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FDA: Urgent device correction, recall for Philips ventilator
The U.S. Food and Drug Administration has announced a Class I recall for Philips Respironics V60 and V60 Plus ventilators, citing a power failure leading to potential oxygen deprivation. Class I recalls, the most severe, are reserved for devices that may cause serious injury or death, as noted in the FDA’s announcement. As of April 14, one death and four injuries have been associated with this device failure.
These ventilators are commonly used in hospitals or under medical supervision for patients who have difficulty regulating breathing on their own. Normally, if oxygen flow is interrupted, the device sounds alarms, alerting supervisors. The failure comes when a power fluctuation causes the device to randomly shut down, which forces the alarm system to reboot. This internal disruption is the reason for the recall.
When the device shuts down out of the blue, it may or may not sound the requisite alarm that would allow providers to intervene. If the device does not sound the alarm, patients may lose oxygen for an extended period, without a provider even knowing.
Philips was notified of these problems and began the recall process on March 10. Currently, it is estimated that 56,671 devices have been distributed throughout the United States. The FDA and Philips Respironics advise that if providers are already using these ventilators, they may continue to do so in accordance with extra set of instructions.
First, customers should connect the device to an external alarm or nurse call system. Second, they should use an external oxygen monitor and a pulse oximeter to keep track of air flow. Finally, if one is available, there should be a backup ventilator on the premises. That way, if there is an interruption in oxygen flow, someone will be alerted and can quickly intervene.
If there is a problem, the patient should be removed from the Philips ventilator and immediately placed on an alternate device. The FDA instructs customers who have experienced problems to report them to its MedWatch database.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration has announced a Class I recall for Philips Respironics V60 and V60 Plus ventilators, citing a power failure leading to potential oxygen deprivation. Class I recalls, the most severe, are reserved for devices that may cause serious injury or death, as noted in the FDA’s announcement. As of April 14, one death and four injuries have been associated with this device failure.
These ventilators are commonly used in hospitals or under medical supervision for patients who have difficulty regulating breathing on their own. Normally, if oxygen flow is interrupted, the device sounds alarms, alerting supervisors. The failure comes when a power fluctuation causes the device to randomly shut down, which forces the alarm system to reboot. This internal disruption is the reason for the recall.
When the device shuts down out of the blue, it may or may not sound the requisite alarm that would allow providers to intervene. If the device does not sound the alarm, patients may lose oxygen for an extended period, without a provider even knowing.
Philips was notified of these problems and began the recall process on March 10. Currently, it is estimated that 56,671 devices have been distributed throughout the United States. The FDA and Philips Respironics advise that if providers are already using these ventilators, they may continue to do so in accordance with extra set of instructions.
First, customers should connect the device to an external alarm or nurse call system. Second, they should use an external oxygen monitor and a pulse oximeter to keep track of air flow. Finally, if one is available, there should be a backup ventilator on the premises. That way, if there is an interruption in oxygen flow, someone will be alerted and can quickly intervene.
If there is a problem, the patient should be removed from the Philips ventilator and immediately placed on an alternate device. The FDA instructs customers who have experienced problems to report them to its MedWatch database.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration has announced a Class I recall for Philips Respironics V60 and V60 Plus ventilators, citing a power failure leading to potential oxygen deprivation. Class I recalls, the most severe, are reserved for devices that may cause serious injury or death, as noted in the FDA’s announcement. As of April 14, one death and four injuries have been associated with this device failure.
These ventilators are commonly used in hospitals or under medical supervision for patients who have difficulty regulating breathing on their own. Normally, if oxygen flow is interrupted, the device sounds alarms, alerting supervisors. The failure comes when a power fluctuation causes the device to randomly shut down, which forces the alarm system to reboot. This internal disruption is the reason for the recall.
When the device shuts down out of the blue, it may or may not sound the requisite alarm that would allow providers to intervene. If the device does not sound the alarm, patients may lose oxygen for an extended period, without a provider even knowing.
Philips was notified of these problems and began the recall process on March 10. Currently, it is estimated that 56,671 devices have been distributed throughout the United States. The FDA and Philips Respironics advise that if providers are already using these ventilators, they may continue to do so in accordance with extra set of instructions.
First, customers should connect the device to an external alarm or nurse call system. Second, they should use an external oxygen monitor and a pulse oximeter to keep track of air flow. Finally, if one is available, there should be a backup ventilator on the premises. That way, if there is an interruption in oxygen flow, someone will be alerted and can quickly intervene.
If there is a problem, the patient should be removed from the Philips ventilator and immediately placed on an alternate device. The FDA instructs customers who have experienced problems to report them to its MedWatch database.
A version of this article first appeared on Medscape.com.
Parkinson’s disease could be hiding behind those nightmares
Living the dream, diagnosing the nightmare
Does a bad dream mean you should be consulting your doctor about an impending neurologic disease? Maybe.
New research published in eClinicalMedicine suggests that, for some people, bad dreams and nightmares have been associated with developing Parkinson’s disease later in life. Dr. Abidemi I. Otaiku of the University of Birmingham (England) analyzed data from a cohort study involving 3,818 older men, of whom 2.3% were diagnosed with Parkinson’s during the 12 years of follow-up.
Dr. Otaiku found those with frequent nightmares – at least once per week – were twice as likely to develop Parkinson’s than were those without, with most of the diagnoses coming in the first 5 years.
Although more research needs to be done, “identifying the significance of bad dreams and nightmares could indicate that individuals who experience changes to their dreams in older age – without any obvious trigger – should seek medical advice,” he said in a Eurekalert statement.
Dr. Otaiku pointed out that studying dreams can tell us a lot about how our brains work and are structured. By using electroencephalography, Dr. Otaiku plans to look into the biological reasons for why we dream the way we do.
So could it be that those killer clowns are actually giving you a heads up on your health?
Maybe next time try a paper route
There’s just no winning with teenagers sometimes. You tell them to go outside, they’ll sit in the dark playing video games all night. You tell them to get better grades, they’ll skip school. You tell them to get a hobby, they’ll scam the German government for millions of euros.
The COVID-19 pandemic has been tricky for governments to manage. Massive amounts of infrastructure needed to be set up, and that means corners got cut. Germany was no exception in this regard; the government entrusted the Kassenärztlichen Vereinigung, a doctor’s association, with overseeing COVID testing and payment at private test centers. To make things a bit easier, all they required private test centers to provide to receive reimbursement was an invoice.
This is where our 17-year-old from Freiburg comes in. In a spark of entrepreneurial genius, he decided to falsify documents and create an entirely fictional COVID test center. The KV approved it, and between March and July of 2021, he sent in thousands of fake invoices. Over that 4-month period, he submitted 500,000 invoices and received 5.7 million euros as compensation. That’s a few thousand tests per day, which was absolutely absurd, but he avoided scrutiny for months.
In the end, it wasn’t even the KV that noticed the fraud, but the bank. A bank employee noticed millions flowing into the account of a teenager and suspected money laundering, alerting the government. Fortunately for our young friend, since he was under 18 when he hatched his scheme, he was tried as a minor, avoiding jail time. His ill-gotten gains were confiscated, he has to pay a relatively minimal fine, and he will be on probation for 1 year. And presumably, he’ll be on the receiving end of the grounding of a lifetime.
You look like I need more sleep
Like most people, not getting our beauty sleep can make us look tired and feel less attractive, but a new study from Sweden shows that the sleep deprived also are more likely to find others less attractive. That’s probably not a good finding for singles who often go out trying to meet someone after a long day of work.
For the study, 45 young men and women were required to spend one night with no sleep and then another night with the possibility of 8 hours of sleep. The following mornings, eye-tracking technology was used as they looked at images of happy, angry, fearful, and neutral faces. The subjects then rated the faces for attractiveness, trustworthiness, and healthiness.
“The finding that sleep-deprived subjects in our experiment rated angry faces as less trustworthy and healthy-looking and neutral and fearful faces as less attractive indicates that sleep loss is associated with more negative social impressions of others,” senior author Christian Benedict of Uppsala University said in a statement.
When we are sleep deprived, the researchers added, we might not stop to really look at someone else, which has a negative impact on how we perceive people because we are not focusing on what their facial expressions are really telling us.
We already knew that not sleeping well has many negative effects on us, but now – thank you very much, science – we have something else to think about. Better hope your crush at work gets enough sleep so you’ll be accurately noticed.
The expanding-hole illusion of science
Time for a LOTME-style reality check: I think, therefore I am.
So far, so good. Next step: I think, therefore I am. I think.
Works for us. Now for the biggie: I think I am seeing the black hole in the middle of this image expanding.
Does that work for you? Do you perceive the black hole as expanding? If you do, then you fit in with the 86% of subjects in a recent study who perceived the same thing.
Lead author Bruno Laeng of the University of Oslo explained the effect in a statement from Frontiers Science News. “The circular smear or shadow gradient of the central black hole evokes a marked impression of optic flow, as if the observer were heading forward into a hole or tunnel. ... The pupil reacts to how we perceive light – even if this ‘light’ is imaginary like in the illusion – and not just to the amount of light energy that actually enters the eye.”
The illusion is so good at deceiving the brain “that it even prompts a dilation reflex of the pupils to let in more light, just as would happen if we were really moving into a dark area,” the investigators said.
Of the 50 men and women who had their eye movements measured while looking at the illusion, only 14% didn’t perceive the illusion when the hole was black. When the hole was a color, that figure went up to 20%. There also was a strong dilation reflex with black holes, but colored holes caused the subjects’ pupils to constrict, they noted.
Dr. Laeng and his associates can’t explain why some people don’t see the movement, but they did offer this: “Pupils’ dilation or contraction reflex is not a closed-loop mechanism, like a photocell opening a door, impervious to any other information than the actual amount of light stimulating the photoreceptor. Rather, the eye adjusts to perceived and even imagined light, not simply to physical energy.”
And now, back to our reality check: We think we perceive the light of a cheeseburger, therefore it’s time for lunch.
Living the dream, diagnosing the nightmare
Does a bad dream mean you should be consulting your doctor about an impending neurologic disease? Maybe.
New research published in eClinicalMedicine suggests that, for some people, bad dreams and nightmares have been associated with developing Parkinson’s disease later in life. Dr. Abidemi I. Otaiku of the University of Birmingham (England) analyzed data from a cohort study involving 3,818 older men, of whom 2.3% were diagnosed with Parkinson’s during the 12 years of follow-up.
Dr. Otaiku found those with frequent nightmares – at least once per week – were twice as likely to develop Parkinson’s than were those without, with most of the diagnoses coming in the first 5 years.
Although more research needs to be done, “identifying the significance of bad dreams and nightmares could indicate that individuals who experience changes to their dreams in older age – without any obvious trigger – should seek medical advice,” he said in a Eurekalert statement.
Dr. Otaiku pointed out that studying dreams can tell us a lot about how our brains work and are structured. By using electroencephalography, Dr. Otaiku plans to look into the biological reasons for why we dream the way we do.
So could it be that those killer clowns are actually giving you a heads up on your health?
Maybe next time try a paper route
There’s just no winning with teenagers sometimes. You tell them to go outside, they’ll sit in the dark playing video games all night. You tell them to get better grades, they’ll skip school. You tell them to get a hobby, they’ll scam the German government for millions of euros.
The COVID-19 pandemic has been tricky for governments to manage. Massive amounts of infrastructure needed to be set up, and that means corners got cut. Germany was no exception in this regard; the government entrusted the Kassenärztlichen Vereinigung, a doctor’s association, with overseeing COVID testing and payment at private test centers. To make things a bit easier, all they required private test centers to provide to receive reimbursement was an invoice.
This is where our 17-year-old from Freiburg comes in. In a spark of entrepreneurial genius, he decided to falsify documents and create an entirely fictional COVID test center. The KV approved it, and between March and July of 2021, he sent in thousands of fake invoices. Over that 4-month period, he submitted 500,000 invoices and received 5.7 million euros as compensation. That’s a few thousand tests per day, which was absolutely absurd, but he avoided scrutiny for months.
In the end, it wasn’t even the KV that noticed the fraud, but the bank. A bank employee noticed millions flowing into the account of a teenager and suspected money laundering, alerting the government. Fortunately for our young friend, since he was under 18 when he hatched his scheme, he was tried as a minor, avoiding jail time. His ill-gotten gains were confiscated, he has to pay a relatively minimal fine, and he will be on probation for 1 year. And presumably, he’ll be on the receiving end of the grounding of a lifetime.
You look like I need more sleep
Like most people, not getting our beauty sleep can make us look tired and feel less attractive, but a new study from Sweden shows that the sleep deprived also are more likely to find others less attractive. That’s probably not a good finding for singles who often go out trying to meet someone after a long day of work.
For the study, 45 young men and women were required to spend one night with no sleep and then another night with the possibility of 8 hours of sleep. The following mornings, eye-tracking technology was used as they looked at images of happy, angry, fearful, and neutral faces. The subjects then rated the faces for attractiveness, trustworthiness, and healthiness.
“The finding that sleep-deprived subjects in our experiment rated angry faces as less trustworthy and healthy-looking and neutral and fearful faces as less attractive indicates that sleep loss is associated with more negative social impressions of others,” senior author Christian Benedict of Uppsala University said in a statement.
When we are sleep deprived, the researchers added, we might not stop to really look at someone else, which has a negative impact on how we perceive people because we are not focusing on what their facial expressions are really telling us.
We already knew that not sleeping well has many negative effects on us, but now – thank you very much, science – we have something else to think about. Better hope your crush at work gets enough sleep so you’ll be accurately noticed.
The expanding-hole illusion of science
Time for a LOTME-style reality check: I think, therefore I am.
So far, so good. Next step: I think, therefore I am. I think.
Works for us. Now for the biggie: I think I am seeing the black hole in the middle of this image expanding.
Does that work for you? Do you perceive the black hole as expanding? If you do, then you fit in with the 86% of subjects in a recent study who perceived the same thing.
Lead author Bruno Laeng of the University of Oslo explained the effect in a statement from Frontiers Science News. “The circular smear or shadow gradient of the central black hole evokes a marked impression of optic flow, as if the observer were heading forward into a hole or tunnel. ... The pupil reacts to how we perceive light – even if this ‘light’ is imaginary like in the illusion – and not just to the amount of light energy that actually enters the eye.”
The illusion is so good at deceiving the brain “that it even prompts a dilation reflex of the pupils to let in more light, just as would happen if we were really moving into a dark area,” the investigators said.
Of the 50 men and women who had their eye movements measured while looking at the illusion, only 14% didn’t perceive the illusion when the hole was black. When the hole was a color, that figure went up to 20%. There also was a strong dilation reflex with black holes, but colored holes caused the subjects’ pupils to constrict, they noted.
Dr. Laeng and his associates can’t explain why some people don’t see the movement, but they did offer this: “Pupils’ dilation or contraction reflex is not a closed-loop mechanism, like a photocell opening a door, impervious to any other information than the actual amount of light stimulating the photoreceptor. Rather, the eye adjusts to perceived and even imagined light, not simply to physical energy.”
And now, back to our reality check: We think we perceive the light of a cheeseburger, therefore it’s time for lunch.
Living the dream, diagnosing the nightmare
Does a bad dream mean you should be consulting your doctor about an impending neurologic disease? Maybe.
New research published in eClinicalMedicine suggests that, for some people, bad dreams and nightmares have been associated with developing Parkinson’s disease later in life. Dr. Abidemi I. Otaiku of the University of Birmingham (England) analyzed data from a cohort study involving 3,818 older men, of whom 2.3% were diagnosed with Parkinson’s during the 12 years of follow-up.
Dr. Otaiku found those with frequent nightmares – at least once per week – were twice as likely to develop Parkinson’s than were those without, with most of the diagnoses coming in the first 5 years.
Although more research needs to be done, “identifying the significance of bad dreams and nightmares could indicate that individuals who experience changes to their dreams in older age – without any obvious trigger – should seek medical advice,” he said in a Eurekalert statement.
Dr. Otaiku pointed out that studying dreams can tell us a lot about how our brains work and are structured. By using electroencephalography, Dr. Otaiku plans to look into the biological reasons for why we dream the way we do.
So could it be that those killer clowns are actually giving you a heads up on your health?
Maybe next time try a paper route
There’s just no winning with teenagers sometimes. You tell them to go outside, they’ll sit in the dark playing video games all night. You tell them to get better grades, they’ll skip school. You tell them to get a hobby, they’ll scam the German government for millions of euros.
The COVID-19 pandemic has been tricky for governments to manage. Massive amounts of infrastructure needed to be set up, and that means corners got cut. Germany was no exception in this regard; the government entrusted the Kassenärztlichen Vereinigung, a doctor’s association, with overseeing COVID testing and payment at private test centers. To make things a bit easier, all they required private test centers to provide to receive reimbursement was an invoice.
This is where our 17-year-old from Freiburg comes in. In a spark of entrepreneurial genius, he decided to falsify documents and create an entirely fictional COVID test center. The KV approved it, and between March and July of 2021, he sent in thousands of fake invoices. Over that 4-month period, he submitted 500,000 invoices and received 5.7 million euros as compensation. That’s a few thousand tests per day, which was absolutely absurd, but he avoided scrutiny for months.
In the end, it wasn’t even the KV that noticed the fraud, but the bank. A bank employee noticed millions flowing into the account of a teenager and suspected money laundering, alerting the government. Fortunately for our young friend, since he was under 18 when he hatched his scheme, he was tried as a minor, avoiding jail time. His ill-gotten gains were confiscated, he has to pay a relatively minimal fine, and he will be on probation for 1 year. And presumably, he’ll be on the receiving end of the grounding of a lifetime.
You look like I need more sleep
Like most people, not getting our beauty sleep can make us look tired and feel less attractive, but a new study from Sweden shows that the sleep deprived also are more likely to find others less attractive. That’s probably not a good finding for singles who often go out trying to meet someone after a long day of work.
For the study, 45 young men and women were required to spend one night with no sleep and then another night with the possibility of 8 hours of sleep. The following mornings, eye-tracking technology was used as they looked at images of happy, angry, fearful, and neutral faces. The subjects then rated the faces for attractiveness, trustworthiness, and healthiness.
“The finding that sleep-deprived subjects in our experiment rated angry faces as less trustworthy and healthy-looking and neutral and fearful faces as less attractive indicates that sleep loss is associated with more negative social impressions of others,” senior author Christian Benedict of Uppsala University said in a statement.
When we are sleep deprived, the researchers added, we might not stop to really look at someone else, which has a negative impact on how we perceive people because we are not focusing on what their facial expressions are really telling us.
We already knew that not sleeping well has many negative effects on us, but now – thank you very much, science – we have something else to think about. Better hope your crush at work gets enough sleep so you’ll be accurately noticed.
The expanding-hole illusion of science
Time for a LOTME-style reality check: I think, therefore I am.
So far, so good. Next step: I think, therefore I am. I think.
Works for us. Now for the biggie: I think I am seeing the black hole in the middle of this image expanding.
Does that work for you? Do you perceive the black hole as expanding? If you do, then you fit in with the 86% of subjects in a recent study who perceived the same thing.
Lead author Bruno Laeng of the University of Oslo explained the effect in a statement from Frontiers Science News. “The circular smear or shadow gradient of the central black hole evokes a marked impression of optic flow, as if the observer were heading forward into a hole or tunnel. ... The pupil reacts to how we perceive light – even if this ‘light’ is imaginary like in the illusion – and not just to the amount of light energy that actually enters the eye.”
The illusion is so good at deceiving the brain “that it even prompts a dilation reflex of the pupils to let in more light, just as would happen if we were really moving into a dark area,” the investigators said.
Of the 50 men and women who had their eye movements measured while looking at the illusion, only 14% didn’t perceive the illusion when the hole was black. When the hole was a color, that figure went up to 20%. There also was a strong dilation reflex with black holes, but colored holes caused the subjects’ pupils to constrict, they noted.
Dr. Laeng and his associates can’t explain why some people don’t see the movement, but they did offer this: “Pupils’ dilation or contraction reflex is not a closed-loop mechanism, like a photocell opening a door, impervious to any other information than the actual amount of light stimulating the photoreceptor. Rather, the eye adjusts to perceived and even imagined light, not simply to physical energy.”
And now, back to our reality check: We think we perceive the light of a cheeseburger, therefore it’s time for lunch.
Effect modification: An important, but often underappreciated, statistical concept
In previous articles, we explored the meaning of two statistical concepts: that of the P value1 and that of confounding.2 In today’s article, we will focus on another important, though often underrecognized, statistical concept: that of effect modification (sometimes also called “interaction,” although many authors draw a distinction between these terms).3-5 In brief, effect modification is the recognition that the relationship between two variables can be different based on the values of a third variable. Let me illustrate with an example. Suppose that you give a weight-loss drug to a group of people. After a predetermined time, say 3 months, you weigh them to measure the effects of the drug, and you record that on average each individual lost about 10 pounds. Suppose, however, that you are curious to see the effect of the drug in men and women separately. You perform an analysis stratified by sex, and you notice that men lost on average only about 1 pound each, whereas women lost on average about 30 pounds each. What do these results mean? It seems that the effect of the drug on weight loss is different depending on the value of a third variable, namely sex. That is, in this case, sex acts as an effect modifier. Based on this analysis, we may conclude that the drug has real effects on women but not on men.
Before reaching this conclusion, however, it is appropriate to ask whether we have made a mistake. The first obvious thing is to make sure that we have not made a mistake in our collection of data. Once we have excluded the presence of structural bias in our dataset, how can we ascertain that these results, which at eyeballing seem so different, have not been so as a result of chance? Fortunately, we do not have to guess. There is a way to formally test for this hypothesis. If sex is truly an effect modifier, then we can perform what is called in statistical terms an “interaction term” between the exposure (in this case the drug) and the potential effect modifier (in this case sex) in a multivariable model that includes both as exposures. If the P value for that interaction term is less than .05, then the interaction term is statistically significant, and therefore the variable (in this case sex) is confirmed to be an effect modifier. Hence, the results are not due to chance, and the different effects in men and women are plausibly attributable to different biological responses to the medication.
Difference between confounding and effect modification
At this point someone might ask, “What then is the difference between confounding and effect modification? In both cases, we do stratified analysis of the relationship between an exposure (in this case the weight-loss drug) and an outcome (in this case weight loss) based on strata of a third variable (in this case sex).” The difference is fundamental. Confounding, as we explored in a previous article,2 is something that we would like to get rid of. It is the effect of an outside variable on both the exposure and outcome that does not allow us to properly evaluate the real relationship between the two. As such, we try to adjust for this variable, so that its effect is eliminated and we can only observe the relationship between the exposure and the outcome. Effect modification, on the other side, is not something we would like to get rid of. On the contrary, effect modification is part of what we would like to explore and describe because it is part of the biological mechanism that explains the real relationship between the exposure and the outcome. In the example above, if effect modification by sex is confirmed, it implies that there is something in female biology that is not found in male biology (or vice-versa) that makes their response to the medication different and therefore something of interest to study further. Thus, differently from confounding, effect modification is part of the objective reality of the world which we would like to explore and evaluate.
Several questions then arise. How can we know whether a variable is a confounder, an effect modifier, or both? As a general rule of thumb, a confounder would be a variable which, when a stratified analysis is done (or when added to a multivariable model), will change the relationship between the exposure and outcome by 10% or more. However, the relationship between the exposure and the outcome in both strata will be similar. In the example above, it would mean that if sex was only a confounder, then stratifying by sex would show roughly a similar change in the effect (say 9 kg for men and 11 kg for women). An effect modifier on the other hand is one which, when a stratified analysis is done, the association between the exposure and the outcome is very different in the two strata, as illustrated in the example above (for simplicity I am only considering two-level effect modifiers in this article).
Can a variable be both a confounder and an effect modifier? Yes, that is possible. What can be done in this case? The most common approach is to behave the same as when only effect modification is present, namely to show with the interaction term that effect modification exists and present the results between the exposure and outcome separately by the level of the effect modifier (in this example, it means that we need to describe the effects of the weight-loss drug separately for men and women). The stratified analysis/presentation will, by definition, take care of confounding as well.2
Should we always look for effect modification? Not necessarily. As a general rule, we need to test for effect modification only if there is some biological rationale that would compel us to do so, and testing should be hypothesis-driven. A common mistake that some authors make is to perform too many interaction tests and then describe as “positive findings” any test for which P value happens to be less than .05. However, as we pointed out in the article on P value,1 if we perform multiple tests, this increases the probability of false positives, and therefore the probability of spurious findings. Thus, effect modification analysis (with interaction terms) should, generally speaking, be performed with a biological rationale and/or be hypothesis driven.
Conclusion
Effect modification is an essential statistical concept that describes an underlying biological reality in which the association between an exposure and an outcome is different based on the values of a third variable. Differently from confounding, which clouds the association between exposure and outcome, and therefore is something that we try to get rid of, effect modification serves to bring to light a more proper understanding of the biological reality underlying the true association between an exposure and an outcome and as such is something that needs to be explored and described.
Dr. Jovani is assistant professor of medicine, therapeutic endoscopy, digestive diseases, and nutrition at the University of Kentucky Albert B. Chandler Hospital, Lexington. He has no conflicts of interest.
References
1. “The P value: What to make of it? A simple guide for the uninitiated.” GI & Hepatology News. 2019 Sep 23. www.mdedge.com/gihepnews/article/208601/mixed-topics/p-value-what-make-it-simple-guide-uninitiated
2. “Evaluating a paper: Take care not to be confounded.” GI & Hepatology News. 2020 Sep 18. www.mdedge.com/gihepnews/article/228765/mixed-topics/evaluating-paper-take-care-not-be-confounded
3. Corraini P et al. Clin Epidemiol. 2017;9:331-8. doi: 10.2147/CLEP.S162236.
4. VanderWeele TJ. Epidemiology. 2009 Nov;20(6):863-71. doi: 10.1097/EDE.0b013e3181ba333c.
5. Shahar E and Shahar DJ. Epidemiology. 2010 Jul;21(4):587. doi: 10.1097/EDE.0b013e3181e0995c. Author reply 587-8.
In previous articles, we explored the meaning of two statistical concepts: that of the P value1 and that of confounding.2 In today’s article, we will focus on another important, though often underrecognized, statistical concept: that of effect modification (sometimes also called “interaction,” although many authors draw a distinction between these terms).3-5 In brief, effect modification is the recognition that the relationship between two variables can be different based on the values of a third variable. Let me illustrate with an example. Suppose that you give a weight-loss drug to a group of people. After a predetermined time, say 3 months, you weigh them to measure the effects of the drug, and you record that on average each individual lost about 10 pounds. Suppose, however, that you are curious to see the effect of the drug in men and women separately. You perform an analysis stratified by sex, and you notice that men lost on average only about 1 pound each, whereas women lost on average about 30 pounds each. What do these results mean? It seems that the effect of the drug on weight loss is different depending on the value of a third variable, namely sex. That is, in this case, sex acts as an effect modifier. Based on this analysis, we may conclude that the drug has real effects on women but not on men.
Before reaching this conclusion, however, it is appropriate to ask whether we have made a mistake. The first obvious thing is to make sure that we have not made a mistake in our collection of data. Once we have excluded the presence of structural bias in our dataset, how can we ascertain that these results, which at eyeballing seem so different, have not been so as a result of chance? Fortunately, we do not have to guess. There is a way to formally test for this hypothesis. If sex is truly an effect modifier, then we can perform what is called in statistical terms an “interaction term” between the exposure (in this case the drug) and the potential effect modifier (in this case sex) in a multivariable model that includes both as exposures. If the P value for that interaction term is less than .05, then the interaction term is statistically significant, and therefore the variable (in this case sex) is confirmed to be an effect modifier. Hence, the results are not due to chance, and the different effects in men and women are plausibly attributable to different biological responses to the medication.
Difference between confounding and effect modification
At this point someone might ask, “What then is the difference between confounding and effect modification? In both cases, we do stratified analysis of the relationship between an exposure (in this case the weight-loss drug) and an outcome (in this case weight loss) based on strata of a third variable (in this case sex).” The difference is fundamental. Confounding, as we explored in a previous article,2 is something that we would like to get rid of. It is the effect of an outside variable on both the exposure and outcome that does not allow us to properly evaluate the real relationship between the two. As such, we try to adjust for this variable, so that its effect is eliminated and we can only observe the relationship between the exposure and the outcome. Effect modification, on the other side, is not something we would like to get rid of. On the contrary, effect modification is part of what we would like to explore and describe because it is part of the biological mechanism that explains the real relationship between the exposure and the outcome. In the example above, if effect modification by sex is confirmed, it implies that there is something in female biology that is not found in male biology (or vice-versa) that makes their response to the medication different and therefore something of interest to study further. Thus, differently from confounding, effect modification is part of the objective reality of the world which we would like to explore and evaluate.
Several questions then arise. How can we know whether a variable is a confounder, an effect modifier, or both? As a general rule of thumb, a confounder would be a variable which, when a stratified analysis is done (or when added to a multivariable model), will change the relationship between the exposure and outcome by 10% or more. However, the relationship between the exposure and the outcome in both strata will be similar. In the example above, it would mean that if sex was only a confounder, then stratifying by sex would show roughly a similar change in the effect (say 9 kg for men and 11 kg for women). An effect modifier on the other hand is one which, when a stratified analysis is done, the association between the exposure and the outcome is very different in the two strata, as illustrated in the example above (for simplicity I am only considering two-level effect modifiers in this article).
Can a variable be both a confounder and an effect modifier? Yes, that is possible. What can be done in this case? The most common approach is to behave the same as when only effect modification is present, namely to show with the interaction term that effect modification exists and present the results between the exposure and outcome separately by the level of the effect modifier (in this example, it means that we need to describe the effects of the weight-loss drug separately for men and women). The stratified analysis/presentation will, by definition, take care of confounding as well.2
Should we always look for effect modification? Not necessarily. As a general rule, we need to test for effect modification only if there is some biological rationale that would compel us to do so, and testing should be hypothesis-driven. A common mistake that some authors make is to perform too many interaction tests and then describe as “positive findings” any test for which P value happens to be less than .05. However, as we pointed out in the article on P value,1 if we perform multiple tests, this increases the probability of false positives, and therefore the probability of spurious findings. Thus, effect modification analysis (with interaction terms) should, generally speaking, be performed with a biological rationale and/or be hypothesis driven.
Conclusion
Effect modification is an essential statistical concept that describes an underlying biological reality in which the association between an exposure and an outcome is different based on the values of a third variable. Differently from confounding, which clouds the association between exposure and outcome, and therefore is something that we try to get rid of, effect modification serves to bring to light a more proper understanding of the biological reality underlying the true association between an exposure and an outcome and as such is something that needs to be explored and described.
Dr. Jovani is assistant professor of medicine, therapeutic endoscopy, digestive diseases, and nutrition at the University of Kentucky Albert B. Chandler Hospital, Lexington. He has no conflicts of interest.
References
1. “The P value: What to make of it? A simple guide for the uninitiated.” GI & Hepatology News. 2019 Sep 23. www.mdedge.com/gihepnews/article/208601/mixed-topics/p-value-what-make-it-simple-guide-uninitiated
2. “Evaluating a paper: Take care not to be confounded.” GI & Hepatology News. 2020 Sep 18. www.mdedge.com/gihepnews/article/228765/mixed-topics/evaluating-paper-take-care-not-be-confounded
3. Corraini P et al. Clin Epidemiol. 2017;9:331-8. doi: 10.2147/CLEP.S162236.
4. VanderWeele TJ. Epidemiology. 2009 Nov;20(6):863-71. doi: 10.1097/EDE.0b013e3181ba333c.
5. Shahar E and Shahar DJ. Epidemiology. 2010 Jul;21(4):587. doi: 10.1097/EDE.0b013e3181e0995c. Author reply 587-8.
In previous articles, we explored the meaning of two statistical concepts: that of the P value1 and that of confounding.2 In today’s article, we will focus on another important, though often underrecognized, statistical concept: that of effect modification (sometimes also called “interaction,” although many authors draw a distinction between these terms).3-5 In brief, effect modification is the recognition that the relationship between two variables can be different based on the values of a third variable. Let me illustrate with an example. Suppose that you give a weight-loss drug to a group of people. After a predetermined time, say 3 months, you weigh them to measure the effects of the drug, and you record that on average each individual lost about 10 pounds. Suppose, however, that you are curious to see the effect of the drug in men and women separately. You perform an analysis stratified by sex, and you notice that men lost on average only about 1 pound each, whereas women lost on average about 30 pounds each. What do these results mean? It seems that the effect of the drug on weight loss is different depending on the value of a third variable, namely sex. That is, in this case, sex acts as an effect modifier. Based on this analysis, we may conclude that the drug has real effects on women but not on men.
Before reaching this conclusion, however, it is appropriate to ask whether we have made a mistake. The first obvious thing is to make sure that we have not made a mistake in our collection of data. Once we have excluded the presence of structural bias in our dataset, how can we ascertain that these results, which at eyeballing seem so different, have not been so as a result of chance? Fortunately, we do not have to guess. There is a way to formally test for this hypothesis. If sex is truly an effect modifier, then we can perform what is called in statistical terms an “interaction term” between the exposure (in this case the drug) and the potential effect modifier (in this case sex) in a multivariable model that includes both as exposures. If the P value for that interaction term is less than .05, then the interaction term is statistically significant, and therefore the variable (in this case sex) is confirmed to be an effect modifier. Hence, the results are not due to chance, and the different effects in men and women are plausibly attributable to different biological responses to the medication.
Difference between confounding and effect modification
At this point someone might ask, “What then is the difference between confounding and effect modification? In both cases, we do stratified analysis of the relationship between an exposure (in this case the weight-loss drug) and an outcome (in this case weight loss) based on strata of a third variable (in this case sex).” The difference is fundamental. Confounding, as we explored in a previous article,2 is something that we would like to get rid of. It is the effect of an outside variable on both the exposure and outcome that does not allow us to properly evaluate the real relationship between the two. As such, we try to adjust for this variable, so that its effect is eliminated and we can only observe the relationship between the exposure and the outcome. Effect modification, on the other side, is not something we would like to get rid of. On the contrary, effect modification is part of what we would like to explore and describe because it is part of the biological mechanism that explains the real relationship between the exposure and the outcome. In the example above, if effect modification by sex is confirmed, it implies that there is something in female biology that is not found in male biology (or vice-versa) that makes their response to the medication different and therefore something of interest to study further. Thus, differently from confounding, effect modification is part of the objective reality of the world which we would like to explore and evaluate.
Several questions then arise. How can we know whether a variable is a confounder, an effect modifier, or both? As a general rule of thumb, a confounder would be a variable which, when a stratified analysis is done (or when added to a multivariable model), will change the relationship between the exposure and outcome by 10% or more. However, the relationship between the exposure and the outcome in both strata will be similar. In the example above, it would mean that if sex was only a confounder, then stratifying by sex would show roughly a similar change in the effect (say 9 kg for men and 11 kg for women). An effect modifier on the other hand is one which, when a stratified analysis is done, the association between the exposure and the outcome is very different in the two strata, as illustrated in the example above (for simplicity I am only considering two-level effect modifiers in this article).
Can a variable be both a confounder and an effect modifier? Yes, that is possible. What can be done in this case? The most common approach is to behave the same as when only effect modification is present, namely to show with the interaction term that effect modification exists and present the results between the exposure and outcome separately by the level of the effect modifier (in this example, it means that we need to describe the effects of the weight-loss drug separately for men and women). The stratified analysis/presentation will, by definition, take care of confounding as well.2
Should we always look for effect modification? Not necessarily. As a general rule, we need to test for effect modification only if there is some biological rationale that would compel us to do so, and testing should be hypothesis-driven. A common mistake that some authors make is to perform too many interaction tests and then describe as “positive findings” any test for which P value happens to be less than .05. However, as we pointed out in the article on P value,1 if we perform multiple tests, this increases the probability of false positives, and therefore the probability of spurious findings. Thus, effect modification analysis (with interaction terms) should, generally speaking, be performed with a biological rationale and/or be hypothesis driven.
Conclusion
Effect modification is an essential statistical concept that describes an underlying biological reality in which the association between an exposure and an outcome is different based on the values of a third variable. Differently from confounding, which clouds the association between exposure and outcome, and therefore is something that we try to get rid of, effect modification serves to bring to light a more proper understanding of the biological reality underlying the true association between an exposure and an outcome and as such is something that needs to be explored and described.
Dr. Jovani is assistant professor of medicine, therapeutic endoscopy, digestive diseases, and nutrition at the University of Kentucky Albert B. Chandler Hospital, Lexington. He has no conflicts of interest.
References
1. “The P value: What to make of it? A simple guide for the uninitiated.” GI & Hepatology News. 2019 Sep 23. www.mdedge.com/gihepnews/article/208601/mixed-topics/p-value-what-make-it-simple-guide-uninitiated
2. “Evaluating a paper: Take care not to be confounded.” GI & Hepatology News. 2020 Sep 18. www.mdedge.com/gihepnews/article/228765/mixed-topics/evaluating-paper-take-care-not-be-confounded
3. Corraini P et al. Clin Epidemiol. 2017;9:331-8. doi: 10.2147/CLEP.S162236.
4. VanderWeele TJ. Epidemiology. 2009 Nov;20(6):863-71. doi: 10.1097/EDE.0b013e3181ba333c.
5. Shahar E and Shahar DJ. Epidemiology. 2010 Jul;21(4):587. doi: 10.1097/EDE.0b013e3181e0995c. Author reply 587-8.
‘Genetic’ height linked to peripheral neuropathy and certain skin and bone infections
, according to a study published in PLOS Genetics.
Prior studies have investigated height as a risk factor for chronic diseases, such as a higher risk for atrial fibrillation and a reduced risk of cardiovascular disease. It’s been consistently difficult, however, to eliminate the confounding influences of diet, socioeconomics, lifestyle behaviors, and other environmental factors that may interfere with a person’s reaching their expected height based on their genes.
This study, however, was able to better parse those differences by using Mendelian randomization within the comprehensive clinical and genetic dataset of a national health care system biobank. Mendelian randomization uses “genetic instruments for exposures of interest under the assumption that genotype is less susceptible to confounding than measured exposures,” the authors explained. The findings confirmed previously suspected associations between height and a range of cardiovascular and metabolic conditions as well as revealing new associations with several other conditions.
Prior associations confirmed, new associations uncovered
The results confirmed that being tall is linked to a higher risk of atrial fibrillation and varicose veins, and a lower risk of coronary heart disease, high blood pressure, and high cholesterol. The study also uncovered new associations between greater height and a higher risk of peripheral neuropathy, which is caused by damage to nerves on the extremities, as well as skin and bone infections, such as leg and foot ulcers.
The meta-analysis “identified five additional traits associated with genetically-predicted height,” wrote Sridharan Raghavan, MD, assistant professor of medicine at the University of Colorado Anschutz Medical Campus, and colleagues. “Two were genitourinary conditions – erectile dysfunction and urinary retention – that can be associated with neuropathy, and a third was a phecode for nonspecific skin disorders that may be related to skin infections – consistent with the race/ethnicity stratified results.”
Removing potential confounders
F. Perry Wilson, MD, associate professor of medicine at Yale University, New Haven, Conn., who was not involved in the study, said the findings were not particularly surprising overall, but it’s striking that the researchers had ”such a large cohort with such detailed electronic health records allowing for the comparison of genetic height with a variety of clinical outcomes.” He also noted the study’s strength in using Mendelian randomization so that the exposure is the predicted genetic height instead of a person’s measured height.
“This is key, since lots of things affect actual height – nutrition is an important one that could certainly be linked to disease as well,” Dr. Wilson said. ”By using genetic height, the authors remove these potential confounders. Since genetic height is “assigned” at birth (or conception), there is little opportunity for confounding. Of course, it is possible that some of the gene variants used to predict genetic height actually do something else, such as make you seek out less nutritious meals, but by and large this is how these types of studies need to be done.”
Height may impact over 100 clinical traits
The study relied on data from the U.S. Veteran Affairs Million Veteran Program with 222,300 non-Hispanic White and 58,151 non-Hispanic Black participants. The researchers first estimated the likelihood of participants’ genetic height based on 3,290 genetic variants determined to affect genetic height in a recent European-ancestry genome-wide meta-analysis. Then they compared these estimates with participants’ actual height in the VA medical record, adjusting for age, sex, and other genetic characteristics.
In doing so, the researchers found 345 clinical traits that were associated with the actual measured height in White participants plus another 17 clinical trials linked to actual measured height in Black participants. An overall 127 of these clinical traits were significantly associated with White participants’ genetically predicted height, and two of them were significantly associated with Black participants’ genetically predicted height.
In analyzing all these data together, the researchers were largely able to separate out those associations between genetically predicted height and certain health conditions from those associations between health conditions and a person’s actual measured height. They also determined that including body mass index as a covariate had little impact on the results. The researchers conducted the appropriate statistical correction to ensure the use of so many variables did not result in spurious statistical significance in some associations.
“Using genetic methods applied to the VA Million Veteran Program, we found evidence that adult height may impact over 100 clinical traits, including several conditions associated with poor outcomes and quality of life – peripheral neuropathy, lower extremity ulcers, and chronic venous insufficiency. We conclude that height may be an unrecognized nonmodifiable risk factor for several common conditions in adults.”
Height linked with health conditions
Genetically predicted height predicted a reduced risk of hyperlipidemia and hypertension independent of coronary heart disease, the analysis revealed. Genetically predicted height was also linked to an approximately 51% increased risk of atrial fibrillation in participants without coronary heart disease but, paradoxically, only a 39% increased risk in those with coronary heart disease, despite coronary heart disease being a risk factor for atrial fibrillation. Genetically predicted height was also associated with a greater risk of varicose veins in the legs and deep vein thrombosis.
Another novel association uncovered by the analysis was between women’s genetically predicted height and both asthma and nonspecific peripheral nerve disorders. “Whether these associations reflect differences by sex in disease pathophysiology related to height may warrant exploration in a sample with better balance between men and women,” the authors wrote. “In sum, our results suggest that an individual’s height may warrant consideration as a nonmodifiable predictor for several common conditions, particularly those affecting peripheral/distal extremities that are most physically impacted by tall stature.”
A substantial limitation of the study was its homogeneity of participants, who were 92% male with an average height of 176 cm and an average BMI of 30.1. The Black participants tended to be younger, with an average age of 58 compared with 64 years in the White participants, but the groups were otherwise similar in height and weight.* The database included data from Hispanic participants, but the researchers excluded these data because of the small sample size.
The smaller dataset for Black participants was a limitation as well as the fact that the genome-wide association study the researchers relied on came from a European population, which may not be as accurate in people with other ancestry, Dr. Wilson said. The bigger limitation, however, is what the findings’ clinical relevance is.
What does it all mean?
“Genetic height is in your genes – there is nothing to be done about it – so it is more of academic interest than clinical interest,” Dr. Wilson said. It’s not even clear whether incorporating a person’s height – actual or genetically predicted, if it could be easily determined for each person – into risk calculators. ”To know whether it would be beneficial to use height (or genetic height) as a risk factor, you’d need to examine each condition of interest, adjusting for all known risk factors, to see if height improved the prediction,” Dr. Wilson said. “I suspect for most conditions, the well-known risk factors would swamp height. For example, high genetic height might truly increase risk for neuropathy. But diabetes might increase the risk so much more that height is not particularly relevant.”
On the other hand, the fact that height in general has any potential influence at all on disease risk may inspire physicians to consider other risk factors in especially tall individuals.
”Physicians may find it interesting that we have some confirmation that height does increase the risk of certain conditions,” Dr. Wilson said. “While this is unlikely to dramatically change practice, they may be a bit more diligent in looking for other relevant risk factors for the diseases found in this study in their very tall patients.”
The research was funded by the U.S. Department of Veteran Affairs, the Boettcher Foundation’s Webb-Waring Biomedical Research Program, the National Institutes of Health, and a Linda Pechenik Montague Investigator award. One study coauthor is a full-time employee of Novartis Institutes of Biomedical Research. The other authors and Dr. Wilson had no disclosures.
*Correction, 6/29/22: An earlier version of this article misstated the average age of Black participants.
, according to a study published in PLOS Genetics.
Prior studies have investigated height as a risk factor for chronic diseases, such as a higher risk for atrial fibrillation and a reduced risk of cardiovascular disease. It’s been consistently difficult, however, to eliminate the confounding influences of diet, socioeconomics, lifestyle behaviors, and other environmental factors that may interfere with a person’s reaching their expected height based on their genes.
This study, however, was able to better parse those differences by using Mendelian randomization within the comprehensive clinical and genetic dataset of a national health care system biobank. Mendelian randomization uses “genetic instruments for exposures of interest under the assumption that genotype is less susceptible to confounding than measured exposures,” the authors explained. The findings confirmed previously suspected associations between height and a range of cardiovascular and metabolic conditions as well as revealing new associations with several other conditions.
Prior associations confirmed, new associations uncovered
The results confirmed that being tall is linked to a higher risk of atrial fibrillation and varicose veins, and a lower risk of coronary heart disease, high blood pressure, and high cholesterol. The study also uncovered new associations between greater height and a higher risk of peripheral neuropathy, which is caused by damage to nerves on the extremities, as well as skin and bone infections, such as leg and foot ulcers.
The meta-analysis “identified five additional traits associated with genetically-predicted height,” wrote Sridharan Raghavan, MD, assistant professor of medicine at the University of Colorado Anschutz Medical Campus, and colleagues. “Two were genitourinary conditions – erectile dysfunction and urinary retention – that can be associated with neuropathy, and a third was a phecode for nonspecific skin disorders that may be related to skin infections – consistent with the race/ethnicity stratified results.”
Removing potential confounders
F. Perry Wilson, MD, associate professor of medicine at Yale University, New Haven, Conn., who was not involved in the study, said the findings were not particularly surprising overall, but it’s striking that the researchers had ”such a large cohort with such detailed electronic health records allowing for the comparison of genetic height with a variety of clinical outcomes.” He also noted the study’s strength in using Mendelian randomization so that the exposure is the predicted genetic height instead of a person’s measured height.
“This is key, since lots of things affect actual height – nutrition is an important one that could certainly be linked to disease as well,” Dr. Wilson said. ”By using genetic height, the authors remove these potential confounders. Since genetic height is “assigned” at birth (or conception), there is little opportunity for confounding. Of course, it is possible that some of the gene variants used to predict genetic height actually do something else, such as make you seek out less nutritious meals, but by and large this is how these types of studies need to be done.”
Height may impact over 100 clinical traits
The study relied on data from the U.S. Veteran Affairs Million Veteran Program with 222,300 non-Hispanic White and 58,151 non-Hispanic Black participants. The researchers first estimated the likelihood of participants’ genetic height based on 3,290 genetic variants determined to affect genetic height in a recent European-ancestry genome-wide meta-analysis. Then they compared these estimates with participants’ actual height in the VA medical record, adjusting for age, sex, and other genetic characteristics.
In doing so, the researchers found 345 clinical traits that were associated with the actual measured height in White participants plus another 17 clinical trials linked to actual measured height in Black participants. An overall 127 of these clinical traits were significantly associated with White participants’ genetically predicted height, and two of them were significantly associated with Black participants’ genetically predicted height.
In analyzing all these data together, the researchers were largely able to separate out those associations between genetically predicted height and certain health conditions from those associations between health conditions and a person’s actual measured height. They also determined that including body mass index as a covariate had little impact on the results. The researchers conducted the appropriate statistical correction to ensure the use of so many variables did not result in spurious statistical significance in some associations.
“Using genetic methods applied to the VA Million Veteran Program, we found evidence that adult height may impact over 100 clinical traits, including several conditions associated with poor outcomes and quality of life – peripheral neuropathy, lower extremity ulcers, and chronic venous insufficiency. We conclude that height may be an unrecognized nonmodifiable risk factor for several common conditions in adults.”
Height linked with health conditions
Genetically predicted height predicted a reduced risk of hyperlipidemia and hypertension independent of coronary heart disease, the analysis revealed. Genetically predicted height was also linked to an approximately 51% increased risk of atrial fibrillation in participants without coronary heart disease but, paradoxically, only a 39% increased risk in those with coronary heart disease, despite coronary heart disease being a risk factor for atrial fibrillation. Genetically predicted height was also associated with a greater risk of varicose veins in the legs and deep vein thrombosis.
Another novel association uncovered by the analysis was between women’s genetically predicted height and both asthma and nonspecific peripheral nerve disorders. “Whether these associations reflect differences by sex in disease pathophysiology related to height may warrant exploration in a sample with better balance between men and women,” the authors wrote. “In sum, our results suggest that an individual’s height may warrant consideration as a nonmodifiable predictor for several common conditions, particularly those affecting peripheral/distal extremities that are most physically impacted by tall stature.”
A substantial limitation of the study was its homogeneity of participants, who were 92% male with an average height of 176 cm and an average BMI of 30.1. The Black participants tended to be younger, with an average age of 58 compared with 64 years in the White participants, but the groups were otherwise similar in height and weight.* The database included data from Hispanic participants, but the researchers excluded these data because of the small sample size.
The smaller dataset for Black participants was a limitation as well as the fact that the genome-wide association study the researchers relied on came from a European population, which may not be as accurate in people with other ancestry, Dr. Wilson said. The bigger limitation, however, is what the findings’ clinical relevance is.
What does it all mean?
“Genetic height is in your genes – there is nothing to be done about it – so it is more of academic interest than clinical interest,” Dr. Wilson said. It’s not even clear whether incorporating a person’s height – actual or genetically predicted, if it could be easily determined for each person – into risk calculators. ”To know whether it would be beneficial to use height (or genetic height) as a risk factor, you’d need to examine each condition of interest, adjusting for all known risk factors, to see if height improved the prediction,” Dr. Wilson said. “I suspect for most conditions, the well-known risk factors would swamp height. For example, high genetic height might truly increase risk for neuropathy. But diabetes might increase the risk so much more that height is not particularly relevant.”
On the other hand, the fact that height in general has any potential influence at all on disease risk may inspire physicians to consider other risk factors in especially tall individuals.
”Physicians may find it interesting that we have some confirmation that height does increase the risk of certain conditions,” Dr. Wilson said. “While this is unlikely to dramatically change practice, they may be a bit more diligent in looking for other relevant risk factors for the diseases found in this study in their very tall patients.”
The research was funded by the U.S. Department of Veteran Affairs, the Boettcher Foundation’s Webb-Waring Biomedical Research Program, the National Institutes of Health, and a Linda Pechenik Montague Investigator award. One study coauthor is a full-time employee of Novartis Institutes of Biomedical Research. The other authors and Dr. Wilson had no disclosures.
*Correction, 6/29/22: An earlier version of this article misstated the average age of Black participants.
, according to a study published in PLOS Genetics.
Prior studies have investigated height as a risk factor for chronic diseases, such as a higher risk for atrial fibrillation and a reduced risk of cardiovascular disease. It’s been consistently difficult, however, to eliminate the confounding influences of diet, socioeconomics, lifestyle behaviors, and other environmental factors that may interfere with a person’s reaching their expected height based on their genes.
This study, however, was able to better parse those differences by using Mendelian randomization within the comprehensive clinical and genetic dataset of a national health care system biobank. Mendelian randomization uses “genetic instruments for exposures of interest under the assumption that genotype is less susceptible to confounding than measured exposures,” the authors explained. The findings confirmed previously suspected associations between height and a range of cardiovascular and metabolic conditions as well as revealing new associations with several other conditions.
Prior associations confirmed, new associations uncovered
The results confirmed that being tall is linked to a higher risk of atrial fibrillation and varicose veins, and a lower risk of coronary heart disease, high blood pressure, and high cholesterol. The study also uncovered new associations between greater height and a higher risk of peripheral neuropathy, which is caused by damage to nerves on the extremities, as well as skin and bone infections, such as leg and foot ulcers.
The meta-analysis “identified five additional traits associated with genetically-predicted height,” wrote Sridharan Raghavan, MD, assistant professor of medicine at the University of Colorado Anschutz Medical Campus, and colleagues. “Two were genitourinary conditions – erectile dysfunction and urinary retention – that can be associated with neuropathy, and a third was a phecode for nonspecific skin disorders that may be related to skin infections – consistent with the race/ethnicity stratified results.”
Removing potential confounders
F. Perry Wilson, MD, associate professor of medicine at Yale University, New Haven, Conn., who was not involved in the study, said the findings were not particularly surprising overall, but it’s striking that the researchers had ”such a large cohort with such detailed electronic health records allowing for the comparison of genetic height with a variety of clinical outcomes.” He also noted the study’s strength in using Mendelian randomization so that the exposure is the predicted genetic height instead of a person’s measured height.
“This is key, since lots of things affect actual height – nutrition is an important one that could certainly be linked to disease as well,” Dr. Wilson said. ”By using genetic height, the authors remove these potential confounders. Since genetic height is “assigned” at birth (or conception), there is little opportunity for confounding. Of course, it is possible that some of the gene variants used to predict genetic height actually do something else, such as make you seek out less nutritious meals, but by and large this is how these types of studies need to be done.”
Height may impact over 100 clinical traits
The study relied on data from the U.S. Veteran Affairs Million Veteran Program with 222,300 non-Hispanic White and 58,151 non-Hispanic Black participants. The researchers first estimated the likelihood of participants’ genetic height based on 3,290 genetic variants determined to affect genetic height in a recent European-ancestry genome-wide meta-analysis. Then they compared these estimates with participants’ actual height in the VA medical record, adjusting for age, sex, and other genetic characteristics.
In doing so, the researchers found 345 clinical traits that were associated with the actual measured height in White participants plus another 17 clinical trials linked to actual measured height in Black participants. An overall 127 of these clinical traits were significantly associated with White participants’ genetically predicted height, and two of them were significantly associated with Black participants’ genetically predicted height.
In analyzing all these data together, the researchers were largely able to separate out those associations between genetically predicted height and certain health conditions from those associations between health conditions and a person’s actual measured height. They also determined that including body mass index as a covariate had little impact on the results. The researchers conducted the appropriate statistical correction to ensure the use of so many variables did not result in spurious statistical significance in some associations.
“Using genetic methods applied to the VA Million Veteran Program, we found evidence that adult height may impact over 100 clinical traits, including several conditions associated with poor outcomes and quality of life – peripheral neuropathy, lower extremity ulcers, and chronic venous insufficiency. We conclude that height may be an unrecognized nonmodifiable risk factor for several common conditions in adults.”
Height linked with health conditions
Genetically predicted height predicted a reduced risk of hyperlipidemia and hypertension independent of coronary heart disease, the analysis revealed. Genetically predicted height was also linked to an approximately 51% increased risk of atrial fibrillation in participants without coronary heart disease but, paradoxically, only a 39% increased risk in those with coronary heart disease, despite coronary heart disease being a risk factor for atrial fibrillation. Genetically predicted height was also associated with a greater risk of varicose veins in the legs and deep vein thrombosis.
Another novel association uncovered by the analysis was between women’s genetically predicted height and both asthma and nonspecific peripheral nerve disorders. “Whether these associations reflect differences by sex in disease pathophysiology related to height may warrant exploration in a sample with better balance between men and women,” the authors wrote. “In sum, our results suggest that an individual’s height may warrant consideration as a nonmodifiable predictor for several common conditions, particularly those affecting peripheral/distal extremities that are most physically impacted by tall stature.”
A substantial limitation of the study was its homogeneity of participants, who were 92% male with an average height of 176 cm and an average BMI of 30.1. The Black participants tended to be younger, with an average age of 58 compared with 64 years in the White participants, but the groups were otherwise similar in height and weight.* The database included data from Hispanic participants, but the researchers excluded these data because of the small sample size.
The smaller dataset for Black participants was a limitation as well as the fact that the genome-wide association study the researchers relied on came from a European population, which may not be as accurate in people with other ancestry, Dr. Wilson said. The bigger limitation, however, is what the findings’ clinical relevance is.
What does it all mean?
“Genetic height is in your genes – there is nothing to be done about it – so it is more of academic interest than clinical interest,” Dr. Wilson said. It’s not even clear whether incorporating a person’s height – actual or genetically predicted, if it could be easily determined for each person – into risk calculators. ”To know whether it would be beneficial to use height (or genetic height) as a risk factor, you’d need to examine each condition of interest, adjusting for all known risk factors, to see if height improved the prediction,” Dr. Wilson said. “I suspect for most conditions, the well-known risk factors would swamp height. For example, high genetic height might truly increase risk for neuropathy. But diabetes might increase the risk so much more that height is not particularly relevant.”
On the other hand, the fact that height in general has any potential influence at all on disease risk may inspire physicians to consider other risk factors in especially tall individuals.
”Physicians may find it interesting that we have some confirmation that height does increase the risk of certain conditions,” Dr. Wilson said. “While this is unlikely to dramatically change practice, they may be a bit more diligent in looking for other relevant risk factors for the diseases found in this study in their very tall patients.”
The research was funded by the U.S. Department of Veteran Affairs, the Boettcher Foundation’s Webb-Waring Biomedical Research Program, the National Institutes of Health, and a Linda Pechenik Montague Investigator award. One study coauthor is a full-time employee of Novartis Institutes of Biomedical Research. The other authors and Dr. Wilson had no disclosures.
*Correction, 6/29/22: An earlier version of this article misstated the average age of Black participants.
FROM PLOS GENETICS
Using the skin to probe within: the promise of intradermal microdialysis
SAN DIEGO – When Lacy M. Alexander, PhD, began her career as a kinesiology researcher, she focused on the skin as a model of circulation for examining mechanisms of vascular function and dysfunction in diseases, as well as the influence of drug interventions.
“The skin is an accessible circulation; we see many of the same neural and endothelial pathways mediating vasodilation that we see throughout the entire vascular system,” Dr. Alexander, professor of kinesiology at Penn State University’s College of Health and Human Development, University Park, Pa., said during a lecture at the annual meeting of the American College for Sports Medicine.
The main . “This catheter has the ability to perfuse or infuse various substances into a bidirectional membrane,” Dr. Alexander explained. “This enables us to recover various substances into that catheter. We pair this with a measurement of skin blood flow with Doppler probes as well as the ability to control local temperature to either isolate reflex control of the human cutaneous circulation or elicit local changes in temperature to elicit vasodilation and vasoconstriction.”
In a 2005 article on evaluating the microcirculation in vascular disease, microvascular dysfunction is described as “a systemic disease process that occurs in a similar fashion in multiple tissue beds throughout the body”. Therefore, early identification of the mechanism leading to microvascular dysfunction is important, Dr. Alexander said. “We can also monitor the progression of disease and the progression of a given treatment if we have a noninvasive way to do that.”
A question that clinicians often ask Dr. Alexander is, do changes in forearm skin blood flow represent changes in, say, leg skin blood flow, or blood flow in other parts of the body? “The answer to that question is yes; we see similar changes in forearm skin that we see in other regions of the body,” she said. “We tend to use the forearm skin because there’s less UV damage, especially when we’re looking at questions related to human aging.”
Over the years, she and other investigators have used intradermal microdialysis to develop and refine many skin-specific approaches for examining endothelial function, including reactive hyperemia, direct drug delivery, local heating, whole body heating, local cooling, whole body cooling, and spectral analysis. For example, using this approach in the direct drug delivery realm, researchers have discovered that oral atorvastatin therapy restores cutaneous microvascular function by decreasing arginase activity in hypercholesterolemic middle-aged adults.
In more recent work using intradermal microdialysis, researchers have observed that peripheral microvascular function is impaired in adults with hypertension.
Another study using intradermal microdialysis found that 16 weeks of a sulfhydryl intervention improved endothelial function through nitric oxide and hydrogen sulfide-dependent mechanisms in adults with hypertension.
The technology has also helped to further understanding of nontraditional risk factors of microvascular dysfunction. In one study, researchers found that endothelium-dependent vasodilation is blunted in adults with major depressive disorder due to a reduced functional contribution of nitric oxide.
According to Dr. Alexander, a study being reviewed for publication found that microvascular endothelial function is impaired in women with endometriosis.
Also in 2019, a European Academy of Allergy and Clinical Immunology (EAACI) position paper on the use of intradermal microdialysis in investigations of the pathogenesis of chronic inflammatory skin diseases was published.
The broad focus of Dr. Alexander’s current projects includes examining the roles of arginase in nitric oxide synthase uncoupling in human vasculature with hypercholesterolemia and hypertension; inflammation-induced alteration in vasodilatory signaling with essential hypertension; the role of reactive oxygen species in altering vasoconstriction and vascular remodeling with hypertension, and the effects of common platelet inhibitors on microvascular function in human skin as they relate to basic mechanisms of skin blood flow and functional thermoregulatory outcomes. “The hope is that we can intervene with things like dietary and exercise interventions early on to mitigate this progression to avert cardiovascular disease,” she said.
Dr. Alexander disclosed that she has received research support from the National Heart, Lung, and Blood Institute, the National Dairy Council, the American College of Sports Medicine, and the American Heart Association.
SAN DIEGO – When Lacy M. Alexander, PhD, began her career as a kinesiology researcher, she focused on the skin as a model of circulation for examining mechanisms of vascular function and dysfunction in diseases, as well as the influence of drug interventions.
“The skin is an accessible circulation; we see many of the same neural and endothelial pathways mediating vasodilation that we see throughout the entire vascular system,” Dr. Alexander, professor of kinesiology at Penn State University’s College of Health and Human Development, University Park, Pa., said during a lecture at the annual meeting of the American College for Sports Medicine.
The main . “This catheter has the ability to perfuse or infuse various substances into a bidirectional membrane,” Dr. Alexander explained. “This enables us to recover various substances into that catheter. We pair this with a measurement of skin blood flow with Doppler probes as well as the ability to control local temperature to either isolate reflex control of the human cutaneous circulation or elicit local changes in temperature to elicit vasodilation and vasoconstriction.”
In a 2005 article on evaluating the microcirculation in vascular disease, microvascular dysfunction is described as “a systemic disease process that occurs in a similar fashion in multiple tissue beds throughout the body”. Therefore, early identification of the mechanism leading to microvascular dysfunction is important, Dr. Alexander said. “We can also monitor the progression of disease and the progression of a given treatment if we have a noninvasive way to do that.”
A question that clinicians often ask Dr. Alexander is, do changes in forearm skin blood flow represent changes in, say, leg skin blood flow, or blood flow in other parts of the body? “The answer to that question is yes; we see similar changes in forearm skin that we see in other regions of the body,” she said. “We tend to use the forearm skin because there’s less UV damage, especially when we’re looking at questions related to human aging.”
Over the years, she and other investigators have used intradermal microdialysis to develop and refine many skin-specific approaches for examining endothelial function, including reactive hyperemia, direct drug delivery, local heating, whole body heating, local cooling, whole body cooling, and spectral analysis. For example, using this approach in the direct drug delivery realm, researchers have discovered that oral atorvastatin therapy restores cutaneous microvascular function by decreasing arginase activity in hypercholesterolemic middle-aged adults.
In more recent work using intradermal microdialysis, researchers have observed that peripheral microvascular function is impaired in adults with hypertension.
Another study using intradermal microdialysis found that 16 weeks of a sulfhydryl intervention improved endothelial function through nitric oxide and hydrogen sulfide-dependent mechanisms in adults with hypertension.
The technology has also helped to further understanding of nontraditional risk factors of microvascular dysfunction. In one study, researchers found that endothelium-dependent vasodilation is blunted in adults with major depressive disorder due to a reduced functional contribution of nitric oxide.
According to Dr. Alexander, a study being reviewed for publication found that microvascular endothelial function is impaired in women with endometriosis.
Also in 2019, a European Academy of Allergy and Clinical Immunology (EAACI) position paper on the use of intradermal microdialysis in investigations of the pathogenesis of chronic inflammatory skin diseases was published.
The broad focus of Dr. Alexander’s current projects includes examining the roles of arginase in nitric oxide synthase uncoupling in human vasculature with hypercholesterolemia and hypertension; inflammation-induced alteration in vasodilatory signaling with essential hypertension; the role of reactive oxygen species in altering vasoconstriction and vascular remodeling with hypertension, and the effects of common platelet inhibitors on microvascular function in human skin as they relate to basic mechanisms of skin blood flow and functional thermoregulatory outcomes. “The hope is that we can intervene with things like dietary and exercise interventions early on to mitigate this progression to avert cardiovascular disease,” she said.
Dr. Alexander disclosed that she has received research support from the National Heart, Lung, and Blood Institute, the National Dairy Council, the American College of Sports Medicine, and the American Heart Association.
SAN DIEGO – When Lacy M. Alexander, PhD, began her career as a kinesiology researcher, she focused on the skin as a model of circulation for examining mechanisms of vascular function and dysfunction in diseases, as well as the influence of drug interventions.
“The skin is an accessible circulation; we see many of the same neural and endothelial pathways mediating vasodilation that we see throughout the entire vascular system,” Dr. Alexander, professor of kinesiology at Penn State University’s College of Health and Human Development, University Park, Pa., said during a lecture at the annual meeting of the American College for Sports Medicine.
The main . “This catheter has the ability to perfuse or infuse various substances into a bidirectional membrane,” Dr. Alexander explained. “This enables us to recover various substances into that catheter. We pair this with a measurement of skin blood flow with Doppler probes as well as the ability to control local temperature to either isolate reflex control of the human cutaneous circulation or elicit local changes in temperature to elicit vasodilation and vasoconstriction.”
In a 2005 article on evaluating the microcirculation in vascular disease, microvascular dysfunction is described as “a systemic disease process that occurs in a similar fashion in multiple tissue beds throughout the body”. Therefore, early identification of the mechanism leading to microvascular dysfunction is important, Dr. Alexander said. “We can also monitor the progression of disease and the progression of a given treatment if we have a noninvasive way to do that.”
A question that clinicians often ask Dr. Alexander is, do changes in forearm skin blood flow represent changes in, say, leg skin blood flow, or blood flow in other parts of the body? “The answer to that question is yes; we see similar changes in forearm skin that we see in other regions of the body,” she said. “We tend to use the forearm skin because there’s less UV damage, especially when we’re looking at questions related to human aging.”
Over the years, she and other investigators have used intradermal microdialysis to develop and refine many skin-specific approaches for examining endothelial function, including reactive hyperemia, direct drug delivery, local heating, whole body heating, local cooling, whole body cooling, and spectral analysis. For example, using this approach in the direct drug delivery realm, researchers have discovered that oral atorvastatin therapy restores cutaneous microvascular function by decreasing arginase activity in hypercholesterolemic middle-aged adults.
In more recent work using intradermal microdialysis, researchers have observed that peripheral microvascular function is impaired in adults with hypertension.
Another study using intradermal microdialysis found that 16 weeks of a sulfhydryl intervention improved endothelial function through nitric oxide and hydrogen sulfide-dependent mechanisms in adults with hypertension.
The technology has also helped to further understanding of nontraditional risk factors of microvascular dysfunction. In one study, researchers found that endothelium-dependent vasodilation is blunted in adults with major depressive disorder due to a reduced functional contribution of nitric oxide.
According to Dr. Alexander, a study being reviewed for publication found that microvascular endothelial function is impaired in women with endometriosis.
Also in 2019, a European Academy of Allergy and Clinical Immunology (EAACI) position paper on the use of intradermal microdialysis in investigations of the pathogenesis of chronic inflammatory skin diseases was published.
The broad focus of Dr. Alexander’s current projects includes examining the roles of arginase in nitric oxide synthase uncoupling in human vasculature with hypercholesterolemia and hypertension; inflammation-induced alteration in vasodilatory signaling with essential hypertension; the role of reactive oxygen species in altering vasoconstriction and vascular remodeling with hypertension, and the effects of common platelet inhibitors on microvascular function in human skin as they relate to basic mechanisms of skin blood flow and functional thermoregulatory outcomes. “The hope is that we can intervene with things like dietary and exercise interventions early on to mitigate this progression to avert cardiovascular disease,” she said.
Dr. Alexander disclosed that she has received research support from the National Heart, Lung, and Blood Institute, the National Dairy Council, the American College of Sports Medicine, and the American Heart Association.
AT ACSM 2022
‘Medical maximizers’ dole out unneeded antibiotics for ASB
So why did you get that prescription?
The Infectious Diseases Society of America recommends against antibiotics in this scenario, with exceptions for patients who are pregnant or undergoing certain urologic procedures.
Antibiotics for asymptomatic bacteriuria (ASB) generally do not help; are costly; and can cause side effects, Clostridioides difficile infection, and antibiotic resistance.
Still, antibiotic treatment for asymptomatic bacteriuria remains common, despite guidelines.
And when researchers recently surveyed 551 primary care clinicians to see which ones would inappropriately prescribe antibiotics for a positive urine culture, the answer was most of them: 71%.
“Regardless of years in practice, training background, or professional degree, most clinicians indicated that they would prescribe antibiotics for asymptomatic bacteriuria,” the researchers reported in JAMA Network Open.
Some groups of clinicians seemed especially likely to prescribe antibiotics unnecessarily.
“Medical maximizers” – clinicians who prefer treatment even when its value is ambiguous – and family medicine clinicians were more likely to prescribe antibiotics in response to a hypothetical case.
On the other hand, resident physicians and clinicians in the U.S. Pacific Northwest were less likely to provide antibiotics inappropriately, the researchers found.
Study author Jonathan D. Baghdadi, MD, PhD, with the department of epidemiology and public health at the University of Maryland and the Veterans Affairs Maryland Healthcare System in Baltimore, summed up the findings on Twitter: “ ... who prescribes antibiotics for asymptomatic bacteriuria? The answer is most primary care clinicians in every category, but it’s more common among clinicians who want to ‘do everything.’ ”
Dr. Baghdadi said the gaps reflect problems with the medical system rather than individual clinicians.
“I don’t believe that individual clinicians knowingly choose to prescribe inappropriate antibiotics in defiance of guidelines,” Dr. Baghdadi told this news organization. “Clinical decision-making is complicated, and the decision to prescribe inappropriate antibiotics depends on patient expectations, clinician perception of patient expectations, time pressure in the clinic, regional variation in medical practice, the culture of antibiotic use, and likely in some cases the perception that doing more is better.”
In addition, researchers have used various definitions of ASB over time and in different contexts, he said.
What to do for Mr. Williams?
To examine clinician attitudes and characteristics associated with prescribing antibiotics for asymptomatic bacteriuria, Dr. Baghdadi and his colleagues analyzed survey responses from 490 physicians and 61 advanced practice clinicians.
Study participants completed tests that measure numeracy, risk-taking preferences, burnout, and tendency to maximize care. They were presented with four hypothetical clinical scenarios, including a case of asymptomatic bacteriuria: “Mr. Williams, a 65-year-old man, comes to the office for follow-up of his osteoarthritis. He has noted foul-smelling urine and no pain or difficulty with urination. A urine dipstick shows trace blood. He has no particular preference for testing and wants your advice.”
Clinicians who had been in practice for at least 10 years were more likely to prescribe antibiotics (82%) to “Mr. Williams” than were those with 3-9 years in practice (73%) or less than 3 years in practice (64%).
Of 120 clinicians with a background in family medicine, 85% said they would have prescribed antibiotics, versus 62% of 207 clinicians with a background in internal medicine.
Nurse practitioners and physician assistants were more likely to prescribe antibiotics (90%) than were attending (78%) and resident physicians (63%).
In one analysis, a background in family medicine was associated with nearly three times higher odds of prescribing antibiotics. And a high “medical maximizer” score was associated with about twice the odds of prescribing the medications.
Meanwhile, resident physicians and clinicians in the Pacific Northwest had a lower likelihood of prescribing antibiotics, with odds ratios of 0.57 and 0.49, respectively.
The respondents who prescribed antibiotics estimated a 90% probability of UTI, whereas those who did not prescribe antibiotics estimated a 15% probability of the condition.
Breaking a habit
Some prescribers may know not to treat asymptomatic bacteriuria but mistakenly consider certain findings to be symptoms of UTI.
Bradley Langford, PharmD, an antimicrobial stewardship expert with Public Health Ontario, said in his experience, most clinicians who say they know not to treat ASB incorrectly believe that cloudy urine, altered cognition, and other nonspecific symptoms indicate a UTI.
“The fact that most clinicians would treat ASB suggests that there is still a lot of work to do to improve antimicrobial stewardship, particularly outside of the hospital setting,” Dr. Langford told this news organization.
Avoiding unnecessary antibiotics is important not just because of the lack of benefit, but also because of the potential harms, said Dr. Langford. He has created a list of rebuttals for commonly given reasons for testing and treating asymptomatic bacteriuria.
“Using antibiotics for ASB can counterintuitively increase the risk for symptomatic UTI due to the disruption of protective local microflora, allowing for the growth of more pathogenic/resistant organisms,” he said.
One approach to addressing the problem: Don’t test urine in the first place if patients are asymptomatic. Virtual learning sessions have been shown to reduce urine culturing and urinary antibiotic prescribing in long-term care homes, Dr. Langford noted.
Updated training for health care professionals from the outset may also be key, and the lower rate of prescribing intent among resident physicians is reassuring, he said.
A role for patients
Patients could also help decrease the inappropriate use of antibiotics.
“Be clear with your doctor about your expectations for the health care interaction, including whether you are expecting to receive antibiotics,” Dr. Baghdadi said. “Your doctor may assume you contacted them because you wanted a prescription. If you are not expecting antibiotics, you should feel free to say so. And if you are asymptomatic, you may not need antibiotics, even if the urine culture is positive.”
The study was funded by a grant from the National Institutes of Health, and Dr. Baghdadi received grant support from the University of Maryland, Baltimore Institute for Clinical and Translational Research. Coauthors disclosed government grants and ties to Memorial Sloan Kettering Cancer Center, Vedanta Biosciences, Opentrons, and Fimbrion. Dr. Langford reported no relevant financial conflicts of interest.
A version of this article first appeared on Medscape.com.
So why did you get that prescription?
The Infectious Diseases Society of America recommends against antibiotics in this scenario, with exceptions for patients who are pregnant or undergoing certain urologic procedures.
Antibiotics for asymptomatic bacteriuria (ASB) generally do not help; are costly; and can cause side effects, Clostridioides difficile infection, and antibiotic resistance.
Still, antibiotic treatment for asymptomatic bacteriuria remains common, despite guidelines.
And when researchers recently surveyed 551 primary care clinicians to see which ones would inappropriately prescribe antibiotics for a positive urine culture, the answer was most of them: 71%.
“Regardless of years in practice, training background, or professional degree, most clinicians indicated that they would prescribe antibiotics for asymptomatic bacteriuria,” the researchers reported in JAMA Network Open.
Some groups of clinicians seemed especially likely to prescribe antibiotics unnecessarily.
“Medical maximizers” – clinicians who prefer treatment even when its value is ambiguous – and family medicine clinicians were more likely to prescribe antibiotics in response to a hypothetical case.
On the other hand, resident physicians and clinicians in the U.S. Pacific Northwest were less likely to provide antibiotics inappropriately, the researchers found.
Study author Jonathan D. Baghdadi, MD, PhD, with the department of epidemiology and public health at the University of Maryland and the Veterans Affairs Maryland Healthcare System in Baltimore, summed up the findings on Twitter: “ ... who prescribes antibiotics for asymptomatic bacteriuria? The answer is most primary care clinicians in every category, but it’s more common among clinicians who want to ‘do everything.’ ”
Dr. Baghdadi said the gaps reflect problems with the medical system rather than individual clinicians.
“I don’t believe that individual clinicians knowingly choose to prescribe inappropriate antibiotics in defiance of guidelines,” Dr. Baghdadi told this news organization. “Clinical decision-making is complicated, and the decision to prescribe inappropriate antibiotics depends on patient expectations, clinician perception of patient expectations, time pressure in the clinic, regional variation in medical practice, the culture of antibiotic use, and likely in some cases the perception that doing more is better.”
In addition, researchers have used various definitions of ASB over time and in different contexts, he said.
What to do for Mr. Williams?
To examine clinician attitudes and characteristics associated with prescribing antibiotics for asymptomatic bacteriuria, Dr. Baghdadi and his colleagues analyzed survey responses from 490 physicians and 61 advanced practice clinicians.
Study participants completed tests that measure numeracy, risk-taking preferences, burnout, and tendency to maximize care. They were presented with four hypothetical clinical scenarios, including a case of asymptomatic bacteriuria: “Mr. Williams, a 65-year-old man, comes to the office for follow-up of his osteoarthritis. He has noted foul-smelling urine and no pain or difficulty with urination. A urine dipstick shows trace blood. He has no particular preference for testing and wants your advice.”
Clinicians who had been in practice for at least 10 years were more likely to prescribe antibiotics (82%) to “Mr. Williams” than were those with 3-9 years in practice (73%) or less than 3 years in practice (64%).
Of 120 clinicians with a background in family medicine, 85% said they would have prescribed antibiotics, versus 62% of 207 clinicians with a background in internal medicine.
Nurse practitioners and physician assistants were more likely to prescribe antibiotics (90%) than were attending (78%) and resident physicians (63%).
In one analysis, a background in family medicine was associated with nearly three times higher odds of prescribing antibiotics. And a high “medical maximizer” score was associated with about twice the odds of prescribing the medications.
Meanwhile, resident physicians and clinicians in the Pacific Northwest had a lower likelihood of prescribing antibiotics, with odds ratios of 0.57 and 0.49, respectively.
The respondents who prescribed antibiotics estimated a 90% probability of UTI, whereas those who did not prescribe antibiotics estimated a 15% probability of the condition.
Breaking a habit
Some prescribers may know not to treat asymptomatic bacteriuria but mistakenly consider certain findings to be symptoms of UTI.
Bradley Langford, PharmD, an antimicrobial stewardship expert with Public Health Ontario, said in his experience, most clinicians who say they know not to treat ASB incorrectly believe that cloudy urine, altered cognition, and other nonspecific symptoms indicate a UTI.
“The fact that most clinicians would treat ASB suggests that there is still a lot of work to do to improve antimicrobial stewardship, particularly outside of the hospital setting,” Dr. Langford told this news organization.
Avoiding unnecessary antibiotics is important not just because of the lack of benefit, but also because of the potential harms, said Dr. Langford. He has created a list of rebuttals for commonly given reasons for testing and treating asymptomatic bacteriuria.
“Using antibiotics for ASB can counterintuitively increase the risk for symptomatic UTI due to the disruption of protective local microflora, allowing for the growth of more pathogenic/resistant organisms,” he said.
One approach to addressing the problem: Don’t test urine in the first place if patients are asymptomatic. Virtual learning sessions have been shown to reduce urine culturing and urinary antibiotic prescribing in long-term care homes, Dr. Langford noted.
Updated training for health care professionals from the outset may also be key, and the lower rate of prescribing intent among resident physicians is reassuring, he said.
A role for patients
Patients could also help decrease the inappropriate use of antibiotics.
“Be clear with your doctor about your expectations for the health care interaction, including whether you are expecting to receive antibiotics,” Dr. Baghdadi said. “Your doctor may assume you contacted them because you wanted a prescription. If you are not expecting antibiotics, you should feel free to say so. And if you are asymptomatic, you may not need antibiotics, even if the urine culture is positive.”
The study was funded by a grant from the National Institutes of Health, and Dr. Baghdadi received grant support from the University of Maryland, Baltimore Institute for Clinical and Translational Research. Coauthors disclosed government grants and ties to Memorial Sloan Kettering Cancer Center, Vedanta Biosciences, Opentrons, and Fimbrion. Dr. Langford reported no relevant financial conflicts of interest.
A version of this article first appeared on Medscape.com.
So why did you get that prescription?
The Infectious Diseases Society of America recommends against antibiotics in this scenario, with exceptions for patients who are pregnant or undergoing certain urologic procedures.
Antibiotics for asymptomatic bacteriuria (ASB) generally do not help; are costly; and can cause side effects, Clostridioides difficile infection, and antibiotic resistance.
Still, antibiotic treatment for asymptomatic bacteriuria remains common, despite guidelines.
And when researchers recently surveyed 551 primary care clinicians to see which ones would inappropriately prescribe antibiotics for a positive urine culture, the answer was most of them: 71%.
“Regardless of years in practice, training background, or professional degree, most clinicians indicated that they would prescribe antibiotics for asymptomatic bacteriuria,” the researchers reported in JAMA Network Open.
Some groups of clinicians seemed especially likely to prescribe antibiotics unnecessarily.
“Medical maximizers” – clinicians who prefer treatment even when its value is ambiguous – and family medicine clinicians were more likely to prescribe antibiotics in response to a hypothetical case.
On the other hand, resident physicians and clinicians in the U.S. Pacific Northwest were less likely to provide antibiotics inappropriately, the researchers found.
Study author Jonathan D. Baghdadi, MD, PhD, with the department of epidemiology and public health at the University of Maryland and the Veterans Affairs Maryland Healthcare System in Baltimore, summed up the findings on Twitter: “ ... who prescribes antibiotics for asymptomatic bacteriuria? The answer is most primary care clinicians in every category, but it’s more common among clinicians who want to ‘do everything.’ ”
Dr. Baghdadi said the gaps reflect problems with the medical system rather than individual clinicians.
“I don’t believe that individual clinicians knowingly choose to prescribe inappropriate antibiotics in defiance of guidelines,” Dr. Baghdadi told this news organization. “Clinical decision-making is complicated, and the decision to prescribe inappropriate antibiotics depends on patient expectations, clinician perception of patient expectations, time pressure in the clinic, regional variation in medical practice, the culture of antibiotic use, and likely in some cases the perception that doing more is better.”
In addition, researchers have used various definitions of ASB over time and in different contexts, he said.
What to do for Mr. Williams?
To examine clinician attitudes and characteristics associated with prescribing antibiotics for asymptomatic bacteriuria, Dr. Baghdadi and his colleagues analyzed survey responses from 490 physicians and 61 advanced practice clinicians.
Study participants completed tests that measure numeracy, risk-taking preferences, burnout, and tendency to maximize care. They were presented with four hypothetical clinical scenarios, including a case of asymptomatic bacteriuria: “Mr. Williams, a 65-year-old man, comes to the office for follow-up of his osteoarthritis. He has noted foul-smelling urine and no pain or difficulty with urination. A urine dipstick shows trace blood. He has no particular preference for testing and wants your advice.”
Clinicians who had been in practice for at least 10 years were more likely to prescribe antibiotics (82%) to “Mr. Williams” than were those with 3-9 years in practice (73%) or less than 3 years in practice (64%).
Of 120 clinicians with a background in family medicine, 85% said they would have prescribed antibiotics, versus 62% of 207 clinicians with a background in internal medicine.
Nurse practitioners and physician assistants were more likely to prescribe antibiotics (90%) than were attending (78%) and resident physicians (63%).
In one analysis, a background in family medicine was associated with nearly three times higher odds of prescribing antibiotics. And a high “medical maximizer” score was associated with about twice the odds of prescribing the medications.
Meanwhile, resident physicians and clinicians in the Pacific Northwest had a lower likelihood of prescribing antibiotics, with odds ratios of 0.57 and 0.49, respectively.
The respondents who prescribed antibiotics estimated a 90% probability of UTI, whereas those who did not prescribe antibiotics estimated a 15% probability of the condition.
Breaking a habit
Some prescribers may know not to treat asymptomatic bacteriuria but mistakenly consider certain findings to be symptoms of UTI.
Bradley Langford, PharmD, an antimicrobial stewardship expert with Public Health Ontario, said in his experience, most clinicians who say they know not to treat ASB incorrectly believe that cloudy urine, altered cognition, and other nonspecific symptoms indicate a UTI.
“The fact that most clinicians would treat ASB suggests that there is still a lot of work to do to improve antimicrobial stewardship, particularly outside of the hospital setting,” Dr. Langford told this news organization.
Avoiding unnecessary antibiotics is important not just because of the lack of benefit, but also because of the potential harms, said Dr. Langford. He has created a list of rebuttals for commonly given reasons for testing and treating asymptomatic bacteriuria.
“Using antibiotics for ASB can counterintuitively increase the risk for symptomatic UTI due to the disruption of protective local microflora, allowing for the growth of more pathogenic/resistant organisms,” he said.
One approach to addressing the problem: Don’t test urine in the first place if patients are asymptomatic. Virtual learning sessions have been shown to reduce urine culturing and urinary antibiotic prescribing in long-term care homes, Dr. Langford noted.
Updated training for health care professionals from the outset may also be key, and the lower rate of prescribing intent among resident physicians is reassuring, he said.
A role for patients
Patients could also help decrease the inappropriate use of antibiotics.
“Be clear with your doctor about your expectations for the health care interaction, including whether you are expecting to receive antibiotics,” Dr. Baghdadi said. “Your doctor may assume you contacted them because you wanted a prescription. If you are not expecting antibiotics, you should feel free to say so. And if you are asymptomatic, you may not need antibiotics, even if the urine culture is positive.”
The study was funded by a grant from the National Institutes of Health, and Dr. Baghdadi received grant support from the University of Maryland, Baltimore Institute for Clinical and Translational Research. Coauthors disclosed government grants and ties to Memorial Sloan Kettering Cancer Center, Vedanta Biosciences, Opentrons, and Fimbrion. Dr. Langford reported no relevant financial conflicts of interest.
A version of this article first appeared on Medscape.com.
Is benzophenone safe in skin care? Part 2: Environmental effects
Although it has been . DiNardo and Downs point out that BP-3 has been linked to contact and photocontact allergies in humans and implicated as a potential endocrine disruptor. They add that it can yield deleterious by-products when reacting with chlorine in swimming pools and wastewater treatment plants and can cause additional side effects in humans who ingest fish.1 This column will focus on recent studies, mainly on the role of benzophenones in sunscreen agents that pose considerable risks to waterways and marine life, with concomitant effects on the food chain.
Environmental effects of BPs and legislative responses
Various UV filters, including BP-3, octinoxate, octocrylene, and ethylhexyl salicylate, are thought to pose considerable peril to the marine environment.2,3 In particular, BP-3 has been demonstrated to provoke coral reef bleaching in vitro, leading to ossification and deforming DNA in the larval stage.3,4
According to a 2018 report, BP-3 is believed to be present in approximately two thirds of organic sunscreens used in the United States.3 In addition, several studies have revealed that detectable levels of organic sunscreen ingredients, including BP-3, have been identified in coastal waters around the globe, including Hawaii and the U.S. Virgin Islands.4-8
A surfeit of tourists has been blamed in part, given that an estimated 25% of applied sunscreen is eliminated within 20 minutes of entering the water and thought to release about 4,000-6,000 tons/year into the surrounding coral reefs.9,10 In Hawaii in particular, sewage contamination of the waterways has resulted from wastewater treatment facilities ill-equipped to filter out organic substances such as BP-3 and octinoxate.10,11 In light of such circumstances, the use of sunscreens containing BP-3 and octinoxate have been restricted in Hawaii, particularly in proximity to beaches, since Jan. 1, 2021, because of their apparent environmental impact.10
The exposure of coral to these compounds is believed to result in bleaching because of impaired membrane integrity and photosynthetic pigment loss in the zooxanthellae that coral releases.9,10 Coral and the algae zooxanthellae have a symbiotic relationship, Siller et al. explain, with the coral delivering protection and components essential for photosynthesis and the algae ultimately serving as nutrients for the coral.10 Stress endured by coral is believed to cause algae to detach, rendering coral more vulnerable to disease and less viable overall.10
In 2016, Downs et al. showed that four out of five sampled locations had detectable levels of BP-3 (100 pp trillion) with a fifth tested site measured at 19.2 pp billion.4
In 2019, Sirois acknowledges the problem of coral bleaching around the world but speculates that banning sunscreen ingredients for this purpose will delude people that such a measure will reverse the decline of coral and may lead to the unintended consequence of lower use of sunscreens. Sirois adds that a more comprehensive investigation of the multiple causes of coral reef bleaching is warranted, as are deeper examinations of studies using higher concentrations of sunscreen ingredients in artificial conditions.12
In the same year, Raffa et al. discussed the impending ban in Hawaii of the two sunscreen ingredients (BP-3 and octinoxate) to help preserve coral reefs. In so doing, they detailed the natural and human-induced harm to coral reefs, including pollution, fishing practices, overall impact of global climate change, and alterations in ocean temperature and chemistry. The implication is that sunscreen ingredients, which help prevent sun damage in users, are not the only causes of harm to coral reefs. Nevertheless, they point out that concentration estimates and mechanism studies buttress the argument that sunscreen ingredients contribute to coral bleaching. Still, the ban in Hawaii is thought to be a trend. Opponents of the ban are concerned that human skin cancers will rise in such circumstances. Alternative chemical sunscreens are being investigated, and physical sunscreens have emerged as the go-to recommendation.13
Notably, oxybenzone has been virtually replaced in the European Union with other UV filters with broad-spectrum action, but the majority of such filters have not yet been approved for use in the United States by the Food and Drug Administration.3
Food chain implications
BP-3 and other UV filters have been investigated for their effects on fish and mammals. Schneider and Lim illustrate that BP-3 is among the frequently used organic UV filters (along with 4-methylbenzylidene camphor, octocrylene, and octinoxate [ethylhexyl methoxycinnamate]) found in most water sources in the world, as well as multiple fish species.2 Cod liver in Norway, for instance, was found to contain octocrylene in 80% of cod, with BP-3 identified in 50% of the sample. BP-3 and octinoxate were also found in white fish.2,14 In laboratory studies, BP-3 in particular has been found in high concentrations in rainbow trout and Japanese rice fish (medaka), causing reduced egg production and hatchlings in females and increased vitellogenin protein production in males, suggesting potential feminization.2,15
Schneider and Lim note that standard wastewater treatment approaches cannot address this issue and the presence of such contaminants in fish can pose dangerous ramifications in the food chain. They assert that, despite relatively low concentrations in the fish, bioaccumulation and biomagnification present the potential for chemicals accumulating over time and becoming more deleterious as such ingredients travel up the food chain. As higher-chain organisms absorb higher concentrations of the chemicals not broken down in the lower-chain organisms, though, there have not yet been reports of adverse effects of biomagnification in humans.2
BP-3 has been found by Brausch and Rand to have bioaccumulated in fish at higher levels than the ambient water, however.1,2,16 Schneider and Lim present these issues as relevant to the sun protection discussion, while advocating for dermatologists to continue to counsel wise sun-protective behaviors.2
Conclusion
While calls for additional research are necessary and encouraging, I think human, and likely environmental, health would be better protected by the use of inorganic sunscreens in general and near or in coastal waterways. In light of legislative actions, in particular, it is important for dermatologists to intervene to ensure that patients do not engage in riskier behaviors in the sun in areas facing imminent organic sunscreen bans.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].
References
1. DiNardo JC and Downs CA. J Cosmet Dermatol. 2018 Feb;17(1):15-9.
2. Schneider SL and Lim HW. J Am Acad Dermatol. 2019 Jan;80(1):266-71.
3. Yeager DG and Lim HW. Dermatol Clin. 2019 Apr;37(2):149-57.
4. Downs CA et al. Arch Environ Contam Toxicol 2016 Feb;70(2):265-88.
5. Sánchez Rodríguez A et al. Chemosphere. 2015 Jul;131:85-90.
6. Tovar-Sánchez A et al. PLoS One. 2013 Jun 5;8(6):e65451.
7. Danovaro R and Corinaldesi C. Microb Ecol. 2003 Feb;45(2):109-18.
8. Daughton CG and Ternes TA. Environ Health Perspect. 1999 Dec;107 Suppl 6:907-38.
9. Danovaro R et al. Environ Health Perspect. 2008 Apr;116(4):441-7.
10. Siller A et al. Plast Surg Nur. 2019 Oct/Dec;39(4):157-60.
11. Ramos S et al. Sci Total Environ. 2015 Sep 1;526:278-311.
12. Sirois J. Sci Total Environ. 2019 Jul 15;674:211-2.
13. Raffa RB et al. J Clin Pharm Ther. 2019 Feb;44(1):134-9.
14. Langford KH et al. Environ Int. 2015 Jul;80:1-7.
15. Coronado M et al. Aquat Toxicol. 2008 Nov 21;90(3):182-7.
16. Brausch JM and Rand GM. Chemosphere. 2011 Mar;82(11):1518-32.
Although it has been . DiNardo and Downs point out that BP-3 has been linked to contact and photocontact allergies in humans and implicated as a potential endocrine disruptor. They add that it can yield deleterious by-products when reacting with chlorine in swimming pools and wastewater treatment plants and can cause additional side effects in humans who ingest fish.1 This column will focus on recent studies, mainly on the role of benzophenones in sunscreen agents that pose considerable risks to waterways and marine life, with concomitant effects on the food chain.
Environmental effects of BPs and legislative responses
Various UV filters, including BP-3, octinoxate, octocrylene, and ethylhexyl salicylate, are thought to pose considerable peril to the marine environment.2,3 In particular, BP-3 has been demonstrated to provoke coral reef bleaching in vitro, leading to ossification and deforming DNA in the larval stage.3,4
According to a 2018 report, BP-3 is believed to be present in approximately two thirds of organic sunscreens used in the United States.3 In addition, several studies have revealed that detectable levels of organic sunscreen ingredients, including BP-3, have been identified in coastal waters around the globe, including Hawaii and the U.S. Virgin Islands.4-8
A surfeit of tourists has been blamed in part, given that an estimated 25% of applied sunscreen is eliminated within 20 minutes of entering the water and thought to release about 4,000-6,000 tons/year into the surrounding coral reefs.9,10 In Hawaii in particular, sewage contamination of the waterways has resulted from wastewater treatment facilities ill-equipped to filter out organic substances such as BP-3 and octinoxate.10,11 In light of such circumstances, the use of sunscreens containing BP-3 and octinoxate have been restricted in Hawaii, particularly in proximity to beaches, since Jan. 1, 2021, because of their apparent environmental impact.10
The exposure of coral to these compounds is believed to result in bleaching because of impaired membrane integrity and photosynthetic pigment loss in the zooxanthellae that coral releases.9,10 Coral and the algae zooxanthellae have a symbiotic relationship, Siller et al. explain, with the coral delivering protection and components essential for photosynthesis and the algae ultimately serving as nutrients for the coral.10 Stress endured by coral is believed to cause algae to detach, rendering coral more vulnerable to disease and less viable overall.10
In 2016, Downs et al. showed that four out of five sampled locations had detectable levels of BP-3 (100 pp trillion) with a fifth tested site measured at 19.2 pp billion.4
In 2019, Sirois acknowledges the problem of coral bleaching around the world but speculates that banning sunscreen ingredients for this purpose will delude people that such a measure will reverse the decline of coral and may lead to the unintended consequence of lower use of sunscreens. Sirois adds that a more comprehensive investigation of the multiple causes of coral reef bleaching is warranted, as are deeper examinations of studies using higher concentrations of sunscreen ingredients in artificial conditions.12
In the same year, Raffa et al. discussed the impending ban in Hawaii of the two sunscreen ingredients (BP-3 and octinoxate) to help preserve coral reefs. In so doing, they detailed the natural and human-induced harm to coral reefs, including pollution, fishing practices, overall impact of global climate change, and alterations in ocean temperature and chemistry. The implication is that sunscreen ingredients, which help prevent sun damage in users, are not the only causes of harm to coral reefs. Nevertheless, they point out that concentration estimates and mechanism studies buttress the argument that sunscreen ingredients contribute to coral bleaching. Still, the ban in Hawaii is thought to be a trend. Opponents of the ban are concerned that human skin cancers will rise in such circumstances. Alternative chemical sunscreens are being investigated, and physical sunscreens have emerged as the go-to recommendation.13
Notably, oxybenzone has been virtually replaced in the European Union with other UV filters with broad-spectrum action, but the majority of such filters have not yet been approved for use in the United States by the Food and Drug Administration.3
Food chain implications
BP-3 and other UV filters have been investigated for their effects on fish and mammals. Schneider and Lim illustrate that BP-3 is among the frequently used organic UV filters (along with 4-methylbenzylidene camphor, octocrylene, and octinoxate [ethylhexyl methoxycinnamate]) found in most water sources in the world, as well as multiple fish species.2 Cod liver in Norway, for instance, was found to contain octocrylene in 80% of cod, with BP-3 identified in 50% of the sample. BP-3 and octinoxate were also found in white fish.2,14 In laboratory studies, BP-3 in particular has been found in high concentrations in rainbow trout and Japanese rice fish (medaka), causing reduced egg production and hatchlings in females and increased vitellogenin protein production in males, suggesting potential feminization.2,15
Schneider and Lim note that standard wastewater treatment approaches cannot address this issue and the presence of such contaminants in fish can pose dangerous ramifications in the food chain. They assert that, despite relatively low concentrations in the fish, bioaccumulation and biomagnification present the potential for chemicals accumulating over time and becoming more deleterious as such ingredients travel up the food chain. As higher-chain organisms absorb higher concentrations of the chemicals not broken down in the lower-chain organisms, though, there have not yet been reports of adverse effects of biomagnification in humans.2
BP-3 has been found by Brausch and Rand to have bioaccumulated in fish at higher levels than the ambient water, however.1,2,16 Schneider and Lim present these issues as relevant to the sun protection discussion, while advocating for dermatologists to continue to counsel wise sun-protective behaviors.2
Conclusion
While calls for additional research are necessary and encouraging, I think human, and likely environmental, health would be better protected by the use of inorganic sunscreens in general and near or in coastal waterways. In light of legislative actions, in particular, it is important for dermatologists to intervene to ensure that patients do not engage in riskier behaviors in the sun in areas facing imminent organic sunscreen bans.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].
References
1. DiNardo JC and Downs CA. J Cosmet Dermatol. 2018 Feb;17(1):15-9.
2. Schneider SL and Lim HW. J Am Acad Dermatol. 2019 Jan;80(1):266-71.
3. Yeager DG and Lim HW. Dermatol Clin. 2019 Apr;37(2):149-57.
4. Downs CA et al. Arch Environ Contam Toxicol 2016 Feb;70(2):265-88.
5. Sánchez Rodríguez A et al. Chemosphere. 2015 Jul;131:85-90.
6. Tovar-Sánchez A et al. PLoS One. 2013 Jun 5;8(6):e65451.
7. Danovaro R and Corinaldesi C. Microb Ecol. 2003 Feb;45(2):109-18.
8. Daughton CG and Ternes TA. Environ Health Perspect. 1999 Dec;107 Suppl 6:907-38.
9. Danovaro R et al. Environ Health Perspect. 2008 Apr;116(4):441-7.
10. Siller A et al. Plast Surg Nur. 2019 Oct/Dec;39(4):157-60.
11. Ramos S et al. Sci Total Environ. 2015 Sep 1;526:278-311.
12. Sirois J. Sci Total Environ. 2019 Jul 15;674:211-2.
13. Raffa RB et al. J Clin Pharm Ther. 2019 Feb;44(1):134-9.
14. Langford KH et al. Environ Int. 2015 Jul;80:1-7.
15. Coronado M et al. Aquat Toxicol. 2008 Nov 21;90(3):182-7.
16. Brausch JM and Rand GM. Chemosphere. 2011 Mar;82(11):1518-32.
Although it has been . DiNardo and Downs point out that BP-3 has been linked to contact and photocontact allergies in humans and implicated as a potential endocrine disruptor. They add that it can yield deleterious by-products when reacting with chlorine in swimming pools and wastewater treatment plants and can cause additional side effects in humans who ingest fish.1 This column will focus on recent studies, mainly on the role of benzophenones in sunscreen agents that pose considerable risks to waterways and marine life, with concomitant effects on the food chain.
Environmental effects of BPs and legislative responses
Various UV filters, including BP-3, octinoxate, octocrylene, and ethylhexyl salicylate, are thought to pose considerable peril to the marine environment.2,3 In particular, BP-3 has been demonstrated to provoke coral reef bleaching in vitro, leading to ossification and deforming DNA in the larval stage.3,4
According to a 2018 report, BP-3 is believed to be present in approximately two thirds of organic sunscreens used in the United States.3 In addition, several studies have revealed that detectable levels of organic sunscreen ingredients, including BP-3, have been identified in coastal waters around the globe, including Hawaii and the U.S. Virgin Islands.4-8
A surfeit of tourists has been blamed in part, given that an estimated 25% of applied sunscreen is eliminated within 20 minutes of entering the water and thought to release about 4,000-6,000 tons/year into the surrounding coral reefs.9,10 In Hawaii in particular, sewage contamination of the waterways has resulted from wastewater treatment facilities ill-equipped to filter out organic substances such as BP-3 and octinoxate.10,11 In light of such circumstances, the use of sunscreens containing BP-3 and octinoxate have been restricted in Hawaii, particularly in proximity to beaches, since Jan. 1, 2021, because of their apparent environmental impact.10
The exposure of coral to these compounds is believed to result in bleaching because of impaired membrane integrity and photosynthetic pigment loss in the zooxanthellae that coral releases.9,10 Coral and the algae zooxanthellae have a symbiotic relationship, Siller et al. explain, with the coral delivering protection and components essential for photosynthesis and the algae ultimately serving as nutrients for the coral.10 Stress endured by coral is believed to cause algae to detach, rendering coral more vulnerable to disease and less viable overall.10
In 2016, Downs et al. showed that four out of five sampled locations had detectable levels of BP-3 (100 pp trillion) with a fifth tested site measured at 19.2 pp billion.4
In 2019, Sirois acknowledges the problem of coral bleaching around the world but speculates that banning sunscreen ingredients for this purpose will delude people that such a measure will reverse the decline of coral and may lead to the unintended consequence of lower use of sunscreens. Sirois adds that a more comprehensive investigation of the multiple causes of coral reef bleaching is warranted, as are deeper examinations of studies using higher concentrations of sunscreen ingredients in artificial conditions.12
In the same year, Raffa et al. discussed the impending ban in Hawaii of the two sunscreen ingredients (BP-3 and octinoxate) to help preserve coral reefs. In so doing, they detailed the natural and human-induced harm to coral reefs, including pollution, fishing practices, overall impact of global climate change, and alterations in ocean temperature and chemistry. The implication is that sunscreen ingredients, which help prevent sun damage in users, are not the only causes of harm to coral reefs. Nevertheless, they point out that concentration estimates and mechanism studies buttress the argument that sunscreen ingredients contribute to coral bleaching. Still, the ban in Hawaii is thought to be a trend. Opponents of the ban are concerned that human skin cancers will rise in such circumstances. Alternative chemical sunscreens are being investigated, and physical sunscreens have emerged as the go-to recommendation.13
Notably, oxybenzone has been virtually replaced in the European Union with other UV filters with broad-spectrum action, but the majority of such filters have not yet been approved for use in the United States by the Food and Drug Administration.3
Food chain implications
BP-3 and other UV filters have been investigated for their effects on fish and mammals. Schneider and Lim illustrate that BP-3 is among the frequently used organic UV filters (along with 4-methylbenzylidene camphor, octocrylene, and octinoxate [ethylhexyl methoxycinnamate]) found in most water sources in the world, as well as multiple fish species.2 Cod liver in Norway, for instance, was found to contain octocrylene in 80% of cod, with BP-3 identified in 50% of the sample. BP-3 and octinoxate were also found in white fish.2,14 In laboratory studies, BP-3 in particular has been found in high concentrations in rainbow trout and Japanese rice fish (medaka), causing reduced egg production and hatchlings in females and increased vitellogenin protein production in males, suggesting potential feminization.2,15
Schneider and Lim note that standard wastewater treatment approaches cannot address this issue and the presence of such contaminants in fish can pose dangerous ramifications in the food chain. They assert that, despite relatively low concentrations in the fish, bioaccumulation and biomagnification present the potential for chemicals accumulating over time and becoming more deleterious as such ingredients travel up the food chain. As higher-chain organisms absorb higher concentrations of the chemicals not broken down in the lower-chain organisms, though, there have not yet been reports of adverse effects of biomagnification in humans.2
BP-3 has been found by Brausch and Rand to have bioaccumulated in fish at higher levels than the ambient water, however.1,2,16 Schneider and Lim present these issues as relevant to the sun protection discussion, while advocating for dermatologists to continue to counsel wise sun-protective behaviors.2
Conclusion
While calls for additional research are necessary and encouraging, I think human, and likely environmental, health would be better protected by the use of inorganic sunscreens in general and near or in coastal waterways. In light of legislative actions, in particular, it is important for dermatologists to intervene to ensure that patients do not engage in riskier behaviors in the sun in areas facing imminent organic sunscreen bans.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].
References
1. DiNardo JC and Downs CA. J Cosmet Dermatol. 2018 Feb;17(1):15-9.
2. Schneider SL and Lim HW. J Am Acad Dermatol. 2019 Jan;80(1):266-71.
3. Yeager DG and Lim HW. Dermatol Clin. 2019 Apr;37(2):149-57.
4. Downs CA et al. Arch Environ Contam Toxicol 2016 Feb;70(2):265-88.
5. Sánchez Rodríguez A et al. Chemosphere. 2015 Jul;131:85-90.
6. Tovar-Sánchez A et al. PLoS One. 2013 Jun 5;8(6):e65451.
7. Danovaro R and Corinaldesi C. Microb Ecol. 2003 Feb;45(2):109-18.
8. Daughton CG and Ternes TA. Environ Health Perspect. 1999 Dec;107 Suppl 6:907-38.
9. Danovaro R et al. Environ Health Perspect. 2008 Apr;116(4):441-7.
10. Siller A et al. Plast Surg Nur. 2019 Oct/Dec;39(4):157-60.
11. Ramos S et al. Sci Total Environ. 2015 Sep 1;526:278-311.
12. Sirois J. Sci Total Environ. 2019 Jul 15;674:211-2.
13. Raffa RB et al. J Clin Pharm Ther. 2019 Feb;44(1):134-9.
14. Langford KH et al. Environ Int. 2015 Jul;80:1-7.
15. Coronado M et al. Aquat Toxicol. 2008 Nov 21;90(3):182-7.
16. Brausch JM and Rand GM. Chemosphere. 2011 Mar;82(11):1518-32.
The ERAS Supplemental Application: Current Status and Recommendations for Dermatology Applicants and Programs
In the 2021-2022 residency application cycle, the Association of American Medical Colleges (AAMC) piloted a supplemental application to accompany the standard residency application submitted via the AAMC’s Electronic Residency Application Service (ERAS).1 Dermatology was 1 of 3 specialties to participate in the pilot alongside internal medicine and general surgery. The goal was to develop a tool that could align applicants with programs that best matched their career goals as well as program and geographic preferences. The Association of Professors of Dermatology Residency Program Directors Section was an early advocate for the supplemental application, and members of our leadership were involved in the design, implementation, and evaluation of the pilot supplemental application.
Participating in the supplemental application was optional for both applicants and programs. The supplemental application included a Past Experiences section, which allowed applicants to highlight their 5 most meaningful research, work, and/or volunteer experiences and to describe a challenging life event that might not otherwise be included with their application. The geographic preferences section permitted applicants to select up to 3 regions of interest as well as to indicate an urban vs rural preference. Lastly, a preference-signaling section allowed dermatology applicants to send signals to up to 3 programs of particular interest.
With the close of another application cycle, applicants and programs will begin preparing for the 2022-2023 recruitment season. In this column, we present dermatology-specific data regarding the supplemental application, highlight tentative changes for the upcoming application cycle, and offer tips for applicants and programs as we approach year 2 of the supplemental application.
Results of Supplemental Application Evaluation Surveys
During the 2021-2022 recruitment season, 93% (950/1019) of dermatology applicants submitted the supplemental application, and 87% (117/135) of dermatology residency programs participated in the pilot.2 Surveys conducted by the AAMC between October 2021 and January 2022 showed that a large majority of dermatology programs used supplemental application data during initial application review when deciding who to interview. Eighty-three percent (40/48) of program directors felt that preference signals in particular helped them identify applicants they would have otherwise overlooked. Fifty-seven percent (4288/7516) of applicants across all specialties that participated in the pilot felt that preference signals would help them be noticed by their preferred programs.2 Preference signals were not evenly distributed among dermatology programs. Programs received an average of 23 signals, with a range of 2 to 87 (AAMC, unpublished data, February 2022).
Additional questions remain to be answered: How does the number of signals received affect application review? How often do geographic and program signals convert to interview offers and matches? Regardless, enthusiasm among dermatology programs for the supplemental application remains. In a recent survey of Association of Professors of Dermatology program directors, all 43 respondents planned to participate in the supplemental application again in the upcoming year (Ilana Rosman, MD; unpublished data; February 2022). The pilot will be expanded to include at least 12 other specialties.1As many who reviewed residency applications in 2021-2022 will attest, there was difficulty accessing the supplemental application data because it was not integrated into the Program Directors’ Work Station, the ERAS platform for programs to access applications, which will be remedied for the 2022-2023 iteration. Other tentative changes include modifications to the past experiences sections and timeline of the application.2
Utilizing the Supplemental Application: Recommendations to Applicants
Format of the Application—Applicants should familiarize themselves with the format of the supplemental application in advance and give themselves sufficient time to complete the application. In general, 3 to 4 hours of focused work should be enough time. Applicants should proofread for grammar and spelling before submitting.
Past Experiences—The past experiences section is intended to provide a focused snapshot of an applicant’s most meaningful activities and unique path to residency. Applicants should answer honestly based on their interests. If a student’s focus has been on volunteerism, the bulk of their 5 experiences listed may be related to service. Similarly, a student who has focused on research may preferentially highlight those experiences. In place of the long list of research, volunteer, and work experiences in the traditional ERAS application, applicants can highlight those activities in which they have been most invested. Applicants are encouraged to reflect on all genres of activities at any stage of their careers, even those not medical in nature, including work experience, military service, college athletics, or sustained musical or artistic achievement. Applicants should explain why each experience is meaningful rather than simply describing the activity.
Applicants also have the option to share a notable challenge they have overcome. It is not expected that each applicant will complete this question; in general, applicants who have not faced notable personal or professional obstacles should avoid answering. Additionally, if these challenges have been discussed in other areas of the application—for example, in the personal statement or medical student performance evaluation—it is not necessary to restate them here, though applicants can choose to do so. Examples of topics a student might discuss include being a first-generation college or medical student, growing up in poverty, facing notable personal or family health challenges, or having limited educational opportunities. It is important to share how this experience impacted an applicant’s journey to dermatology residency.
Geographic Preferences—The geographic preferences section can be difficult for applicants to navigate, as it may involve balancing a desire to attend a residency program in a particular region vs a greater desire to simply match in dermatology. In the past, programs may have made assumptions about geographic preferences based on an applicant’s birthplace, hometown, or medical school. In the supplemental application, applicants have the opportunity to directly reveal their preferences. We encourage applicants to be candid. Selecting a geographic region will not necessarily exclude applicants from consideration at other programs. For some applicants, program qualities may be more important than geography, or there may be no regional preferences. Those applicants can choose “no geographic preference.” There is considerable variability in how programs use geographic preferences. For this reason, it is in the best interest of applicants to simply respond honestly.
Preference Signaling—Preference signaling allows applicants to signal up to 3 preferred programs. Dermatology program directors agree that applicants should not signal their home program or programs at which they did in-person away rotations, as those programs would already be aware of the applicant’s interest. Although a signal increases the chances that the application will be reviewed holistically, it does not guarantee an interview offer. Programs may differentially utilize signals depending on multiple factors, including the number of signals received. We encourage applicants to discuss preference signaling strategies with advisors and focus on signaling programs in which they have genuine interest.
Recommendations to Selection Committees and Program Directors
The intent of the supplemental application is to provide a more meaningful picture of applicants and their experiences and preferences, with the goal of optimizing applicant-program fit. Programs should explicitly define for themselves the applicant characteristics and experiences they prioritize as well as their program goals. The supplemental application offers the potential to streamline holistic application review based on these elements. The short essay answers in the past experiences section permit reviewers to quickly scan for important experiences that align with the program’s recruitment goals. Importantly, reviewers should not penalize applicants who have not completed the question regarding other impactful life experiences, as not all applicants will have relevant information to share.
Some programs may find the geographic preferences section more valuable than others. Multiple factors affect how much weight will be given to geographic preferences, including program location and other characteristics that affect the desirability of the program to applicants. The competitiveness of the field, relatively low match rate, and limited number of programs may lead to less emphasis on geographic preferences in dermatology compared to other specialties. The purpose of this section is not to exclude applicants but to give programs more information that may help with alignment.
Anecdotally, many dermatology program directors were most interested in the preference signaling section of the supplemental application. Programs should consider signals to be evidence of strong preliminary interest. Programs may utilize signals differently depending on many factors such as the overall competitiveness of the program, program location, and the total number of signals the program receives. We recommend that programs holistically review all applications accompanied by a signal. Programs that utilize a points system may choose to award a certain number of points for a signal to their program. A signal might have a higher value at a program that receives only a few signals; conversely, a program that receives a large number of signals might not place tremendous value on the signal but may use it as a tiebreaker between similarly qualified applicants. Preference signaling is solely a tool for application review; because applicants’ preferences may change after the interview process, signals should not be utilized during ranking.
Next Steps
For program directors who have excitedly awaited residency application reform, the supplemental ERAS application is an important first step. Ultimately, we hope the supplemental application supplants much of the current residency application, serving as an efficient high-yield tool for holistically evaluating applicants’ academic and service records, accomplishments, and training preferences. Arriving at a new application will undoubtedly take time and discussion among the various stakeholders. Please continue to complete surveys from the AAMC, as feedback is the best method for refining the tool to serve its intended purpose.
Optimization of the application content is only one component of the reforms needed to improve the application process. Even with a revamped application tool, holistic review is challenging when programs are inundated with an ever-increasing number of applications. As such, we encourage stakeholders to simultaneously consider other potential reforms, such as caps on the number of applications, to allow programs and applicants the best opportunity for a mutually successful match.
- Supplemental ERAS application. Association of American Medical Colleges website. Accessed May 9, 2022. https://students-residents.aamc.org/applying-residencies-eras/supplemental-eras-application-eras-2023-cycle
- Association of American Medical Colleges. Supplemental application data and reports. Accessed May 9, 2022. https://www.aamc.org/data-reports/students-residents/report/supplemental-eras-application-data-and-reports
In the 2021-2022 residency application cycle, the Association of American Medical Colleges (AAMC) piloted a supplemental application to accompany the standard residency application submitted via the AAMC’s Electronic Residency Application Service (ERAS).1 Dermatology was 1 of 3 specialties to participate in the pilot alongside internal medicine and general surgery. The goal was to develop a tool that could align applicants with programs that best matched their career goals as well as program and geographic preferences. The Association of Professors of Dermatology Residency Program Directors Section was an early advocate for the supplemental application, and members of our leadership were involved in the design, implementation, and evaluation of the pilot supplemental application.
Participating in the supplemental application was optional for both applicants and programs. The supplemental application included a Past Experiences section, which allowed applicants to highlight their 5 most meaningful research, work, and/or volunteer experiences and to describe a challenging life event that might not otherwise be included with their application. The geographic preferences section permitted applicants to select up to 3 regions of interest as well as to indicate an urban vs rural preference. Lastly, a preference-signaling section allowed dermatology applicants to send signals to up to 3 programs of particular interest.
With the close of another application cycle, applicants and programs will begin preparing for the 2022-2023 recruitment season. In this column, we present dermatology-specific data regarding the supplemental application, highlight tentative changes for the upcoming application cycle, and offer tips for applicants and programs as we approach year 2 of the supplemental application.
Results of Supplemental Application Evaluation Surveys
During the 2021-2022 recruitment season, 93% (950/1019) of dermatology applicants submitted the supplemental application, and 87% (117/135) of dermatology residency programs participated in the pilot.2 Surveys conducted by the AAMC between October 2021 and January 2022 showed that a large majority of dermatology programs used supplemental application data during initial application review when deciding who to interview. Eighty-three percent (40/48) of program directors felt that preference signals in particular helped them identify applicants they would have otherwise overlooked. Fifty-seven percent (4288/7516) of applicants across all specialties that participated in the pilot felt that preference signals would help them be noticed by their preferred programs.2 Preference signals were not evenly distributed among dermatology programs. Programs received an average of 23 signals, with a range of 2 to 87 (AAMC, unpublished data, February 2022).
Additional questions remain to be answered: How does the number of signals received affect application review? How often do geographic and program signals convert to interview offers and matches? Regardless, enthusiasm among dermatology programs for the supplemental application remains. In a recent survey of Association of Professors of Dermatology program directors, all 43 respondents planned to participate in the supplemental application again in the upcoming year (Ilana Rosman, MD; unpublished data; February 2022). The pilot will be expanded to include at least 12 other specialties.1As many who reviewed residency applications in 2021-2022 will attest, there was difficulty accessing the supplemental application data because it was not integrated into the Program Directors’ Work Station, the ERAS platform for programs to access applications, which will be remedied for the 2022-2023 iteration. Other tentative changes include modifications to the past experiences sections and timeline of the application.2
Utilizing the Supplemental Application: Recommendations to Applicants
Format of the Application—Applicants should familiarize themselves with the format of the supplemental application in advance and give themselves sufficient time to complete the application. In general, 3 to 4 hours of focused work should be enough time. Applicants should proofread for grammar and spelling before submitting.
Past Experiences—The past experiences section is intended to provide a focused snapshot of an applicant’s most meaningful activities and unique path to residency. Applicants should answer honestly based on their interests. If a student’s focus has been on volunteerism, the bulk of their 5 experiences listed may be related to service. Similarly, a student who has focused on research may preferentially highlight those experiences. In place of the long list of research, volunteer, and work experiences in the traditional ERAS application, applicants can highlight those activities in which they have been most invested. Applicants are encouraged to reflect on all genres of activities at any stage of their careers, even those not medical in nature, including work experience, military service, college athletics, or sustained musical or artistic achievement. Applicants should explain why each experience is meaningful rather than simply describing the activity.
Applicants also have the option to share a notable challenge they have overcome. It is not expected that each applicant will complete this question; in general, applicants who have not faced notable personal or professional obstacles should avoid answering. Additionally, if these challenges have been discussed in other areas of the application—for example, in the personal statement or medical student performance evaluation—it is not necessary to restate them here, though applicants can choose to do so. Examples of topics a student might discuss include being a first-generation college or medical student, growing up in poverty, facing notable personal or family health challenges, or having limited educational opportunities. It is important to share how this experience impacted an applicant’s journey to dermatology residency.
Geographic Preferences—The geographic preferences section can be difficult for applicants to navigate, as it may involve balancing a desire to attend a residency program in a particular region vs a greater desire to simply match in dermatology. In the past, programs may have made assumptions about geographic preferences based on an applicant’s birthplace, hometown, or medical school. In the supplemental application, applicants have the opportunity to directly reveal their preferences. We encourage applicants to be candid. Selecting a geographic region will not necessarily exclude applicants from consideration at other programs. For some applicants, program qualities may be more important than geography, or there may be no regional preferences. Those applicants can choose “no geographic preference.” There is considerable variability in how programs use geographic preferences. For this reason, it is in the best interest of applicants to simply respond honestly.
Preference Signaling—Preference signaling allows applicants to signal up to 3 preferred programs. Dermatology program directors agree that applicants should not signal their home program or programs at which they did in-person away rotations, as those programs would already be aware of the applicant’s interest. Although a signal increases the chances that the application will be reviewed holistically, it does not guarantee an interview offer. Programs may differentially utilize signals depending on multiple factors, including the number of signals received. We encourage applicants to discuss preference signaling strategies with advisors and focus on signaling programs in which they have genuine interest.
Recommendations to Selection Committees and Program Directors
The intent of the supplemental application is to provide a more meaningful picture of applicants and their experiences and preferences, with the goal of optimizing applicant-program fit. Programs should explicitly define for themselves the applicant characteristics and experiences they prioritize as well as their program goals. The supplemental application offers the potential to streamline holistic application review based on these elements. The short essay answers in the past experiences section permit reviewers to quickly scan for important experiences that align with the program’s recruitment goals. Importantly, reviewers should not penalize applicants who have not completed the question regarding other impactful life experiences, as not all applicants will have relevant information to share.
Some programs may find the geographic preferences section more valuable than others. Multiple factors affect how much weight will be given to geographic preferences, including program location and other characteristics that affect the desirability of the program to applicants. The competitiveness of the field, relatively low match rate, and limited number of programs may lead to less emphasis on geographic preferences in dermatology compared to other specialties. The purpose of this section is not to exclude applicants but to give programs more information that may help with alignment.
Anecdotally, many dermatology program directors were most interested in the preference signaling section of the supplemental application. Programs should consider signals to be evidence of strong preliminary interest. Programs may utilize signals differently depending on many factors such as the overall competitiveness of the program, program location, and the total number of signals the program receives. We recommend that programs holistically review all applications accompanied by a signal. Programs that utilize a points system may choose to award a certain number of points for a signal to their program. A signal might have a higher value at a program that receives only a few signals; conversely, a program that receives a large number of signals might not place tremendous value on the signal but may use it as a tiebreaker between similarly qualified applicants. Preference signaling is solely a tool for application review; because applicants’ preferences may change after the interview process, signals should not be utilized during ranking.
Next Steps
For program directors who have excitedly awaited residency application reform, the supplemental ERAS application is an important first step. Ultimately, we hope the supplemental application supplants much of the current residency application, serving as an efficient high-yield tool for holistically evaluating applicants’ academic and service records, accomplishments, and training preferences. Arriving at a new application will undoubtedly take time and discussion among the various stakeholders. Please continue to complete surveys from the AAMC, as feedback is the best method for refining the tool to serve its intended purpose.
Optimization of the application content is only one component of the reforms needed to improve the application process. Even with a revamped application tool, holistic review is challenging when programs are inundated with an ever-increasing number of applications. As such, we encourage stakeholders to simultaneously consider other potential reforms, such as caps on the number of applications, to allow programs and applicants the best opportunity for a mutually successful match.
In the 2021-2022 residency application cycle, the Association of American Medical Colleges (AAMC) piloted a supplemental application to accompany the standard residency application submitted via the AAMC’s Electronic Residency Application Service (ERAS).1 Dermatology was 1 of 3 specialties to participate in the pilot alongside internal medicine and general surgery. The goal was to develop a tool that could align applicants with programs that best matched their career goals as well as program and geographic preferences. The Association of Professors of Dermatology Residency Program Directors Section was an early advocate for the supplemental application, and members of our leadership were involved in the design, implementation, and evaluation of the pilot supplemental application.
Participating in the supplemental application was optional for both applicants and programs. The supplemental application included a Past Experiences section, which allowed applicants to highlight their 5 most meaningful research, work, and/or volunteer experiences and to describe a challenging life event that might not otherwise be included with their application. The geographic preferences section permitted applicants to select up to 3 regions of interest as well as to indicate an urban vs rural preference. Lastly, a preference-signaling section allowed dermatology applicants to send signals to up to 3 programs of particular interest.
With the close of another application cycle, applicants and programs will begin preparing for the 2022-2023 recruitment season. In this column, we present dermatology-specific data regarding the supplemental application, highlight tentative changes for the upcoming application cycle, and offer tips for applicants and programs as we approach year 2 of the supplemental application.
Results of Supplemental Application Evaluation Surveys
During the 2021-2022 recruitment season, 93% (950/1019) of dermatology applicants submitted the supplemental application, and 87% (117/135) of dermatology residency programs participated in the pilot.2 Surveys conducted by the AAMC between October 2021 and January 2022 showed that a large majority of dermatology programs used supplemental application data during initial application review when deciding who to interview. Eighty-three percent (40/48) of program directors felt that preference signals in particular helped them identify applicants they would have otherwise overlooked. Fifty-seven percent (4288/7516) of applicants across all specialties that participated in the pilot felt that preference signals would help them be noticed by their preferred programs.2 Preference signals were not evenly distributed among dermatology programs. Programs received an average of 23 signals, with a range of 2 to 87 (AAMC, unpublished data, February 2022).
Additional questions remain to be answered: How does the number of signals received affect application review? How often do geographic and program signals convert to interview offers and matches? Regardless, enthusiasm among dermatology programs for the supplemental application remains. In a recent survey of Association of Professors of Dermatology program directors, all 43 respondents planned to participate in the supplemental application again in the upcoming year (Ilana Rosman, MD; unpublished data; February 2022). The pilot will be expanded to include at least 12 other specialties.1As many who reviewed residency applications in 2021-2022 will attest, there was difficulty accessing the supplemental application data because it was not integrated into the Program Directors’ Work Station, the ERAS platform for programs to access applications, which will be remedied for the 2022-2023 iteration. Other tentative changes include modifications to the past experiences sections and timeline of the application.2
Utilizing the Supplemental Application: Recommendations to Applicants
Format of the Application—Applicants should familiarize themselves with the format of the supplemental application in advance and give themselves sufficient time to complete the application. In general, 3 to 4 hours of focused work should be enough time. Applicants should proofread for grammar and spelling before submitting.
Past Experiences—The past experiences section is intended to provide a focused snapshot of an applicant’s most meaningful activities and unique path to residency. Applicants should answer honestly based on their interests. If a student’s focus has been on volunteerism, the bulk of their 5 experiences listed may be related to service. Similarly, a student who has focused on research may preferentially highlight those experiences. In place of the long list of research, volunteer, and work experiences in the traditional ERAS application, applicants can highlight those activities in which they have been most invested. Applicants are encouraged to reflect on all genres of activities at any stage of their careers, even those not medical in nature, including work experience, military service, college athletics, or sustained musical or artistic achievement. Applicants should explain why each experience is meaningful rather than simply describing the activity.
Applicants also have the option to share a notable challenge they have overcome. It is not expected that each applicant will complete this question; in general, applicants who have not faced notable personal or professional obstacles should avoid answering. Additionally, if these challenges have been discussed in other areas of the application—for example, in the personal statement or medical student performance evaluation—it is not necessary to restate them here, though applicants can choose to do so. Examples of topics a student might discuss include being a first-generation college or medical student, growing up in poverty, facing notable personal or family health challenges, or having limited educational opportunities. It is important to share how this experience impacted an applicant’s journey to dermatology residency.
Geographic Preferences—The geographic preferences section can be difficult for applicants to navigate, as it may involve balancing a desire to attend a residency program in a particular region vs a greater desire to simply match in dermatology. In the past, programs may have made assumptions about geographic preferences based on an applicant’s birthplace, hometown, or medical school. In the supplemental application, applicants have the opportunity to directly reveal their preferences. We encourage applicants to be candid. Selecting a geographic region will not necessarily exclude applicants from consideration at other programs. For some applicants, program qualities may be more important than geography, or there may be no regional preferences. Those applicants can choose “no geographic preference.” There is considerable variability in how programs use geographic preferences. For this reason, it is in the best interest of applicants to simply respond honestly.
Preference Signaling—Preference signaling allows applicants to signal up to 3 preferred programs. Dermatology program directors agree that applicants should not signal their home program or programs at which they did in-person away rotations, as those programs would already be aware of the applicant’s interest. Although a signal increases the chances that the application will be reviewed holistically, it does not guarantee an interview offer. Programs may differentially utilize signals depending on multiple factors, including the number of signals received. We encourage applicants to discuss preference signaling strategies with advisors and focus on signaling programs in which they have genuine interest.
Recommendations to Selection Committees and Program Directors
The intent of the supplemental application is to provide a more meaningful picture of applicants and their experiences and preferences, with the goal of optimizing applicant-program fit. Programs should explicitly define for themselves the applicant characteristics and experiences they prioritize as well as their program goals. The supplemental application offers the potential to streamline holistic application review based on these elements. The short essay answers in the past experiences section permit reviewers to quickly scan for important experiences that align with the program’s recruitment goals. Importantly, reviewers should not penalize applicants who have not completed the question regarding other impactful life experiences, as not all applicants will have relevant information to share.
Some programs may find the geographic preferences section more valuable than others. Multiple factors affect how much weight will be given to geographic preferences, including program location and other characteristics that affect the desirability of the program to applicants. The competitiveness of the field, relatively low match rate, and limited number of programs may lead to less emphasis on geographic preferences in dermatology compared to other specialties. The purpose of this section is not to exclude applicants but to give programs more information that may help with alignment.
Anecdotally, many dermatology program directors were most interested in the preference signaling section of the supplemental application. Programs should consider signals to be evidence of strong preliminary interest. Programs may utilize signals differently depending on many factors such as the overall competitiveness of the program, program location, and the total number of signals the program receives. We recommend that programs holistically review all applications accompanied by a signal. Programs that utilize a points system may choose to award a certain number of points for a signal to their program. A signal might have a higher value at a program that receives only a few signals; conversely, a program that receives a large number of signals might not place tremendous value on the signal but may use it as a tiebreaker between similarly qualified applicants. Preference signaling is solely a tool for application review; because applicants’ preferences may change after the interview process, signals should not be utilized during ranking.
Next Steps
For program directors who have excitedly awaited residency application reform, the supplemental ERAS application is an important first step. Ultimately, we hope the supplemental application supplants much of the current residency application, serving as an efficient high-yield tool for holistically evaluating applicants’ academic and service records, accomplishments, and training preferences. Arriving at a new application will undoubtedly take time and discussion among the various stakeholders. Please continue to complete surveys from the AAMC, as feedback is the best method for refining the tool to serve its intended purpose.
Optimization of the application content is only one component of the reforms needed to improve the application process. Even with a revamped application tool, holistic review is challenging when programs are inundated with an ever-increasing number of applications. As such, we encourage stakeholders to simultaneously consider other potential reforms, such as caps on the number of applications, to allow programs and applicants the best opportunity for a mutually successful match.
- Supplemental ERAS application. Association of American Medical Colleges website. Accessed May 9, 2022. https://students-residents.aamc.org/applying-residencies-eras/supplemental-eras-application-eras-2023-cycle
- Association of American Medical Colleges. Supplemental application data and reports. Accessed May 9, 2022. https://www.aamc.org/data-reports/students-residents/report/supplemental-eras-application-data-and-reports
- Supplemental ERAS application. Association of American Medical Colleges website. Accessed May 9, 2022. https://students-residents.aamc.org/applying-residencies-eras/supplemental-eras-application-eras-2023-cycle
- Association of American Medical Colleges. Supplemental application data and reports. Accessed May 9, 2022. https://www.aamc.org/data-reports/students-residents/report/supplemental-eras-application-data-and-reports
Practice Points
- The Electronic Residency Application Service (ERAS) Supplemental Application was piloted in the 2021-2022 residency application cycle and was utilized by the vast majority of dermatology applicants and programs.
- Survey data suggested that both applicants and programs found the supplemental application useful, particularly the preference signaling portion.
- The supplemental application will return for the 2022-2023 application cycle and will be integrated into the MyERAS workstation platform for easier access by programs.
Rippled Macules and Papules on the Legs
The Diagnosis: Cutaneous Amyloidosis
A punch biopsy confirmed the diagnosis of cutaneous amyloidosis, which is characterized by the deposition of amyloid proteins in the skin without systemic involvement. Subtypes of cutaneous amyloidosis include lichenoid, macular, and nodular amyloidosis. A mixed or biphasic amyloidosis can occur when both lichenoid and macular lesions are present.1 Lichenoid and macular amyloidosis generally are characterized by moderate to severe pruritus. Lichenoid amyloidosis favors the shins, calves, ankles, and extensor extremities; macular amyloidosis has a predilection for the interscapular area and less frequently the upper arms, chest, and thighs.2 Atypical variants also have been reported, including amyloidosis cutis dyschromica, poikilodermalike amyloidosis, and bullous amyloidosis, as well as incontinentia pigmenti–like, linear, and nevoid types.3 Macular amyloidosis has been reported to occur in association with progressive systemic sclerosis, primary biliary cirrhosis, systemic lupus erythematosus, paronychia, and multiple endocrine neoplasia type 2.2
Acanthosis nigricans typically presents on the neck and intertriginous areas as velvety hyperpigmented plaques. Confluent and reticulated papillomatosis also appears as slightly elevated papules; however, it occurs in the intermammary region in a reticulated pattern. Ichthyosis vulgaris also may occur on the lower extremities but presents with adherent large scales rather than papules. Keratosis pilaris may present on the proximal lower extremities with smaller, folliculocentric, fleshcolored to pink papules.
Treatment of cutaneous amyloidosis has long been challenging for dermatologists. The primary focus should be treatment of any underlying disease that is causing the pruritus and subsequent manipulation of skin lesions. Topical calcipotriol, phototherapy, oral cyclophosphamide, and Nd:YAG laser have demonstrated beneficial outcomes. IL-31 antibodies may be a potential future treatment.1
1. Weidner T, Illing T, Elsner P. Primary localized cutaneous amyloidosis: a systematic treatment review. Am J Clin Dermatol. 2017;18:629-642. doi:10.1007/s40257-017-0278-9 2. Rasi A, Khatami A, Javaheri SM. Macular amyloidosis: an assessment of prevalence, sex, and age. Int J Dermatol. 2004;43:898-899. doi:10.1111 /j.1365-4632.2004.01935.x 3. Hamie L, Haddad I, Nasser N, et al. Primary localized cutaneous amyloidosis of keratinocyte origin: an update with emphasis on atypical clinical variants [published online July 21, 2021]. 2021;22:667-680. Am J Clin Dermatol. doi:10.1007/s40257-021-00620-9
The Diagnosis: Cutaneous Amyloidosis
A punch biopsy confirmed the diagnosis of cutaneous amyloidosis, which is characterized by the deposition of amyloid proteins in the skin without systemic involvement. Subtypes of cutaneous amyloidosis include lichenoid, macular, and nodular amyloidosis. A mixed or biphasic amyloidosis can occur when both lichenoid and macular lesions are present.1 Lichenoid and macular amyloidosis generally are characterized by moderate to severe pruritus. Lichenoid amyloidosis favors the shins, calves, ankles, and extensor extremities; macular amyloidosis has a predilection for the interscapular area and less frequently the upper arms, chest, and thighs.2 Atypical variants also have been reported, including amyloidosis cutis dyschromica, poikilodermalike amyloidosis, and bullous amyloidosis, as well as incontinentia pigmenti–like, linear, and nevoid types.3 Macular amyloidosis has been reported to occur in association with progressive systemic sclerosis, primary biliary cirrhosis, systemic lupus erythematosus, paronychia, and multiple endocrine neoplasia type 2.2
Acanthosis nigricans typically presents on the neck and intertriginous areas as velvety hyperpigmented plaques. Confluent and reticulated papillomatosis also appears as slightly elevated papules; however, it occurs in the intermammary region in a reticulated pattern. Ichthyosis vulgaris also may occur on the lower extremities but presents with adherent large scales rather than papules. Keratosis pilaris may present on the proximal lower extremities with smaller, folliculocentric, fleshcolored to pink papules.
Treatment of cutaneous amyloidosis has long been challenging for dermatologists. The primary focus should be treatment of any underlying disease that is causing the pruritus and subsequent manipulation of skin lesions. Topical calcipotriol, phototherapy, oral cyclophosphamide, and Nd:YAG laser have demonstrated beneficial outcomes. IL-31 antibodies may be a potential future treatment.1
The Diagnosis: Cutaneous Amyloidosis
A punch biopsy confirmed the diagnosis of cutaneous amyloidosis, which is characterized by the deposition of amyloid proteins in the skin without systemic involvement. Subtypes of cutaneous amyloidosis include lichenoid, macular, and nodular amyloidosis. A mixed or biphasic amyloidosis can occur when both lichenoid and macular lesions are present.1 Lichenoid and macular amyloidosis generally are characterized by moderate to severe pruritus. Lichenoid amyloidosis favors the shins, calves, ankles, and extensor extremities; macular amyloidosis has a predilection for the interscapular area and less frequently the upper arms, chest, and thighs.2 Atypical variants also have been reported, including amyloidosis cutis dyschromica, poikilodermalike amyloidosis, and bullous amyloidosis, as well as incontinentia pigmenti–like, linear, and nevoid types.3 Macular amyloidosis has been reported to occur in association with progressive systemic sclerosis, primary biliary cirrhosis, systemic lupus erythematosus, paronychia, and multiple endocrine neoplasia type 2.2
Acanthosis nigricans typically presents on the neck and intertriginous areas as velvety hyperpigmented plaques. Confluent and reticulated papillomatosis also appears as slightly elevated papules; however, it occurs in the intermammary region in a reticulated pattern. Ichthyosis vulgaris also may occur on the lower extremities but presents with adherent large scales rather than papules. Keratosis pilaris may present on the proximal lower extremities with smaller, folliculocentric, fleshcolored to pink papules.
Treatment of cutaneous amyloidosis has long been challenging for dermatologists. The primary focus should be treatment of any underlying disease that is causing the pruritus and subsequent manipulation of skin lesions. Topical calcipotriol, phototherapy, oral cyclophosphamide, and Nd:YAG laser have demonstrated beneficial outcomes. IL-31 antibodies may be a potential future treatment.1
1. Weidner T, Illing T, Elsner P. Primary localized cutaneous amyloidosis: a systematic treatment review. Am J Clin Dermatol. 2017;18:629-642. doi:10.1007/s40257-017-0278-9 2. Rasi A, Khatami A, Javaheri SM. Macular amyloidosis: an assessment of prevalence, sex, and age. Int J Dermatol. 2004;43:898-899. doi:10.1111 /j.1365-4632.2004.01935.x 3. Hamie L, Haddad I, Nasser N, et al. Primary localized cutaneous amyloidosis of keratinocyte origin: an update with emphasis on atypical clinical variants [published online July 21, 2021]. 2021;22:667-680. Am J Clin Dermatol. doi:10.1007/s40257-021-00620-9
1. Weidner T, Illing T, Elsner P. Primary localized cutaneous amyloidosis: a systematic treatment review. Am J Clin Dermatol. 2017;18:629-642. doi:10.1007/s40257-017-0278-9 2. Rasi A, Khatami A, Javaheri SM. Macular amyloidosis: an assessment of prevalence, sex, and age. Int J Dermatol. 2004;43:898-899. doi:10.1111 /j.1365-4632.2004.01935.x 3. Hamie L, Haddad I, Nasser N, et al. Primary localized cutaneous amyloidosis of keratinocyte origin: an update with emphasis on atypical clinical variants [published online July 21, 2021]. 2021;22:667-680. Am J Clin Dermatol. doi:10.1007/s40257-021-00620-9
A 34-year-old woman presented to our dermatology clinic with an intensely pruritic rash on the legs of 2 years’ duration. The pruritus had waxed and waned in intensity, and the skin lesions were refractory to treatment with low-potency topical steroids. She had no other chronic medical conditions and was not taking any other medications.
‘Extremely exciting’ study results guide MM treatment options
CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.
Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.
However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.
In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.
The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.
“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.
Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.
“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
Study details
In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.
At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.
The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).
The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.
“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.
Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.
“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.
When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).
However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.
“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”
He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.
“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
Lack of difference in overall survival
These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.
“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.”
Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.
The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.”
Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.
Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.
However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.
In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.
The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.
“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.
Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.
“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
Study details
In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.
At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.
The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).
The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.
“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.
Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.
“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.
When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).
However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.
“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”
He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.
“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
Lack of difference in overall survival
These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.
“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.”
Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.
The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.”
Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.
Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.
However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.
In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.
The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.
“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.
Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.
“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
Study details
In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.
At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.
The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).
The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.
“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.
Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.
“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.
When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).
However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.
“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”
He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.
“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
Lack of difference in overall survival
These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.
“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.”
Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.
The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.”
Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ASCO 2022