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It is time to separate the O from the G
Two very different specialties, obstetrics (O) and gynecology (G), were fused into one in 1889. It is difficult to conceive that, with the expansion of both specialties in knowledge, procedures, and subspecialties, they still remain as one after 130 years. The American College of Obstetricians and Gynecologists was founded in 1952, and after 68 years no major changes have been made to accept or incorporate that there is a need to consider O and G as two different specialties.
Obstetrics and gynecology are the only specialties dedicated exclusively to women but with a very different purpose: the O is for reproduction, the G is for prevention and management of genital diseases. The specialties of O and G are so different the only thing in common is the patient.
It is time to separate the O from the G.
Are we training surgically competent residents?
No, we are not. There is an adequate volume for training and practice in O with close to 3.8 million births a year (the number cited by the Centers for Disease Control and Prevention in 2018). Not surprisingly, there is a need for trainees and also for practitioners in rural areas. As a result, the surgical training and practice in G is not optimal. If the number of hysterectomies was even near that of deliveries, there would be an adequate volume for everyone in training and in practice. But this is not the case.
The Accreditation Council for Graduate Medical Education (ACGME) mandates OG residents to graduate with a minimum of 70 minimally invasive hysterectomies (MIH), including laparoscopic (LH), vaginal (VH), and laparoscopic vaginally assisted (LAVH). In 2017, 51% of graduating residents fell below the minimum of 70 MIH.1 Because the learning curve of LH ranges from 30 to 80 cases,2 it is not surprising most residents feel surgically inadequate at graduation to function independently.
Increased procedures and technologies with reduced training hours
Let’s look at hysterectomies. From two techniques, vaginal and abdominal, they have expanded to LH, LAVH, robotic, single-site LH, single-site robotic, and recently single-port robotic. In addition, different and new technologies for hysteroscopy and myomectomy procedures have been developed.
All these operations are supposed to be part of any training program as ACGME demands “OG residents must be able to competently perform all medical, diagnostic, and surgical procedures considered essential for the area of practice.”3 In addition, primary care has been added to OG residency training: “Primary health care management from adolescence through reproductive age to midlife and beyond is integral to any ob.gyn.’s practice” and “Obstetrician-gynecologists are viewed by some entities as being primary care physicians for women, especially as coordinators of care among most reproductive-aged women,” according to ACOG.4
All this with reduced training hours.
The number of training hours a week has been reduced to 80, while it used to be over 100 hours. If you do the math, 20 fewer hours a week for 4 years amounts to 4,240 hours, equivalent to 180 days, equal to 6 months.
Graduating residents must pass a written and an oral exam for certification and with this are approved to enter the operating room and operate on women without a surgical skills test.
A simple test shows that elimination of the O for 1 year improves laparoscopic performance
We compared the time to perform three basic laparoscopic skills by fourth-year OG residents with that of fellows at the end of their first year in a minimally invasive G fellowship.5 The mean time for the residents completing the three tasks within the allotted time was 16 minutes, compared with 3.5 minutes for fellows: a four times faster performance.
Are there enough patients to maintain surgical skills after residency?
No, there are not.
Consider the following reality after residency. Decreasing number of surgeries and increasing numbers of OGs results in what you have already guessed: a lower surgical volume per OG.
Since 1979, the number of G surgeries has decreased by almost half (46%) while the number of OGs has doubled (54%) resulting in an 81% decrease of number of surgeries per OG, from 132 in 1979 to 25 in 2007.6 For hysterectomies, there has been a continuous yearly decline per G from 28 in 1980 to 9.8 in 2007 and to 8.5 in 2010.7,8
Would any mother feel comfortable having an obstetrician for her pregnancy and delivery performing only 8.5 deliveries a year?
Where do we go from here?
Separate the training and practice of O and G, an initiative already started in some residency programs and in some institutions in the United States. The O and the G both include a medical and a surgical practice.
We need to start accepting there is a need for different practices: medical O, medical G, surgical O, and surgical G. It is not new, it is already happening, it is the case in our institution since inception, and it is expanding across the country because it is needed. Graduating residents recognize this need as noticed by the increasing number seeking subspecialty training, from 7% in 2000 to 19.5% in 2012.4
Will this require some patients to drive away from home to obtain the best possible care? Yes. It is not a new concept, and it already is occurring for patients traveling to specialized centers away from home for certain conditions. In some countries, the practice is restricted to only a few centers. In Sweden, for instance, patients diagnosed with gynecologic cancer must travel to one of only seven centers subspecialized in gynecologic malignancies.
Conclusion
We need to start someday. We already are late after 130 years. We need to provide optimal care for women. They are our mothers. They deserve it. Let the O deliver O care, let the G provide G care, and we will reap improved results.
Dr. Magrina is with the department of medical and surgical gynecology at the Mayo Clinic in Phoenix. The author has no conflict of interest or financial involvement with this manuscript.
References
1. Am J Obstet Gynecol. 2019 Nov 22. doi: 10.1016/j.ajog.2019.11.1258.
2. Clin Obstet Gynecol. 2011 Sep;54(3):376-81.
3. Accreditation Council for Graduate Medical Education. Program requirements for GME in Obstetrics and Gynecology 2017.
4. “The obstetrician-gynecologist workforce in the United States: Facts, figures, and implications, 2017” (Washington, D.C.: ACOG, 2017).
5. J Minim Invasive Gynecol. 2008 Jul-Aug;15(4):410-3.
6. J Minim Invasive Gynecol. 2014 Jul-Aug;21(4):501-3.
7. National Health Statistics Report. Hysterectomy in the U.S. and oophorectomy 1979-2007. http://www.cdc.gov/nchs/products/nhsr.htm.
8. The Healthcare Cost and Utilization Project – Nationwide Inpatient Sample: Agency for Health Care Research Quality. 2013.
Two very different specialties, obstetrics (O) and gynecology (G), were fused into one in 1889. It is difficult to conceive that, with the expansion of both specialties in knowledge, procedures, and subspecialties, they still remain as one after 130 years. The American College of Obstetricians and Gynecologists was founded in 1952, and after 68 years no major changes have been made to accept or incorporate that there is a need to consider O and G as two different specialties.
Obstetrics and gynecology are the only specialties dedicated exclusively to women but with a very different purpose: the O is for reproduction, the G is for prevention and management of genital diseases. The specialties of O and G are so different the only thing in common is the patient.
It is time to separate the O from the G.
Are we training surgically competent residents?
No, we are not. There is an adequate volume for training and practice in O with close to 3.8 million births a year (the number cited by the Centers for Disease Control and Prevention in 2018). Not surprisingly, there is a need for trainees and also for practitioners in rural areas. As a result, the surgical training and practice in G is not optimal. If the number of hysterectomies was even near that of deliveries, there would be an adequate volume for everyone in training and in practice. But this is not the case.
The Accreditation Council for Graduate Medical Education (ACGME) mandates OG residents to graduate with a minimum of 70 minimally invasive hysterectomies (MIH), including laparoscopic (LH), vaginal (VH), and laparoscopic vaginally assisted (LAVH). In 2017, 51% of graduating residents fell below the minimum of 70 MIH.1 Because the learning curve of LH ranges from 30 to 80 cases,2 it is not surprising most residents feel surgically inadequate at graduation to function independently.
Increased procedures and technologies with reduced training hours
Let’s look at hysterectomies. From two techniques, vaginal and abdominal, they have expanded to LH, LAVH, robotic, single-site LH, single-site robotic, and recently single-port robotic. In addition, different and new technologies for hysteroscopy and myomectomy procedures have been developed.
All these operations are supposed to be part of any training program as ACGME demands “OG residents must be able to competently perform all medical, diagnostic, and surgical procedures considered essential for the area of practice.”3 In addition, primary care has been added to OG residency training: “Primary health care management from adolescence through reproductive age to midlife and beyond is integral to any ob.gyn.’s practice” and “Obstetrician-gynecologists are viewed by some entities as being primary care physicians for women, especially as coordinators of care among most reproductive-aged women,” according to ACOG.4
All this with reduced training hours.
The number of training hours a week has been reduced to 80, while it used to be over 100 hours. If you do the math, 20 fewer hours a week for 4 years amounts to 4,240 hours, equivalent to 180 days, equal to 6 months.
Graduating residents must pass a written and an oral exam for certification and with this are approved to enter the operating room and operate on women without a surgical skills test.
A simple test shows that elimination of the O for 1 year improves laparoscopic performance
We compared the time to perform three basic laparoscopic skills by fourth-year OG residents with that of fellows at the end of their first year in a minimally invasive G fellowship.5 The mean time for the residents completing the three tasks within the allotted time was 16 minutes, compared with 3.5 minutes for fellows: a four times faster performance.
Are there enough patients to maintain surgical skills after residency?
No, there are not.
Consider the following reality after residency. Decreasing number of surgeries and increasing numbers of OGs results in what you have already guessed: a lower surgical volume per OG.
Since 1979, the number of G surgeries has decreased by almost half (46%) while the number of OGs has doubled (54%) resulting in an 81% decrease of number of surgeries per OG, from 132 in 1979 to 25 in 2007.6 For hysterectomies, there has been a continuous yearly decline per G from 28 in 1980 to 9.8 in 2007 and to 8.5 in 2010.7,8
Would any mother feel comfortable having an obstetrician for her pregnancy and delivery performing only 8.5 deliveries a year?
Where do we go from here?
Separate the training and practice of O and G, an initiative already started in some residency programs and in some institutions in the United States. The O and the G both include a medical and a surgical practice.
We need to start accepting there is a need for different practices: medical O, medical G, surgical O, and surgical G. It is not new, it is already happening, it is the case in our institution since inception, and it is expanding across the country because it is needed. Graduating residents recognize this need as noticed by the increasing number seeking subspecialty training, from 7% in 2000 to 19.5% in 2012.4
Will this require some patients to drive away from home to obtain the best possible care? Yes. It is not a new concept, and it already is occurring for patients traveling to specialized centers away from home for certain conditions. In some countries, the practice is restricted to only a few centers. In Sweden, for instance, patients diagnosed with gynecologic cancer must travel to one of only seven centers subspecialized in gynecologic malignancies.
Conclusion
We need to start someday. We already are late after 130 years. We need to provide optimal care for women. They are our mothers. They deserve it. Let the O deliver O care, let the G provide G care, and we will reap improved results.
Dr. Magrina is with the department of medical and surgical gynecology at the Mayo Clinic in Phoenix. The author has no conflict of interest or financial involvement with this manuscript.
References
1. Am J Obstet Gynecol. 2019 Nov 22. doi: 10.1016/j.ajog.2019.11.1258.
2. Clin Obstet Gynecol. 2011 Sep;54(3):376-81.
3. Accreditation Council for Graduate Medical Education. Program requirements for GME in Obstetrics and Gynecology 2017.
4. “The obstetrician-gynecologist workforce in the United States: Facts, figures, and implications, 2017” (Washington, D.C.: ACOG, 2017).
5. J Minim Invasive Gynecol. 2008 Jul-Aug;15(4):410-3.
6. J Minim Invasive Gynecol. 2014 Jul-Aug;21(4):501-3.
7. National Health Statistics Report. Hysterectomy in the U.S. and oophorectomy 1979-2007. http://www.cdc.gov/nchs/products/nhsr.htm.
8. The Healthcare Cost and Utilization Project – Nationwide Inpatient Sample: Agency for Health Care Research Quality. 2013.
Two very different specialties, obstetrics (O) and gynecology (G), were fused into one in 1889. It is difficult to conceive that, with the expansion of both specialties in knowledge, procedures, and subspecialties, they still remain as one after 130 years. The American College of Obstetricians and Gynecologists was founded in 1952, and after 68 years no major changes have been made to accept or incorporate that there is a need to consider O and G as two different specialties.
Obstetrics and gynecology are the only specialties dedicated exclusively to women but with a very different purpose: the O is for reproduction, the G is for prevention and management of genital diseases. The specialties of O and G are so different the only thing in common is the patient.
It is time to separate the O from the G.
Are we training surgically competent residents?
No, we are not. There is an adequate volume for training and practice in O with close to 3.8 million births a year (the number cited by the Centers for Disease Control and Prevention in 2018). Not surprisingly, there is a need for trainees and also for practitioners in rural areas. As a result, the surgical training and practice in G is not optimal. If the number of hysterectomies was even near that of deliveries, there would be an adequate volume for everyone in training and in practice. But this is not the case.
The Accreditation Council for Graduate Medical Education (ACGME) mandates OG residents to graduate with a minimum of 70 minimally invasive hysterectomies (MIH), including laparoscopic (LH), vaginal (VH), and laparoscopic vaginally assisted (LAVH). In 2017, 51% of graduating residents fell below the minimum of 70 MIH.1 Because the learning curve of LH ranges from 30 to 80 cases,2 it is not surprising most residents feel surgically inadequate at graduation to function independently.
Increased procedures and technologies with reduced training hours
Let’s look at hysterectomies. From two techniques, vaginal and abdominal, they have expanded to LH, LAVH, robotic, single-site LH, single-site robotic, and recently single-port robotic. In addition, different and new technologies for hysteroscopy and myomectomy procedures have been developed.
All these operations are supposed to be part of any training program as ACGME demands “OG residents must be able to competently perform all medical, diagnostic, and surgical procedures considered essential for the area of practice.”3 In addition, primary care has been added to OG residency training: “Primary health care management from adolescence through reproductive age to midlife and beyond is integral to any ob.gyn.’s practice” and “Obstetrician-gynecologists are viewed by some entities as being primary care physicians for women, especially as coordinators of care among most reproductive-aged women,” according to ACOG.4
All this with reduced training hours.
The number of training hours a week has been reduced to 80, while it used to be over 100 hours. If you do the math, 20 fewer hours a week for 4 years amounts to 4,240 hours, equivalent to 180 days, equal to 6 months.
Graduating residents must pass a written and an oral exam for certification and with this are approved to enter the operating room and operate on women without a surgical skills test.
A simple test shows that elimination of the O for 1 year improves laparoscopic performance
We compared the time to perform three basic laparoscopic skills by fourth-year OG residents with that of fellows at the end of their first year in a minimally invasive G fellowship.5 The mean time for the residents completing the three tasks within the allotted time was 16 minutes, compared with 3.5 minutes for fellows: a four times faster performance.
Are there enough patients to maintain surgical skills after residency?
No, there are not.
Consider the following reality after residency. Decreasing number of surgeries and increasing numbers of OGs results in what you have already guessed: a lower surgical volume per OG.
Since 1979, the number of G surgeries has decreased by almost half (46%) while the number of OGs has doubled (54%) resulting in an 81% decrease of number of surgeries per OG, from 132 in 1979 to 25 in 2007.6 For hysterectomies, there has been a continuous yearly decline per G from 28 in 1980 to 9.8 in 2007 and to 8.5 in 2010.7,8
Would any mother feel comfortable having an obstetrician for her pregnancy and delivery performing only 8.5 deliveries a year?
Where do we go from here?
Separate the training and practice of O and G, an initiative already started in some residency programs and in some institutions in the United States. The O and the G both include a medical and a surgical practice.
We need to start accepting there is a need for different practices: medical O, medical G, surgical O, and surgical G. It is not new, it is already happening, it is the case in our institution since inception, and it is expanding across the country because it is needed. Graduating residents recognize this need as noticed by the increasing number seeking subspecialty training, from 7% in 2000 to 19.5% in 2012.4
Will this require some patients to drive away from home to obtain the best possible care? Yes. It is not a new concept, and it already is occurring for patients traveling to specialized centers away from home for certain conditions. In some countries, the practice is restricted to only a few centers. In Sweden, for instance, patients diagnosed with gynecologic cancer must travel to one of only seven centers subspecialized in gynecologic malignancies.
Conclusion
We need to start someday. We already are late after 130 years. We need to provide optimal care for women. They are our mothers. They deserve it. Let the O deliver O care, let the G provide G care, and we will reap improved results.
Dr. Magrina is with the department of medical and surgical gynecology at the Mayo Clinic in Phoenix. The author has no conflict of interest or financial involvement with this manuscript.
References
1. Am J Obstet Gynecol. 2019 Nov 22. doi: 10.1016/j.ajog.2019.11.1258.
2. Clin Obstet Gynecol. 2011 Sep;54(3):376-81.
3. Accreditation Council for Graduate Medical Education. Program requirements for GME in Obstetrics and Gynecology 2017.
4. “The obstetrician-gynecologist workforce in the United States: Facts, figures, and implications, 2017” (Washington, D.C.: ACOG, 2017).
5. J Minim Invasive Gynecol. 2008 Jul-Aug;15(4):410-3.
6. J Minim Invasive Gynecol. 2014 Jul-Aug;21(4):501-3.
7. National Health Statistics Report. Hysterectomy in the U.S. and oophorectomy 1979-2007. http://www.cdc.gov/nchs/products/nhsr.htm.
8. The Healthcare Cost and Utilization Project – Nationwide Inpatient Sample: Agency for Health Care Research Quality. 2013.
A bladder brewery and a neurosurgical violin solo
One bikram, one shakti, one beer
Novelty yoga is a thing, and there’s no stopping it now.
There’s cat yoga, aerial yoga (performed in a harness or hammock suspended above the ground), karaoke yoga, laughter yoga (done while listening to the LOTME podcast, no doubt), snake yoga, toega (yoga for toes), and, of course, goat yoga. So what’s next, beer yoga?
Why, yes, it is beer yoga.
In our travels around the dark, deserted corners of the Internet, we came across an article on Educatedbox.com that said a beer yoga class “involves picking up a beer, drinking it, and putting it back down again, in many different ways.”
Pretty straightforward. Then we saw a photo on Germany’s Bieryoga.de that showed all of the participants doing the tree pose while balancing a beer bottle on their heads. Not so straightforward. Trust us, we tried.
Bieryoga explains that “the exuberance that comes with drinking beer and the body awareness of yoga can be combined into an energizing experience. In the beer and now.”
How can we say no to “in the beer and now”? Well, we can’t, but we do have one teeny tiny problem: We’ve gotten into “downward-facing dog with IPA on rump,” and now we can’t get up.
Little help … anyone?
A surgical symphony
A patient playing the violin during her own brain surgery? That sounds way more interesting than paying hundreds of dollars to attend any old normal concert.
Violinist Dagmar Turner found out in 2013 that she had a brain tumor that was gradually advancing in size. After learning the tumor needed to be removed, Ms. Turner worried she might lose her talents if the parts of her brain crucial to playing the violin were destroyed.
Luckily, her well-orchestrated surgical team composed a plan to ensure they spared the vital parts of the brain used when playing the violin: They would wake their patient during brain surgery and have her play her violin. Yes, you read that right – she played the violin during surgery to help her surgeons make certain there was no damage to the violin-related areas of her brain.
Personally, we here at the profit-minded Bureau of LOTME believe the surgical team missed a perfect opportunity to sell tickets to this event. Ms. Turner successfully made it through the surgery both 90% tumor free and fully able to play her violin. We love a happy ending! Bravo! Though maybe not “Encore!”
Belly up to the bar, boys
Quick, what would be the worst superpower? No doubt your head is flooding with ideas, each more comical than the last. But did you think of “able to pee beer?”
That’s right, it’s the return of an old LOTME favorite – auto-brewery syndrome. But this time, there’s a twist.
Our daring hero in today’s exciting case report from Annals of Internal Medicine is a 61-year-old woman from Pittsburgh who presented with liver damage and poorly controlled diabetes, and who sought placement on the liver transplant list.
But hang on, the woman’s history seemed to indicate her liver problems stemmed from alcohol addiction, because her urine tests were always positive for alcohol, and the current tests said the same. Hmm, this is sounding slightly villainous!
There were, however, some discrepancies. The woman didn’t appear to be intoxicated during clinic visits, tests for ethanol metabolites were negative while urine tests for ethanol were positive, and there were large quantities of glucose and budding yeast in the urine. Something strange was going on, so the doctors decided to dig deeper.
The yeast in question was Candida glabrata, which is closely related to brewer’s yeast. The doctors found high levels of ethanol production in the urine, suggesting that the yeast was fermenting sugar inside the bladder. The patient was quite literally urinating alcohol, becoming the first documented case in a living person of what the doctors dubbed “urinary auto-brewery syndrome.”
As much as we love a good drink here at LOTME world headquarters, we’ll have to pass on the urine cocktail. Just don’t tell all the beer yoga enthusiasts, this seems right up their alley. You know, positive natural energy flow or something like that.
One bikram, one shakti, one beer
Novelty yoga is a thing, and there’s no stopping it now.
There’s cat yoga, aerial yoga (performed in a harness or hammock suspended above the ground), karaoke yoga, laughter yoga (done while listening to the LOTME podcast, no doubt), snake yoga, toega (yoga for toes), and, of course, goat yoga. So what’s next, beer yoga?
Why, yes, it is beer yoga.
In our travels around the dark, deserted corners of the Internet, we came across an article on Educatedbox.com that said a beer yoga class “involves picking up a beer, drinking it, and putting it back down again, in many different ways.”
Pretty straightforward. Then we saw a photo on Germany’s Bieryoga.de that showed all of the participants doing the tree pose while balancing a beer bottle on their heads. Not so straightforward. Trust us, we tried.
Bieryoga explains that “the exuberance that comes with drinking beer and the body awareness of yoga can be combined into an energizing experience. In the beer and now.”
How can we say no to “in the beer and now”? Well, we can’t, but we do have one teeny tiny problem: We’ve gotten into “downward-facing dog with IPA on rump,” and now we can’t get up.
Little help … anyone?
A surgical symphony
A patient playing the violin during her own brain surgery? That sounds way more interesting than paying hundreds of dollars to attend any old normal concert.
Violinist Dagmar Turner found out in 2013 that she had a brain tumor that was gradually advancing in size. After learning the tumor needed to be removed, Ms. Turner worried she might lose her talents if the parts of her brain crucial to playing the violin were destroyed.
Luckily, her well-orchestrated surgical team composed a plan to ensure they spared the vital parts of the brain used when playing the violin: They would wake their patient during brain surgery and have her play her violin. Yes, you read that right – she played the violin during surgery to help her surgeons make certain there was no damage to the violin-related areas of her brain.
Personally, we here at the profit-minded Bureau of LOTME believe the surgical team missed a perfect opportunity to sell tickets to this event. Ms. Turner successfully made it through the surgery both 90% tumor free and fully able to play her violin. We love a happy ending! Bravo! Though maybe not “Encore!”
Belly up to the bar, boys
Quick, what would be the worst superpower? No doubt your head is flooding with ideas, each more comical than the last. But did you think of “able to pee beer?”
That’s right, it’s the return of an old LOTME favorite – auto-brewery syndrome. But this time, there’s a twist.
Our daring hero in today’s exciting case report from Annals of Internal Medicine is a 61-year-old woman from Pittsburgh who presented with liver damage and poorly controlled diabetes, and who sought placement on the liver transplant list.
But hang on, the woman’s history seemed to indicate her liver problems stemmed from alcohol addiction, because her urine tests were always positive for alcohol, and the current tests said the same. Hmm, this is sounding slightly villainous!
There were, however, some discrepancies. The woman didn’t appear to be intoxicated during clinic visits, tests for ethanol metabolites were negative while urine tests for ethanol were positive, and there were large quantities of glucose and budding yeast in the urine. Something strange was going on, so the doctors decided to dig deeper.
The yeast in question was Candida glabrata, which is closely related to brewer’s yeast. The doctors found high levels of ethanol production in the urine, suggesting that the yeast was fermenting sugar inside the bladder. The patient was quite literally urinating alcohol, becoming the first documented case in a living person of what the doctors dubbed “urinary auto-brewery syndrome.”
As much as we love a good drink here at LOTME world headquarters, we’ll have to pass on the urine cocktail. Just don’t tell all the beer yoga enthusiasts, this seems right up their alley. You know, positive natural energy flow or something like that.
One bikram, one shakti, one beer
Novelty yoga is a thing, and there’s no stopping it now.
There’s cat yoga, aerial yoga (performed in a harness or hammock suspended above the ground), karaoke yoga, laughter yoga (done while listening to the LOTME podcast, no doubt), snake yoga, toega (yoga for toes), and, of course, goat yoga. So what’s next, beer yoga?
Why, yes, it is beer yoga.
In our travels around the dark, deserted corners of the Internet, we came across an article on Educatedbox.com that said a beer yoga class “involves picking up a beer, drinking it, and putting it back down again, in many different ways.”
Pretty straightforward. Then we saw a photo on Germany’s Bieryoga.de that showed all of the participants doing the tree pose while balancing a beer bottle on their heads. Not so straightforward. Trust us, we tried.
Bieryoga explains that “the exuberance that comes with drinking beer and the body awareness of yoga can be combined into an energizing experience. In the beer and now.”
How can we say no to “in the beer and now”? Well, we can’t, but we do have one teeny tiny problem: We’ve gotten into “downward-facing dog with IPA on rump,” and now we can’t get up.
Little help … anyone?
A surgical symphony
A patient playing the violin during her own brain surgery? That sounds way more interesting than paying hundreds of dollars to attend any old normal concert.
Violinist Dagmar Turner found out in 2013 that she had a brain tumor that was gradually advancing in size. After learning the tumor needed to be removed, Ms. Turner worried she might lose her talents if the parts of her brain crucial to playing the violin were destroyed.
Luckily, her well-orchestrated surgical team composed a plan to ensure they spared the vital parts of the brain used when playing the violin: They would wake their patient during brain surgery and have her play her violin. Yes, you read that right – she played the violin during surgery to help her surgeons make certain there was no damage to the violin-related areas of her brain.
Personally, we here at the profit-minded Bureau of LOTME believe the surgical team missed a perfect opportunity to sell tickets to this event. Ms. Turner successfully made it through the surgery both 90% tumor free and fully able to play her violin. We love a happy ending! Bravo! Though maybe not “Encore!”
Belly up to the bar, boys
Quick, what would be the worst superpower? No doubt your head is flooding with ideas, each more comical than the last. But did you think of “able to pee beer?”
That’s right, it’s the return of an old LOTME favorite – auto-brewery syndrome. But this time, there’s a twist.
Our daring hero in today’s exciting case report from Annals of Internal Medicine is a 61-year-old woman from Pittsburgh who presented with liver damage and poorly controlled diabetes, and who sought placement on the liver transplant list.
But hang on, the woman’s history seemed to indicate her liver problems stemmed from alcohol addiction, because her urine tests were always positive for alcohol, and the current tests said the same. Hmm, this is sounding slightly villainous!
There were, however, some discrepancies. The woman didn’t appear to be intoxicated during clinic visits, tests for ethanol metabolites were negative while urine tests for ethanol were positive, and there were large quantities of glucose and budding yeast in the urine. Something strange was going on, so the doctors decided to dig deeper.
The yeast in question was Candida glabrata, which is closely related to brewer’s yeast. The doctors found high levels of ethanol production in the urine, suggesting that the yeast was fermenting sugar inside the bladder. The patient was quite literally urinating alcohol, becoming the first documented case in a living person of what the doctors dubbed “urinary auto-brewery syndrome.”
As much as we love a good drink here at LOTME world headquarters, we’ll have to pass on the urine cocktail. Just don’t tell all the beer yoga enthusiasts, this seems right up their alley. You know, positive natural energy flow or something like that.
Rising number of young people dying after heavy drinking
MAUI, HAWAII – Alcohol use and deaths related to alcohol-use disorders are increasing, and young adults might be the group to watch, said Norah Terrault, MD, MPH, professor at the Keck School of Medicine of USC in Los Angeles.
“A lot of young people are drinking large amounts and they don’t know they’re at risk. They may not drink much during the week but then drink 30 drinks on the weekend,” Dr. Terrault told Medscape Medical News.
The largest relative increase in deaths from alcoholic cirrhosis – 10.5% from 2009 to 2016 – was in the 25- to 34-year age group, she reported here at the Gastroenterology Updates IBD Liver Disease Conference 2020.
This highlights the importance of asking for details about alcohol use during primary care visits; not only how much, but also what time of day, for instance, she explained.
Dr. Terrault’s team at Keck is part of the ACCELERATE-AH consortium, a group of 12 transplant centers looking at patterns of alcohol use before and after liver transplantation.
In their retrospective study of 147 consecutive transplant patients from 2006 to 2018, they found that young age, a history of multiple rehab attempts, and overt encephalopathy at time of transplantation were predictors of alcohol use after the procedure.
Corticosteroids remain the only proven therapy for alcoholic hepatitis. “We have not seen a new therapy in this arena in decades,” said Dr. Terrault. “We really have nothing to offer these patients, yet it’s an incredibly common presentation with a high mortality.”
More treatment options
The good news is that some phase 2 data look promising for new therapies, she reported.
“Some of them are targeting injury and regeneration primarily. Others are looking at the anti-inflammatory and antifibrotic effects. Some are also looking at how gut permeability and the microbiome are influencing outcomes,” she explained.
Transplantation has become very important for patients who do not respond to current therapy, and selection criteria have evolved over the years to take this into account, she pointed out.
In the early 1980s, alcoholic hepatitis was considered an inappropriate indication for liver transplantation. In the early 2000s, the guidance moved to setting 6 months of alcohol abstinence as a criterion for transplantation. The 6-month rule effectively eliminated patients with severe alcoholic hepatitis, who, by the time they needed a new liver, would not have 6 months to live.
Recently, guidelines have added the option of transplantation for patients with alcoholic hepatitis. The option was always there for people who developed alcohol cirrhosis or liver cancer, but now alcoholic hepatitis is recognized as a potential indication for transplantation, Dr. Terrault explained.
Today, transplant centers are moving away from the 6-month rule for two main reasons, she said. One is that few data support the 6-month time period as the duration that makes a difference.
“There is nothing magical about 6 months vs. 3 months or 12 months,” she said, adding that studies have shown that other factors might be better indicators, such as family support and whether the person is employed.
Second, recent studies have shown that rates of 3-year survival are similar in people who did not abstain at all before the procedure and those who undergo transplantation for other reasons.
The ACCELERATE-AH consortium also found that 70% of patients with severe alcoholic hepatitis remained abstinent up to 3 years after transplantation.
Anytime we give an organ to anyone on the list, someone else may die without one. Every year, 20% of patients on the list die without a transplant.
The selection process remains complicated and controversial, Dr. Terrault acknowledged.
“Anytime we give an organ to anyone on the list, someone else may die without one. Every year, 20% of patients on the list die without a transplant,” she said.
And there is concern that because patients with severe alcoholic hepatitis present with severe illness, they get moved to the top of the wait list. The rationale for that, she explained, is that it is done that way in other acute situations.
“We transplant individuals who have an acetaminophen overdose, for example. That’s common in many programs,” she said.
“My issue is that some patients with acute alcoholic hepatitis that have a very high severity score, but some of them, just with abstinence, will get better,” said Guadalupe Garcia-Tsao, MD, professor of medicine at Yale University in New Haven, Conn.
There are cases in which acute alcoholic hepatitis will resolve with abstinence, “and patients can return to an entirely compensated state of cirrhosis, in which they are entirely asymptomatic and they can live,” she told Medscape Medical News.
But it’s hard to know without a control group which patients would have that kind of success with just abstinence, she acknowledged.
Terrault said she agreed, and added that “our tools are not that good,” so determining which patients can be “pulled back from the brink” without transplantation is a challenge.
“There’s still a lot to learn about how we do this, and how we do it well,” she said.
Alcoholic hepatitis as an indication for liver transplantation is rare – less than 1% – but growing.
“This is a potential therapy for your patient who is sick in the ICU with a high severity of disease who has failed steroids. We should call out to see if there’s a transplant program that might be willing to evaluate them,” she said.
This article first appeared on Medscape.com.
MAUI, HAWAII – Alcohol use and deaths related to alcohol-use disorders are increasing, and young adults might be the group to watch, said Norah Terrault, MD, MPH, professor at the Keck School of Medicine of USC in Los Angeles.
“A lot of young people are drinking large amounts and they don’t know they’re at risk. They may not drink much during the week but then drink 30 drinks on the weekend,” Dr. Terrault told Medscape Medical News.
The largest relative increase in deaths from alcoholic cirrhosis – 10.5% from 2009 to 2016 – was in the 25- to 34-year age group, she reported here at the Gastroenterology Updates IBD Liver Disease Conference 2020.
This highlights the importance of asking for details about alcohol use during primary care visits; not only how much, but also what time of day, for instance, she explained.
Dr. Terrault’s team at Keck is part of the ACCELERATE-AH consortium, a group of 12 transplant centers looking at patterns of alcohol use before and after liver transplantation.
In their retrospective study of 147 consecutive transplant patients from 2006 to 2018, they found that young age, a history of multiple rehab attempts, and overt encephalopathy at time of transplantation were predictors of alcohol use after the procedure.
Corticosteroids remain the only proven therapy for alcoholic hepatitis. “We have not seen a new therapy in this arena in decades,” said Dr. Terrault. “We really have nothing to offer these patients, yet it’s an incredibly common presentation with a high mortality.”
More treatment options
The good news is that some phase 2 data look promising for new therapies, she reported.
“Some of them are targeting injury and regeneration primarily. Others are looking at the anti-inflammatory and antifibrotic effects. Some are also looking at how gut permeability and the microbiome are influencing outcomes,” she explained.
Transplantation has become very important for patients who do not respond to current therapy, and selection criteria have evolved over the years to take this into account, she pointed out.
In the early 1980s, alcoholic hepatitis was considered an inappropriate indication for liver transplantation. In the early 2000s, the guidance moved to setting 6 months of alcohol abstinence as a criterion for transplantation. The 6-month rule effectively eliminated patients with severe alcoholic hepatitis, who, by the time they needed a new liver, would not have 6 months to live.
Recently, guidelines have added the option of transplantation for patients with alcoholic hepatitis. The option was always there for people who developed alcohol cirrhosis or liver cancer, but now alcoholic hepatitis is recognized as a potential indication for transplantation, Dr. Terrault explained.
Today, transplant centers are moving away from the 6-month rule for two main reasons, she said. One is that few data support the 6-month time period as the duration that makes a difference.
“There is nothing magical about 6 months vs. 3 months or 12 months,” she said, adding that studies have shown that other factors might be better indicators, such as family support and whether the person is employed.
Second, recent studies have shown that rates of 3-year survival are similar in people who did not abstain at all before the procedure and those who undergo transplantation for other reasons.
The ACCELERATE-AH consortium also found that 70% of patients with severe alcoholic hepatitis remained abstinent up to 3 years after transplantation.
Anytime we give an organ to anyone on the list, someone else may die without one. Every year, 20% of patients on the list die without a transplant.
The selection process remains complicated and controversial, Dr. Terrault acknowledged.
“Anytime we give an organ to anyone on the list, someone else may die without one. Every year, 20% of patients on the list die without a transplant,” she said.
And there is concern that because patients with severe alcoholic hepatitis present with severe illness, they get moved to the top of the wait list. The rationale for that, she explained, is that it is done that way in other acute situations.
“We transplant individuals who have an acetaminophen overdose, for example. That’s common in many programs,” she said.
“My issue is that some patients with acute alcoholic hepatitis that have a very high severity score, but some of them, just with abstinence, will get better,” said Guadalupe Garcia-Tsao, MD, professor of medicine at Yale University in New Haven, Conn.
There are cases in which acute alcoholic hepatitis will resolve with abstinence, “and patients can return to an entirely compensated state of cirrhosis, in which they are entirely asymptomatic and they can live,” she told Medscape Medical News.
But it’s hard to know without a control group which patients would have that kind of success with just abstinence, she acknowledged.
Terrault said she agreed, and added that “our tools are not that good,” so determining which patients can be “pulled back from the brink” without transplantation is a challenge.
“There’s still a lot to learn about how we do this, and how we do it well,” she said.
Alcoholic hepatitis as an indication for liver transplantation is rare – less than 1% – but growing.
“This is a potential therapy for your patient who is sick in the ICU with a high severity of disease who has failed steroids. We should call out to see if there’s a transplant program that might be willing to evaluate them,” she said.
This article first appeared on Medscape.com.
MAUI, HAWAII – Alcohol use and deaths related to alcohol-use disorders are increasing, and young adults might be the group to watch, said Norah Terrault, MD, MPH, professor at the Keck School of Medicine of USC in Los Angeles.
“A lot of young people are drinking large amounts and they don’t know they’re at risk. They may not drink much during the week but then drink 30 drinks on the weekend,” Dr. Terrault told Medscape Medical News.
The largest relative increase in deaths from alcoholic cirrhosis – 10.5% from 2009 to 2016 – was in the 25- to 34-year age group, she reported here at the Gastroenterology Updates IBD Liver Disease Conference 2020.
This highlights the importance of asking for details about alcohol use during primary care visits; not only how much, but also what time of day, for instance, she explained.
Dr. Terrault’s team at Keck is part of the ACCELERATE-AH consortium, a group of 12 transplant centers looking at patterns of alcohol use before and after liver transplantation.
In their retrospective study of 147 consecutive transplant patients from 2006 to 2018, they found that young age, a history of multiple rehab attempts, and overt encephalopathy at time of transplantation were predictors of alcohol use after the procedure.
Corticosteroids remain the only proven therapy for alcoholic hepatitis. “We have not seen a new therapy in this arena in decades,” said Dr. Terrault. “We really have nothing to offer these patients, yet it’s an incredibly common presentation with a high mortality.”
More treatment options
The good news is that some phase 2 data look promising for new therapies, she reported.
“Some of them are targeting injury and regeneration primarily. Others are looking at the anti-inflammatory and antifibrotic effects. Some are also looking at how gut permeability and the microbiome are influencing outcomes,” she explained.
Transplantation has become very important for patients who do not respond to current therapy, and selection criteria have evolved over the years to take this into account, she pointed out.
In the early 1980s, alcoholic hepatitis was considered an inappropriate indication for liver transplantation. In the early 2000s, the guidance moved to setting 6 months of alcohol abstinence as a criterion for transplantation. The 6-month rule effectively eliminated patients with severe alcoholic hepatitis, who, by the time they needed a new liver, would not have 6 months to live.
Recently, guidelines have added the option of transplantation for patients with alcoholic hepatitis. The option was always there for people who developed alcohol cirrhosis or liver cancer, but now alcoholic hepatitis is recognized as a potential indication for transplantation, Dr. Terrault explained.
Today, transplant centers are moving away from the 6-month rule for two main reasons, she said. One is that few data support the 6-month time period as the duration that makes a difference.
“There is nothing magical about 6 months vs. 3 months or 12 months,” she said, adding that studies have shown that other factors might be better indicators, such as family support and whether the person is employed.
Second, recent studies have shown that rates of 3-year survival are similar in people who did not abstain at all before the procedure and those who undergo transplantation for other reasons.
The ACCELERATE-AH consortium also found that 70% of patients with severe alcoholic hepatitis remained abstinent up to 3 years after transplantation.
Anytime we give an organ to anyone on the list, someone else may die without one. Every year, 20% of patients on the list die without a transplant.
The selection process remains complicated and controversial, Dr. Terrault acknowledged.
“Anytime we give an organ to anyone on the list, someone else may die without one. Every year, 20% of patients on the list die without a transplant,” she said.
And there is concern that because patients with severe alcoholic hepatitis present with severe illness, they get moved to the top of the wait list. The rationale for that, she explained, is that it is done that way in other acute situations.
“We transplant individuals who have an acetaminophen overdose, for example. That’s common in many programs,” she said.
“My issue is that some patients with acute alcoholic hepatitis that have a very high severity score, but some of them, just with abstinence, will get better,” said Guadalupe Garcia-Tsao, MD, professor of medicine at Yale University in New Haven, Conn.
There are cases in which acute alcoholic hepatitis will resolve with abstinence, “and patients can return to an entirely compensated state of cirrhosis, in which they are entirely asymptomatic and they can live,” she told Medscape Medical News.
But it’s hard to know without a control group which patients would have that kind of success with just abstinence, she acknowledged.
Terrault said she agreed, and added that “our tools are not that good,” so determining which patients can be “pulled back from the brink” without transplantation is a challenge.
“There’s still a lot to learn about how we do this, and how we do it well,” she said.
Alcoholic hepatitis as an indication for liver transplantation is rare – less than 1% – but growing.
“This is a potential therapy for your patient who is sick in the ICU with a high severity of disease who has failed steroids. We should call out to see if there’s a transplant program that might be willing to evaluate them,” she said.
This article first appeared on Medscape.com.
EXPERT ANALYSIS FROM GUILD 2020
Secukinumab outperforms adalimumab overall for PsA
MAUI, HAWAII – The interleukin-17A inhibitor secukinumab made a strong showing versus the tumor necrosis factor inhibitor adalimumab for the treatment of psoriatic arthritis in the 52-week, randomized, head-to-head phase 3b EXCEED study, Arthur Kavanaugh, MD, reported at the 2020 Rheumatology Winter Clinical Symposium.
EXCEED was the first double-blind, randomized comparison of an IL-17A inhibitor versus a tumor necrosis factor inhibitor as first-line biologic monotherapy in 853 psoriatic arthritis (PsA) patients with an inadequate response to conventional disease-modifying antirheumatic drugs. And while secukinumab (Cosentyx) narrowly failed to demonstrate superiority over adalimumab (Humira) on the primary endpoint of at least a 20% improvement over baseline on American College of Rheumatology disease criteria at 52 weeks, or ACR20 response, the IL-17A inhibitor demonstrated far greater efficacy for the skin disease, noted Dr. Kavanaugh, a rheumatologist who is professor of medicine at the University of California, San Diego, and RWCS program director. Patients received standard dosing of either drug: secukinumab at 300 mg every 4 weeks or adalimumab at 40 mg every 2 weeks.
Dr. Kavanaugh, an EXCEED coinvestigator, characterized the articular outcomes as similar in the two study arms. The ACR20 primary outcome rate was 67.4% in the secukinumab-treated patients and 61.5% with adalimumab, a difference that didn’t quite reach statistical significance (P = .07). However, in a prespecified secondary analysis of ACR20 rates based upon nonresponder imputation – the most conservative method of statistical analysis, in which all subjects who don’t complete the full study period are counted as treatment failures – secukinumab proved superior to adalimumab by a margin of 66.9% versus 59.5% (P = .02). That result was heavily influenced by the significantly higher dropout rate in the adalimumab group: 23.7%, compared with 14.2% in the secukinumab group.
The ACR50 response rate was 49% in the secukinumab group and 44.6% with adalimumab, a nonsignificant difference. Enthesitis resolution rates at 52 weeks were 60.5% and 54.2%, respectively, also a nonsignificant difference. The mean improvement in Health Assessment Questionnaire–Disability Index scores was closely similar in the two groups. However, a 90% improvement in Psoriasis Area and Severity Index scores, or PASI90 response, was achieved in 65.4% of the secukinumab group, far better than the 43.2% rate with adalimumab.
Dr. Kavanaugh observed that the EXCEED outcomes are consistent with the recently published 24-week results of the SPIRIT-H2H trial, an open-label, assessor-blinded randomized comparison of adalimumab versus another IL-17A inhibitor, ixekizumab (Taltz), in 566 PsA patients. Ixekizumab proved superior to adalimumab for the primary composite endpoint composed of an ACR50 response and simultaneous achievement of a PASI100 response, with rates of 36% and 28%, respectively. The ACR50 rates were similar for the two biologics, while the skin results were superior with ixekizumab.
Eric M. Ruderman, MD, said that, taken together, the EXCEED and SPIRIT-H2H results raise an important issue for clinical practice: Even though both secukinumab and ixekizumab are approved for the treatment of PsA, rheumatologists tend to reflexively reach for a TNF inhibitor as the first biologic in affected patients.
“I don’t know that that necessarily needs to be so. There’s absolutely no reason why an IL-17 inhibitor shouldn’t be equally an option as first-line treatment when you think about starting a biologic in these patients. It’s inertia: We like what we like, we do what we’ve been doing for a long time,” said Dr. Ruderman, professor of medicine and associate chief for clinical affairs in the division of rheumatology at Northwestern University, Chicago.
Indeed, an IL-17A inhibitor may actually be a better first-line option in certain circumstances, such as in the PsA patient with more extensive skin involvement, he continued. Also, there is a possibility that the IL-17A inhibitors are less immunogenic than the anti-TNF biologics, which may result in a more durable response. This concept, while still speculative, is supported by the recently published results of the long-term extension of the phase 3 FUTURE 1 study, in which 82% of patients randomized to secukinumab were still on the biologic after 5 years. That’s a far better retention rate than is seen with TNF inhibitors, he noted.
In addition, SPIRIT-H2H participants randomized to ixekizumab didn’t derive added benefit from concomitant methotrexate, while those on adalimumab did. Thus, PsA patients who desire a simpler, methotrexate-free regimen may prefer an IL-17A inhibitor, Dr. Ruderman said.
Dr. Kavanaugh noted that differences in the side effect profiles of the two classes of biologics may be relevant in treatment decisions. The TNF inhibitors have a higher risk of serious infections than do the IL-17A inhibitors, which in turn are associated with more Candida infections.
Dr. Kavanaugh reported receiving research funding from and serving as a consultant to Novartis, which sponsored EXCEED, as well as more than a dozen other pharmaceutical companies. Dr. Ruderman reported serving as a consultant to Pfizer.
MAUI, HAWAII – The interleukin-17A inhibitor secukinumab made a strong showing versus the tumor necrosis factor inhibitor adalimumab for the treatment of psoriatic arthritis in the 52-week, randomized, head-to-head phase 3b EXCEED study, Arthur Kavanaugh, MD, reported at the 2020 Rheumatology Winter Clinical Symposium.
EXCEED was the first double-blind, randomized comparison of an IL-17A inhibitor versus a tumor necrosis factor inhibitor as first-line biologic monotherapy in 853 psoriatic arthritis (PsA) patients with an inadequate response to conventional disease-modifying antirheumatic drugs. And while secukinumab (Cosentyx) narrowly failed to demonstrate superiority over adalimumab (Humira) on the primary endpoint of at least a 20% improvement over baseline on American College of Rheumatology disease criteria at 52 weeks, or ACR20 response, the IL-17A inhibitor demonstrated far greater efficacy for the skin disease, noted Dr. Kavanaugh, a rheumatologist who is professor of medicine at the University of California, San Diego, and RWCS program director. Patients received standard dosing of either drug: secukinumab at 300 mg every 4 weeks or adalimumab at 40 mg every 2 weeks.
Dr. Kavanaugh, an EXCEED coinvestigator, characterized the articular outcomes as similar in the two study arms. The ACR20 primary outcome rate was 67.4% in the secukinumab-treated patients and 61.5% with adalimumab, a difference that didn’t quite reach statistical significance (P = .07). However, in a prespecified secondary analysis of ACR20 rates based upon nonresponder imputation – the most conservative method of statistical analysis, in which all subjects who don’t complete the full study period are counted as treatment failures – secukinumab proved superior to adalimumab by a margin of 66.9% versus 59.5% (P = .02). That result was heavily influenced by the significantly higher dropout rate in the adalimumab group: 23.7%, compared with 14.2% in the secukinumab group.
The ACR50 response rate was 49% in the secukinumab group and 44.6% with adalimumab, a nonsignificant difference. Enthesitis resolution rates at 52 weeks were 60.5% and 54.2%, respectively, also a nonsignificant difference. The mean improvement in Health Assessment Questionnaire–Disability Index scores was closely similar in the two groups. However, a 90% improvement in Psoriasis Area and Severity Index scores, or PASI90 response, was achieved in 65.4% of the secukinumab group, far better than the 43.2% rate with adalimumab.
Dr. Kavanaugh observed that the EXCEED outcomes are consistent with the recently published 24-week results of the SPIRIT-H2H trial, an open-label, assessor-blinded randomized comparison of adalimumab versus another IL-17A inhibitor, ixekizumab (Taltz), in 566 PsA patients. Ixekizumab proved superior to adalimumab for the primary composite endpoint composed of an ACR50 response and simultaneous achievement of a PASI100 response, with rates of 36% and 28%, respectively. The ACR50 rates were similar for the two biologics, while the skin results were superior with ixekizumab.
Eric M. Ruderman, MD, said that, taken together, the EXCEED and SPIRIT-H2H results raise an important issue for clinical practice: Even though both secukinumab and ixekizumab are approved for the treatment of PsA, rheumatologists tend to reflexively reach for a TNF inhibitor as the first biologic in affected patients.
“I don’t know that that necessarily needs to be so. There’s absolutely no reason why an IL-17 inhibitor shouldn’t be equally an option as first-line treatment when you think about starting a biologic in these patients. It’s inertia: We like what we like, we do what we’ve been doing for a long time,” said Dr. Ruderman, professor of medicine and associate chief for clinical affairs in the division of rheumatology at Northwestern University, Chicago.
Indeed, an IL-17A inhibitor may actually be a better first-line option in certain circumstances, such as in the PsA patient with more extensive skin involvement, he continued. Also, there is a possibility that the IL-17A inhibitors are less immunogenic than the anti-TNF biologics, which may result in a more durable response. This concept, while still speculative, is supported by the recently published results of the long-term extension of the phase 3 FUTURE 1 study, in which 82% of patients randomized to secukinumab were still on the biologic after 5 years. That’s a far better retention rate than is seen with TNF inhibitors, he noted.
In addition, SPIRIT-H2H participants randomized to ixekizumab didn’t derive added benefit from concomitant methotrexate, while those on adalimumab did. Thus, PsA patients who desire a simpler, methotrexate-free regimen may prefer an IL-17A inhibitor, Dr. Ruderman said.
Dr. Kavanaugh noted that differences in the side effect profiles of the two classes of biologics may be relevant in treatment decisions. The TNF inhibitors have a higher risk of serious infections than do the IL-17A inhibitors, which in turn are associated with more Candida infections.
Dr. Kavanaugh reported receiving research funding from and serving as a consultant to Novartis, which sponsored EXCEED, as well as more than a dozen other pharmaceutical companies. Dr. Ruderman reported serving as a consultant to Pfizer.
MAUI, HAWAII – The interleukin-17A inhibitor secukinumab made a strong showing versus the tumor necrosis factor inhibitor adalimumab for the treatment of psoriatic arthritis in the 52-week, randomized, head-to-head phase 3b EXCEED study, Arthur Kavanaugh, MD, reported at the 2020 Rheumatology Winter Clinical Symposium.
EXCEED was the first double-blind, randomized comparison of an IL-17A inhibitor versus a tumor necrosis factor inhibitor as first-line biologic monotherapy in 853 psoriatic arthritis (PsA) patients with an inadequate response to conventional disease-modifying antirheumatic drugs. And while secukinumab (Cosentyx) narrowly failed to demonstrate superiority over adalimumab (Humira) on the primary endpoint of at least a 20% improvement over baseline on American College of Rheumatology disease criteria at 52 weeks, or ACR20 response, the IL-17A inhibitor demonstrated far greater efficacy for the skin disease, noted Dr. Kavanaugh, a rheumatologist who is professor of medicine at the University of California, San Diego, and RWCS program director. Patients received standard dosing of either drug: secukinumab at 300 mg every 4 weeks or adalimumab at 40 mg every 2 weeks.
Dr. Kavanaugh, an EXCEED coinvestigator, characterized the articular outcomes as similar in the two study arms. The ACR20 primary outcome rate was 67.4% in the secukinumab-treated patients and 61.5% with adalimumab, a difference that didn’t quite reach statistical significance (P = .07). However, in a prespecified secondary analysis of ACR20 rates based upon nonresponder imputation – the most conservative method of statistical analysis, in which all subjects who don’t complete the full study period are counted as treatment failures – secukinumab proved superior to adalimumab by a margin of 66.9% versus 59.5% (P = .02). That result was heavily influenced by the significantly higher dropout rate in the adalimumab group: 23.7%, compared with 14.2% in the secukinumab group.
The ACR50 response rate was 49% in the secukinumab group and 44.6% with adalimumab, a nonsignificant difference. Enthesitis resolution rates at 52 weeks were 60.5% and 54.2%, respectively, also a nonsignificant difference. The mean improvement in Health Assessment Questionnaire–Disability Index scores was closely similar in the two groups. However, a 90% improvement in Psoriasis Area and Severity Index scores, or PASI90 response, was achieved in 65.4% of the secukinumab group, far better than the 43.2% rate with adalimumab.
Dr. Kavanaugh observed that the EXCEED outcomes are consistent with the recently published 24-week results of the SPIRIT-H2H trial, an open-label, assessor-blinded randomized comparison of adalimumab versus another IL-17A inhibitor, ixekizumab (Taltz), in 566 PsA patients. Ixekizumab proved superior to adalimumab for the primary composite endpoint composed of an ACR50 response and simultaneous achievement of a PASI100 response, with rates of 36% and 28%, respectively. The ACR50 rates were similar for the two biologics, while the skin results were superior with ixekizumab.
Eric M. Ruderman, MD, said that, taken together, the EXCEED and SPIRIT-H2H results raise an important issue for clinical practice: Even though both secukinumab and ixekizumab are approved for the treatment of PsA, rheumatologists tend to reflexively reach for a TNF inhibitor as the first biologic in affected patients.
“I don’t know that that necessarily needs to be so. There’s absolutely no reason why an IL-17 inhibitor shouldn’t be equally an option as first-line treatment when you think about starting a biologic in these patients. It’s inertia: We like what we like, we do what we’ve been doing for a long time,” said Dr. Ruderman, professor of medicine and associate chief for clinical affairs in the division of rheumatology at Northwestern University, Chicago.
Indeed, an IL-17A inhibitor may actually be a better first-line option in certain circumstances, such as in the PsA patient with more extensive skin involvement, he continued. Also, there is a possibility that the IL-17A inhibitors are less immunogenic than the anti-TNF biologics, which may result in a more durable response. This concept, while still speculative, is supported by the recently published results of the long-term extension of the phase 3 FUTURE 1 study, in which 82% of patients randomized to secukinumab were still on the biologic after 5 years. That’s a far better retention rate than is seen with TNF inhibitors, he noted.
In addition, SPIRIT-H2H participants randomized to ixekizumab didn’t derive added benefit from concomitant methotrexate, while those on adalimumab did. Thus, PsA patients who desire a simpler, methotrexate-free regimen may prefer an IL-17A inhibitor, Dr. Ruderman said.
Dr. Kavanaugh noted that differences in the side effect profiles of the two classes of biologics may be relevant in treatment decisions. The TNF inhibitors have a higher risk of serious infections than do the IL-17A inhibitors, which in turn are associated with more Candida infections.
Dr. Kavanaugh reported receiving research funding from and serving as a consultant to Novartis, which sponsored EXCEED, as well as more than a dozen other pharmaceutical companies. Dr. Ruderman reported serving as a consultant to Pfizer.
REPORTING FROM RWCS 2020
Understanding the cervicovaginal microbiome and how it affects preterm birth
Prematurity remains the leading cause of neonatal morbidity and mortality, accounting for $26 billion a year in immediate costs, despite the implementation in obstetrics of a host of risk stratification algorithms and strategies for risk reduction, including the use of some medications.
It now is questionable whether injectable 17-alpha hydroxyprogesterone caproate (Makena) truly is efficacious in women who’ve had a prior spontaneous preterm birth (sPTB) – a Food and Drug Administration advisory committee last year recommended withdrawing it from the market based on results of an FDA confirmatory study. Even if the drug were efficacious, only a small percentage of the women who have an sPTB have had a prior one. The majority of sPTB occurs among women without such a history.
Vaginal progesterone appears to confer some protection in women found to have a short cervix during the second trimester, but this approach also has limited reach: Only 9% of women with sPTB had an antecedent short cervix in a 2017 study.1 Like a history of sPTB, screening for short cervical length is a potentially helpful strategy for risk reduction, but it is not a strategy that will significantly impact the overall rate of prematurity.
We’ve fallen short in our goals to significantly reduce the public health impact of prematurity partly because we still do not understand the exact pathways and mechanisms by which sPTB occurs. The main working paradigm for myself and many other researchers over the past 2 decades has centered on infection in the uterus triggering inflammation, followed by cervical remodeling and ripening. Research in animal models, as well as human clinical trials targeting various infections and inflammation, have led to some insights and discoveries, but no successful interventions.
In the past decade, however, our research framework for understanding sPTB incorporates new questions about immunologic, microbiological, and molecular/cellular events that happen in the cervicovaginal space. We’ve learned more about the cervicovaginal microbiota, and most recently, our research at the University of Pennsylvania has elucidated the role that nonoptimal bacteria play in disrupting the cervical endothelial barrier and initiating the process of cervical remodeling that likely precedes sPTB.
We also know that this association is stronger in black women and may help explain some of the observed racial disparities in sPTB. Although more research is needed to determine specific therapeutic strategies, new doors are open.
Host immune-microbial interactions
This new research paradigm has involved stepping back and asking basic questions, such as, what do we really know about the cervicovaginal space? In actuality, we know very little. We know little about the immune function of the vaginal and cervical epithelial cells in pregnancy, for instance, and there is a large gap in knowledge regarding the biomechanics of the cervix – a remarkable organ that can change shape and function in a matter of minutes. Studies on the biomechanics of the cervix during pregnancy and in labor are still in their infancy.
However, lessons can be drawn from research on inflammatory bowel disease and other disorders involving the gut. In the gastrointestinal tract, epithelial cells have been found to act as sentinels, forming a mucosal barrier against bacterial pathogens and secreting various immune factors. Research in this field also has shown that microbes living in the gut produce metabolites; that these microbial metabolites may be the key messengers from the microbial communities to the epithelial barrier; and that the microbes, microbial metabolites, and immune responses are responsible for triggering inflammatory processes in the tissues underneath.
In 2011, Jacques Ravel, PhD, who was part of the National Institutes of Health’s Human Microbiome Project, characterized the vaginal microbiome of reproductive-age women for the first time.2 His paper classified the vaginal microbial communities of approximately 400 asymptomatic women of various ethnicities into five “community state types” (CSTs) based on the predominant bacteria found in the cervicovaginal space.3
On the heels of his research, Dr. Ravel and I launched an NIH-funded study involving a prospective cohort of 2,000 women with singleton pregnancies – the Motherhood & Microbiome cohort – to look at the cervicovaginal microbiota, the local immune response, and the risk of sPTB.4 Cervicovaginal samples were collected at 16-20 weeks’ gestation and during two subsequent clinical visits. From this cohort, which was composed mostly of African American women (74.5%), we conducted a nested case-controlled study of 103 cases of sPTB and 432 women who delivered at term, matched for race.
We carefully adjudicated the deliveries in our 2,000-person cohort so that we homed in on sPTB as opposed to preterm births that are medically indicated for reasons such as fetal distress or preeclampsia. (Several prior studies looking at the associations between the cervicovaginal microbiome had a heterogeneous phenotyping of PTB that made it hard to draw definitive conclusions.)
Our focus in assessing the microbiome and immunologic profiles was on the samples collected at the earliest time points in pregnancy because we hoped to detect a “signature” that could predict an outcome months later. Indeed, we found that the nonoptimal microbiota, known in microbiological terms as CST IV, was associated with about a 150% increased risk of sPTB. This community comprises a dominant array of anaerobic bacteria and a paucity of Lactobacillus species.
We also found that a larger proportion of African American women, compared with non–African American women, had this nonoptimal microbiota early in pregnancy (40% vs. 15%), which is consistent with previous studies in pregnancy and nonpregnancy showing lower levels of Lactobacillus species in the cervicovaginal microbiome of African American women.
Even more interesting was the finding that, although the rate of sPTB was higher in African American women and the effect of CST IV on sPTB was stronger in these women, the risk of sPTB couldn’t be explained solely by the presence of CST IV. Some women with this nonoptimal microbiome delivered at term, whereas others with more optimal microbiome types had sPTBs. This suggests that other factors contribute to African American women having a nonoptimal microbiota and being especially predisposed to sPTB.
Through the study’s immunologic profiling, we found a significant difference in the cervicovaginal levels of an immune factor, beta-defensin 2, between African American women who delivered at term and those who had a sPTB. Women who had a sPTB, even those who had higher levels of Lactobacillus species, had lower levels of beta-defensin 2. This association was not found in non–African American women.
Beta-defensin 2 is a host-derived antimicrobial peptide that, like other antimicrobial peptides, works at epithelial-mucosal barriers to combat bacteria; we have knowledge of its action from research on the gut, as well as some studies of the vaginal space in nonpregnant women that have focused on sexually transmitted infections.
Most exciting for us was the finding that higher levels of beta-defensin 2 appeared to lower the risk of sPTB in women who had a nonoptimal cervicovaginal microbiota. There’s an interplay between the host and the microbiota, in other words, and it’s one that could be essential to manipulate as we seek to reduce sPTB.
The cervical epithelial barrier
In the laboratory, meanwhile, we are learning how certain microbes are mechanistically involved in the pathogenesis of sPTB. Research over the last decade has suggested that disruption or breakdown of the cervical epithelial barrier drives cervical remodeling processes that precede sPTB. The question now is, do cervicovaginal bacteria associated with sPTB, or a nonoptimal cervicovaginal microbiota, cause disruption of the vaginal and cervical epithelial barrier – and how?
Using an in vitro model system, we found that Mobiluncus curtisii/mulieris, the bacterial taxa with the strongest association with sPTB in our Motherhood & Microbiome cohort and one that has long been associated with bacterial vaginosis, had a plethora of effects. It increased cell permeability and the expression of inflammatory mediators associated with cervical epithelial breakdown, and it altered expression of microRNAs that have been associated with sPTB in human studies.
Our study on Mobiluncus has served as proof of concept to us that, not only is the bacteria associated with sPTB, but that there are multiple mechanisms by which it can disrupt the cervicovaginal barrier and lead to cervical remodeling.5
The findings echo previous in vitro research on Gardnerella vaginalis, another anaerobic bacterium that has been associated with bacterial vaginosis and adverse obstetric outcomes, including sPTB.6 Using similar models, we found that G. vaginalis disrupts the cervical epithelial barrier through diverse mechanisms including the cleavage of certain proteins, the up-regulation of proinflammatory immune mediators, and altered gene expression.
Lactobacillus crispatus, on the other hand, conferred protection to the cervical epithelial barrier in this study by mitigating various G. vaginalis–induced effects.
Learning more about host-microbe interactions and the role of microbial metabolites in these interactions, as well as the role of altered gene expression in cervical function, will help us to more fully understand the biological mechanisms regulating cervicovaginal epithelial cells. At this point, we know that, as in the gut, bacteria commonly found in the cervicovaginal space play a significant role in regulating the function of epithelial cells (in both optimal and nonoptimal microbiota), and that various bacteria associated with sPTB contribute to poor outcomes by breaking down the cervical epithelium.
Therapeutic implications
Our growing knowledge of the cervicovaginal microbiota does not yet support screening or any particular interventions. We don’t know, for instance, that administering probiotics or prebiotics orally or vaginally will have any effect on rates of sPTB.
Ongoing research at all levels holds promise, however, for the development of diagnostics to identify women at risk for sPTB, and for the development of therapeutic strategies that aim to modify the microbiome and/or modify the immune response. We know from other areas of medicine that there are realistic ways to modulate the immune response and/or microbiota in a system to alter risk.
We need to more thoroughly understand the risk of particular microbiota and immune response factors – and how they vary by race and ethnicity – and we need to study the cervicovaginal microbiota of women before and during pregnancy to learn whether there is something about pregnancy or even about intercourse that can change one’s microbiome to a less favorable state.
It may well be possible in the near future to identify high-risk states of nonoptimal microbiota before conception – microbiota that, in and of themselves, may not be pathogenic but that become detrimental during pregnancy – and it should be possible to screen women early in pregnancy for microbial or immune signatures or both.
The question often arises in medicine of the validity of screening without having achieved certainty about treatments. However, in obstetrics, where we have different levels of care and the ability to personalize monitoring and care, identifying those at greatest risk still has value. Ultimately, with enough investment in all levels of research (basic, translational, and clinical), we can develop interventions and therapeutics that address a biologically plausible mechanism of sPTB and, as a result, achieve significant reductions in the rate of prematurity.
Dr. Elovitz is the Hilarie L. Morgan and Mitchell L. Morgan President’s Distinguished Professor in Women’s Health, vice chair of translational research, and director of the Maternal and Child Health Research Center, department of obstetrics and gynecology, at the University of Pennsylvania, Philadelphia. She disclosed holding a patent on a method to determine risk of preterm birth that relates to the microbiome. Email her at obnews@mdedge.com.
References
1. JAMA. 2017 Mar 14;317(10):1047-56.
2. NIH Human Microbiome Project. https://hmpdacc.org/.
3. PNAS. 2011 Mar 15;108 (Supplement 1):4680-7.
4. Nat Commun. 2019 Mar 21. doi: 10.1038/s41467-019-09285-9.
5. Anaerobe. 2019 Nov 21. doi: 10.1016/j.anaerobe.2019.102127.
6. Front Microbiol. 2018 Oct 8. doi: 10.3389/fmicb.2018.02181.
Prematurity remains the leading cause of neonatal morbidity and mortality, accounting for $26 billion a year in immediate costs, despite the implementation in obstetrics of a host of risk stratification algorithms and strategies for risk reduction, including the use of some medications.
It now is questionable whether injectable 17-alpha hydroxyprogesterone caproate (Makena) truly is efficacious in women who’ve had a prior spontaneous preterm birth (sPTB) – a Food and Drug Administration advisory committee last year recommended withdrawing it from the market based on results of an FDA confirmatory study. Even if the drug were efficacious, only a small percentage of the women who have an sPTB have had a prior one. The majority of sPTB occurs among women without such a history.
Vaginal progesterone appears to confer some protection in women found to have a short cervix during the second trimester, but this approach also has limited reach: Only 9% of women with sPTB had an antecedent short cervix in a 2017 study.1 Like a history of sPTB, screening for short cervical length is a potentially helpful strategy for risk reduction, but it is not a strategy that will significantly impact the overall rate of prematurity.
We’ve fallen short in our goals to significantly reduce the public health impact of prematurity partly because we still do not understand the exact pathways and mechanisms by which sPTB occurs. The main working paradigm for myself and many other researchers over the past 2 decades has centered on infection in the uterus triggering inflammation, followed by cervical remodeling and ripening. Research in animal models, as well as human clinical trials targeting various infections and inflammation, have led to some insights and discoveries, but no successful interventions.
In the past decade, however, our research framework for understanding sPTB incorporates new questions about immunologic, microbiological, and molecular/cellular events that happen in the cervicovaginal space. We’ve learned more about the cervicovaginal microbiota, and most recently, our research at the University of Pennsylvania has elucidated the role that nonoptimal bacteria play in disrupting the cervical endothelial barrier and initiating the process of cervical remodeling that likely precedes sPTB.
We also know that this association is stronger in black women and may help explain some of the observed racial disparities in sPTB. Although more research is needed to determine specific therapeutic strategies, new doors are open.
Host immune-microbial interactions
This new research paradigm has involved stepping back and asking basic questions, such as, what do we really know about the cervicovaginal space? In actuality, we know very little. We know little about the immune function of the vaginal and cervical epithelial cells in pregnancy, for instance, and there is a large gap in knowledge regarding the biomechanics of the cervix – a remarkable organ that can change shape and function in a matter of minutes. Studies on the biomechanics of the cervix during pregnancy and in labor are still in their infancy.
However, lessons can be drawn from research on inflammatory bowel disease and other disorders involving the gut. In the gastrointestinal tract, epithelial cells have been found to act as sentinels, forming a mucosal barrier against bacterial pathogens and secreting various immune factors. Research in this field also has shown that microbes living in the gut produce metabolites; that these microbial metabolites may be the key messengers from the microbial communities to the epithelial barrier; and that the microbes, microbial metabolites, and immune responses are responsible for triggering inflammatory processes in the tissues underneath.
In 2011, Jacques Ravel, PhD, who was part of the National Institutes of Health’s Human Microbiome Project, characterized the vaginal microbiome of reproductive-age women for the first time.2 His paper classified the vaginal microbial communities of approximately 400 asymptomatic women of various ethnicities into five “community state types” (CSTs) based on the predominant bacteria found in the cervicovaginal space.3
On the heels of his research, Dr. Ravel and I launched an NIH-funded study involving a prospective cohort of 2,000 women with singleton pregnancies – the Motherhood & Microbiome cohort – to look at the cervicovaginal microbiota, the local immune response, and the risk of sPTB.4 Cervicovaginal samples were collected at 16-20 weeks’ gestation and during two subsequent clinical visits. From this cohort, which was composed mostly of African American women (74.5%), we conducted a nested case-controlled study of 103 cases of sPTB and 432 women who delivered at term, matched for race.
We carefully adjudicated the deliveries in our 2,000-person cohort so that we homed in on sPTB as opposed to preterm births that are medically indicated for reasons such as fetal distress or preeclampsia. (Several prior studies looking at the associations between the cervicovaginal microbiome had a heterogeneous phenotyping of PTB that made it hard to draw definitive conclusions.)
Our focus in assessing the microbiome and immunologic profiles was on the samples collected at the earliest time points in pregnancy because we hoped to detect a “signature” that could predict an outcome months later. Indeed, we found that the nonoptimal microbiota, known in microbiological terms as CST IV, was associated with about a 150% increased risk of sPTB. This community comprises a dominant array of anaerobic bacteria and a paucity of Lactobacillus species.
We also found that a larger proportion of African American women, compared with non–African American women, had this nonoptimal microbiota early in pregnancy (40% vs. 15%), which is consistent with previous studies in pregnancy and nonpregnancy showing lower levels of Lactobacillus species in the cervicovaginal microbiome of African American women.
Even more interesting was the finding that, although the rate of sPTB was higher in African American women and the effect of CST IV on sPTB was stronger in these women, the risk of sPTB couldn’t be explained solely by the presence of CST IV. Some women with this nonoptimal microbiome delivered at term, whereas others with more optimal microbiome types had sPTBs. This suggests that other factors contribute to African American women having a nonoptimal microbiota and being especially predisposed to sPTB.
Through the study’s immunologic profiling, we found a significant difference in the cervicovaginal levels of an immune factor, beta-defensin 2, between African American women who delivered at term and those who had a sPTB. Women who had a sPTB, even those who had higher levels of Lactobacillus species, had lower levels of beta-defensin 2. This association was not found in non–African American women.
Beta-defensin 2 is a host-derived antimicrobial peptide that, like other antimicrobial peptides, works at epithelial-mucosal barriers to combat bacteria; we have knowledge of its action from research on the gut, as well as some studies of the vaginal space in nonpregnant women that have focused on sexually transmitted infections.
Most exciting for us was the finding that higher levels of beta-defensin 2 appeared to lower the risk of sPTB in women who had a nonoptimal cervicovaginal microbiota. There’s an interplay between the host and the microbiota, in other words, and it’s one that could be essential to manipulate as we seek to reduce sPTB.
The cervical epithelial barrier
In the laboratory, meanwhile, we are learning how certain microbes are mechanistically involved in the pathogenesis of sPTB. Research over the last decade has suggested that disruption or breakdown of the cervical epithelial barrier drives cervical remodeling processes that precede sPTB. The question now is, do cervicovaginal bacteria associated with sPTB, or a nonoptimal cervicovaginal microbiota, cause disruption of the vaginal and cervical epithelial barrier – and how?
Using an in vitro model system, we found that Mobiluncus curtisii/mulieris, the bacterial taxa with the strongest association with sPTB in our Motherhood & Microbiome cohort and one that has long been associated with bacterial vaginosis, had a plethora of effects. It increased cell permeability and the expression of inflammatory mediators associated with cervical epithelial breakdown, and it altered expression of microRNAs that have been associated with sPTB in human studies.
Our study on Mobiluncus has served as proof of concept to us that, not only is the bacteria associated with sPTB, but that there are multiple mechanisms by which it can disrupt the cervicovaginal barrier and lead to cervical remodeling.5
The findings echo previous in vitro research on Gardnerella vaginalis, another anaerobic bacterium that has been associated with bacterial vaginosis and adverse obstetric outcomes, including sPTB.6 Using similar models, we found that G. vaginalis disrupts the cervical epithelial barrier through diverse mechanisms including the cleavage of certain proteins, the up-regulation of proinflammatory immune mediators, and altered gene expression.
Lactobacillus crispatus, on the other hand, conferred protection to the cervical epithelial barrier in this study by mitigating various G. vaginalis–induced effects.
Learning more about host-microbe interactions and the role of microbial metabolites in these interactions, as well as the role of altered gene expression in cervical function, will help us to more fully understand the biological mechanisms regulating cervicovaginal epithelial cells. At this point, we know that, as in the gut, bacteria commonly found in the cervicovaginal space play a significant role in regulating the function of epithelial cells (in both optimal and nonoptimal microbiota), and that various bacteria associated with sPTB contribute to poor outcomes by breaking down the cervical epithelium.
Therapeutic implications
Our growing knowledge of the cervicovaginal microbiota does not yet support screening or any particular interventions. We don’t know, for instance, that administering probiotics or prebiotics orally or vaginally will have any effect on rates of sPTB.
Ongoing research at all levels holds promise, however, for the development of diagnostics to identify women at risk for sPTB, and for the development of therapeutic strategies that aim to modify the microbiome and/or modify the immune response. We know from other areas of medicine that there are realistic ways to modulate the immune response and/or microbiota in a system to alter risk.
We need to more thoroughly understand the risk of particular microbiota and immune response factors – and how they vary by race and ethnicity – and we need to study the cervicovaginal microbiota of women before and during pregnancy to learn whether there is something about pregnancy or even about intercourse that can change one’s microbiome to a less favorable state.
It may well be possible in the near future to identify high-risk states of nonoptimal microbiota before conception – microbiota that, in and of themselves, may not be pathogenic but that become detrimental during pregnancy – and it should be possible to screen women early in pregnancy for microbial or immune signatures or both.
The question often arises in medicine of the validity of screening without having achieved certainty about treatments. However, in obstetrics, where we have different levels of care and the ability to personalize monitoring and care, identifying those at greatest risk still has value. Ultimately, with enough investment in all levels of research (basic, translational, and clinical), we can develop interventions and therapeutics that address a biologically plausible mechanism of sPTB and, as a result, achieve significant reductions in the rate of prematurity.
Dr. Elovitz is the Hilarie L. Morgan and Mitchell L. Morgan President’s Distinguished Professor in Women’s Health, vice chair of translational research, and director of the Maternal and Child Health Research Center, department of obstetrics and gynecology, at the University of Pennsylvania, Philadelphia. She disclosed holding a patent on a method to determine risk of preterm birth that relates to the microbiome. Email her at obnews@mdedge.com.
References
1. JAMA. 2017 Mar 14;317(10):1047-56.
2. NIH Human Microbiome Project. https://hmpdacc.org/.
3. PNAS. 2011 Mar 15;108 (Supplement 1):4680-7.
4. Nat Commun. 2019 Mar 21. doi: 10.1038/s41467-019-09285-9.
5. Anaerobe. 2019 Nov 21. doi: 10.1016/j.anaerobe.2019.102127.
6. Front Microbiol. 2018 Oct 8. doi: 10.3389/fmicb.2018.02181.
Prematurity remains the leading cause of neonatal morbidity and mortality, accounting for $26 billion a year in immediate costs, despite the implementation in obstetrics of a host of risk stratification algorithms and strategies for risk reduction, including the use of some medications.
It now is questionable whether injectable 17-alpha hydroxyprogesterone caproate (Makena) truly is efficacious in women who’ve had a prior spontaneous preterm birth (sPTB) – a Food and Drug Administration advisory committee last year recommended withdrawing it from the market based on results of an FDA confirmatory study. Even if the drug were efficacious, only a small percentage of the women who have an sPTB have had a prior one. The majority of sPTB occurs among women without such a history.
Vaginal progesterone appears to confer some protection in women found to have a short cervix during the second trimester, but this approach also has limited reach: Only 9% of women with sPTB had an antecedent short cervix in a 2017 study.1 Like a history of sPTB, screening for short cervical length is a potentially helpful strategy for risk reduction, but it is not a strategy that will significantly impact the overall rate of prematurity.
We’ve fallen short in our goals to significantly reduce the public health impact of prematurity partly because we still do not understand the exact pathways and mechanisms by which sPTB occurs. The main working paradigm for myself and many other researchers over the past 2 decades has centered on infection in the uterus triggering inflammation, followed by cervical remodeling and ripening. Research in animal models, as well as human clinical trials targeting various infections and inflammation, have led to some insights and discoveries, but no successful interventions.
In the past decade, however, our research framework for understanding sPTB incorporates new questions about immunologic, microbiological, and molecular/cellular events that happen in the cervicovaginal space. We’ve learned more about the cervicovaginal microbiota, and most recently, our research at the University of Pennsylvania has elucidated the role that nonoptimal bacteria play in disrupting the cervical endothelial barrier and initiating the process of cervical remodeling that likely precedes sPTB.
We also know that this association is stronger in black women and may help explain some of the observed racial disparities in sPTB. Although more research is needed to determine specific therapeutic strategies, new doors are open.
Host immune-microbial interactions
This new research paradigm has involved stepping back and asking basic questions, such as, what do we really know about the cervicovaginal space? In actuality, we know very little. We know little about the immune function of the vaginal and cervical epithelial cells in pregnancy, for instance, and there is a large gap in knowledge regarding the biomechanics of the cervix – a remarkable organ that can change shape and function in a matter of minutes. Studies on the biomechanics of the cervix during pregnancy and in labor are still in their infancy.
However, lessons can be drawn from research on inflammatory bowel disease and other disorders involving the gut. In the gastrointestinal tract, epithelial cells have been found to act as sentinels, forming a mucosal barrier against bacterial pathogens and secreting various immune factors. Research in this field also has shown that microbes living in the gut produce metabolites; that these microbial metabolites may be the key messengers from the microbial communities to the epithelial barrier; and that the microbes, microbial metabolites, and immune responses are responsible for triggering inflammatory processes in the tissues underneath.
In 2011, Jacques Ravel, PhD, who was part of the National Institutes of Health’s Human Microbiome Project, characterized the vaginal microbiome of reproductive-age women for the first time.2 His paper classified the vaginal microbial communities of approximately 400 asymptomatic women of various ethnicities into five “community state types” (CSTs) based on the predominant bacteria found in the cervicovaginal space.3
On the heels of his research, Dr. Ravel and I launched an NIH-funded study involving a prospective cohort of 2,000 women with singleton pregnancies – the Motherhood & Microbiome cohort – to look at the cervicovaginal microbiota, the local immune response, and the risk of sPTB.4 Cervicovaginal samples were collected at 16-20 weeks’ gestation and during two subsequent clinical visits. From this cohort, which was composed mostly of African American women (74.5%), we conducted a nested case-controlled study of 103 cases of sPTB and 432 women who delivered at term, matched for race.
We carefully adjudicated the deliveries in our 2,000-person cohort so that we homed in on sPTB as opposed to preterm births that are medically indicated for reasons such as fetal distress or preeclampsia. (Several prior studies looking at the associations between the cervicovaginal microbiome had a heterogeneous phenotyping of PTB that made it hard to draw definitive conclusions.)
Our focus in assessing the microbiome and immunologic profiles was on the samples collected at the earliest time points in pregnancy because we hoped to detect a “signature” that could predict an outcome months later. Indeed, we found that the nonoptimal microbiota, known in microbiological terms as CST IV, was associated with about a 150% increased risk of sPTB. This community comprises a dominant array of anaerobic bacteria and a paucity of Lactobacillus species.
We also found that a larger proportion of African American women, compared with non–African American women, had this nonoptimal microbiota early in pregnancy (40% vs. 15%), which is consistent with previous studies in pregnancy and nonpregnancy showing lower levels of Lactobacillus species in the cervicovaginal microbiome of African American women.
Even more interesting was the finding that, although the rate of sPTB was higher in African American women and the effect of CST IV on sPTB was stronger in these women, the risk of sPTB couldn’t be explained solely by the presence of CST IV. Some women with this nonoptimal microbiome delivered at term, whereas others with more optimal microbiome types had sPTBs. This suggests that other factors contribute to African American women having a nonoptimal microbiota and being especially predisposed to sPTB.
Through the study’s immunologic profiling, we found a significant difference in the cervicovaginal levels of an immune factor, beta-defensin 2, between African American women who delivered at term and those who had a sPTB. Women who had a sPTB, even those who had higher levels of Lactobacillus species, had lower levels of beta-defensin 2. This association was not found in non–African American women.
Beta-defensin 2 is a host-derived antimicrobial peptide that, like other antimicrobial peptides, works at epithelial-mucosal barriers to combat bacteria; we have knowledge of its action from research on the gut, as well as some studies of the vaginal space in nonpregnant women that have focused on sexually transmitted infections.
Most exciting for us was the finding that higher levels of beta-defensin 2 appeared to lower the risk of sPTB in women who had a nonoptimal cervicovaginal microbiota. There’s an interplay between the host and the microbiota, in other words, and it’s one that could be essential to manipulate as we seek to reduce sPTB.
The cervical epithelial barrier
In the laboratory, meanwhile, we are learning how certain microbes are mechanistically involved in the pathogenesis of sPTB. Research over the last decade has suggested that disruption or breakdown of the cervical epithelial barrier drives cervical remodeling processes that precede sPTB. The question now is, do cervicovaginal bacteria associated with sPTB, or a nonoptimal cervicovaginal microbiota, cause disruption of the vaginal and cervical epithelial barrier – and how?
Using an in vitro model system, we found that Mobiluncus curtisii/mulieris, the bacterial taxa with the strongest association with sPTB in our Motherhood & Microbiome cohort and one that has long been associated with bacterial vaginosis, had a plethora of effects. It increased cell permeability and the expression of inflammatory mediators associated with cervical epithelial breakdown, and it altered expression of microRNAs that have been associated with sPTB in human studies.
Our study on Mobiluncus has served as proof of concept to us that, not only is the bacteria associated with sPTB, but that there are multiple mechanisms by which it can disrupt the cervicovaginal barrier and lead to cervical remodeling.5
The findings echo previous in vitro research on Gardnerella vaginalis, another anaerobic bacterium that has been associated with bacterial vaginosis and adverse obstetric outcomes, including sPTB.6 Using similar models, we found that G. vaginalis disrupts the cervical epithelial barrier through diverse mechanisms including the cleavage of certain proteins, the up-regulation of proinflammatory immune mediators, and altered gene expression.
Lactobacillus crispatus, on the other hand, conferred protection to the cervical epithelial barrier in this study by mitigating various G. vaginalis–induced effects.
Learning more about host-microbe interactions and the role of microbial metabolites in these interactions, as well as the role of altered gene expression in cervical function, will help us to more fully understand the biological mechanisms regulating cervicovaginal epithelial cells. At this point, we know that, as in the gut, bacteria commonly found in the cervicovaginal space play a significant role in regulating the function of epithelial cells (in both optimal and nonoptimal microbiota), and that various bacteria associated with sPTB contribute to poor outcomes by breaking down the cervical epithelium.
Therapeutic implications
Our growing knowledge of the cervicovaginal microbiota does not yet support screening or any particular interventions. We don’t know, for instance, that administering probiotics or prebiotics orally or vaginally will have any effect on rates of sPTB.
Ongoing research at all levels holds promise, however, for the development of diagnostics to identify women at risk for sPTB, and for the development of therapeutic strategies that aim to modify the microbiome and/or modify the immune response. We know from other areas of medicine that there are realistic ways to modulate the immune response and/or microbiota in a system to alter risk.
We need to more thoroughly understand the risk of particular microbiota and immune response factors – and how they vary by race and ethnicity – and we need to study the cervicovaginal microbiota of women before and during pregnancy to learn whether there is something about pregnancy or even about intercourse that can change one’s microbiome to a less favorable state.
It may well be possible in the near future to identify high-risk states of nonoptimal microbiota before conception – microbiota that, in and of themselves, may not be pathogenic but that become detrimental during pregnancy – and it should be possible to screen women early in pregnancy for microbial or immune signatures or both.
The question often arises in medicine of the validity of screening without having achieved certainty about treatments. However, in obstetrics, where we have different levels of care and the ability to personalize monitoring and care, identifying those at greatest risk still has value. Ultimately, with enough investment in all levels of research (basic, translational, and clinical), we can develop interventions and therapeutics that address a biologically plausible mechanism of sPTB and, as a result, achieve significant reductions in the rate of prematurity.
Dr. Elovitz is the Hilarie L. Morgan and Mitchell L. Morgan President’s Distinguished Professor in Women’s Health, vice chair of translational research, and director of the Maternal and Child Health Research Center, department of obstetrics and gynecology, at the University of Pennsylvania, Philadelphia. She disclosed holding a patent on a method to determine risk of preterm birth that relates to the microbiome. Email her at obnews@mdedge.com.
References
1. JAMA. 2017 Mar 14;317(10):1047-56.
2. NIH Human Microbiome Project. https://hmpdacc.org/.
3. PNAS. 2011 Mar 15;108 (Supplement 1):4680-7.
4. Nat Commun. 2019 Mar 21. doi: 10.1038/s41467-019-09285-9.
5. Anaerobe. 2019 Nov 21. doi: 10.1016/j.anaerobe.2019.102127.
6. Front Microbiol. 2018 Oct 8. doi: 10.3389/fmicb.2018.02181.
Preterm birth: Under the microscope
Preventing infant mortality remains a significant challenge for ob.gyns. Despite the availability of a multitude of preventive and treatment options and some of the best possible medical care offered in the world, the United States lags behind many other developed and developing countries in its rate of infant deaths, which was an estimated 5.8 deaths per 1,000 live births in 2017. We can, and must, do better.
One of the major contributing factors to infant mortality is preterm birth. Defined as birth occurring prior to 37 weeks’ gestation, preterm birth is associated with a myriad of severe neonatal sequelae: low birth weight, bacterial sepsis, neonatal hemorrhage, and respiratory distress syndrome, among others. Therefore, many within the clinical and biomedical research spheres recognize that preventing preterm birth means reducing infant deaths.
However, therein lies the conundrum. We know very little about what causes preterm birth, which renders the current therapeutic strategies – such as use of progesterone supplements or cerclage placement – good for some but not all patients. It is thus vital to continue research to unravel the underlying mechanisms of preterm birth.
A promising area of investigation is the field of microbiome research, which has made great strides in advancing our awareness of the critical role of the millions of organisms living on and within us in maintaining health and fighting disease. For example, we now realize that eradicating all the commensals in our gastrointestinal tract has unintended and very negative consequences and, for patients whose good bacteria have been eliminated, fecal transplant is a therapeutic option. Therefore, it stands to reason that the microbes found in the vagina contribute significantly to women’s overall reproductive health.
The publication of the groundbreaking study characterizing the vaginal microbiome species in reproductive-age women opened new avenues of research into how these organisms contribute to women’s health. Importantly, this work, led initially by Jacques Ravel, PhD, a professor in the department of microbiology & immunology and associate director of the Institute for Genome Sciences at the University of Maryland School of Medicine, has spawned additional investigations into the potential role of the vaginal microbiome in preterm birth.
To provide some insight into the research around how the microorganisms in the vagina may induce or prevent preterm birth is our guest author, Michal A. Elovitz, MD, the Hilarie L. Morgan and Mitchell L. Morgan President’s Distinguished Professor in Women’s Health, vice chair of translational research, and director of the Maternal and Child Health Research Center, department of obstetrics and gynecology, at the University of Pennsylvania, Philadelphia.
Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland School of Medicine as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at obnews@mdedge.com.
Preventing infant mortality remains a significant challenge for ob.gyns. Despite the availability of a multitude of preventive and treatment options and some of the best possible medical care offered in the world, the United States lags behind many other developed and developing countries in its rate of infant deaths, which was an estimated 5.8 deaths per 1,000 live births in 2017. We can, and must, do better.
One of the major contributing factors to infant mortality is preterm birth. Defined as birth occurring prior to 37 weeks’ gestation, preterm birth is associated with a myriad of severe neonatal sequelae: low birth weight, bacterial sepsis, neonatal hemorrhage, and respiratory distress syndrome, among others. Therefore, many within the clinical and biomedical research spheres recognize that preventing preterm birth means reducing infant deaths.
However, therein lies the conundrum. We know very little about what causes preterm birth, which renders the current therapeutic strategies – such as use of progesterone supplements or cerclage placement – good for some but not all patients. It is thus vital to continue research to unravel the underlying mechanisms of preterm birth.
A promising area of investigation is the field of microbiome research, which has made great strides in advancing our awareness of the critical role of the millions of organisms living on and within us in maintaining health and fighting disease. For example, we now realize that eradicating all the commensals in our gastrointestinal tract has unintended and very negative consequences and, for patients whose good bacteria have been eliminated, fecal transplant is a therapeutic option. Therefore, it stands to reason that the microbes found in the vagina contribute significantly to women’s overall reproductive health.
The publication of the groundbreaking study characterizing the vaginal microbiome species in reproductive-age women opened new avenues of research into how these organisms contribute to women’s health. Importantly, this work, led initially by Jacques Ravel, PhD, a professor in the department of microbiology & immunology and associate director of the Institute for Genome Sciences at the University of Maryland School of Medicine, has spawned additional investigations into the potential role of the vaginal microbiome in preterm birth.
To provide some insight into the research around how the microorganisms in the vagina may induce or prevent preterm birth is our guest author, Michal A. Elovitz, MD, the Hilarie L. Morgan and Mitchell L. Morgan President’s Distinguished Professor in Women’s Health, vice chair of translational research, and director of the Maternal and Child Health Research Center, department of obstetrics and gynecology, at the University of Pennsylvania, Philadelphia.
Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland School of Medicine as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at obnews@mdedge.com.
Preventing infant mortality remains a significant challenge for ob.gyns. Despite the availability of a multitude of preventive and treatment options and some of the best possible medical care offered in the world, the United States lags behind many other developed and developing countries in its rate of infant deaths, which was an estimated 5.8 deaths per 1,000 live births in 2017. We can, and must, do better.
One of the major contributing factors to infant mortality is preterm birth. Defined as birth occurring prior to 37 weeks’ gestation, preterm birth is associated with a myriad of severe neonatal sequelae: low birth weight, bacterial sepsis, neonatal hemorrhage, and respiratory distress syndrome, among others. Therefore, many within the clinical and biomedical research spheres recognize that preventing preterm birth means reducing infant deaths.
However, therein lies the conundrum. We know very little about what causes preterm birth, which renders the current therapeutic strategies – such as use of progesterone supplements or cerclage placement – good for some but not all patients. It is thus vital to continue research to unravel the underlying mechanisms of preterm birth.
A promising area of investigation is the field of microbiome research, which has made great strides in advancing our awareness of the critical role of the millions of organisms living on and within us in maintaining health and fighting disease. For example, we now realize that eradicating all the commensals in our gastrointestinal tract has unintended and very negative consequences and, for patients whose good bacteria have been eliminated, fecal transplant is a therapeutic option. Therefore, it stands to reason that the microbes found in the vagina contribute significantly to women’s overall reproductive health.
The publication of the groundbreaking study characterizing the vaginal microbiome species in reproductive-age women opened new avenues of research into how these organisms contribute to women’s health. Importantly, this work, led initially by Jacques Ravel, PhD, a professor in the department of microbiology & immunology and associate director of the Institute for Genome Sciences at the University of Maryland School of Medicine, has spawned additional investigations into the potential role of the vaginal microbiome in preterm birth.
To provide some insight into the research around how the microorganisms in the vagina may induce or prevent preterm birth is our guest author, Michal A. Elovitz, MD, the Hilarie L. Morgan and Mitchell L. Morgan President’s Distinguished Professor in Women’s Health, vice chair of translational research, and director of the Maternal and Child Health Research Center, department of obstetrics and gynecology, at the University of Pennsylvania, Philadelphia.
Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland School of Medicine as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at obnews@mdedge.com.
Labor & Delivery: An overlooked entry point for the spread of viral infection
OB hospitalists have a key role to play
A novel coronavirus originating in Wuhan, China, has killed more than 2,800 people and infected more than 81,000 individuals globally. Public health officials around the world and in the United States are working together to contain the outbreak.
There are 57 confirmed cases in the United States, including 18 people evacuated from the Diamond Princess, a cruise ship docked in Yokohama, Japan.1 But the focus on coronavirus, even in early months of the epidemic, serves as an opportunity to revisit the spread of viral disease in hospital settings.
Multiple points of viral entry
In truth, most hospitals are well prepared for the coronavirus, starting with the same place they prepare for most infectious disease epidemics – the emergency department. Patients who seek treatment for early onset symptoms may start with their primary care physicians, but increasing numbers of patients with respiratory concerns and/or infection-related symptoms will first seek medical attention in an emergency care setting.2
Many experts have acknowledged the ED as a viral point of entry, including the American College of Emergency Physicians (ACEP), which produced an excellent guide for management of influenza that details prevention, diagnoses, and treatment protocols in an ED setting.3
But another important, and often forgotten, point of entry in a hospital setting is the obstetrical (OB) Labor & Delivery (L&D) department. Although triage for most patients begins in the main ED, in almost every hospital in the United States, women who present with pregnancy-related issues are sent directly to and triaged in L&D, where – when the proper protocols are not in place – they may transmit viral infection to others.
Pregnancy imparts higher risk
“High risk” is often associated with older, immune-compromised adults. But pregnant women who may appear “healthy” are actually in a state that a 2015 study calls “immunosuppressed” whereby the “… pregnant woman actually undergoes an immunological transformation, where the immune system is necessary to promote and support the pregnancy and growing fetus.”4 Pregnant women, or women with newborns or babies, are at higher risk when exposed to viral infection, with a higher mortality risk than the general population.5 In the best cases, women who contract viral infections are treated carefully and recover fully. In the worst cases, they end up on ventilators and can even die as a result.
Although we are still learning about the Wuhan coronavirus, we already know it is a respiratory illness with a lot of the same characteristics as the influenza virus, and that it is transmitted through droplets (such as a sneeze) or via bodily secretions. Given the extreme vulnerability and physician exposure of women giving birth – in which not one, but two lives are involved – viruses like coronavirus can pose extreme risk. What’s more, public health researchers are still learning about potential transmission of coronavirus from mothers to babies. In the international cases of infant exposure to coronavirus, the newborn showed symptoms within 36 hours of being born, but it is unclear if exposure happened in utero or was vertical transmission after birth.6
Role of OB hospitalists in identifying risk and treating viral infection
Regardless of the type of virus, OB hospitalists are key to screening for viral exposure and care for women, fetuses, and newborns. Given their 24/7 presence and experience with women in L&D, they must champion protocols and precautions that align with those in an ED.
For coronavirus, if a woman presents in L&D with a cough, difficulty breathing, or signs of pneumonia, clinicians should be accustomed to asking about travel to China within the last 14 days and whether the patient has been around someone who has recently traveled to China. If the answer to either question is yes, the woman needs to be immediately placed in a single patient room at negative pressure relative to the surrounding areas, with a minimum of six air changes per hour.
Diagnostic testing should immediately follow. The U.S. Food and Drug Administration just issued Emergency Use Authorization (EUA) for the first commercially-available coronavirus diagnostic test, allowing the use of the test at any lab across the country qualified by the Centers for Disease Control and Prevention.7
If exposure is suspected, containment is paramount until definitive results of diagnostic testing are received. The CDC recommends “Standard Precautions,” which assume that every person is potentially infected or colonized with a pathogen that could be transmitted in the health care setting. These precautions include hand hygiene and personal protective equipment (PPE) to ensure health care workers are not exposed.8
In short, protocols in L&D should mirror those of the ED. But in L&D, clinicians and staff haven’t necessarily been trained to look for or ask for these conditions. Hospitalists can educate their peers and colleagues and advocate for changes at the administrative level.
Biggest current threat: The flu
The coronavirus may eventually present a threat in the United States, but as yet, it is a largely unrealized one. From the perspective of an obstetrician, more immediately concerning is the risk of other viral infections. Although viruses like Ebola and Zika capture headlines, influenza remains the most serious threat to pregnant women in the United States.
According to an article by my colleague, Dr. Mark Simon, “pregnant women and their unborn babies are especially vulnerable to influenza and are more likely to develop serious complications from it … pregnant women who develop the flu are more likely to give birth to children with birth defects of the brain and spine.”9
As of Feb. 1, 2020, the CDC estimates there have been at least 22 million flu illnesses, 210,000 hospitalizations, and 12,000 deaths from flu in the 2019-2020 flu season.10 But the CDC data also suggest that only 54% of pregnant women were vaccinated for influenza in 2019 before or during their pregnancy.11 Hospitalists should ensure that patients diagnosed with flu are quickly and safely treated with antivirals at all stages of their pregnancy to keep them and their babies safe, as well as keep others safe from infection.
Hospitalists can also advocate for across-the-board protocols for the spread of viral illness. The same protocols that protect us from the flu will also protect against coronavirus and viruses that will emerge in the future. Foremost, pregnant women, regardless of trimester, need to receive a flu shot. Women who are pregnant and receive a flu shot can pass on immunity in vitro, and nursing mothers can deliver immunizing agents in their breast milk to their newborn.
Given that hospitalists serve in roles as patient-facing physicians, we should be doing more to protect the public from viral spread, whether coronavirus, influenza, or whatever new viruses the future may hold.
Dr. Dimino is a board-certified ob.gyn. and a Houston-based OB hospitalist with Ob Hospitalist Group. She serves as a faculty member of the TexasAIM Plus Obstetric Hemorrhage Learning Collaborative and currently serves on the Texas Medical Association Council of Science and Public Health.
References
1. The New York Times. Tracking the Coronavirus Map: Tracking the Spread of the Outbreak. Accessed Feb 24, 2020.
2. Agency for Healthcare Research and Quality. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. Accessed Feb 10, 2020.
3. Influenza Emergency Department Best Practices. ACEP Public Health & Injury Prevention Committee, Epidemic Expert Panel, https://www.acep.org/globalassets/uploads/uploaded-files/acep/by-medical-focus/influenza-emergency-department-best-practices.pdf.
4. Silasi M, Cardenas I, Kwon JY, Racicot K, Aldo P, Mor G. Viral infections during pregnancy. Am J Reprod Immunol. 2015;73(3):199-213.
5. Kwon JY, Romero R, Mor G. New insights into the relationship between viral infection and pregnancy complications. Am J Reprod Immunol. 2014;71:387-390.
6. BBC. Coronavirus: Newborn becomes youngest person diagnosed with virus. Accessed Feb 10, 2020.
7. FDA press release. FDA Takes Significant Step in Coronavirus Response Efforts, Issues Emergency Use Authorization for the First 2019 Novel Coronavirus Diagnostic. Feb 4, 2020.
8. CDC. Interim Infection Prevention and Control Recommendations for Patients with Confirmed 2019 Novel Coronavirus (2019-nCoV) or Persons Under Investigation for 2019-nCoV in Healthcare Settings. Accessed Feb 10, 2020.
9. STAT First Opinion. Two-thirds of pregnant women aren’t getting the flu vaccine. That needs to change. Jan 18, 2018.
10. CDC. Weekly U.S. Influenza Surveillance Report, Key Updates for Week 5, ending February 1, 2020.
11. CDC. Vaccinating Pregnant Women Protects Moms and Babies. Accessed Feb 10, 2020.
OB hospitalists have a key role to play
OB hospitalists have a key role to play
A novel coronavirus originating in Wuhan, China, has killed more than 2,800 people and infected more than 81,000 individuals globally. Public health officials around the world and in the United States are working together to contain the outbreak.
There are 57 confirmed cases in the United States, including 18 people evacuated from the Diamond Princess, a cruise ship docked in Yokohama, Japan.1 But the focus on coronavirus, even in early months of the epidemic, serves as an opportunity to revisit the spread of viral disease in hospital settings.
Multiple points of viral entry
In truth, most hospitals are well prepared for the coronavirus, starting with the same place they prepare for most infectious disease epidemics – the emergency department. Patients who seek treatment for early onset symptoms may start with their primary care physicians, but increasing numbers of patients with respiratory concerns and/or infection-related symptoms will first seek medical attention in an emergency care setting.2
Many experts have acknowledged the ED as a viral point of entry, including the American College of Emergency Physicians (ACEP), which produced an excellent guide for management of influenza that details prevention, diagnoses, and treatment protocols in an ED setting.3
But another important, and often forgotten, point of entry in a hospital setting is the obstetrical (OB) Labor & Delivery (L&D) department. Although triage for most patients begins in the main ED, in almost every hospital in the United States, women who present with pregnancy-related issues are sent directly to and triaged in L&D, where – when the proper protocols are not in place – they may transmit viral infection to others.
Pregnancy imparts higher risk
“High risk” is often associated with older, immune-compromised adults. But pregnant women who may appear “healthy” are actually in a state that a 2015 study calls “immunosuppressed” whereby the “… pregnant woman actually undergoes an immunological transformation, where the immune system is necessary to promote and support the pregnancy and growing fetus.”4 Pregnant women, or women with newborns or babies, are at higher risk when exposed to viral infection, with a higher mortality risk than the general population.5 In the best cases, women who contract viral infections are treated carefully and recover fully. In the worst cases, they end up on ventilators and can even die as a result.
Although we are still learning about the Wuhan coronavirus, we already know it is a respiratory illness with a lot of the same characteristics as the influenza virus, and that it is transmitted through droplets (such as a sneeze) or via bodily secretions. Given the extreme vulnerability and physician exposure of women giving birth – in which not one, but two lives are involved – viruses like coronavirus can pose extreme risk. What’s more, public health researchers are still learning about potential transmission of coronavirus from mothers to babies. In the international cases of infant exposure to coronavirus, the newborn showed symptoms within 36 hours of being born, but it is unclear if exposure happened in utero or was vertical transmission after birth.6
Role of OB hospitalists in identifying risk and treating viral infection
Regardless of the type of virus, OB hospitalists are key to screening for viral exposure and care for women, fetuses, and newborns. Given their 24/7 presence and experience with women in L&D, they must champion protocols and precautions that align with those in an ED.
For coronavirus, if a woman presents in L&D with a cough, difficulty breathing, or signs of pneumonia, clinicians should be accustomed to asking about travel to China within the last 14 days and whether the patient has been around someone who has recently traveled to China. If the answer to either question is yes, the woman needs to be immediately placed in a single patient room at negative pressure relative to the surrounding areas, with a minimum of six air changes per hour.
Diagnostic testing should immediately follow. The U.S. Food and Drug Administration just issued Emergency Use Authorization (EUA) for the first commercially-available coronavirus diagnostic test, allowing the use of the test at any lab across the country qualified by the Centers for Disease Control and Prevention.7
If exposure is suspected, containment is paramount until definitive results of diagnostic testing are received. The CDC recommends “Standard Precautions,” which assume that every person is potentially infected or colonized with a pathogen that could be transmitted in the health care setting. These precautions include hand hygiene and personal protective equipment (PPE) to ensure health care workers are not exposed.8
In short, protocols in L&D should mirror those of the ED. But in L&D, clinicians and staff haven’t necessarily been trained to look for or ask for these conditions. Hospitalists can educate their peers and colleagues and advocate for changes at the administrative level.
Biggest current threat: The flu
The coronavirus may eventually present a threat in the United States, but as yet, it is a largely unrealized one. From the perspective of an obstetrician, more immediately concerning is the risk of other viral infections. Although viruses like Ebola and Zika capture headlines, influenza remains the most serious threat to pregnant women in the United States.
According to an article by my colleague, Dr. Mark Simon, “pregnant women and their unborn babies are especially vulnerable to influenza and are more likely to develop serious complications from it … pregnant women who develop the flu are more likely to give birth to children with birth defects of the brain and spine.”9
As of Feb. 1, 2020, the CDC estimates there have been at least 22 million flu illnesses, 210,000 hospitalizations, and 12,000 deaths from flu in the 2019-2020 flu season.10 But the CDC data also suggest that only 54% of pregnant women were vaccinated for influenza in 2019 before or during their pregnancy.11 Hospitalists should ensure that patients diagnosed with flu are quickly and safely treated with antivirals at all stages of their pregnancy to keep them and their babies safe, as well as keep others safe from infection.
Hospitalists can also advocate for across-the-board protocols for the spread of viral illness. The same protocols that protect us from the flu will also protect against coronavirus and viruses that will emerge in the future. Foremost, pregnant women, regardless of trimester, need to receive a flu shot. Women who are pregnant and receive a flu shot can pass on immunity in vitro, and nursing mothers can deliver immunizing agents in their breast milk to their newborn.
Given that hospitalists serve in roles as patient-facing physicians, we should be doing more to protect the public from viral spread, whether coronavirus, influenza, or whatever new viruses the future may hold.
Dr. Dimino is a board-certified ob.gyn. and a Houston-based OB hospitalist with Ob Hospitalist Group. She serves as a faculty member of the TexasAIM Plus Obstetric Hemorrhage Learning Collaborative and currently serves on the Texas Medical Association Council of Science and Public Health.
References
1. The New York Times. Tracking the Coronavirus Map: Tracking the Spread of the Outbreak. Accessed Feb 24, 2020.
2. Agency for Healthcare Research and Quality. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. Accessed Feb 10, 2020.
3. Influenza Emergency Department Best Practices. ACEP Public Health & Injury Prevention Committee, Epidemic Expert Panel, https://www.acep.org/globalassets/uploads/uploaded-files/acep/by-medical-focus/influenza-emergency-department-best-practices.pdf.
4. Silasi M, Cardenas I, Kwon JY, Racicot K, Aldo P, Mor G. Viral infections during pregnancy. Am J Reprod Immunol. 2015;73(3):199-213.
5. Kwon JY, Romero R, Mor G. New insights into the relationship between viral infection and pregnancy complications. Am J Reprod Immunol. 2014;71:387-390.
6. BBC. Coronavirus: Newborn becomes youngest person diagnosed with virus. Accessed Feb 10, 2020.
7. FDA press release. FDA Takes Significant Step in Coronavirus Response Efforts, Issues Emergency Use Authorization for the First 2019 Novel Coronavirus Diagnostic. Feb 4, 2020.
8. CDC. Interim Infection Prevention and Control Recommendations for Patients with Confirmed 2019 Novel Coronavirus (2019-nCoV) or Persons Under Investigation for 2019-nCoV in Healthcare Settings. Accessed Feb 10, 2020.
9. STAT First Opinion. Two-thirds of pregnant women aren’t getting the flu vaccine. That needs to change. Jan 18, 2018.
10. CDC. Weekly U.S. Influenza Surveillance Report, Key Updates for Week 5, ending February 1, 2020.
11. CDC. Vaccinating Pregnant Women Protects Moms and Babies. Accessed Feb 10, 2020.
A novel coronavirus originating in Wuhan, China, has killed more than 2,800 people and infected more than 81,000 individuals globally. Public health officials around the world and in the United States are working together to contain the outbreak.
There are 57 confirmed cases in the United States, including 18 people evacuated from the Diamond Princess, a cruise ship docked in Yokohama, Japan.1 But the focus on coronavirus, even in early months of the epidemic, serves as an opportunity to revisit the spread of viral disease in hospital settings.
Multiple points of viral entry
In truth, most hospitals are well prepared for the coronavirus, starting with the same place they prepare for most infectious disease epidemics – the emergency department. Patients who seek treatment for early onset symptoms may start with their primary care physicians, but increasing numbers of patients with respiratory concerns and/or infection-related symptoms will first seek medical attention in an emergency care setting.2
Many experts have acknowledged the ED as a viral point of entry, including the American College of Emergency Physicians (ACEP), which produced an excellent guide for management of influenza that details prevention, diagnoses, and treatment protocols in an ED setting.3
But another important, and often forgotten, point of entry in a hospital setting is the obstetrical (OB) Labor & Delivery (L&D) department. Although triage for most patients begins in the main ED, in almost every hospital in the United States, women who present with pregnancy-related issues are sent directly to and triaged in L&D, where – when the proper protocols are not in place – they may transmit viral infection to others.
Pregnancy imparts higher risk
“High risk” is often associated with older, immune-compromised adults. But pregnant women who may appear “healthy” are actually in a state that a 2015 study calls “immunosuppressed” whereby the “… pregnant woman actually undergoes an immunological transformation, where the immune system is necessary to promote and support the pregnancy and growing fetus.”4 Pregnant women, or women with newborns or babies, are at higher risk when exposed to viral infection, with a higher mortality risk than the general population.5 In the best cases, women who contract viral infections are treated carefully and recover fully. In the worst cases, they end up on ventilators and can even die as a result.
Although we are still learning about the Wuhan coronavirus, we already know it is a respiratory illness with a lot of the same characteristics as the influenza virus, and that it is transmitted through droplets (such as a sneeze) or via bodily secretions. Given the extreme vulnerability and physician exposure of women giving birth – in which not one, but two lives are involved – viruses like coronavirus can pose extreme risk. What’s more, public health researchers are still learning about potential transmission of coronavirus from mothers to babies. In the international cases of infant exposure to coronavirus, the newborn showed symptoms within 36 hours of being born, but it is unclear if exposure happened in utero or was vertical transmission after birth.6
Role of OB hospitalists in identifying risk and treating viral infection
Regardless of the type of virus, OB hospitalists are key to screening for viral exposure and care for women, fetuses, and newborns. Given their 24/7 presence and experience with women in L&D, they must champion protocols and precautions that align with those in an ED.
For coronavirus, if a woman presents in L&D with a cough, difficulty breathing, or signs of pneumonia, clinicians should be accustomed to asking about travel to China within the last 14 days and whether the patient has been around someone who has recently traveled to China. If the answer to either question is yes, the woman needs to be immediately placed in a single patient room at negative pressure relative to the surrounding areas, with a minimum of six air changes per hour.
Diagnostic testing should immediately follow. The U.S. Food and Drug Administration just issued Emergency Use Authorization (EUA) for the first commercially-available coronavirus diagnostic test, allowing the use of the test at any lab across the country qualified by the Centers for Disease Control and Prevention.7
If exposure is suspected, containment is paramount until definitive results of diagnostic testing are received. The CDC recommends “Standard Precautions,” which assume that every person is potentially infected or colonized with a pathogen that could be transmitted in the health care setting. These precautions include hand hygiene and personal protective equipment (PPE) to ensure health care workers are not exposed.8
In short, protocols in L&D should mirror those of the ED. But in L&D, clinicians and staff haven’t necessarily been trained to look for or ask for these conditions. Hospitalists can educate their peers and colleagues and advocate for changes at the administrative level.
Biggest current threat: The flu
The coronavirus may eventually present a threat in the United States, but as yet, it is a largely unrealized one. From the perspective of an obstetrician, more immediately concerning is the risk of other viral infections. Although viruses like Ebola and Zika capture headlines, influenza remains the most serious threat to pregnant women in the United States.
According to an article by my colleague, Dr. Mark Simon, “pregnant women and their unborn babies are especially vulnerable to influenza and are more likely to develop serious complications from it … pregnant women who develop the flu are more likely to give birth to children with birth defects of the brain and spine.”9
As of Feb. 1, 2020, the CDC estimates there have been at least 22 million flu illnesses, 210,000 hospitalizations, and 12,000 deaths from flu in the 2019-2020 flu season.10 But the CDC data also suggest that only 54% of pregnant women were vaccinated for influenza in 2019 before or during their pregnancy.11 Hospitalists should ensure that patients diagnosed with flu are quickly and safely treated with antivirals at all stages of their pregnancy to keep them and their babies safe, as well as keep others safe from infection.
Hospitalists can also advocate for across-the-board protocols for the spread of viral illness. The same protocols that protect us from the flu will also protect against coronavirus and viruses that will emerge in the future. Foremost, pregnant women, regardless of trimester, need to receive a flu shot. Women who are pregnant and receive a flu shot can pass on immunity in vitro, and nursing mothers can deliver immunizing agents in their breast milk to their newborn.
Given that hospitalists serve in roles as patient-facing physicians, we should be doing more to protect the public from viral spread, whether coronavirus, influenza, or whatever new viruses the future may hold.
Dr. Dimino is a board-certified ob.gyn. and a Houston-based OB hospitalist with Ob Hospitalist Group. She serves as a faculty member of the TexasAIM Plus Obstetric Hemorrhage Learning Collaborative and currently serves on the Texas Medical Association Council of Science and Public Health.
References
1. The New York Times. Tracking the Coronavirus Map: Tracking the Spread of the Outbreak. Accessed Feb 24, 2020.
2. Agency for Healthcare Research and Quality. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. Accessed Feb 10, 2020.
3. Influenza Emergency Department Best Practices. ACEP Public Health & Injury Prevention Committee, Epidemic Expert Panel, https://www.acep.org/globalassets/uploads/uploaded-files/acep/by-medical-focus/influenza-emergency-department-best-practices.pdf.
4. Silasi M, Cardenas I, Kwon JY, Racicot K, Aldo P, Mor G. Viral infections during pregnancy. Am J Reprod Immunol. 2015;73(3):199-213.
5. Kwon JY, Romero R, Mor G. New insights into the relationship between viral infection and pregnancy complications. Am J Reprod Immunol. 2014;71:387-390.
6. BBC. Coronavirus: Newborn becomes youngest person diagnosed with virus. Accessed Feb 10, 2020.
7. FDA press release. FDA Takes Significant Step in Coronavirus Response Efforts, Issues Emergency Use Authorization for the First 2019 Novel Coronavirus Diagnostic. Feb 4, 2020.
8. CDC. Interim Infection Prevention and Control Recommendations for Patients with Confirmed 2019 Novel Coronavirus (2019-nCoV) or Persons Under Investigation for 2019-nCoV in Healthcare Settings. Accessed Feb 10, 2020.
9. STAT First Opinion. Two-thirds of pregnant women aren’t getting the flu vaccine. That needs to change. Jan 18, 2018.
10. CDC. Weekly U.S. Influenza Surveillance Report, Key Updates for Week 5, ending February 1, 2020.
11. CDC. Vaccinating Pregnant Women Protects Moms and Babies. Accessed Feb 10, 2020.
ACIP: Flu vaccines for older adults show similar safety profiles
The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) recommends that age-appropriate vaccines be used when possible, said Kenneth E. Schmader, MD, professor of medicine at Duke University, Durham, N.C. However, no study to date had directly compared the safety of the trivalent high dose (HD-IIV3) and adjuvanted (aIIV3) vaccines or their impact on health-related quality of life. Dr. Schmader presented findings from a randomized trial at the February ACIP meeting.
To compare the safety of the vaccines, the researchers recruited community-dwelling volunteers aged 65 years and older who were cognitively intact, not immunosuppressed, and had no contraindications for influenza vaccination. A total of 378 individuals were randomized to aIIV3 and 379 to HD-IIV3. The average age was 72 years; 80 individuals in the aIIV3 group and 83 in the HDIIV3 group were 80 years and older. The primary outcome was moderate or severe injection site pain.
Overall, the proportion of participants with moderate or severe injection site pain was not significantly different after aIIV3 vs. HD-IIV3 (3.2% vs. 5.8%).
Nine participants in the aIIV3 group and three participants in the HD-IIV3 group experienced at least one serious adverse event, but no serious adverse events were deemed vaccine related, and the occurrence of serious adverse events was not significantly different between groups.
In addition, measures of short-term, postvaccination health-related quality of life were not significantly different between the groups. Changes in scores from day 1 prevaccination to day 3 postvaccination on the EuroQOL-5 dimensions-5 levels (EQ-5D-5L) were –0.05 for both groups.
The findings were limited in part by the lack of inclusion of older adults in nursing homes or similar settings, Dr. Schmader noted. However, the results suggest that “from the standpoint of safety, either vaccine is an acceptable option for the prevention of influenza in older adults.”
Studies comparing the immunogenicity of the vaccines are ongoing, and the data should be available within the next few months, he noted.
Dr. Schmader had no financial conflicts to disclose.
The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) recommends that age-appropriate vaccines be used when possible, said Kenneth E. Schmader, MD, professor of medicine at Duke University, Durham, N.C. However, no study to date had directly compared the safety of the trivalent high dose (HD-IIV3) and adjuvanted (aIIV3) vaccines or their impact on health-related quality of life. Dr. Schmader presented findings from a randomized trial at the February ACIP meeting.
To compare the safety of the vaccines, the researchers recruited community-dwelling volunteers aged 65 years and older who were cognitively intact, not immunosuppressed, and had no contraindications for influenza vaccination. A total of 378 individuals were randomized to aIIV3 and 379 to HD-IIV3. The average age was 72 years; 80 individuals in the aIIV3 group and 83 in the HDIIV3 group were 80 years and older. The primary outcome was moderate or severe injection site pain.
Overall, the proportion of participants with moderate or severe injection site pain was not significantly different after aIIV3 vs. HD-IIV3 (3.2% vs. 5.8%).
Nine participants in the aIIV3 group and three participants in the HD-IIV3 group experienced at least one serious adverse event, but no serious adverse events were deemed vaccine related, and the occurrence of serious adverse events was not significantly different between groups.
In addition, measures of short-term, postvaccination health-related quality of life were not significantly different between the groups. Changes in scores from day 1 prevaccination to day 3 postvaccination on the EuroQOL-5 dimensions-5 levels (EQ-5D-5L) were –0.05 for both groups.
The findings were limited in part by the lack of inclusion of older adults in nursing homes or similar settings, Dr. Schmader noted. However, the results suggest that “from the standpoint of safety, either vaccine is an acceptable option for the prevention of influenza in older adults.”
Studies comparing the immunogenicity of the vaccines are ongoing, and the data should be available within the next few months, he noted.
Dr. Schmader had no financial conflicts to disclose.
The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) recommends that age-appropriate vaccines be used when possible, said Kenneth E. Schmader, MD, professor of medicine at Duke University, Durham, N.C. However, no study to date had directly compared the safety of the trivalent high dose (HD-IIV3) and adjuvanted (aIIV3) vaccines or their impact on health-related quality of life. Dr. Schmader presented findings from a randomized trial at the February ACIP meeting.
To compare the safety of the vaccines, the researchers recruited community-dwelling volunteers aged 65 years and older who were cognitively intact, not immunosuppressed, and had no contraindications for influenza vaccination. A total of 378 individuals were randomized to aIIV3 and 379 to HD-IIV3. The average age was 72 years; 80 individuals in the aIIV3 group and 83 in the HDIIV3 group were 80 years and older. The primary outcome was moderate or severe injection site pain.
Overall, the proportion of participants with moderate or severe injection site pain was not significantly different after aIIV3 vs. HD-IIV3 (3.2% vs. 5.8%).
Nine participants in the aIIV3 group and three participants in the HD-IIV3 group experienced at least one serious adverse event, but no serious adverse events were deemed vaccine related, and the occurrence of serious adverse events was not significantly different between groups.
In addition, measures of short-term, postvaccination health-related quality of life were not significantly different between the groups. Changes in scores from day 1 prevaccination to day 3 postvaccination on the EuroQOL-5 dimensions-5 levels (EQ-5D-5L) were –0.05 for both groups.
The findings were limited in part by the lack of inclusion of older adults in nursing homes or similar settings, Dr. Schmader noted. However, the results suggest that “from the standpoint of safety, either vaccine is an acceptable option for the prevention of influenza in older adults.”
Studies comparing the immunogenicity of the vaccines are ongoing, and the data should be available within the next few months, he noted.
Dr. Schmader had no financial conflicts to disclose.
FROM AN ACIP MEETING
Research protocol overkill
This is a lot of paper.
It’s not a chart. Or mortgage forms. Or Family and Medical Leave Act paperwork.
It’s a research protocol for a study I’m involved in.
Now, I understand that research needs detailed protocols. It’s serious business, and when it’s happening at multiple sites they all need to know exactly what the plan is, what steps should be followed, who qualifies and who doesn’t, and so on.
But here’s what irritates me: That huge pile showed up at my office about an hour after all of the same documents were delivered to me by email, as PDFs.
Not only that, but someone had paid a messenger service to get them to me promptly. When I asked why I was told “because it’s the protocol that each site have both paper and digital copies.”
I don’t understand this at all. To me, the whole thing seems pretty wasteful on multiple levels. I’m told there are 28 sites for this study, so there’s a minimum stack of 28 times that one involved. Of course, each site probably has three to five copies (at least). Then, if the protocol is amended in a few months ... you get the idea.
To me this seems ridiculously wasteful. That’s a lot of paper and ink and shipping charges. If the whole thing can be sent digitally for a lot less money, why are they requiring both? If they need a signed signature sheet saying I read it, why not just print up that sheet? It’s one page instead of a huge pile. If I can digitally sign a document to refinance my house, why can’t I do it to acknowledge reading the protocol? I’m more likely to read study data on my iPad, anyway.
Not only that, now I have to store that stack in my office for several years, in spite of also having it on my hard drive.
Obviously, this is just a fraction of research costs, but it’s still money wasted.
The environmental issues of trees, water to make paper, the ink cartridges, and fuel to transport documents are all there, too. I could certainly go on.
I guess the overlying problem is that we’re still between two worlds (paper and digital) and, in spite of the marked shift to the latter, many are still insisting we try to live in both. At some point it gets silly. And costly.
I’m sure we won’t become completely paperless in my career, but there are plenty of ways we can eliminate its often-unnecessary overhead. Money is just the most obvious one.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
This is a lot of paper.
It’s not a chart. Or mortgage forms. Or Family and Medical Leave Act paperwork.
It’s a research protocol for a study I’m involved in.
Now, I understand that research needs detailed protocols. It’s serious business, and when it’s happening at multiple sites they all need to know exactly what the plan is, what steps should be followed, who qualifies and who doesn’t, and so on.
But here’s what irritates me: That huge pile showed up at my office about an hour after all of the same documents were delivered to me by email, as PDFs.
Not only that, but someone had paid a messenger service to get them to me promptly. When I asked why I was told “because it’s the protocol that each site have both paper and digital copies.”
I don’t understand this at all. To me, the whole thing seems pretty wasteful on multiple levels. I’m told there are 28 sites for this study, so there’s a minimum stack of 28 times that one involved. Of course, each site probably has three to five copies (at least). Then, if the protocol is amended in a few months ... you get the idea.
To me this seems ridiculously wasteful. That’s a lot of paper and ink and shipping charges. If the whole thing can be sent digitally for a lot less money, why are they requiring both? If they need a signed signature sheet saying I read it, why not just print up that sheet? It’s one page instead of a huge pile. If I can digitally sign a document to refinance my house, why can’t I do it to acknowledge reading the protocol? I’m more likely to read study data on my iPad, anyway.
Not only that, now I have to store that stack in my office for several years, in spite of also having it on my hard drive.
Obviously, this is just a fraction of research costs, but it’s still money wasted.
The environmental issues of trees, water to make paper, the ink cartridges, and fuel to transport documents are all there, too. I could certainly go on.
I guess the overlying problem is that we’re still between two worlds (paper and digital) and, in spite of the marked shift to the latter, many are still insisting we try to live in both. At some point it gets silly. And costly.
I’m sure we won’t become completely paperless in my career, but there are plenty of ways we can eliminate its often-unnecessary overhead. Money is just the most obvious one.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
This is a lot of paper.
It’s not a chart. Or mortgage forms. Or Family and Medical Leave Act paperwork.
It’s a research protocol for a study I’m involved in.
Now, I understand that research needs detailed protocols. It’s serious business, and when it’s happening at multiple sites they all need to know exactly what the plan is, what steps should be followed, who qualifies and who doesn’t, and so on.
But here’s what irritates me: That huge pile showed up at my office about an hour after all of the same documents were delivered to me by email, as PDFs.
Not only that, but someone had paid a messenger service to get them to me promptly. When I asked why I was told “because it’s the protocol that each site have both paper and digital copies.”
I don’t understand this at all. To me, the whole thing seems pretty wasteful on multiple levels. I’m told there are 28 sites for this study, so there’s a minimum stack of 28 times that one involved. Of course, each site probably has three to five copies (at least). Then, if the protocol is amended in a few months ... you get the idea.
To me this seems ridiculously wasteful. That’s a lot of paper and ink and shipping charges. If the whole thing can be sent digitally for a lot less money, why are they requiring both? If they need a signed signature sheet saying I read it, why not just print up that sheet? It’s one page instead of a huge pile. If I can digitally sign a document to refinance my house, why can’t I do it to acknowledge reading the protocol? I’m more likely to read study data on my iPad, anyway.
Not only that, now I have to store that stack in my office for several years, in spite of also having it on my hard drive.
Obviously, this is just a fraction of research costs, but it’s still money wasted.
The environmental issues of trees, water to make paper, the ink cartridges, and fuel to transport documents are all there, too. I could certainly go on.
I guess the overlying problem is that we’re still between two worlds (paper and digital) and, in spite of the marked shift to the latter, many are still insisting we try to live in both. At some point it gets silly. And costly.
I’m sure we won’t become completely paperless in my career, but there are plenty of ways we can eliminate its often-unnecessary overhead. Money is just the most obvious one.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
FDA approves neratinib in combination for metastatic HER2-positive breast cancer
The Food and Drug Administration has approved neratinib (NERLYNX) in combination with capecitabine for use in adults with advanced or metastatic HER2-positive breast cancer who have received at least two prior anti-HER2 based regimens in the metastatic setting.
The recommended dose for neratinib in this population is 240 mg once daily with food on days 1-21 of a 21-day cycle. Neratinib should be given with capecitabine at 750 mg/m2 twice daily on days 1-14 until progression or unacceptable toxicity.
The full prescribing information for neratinib is available from the FDA website.
The FDA’s new approval of neratinib is based on results from the NALA trial (NCT01808573). The trial enrolled 621 patients with metastatic HER2-positive breast cancer who had received at least two prior anti-HER2 based regimens in the metastatic setting.
The patients were randomized to neratinib plus capecitabine or lapatinib plus capecitabine and received treatment until progression or unacceptable toxicity.
The objective response rate was 32.8% in the neratinib arm and 26.7% in the lapatinib arm. The median duration of response was 8.5 months and 5.6 months, respectively.
The median progression-free survival was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (hazard ratio 0.76; P = .0059). The median overall survival was 21 months and 18.7 months, respectively (HR 0.88; P = .2086).
The most common grade 3/4 adverse events in the neratinib arm were diarrhea, nausea, vomiting, fatigue, and decreased appetite.
The Food and Drug Administration has approved neratinib (NERLYNX) in combination with capecitabine for use in adults with advanced or metastatic HER2-positive breast cancer who have received at least two prior anti-HER2 based regimens in the metastatic setting.
The recommended dose for neratinib in this population is 240 mg once daily with food on days 1-21 of a 21-day cycle. Neratinib should be given with capecitabine at 750 mg/m2 twice daily on days 1-14 until progression or unacceptable toxicity.
The full prescribing information for neratinib is available from the FDA website.
The FDA’s new approval of neratinib is based on results from the NALA trial (NCT01808573). The trial enrolled 621 patients with metastatic HER2-positive breast cancer who had received at least two prior anti-HER2 based regimens in the metastatic setting.
The patients were randomized to neratinib plus capecitabine or lapatinib plus capecitabine and received treatment until progression or unacceptable toxicity.
The objective response rate was 32.8% in the neratinib arm and 26.7% in the lapatinib arm. The median duration of response was 8.5 months and 5.6 months, respectively.
The median progression-free survival was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (hazard ratio 0.76; P = .0059). The median overall survival was 21 months and 18.7 months, respectively (HR 0.88; P = .2086).
The most common grade 3/4 adverse events in the neratinib arm were diarrhea, nausea, vomiting, fatigue, and decreased appetite.
The Food and Drug Administration has approved neratinib (NERLYNX) in combination with capecitabine for use in adults with advanced or metastatic HER2-positive breast cancer who have received at least two prior anti-HER2 based regimens in the metastatic setting.
The recommended dose for neratinib in this population is 240 mg once daily with food on days 1-21 of a 21-day cycle. Neratinib should be given with capecitabine at 750 mg/m2 twice daily on days 1-14 until progression or unacceptable toxicity.
The full prescribing information for neratinib is available from the FDA website.
The FDA’s new approval of neratinib is based on results from the NALA trial (NCT01808573). The trial enrolled 621 patients with metastatic HER2-positive breast cancer who had received at least two prior anti-HER2 based regimens in the metastatic setting.
The patients were randomized to neratinib plus capecitabine or lapatinib plus capecitabine and received treatment until progression or unacceptable toxicity.
The objective response rate was 32.8% in the neratinib arm and 26.7% in the lapatinib arm. The median duration of response was 8.5 months and 5.6 months, respectively.
The median progression-free survival was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (hazard ratio 0.76; P = .0059). The median overall survival was 21 months and 18.7 months, respectively (HR 0.88; P = .2086).
The most common grade 3/4 adverse events in the neratinib arm were diarrhea, nausea, vomiting, fatigue, and decreased appetite.