Commentary

A toddler has had several brief episodes of mild perioral cyanosis noticed at day care. The parents see the primary care provider. The exam is normal. The child is admitted for a work-up. The CBC and comprehensive metabolic profile are unremarkable. The chest x-ray is normal. An ECG is normal. An echocardiogram is normal. The EEG is normal. Now what?

I was taught that an uncommon presentation of a common disease is still more common than a common presentation of an uncommon disease. Or simply, odd-looking horses are more common than zebras unless you practice in the savanna. There is a point in any safari at which you have to decide whether you are hunting a zebra or chasing a shadow. Clinical judgment is balancing the risk of missing something preventable that will actually harm the child against the harms of more tests.

The modern hospital has an array of equipment available. They are Greek Sirens calling to us. There is the video EEG room, the MR angiogram, the cardiac cath lab, and an endless list of blood tests. We are not even stopped by the walls of the hospital. We can order a follow-up ambulatory Holter ECG to search for intermittent arrhythmias. But are these Sirens really good medicine? At what point should we simply reassure the parents that the child is fine?

Physicians all worry about missing something. This fear was instilled when we were medical students and reinforced with the stress of residency. With years of experience, all physicians acquire a list of missed diagnoses. But I also have collected a list of times when the diagnostic tests themselves have caused harm, including death. I have a list of cases where nonspecific diagnostic testing has mislabeled a child with an obscure diagnosis that was later proven false, but not before harm was caused. There were patients with Stevens-Johnson syndrome who suffered serious harm from treatments for minor illnesses. Then there were the terrified families who, after extensive testing, became convinced that the child must have some horrible unknown disease because surely we wouldn’t have traumatized the child with all this work-up if there wasn’t really something seriously wrong. Each new test stoked their fear rather than soothed it.

©Jupiterimages/Thinkstockphotos.com

A careful history is still the weapon of choice in the zebra hunt. On a first presentation of mild cyanosis, sepsis is the charging rhinoceros of preventable harm that will run you over if you are too slow to react. But this child has now had several episodes that have occurred: 1. in multiple settings, 2. with no distress, 3. while the child remained playful, and 4. that were self-limited. That history is incompatible with sepsis, so reflexively ordering a blood culture is an illogical choice. The history should be progressively explored using the differential diagnosis and an organ-based systematic approach to guide it. The thoroughness and thoughtfulness I put into the history taking can be key to finding the correct diagnosis. They also are a means of building trust and rapport with the parents. That will be important later if no definitive diagnosis is found.

Unclear and unusual presentations may merit a consult. The cardiologist knows the limits of an echo. Along with the technical expertise comes a new set of eyes and the additional perspective of a second opinion. It is great when a colleague can tell you that he or she too had a case like this years ago that was never solved, but did resolve on its own.

One advantage of being an office-based pediatrician, with an established relationship with a family over several years and a couple other children, is that parents do value and trust your clinical judgment. As a pediatrician, I know the most common product I sell is reassurance. It is not snake oil. There is a bedside manner in selling it. Put a positive spin on all the negative tests. Indicate that you and the parents can be vigilant in watching for new signs. Instruct the parents to bring the child back if the events are distressing for the child, which could justify more invasive testing. Arrange to recheck the child in the office in a week, then a month, then at the next well visit. Parents know that medicine isn’t perfect. Humans deal with fear and uncertainty better by knowing we aren’t facing the future alone. And that is why even with all this technology, I still lay a stethoscope on every child.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Dr. Powell said he had no relevant financial disclosures.

A toddler has had several brief episodes of mild perioral cyanosis noticed at day care. The parents see the primary care provider. The exam is normal. The child is admitted for a work-up. The CBC and comprehensive metabolic profile are unremarkable. The chest x-ray is normal. An ECG is normal. An echocardiogram is normal. The EEG is normal. Now what?

I was taught that an uncommon presentation of a common disease is still more common than a common presentation of an uncommon disease. Or simply, odd-looking horses are more common than zebras unless you practice in the savanna. There is a point in any safari at which you have to decide whether you are hunting a zebra or chasing a shadow. Clinical judgment is balancing the risk of missing something preventable that will actually harm the child against the harms of more tests.

The modern hospital has an array of equipment available. They are Greek Sirens calling to us. There is the video EEG room, the MR angiogram, the cardiac cath lab, and an endless list of blood tests. We are not even stopped by the walls of the hospital. We can order a follow-up ambulatory Holter ECG to search for intermittent arrhythmias. But are these Sirens really good medicine? At what point should we simply reassure the parents that the child is fine?

Physicians all worry about missing something. This fear was instilled when we were medical students and reinforced with the stress of residency. With years of experience, all physicians acquire a list of missed diagnoses. But I also have collected a list of times when the diagnostic tests themselves have caused harm, including death. I have a list of cases where nonspecific diagnostic testing has mislabeled a child with an obscure diagnosis that was later proven false, but not before harm was caused. There were patients with Stevens-Johnson syndrome who suffered serious harm from treatments for minor illnesses. Then there were the terrified families who, after extensive testing, became convinced that the child must have some horrible unknown disease because surely we wouldn’t have traumatized the child with all this work-up if there wasn’t really something seriously wrong. Each new test stoked their fear rather than soothed it.

©Jupiterimages/Thinkstockphotos.com

A careful history is still the weapon of choice in the zebra hunt. On a first presentation of mild cyanosis, sepsis is the charging rhinoceros of preventable harm that will run you over if you are too slow to react. But this child has now had several episodes that have occurred: 1. in multiple settings, 2. with no distress, 3. while the child remained playful, and 4. that were self-limited. That history is incompatible with sepsis, so reflexively ordering a blood culture is an illogical choice. The history should be progressively explored using the differential diagnosis and an organ-based systematic approach to guide it. The thoroughness and thoughtfulness I put into the history taking can be key to finding the correct diagnosis. They also are a means of building trust and rapport with the parents. That will be important later if no definitive diagnosis is found.

Unclear and unusual presentations may merit a consult. The cardiologist knows the limits of an echo. Along with the technical expertise comes a new set of eyes and the additional perspective of a second opinion. It is great when a colleague can tell you that he or she too had a case like this years ago that was never solved, but did resolve on its own.

One advantage of being an office-based pediatrician, with an established relationship with a family over several years and a couple other children, is that parents do value and trust your clinical judgment. As a pediatrician, I know the most common product I sell is reassurance. It is not snake oil. There is a bedside manner in selling it. Put a positive spin on all the negative tests. Indicate that you and the parents can be vigilant in watching for new signs. Instruct the parents to bring the child back if the events are distressing for the child, which could justify more invasive testing. Arrange to recheck the child in the office in a week, then a month, then at the next well visit. Parents know that medicine isn’t perfect. Humans deal with fear and uncertainty better by knowing we aren’t facing the future alone. And that is why even with all this technology, I still lay a stethoscope on every child.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Dr. Powell said he had no relevant financial disclosures.

A toddler has had several brief episodes of mild perioral cyanosis noticed at day care. The parents see the primary care provider. The exam is normal. The child is admitted for a work-up. The CBC and comprehensive metabolic profile are unremarkable. The chest x-ray is normal. An ECG is normal. An echocardiogram is normal. The EEG is normal. Now what?

I was taught that an uncommon presentation of a common disease is still more common than a common presentation of an uncommon disease. Or simply, odd-looking horses are more common than zebras unless you practice in the savanna. There is a point in any safari at which you have to decide whether you are hunting a zebra or chasing a shadow. Clinical judgment is balancing the risk of missing something preventable that will actually harm the child against the harms of more tests.

The modern hospital has an array of equipment available. They are Greek Sirens calling to us. There is the video EEG room, the MR angiogram, the cardiac cath lab, and an endless list of blood tests. We are not even stopped by the walls of the hospital. We can order a follow-up ambulatory Holter ECG to search for intermittent arrhythmias. But are these Sirens really good medicine? At what point should we simply reassure the parents that the child is fine?

Physicians all worry about missing something. This fear was instilled when we were medical students and reinforced with the stress of residency. With years of experience, all physicians acquire a list of missed diagnoses. But I also have collected a list of times when the diagnostic tests themselves have caused harm, including death. I have a list of cases where nonspecific diagnostic testing has mislabeled a child with an obscure diagnosis that was later proven false, but not before harm was caused. There were patients with Stevens-Johnson syndrome who suffered serious harm from treatments for minor illnesses. Then there were the terrified families who, after extensive testing, became convinced that the child must have some horrible unknown disease because surely we wouldn’t have traumatized the child with all this work-up if there wasn’t really something seriously wrong. Each new test stoked their fear rather than soothed it.

©Jupiterimages/Thinkstockphotos.com

A careful history is still the weapon of choice in the zebra hunt. On a first presentation of mild cyanosis, sepsis is the charging rhinoceros of preventable harm that will run you over if you are too slow to react. But this child has now had several episodes that have occurred: 1. in multiple settings, 2. with no distress, 3. while the child remained playful, and 4. that were self-limited. That history is incompatible with sepsis, so reflexively ordering a blood culture is an illogical choice. The history should be progressively explored using the differential diagnosis and an organ-based systematic approach to guide it. The thoroughness and thoughtfulness I put into the history taking can be key to finding the correct diagnosis. They also are a means of building trust and rapport with the parents. That will be important later if no definitive diagnosis is found.

Unclear and unusual presentations may merit a consult. The cardiologist knows the limits of an echo. Along with the technical expertise comes a new set of eyes and the additional perspective of a second opinion. It is great when a colleague can tell you that he or she too had a case like this years ago that was never solved, but did resolve on its own.

One advantage of being an office-based pediatrician, with an established relationship with a family over several years and a couple other children, is that parents do value and trust your clinical judgment. As a pediatrician, I know the most common product I sell is reassurance. It is not snake oil. There is a bedside manner in selling it. Put a positive spin on all the negative tests. Indicate that you and the parents can be vigilant in watching for new signs. Instruct the parents to bring the child back if the events are distressing for the child, which could justify more invasive testing. Arrange to recheck the child in the office in a week, then a month, then at the next well visit. Parents know that medicine isn’t perfect. Humans deal with fear and uncertainty better by knowing we aren’t facing the future alone. And that is why even with all this technology, I still lay a stethoscope on every child.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Dr. Powell said he had no relevant financial disclosures.

Yes: MRI should be considered in the preoperative setting for specific clinical indications.

MRI, like any technology, has its strengths and weaknesses, with high sensitivity but low specificity. Importantly, MRI provides excellent soft tissue contrast with anatomic 3-D detail, and is not impeded by high breast density.

Admittedly, MRI only incrementally increases cancer detection rates in either the ipsilateral or contralateral breasts of all patients, and when used in the preoperative setting does not affect short-term surgical outcomes for all patients. Therefore, MRI should not be used for routine screening or routine preoperative screening.

That said, there are specific clinical situations where preoperative MRI may provide surgeons with valuable information. These include patients who have:

• Invasive lobular carcinoma.

• Neoadjuvant chemotherapy.

• Occult primaries in extremely dense breasts.

Invasive lobular carcinomas are more likely to be multi-centric, multi-focal, and/or bilateral than other breast cancer types, and they are more difficult to diagnose because they infiltrate into tissue, making it extremely difficult to determine the extent of disease. In this setting, MRI can more accurately determine tumor size than mammography. Mammography underestimates the tumor size significantly more frequently than does MRI. In addition, among women with this cancer subtype, MRI can significantly reduce the rate of excision (Breast Cancer Res Treat. 2010;119;415-22).

We know that women at risk for systemic recurrence will not be cured with surgery alone. Neoadjuvant therapies give us the opportunity to refine local therapy options, better understand the patient’s response to therapy and prognosis, and accelerate targeted drug development to improve outcomes. To accomplish all of these goals, we need a noninvasive way to assess tumors before, during, and after neoadjuvant treatment. MRI is unsurpassed for evaluating the extent of tumors, showing in larger tumors, for example, the complexity of tumor and stroma.

MRI is also a biomarker for response to therapy and has been shown to be an independent predictor of event-free survival. In addition, MRI is more accurate than either clinical exam, mammography, or ultrasound for determining residual tumor size following neoadjuvant chemotherapy (Radiology. 2012;263:663-72).

Lastly, for patients with an occult primary (by imaging) breast cancer or primary presentation of axillary node involvement, MRI has been found to have an approximately 90% sensitivity for identifying a primary tumor, and a 95% accuracy at locating the tumor in patients who undergo surgical excision. Mammography cannot distinguish a tumor mass that is dense relative to surrounding tissue. However, MRI can distinguish a tumor which is obscured by dense breast tissue because tumors are visualized on MRI by rapid contrast uptake and washout.

MRI is a catalyst for change, but you have to use it and all technology wisely: At the time of diagnosis for select patients, for screening only those patients with very breast dense tissue and very high risk for developing breast cancer, and, perhaps most importantly, for postcancer surveillance only in women at very high risk of recurrence where standard tools such as mammography are expected to have lower performance (for example, very dense breast tissue). Overuse of MRI will increase false positives, anxiety, and cost. However, used appropriately, MRI can be used to help usher in a change in practice through the evaluation of response to neoadjuvant therapy and novel therapeutic approaches to both invasive and in situ lesions.

With improvements in technology and techniques such as diffusion-weighted imaging, the value of MRI in the preoperative setting can only continue to grow. We can also expect greater performance for presurgical staging with more refined technologies for breast imaging, localization, and biopsy, but the costs have to come down. Breast-dedicated MRI technologies may address this need.

Laura Esserman, MD, is a professor of surgery and radiology at the University of California, San Francisco, and Director of the Carol Franc Buck Breast Care Center at the UCSF Mount Zion campus.

No: MRI leads to unnecessary surgeries and does not improve short-term surgical outcomes.

The key word in this debate is “routinely.” I agree that preoperative MRI may have a role in about 5% of all cases – namely in women with occult primaries and those who undergo neoadjuvant chemotherapy. But for the vast majority of patients, the 95%, I would argue that preoperative MRI has the potential to do more harm than good.

Thirty years of experience providing breast conserving therapies without MRI has taught us several important lessons:

• Selection of patients for breast-conserving therapy is not a big problem.

• The incidences of local recurrence and contralateral breast cancers have decreased over time, antedating the use of MRI.

• Surgical excision of all microscopic subclinical disease is not necessary to achieve good long-term outcomes.

In National Surgical Adjuvant Breast and Bowel Project studies from the 1990s, in the era before the use of aromatase inhibitors or HER-2 blockade, the 10-year incidence of ipsilateral breast tumor recurrence ranged from 3.5% to 6.5% in the breast cancer population at large.

In addition, the incidence of contralateral breast cancers has been declining at a rate of approximately 3% per year, thanks to the use of adjuvant systemic therapies.

We have known since the 1960s, thanks to our colleagues in pathology, that somewhere between 30% and 60% of breast cancers that appear to be localized have microscopic subclinical disease which is treated with breast irradiation. More recently, we have recognized that we can leave behind cancer in the axilla in anywhere from 13% to 27% of patients who are not receiving direct axillary radiation, and see failure rates of 1% or less.

In the context, then, of our current understanding of breast cancer biology, what outcomes could MRI be expected to improve, since the purpose of a test is to improve patient outcomes?

We know that MRI will not improve survival, because 30 years ago randomized trials showed us that survival was equal between breast conservation and mastectomy.

MRI has no apparent effect on reducing local recurrences either, as shown in an analysis of data on 3,180 patients published in 2014 (J Clin Oncol. 2014;32:292).

Regarding contralateral breast cancer, a 2007 study (N Engl J Med. 2007;356:1295-303) showed that among 969 women, MRI found unsuspected cancer in the contralateral breast within 1 year of diagnosis in 3.1%, a finding used to support the argument that all women with breast cancer should have an MRI. But a second study using Surveillance, Epidemiology and End Results (SEER) data on 339,790 women with 2.5 million person-years of follow-up found that the 10-year rate of contralateral cancers was 2%-3% of women with estrogen-receptor–positive tumors, and in 5%-6% of those with estrogen-receptor–negative tumors, strongly suggesting that MRI leads to detection and treatment of disease that would never become clinically evident.

Finally, I would point to evidence that MRI does not improve short-term surgical outcomes, as shown in a meta-analysis my colleagues and I conducted of two randomized controlled trials and seven cohort studies, involving a total of 3,112 patients (Ann Surg. 2013;257:249-55).

We found that after adjustment for age, having an MRI was associated with a three-fold greater chance of having a mastectomy, and MRI did not significantly reduce either the need for re-excision or unexpected conversion to mastectomy. We also performed a subanalysis of infiltrating lobular cancers, and found that there was no statistically significant benefit for MRI in these patients.

The overall rate of mastectomy was 25.5% among patients who had an MRI, vs. 18.2% for those who did not.

So to summarize: MRI finds two to three times more cancer than observed rates of local recurrence, leading to unnecessary mastectomies and does not improve short-term surgical outcomes, and there is no evidence indicating that MRI decreases local recurrence.

Monica Morrow, MD, FACS, is chief of the breast service in the department of surgery and holds the Anne Burnett Windfohr Chair of Clinical Oncology at Memorial Sloan Kettering Cancer Center in New York.

Yes: MRI should be considered in the preoperative setting for specific clinical indications.

MRI, like any technology, has its strengths and weaknesses, with high sensitivity but low specificity. Importantly, MRI provides excellent soft tissue contrast with anatomic 3-D detail, and is not impeded by high breast density.

Admittedly, MRI only incrementally increases cancer detection rates in either the ipsilateral or contralateral breasts of all patients, and when used in the preoperative setting does not affect short-term surgical outcomes for all patients. Therefore, MRI should not be used for routine screening or routine preoperative screening.

That said, there are specific clinical situations where preoperative MRI may provide surgeons with valuable information. These include patients who have:

• Invasive lobular carcinoma.

• Neoadjuvant chemotherapy.

• Occult primaries in extremely dense breasts.

Invasive lobular carcinomas are more likely to be multi-centric, multi-focal, and/or bilateral than other breast cancer types, and they are more difficult to diagnose because they infiltrate into tissue, making it extremely difficult to determine the extent of disease. In this setting, MRI can more accurately determine tumor size than mammography. Mammography underestimates the tumor size significantly more frequently than does MRI. In addition, among women with this cancer subtype, MRI can significantly reduce the rate of excision (Breast Cancer Res Treat. 2010;119;415-22).

We know that women at risk for systemic recurrence will not be cured with surgery alone. Neoadjuvant therapies give us the opportunity to refine local therapy options, better understand the patient’s response to therapy and prognosis, and accelerate targeted drug development to improve outcomes. To accomplish all of these goals, we need a noninvasive way to assess tumors before, during, and after neoadjuvant treatment. MRI is unsurpassed for evaluating the extent of tumors, showing in larger tumors, for example, the complexity of tumor and stroma.

MRI is also a biomarker for response to therapy and has been shown to be an independent predictor of event-free survival. In addition, MRI is more accurate than either clinical exam, mammography, or ultrasound for determining residual tumor size following neoadjuvant chemotherapy (Radiology. 2012;263:663-72).

Lastly, for patients with an occult primary (by imaging) breast cancer or primary presentation of axillary node involvement, MRI has been found to have an approximately 90% sensitivity for identifying a primary tumor, and a 95% accuracy at locating the tumor in patients who undergo surgical excision. Mammography cannot distinguish a tumor mass that is dense relative to surrounding tissue. However, MRI can distinguish a tumor which is obscured by dense breast tissue because tumors are visualized on MRI by rapid contrast uptake and washout.

MRI is a catalyst for change, but you have to use it and all technology wisely: At the time of diagnosis for select patients, for screening only those patients with very breast dense tissue and very high risk for developing breast cancer, and, perhaps most importantly, for postcancer surveillance only in women at very high risk of recurrence where standard tools such as mammography are expected to have lower performance (for example, very dense breast tissue). Overuse of MRI will increase false positives, anxiety, and cost. However, used appropriately, MRI can be used to help usher in a change in practice through the evaluation of response to neoadjuvant therapy and novel therapeutic approaches to both invasive and in situ lesions.

With improvements in technology and techniques such as diffusion-weighted imaging, the value of MRI in the preoperative setting can only continue to grow. We can also expect greater performance for presurgical staging with more refined technologies for breast imaging, localization, and biopsy, but the costs have to come down. Breast-dedicated MRI technologies may address this need.

Laura Esserman, MD, is a professor of surgery and radiology at the University of California, San Francisco, and Director of the Carol Franc Buck Breast Care Center at the UCSF Mount Zion campus.

No: MRI leads to unnecessary surgeries and does not improve short-term surgical outcomes.

The key word in this debate is “routinely.” I agree that preoperative MRI may have a role in about 5% of all cases – namely in women with occult primaries and those who undergo neoadjuvant chemotherapy. But for the vast majority of patients, the 95%, I would argue that preoperative MRI has the potential to do more harm than good.

Thirty years of experience providing breast conserving therapies without MRI has taught us several important lessons:

• Selection of patients for breast-conserving therapy is not a big problem.

• The incidences of local recurrence and contralateral breast cancers have decreased over time, antedating the use of MRI.

• Surgical excision of all microscopic subclinical disease is not necessary to achieve good long-term outcomes.

In National Surgical Adjuvant Breast and Bowel Project studies from the 1990s, in the era before the use of aromatase inhibitors or HER-2 blockade, the 10-year incidence of ipsilateral breast tumor recurrence ranged from 3.5% to 6.5% in the breast cancer population at large.

In addition, the incidence of contralateral breast cancers has been declining at a rate of approximately 3% per year, thanks to the use of adjuvant systemic therapies.

We have known since the 1960s, thanks to our colleagues in pathology, that somewhere between 30% and 60% of breast cancers that appear to be localized have microscopic subclinical disease which is treated with breast irradiation. More recently, we have recognized that we can leave behind cancer in the axilla in anywhere from 13% to 27% of patients who are not receiving direct axillary radiation, and see failure rates of 1% or less.

In the context, then, of our current understanding of breast cancer biology, what outcomes could MRI be expected to improve, since the purpose of a test is to improve patient outcomes?

We know that MRI will not improve survival, because 30 years ago randomized trials showed us that survival was equal between breast conservation and mastectomy.

MRI has no apparent effect on reducing local recurrences either, as shown in an analysis of data on 3,180 patients published in 2014 (J Clin Oncol. 2014;32:292).

Regarding contralateral breast cancer, a 2007 study (N Engl J Med. 2007;356:1295-303) showed that among 969 women, MRI found unsuspected cancer in the contralateral breast within 1 year of diagnosis in 3.1%, a finding used to support the argument that all women with breast cancer should have an MRI. But a second study using Surveillance, Epidemiology and End Results (SEER) data on 339,790 women with 2.5 million person-years of follow-up found that the 10-year rate of contralateral cancers was 2%-3% of women with estrogen-receptor–positive tumors, and in 5%-6% of those with estrogen-receptor–negative tumors, strongly suggesting that MRI leads to detection and treatment of disease that would never become clinically evident.

Finally, I would point to evidence that MRI does not improve short-term surgical outcomes, as shown in a meta-analysis my colleagues and I conducted of two randomized controlled trials and seven cohort studies, involving a total of 3,112 patients (Ann Surg. 2013;257:249-55).

We found that after adjustment for age, having an MRI was associated with a three-fold greater chance of having a mastectomy, and MRI did not significantly reduce either the need for re-excision or unexpected conversion to mastectomy. We also performed a subanalysis of infiltrating lobular cancers, and found that there was no statistically significant benefit for MRI in these patients.

The overall rate of mastectomy was 25.5% among patients who had an MRI, vs. 18.2% for those who did not.

So to summarize: MRI finds two to three times more cancer than observed rates of local recurrence, leading to unnecessary mastectomies and does not improve short-term surgical outcomes, and there is no evidence indicating that MRI decreases local recurrence.

Monica Morrow, MD, FACS, is chief of the breast service in the department of surgery and holds the Anne Burnett Windfohr Chair of Clinical Oncology at Memorial Sloan Kettering Cancer Center in New York.

Yes: MRI should be considered in the preoperative setting for specific clinical indications.

MRI, like any technology, has its strengths and weaknesses, with high sensitivity but low specificity. Importantly, MRI provides excellent soft tissue contrast with anatomic 3-D detail, and is not impeded by high breast density.

Admittedly, MRI only incrementally increases cancer detection rates in either the ipsilateral or contralateral breasts of all patients, and when used in the preoperative setting does not affect short-term surgical outcomes for all patients. Therefore, MRI should not be used for routine screening or routine preoperative screening.

That said, there are specific clinical situations where preoperative MRI may provide surgeons with valuable information. These include patients who have:

• Invasive lobular carcinoma.

• Neoadjuvant chemotherapy.

• Occult primaries in extremely dense breasts.

Invasive lobular carcinomas are more likely to be multi-centric, multi-focal, and/or bilateral than other breast cancer types, and they are more difficult to diagnose because they infiltrate into tissue, making it extremely difficult to determine the extent of disease. In this setting, MRI can more accurately determine tumor size than mammography. Mammography underestimates the tumor size significantly more frequently than does MRI. In addition, among women with this cancer subtype, MRI can significantly reduce the rate of excision (Breast Cancer Res Treat. 2010;119;415-22).

We know that women at risk for systemic recurrence will not be cured with surgery alone. Neoadjuvant therapies give us the opportunity to refine local therapy options, better understand the patient’s response to therapy and prognosis, and accelerate targeted drug development to improve outcomes. To accomplish all of these goals, we need a noninvasive way to assess tumors before, during, and after neoadjuvant treatment. MRI is unsurpassed for evaluating the extent of tumors, showing in larger tumors, for example, the complexity of tumor and stroma.

MRI is also a biomarker for response to therapy and has been shown to be an independent predictor of event-free survival. In addition, MRI is more accurate than either clinical exam, mammography, or ultrasound for determining residual tumor size following neoadjuvant chemotherapy (Radiology. 2012;263:663-72).

Lastly, for patients with an occult primary (by imaging) breast cancer or primary presentation of axillary node involvement, MRI has been found to have an approximately 90% sensitivity for identifying a primary tumor, and a 95% accuracy at locating the tumor in patients who undergo surgical excision. Mammography cannot distinguish a tumor mass that is dense relative to surrounding tissue. However, MRI can distinguish a tumor which is obscured by dense breast tissue because tumors are visualized on MRI by rapid contrast uptake and washout.

MRI is a catalyst for change, but you have to use it and all technology wisely: At the time of diagnosis for select patients, for screening only those patients with very breast dense tissue and very high risk for developing breast cancer, and, perhaps most importantly, for postcancer surveillance only in women at very high risk of recurrence where standard tools such as mammography are expected to have lower performance (for example, very dense breast tissue). Overuse of MRI will increase false positives, anxiety, and cost. However, used appropriately, MRI can be used to help usher in a change in practice through the evaluation of response to neoadjuvant therapy and novel therapeutic approaches to both invasive and in situ lesions.

With improvements in technology and techniques such as diffusion-weighted imaging, the value of MRI in the preoperative setting can only continue to grow. We can also expect greater performance for presurgical staging with more refined technologies for breast imaging, localization, and biopsy, but the costs have to come down. Breast-dedicated MRI technologies may address this need.

Laura Esserman, MD, is a professor of surgery and radiology at the University of California, San Francisco, and Director of the Carol Franc Buck Breast Care Center at the UCSF Mount Zion campus.

No: MRI leads to unnecessary surgeries and does not improve short-term surgical outcomes.

The key word in this debate is “routinely.” I agree that preoperative MRI may have a role in about 5% of all cases – namely in women with occult primaries and those who undergo neoadjuvant chemotherapy. But for the vast majority of patients, the 95%, I would argue that preoperative MRI has the potential to do more harm than good.

Thirty years of experience providing breast conserving therapies without MRI has taught us several important lessons:

• Selection of patients for breast-conserving therapy is not a big problem.

• The incidences of local recurrence and contralateral breast cancers have decreased over time, antedating the use of MRI.

• Surgical excision of all microscopic subclinical disease is not necessary to achieve good long-term outcomes.

In National Surgical Adjuvant Breast and Bowel Project studies from the 1990s, in the era before the use of aromatase inhibitors or HER-2 blockade, the 10-year incidence of ipsilateral breast tumor recurrence ranged from 3.5% to 6.5% in the breast cancer population at large.

In addition, the incidence of contralateral breast cancers has been declining at a rate of approximately 3% per year, thanks to the use of adjuvant systemic therapies.

We have known since the 1960s, thanks to our colleagues in pathology, that somewhere between 30% and 60% of breast cancers that appear to be localized have microscopic subclinical disease which is treated with breast irradiation. More recently, we have recognized that we can leave behind cancer in the axilla in anywhere from 13% to 27% of patients who are not receiving direct axillary radiation, and see failure rates of 1% or less.

In the context, then, of our current understanding of breast cancer biology, what outcomes could MRI be expected to improve, since the purpose of a test is to improve patient outcomes?

We know that MRI will not improve survival, because 30 years ago randomized trials showed us that survival was equal between breast conservation and mastectomy.

MRI has no apparent effect on reducing local recurrences either, as shown in an analysis of data on 3,180 patients published in 2014 (J Clin Oncol. 2014;32:292).

Regarding contralateral breast cancer, a 2007 study (N Engl J Med. 2007;356:1295-303) showed that among 969 women, MRI found unsuspected cancer in the contralateral breast within 1 year of diagnosis in 3.1%, a finding used to support the argument that all women with breast cancer should have an MRI. But a second study using Surveillance, Epidemiology and End Results (SEER) data on 339,790 women with 2.5 million person-years of follow-up found that the 10-year rate of contralateral cancers was 2%-3% of women with estrogen-receptor–positive tumors, and in 5%-6% of those with estrogen-receptor–negative tumors, strongly suggesting that MRI leads to detection and treatment of disease that would never become clinically evident.

Finally, I would point to evidence that MRI does not improve short-term surgical outcomes, as shown in a meta-analysis my colleagues and I conducted of two randomized controlled trials and seven cohort studies, involving a total of 3,112 patients (Ann Surg. 2013;257:249-55).

We found that after adjustment for age, having an MRI was associated with a three-fold greater chance of having a mastectomy, and MRI did not significantly reduce either the need for re-excision or unexpected conversion to mastectomy. We also performed a subanalysis of infiltrating lobular cancers, and found that there was no statistically significant benefit for MRI in these patients.

The overall rate of mastectomy was 25.5% among patients who had an MRI, vs. 18.2% for those who did not.

So to summarize: MRI finds two to three times more cancer than observed rates of local recurrence, leading to unnecessary mastectomies and does not improve short-term surgical outcomes, and there is no evidence indicating that MRI decreases local recurrence.

Monica Morrow, MD, FACS, is chief of the breast service in the department of surgery and holds the Anne Burnett Windfohr Chair of Clinical Oncology at Memorial Sloan Kettering Cancer Center in New York.

Despite the lack of clarity about the exact prevalence in youth, particularly prepubertal youth, it’s clear that an increasing number of children and teenagers are presenting to multidisciplinary clinics for evaluation and management of gender identity issues (Pediatrics. 2012 Mar;129[3]:418-25). Recent literature has indicated that the prevalence of individuals overall identifying as transgender and/or experiencing gender dysphoria is about 0.2%-0.3% of the population (JAMA Pediatr. 2016;170[5]:423-4), while being mindful of the variability in the characteristics of the populations included in certain studies.

Although gender variation, in and of itself, is not a disorder, these youth are a considerably underserved and poorly researched population with specific medical and mental health needs. They are at risk for being victims of abuse and developing a range of mental health struggles, including mood disorders, suicidal thinking, self-harming, and anxiety, possibly because of the stresses they experience socially (family rejection, victimization). In addition to these more discrete psychiatric phenomena, co-occurring autism spectrum disorders (or traits thereof) are increasingly being recognized in transgender youth.

Case summary

Maddie is a 20-year-old college sophomore who presents for an autism diagnostic evaluation after being seen by a mental health colleague for consultation regarding medical treatment associated with female-to-male gender transition. In brief, Maddie reports a longstanding history of feeling “socially overwhelmed.” He is an articulate young adult who shares that he’s frequently uncomfortable in social situations, explaining that he has trouble “reading people,” acknowledging a tendency to become overly focused on the details of others and missing the gestalt of interpersonal interactions. Maddie discloses never having close friendships, and although he identifies as lonely, he doesn’t “understand the appeal of casual social interactions.” Maddie and his mother seek an understanding of such social difficulties, wondering about the possibility of Asperger’s syndrome.

Maddie, whose assigned gender at birth was female, now identifies as male. His mother recalls him to have been a precocious preschooler in terms of language development who had no significant developmental delays and became, per report, increasingly withdrawn in elementary school. Over the years, educators have commented repeatedly on the fact that Maddie has needed to work on his “people skills,” with past providers ascribing such struggles to anxiety and social awkwardness that were thought to inherently accompany gender-variant behaviors and thinking. Maddie socially transitioned from a female to male in grade 11 and began taking prescribed testosterone about 4 years ago.

In the interview, Maddie is a hesitant male-appearing individual whose eye contact and spontaneity are limited. He has a guarded manner, and although he is able to answer questions posed to him, rapport is difficult to establish as he appears interpersonally uncomfortable.

Prior to the visit, Maddie’s mother completed the Social Responsiveness Scales, which revealed elevated scores in the area of Social Communication and Social Motivation. Despite appearing cognitively bright and having an array of academic and creative strengths, Maddie’s troubles forming meaningful relationships are striking. Deficits in social-emotional competence are incommensurate with his suspected cognitive abilities, and although he relates learning social skills from film over the years, he endorses pervasively compromised social-communication aptitudes and enduring functional impairments. “I’m always playing catch-up socially,” he shares, wondering how this will affect him in his nursing career.

Discussion

Maddie and his mother participated in an autism diagnostic evaluation, including the administration of the Autism Diagnostic Interview–Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS). The evaluation revealed a profile of social impairments and inflexible thinking dating back to early childhood that supported a diagnosis of an autism spectrum disorder (ASD). Other diagnoses, including anxiety disorders, a depressive disorder, a social pragmatic communication disorder, and a nonverbal learning disorder, were considered, but ultimately it was concluded that ASD best captured Maddie, who also continued to display features consistent with gender dysphoria.

Over the past 30 years, the relationship between gender-related concerns and ASD has begun to be discussed in the scientific literature, beginning with case reports and more recently with a retrospective chart study that yielded results suggesting that subjects diagnosed with ASD were almost eight times more likely to report gender variance than a nonreferred standardization sample of the Child Behavior Checklist (CBCL) (Transgender Health. 2016 Feb;1[1]:63-8). These results echo those of a prior study showing that 7.8% of individuals presenting for an evaluation in a Dutch gender clinic had an ASD diagnosis (J Autism Dev Disord. 2010 Aug;40[8]:930-6).

With the individual prevalences for ASD and gender dysphoria taken into account, these numbers suggest that the prevalence of ASD in gender-dysphoric youth is about four times higher than that found in the general population (Sex Med Rev. 2016;4:3e14). These data raise questions regarding potential shared etiology and the neurobiology between a disorder of social communication and gender identity–related issues; however, to date, despite several theories attempting to explain the connection (the notion of an “extreme male brain,” role of sex hormones, etc.), the relationship remains puzzling. Some have argued that the rigid thinking that can characterize ASD may lead those individuals who display any gender-variant behaviors to automatically identify as the gender opposite their biologic gender, even though they aren’t necessarily experiencing frank gender dysphoria or a core gender identity that is firmly discordant from their anatomical sex. Thinking about the relationship from another perspective, perhaps those with ASD are less aware of the social constructs of gender and are able to express their gender identity (whether it be crossgender or cisgender) more freely and without the worry of how they may be perceived by others. Undoubtedly, a complex interplay between ASD and gender dysphoria/gender-nonconforming behavior is suspected, and more quality research is needed – research that, at a minimum, is informed by the use of representative sample groups drawn from all developmental periods and well-defined diagnostic constructs.

Clinical pearl

Maddie, a transgender man, received a diagnosis of an autism spectrum disorder as a young adult – a full 16 years after the median age of diagnosis (MMWR Surveill Summ. 2016;65[3]:1-23).

The case illustrates some of the difficulties of attempting to parse out the cause of social impairments in an individual who also may have other phenomena that influence interpersonal functioning (attention-deficit/hyperactivity disorder, anxiety, gender dysphoria, etc.) in a developmental manner. Diagnostic “overshadowing” (mistakenly attributing symptoms to a particular condition and paying little attention to other possibilities) is not uncommon in youth with ASD and co-occurring conditions. Given the overlap between gender-nonconforming youth, individuals with gender dysphoria, and ASD, primary care providers may opt to incorporate mental health professionals familiar with ASD into the assessment and care of these children and adolescents. Getting a complete developmental history and paying attention to the possibility of early red flags for ASD can help to elucidate diagnostic possibilities and inform treatment planning. If a co-occurring diagnosis is confirmed, implementation of evidence-based interventions that are provided through the lens of ASD can help to minimize the risk of developing other co-occurring pathology, build resilience, alleviate social impairment, and foster self-advocacy skills in this very vulnerable population. Regardless of whether gender-variant youth and adolescents have an autistic disorder, mental health providers can have an integral role in assisting these individuals and their families to navigate a complicated system of care, address gender dysphoria, and promote healthy identity development (J Am Acad Child Adolesc Psychiatry. 2016 Jun;55[6]:441-3).

Dr. Dickerson, a child and adolescent psychiatrist, is assistant professor of psychiatry at the University of Vermont, where he is director of the autism diagnostic clinic.

Despite the lack of clarity about the exact prevalence in youth, particularly prepubertal youth, it’s clear that an increasing number of children and teenagers are presenting to multidisciplinary clinics for evaluation and management of gender identity issues (Pediatrics. 2012 Mar;129[3]:418-25). Recent literature has indicated that the prevalence of individuals overall identifying as transgender and/or experiencing gender dysphoria is about 0.2%-0.3% of the population (JAMA Pediatr. 2016;170[5]:423-4), while being mindful of the variability in the characteristics of the populations included in certain studies.

Although gender variation, in and of itself, is not a disorder, these youth are a considerably underserved and poorly researched population with specific medical and mental health needs. They are at risk for being victims of abuse and developing a range of mental health struggles, including mood disorders, suicidal thinking, self-harming, and anxiety, possibly because of the stresses they experience socially (family rejection, victimization). In addition to these more discrete psychiatric phenomena, co-occurring autism spectrum disorders (or traits thereof) are increasingly being recognized in transgender youth.

Case summary

Maddie is a 20-year-old college sophomore who presents for an autism diagnostic evaluation after being seen by a mental health colleague for consultation regarding medical treatment associated with female-to-male gender transition. In brief, Maddie reports a longstanding history of feeling “socially overwhelmed.” He is an articulate young adult who shares that he’s frequently uncomfortable in social situations, explaining that he has trouble “reading people,” acknowledging a tendency to become overly focused on the details of others and missing the gestalt of interpersonal interactions. Maddie discloses never having close friendships, and although he identifies as lonely, he doesn’t “understand the appeal of casual social interactions.” Maddie and his mother seek an understanding of such social difficulties, wondering about the possibility of Asperger’s syndrome.

Maddie, whose assigned gender at birth was female, now identifies as male. His mother recalls him to have been a precocious preschooler in terms of language development who had no significant developmental delays and became, per report, increasingly withdrawn in elementary school. Over the years, educators have commented repeatedly on the fact that Maddie has needed to work on his “people skills,” with past providers ascribing such struggles to anxiety and social awkwardness that were thought to inherently accompany gender-variant behaviors and thinking. Maddie socially transitioned from a female to male in grade 11 and began taking prescribed testosterone about 4 years ago.

In the interview, Maddie is a hesitant male-appearing individual whose eye contact and spontaneity are limited. He has a guarded manner, and although he is able to answer questions posed to him, rapport is difficult to establish as he appears interpersonally uncomfortable.

Prior to the visit, Maddie’s mother completed the Social Responsiveness Scales, which revealed elevated scores in the area of Social Communication and Social Motivation. Despite appearing cognitively bright and having an array of academic and creative strengths, Maddie’s troubles forming meaningful relationships are striking. Deficits in social-emotional competence are incommensurate with his suspected cognitive abilities, and although he relates learning social skills from film over the years, he endorses pervasively compromised social-communication aptitudes and enduring functional impairments. “I’m always playing catch-up socially,” he shares, wondering how this will affect him in his nursing career.

Discussion

Maddie and his mother participated in an autism diagnostic evaluation, including the administration of the Autism Diagnostic Interview–Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS). The evaluation revealed a profile of social impairments and inflexible thinking dating back to early childhood that supported a diagnosis of an autism spectrum disorder (ASD). Other diagnoses, including anxiety disorders, a depressive disorder, a social pragmatic communication disorder, and a nonverbal learning disorder, were considered, but ultimately it was concluded that ASD best captured Maddie, who also continued to display features consistent with gender dysphoria.

Over the past 30 years, the relationship between gender-related concerns and ASD has begun to be discussed in the scientific literature, beginning with case reports and more recently with a retrospective chart study that yielded results suggesting that subjects diagnosed with ASD were almost eight times more likely to report gender variance than a nonreferred standardization sample of the Child Behavior Checklist (CBCL) (Transgender Health. 2016 Feb;1[1]:63-8). These results echo those of a prior study showing that 7.8% of individuals presenting for an evaluation in a Dutch gender clinic had an ASD diagnosis (J Autism Dev Disord. 2010 Aug;40[8]:930-6).

With the individual prevalences for ASD and gender dysphoria taken into account, these numbers suggest that the prevalence of ASD in gender-dysphoric youth is about four times higher than that found in the general population (Sex Med Rev. 2016;4:3e14). These data raise questions regarding potential shared etiology and the neurobiology between a disorder of social communication and gender identity–related issues; however, to date, despite several theories attempting to explain the connection (the notion of an “extreme male brain,” role of sex hormones, etc.), the relationship remains puzzling. Some have argued that the rigid thinking that can characterize ASD may lead those individuals who display any gender-variant behaviors to automatically identify as the gender opposite their biologic gender, even though they aren’t necessarily experiencing frank gender dysphoria or a core gender identity that is firmly discordant from their anatomical sex. Thinking about the relationship from another perspective, perhaps those with ASD are less aware of the social constructs of gender and are able to express their gender identity (whether it be crossgender or cisgender) more freely and without the worry of how they may be perceived by others. Undoubtedly, a complex interplay between ASD and gender dysphoria/gender-nonconforming behavior is suspected, and more quality research is needed – research that, at a minimum, is informed by the use of representative sample groups drawn from all developmental periods and well-defined diagnostic constructs.

Clinical pearl

Maddie, a transgender man, received a diagnosis of an autism spectrum disorder as a young adult – a full 16 years after the median age of diagnosis (MMWR Surveill Summ. 2016;65[3]:1-23).

The case illustrates some of the difficulties of attempting to parse out the cause of social impairments in an individual who also may have other phenomena that influence interpersonal functioning (attention-deficit/hyperactivity disorder, anxiety, gender dysphoria, etc.) in a developmental manner. Diagnostic “overshadowing” (mistakenly attributing symptoms to a particular condition and paying little attention to other possibilities) is not uncommon in youth with ASD and co-occurring conditions. Given the overlap between gender-nonconforming youth, individuals with gender dysphoria, and ASD, primary care providers may opt to incorporate mental health professionals familiar with ASD into the assessment and care of these children and adolescents. Getting a complete developmental history and paying attention to the possibility of early red flags for ASD can help to elucidate diagnostic possibilities and inform treatment planning. If a co-occurring diagnosis is confirmed, implementation of evidence-based interventions that are provided through the lens of ASD can help to minimize the risk of developing other co-occurring pathology, build resilience, alleviate social impairment, and foster self-advocacy skills in this very vulnerable population. Regardless of whether gender-variant youth and adolescents have an autistic disorder, mental health providers can have an integral role in assisting these individuals and their families to navigate a complicated system of care, address gender dysphoria, and promote healthy identity development (J Am Acad Child Adolesc Psychiatry. 2016 Jun;55[6]:441-3).

Dr. Dickerson, a child and adolescent psychiatrist, is assistant professor of psychiatry at the University of Vermont, where he is director of the autism diagnostic clinic.

Despite the lack of clarity about the exact prevalence in youth, particularly prepubertal youth, it’s clear that an increasing number of children and teenagers are presenting to multidisciplinary clinics for evaluation and management of gender identity issues (Pediatrics. 2012 Mar;129[3]:418-25). Recent literature has indicated that the prevalence of individuals overall identifying as transgender and/or experiencing gender dysphoria is about 0.2%-0.3% of the population (JAMA Pediatr. 2016;170[5]:423-4), while being mindful of the variability in the characteristics of the populations included in certain studies.

Although gender variation, in and of itself, is not a disorder, these youth are a considerably underserved and poorly researched population with specific medical and mental health needs. They are at risk for being victims of abuse and developing a range of mental health struggles, including mood disorders, suicidal thinking, self-harming, and anxiety, possibly because of the stresses they experience socially (family rejection, victimization). In addition to these more discrete psychiatric phenomena, co-occurring autism spectrum disorders (or traits thereof) are increasingly being recognized in transgender youth.

Case summary

Maddie is a 20-year-old college sophomore who presents for an autism diagnostic evaluation after being seen by a mental health colleague for consultation regarding medical treatment associated with female-to-male gender transition. In brief, Maddie reports a longstanding history of feeling “socially overwhelmed.” He is an articulate young adult who shares that he’s frequently uncomfortable in social situations, explaining that he has trouble “reading people,” acknowledging a tendency to become overly focused on the details of others and missing the gestalt of interpersonal interactions. Maddie discloses never having close friendships, and although he identifies as lonely, he doesn’t “understand the appeal of casual social interactions.” Maddie and his mother seek an understanding of such social difficulties, wondering about the possibility of Asperger’s syndrome.

Maddie, whose assigned gender at birth was female, now identifies as male. His mother recalls him to have been a precocious preschooler in terms of language development who had no significant developmental delays and became, per report, increasingly withdrawn in elementary school. Over the years, educators have commented repeatedly on the fact that Maddie has needed to work on his “people skills,” with past providers ascribing such struggles to anxiety and social awkwardness that were thought to inherently accompany gender-variant behaviors and thinking. Maddie socially transitioned from a female to male in grade 11 and began taking prescribed testosterone about 4 years ago.

In the interview, Maddie is a hesitant male-appearing individual whose eye contact and spontaneity are limited. He has a guarded manner, and although he is able to answer questions posed to him, rapport is difficult to establish as he appears interpersonally uncomfortable.

Prior to the visit, Maddie’s mother completed the Social Responsiveness Scales, which revealed elevated scores in the area of Social Communication and Social Motivation. Despite appearing cognitively bright and having an array of academic and creative strengths, Maddie’s troubles forming meaningful relationships are striking. Deficits in social-emotional competence are incommensurate with his suspected cognitive abilities, and although he relates learning social skills from film over the years, he endorses pervasively compromised social-communication aptitudes and enduring functional impairments. “I’m always playing catch-up socially,” he shares, wondering how this will affect him in his nursing career.

Discussion

Maddie and his mother participated in an autism diagnostic evaluation, including the administration of the Autism Diagnostic Interview–Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS). The evaluation revealed a profile of social impairments and inflexible thinking dating back to early childhood that supported a diagnosis of an autism spectrum disorder (ASD). Other diagnoses, including anxiety disorders, a depressive disorder, a social pragmatic communication disorder, and a nonverbal learning disorder, were considered, but ultimately it was concluded that ASD best captured Maddie, who also continued to display features consistent with gender dysphoria.

Over the past 30 years, the relationship between gender-related concerns and ASD has begun to be discussed in the scientific literature, beginning with case reports and more recently with a retrospective chart study that yielded results suggesting that subjects diagnosed with ASD were almost eight times more likely to report gender variance than a nonreferred standardization sample of the Child Behavior Checklist (CBCL) (Transgender Health. 2016 Feb;1[1]:63-8). These results echo those of a prior study showing that 7.8% of individuals presenting for an evaluation in a Dutch gender clinic had an ASD diagnosis (J Autism Dev Disord. 2010 Aug;40[8]:930-6).

With the individual prevalences for ASD and gender dysphoria taken into account, these numbers suggest that the prevalence of ASD in gender-dysphoric youth is about four times higher than that found in the general population (Sex Med Rev. 2016;4:3e14). These data raise questions regarding potential shared etiology and the neurobiology between a disorder of social communication and gender identity–related issues; however, to date, despite several theories attempting to explain the connection (the notion of an “extreme male brain,” role of sex hormones, etc.), the relationship remains puzzling. Some have argued that the rigid thinking that can characterize ASD may lead those individuals who display any gender-variant behaviors to automatically identify as the gender opposite their biologic gender, even though they aren’t necessarily experiencing frank gender dysphoria or a core gender identity that is firmly discordant from their anatomical sex. Thinking about the relationship from another perspective, perhaps those with ASD are less aware of the social constructs of gender and are able to express their gender identity (whether it be crossgender or cisgender) more freely and without the worry of how they may be perceived by others. Undoubtedly, a complex interplay between ASD and gender dysphoria/gender-nonconforming behavior is suspected, and more quality research is needed – research that, at a minimum, is informed by the use of representative sample groups drawn from all developmental periods and well-defined diagnostic constructs.

Clinical pearl

Maddie, a transgender man, received a diagnosis of an autism spectrum disorder as a young adult – a full 16 years after the median age of diagnosis (MMWR Surveill Summ. 2016;65[3]:1-23).

The case illustrates some of the difficulties of attempting to parse out the cause of social impairments in an individual who also may have other phenomena that influence interpersonal functioning (attention-deficit/hyperactivity disorder, anxiety, gender dysphoria, etc.) in a developmental manner. Diagnostic “overshadowing” (mistakenly attributing symptoms to a particular condition and paying little attention to other possibilities) is not uncommon in youth with ASD and co-occurring conditions. Given the overlap between gender-nonconforming youth, individuals with gender dysphoria, and ASD, primary care providers may opt to incorporate mental health professionals familiar with ASD into the assessment and care of these children and adolescents. Getting a complete developmental history and paying attention to the possibility of early red flags for ASD can help to elucidate diagnostic possibilities and inform treatment planning. If a co-occurring diagnosis is confirmed, implementation of evidence-based interventions that are provided through the lens of ASD can help to minimize the risk of developing other co-occurring pathology, build resilience, alleviate social impairment, and foster self-advocacy skills in this very vulnerable population. Regardless of whether gender-variant youth and adolescents have an autistic disorder, mental health providers can have an integral role in assisting these individuals and their families to navigate a complicated system of care, address gender dysphoria, and promote healthy identity development (J Am Acad Child Adolesc Psychiatry. 2016 Jun;55[6]:441-3).

Dr. Dickerson, a child and adolescent psychiatrist, is assistant professor of psychiatry at the University of Vermont, where he is director of the autism diagnostic clinic.

On June 12, 2016, a man walked into an Orlando, Fla., nightclub and committed the worst mass shooting in U.S. history. When it was over, 49 people lay dead and more than 50 others were wounded. The shooter must have been mentally ill. Only someone with a serious mental illness would commit such a horrible crime, right?

Wrong. Evidence indicating that the perpetrator’s motives lay in his political/religious ideology and possible homophobia quickly knocked mental illness out of the debate about motivation behind this particular shooting. Nevertheless, media speculation about mental illness invariably accompanies mass shootings.

Mass shootings are the most sensational, gut wrenching, and widely publicized form of firearm violence. Nevertheless, statistically speaking, mass shooting homicides are the rarest form of firearm death. These incidents account for less than 1% of firearm mortality each year. About 33,000 people a year are killed by firearms. Firearm suicide accounts for about 65% of these deaths; the rest are overwhelmingly the result of interpersonal violence, not violence committed by a stranger with a gun.

All of us recognize the images of mass shooters who were in fact mentally ill, such as the young man with the dazed look and red hair in Aurora, Colo., and the chilling images of the Virginia Tech shooter posing with his weapons. Individuals in the first throes of psychotic illness are at increased risk of committing some type of violence as their functioning deteriorates, their thoughts become more disordered, and their lack of insight often leads to treatment refusal.

However, most mass shooters are not suffering from serious mental illness. As has been discussed in a recent article, mass shooters often hold “extreme overvalued ideas,” that is, nondelusional, strongly held beliefs, a concept that does not fit neatly into DSM-5 diagnostic categories. As Dr. Tahir Rahman, an assistant professor of psychiatry at the University of Missouri, Columbia, and his colleagues wrote in a recent study: “An extreme overvalued belief is one that is shared by others in a person’s cultural, religious, or subcultural group. The belief is often relished, amplified, and defended by the possessor of the belief and should be differentiated from a delusion or obsession. The idea fulminates in the mind of the individual, growing ever more dominant over time, more refined, and more resistant to challenge. The individual has an intense emotional commitment to the belief and may carry out violent behavior in its service. It is usually associated with an abnormal personality” (p. 33). We used to refer to people who hold such beliefs as “fanatics.”

The line between psychotic delusions and extreme overvalued ideas is not always clear, but some markers and signposts can differentiate between the two. Psychiatric illness is suggested, for example, by the presence of other recognizable symptoms of mental illness, such as other delusions, hallucinations, or thought disorders. In addition, individuals with psychiatric illness demonstrate related functional impairment preceding and unrelated to the mass shooting. Finally, delusions are rarely shared by even two individuals; they are not shared by large groups.

Examples in which large groups of people share social, religious, or political beliefs and some believers resort to violence can be found throughout history: from Masada to 19th century abolitionists such as John Brown to 20th century animal rights activists and 21st century “sovereign citizens.” Finding groups that reinforce and validate extreme beliefs has become even easier in the age of social media.

However, fanatics often function adequately in society until something happens to trigger a choice to act violently. Absent a history of felonious violence, these individuals are not likely to be barred from owning firearms. More non–evidence based firearm ownership restrictions for those with mental illness are not likely to slow down or decrease the rising rate of mass shootings.

We do not have more people with psychosis in the United States nor do we have more people who hold extremist ideology. What we do have are more legally purchased, military-grade weapons in the hands of a civilian population than any other comparable country. An overwhelming number of mass shootings involve assault weapons.

One popular definition of insanity is doing the same thing over and over again and expecting different results. Only one intervention could make a difference in the increasing number of heartbreaking mass shootings. Military-grade semiautomatic weapons and their high-capacity magazines should not be available to civilians with or without mental illness or fanaticism. Moreover, as the Newtown, Conn., families are doing in their lawsuit against Remington Arms, the manufacturers who sell and market such weapons to civilians must be held legally accountable for valuing their profits over our lives.

Dr. Gold is a clinical professor of psychiatry at Georgetown University, Washington. She also is editor of and contributing writer to the book “Gun Violence and Mental Illness” (Arlington [Va]: American Psychiatric Association Publishing, 2016).

On June 12, 2016, a man walked into an Orlando, Fla., nightclub and committed the worst mass shooting in U.S. history. When it was over, 49 people lay dead and more than 50 others were wounded. The shooter must have been mentally ill. Only someone with a serious mental illness would commit such a horrible crime, right?

Wrong. Evidence indicating that the perpetrator’s motives lay in his political/religious ideology and possible homophobia quickly knocked mental illness out of the debate about motivation behind this particular shooting. Nevertheless, media speculation about mental illness invariably accompanies mass shootings.

Mass shootings are the most sensational, gut wrenching, and widely publicized form of firearm violence. Nevertheless, statistically speaking, mass shooting homicides are the rarest form of firearm death. These incidents account for less than 1% of firearm mortality each year. About 33,000 people a year are killed by firearms. Firearm suicide accounts for about 65% of these deaths; the rest are overwhelmingly the result of interpersonal violence, not violence committed by a stranger with a gun.

All of us recognize the images of mass shooters who were in fact mentally ill, such as the young man with the dazed look and red hair in Aurora, Colo., and the chilling images of the Virginia Tech shooter posing with his weapons. Individuals in the first throes of psychotic illness are at increased risk of committing some type of violence as their functioning deteriorates, their thoughts become more disordered, and their lack of insight often leads to treatment refusal.

However, most mass shooters are not suffering from serious mental illness. As has been discussed in a recent article, mass shooters often hold “extreme overvalued ideas,” that is, nondelusional, strongly held beliefs, a concept that does not fit neatly into DSM-5 diagnostic categories. As Dr. Tahir Rahman, an assistant professor of psychiatry at the University of Missouri, Columbia, and his colleagues wrote in a recent study: “An extreme overvalued belief is one that is shared by others in a person’s cultural, religious, or subcultural group. The belief is often relished, amplified, and defended by the possessor of the belief and should be differentiated from a delusion or obsession. The idea fulminates in the mind of the individual, growing ever more dominant over time, more refined, and more resistant to challenge. The individual has an intense emotional commitment to the belief and may carry out violent behavior in its service. It is usually associated with an abnormal personality” (p. 33). We used to refer to people who hold such beliefs as “fanatics.”

The line between psychotic delusions and extreme overvalued ideas is not always clear, but some markers and signposts can differentiate between the two. Psychiatric illness is suggested, for example, by the presence of other recognizable symptoms of mental illness, such as other delusions, hallucinations, or thought disorders. In addition, individuals with psychiatric illness demonstrate related functional impairment preceding and unrelated to the mass shooting. Finally, delusions are rarely shared by even two individuals; they are not shared by large groups.

Examples in which large groups of people share social, religious, or political beliefs and some believers resort to violence can be found throughout history: from Masada to 19th century abolitionists such as John Brown to 20th century animal rights activists and 21st century “sovereign citizens.” Finding groups that reinforce and validate extreme beliefs has become even easier in the age of social media.

However, fanatics often function adequately in society until something happens to trigger a choice to act violently. Absent a history of felonious violence, these individuals are not likely to be barred from owning firearms. More non–evidence based firearm ownership restrictions for those with mental illness are not likely to slow down or decrease the rising rate of mass shootings.

We do not have more people with psychosis in the United States nor do we have more people who hold extremist ideology. What we do have are more legally purchased, military-grade weapons in the hands of a civilian population than any other comparable country. An overwhelming number of mass shootings involve assault weapons.

One popular definition of insanity is doing the same thing over and over again and expecting different results. Only one intervention could make a difference in the increasing number of heartbreaking mass shootings. Military-grade semiautomatic weapons and their high-capacity magazines should not be available to civilians with or without mental illness or fanaticism. Moreover, as the Newtown, Conn., families are doing in their lawsuit against Remington Arms, the manufacturers who sell and market such weapons to civilians must be held legally accountable for valuing their profits over our lives.

Dr. Gold is a clinical professor of psychiatry at Georgetown University, Washington. She also is editor of and contributing writer to the book “Gun Violence and Mental Illness” (Arlington [Va]: American Psychiatric Association Publishing, 2016).

On June 12, 2016, a man walked into an Orlando, Fla., nightclub and committed the worst mass shooting in U.S. history. When it was over, 49 people lay dead and more than 50 others were wounded. The shooter must have been mentally ill. Only someone with a serious mental illness would commit such a horrible crime, right?

Wrong. Evidence indicating that the perpetrator’s motives lay in his political/religious ideology and possible homophobia quickly knocked mental illness out of the debate about motivation behind this particular shooting. Nevertheless, media speculation about mental illness invariably accompanies mass shootings.

Mass shootings are the most sensational, gut wrenching, and widely publicized form of firearm violence. Nevertheless, statistically speaking, mass shooting homicides are the rarest form of firearm death. These incidents account for less than 1% of firearm mortality each year. About 33,000 people a year are killed by firearms. Firearm suicide accounts for about 65% of these deaths; the rest are overwhelmingly the result of interpersonal violence, not violence committed by a stranger with a gun.

All of us recognize the images of mass shooters who were in fact mentally ill, such as the young man with the dazed look and red hair in Aurora, Colo., and the chilling images of the Virginia Tech shooter posing with his weapons. Individuals in the first throes of psychotic illness are at increased risk of committing some type of violence as their functioning deteriorates, their thoughts become more disordered, and their lack of insight often leads to treatment refusal.

However, most mass shooters are not suffering from serious mental illness. As has been discussed in a recent article, mass shooters often hold “extreme overvalued ideas,” that is, nondelusional, strongly held beliefs, a concept that does not fit neatly into DSM-5 diagnostic categories. As Dr. Tahir Rahman, an assistant professor of psychiatry at the University of Missouri, Columbia, and his colleagues wrote in a recent study: “An extreme overvalued belief is one that is shared by others in a person’s cultural, religious, or subcultural group. The belief is often relished, amplified, and defended by the possessor of the belief and should be differentiated from a delusion or obsession. The idea fulminates in the mind of the individual, growing ever more dominant over time, more refined, and more resistant to challenge. The individual has an intense emotional commitment to the belief and may carry out violent behavior in its service. It is usually associated with an abnormal personality” (p. 33). We used to refer to people who hold such beliefs as “fanatics.”

The line between psychotic delusions and extreme overvalued ideas is not always clear, but some markers and signposts can differentiate between the two. Psychiatric illness is suggested, for example, by the presence of other recognizable symptoms of mental illness, such as other delusions, hallucinations, or thought disorders. In addition, individuals with psychiatric illness demonstrate related functional impairment preceding and unrelated to the mass shooting. Finally, delusions are rarely shared by even two individuals; they are not shared by large groups.

Examples in which large groups of people share social, religious, or political beliefs and some believers resort to violence can be found throughout history: from Masada to 19th century abolitionists such as John Brown to 20th century animal rights activists and 21st century “sovereign citizens.” Finding groups that reinforce and validate extreme beliefs has become even easier in the age of social media.

However, fanatics often function adequately in society until something happens to trigger a choice to act violently. Absent a history of felonious violence, these individuals are not likely to be barred from owning firearms. More non–evidence based firearm ownership restrictions for those with mental illness are not likely to slow down or decrease the rising rate of mass shootings.

We do not have more people with psychosis in the United States nor do we have more people who hold extremist ideology. What we do have are more legally purchased, military-grade weapons in the hands of a civilian population than any other comparable country. An overwhelming number of mass shootings involve assault weapons.

One popular definition of insanity is doing the same thing over and over again and expecting different results. Only one intervention could make a difference in the increasing number of heartbreaking mass shootings. Military-grade semiautomatic weapons and their high-capacity magazines should not be available to civilians with or without mental illness or fanaticism. Moreover, as the Newtown, Conn., families are doing in their lawsuit against Remington Arms, the manufacturers who sell and market such weapons to civilians must be held legally accountable for valuing their profits over our lives.

Dr. Gold is a clinical professor of psychiatry at Georgetown University, Washington. She also is editor of and contributing writer to the book “Gun Violence and Mental Illness” (Arlington [Va]: American Psychiatric Association Publishing, 2016).

Summer is upon us, a season of delight for children and teens. School is out, the days are long, warm, and full of activities they get to choose. But we know that summer is also the season of accidents. While adventurous activities can lead to scratches, sprains, and broken bones, many accidents are far more serious. The Centers for Disease Control and Prevention reported that in 2014 (the most recent data available), accidental injuries were the leading cause of death for children from the age of 1 year through young adulthood (age 24 years). Car accidents, drowning, burns, suffocation, poisoning, and being struck while on a bike or other vehicle are the most prominent causes of injury or death in youth.

When something is an “accident,” we understand it to be an unfortunate event that happened by chance, without deliberate cause, and not easily foreseeable or preventable. But many accidents that befall children, while not deliberate, might be more foreseeable and preventable than they first appear. With younger children, parents directly oversee their children, ensuring they wear bike helmets, are placed in appropriate car restraints, cannot play with lighters, are always in sight when learning to swim (with a family pool well fenced and locked), and have no access to guns (and the guns are not loaded and have trigger locks!).

As their children grow older, parents must manage the challenging task of teaching their children to manage risk as they cultivate independence: learning to always put on their bike helmet before riding home from school, avoiding diving into shallow water, and not riding in a car with an impaired driver. Both the direct supervision of younger children and the teaching of older children and teenagers are very demanding of time and energy for parents. Terrible accidents can occur during truly unpredictable moments of distraction, but for too many parents, these moments of distraction are in fact predictable. If parents are strained by financial troubles, a disintegrating marriage, a serious illness in a spouse or elderly parent, or their own mental illness, their ability to be fully present and patient to supervise their children will be predictably impaired. During the summer months, when children may be home all day and looking for adventure, parental stress and distraction result in a high-risk environment that makes serious accidents more likely.

You as a child care provider are wonderful at providing supportive reminders to parents about the basics of child safety and supervision. Every checkup includes questions about whether anyone smokes at home and whether there is a working smoke detector. You ask about bike helmets and booster seats, and whether there are firearms in the home and if so, whether they are properly stored and locked. While there are often no formal questions about the level of family stress at a checkup, it would be simple to add: “Would you say the stress level at home is low, moderate, or high?” Such an open-ended question could lead to discussion of those factors that might be causing stress and give you a quick sense of how equipped the parent (or parents) are to handle it. Without a doubt, physicians’ practices are themselves stressed for time, and asking parents about their own stress may seem like opening Pandora’s box. But by being curious, bringing the important matter of domestic stress into the conversation about a child’s health and well being can by itself be therapeutic. The parents found the time to bring their child to this appointment, despite their stress. By simply bringing their awareness to the impact their stress could have on the safety of their children, you may have made a critical difference.

When parents report a high level of stress, you might follow up with more specific questions about their supports. Who provides them with practical help or a supportive ear? Do they have a strong community of friends, nearby family, or a supportive faith community? Are there practical ways to outsource some of the demands they may be juggling? You should be prepared to offer resources if a parent reports domestic violence. Some pediatric practices will employ social workers who can facilitate connecting stressed families with appropriate resources. But if your practice does not, a little time online can build a database of virtual and community resources that a family can start with.

You are also in a unique position to appreciate that certain children are themselves at higher risk for accidents. Children and adolescents with attention-deficit/hyperactivity disorder may be more distractible and impulsive than their peers. And summer is often a season when families decide to suspend stimulant treatment to promote weight gain or growth. These children and teens are at elevated risk to “leap before they look,” and parents should be reminded of their higher level of risk and need for supervision, at least when having a conversation about whether to suspend stimulant treatment. Children with a history of oppositional behaviors also can prove more challenging to supervise than their peers. Beyond the risk of self-injury or suicide, youth with depressive disorders can have impaired concentration and attention, and may not assess the risk of certain activities very well. These children can be challenging to parent at all times, so their parents likely manage a higher general level of parenting stress, and can benefit from your inquiry and additional resources.

A parent’s task of supervising is different with adolescents than with younger children. It is as much about effective communication and modeling how to assess risk and make judgments as it is about time spent watching the children. But these tasks take time and patience, perhaps even more than the supervision of younger kids. And while a teenager may have good judgment, who her friends are matters as much as her own judgment. Teenagers take more chances when they are with friends, and particularly with thrill-seeking friends. If parents are too distracted or busy to know who their teenager is spending time with, that itself raises the teenager’s chances of risky behaviors and accidental injury.

©shironosov/iStockphoto.com

Of course, when teenagers are experimenting with alcohol or drugs, the risk of serious accidents increases significantly. The Centers for Disease Control and Prevention estimates that approximately half of the nonmedical deaths of 15- to 24-year-olds involve drug or alcohol use. Stressed parents are less likely to be spending time with their teenagers to ask about drugs and alcohol: Who is using them? When and where? What else are they hearing about drugs and alcohol? It also takes time and a calm, clear, and open presence to talk with teenagers about expectations and ground rules around drug or alcohol experimentation (which has been shown to diminish the rate of regular use of drugs or alcohol in teens by as much as half). It takes time for parents to explain to their teenager that they should ALWAYS call home if they are anywhere they do not feel safe, even if it involves drugs or alcohol. It is complex to set rules and expectations while also being clear that their safety always comes first. You can encourage parents to know their teen’s friends, and to have a conversation about the rules around drug and alcohol use and to set a safety plan. Parents who are too stressed to even know where to start will benefit from a longer conversation, and can be referred to some good websites or for a mental health consultation.

Summer should be a time of skill building, adventure, growing independence, and some rest and relaxation. Helping parents to pay attention to their own stress level and access needed supports may be the critical factor in preventing accidents and promoting the health and well being of their children during this wonderful, but risky season.

Dr. Swick is an attending psychiatrist in the division of child psychiatry at Massachusetts General Hospital, Boston, and director of the Parenting at a Challenging Time (PACT) Program at the Vernon Cancer Center at Newton (Mass.) Wellesley Hospital. Dr. Jellinek is professor of psychiatry and of pediatrics at Harvard Medical School, Boston.

Summer is upon us, a season of delight for children and teens. School is out, the days are long, warm, and full of activities they get to choose. But we know that summer is also the season of accidents. While adventurous activities can lead to scratches, sprains, and broken bones, many accidents are far more serious. The Centers for Disease Control and Prevention reported that in 2014 (the most recent data available), accidental injuries were the leading cause of death for children from the age of 1 year through young adulthood (age 24 years). Car accidents, drowning, burns, suffocation, poisoning, and being struck while on a bike or other vehicle are the most prominent causes of injury or death in youth.

When something is an “accident,” we understand it to be an unfortunate event that happened by chance, without deliberate cause, and not easily foreseeable or preventable. But many accidents that befall children, while not deliberate, might be more foreseeable and preventable than they first appear. With younger children, parents directly oversee their children, ensuring they wear bike helmets, are placed in appropriate car restraints, cannot play with lighters, are always in sight when learning to swim (with a family pool well fenced and locked), and have no access to guns (and the guns are not loaded and have trigger locks!).

As their children grow older, parents must manage the challenging task of teaching their children to manage risk as they cultivate independence: learning to always put on their bike helmet before riding home from school, avoiding diving into shallow water, and not riding in a car with an impaired driver. Both the direct supervision of younger children and the teaching of older children and teenagers are very demanding of time and energy for parents. Terrible accidents can occur during truly unpredictable moments of distraction, but for too many parents, these moments of distraction are in fact predictable. If parents are strained by financial troubles, a disintegrating marriage, a serious illness in a spouse or elderly parent, or their own mental illness, their ability to be fully present and patient to supervise their children will be predictably impaired. During the summer months, when children may be home all day and looking for adventure, parental stress and distraction result in a high-risk environment that makes serious accidents more likely.

You as a child care provider are wonderful at providing supportive reminders to parents about the basics of child safety and supervision. Every checkup includes questions about whether anyone smokes at home and whether there is a working smoke detector. You ask about bike helmets and booster seats, and whether there are firearms in the home and if so, whether they are properly stored and locked. While there are often no formal questions about the level of family stress at a checkup, it would be simple to add: “Would you say the stress level at home is low, moderate, or high?” Such an open-ended question could lead to discussion of those factors that might be causing stress and give you a quick sense of how equipped the parent (or parents) are to handle it. Without a doubt, physicians’ practices are themselves stressed for time, and asking parents about their own stress may seem like opening Pandora’s box. But by being curious, bringing the important matter of domestic stress into the conversation about a child’s health and well being can by itself be therapeutic. The parents found the time to bring their child to this appointment, despite their stress. By simply bringing their awareness to the impact their stress could have on the safety of their children, you may have made a critical difference.

When parents report a high level of stress, you might follow up with more specific questions about their supports. Who provides them with practical help or a supportive ear? Do they have a strong community of friends, nearby family, or a supportive faith community? Are there practical ways to outsource some of the demands they may be juggling? You should be prepared to offer resources if a parent reports domestic violence. Some pediatric practices will employ social workers who can facilitate connecting stressed families with appropriate resources. But if your practice does not, a little time online can build a database of virtual and community resources that a family can start with.

You are also in a unique position to appreciate that certain children are themselves at higher risk for accidents. Children and adolescents with attention-deficit/hyperactivity disorder may be more distractible and impulsive than their peers. And summer is often a season when families decide to suspend stimulant treatment to promote weight gain or growth. These children and teens are at elevated risk to “leap before they look,” and parents should be reminded of their higher level of risk and need for supervision, at least when having a conversation about whether to suspend stimulant treatment. Children with a history of oppositional behaviors also can prove more challenging to supervise than their peers. Beyond the risk of self-injury or suicide, youth with depressive disorders can have impaired concentration and attention, and may not assess the risk of certain activities very well. These children can be challenging to parent at all times, so their parents likely manage a higher general level of parenting stress, and can benefit from your inquiry and additional resources.

A parent’s task of supervising is different with adolescents than with younger children. It is as much about effective communication and modeling how to assess risk and make judgments as it is about time spent watching the children. But these tasks take time and patience, perhaps even more than the supervision of younger kids. And while a teenager may have good judgment, who her friends are matters as much as her own judgment. Teenagers take more chances when they are with friends, and particularly with thrill-seeking friends. If parents are too distracted or busy to know who their teenager is spending time with, that itself raises the teenager’s chances of risky behaviors and accidental injury.

©shironosov/iStockphoto.com

Of course, when teenagers are experimenting with alcohol or drugs, the risk of serious accidents increases significantly. The Centers for Disease Control and Prevention estimates that approximately half of the nonmedical deaths of 15- to 24-year-olds involve drug or alcohol use. Stressed parents are less likely to be spending time with their teenagers to ask about drugs and alcohol: Who is using them? When and where? What else are they hearing about drugs and alcohol? It also takes time and a calm, clear, and open presence to talk with teenagers about expectations and ground rules around drug or alcohol experimentation (which has been shown to diminish the rate of regular use of drugs or alcohol in teens by as much as half). It takes time for parents to explain to their teenager that they should ALWAYS call home if they are anywhere they do not feel safe, even if it involves drugs or alcohol. It is complex to set rules and expectations while also being clear that their safety always comes first. You can encourage parents to know their teen’s friends, and to have a conversation about the rules around drug and alcohol use and to set a safety plan. Parents who are too stressed to even know where to start will benefit from a longer conversation, and can be referred to some good websites or for a mental health consultation.

Summer should be a time of skill building, adventure, growing independence, and some rest and relaxation. Helping parents to pay attention to their own stress level and access needed supports may be the critical factor in preventing accidents and promoting the health and well being of their children during this wonderful, but risky season.

Dr. Swick is an attending psychiatrist in the division of child psychiatry at Massachusetts General Hospital, Boston, and director of the Parenting at a Challenging Time (PACT) Program at the Vernon Cancer Center at Newton (Mass.) Wellesley Hospital. Dr. Jellinek is professor of psychiatry and of pediatrics at Harvard Medical School, Boston.

Summer is upon us, a season of delight for children and teens. School is out, the days are long, warm, and full of activities they get to choose. But we know that summer is also the season of accidents. While adventurous activities can lead to scratches, sprains, and broken bones, many accidents are far more serious. The Centers for Disease Control and Prevention reported that in 2014 (the most recent data available), accidental injuries were the leading cause of death for children from the age of 1 year through young adulthood (age 24 years). Car accidents, drowning, burns, suffocation, poisoning, and being struck while on a bike or other vehicle are the most prominent causes of injury or death in youth.

When something is an “accident,” we understand it to be an unfortunate event that happened by chance, without deliberate cause, and not easily foreseeable or preventable. But many accidents that befall children, while not deliberate, might be more foreseeable and preventable than they first appear. With younger children, parents directly oversee their children, ensuring they wear bike helmets, are placed in appropriate car restraints, cannot play with lighters, are always in sight when learning to swim (with a family pool well fenced and locked), and have no access to guns (and the guns are not loaded and have trigger locks!).

As their children grow older, parents must manage the challenging task of teaching their children to manage risk as they cultivate independence: learning to always put on their bike helmet before riding home from school, avoiding diving into shallow water, and not riding in a car with an impaired driver. Both the direct supervision of younger children and the teaching of older children and teenagers are very demanding of time and energy for parents. Terrible accidents can occur during truly unpredictable moments of distraction, but for too many parents, these moments of distraction are in fact predictable. If parents are strained by financial troubles, a disintegrating marriage, a serious illness in a spouse or elderly parent, or their own mental illness, their ability to be fully present and patient to supervise their children will be predictably impaired. During the summer months, when children may be home all day and looking for adventure, parental stress and distraction result in a high-risk environment that makes serious accidents more likely.

You as a child care provider are wonderful at providing supportive reminders to parents about the basics of child safety and supervision. Every checkup includes questions about whether anyone smokes at home and whether there is a working smoke detector. You ask about bike helmets and booster seats, and whether there are firearms in the home and if so, whether they are properly stored and locked. While there are often no formal questions about the level of family stress at a checkup, it would be simple to add: “Would you say the stress level at home is low, moderate, or high?” Such an open-ended question could lead to discussion of those factors that might be causing stress and give you a quick sense of how equipped the parent (or parents) are to handle it. Without a doubt, physicians’ practices are themselves stressed for time, and asking parents about their own stress may seem like opening Pandora’s box. But by being curious, bringing the important matter of domestic stress into the conversation about a child’s health and well being can by itself be therapeutic. The parents found the time to bring their child to this appointment, despite their stress. By simply bringing their awareness to the impact their stress could have on the safety of their children, you may have made a critical difference.

When parents report a high level of stress, you might follow up with more specific questions about their supports. Who provides them with practical help or a supportive ear? Do they have a strong community of friends, nearby family, or a supportive faith community? Are there practical ways to outsource some of the demands they may be juggling? You should be prepared to offer resources if a parent reports domestic violence. Some pediatric practices will employ social workers who can facilitate connecting stressed families with appropriate resources. But if your practice does not, a little time online can build a database of virtual and community resources that a family can start with.

You are also in a unique position to appreciate that certain children are themselves at higher risk for accidents. Children and adolescents with attention-deficit/hyperactivity disorder may be more distractible and impulsive than their peers. And summer is often a season when families decide to suspend stimulant treatment to promote weight gain or growth. These children and teens are at elevated risk to “leap before they look,” and parents should be reminded of their higher level of risk and need for supervision, at least when having a conversation about whether to suspend stimulant treatment. Children with a history of oppositional behaviors also can prove more challenging to supervise than their peers. Beyond the risk of self-injury or suicide, youth with depressive disorders can have impaired concentration and attention, and may not assess the risk of certain activities very well. These children can be challenging to parent at all times, so their parents likely manage a higher general level of parenting stress, and can benefit from your inquiry and additional resources.

A parent’s task of supervising is different with adolescents than with younger children. It is as much about effective communication and modeling how to assess risk and make judgments as it is about time spent watching the children. But these tasks take time and patience, perhaps even more than the supervision of younger kids. And while a teenager may have good judgment, who her friends are matters as much as her own judgment. Teenagers take more chances when they are with friends, and particularly with thrill-seeking friends. If parents are too distracted or busy to know who their teenager is spending time with, that itself raises the teenager’s chances of risky behaviors and accidental injury.

©shironosov/iStockphoto.com

Of course, when teenagers are experimenting with alcohol or drugs, the risk of serious accidents increases significantly. The Centers for Disease Control and Prevention estimates that approximately half of the nonmedical deaths of 15- to 24-year-olds involve drug or alcohol use. Stressed parents are less likely to be spending time with their teenagers to ask about drugs and alcohol: Who is using them? When and where? What else are they hearing about drugs and alcohol? It also takes time and a calm, clear, and open presence to talk with teenagers about expectations and ground rules around drug or alcohol experimentation (which has been shown to diminish the rate of regular use of drugs or alcohol in teens by as much as half). It takes time for parents to explain to their teenager that they should ALWAYS call home if they are anywhere they do not feel safe, even if it involves drugs or alcohol. It is complex to set rules and expectations while also being clear that their safety always comes first. You can encourage parents to know their teen’s friends, and to have a conversation about the rules around drug and alcohol use and to set a safety plan. Parents who are too stressed to even know where to start will benefit from a longer conversation, and can be referred to some good websites or for a mental health consultation.

Summer should be a time of skill building, adventure, growing independence, and some rest and relaxation. Helping parents to pay attention to their own stress level and access needed supports may be the critical factor in preventing accidents and promoting the health and well being of their children during this wonderful, but risky season.

Dr. Swick is an attending psychiatrist in the division of child psychiatry at Massachusetts General Hospital, Boston, and director of the Parenting at a Challenging Time (PACT) Program at the Vernon Cancer Center at Newton (Mass.) Wellesley Hospital. Dr. Jellinek is professor of psychiatry and of pediatrics at Harvard Medical School, Boston.

At a time when therapeutics is emphasizing personalized therapy, it is reassuring that someone is interested in the big picture. Treating a single patient with drugs that cost $500 a pill seems in conflict with the needs of millions of individuals who might have the expression of cardiovascular disease delayed with a pill that might cost pennies.

Dr. Saleem Yusuf originated the concept of the polypill more than 10 years ago by proposing to make one simple pill to mitigate the effect of aging on cardiovascular mortality, particularly in the underdeveloped and rapidly aging countries of the world. Working at the Population Health Research Institute at the McMaster University in Canada, he has moved through a number of iterations of the original Polypill, the most recent reported from the Heart Outcomes Evaluation (HOPE-3) trial (N Engl J Med. 2016 May; 374:2021-31). HOPE-3 distilled the initial polypill array of five drugs (three antihypertensives, a statin, and an aspirin) down to a combination of three drugs; two hypertensives and a statin. One hypertension drug was discarded in the face of concerns of the potential of symptomatic hypotension, and aspirin because of its bleeding potential.

HOPE-3 included 12,705 patients in 21 countries around the world with 50% coming from Asia and China, 80% of whom were nonwhite. Patients aged at least 55 (men) and 65 (women) years with only one cardiovascular risk factor and with systolic pressure less than 160 mm Hg, were followed for 5.6 years. Patients were randomized to a combination of hypertension medications (candesartan, 16 mg, and hydrochlorothiazide, 12.5 mg), a statin (rosuvastatin, 10 mg) or both, or to placebo. The hypertension drug combination was successful in lowering the systolic pressure at randomization of 138/81 by 10 mm Hg but had no effect on cardiovascular mortality or morbidity. In contrast, the rosuvastatin arm successfully lowered the mean LDL cholesterol of 127.8 mg/dL by 26.5% at the conclusion of the trial. This was associated with a 24% decrease in the combined cardiovascular morbidity and mortality endpoint and a decrease in myocardial infarction and stroke of 35% and 30% respectively. The addition of the hypertension drugs to rosuvastatin added little to the morbidity and mortality benefit observed with rosuvastatin alone.

The initial concept of the polypill was greeted with considerable skepticism by the medical community, which has viewed attacking cardiovascular mortality as a one-on-one experience between patient and doctor. This, despite the benefit of a broad array of prevention efforts, including lifestyle and hypertension therapy that has occurred over the last half-century.

The concept of a polypill with five different medications appears to have failed, but its outcome refined to just to one statin is a message of great importance. In a universe of indigent and undertreated humans, the need for some form of intervention seems to be a crying one. The results of HOPE-3 are consistent with JUPITER and other statin lipid-lowering trials and indicates that just treating cholesterol alone in this low-risk population achieved significant benefit of itself. Application of such an intervention in the Third World could have an important benefit. The cost of such an intervention is minimal, compared with the recent additions to the cardiovascular pharmacopeia in both heart failure and lipid therapy.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

At a time when therapeutics is emphasizing personalized therapy, it is reassuring that someone is interested in the big picture. Treating a single patient with drugs that cost $500 a pill seems in conflict with the needs of millions of individuals who might have the expression of cardiovascular disease delayed with a pill that might cost pennies.

Dr. Saleem Yusuf originated the concept of the polypill more than 10 years ago by proposing to make one simple pill to mitigate the effect of aging on cardiovascular mortality, particularly in the underdeveloped and rapidly aging countries of the world. Working at the Population Health Research Institute at the McMaster University in Canada, he has moved through a number of iterations of the original Polypill, the most recent reported from the Heart Outcomes Evaluation (HOPE-3) trial (N Engl J Med. 2016 May; 374:2021-31). HOPE-3 distilled the initial polypill array of five drugs (three antihypertensives, a statin, and an aspirin) down to a combination of three drugs; two hypertensives and a statin. One hypertension drug was discarded in the face of concerns of the potential of symptomatic hypotension, and aspirin because of its bleeding potential.

HOPE-3 included 12,705 patients in 21 countries around the world with 50% coming from Asia and China, 80% of whom were nonwhite. Patients aged at least 55 (men) and 65 (women) years with only one cardiovascular risk factor and with systolic pressure less than 160 mm Hg, were followed for 5.6 years. Patients were randomized to a combination of hypertension medications (candesartan, 16 mg, and hydrochlorothiazide, 12.5 mg), a statin (rosuvastatin, 10 mg) or both, or to placebo. The hypertension drug combination was successful in lowering the systolic pressure at randomization of 138/81 by 10 mm Hg but had no effect on cardiovascular mortality or morbidity. In contrast, the rosuvastatin arm successfully lowered the mean LDL cholesterol of 127.8 mg/dL by 26.5% at the conclusion of the trial. This was associated with a 24% decrease in the combined cardiovascular morbidity and mortality endpoint and a decrease in myocardial infarction and stroke of 35% and 30% respectively. The addition of the hypertension drugs to rosuvastatin added little to the morbidity and mortality benefit observed with rosuvastatin alone.

The initial concept of the polypill was greeted with considerable skepticism by the medical community, which has viewed attacking cardiovascular mortality as a one-on-one experience between patient and doctor. This, despite the benefit of a broad array of prevention efforts, including lifestyle and hypertension therapy that has occurred over the last half-century.

The concept of a polypill with five different medications appears to have failed, but its outcome refined to just to one statin is a message of great importance. In a universe of indigent and undertreated humans, the need for some form of intervention seems to be a crying one. The results of HOPE-3 are consistent with JUPITER and other statin lipid-lowering trials and indicates that just treating cholesterol alone in this low-risk population achieved significant benefit of itself. Application of such an intervention in the Third World could have an important benefit. The cost of such an intervention is minimal, compared with the recent additions to the cardiovascular pharmacopeia in both heart failure and lipid therapy.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

At a time when therapeutics is emphasizing personalized therapy, it is reassuring that someone is interested in the big picture. Treating a single patient with drugs that cost $500 a pill seems in conflict with the needs of millions of individuals who might have the expression of cardiovascular disease delayed with a pill that might cost pennies.

Dr. Saleem Yusuf originated the concept of the polypill more than 10 years ago by proposing to make one simple pill to mitigate the effect of aging on cardiovascular mortality, particularly in the underdeveloped and rapidly aging countries of the world. Working at the Population Health Research Institute at the McMaster University in Canada, he has moved through a number of iterations of the original Polypill, the most recent reported from the Heart Outcomes Evaluation (HOPE-3) trial (N Engl J Med. 2016 May; 374:2021-31). HOPE-3 distilled the initial polypill array of five drugs (three antihypertensives, a statin, and an aspirin) down to a combination of three drugs; two hypertensives and a statin. One hypertension drug was discarded in the face of concerns of the potential of symptomatic hypotension, and aspirin because of its bleeding potential.

HOPE-3 included 12,705 patients in 21 countries around the world with 50% coming from Asia and China, 80% of whom were nonwhite. Patients aged at least 55 (men) and 65 (women) years with only one cardiovascular risk factor and with systolic pressure less than 160 mm Hg, were followed for 5.6 years. Patients were randomized to a combination of hypertension medications (candesartan, 16 mg, and hydrochlorothiazide, 12.5 mg), a statin (rosuvastatin, 10 mg) or both, or to placebo. The hypertension drug combination was successful in lowering the systolic pressure at randomization of 138/81 by 10 mm Hg but had no effect on cardiovascular mortality or morbidity. In contrast, the rosuvastatin arm successfully lowered the mean LDL cholesterol of 127.8 mg/dL by 26.5% at the conclusion of the trial. This was associated with a 24% decrease in the combined cardiovascular morbidity and mortality endpoint and a decrease in myocardial infarction and stroke of 35% and 30% respectively. The addition of the hypertension drugs to rosuvastatin added little to the morbidity and mortality benefit observed with rosuvastatin alone.

The initial concept of the polypill was greeted with considerable skepticism by the medical community, which has viewed attacking cardiovascular mortality as a one-on-one experience between patient and doctor. This, despite the benefit of a broad array of prevention efforts, including lifestyle and hypertension therapy that has occurred over the last half-century.

The concept of a polypill with five different medications appears to have failed, but its outcome refined to just to one statin is a message of great importance. In a universe of indigent and undertreated humans, the need for some form of intervention seems to be a crying one. The results of HOPE-3 are consistent with JUPITER and other statin lipid-lowering trials and indicates that just treating cholesterol alone in this low-risk population achieved significant benefit of itself. Application of such an intervention in the Third World could have an important benefit. The cost of such an intervention is minimal, compared with the recent additions to the cardiovascular pharmacopeia in both heart failure and lipid therapy.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

I was in London for the just-concluded EULAR congress. Oh, the United Kingdom, that bastion of socialist medicine, where the National Health Service is the great equalizer. Heaven sent to some, death spiral of long wait times and old-fashioned medicine to others. While there, I chatted with people who have had experience with the NHS.

I spoke with a health care consultant, whose job is to make hospitals less wasteful. He says the U.K.’s health care expenditure as a percent of GDP [gross domestic product] is too high, compared with other Western nations. I suspect this was a line that he probably heard somewhere and blindly repeated, because when I pressed, he could not tell me what the numbers were, nor could he name the countries he was referring to.

I asked him for examples of how he thought the hospitals he’d served might save money. His biggest complaint was that many patients stay in hospital for months not out of medical necessity but because there is no system in place for lower-level care.

Another friend is the director of a home care service just outside Central London. She tells me that patients have access to an extraordinary amount of resources that allows them to stay at home: suction machines, dialysis machines, home aides. This is great for patients, but she is astounded by how many people got services that she thought were undeserved.

She also told me that, apropos of the impending Brexit, many of their home health aides come from other Eurozone countries. The British do not want to do these jobs, so should the Brexit happen, home health aides will be much harder to come by.

Of course, the most common complaint I heard was that wait times to see a physician are ridiculous. Those who can afford it, can get private insurance, which would allow them access to physicians sooner. In fact, private insurance is often an incentive for people to get promoted.

The British think their health care system is wasteful, as we do for ours. But according to the World Bank’s data from 2014, their health care spending as a percent of GDP is 9.1%, which is much better than ours at 17.1%. And although I was told by the health care consultant that their figure is higher than their neighbors, that just isn’t true. France’s figure is 11.5%, Belgium’s 10.6%, and Spain’s 9.0%. So what I took away from it was this: As different as our health care systems are, they are problematic in the same ways. People have health care that works. But hospital stays are often unnecessary, people take advantage of social safety nets, and there are jobs that mostly only immigrants are willing to perform. Wealthy people can afford to pay for private insurance. And the wait times! People will always complain about wait times, just like they do here, and elsewhere.

Dr. Chan practices rheumatology in Pawtucket, R.I.

I was in London for the just-concluded EULAR congress. Oh, the United Kingdom, that bastion of socialist medicine, where the National Health Service is the great equalizer. Heaven sent to some, death spiral of long wait times and old-fashioned medicine to others. While there, I chatted with people who have had experience with the NHS.

I spoke with a health care consultant, whose job is to make hospitals less wasteful. He says the U.K.’s health care expenditure as a percent of GDP [gross domestic product] is too high, compared with other Western nations. I suspect this was a line that he probably heard somewhere and blindly repeated, because when I pressed, he could not tell me what the numbers were, nor could he name the countries he was referring to.

I asked him for examples of how he thought the hospitals he’d served might save money. His biggest complaint was that many patients stay in hospital for months not out of medical necessity but because there is no system in place for lower-level care.

Another friend is the director of a home care service just outside Central London. She tells me that patients have access to an extraordinary amount of resources that allows them to stay at home: suction machines, dialysis machines, home aides. This is great for patients, but she is astounded by how many people got services that she thought were undeserved.

She also told me that, apropos of the impending Brexit, many of their home health aides come from other Eurozone countries. The British do not want to do these jobs, so should the Brexit happen, home health aides will be much harder to come by.

Of course, the most common complaint I heard was that wait times to see a physician are ridiculous. Those who can afford it, can get private insurance, which would allow them access to physicians sooner. In fact, private insurance is often an incentive for people to get promoted.

The British think their health care system is wasteful, as we do for ours. But according to the World Bank’s data from 2014, their health care spending as a percent of GDP is 9.1%, which is much better than ours at 17.1%. And although I was told by the health care consultant that their figure is higher than their neighbors, that just isn’t true. France’s figure is 11.5%, Belgium’s 10.6%, and Spain’s 9.0%. So what I took away from it was this: As different as our health care systems are, they are problematic in the same ways. People have health care that works. But hospital stays are often unnecessary, people take advantage of social safety nets, and there are jobs that mostly only immigrants are willing to perform. Wealthy people can afford to pay for private insurance. And the wait times! People will always complain about wait times, just like they do here, and elsewhere.

Dr. Chan practices rheumatology in Pawtucket, R.I.

I was in London for the just-concluded EULAR congress. Oh, the United Kingdom, that bastion of socialist medicine, where the National Health Service is the great equalizer. Heaven sent to some, death spiral of long wait times and old-fashioned medicine to others. While there, I chatted with people who have had experience with the NHS.

I spoke with a health care consultant, whose job is to make hospitals less wasteful. He says the U.K.’s health care expenditure as a percent of GDP [gross domestic product] is too high, compared with other Western nations. I suspect this was a line that he probably heard somewhere and blindly repeated, because when I pressed, he could not tell me what the numbers were, nor could he name the countries he was referring to.

I asked him for examples of how he thought the hospitals he’d served might save money. His biggest complaint was that many patients stay in hospital for months not out of medical necessity but because there is no system in place for lower-level care.

Another friend is the director of a home care service just outside Central London. She tells me that patients have access to an extraordinary amount of resources that allows them to stay at home: suction machines, dialysis machines, home aides. This is great for patients, but she is astounded by how many people got services that she thought were undeserved.

She also told me that, apropos of the impending Brexit, many of their home health aides come from other Eurozone countries. The British do not want to do these jobs, so should the Brexit happen, home health aides will be much harder to come by.

Of course, the most common complaint I heard was that wait times to see a physician are ridiculous. Those who can afford it, can get private insurance, which would allow them access to physicians sooner. In fact, private insurance is often an incentive for people to get promoted.

The British think their health care system is wasteful, as we do for ours. But according to the World Bank’s data from 2014, their health care spending as a percent of GDP is 9.1%, which is much better than ours at 17.1%. And although I was told by the health care consultant that their figure is higher than their neighbors, that just isn’t true. France’s figure is 11.5%, Belgium’s 10.6%, and Spain’s 9.0%. So what I took away from it was this: As different as our health care systems are, they are problematic in the same ways. People have health care that works. But hospital stays are often unnecessary, people take advantage of social safety nets, and there are jobs that mostly only immigrants are willing to perform. Wealthy people can afford to pay for private insurance. And the wait times! People will always complain about wait times, just like they do here, and elsewhere.

Dr. Chan practices rheumatology in Pawtucket, R.I.

The question of how viruses can enter the intrauterine compartment and infect the fetus has long been a focus of research. It is of particular urgency today as the Zika virus spreads and causes perinatal infection that threatens the developing fetus with serious adverse outcomes such microcephaly and other brain anomalies, placental insufficiency, and fetal growth restriction.

We know that viruses can take a variety of routes to the fetal compartment, but we have also learned that the placenta has a robust level of inherent resistance to viruses. This resistance likely explains why we don’t see more viral infections in pregnancy.

Recent studies performed at our institution suggest that placental trophoblasts – the placenta’s primary line of defense – have inherent resistance to viruses such as Zika. It appears, therefore, that the Zika virus invades the intrauterine cavity by crossing the trophoblasts, perhaps earlier in pregnancy and prior to the development of full trophoblast resistance, by entering through breaks in this outer layer, or by utilizing alternative pathways to access the fetal compartment.

Further study of the placenta and its various cell types and mechanisms of viral defense will be critical for designing therapeutic strategies for preventing perinatal infections.

Various routes and affinities

Viruses have long been known to affect mothers and their unborn children. The rubella virus, for instance, posed a significant threat to the fetus until a vaccine program was introduced almost 50 years ago. Cytomegalovirus (CMV), on the other hand, continues be passed from mothers to their unborn children. While not as threatening as rubella once was, it can in some cases cause severe defects.

One might expect viruses to infect the placenta and then secondarily infect the fetus. While this may indeed occur, direct placental infection is not the only route by which viruses may enter the intrauterine compartment. Some viruses may be carried by macrophages or other immune cells through the placenta and into the fetal compartment, while others colonize the uterine cavity prior to conception, ready to proliferate during pregnancy.

In still other cases, viruses may be inadvertently introduced during medical procedures such as amniocentesis or transmitted through transvaginal ascending infection, most likely after rupture of the membranes. Viruses may also be transported through infected sperm (this appears to be one of the Zika virus’s modes of transportation), and as is the case with HIV and herpes simplex viruses, transmission sometimes occurs during delivery.

When we investigate whether or not the fetus is protected against particular viruses, we must therefore think about the multifaceted mechanisms by which viruses may be transmitted. With respect to the placenta specifically, we seek to understand how viruses enter the placenta, and how the placenta resists the propagation of some viruses while allowing other viruses to gain entry to the intrauterine compartment.

An additional consideration – one that is of utmost importance in the case of Zika – is whether viruses have any special affinity for particular fetal tissues. Some viruses, like CMV, infect multiple types of fetal tissue. The Zika virus, on the other hand, appears to target neuronal tissue in the fetus. In May, investigators of two studies reported that a strain of the Zika virus efficiently infected human cortical neural progenitor cells (Cell Stem Cell. 2016 May 5;18[5]:587-90), and that Zika infection of mice early in pregnancy resulted in infection of the placenta and of the fetal brain (Cell. 2016 May 19;165[5]:1081-91).

Interestingly, other flaviviruses such as the dengue and chikungunya viruses have not been associated with microcephaly or other congenital disorders. This suggests that the Zika virus employs unique mechanisms to infect or bypass the placental barrier and, in turn, to cause neuronal-focused damage.

Placental passage

The villous trophoblasts, cells that are bathed in maternal blood, form the placenta’s first line of defense. Viruses, including the Zika virus, must cross or somehow bypass this initial barrier before crossing the placental basement membrane and endothelial cells, if they are to potentially invade the intrauterine cavity and infect the fetal brain and other tissues.

Research has demonstrated that cells of various types of tissue may express certain proteins, such as AXL, MER and TYRO3. While not yet proven, these proteins may mediate the entry of viruses such as Zika, enabling them to cross the placental trophoblast layer. These proteins are indeed expressed in trophoblasts, especially in early pregnancy, but we do not yet know if the proteins actually aid Zika’s passage through the placenta.

Another mechanism that has been postulated in the case of Zika infection is antibody-dependent enhancement, a process by which a current infection is enhanced by prior infection with another virus from the same family. Some experts believe that pre-existing immunity to the dengue virus – another member of the flavivirus family that has been endemic in Brazil – may be enhancing the spread of Zika infection as antibodies against dengue cross-react with the Zika virus.

While antibody-dependent enhancement has been shown to occur and to advance infection in various body systems, it has not been proven to affect the placenta. Until we learn more, we must simply appreciate that the presence of antibodies from another member of a family of viruses does not necessarily confer resistance. Instead, it may enable new infections to advance.

One might view pregnancy as a time of immune compromise, but we have shown in our laboratories that trophoblasts in fact have inherent resistance to a number of viruses. In a recent study, we found that trophoblasts are refractory to direct infection with the Zika virus. We isolated trophoblast cells from healthy full-term human placentas, cultured these cells for several days, and infected them with the Zika virus. We then measured viral replication and compared the infectivity of these cells with the infectivity of human brain microvascular endothelial cells – nontrophoblast cells that served as a control.

Our findings were extremely interesting to us: The trophoblast cells appeared to be significantly more resistant to the Zika virus than the nontrophoblast cells.

We learned, moreover, that this resistance was mediated by a particular interferon released by the trophoblast cells – type III interferon IFN1 – and that this type III interferon appeared to protect not only the trophoblasts but the nontrophoblast cells as well. It acted in both an autocrine and a paracrine manner to protect cells from the Zika virus. When we blocked the antiviral signaling of this interferon, resistance to the virus was attenuated.

These findings suggest that while Zika appears able to cross through the placenta and infect the fetus, the mechanism does not involve direct infection of the trophoblasts, at least in the later stages of pregnancy. The virus must either evade the type III interferon antiviral signals generated by the trophoblasts or somehow bypass these cells to cross the placenta (Cell Host Microbe. 2016 May 11;19[5]:705-12).

Interestingly, the Cell study mentioned above, in which Zika infection of mice early in pregnancy infected placental cells and the brain, also showed reduced Zika presence in the mouse mononuclear trophoblasts and syncytiotrophoblasts, in areas of the placenta analogous to the human villi.

Some experts have suggested, based the study of other viruses, that the Zika virus is better able to infect the placenta when the infection occurs early in the first trimester or the second trimester. It is indeed possible – and makes intuitive sense – that first-trimester trophoblasts confer less resistance and a lower level of protection than the mature trophoblasts we studied. At this point, however, we cannot say with certainty whether or not the placenta is more or less permissive to Zika infection at different points in pregnancy.

Interestingly, investigators who prospectively followed a small cohort of pregnant women in Brazil with suspected Zika infection identified abnormalities in fetuses of women who were infected at various points of their pregnancies, even in the third trimester. Fetuses infected in the first trimester had findings suggestive of pathologic change during embryogenesis, but central nervous system abnormalities were seen in fetuses infected as late as 27 weeks of gestation, the investigators said (N Engl J Med. 2016 Mar 4. doi: 10.1056/NEJMoa1602412).

The interferon-conferred resistance demonstrated in our recent study is one of two mechanisms we’ve identified by which placental trophoblasts orchestrate resistance to viral infection. In earlier research, we found that resistance can be conferred to nontrophoblast cells by the delivery of micro-RNAs. These micro-RNAs (C19MC miRNAs) are uniquely expressed in the placenta and packaged within trophoblast-derived nanovesicles called exosomes. The nanovesicles can latch onto other cells in the vicinity of the trophoblasts, attenuating viral replication in these recipient cells.

This earlier in-vitro study involved a panel of diverse and unrelated viruses, including coxsackievirus B3, poliovirus, vesicular stomatitis virus, and human cytomegalovirus (Proc Natl Acad Sci U S A. 2013 Jul 16;110[29]:12048-53). It did not include the Zika virus, but our ongoing preliminary research suggests that the same mechanisms might be active against Zika.

Furthering research

Research at our institution and in other laboratories has shed light on various ways in which the fetus is protected from viruses, but we must learn more in order to understand how particular viruses, such as Zika, are able to reach the fetal compartment and cause particular birth defects.

We must further investigate the role and importance of antibody-dependent enhancement, and we must continue to study the placenta and its various cell types. Continuing efforts to better elucidate the placenta’s defense mechanisms and to identify cell types that are more or less resistant to the Zika virus – and understand their differences – may lead us to potential therapeutic strategies.

Dr. Sadovsky is scientific director of the Magee-Womens Research Institute, Elsie Hilliard Hillman Chair of Women’s Health Research, and professor of ob.gyn., reproductive sciences, microbiology, and molecular genetics at the University of Pittsburgh. Dr. Coyne is associate professor of microbiology and molecular genetics, and ob.gyn. and reproductive sciences, at the University of Pittsburgh.* Their research addressed in this Master Class was supported by grants from the National Institutes of Health, State of Pennsylvania Formula Research Funds, and Burroughs Wellcome Fund.

 *Correction, 7/05/2016: An earlier version of this article misstated Dr. Coyne's academic title. 

The question of how viruses can enter the intrauterine compartment and infect the fetus has long been a focus of research. It is of particular urgency today as the Zika virus spreads and causes perinatal infection that threatens the developing fetus with serious adverse outcomes such microcephaly and other brain anomalies, placental insufficiency, and fetal growth restriction.

We know that viruses can take a variety of routes to the fetal compartment, but we have also learned that the placenta has a robust level of inherent resistance to viruses. This resistance likely explains why we don’t see more viral infections in pregnancy.

Recent studies performed at our institution suggest that placental trophoblasts – the placenta’s primary line of defense – have inherent resistance to viruses such as Zika. It appears, therefore, that the Zika virus invades the intrauterine cavity by crossing the trophoblasts, perhaps earlier in pregnancy and prior to the development of full trophoblast resistance, by entering through breaks in this outer layer, or by utilizing alternative pathways to access the fetal compartment.

Further study of the placenta and its various cell types and mechanisms of viral defense will be critical for designing therapeutic strategies for preventing perinatal infections.

Various routes and affinities

Viruses have long been known to affect mothers and their unborn children. The rubella virus, for instance, posed a significant threat to the fetus until a vaccine program was introduced almost 50 years ago. Cytomegalovirus (CMV), on the other hand, continues be passed from mothers to their unborn children. While not as threatening as rubella once was, it can in some cases cause severe defects.

One might expect viruses to infect the placenta and then secondarily infect the fetus. While this may indeed occur, direct placental infection is not the only route by which viruses may enter the intrauterine compartment. Some viruses may be carried by macrophages or other immune cells through the placenta and into the fetal compartment, while others colonize the uterine cavity prior to conception, ready to proliferate during pregnancy.

In still other cases, viruses may be inadvertently introduced during medical procedures such as amniocentesis or transmitted through transvaginal ascending infection, most likely after rupture of the membranes. Viruses may also be transported through infected sperm (this appears to be one of the Zika virus’s modes of transportation), and as is the case with HIV and herpes simplex viruses, transmission sometimes occurs during delivery.

When we investigate whether or not the fetus is protected against particular viruses, we must therefore think about the multifaceted mechanisms by which viruses may be transmitted. With respect to the placenta specifically, we seek to understand how viruses enter the placenta, and how the placenta resists the propagation of some viruses while allowing other viruses to gain entry to the intrauterine compartment.

An additional consideration – one that is of utmost importance in the case of Zika – is whether viruses have any special affinity for particular fetal tissues. Some viruses, like CMV, infect multiple types of fetal tissue. The Zika virus, on the other hand, appears to target neuronal tissue in the fetus. In May, investigators of two studies reported that a strain of the Zika virus efficiently infected human cortical neural progenitor cells (Cell Stem Cell. 2016 May 5;18[5]:587-90), and that Zika infection of mice early in pregnancy resulted in infection of the placenta and of the fetal brain (Cell. 2016 May 19;165[5]:1081-91).

Interestingly, other flaviviruses such as the dengue and chikungunya viruses have not been associated with microcephaly or other congenital disorders. This suggests that the Zika virus employs unique mechanisms to infect or bypass the placental barrier and, in turn, to cause neuronal-focused damage.

Placental passage

The villous trophoblasts, cells that are bathed in maternal blood, form the placenta’s first line of defense. Viruses, including the Zika virus, must cross or somehow bypass this initial barrier before crossing the placental basement membrane and endothelial cells, if they are to potentially invade the intrauterine cavity and infect the fetal brain and other tissues.

Research has demonstrated that cells of various types of tissue may express certain proteins, such as AXL, MER and TYRO3. While not yet proven, these proteins may mediate the entry of viruses such as Zika, enabling them to cross the placental trophoblast layer. These proteins are indeed expressed in trophoblasts, especially in early pregnancy, but we do not yet know if the proteins actually aid Zika’s passage through the placenta.

Another mechanism that has been postulated in the case of Zika infection is antibody-dependent enhancement, a process by which a current infection is enhanced by prior infection with another virus from the same family. Some experts believe that pre-existing immunity to the dengue virus – another member of the flavivirus family that has been endemic in Brazil – may be enhancing the spread of Zika infection as antibodies against dengue cross-react with the Zika virus.

While antibody-dependent enhancement has been shown to occur and to advance infection in various body systems, it has not been proven to affect the placenta. Until we learn more, we must simply appreciate that the presence of antibodies from another member of a family of viruses does not necessarily confer resistance. Instead, it may enable new infections to advance.

One might view pregnancy as a time of immune compromise, but we have shown in our laboratories that trophoblasts in fact have inherent resistance to a number of viruses. In a recent study, we found that trophoblasts are refractory to direct infection with the Zika virus. We isolated trophoblast cells from healthy full-term human placentas, cultured these cells for several days, and infected them with the Zika virus. We then measured viral replication and compared the infectivity of these cells with the infectivity of human brain microvascular endothelial cells – nontrophoblast cells that served as a control.

Our findings were extremely interesting to us: The trophoblast cells appeared to be significantly more resistant to the Zika virus than the nontrophoblast cells.

We learned, moreover, that this resistance was mediated by a particular interferon released by the trophoblast cells – type III interferon IFN1 – and that this type III interferon appeared to protect not only the trophoblasts but the nontrophoblast cells as well. It acted in both an autocrine and a paracrine manner to protect cells from the Zika virus. When we blocked the antiviral signaling of this interferon, resistance to the virus was attenuated.

These findings suggest that while Zika appears able to cross through the placenta and infect the fetus, the mechanism does not involve direct infection of the trophoblasts, at least in the later stages of pregnancy. The virus must either evade the type III interferon antiviral signals generated by the trophoblasts or somehow bypass these cells to cross the placenta (Cell Host Microbe. 2016 May 11;19[5]:705-12).

Interestingly, the Cell study mentioned above, in which Zika infection of mice early in pregnancy infected placental cells and the brain, also showed reduced Zika presence in the mouse mononuclear trophoblasts and syncytiotrophoblasts, in areas of the placenta analogous to the human villi.

Some experts have suggested, based the study of other viruses, that the Zika virus is better able to infect the placenta when the infection occurs early in the first trimester or the second trimester. It is indeed possible – and makes intuitive sense – that first-trimester trophoblasts confer less resistance and a lower level of protection than the mature trophoblasts we studied. At this point, however, we cannot say with certainty whether or not the placenta is more or less permissive to Zika infection at different points in pregnancy.

Interestingly, investigators who prospectively followed a small cohort of pregnant women in Brazil with suspected Zika infection identified abnormalities in fetuses of women who were infected at various points of their pregnancies, even in the third trimester. Fetuses infected in the first trimester had findings suggestive of pathologic change during embryogenesis, but central nervous system abnormalities were seen in fetuses infected as late as 27 weeks of gestation, the investigators said (N Engl J Med. 2016 Mar 4. doi: 10.1056/NEJMoa1602412).

The interferon-conferred resistance demonstrated in our recent study is one of two mechanisms we’ve identified by which placental trophoblasts orchestrate resistance to viral infection. In earlier research, we found that resistance can be conferred to nontrophoblast cells by the delivery of micro-RNAs. These micro-RNAs (C19MC miRNAs) are uniquely expressed in the placenta and packaged within trophoblast-derived nanovesicles called exosomes. The nanovesicles can latch onto other cells in the vicinity of the trophoblasts, attenuating viral replication in these recipient cells.

This earlier in-vitro study involved a panel of diverse and unrelated viruses, including coxsackievirus B3, poliovirus, vesicular stomatitis virus, and human cytomegalovirus (Proc Natl Acad Sci U S A. 2013 Jul 16;110[29]:12048-53). It did not include the Zika virus, but our ongoing preliminary research suggests that the same mechanisms might be active against Zika.

Furthering research

Research at our institution and in other laboratories has shed light on various ways in which the fetus is protected from viruses, but we must learn more in order to understand how particular viruses, such as Zika, are able to reach the fetal compartment and cause particular birth defects.

We must further investigate the role and importance of antibody-dependent enhancement, and we must continue to study the placenta and its various cell types. Continuing efforts to better elucidate the placenta’s defense mechanisms and to identify cell types that are more or less resistant to the Zika virus – and understand their differences – may lead us to potential therapeutic strategies.

Dr. Sadovsky is scientific director of the Magee-Womens Research Institute, Elsie Hilliard Hillman Chair of Women’s Health Research, and professor of ob.gyn., reproductive sciences, microbiology, and molecular genetics at the University of Pittsburgh. Dr. Coyne is associate professor of microbiology and molecular genetics, and ob.gyn. and reproductive sciences, at the University of Pittsburgh.* Their research addressed in this Master Class was supported by grants from the National Institutes of Health, State of Pennsylvania Formula Research Funds, and Burroughs Wellcome Fund.

 *Correction, 7/05/2016: An earlier version of this article misstated Dr. Coyne's academic title. 

The question of how viruses can enter the intrauterine compartment and infect the fetus has long been a focus of research. It is of particular urgency today as the Zika virus spreads and causes perinatal infection that threatens the developing fetus with serious adverse outcomes such microcephaly and other brain anomalies, placental insufficiency, and fetal growth restriction.

We know that viruses can take a variety of routes to the fetal compartment, but we have also learned that the placenta has a robust level of inherent resistance to viruses. This resistance likely explains why we don’t see more viral infections in pregnancy.

Recent studies performed at our institution suggest that placental trophoblasts – the placenta’s primary line of defense – have inherent resistance to viruses such as Zika. It appears, therefore, that the Zika virus invades the intrauterine cavity by crossing the trophoblasts, perhaps earlier in pregnancy and prior to the development of full trophoblast resistance, by entering through breaks in this outer layer, or by utilizing alternative pathways to access the fetal compartment.

Further study of the placenta and its various cell types and mechanisms of viral defense will be critical for designing therapeutic strategies for preventing perinatal infections.

Various routes and affinities

Viruses have long been known to affect mothers and their unborn children. The rubella virus, for instance, posed a significant threat to the fetus until a vaccine program was introduced almost 50 years ago. Cytomegalovirus (CMV), on the other hand, continues be passed from mothers to their unborn children. While not as threatening as rubella once was, it can in some cases cause severe defects.

One might expect viruses to infect the placenta and then secondarily infect the fetus. While this may indeed occur, direct placental infection is not the only route by which viruses may enter the intrauterine compartment. Some viruses may be carried by macrophages or other immune cells through the placenta and into the fetal compartment, while others colonize the uterine cavity prior to conception, ready to proliferate during pregnancy.

In still other cases, viruses may be inadvertently introduced during medical procedures such as amniocentesis or transmitted through transvaginal ascending infection, most likely after rupture of the membranes. Viruses may also be transported through infected sperm (this appears to be one of the Zika virus’s modes of transportation), and as is the case with HIV and herpes simplex viruses, transmission sometimes occurs during delivery.

When we investigate whether or not the fetus is protected against particular viruses, we must therefore think about the multifaceted mechanisms by which viruses may be transmitted. With respect to the placenta specifically, we seek to understand how viruses enter the placenta, and how the placenta resists the propagation of some viruses while allowing other viruses to gain entry to the intrauterine compartment.

An additional consideration – one that is of utmost importance in the case of Zika – is whether viruses have any special affinity for particular fetal tissues. Some viruses, like CMV, infect multiple types of fetal tissue. The Zika virus, on the other hand, appears to target neuronal tissue in the fetus. In May, investigators of two studies reported that a strain of the Zika virus efficiently infected human cortical neural progenitor cells (Cell Stem Cell. 2016 May 5;18[5]:587-90), and that Zika infection of mice early in pregnancy resulted in infection of the placenta and of the fetal brain (Cell. 2016 May 19;165[5]:1081-91).

Interestingly, other flaviviruses such as the dengue and chikungunya viruses have not been associated with microcephaly or other congenital disorders. This suggests that the Zika virus employs unique mechanisms to infect or bypass the placental barrier and, in turn, to cause neuronal-focused damage.

Placental passage

The villous trophoblasts, cells that are bathed in maternal blood, form the placenta’s first line of defense. Viruses, including the Zika virus, must cross or somehow bypass this initial barrier before crossing the placental basement membrane and endothelial cells, if they are to potentially invade the intrauterine cavity and infect the fetal brain and other tissues.

Research has demonstrated that cells of various types of tissue may express certain proteins, such as AXL, MER and TYRO3. While not yet proven, these proteins may mediate the entry of viruses such as Zika, enabling them to cross the placental trophoblast layer. These proteins are indeed expressed in trophoblasts, especially in early pregnancy, but we do not yet know if the proteins actually aid Zika’s passage through the placenta.

Another mechanism that has been postulated in the case of Zika infection is antibody-dependent enhancement, a process by which a current infection is enhanced by prior infection with another virus from the same family. Some experts believe that pre-existing immunity to the dengue virus – another member of the flavivirus family that has been endemic in Brazil – may be enhancing the spread of Zika infection as antibodies against dengue cross-react with the Zika virus.

While antibody-dependent enhancement has been shown to occur and to advance infection in various body systems, it has not been proven to affect the placenta. Until we learn more, we must simply appreciate that the presence of antibodies from another member of a family of viruses does not necessarily confer resistance. Instead, it may enable new infections to advance.

One might view pregnancy as a time of immune compromise, but we have shown in our laboratories that trophoblasts in fact have inherent resistance to a number of viruses. In a recent study, we found that trophoblasts are refractory to direct infection with the Zika virus. We isolated trophoblast cells from healthy full-term human placentas, cultured these cells for several days, and infected them with the Zika virus. We then measured viral replication and compared the infectivity of these cells with the infectivity of human brain microvascular endothelial cells – nontrophoblast cells that served as a control.

Our findings were extremely interesting to us: The trophoblast cells appeared to be significantly more resistant to the Zika virus than the nontrophoblast cells.

We learned, moreover, that this resistance was mediated by a particular interferon released by the trophoblast cells – type III interferon IFN1 – and that this type III interferon appeared to protect not only the trophoblasts but the nontrophoblast cells as well. It acted in both an autocrine and a paracrine manner to protect cells from the Zika virus. When we blocked the antiviral signaling of this interferon, resistance to the virus was attenuated.

These findings suggest that while Zika appears able to cross through the placenta and infect the fetus, the mechanism does not involve direct infection of the trophoblasts, at least in the later stages of pregnancy. The virus must either evade the type III interferon antiviral signals generated by the trophoblasts or somehow bypass these cells to cross the placenta (Cell Host Microbe. 2016 May 11;19[5]:705-12).

Interestingly, the Cell study mentioned above, in which Zika infection of mice early in pregnancy infected placental cells and the brain, also showed reduced Zika presence in the mouse mononuclear trophoblasts and syncytiotrophoblasts, in areas of the placenta analogous to the human villi.

Some experts have suggested, based the study of other viruses, that the Zika virus is better able to infect the placenta when the infection occurs early in the first trimester or the second trimester. It is indeed possible – and makes intuitive sense – that first-trimester trophoblasts confer less resistance and a lower level of protection than the mature trophoblasts we studied. At this point, however, we cannot say with certainty whether or not the placenta is more or less permissive to Zika infection at different points in pregnancy.

Interestingly, investigators who prospectively followed a small cohort of pregnant women in Brazil with suspected Zika infection identified abnormalities in fetuses of women who were infected at various points of their pregnancies, even in the third trimester. Fetuses infected in the first trimester had findings suggestive of pathologic change during embryogenesis, but central nervous system abnormalities were seen in fetuses infected as late as 27 weeks of gestation, the investigators said (N Engl J Med. 2016 Mar 4. doi: 10.1056/NEJMoa1602412).

The interferon-conferred resistance demonstrated in our recent study is one of two mechanisms we’ve identified by which placental trophoblasts orchestrate resistance to viral infection. In earlier research, we found that resistance can be conferred to nontrophoblast cells by the delivery of micro-RNAs. These micro-RNAs (C19MC miRNAs) are uniquely expressed in the placenta and packaged within trophoblast-derived nanovesicles called exosomes. The nanovesicles can latch onto other cells in the vicinity of the trophoblasts, attenuating viral replication in these recipient cells.

This earlier in-vitro study involved a panel of diverse and unrelated viruses, including coxsackievirus B3, poliovirus, vesicular stomatitis virus, and human cytomegalovirus (Proc Natl Acad Sci U S A. 2013 Jul 16;110[29]:12048-53). It did not include the Zika virus, but our ongoing preliminary research suggests that the same mechanisms might be active against Zika.

Furthering research

Research at our institution and in other laboratories has shed light on various ways in which the fetus is protected from viruses, but we must learn more in order to understand how particular viruses, such as Zika, are able to reach the fetal compartment and cause particular birth defects.

We must further investigate the role and importance of antibody-dependent enhancement, and we must continue to study the placenta and its various cell types. Continuing efforts to better elucidate the placenta’s defense mechanisms and to identify cell types that are more or less resistant to the Zika virus – and understand their differences – may lead us to potential therapeutic strategies.

Dr. Sadovsky is scientific director of the Magee-Womens Research Institute, Elsie Hilliard Hillman Chair of Women’s Health Research, and professor of ob.gyn., reproductive sciences, microbiology, and molecular genetics at the University of Pittsburgh. Dr. Coyne is associate professor of microbiology and molecular genetics, and ob.gyn. and reproductive sciences, at the University of Pittsburgh.* Their research addressed in this Master Class was supported by grants from the National Institutes of Health, State of Pennsylvania Formula Research Funds, and Burroughs Wellcome Fund.

 *Correction, 7/05/2016: An earlier version of this article misstated Dr. Coyne's academic title. 

Viral illnesses in pregnancy are not unheard of. When a patient presents with symptoms, we often think of an influenza type of infection that will be cleared within a short period of time and with few negative consequences for the developing fetus. Other infections that can occur include TORCH – Toxoplasmosis, Other (syphilis, varicella-zoster, parvovirus B19), Rubella, Cytomegalovirus (CMV), and Herpes – infections, but these are also relatively common.

Rarely do we in the United States consider a gravida’s vulnerability to tropical infectious diseases such as dengue, chikungunya, and now Zika virus. With the popularity and ease of international travel, and the potential for women’s exposure to more exotic diseases, the practice of ob.gyn. must undergo a significant transition in perspective. It is vital for us to understand these illnesses because of their potency and reported injury to both the mother and baby, for several reasons.

First, there is the public health concern. As of June 16, 2016, the Pan American Health Organization of the World Health Organization, reported 39 countries and territories in the Americas with confirmed cases of Zika virus, with 21 of those countries having confirmed cases in pregnant women.

As of June 9, 2016, the Centers for Disease Control and Prevention reported that 234 pregnant women in the United States have laboratory evidence of possible Zika infection, along with 189 pregnant women living in U.S. territories. Since the current outbreak, which began in July 2015 in Brazil, seven countries – accounting for more than 1,600 cases – have reported babies with congenital syndrome associated with Zika virus, the majority of which have been in Brazil. With the Summer Olympics in Rio starting in August 2016, the potential spread of Zika virus is dizzying.

Second, there is the counseling and management concern. Without a treatment or vaccine available, ob.gyns. must stay current on the latest research and findings to inform their patients of the risks associated with travel to an area with confirmed, or areas at risk for developing, Zika virus transmission.

Third, there is a diagnostic concern. Women who have visited areas with Zika virus, or who have had intimate contact with someone who has traveled to these areas, must be diagnosed and then counseled immediately.

We have devoted this Master Class to a discussion of Zika virus and the work being conducted in the United States to understand this disease. We have invited Dr. Yoel Sadovsky, an expert on placental development and trophoblast function, and his colleague, Carolyn Coyne, Ph.D., a leading researcher on host-virus interactions, to address this important topic.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

Viral illnesses in pregnancy are not unheard of. When a patient presents with symptoms, we often think of an influenza type of infection that will be cleared within a short period of time and with few negative consequences for the developing fetus. Other infections that can occur include TORCH – Toxoplasmosis, Other (syphilis, varicella-zoster, parvovirus B19), Rubella, Cytomegalovirus (CMV), and Herpes – infections, but these are also relatively common.

Rarely do we in the United States consider a gravida’s vulnerability to tropical infectious diseases such as dengue, chikungunya, and now Zika virus. With the popularity and ease of international travel, and the potential for women’s exposure to more exotic diseases, the practice of ob.gyn. must undergo a significant transition in perspective. It is vital for us to understand these illnesses because of their potency and reported injury to both the mother and baby, for several reasons.

First, there is the public health concern. As of June 16, 2016, the Pan American Health Organization of the World Health Organization, reported 39 countries and territories in the Americas with confirmed cases of Zika virus, with 21 of those countries having confirmed cases in pregnant women.

As of June 9, 2016, the Centers for Disease Control and Prevention reported that 234 pregnant women in the United States have laboratory evidence of possible Zika infection, along with 189 pregnant women living in U.S. territories. Since the current outbreak, which began in July 2015 in Brazil, seven countries – accounting for more than 1,600 cases – have reported babies with congenital syndrome associated with Zika virus, the majority of which have been in Brazil. With the Summer Olympics in Rio starting in August 2016, the potential spread of Zika virus is dizzying.

Second, there is the counseling and management concern. Without a treatment or vaccine available, ob.gyns. must stay current on the latest research and findings to inform their patients of the risks associated with travel to an area with confirmed, or areas at risk for developing, Zika virus transmission.

Third, there is a diagnostic concern. Women who have visited areas with Zika virus, or who have had intimate contact with someone who has traveled to these areas, must be diagnosed and then counseled immediately.

We have devoted this Master Class to a discussion of Zika virus and the work being conducted in the United States to understand this disease. We have invited Dr. Yoel Sadovsky, an expert on placental development and trophoblast function, and his colleague, Carolyn Coyne, Ph.D., a leading researcher on host-virus interactions, to address this important topic.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

Viral illnesses in pregnancy are not unheard of. When a patient presents with symptoms, we often think of an influenza type of infection that will be cleared within a short period of time and with few negative consequences for the developing fetus. Other infections that can occur include TORCH – Toxoplasmosis, Other (syphilis, varicella-zoster, parvovirus B19), Rubella, Cytomegalovirus (CMV), and Herpes – infections, but these are also relatively common.

Rarely do we in the United States consider a gravida’s vulnerability to tropical infectious diseases such as dengue, chikungunya, and now Zika virus. With the popularity and ease of international travel, and the potential for women’s exposure to more exotic diseases, the practice of ob.gyn. must undergo a significant transition in perspective. It is vital for us to understand these illnesses because of their potency and reported injury to both the mother and baby, for several reasons.

First, there is the public health concern. As of June 16, 2016, the Pan American Health Organization of the World Health Organization, reported 39 countries and territories in the Americas with confirmed cases of Zika virus, with 21 of those countries having confirmed cases in pregnant women.

As of June 9, 2016, the Centers for Disease Control and Prevention reported that 234 pregnant women in the United States have laboratory evidence of possible Zika infection, along with 189 pregnant women living in U.S. territories. Since the current outbreak, which began in July 2015 in Brazil, seven countries – accounting for more than 1,600 cases – have reported babies with congenital syndrome associated with Zika virus, the majority of which have been in Brazil. With the Summer Olympics in Rio starting in August 2016, the potential spread of Zika virus is dizzying.

Second, there is the counseling and management concern. Without a treatment or vaccine available, ob.gyns. must stay current on the latest research and findings to inform their patients of the risks associated with travel to an area with confirmed, or areas at risk for developing, Zika virus transmission.

Third, there is a diagnostic concern. Women who have visited areas with Zika virus, or who have had intimate contact with someone who has traveled to these areas, must be diagnosed and then counseled immediately.

We have devoted this Master Class to a discussion of Zika virus and the work being conducted in the United States to understand this disease. We have invited Dr. Yoel Sadovsky, an expert on placental development and trophoblast function, and his colleague, Carolyn Coyne, Ph.D., a leading researcher on host-virus interactions, to address this important topic.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

This month I write about one of the College’s current advocacy efforts directed at ensuring an adequate surgical workforce in underserved and rural areas. Evidence indicates a current and growing shortage of surgeons available to serve the needs of populations in certain parts of the country. A shortage of general surgeons is a clear component to the crisis in health care workforce. Accordingly, the American College of Surgeons (ACS) is urging policy makers to recognize that only surgeons are uniquely qualified to provide certain necessary, lifesaving procedures, which other health professionals are neither trained nor competent to provide.

To determine where these areas of shortage are located and where access to surgical care is thus potentially a challenge, the ACS is strongly supporting the efforts of Representatives Larry Bucshon, MD, FACS (R-Ind.) and Ami Bera, MD (D-Calif.) who recently introduced H.R. 4959, the Ensuring Access to General Surgery Act of 2016. This legislation serves to direct the Secretary of the Department of Health and Human Services (HHS) to conduct a study on the designation of surgical Health Professional Shortage Areas (HPSA).

A variety of federal programs use the HPSA designation to improve access to health care by focusing aid and assistance on specific geographic areas and populations with the greatest unmet needs. The division of HHS known as the Health Resources and Services Administration (HRSA) has developed criteria used to determine whether certain geographic areas, population groups, or facilities may be designated as a HPSA. HPSA designation may be applied to urban or rural geographic areas, specific population groups, medical provider groups, or other public health care facilities. Currently, HRSA limits HPSA designations to shortages in primary care services, dental services, or mental health services.

HRSA has never designated an entity as a HPSA purely based upon a shortage of surgical services. In light of the available evidence relative to the shortage of surgical providers in certain parts of the country, ACS believes that research is necessary to determine exactly what constitutes a surgical shortage area, e.g., establish definitional criteria, with subsequent application of those criteria to determine where areas so defined are located. Such would provide HRSA with a valuable tool to utilize in efforts directed at increasing patient access to surgical care. Ultimately, offering incentives to surgeons to locate or remain in HPSA communities could become critical in guaranteeing all Medicare beneficiaries, regardless of geographic location, have access to quality surgical care. Determining what constitutes a surgical shortage area will serve to help HRSA to appropriately focus its resources.

Accordingly, we need your help and urge you to take action today.

Using the information below, please call your representatives today and urge them to join their colleagues and cosponsor H.R. 4959, the Ensuring Access to General Surgery Act of 2016.

Instructions

Call toll-free: 1-877-996-4464

You will be connected to your representative‘s office. Once you are connected, provide your name and indicate that you are a constituent. You should also be prepared to provide additional contact information for follow-up purposes.

Next, we suggest you use the following message:

• As a surgeon and as your constituent, I urge you to join your colleagues and cosponsor H.R. 4959, the Ensuring Access to General Surgery Act of 2016, which would direct the Secretary of Department of Health and Human Services (HHS) to conduct a study to designate General Surgery Health Professional Shortage Areas (HPSA).

• The division of HHS known as the Health Resources and Services Administration (HRSA) has developed designation criteria in order to determine whether certain geographic areas, population groups, or facilities may be designated as a HPSA.

• HRSA has never designated an entity as a HPSA purely based upon a shortage of surgical services.

• In light of evidence relative to a shortage of surgeons, ACS believes that research is necessary to determine exactly what constitutes a surgical shortage area and subsequently where these areas exist.

Alternatively, for those who were seeking a topic on which to initiate a personal in-district meeting with representatives and their staff as was discussed in last month’s edition of this column, H.R. 4959 presents a prime subject for such in order to have a focused meeting with a specific ask on a “white hat” issue that will surely resonate with members of Congress. Currently, in-district work periods are scheduled for the last week of June, the last two weeks of July, and the entire month of August.

As always, those with questions or concerns, or those who need assistance in setting up an in-district meeting may contact staff of the Division of Advocacy and Health Policy by phone at 202-337-2701 or via e-mail at [email protected].

Thank you for taking the time to engage and take action on this critical issue.

Please encourage your colleagues to do likewise.

Until next month ...

Dr. Patrick V. Bailey is an ACS Fellow, a pediatric surgeon, and Medical Director, Advocacy, for the Division of Advocacy and Health Policy, in the ACS offices in Washington, DC.

This month I write about one of the College’s current advocacy efforts directed at ensuring an adequate surgical workforce in underserved and rural areas. Evidence indicates a current and growing shortage of surgeons available to serve the needs of populations in certain parts of the country. A shortage of general surgeons is a clear component to the crisis in health care workforce. Accordingly, the American College of Surgeons (ACS) is urging policy makers to recognize that only surgeons are uniquely qualified to provide certain necessary, lifesaving procedures, which other health professionals are neither trained nor competent to provide.

To determine where these areas of shortage are located and where access to surgical care is thus potentially a challenge, the ACS is strongly supporting the efforts of Representatives Larry Bucshon, MD, FACS (R-Ind.) and Ami Bera, MD (D-Calif.) who recently introduced H.R. 4959, the Ensuring Access to General Surgery Act of 2016. This legislation serves to direct the Secretary of the Department of Health and Human Services (HHS) to conduct a study on the designation of surgical Health Professional Shortage Areas (HPSA).

A variety of federal programs use the HPSA designation to improve access to health care by focusing aid and assistance on specific geographic areas and populations with the greatest unmet needs. The division of HHS known as the Health Resources and Services Administration (HRSA) has developed criteria used to determine whether certain geographic areas, population groups, or facilities may be designated as a HPSA. HPSA designation may be applied to urban or rural geographic areas, specific population groups, medical provider groups, or other public health care facilities. Currently, HRSA limits HPSA designations to shortages in primary care services, dental services, or mental health services.

HRSA has never designated an entity as a HPSA purely based upon a shortage of surgical services. In light of the available evidence relative to the shortage of surgical providers in certain parts of the country, ACS believes that research is necessary to determine exactly what constitutes a surgical shortage area, e.g., establish definitional criteria, with subsequent application of those criteria to determine where areas so defined are located. Such would provide HRSA with a valuable tool to utilize in efforts directed at increasing patient access to surgical care. Ultimately, offering incentives to surgeons to locate or remain in HPSA communities could become critical in guaranteeing all Medicare beneficiaries, regardless of geographic location, have access to quality surgical care. Determining what constitutes a surgical shortage area will serve to help HRSA to appropriately focus its resources.

Accordingly, we need your help and urge you to take action today.

Using the information below, please call your representatives today and urge them to join their colleagues and cosponsor H.R. 4959, the Ensuring Access to General Surgery Act of 2016.

Instructions

Call toll-free: 1-877-996-4464

You will be connected to your representative‘s office. Once you are connected, provide your name and indicate that you are a constituent. You should also be prepared to provide additional contact information for follow-up purposes.

Next, we suggest you use the following message:

• As a surgeon and as your constituent, I urge you to join your colleagues and cosponsor H.R. 4959, the Ensuring Access to General Surgery Act of 2016, which would direct the Secretary of Department of Health and Human Services (HHS) to conduct a study to designate General Surgery Health Professional Shortage Areas (HPSA).

• The division of HHS known as the Health Resources and Services Administration (HRSA) has developed designation criteria in order to determine whether certain geographic areas, population groups, or facilities may be designated as a HPSA.

• HRSA has never designated an entity as a HPSA purely based upon a shortage of surgical services.

• In light of evidence relative to a shortage of surgeons, ACS believes that research is necessary to determine exactly what constitutes a surgical shortage area and subsequently where these areas exist.

Alternatively, for those who were seeking a topic on which to initiate a personal in-district meeting with representatives and their staff as was discussed in last month’s edition of this column, H.R. 4959 presents a prime subject for such in order to have a focused meeting with a specific ask on a “white hat” issue that will surely resonate with members of Congress. Currently, in-district work periods are scheduled for the last week of June, the last two weeks of July, and the entire month of August.

As always, those with questions or concerns, or those who need assistance in setting up an in-district meeting may contact staff of the Division of Advocacy and Health Policy by phone at 202-337-2701 or via e-mail at [email protected].

Thank you for taking the time to engage and take action on this critical issue.

Please encourage your colleagues to do likewise.

Until next month ...

Dr. Patrick V. Bailey is an ACS Fellow, a pediatric surgeon, and Medical Director, Advocacy, for the Division of Advocacy and Health Policy, in the ACS offices in Washington, DC.

This month I write about one of the College’s current advocacy efforts directed at ensuring an adequate surgical workforce in underserved and rural areas. Evidence indicates a current and growing shortage of surgeons available to serve the needs of populations in certain parts of the country. A shortage of general surgeons is a clear component to the crisis in health care workforce. Accordingly, the American College of Surgeons (ACS) is urging policy makers to recognize that only surgeons are uniquely qualified to provide certain necessary, lifesaving procedures, which other health professionals are neither trained nor competent to provide.

To determine where these areas of shortage are located and where access to surgical care is thus potentially a challenge, the ACS is strongly supporting the efforts of Representatives Larry Bucshon, MD, FACS (R-Ind.) and Ami Bera, MD (D-Calif.) who recently introduced H.R. 4959, the Ensuring Access to General Surgery Act of 2016. This legislation serves to direct the Secretary of the Department of Health and Human Services (HHS) to conduct a study on the designation of surgical Health Professional Shortage Areas (HPSA).

A variety of federal programs use the HPSA designation to improve access to health care by focusing aid and assistance on specific geographic areas and populations with the greatest unmet needs. The division of HHS known as the Health Resources and Services Administration (HRSA) has developed criteria used to determine whether certain geographic areas, population groups, or facilities may be designated as a HPSA. HPSA designation may be applied to urban or rural geographic areas, specific population groups, medical provider groups, or other public health care facilities. Currently, HRSA limits HPSA designations to shortages in primary care services, dental services, or mental health services.

HRSA has never designated an entity as a HPSA purely based upon a shortage of surgical services. In light of the available evidence relative to the shortage of surgical providers in certain parts of the country, ACS believes that research is necessary to determine exactly what constitutes a surgical shortage area, e.g., establish definitional criteria, with subsequent application of those criteria to determine where areas so defined are located. Such would provide HRSA with a valuable tool to utilize in efforts directed at increasing patient access to surgical care. Ultimately, offering incentives to surgeons to locate or remain in HPSA communities could become critical in guaranteeing all Medicare beneficiaries, regardless of geographic location, have access to quality surgical care. Determining what constitutes a surgical shortage area will serve to help HRSA to appropriately focus its resources.

Accordingly, we need your help and urge you to take action today.

Using the information below, please call your representatives today and urge them to join their colleagues and cosponsor H.R. 4959, the Ensuring Access to General Surgery Act of 2016.

Instructions

Call toll-free: 1-877-996-4464

You will be connected to your representative‘s office. Once you are connected, provide your name and indicate that you are a constituent. You should also be prepared to provide additional contact information for follow-up purposes.

Next, we suggest you use the following message:

• As a surgeon and as your constituent, I urge you to join your colleagues and cosponsor H.R. 4959, the Ensuring Access to General Surgery Act of 2016, which would direct the Secretary of Department of Health and Human Services (HHS) to conduct a study to designate General Surgery Health Professional Shortage Areas (HPSA).

• The division of HHS known as the Health Resources and Services Administration (HRSA) has developed designation criteria in order to determine whether certain geographic areas, population groups, or facilities may be designated as a HPSA.

• HRSA has never designated an entity as a HPSA purely based upon a shortage of surgical services.

• In light of evidence relative to a shortage of surgeons, ACS believes that research is necessary to determine exactly what constitutes a surgical shortage area and subsequently where these areas exist.

Alternatively, for those who were seeking a topic on which to initiate a personal in-district meeting with representatives and their staff as was discussed in last month’s edition of this column, H.R. 4959 presents a prime subject for such in order to have a focused meeting with a specific ask on a “white hat” issue that will surely resonate with members of Congress. Currently, in-district work periods are scheduled for the last week of June, the last two weeks of July, and the entire month of August.

As always, those with questions or concerns, or those who need assistance in setting up an in-district meeting may contact staff of the Division of Advocacy and Health Policy by phone at 202-337-2701 or via e-mail at [email protected].

Thank you for taking the time to engage and take action on this critical issue.

Please encourage your colleagues to do likewise.

Until next month ...

Dr. Patrick V. Bailey is an ACS Fellow, a pediatric surgeon, and Medical Director, Advocacy, for the Division of Advocacy and Health Policy, in the ACS offices in Washington, DC.