companies, including consulting, research support and stock ownership. He also receives postmarketing royalties from Dana-Farber Cancer Institute–owned intellectual property on EGFR mutations.