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Immigration reforms: Repercussions for hospitalists and the health care industry
International medical graduates (IMGs) have been playing a crucial role in clinician staffing needs for U.S. hospitals, especially in hospital medicine and internal medicine. According to a study, IMGs comprise 25% of the total U.S. physician workforce and 36% of internists.1,2 According to data from the 2008 Today’s Hospitalist Compensation & Career Survey, 32% of practicing hospitalists are IMGs.3
Many IMGs come to work in the U.S. via one of three paths. Just like all roads lead to Rome, all visas lead to a permanent residency pathway, eventually based on the country of origin and number of years waiting. The first path is a green card – cases where IMGs were on a visa and within a certain amount of time they received a green card. The second path is J-1 visa waivers for physicians who trained in the U.S. under a J-1 Visa. Typically, physicians on J-1 Visa waivers need to provide their services for a minimum of 3 years working in underserved areas – where there’s a shortage of health professionals – before they can apply for permanent residency.
The third and most popular path is the H-1B visa, which hospitalists traditionally use as a springboard to apply for permanent residency. Studies have shown that IMGs are more likely to practice medicine in rural and underserved areas. In many instances, physicians end up working in these areas for long periods of time.4
The Department of Homeland Security has considered creating another visa pathway for the technology industry, whereby an alien graduating from a U.S. university with an advanced degree in a STEM (Science, Technology, Engineering, and Math) course of study would receive a new visa and pathway to permanent residency. We believe hospitalists and other physicians should also have an expedited pathway to permanent residency. This step benefits both the U.S. health care system and hospitalists in many ways. It increases hospitalists’ portability and flexibility with schedules. With a traditional H-1B visa, hospitalists are bound to work with the one hospital/system that sponsors the H-1B, and would not be able to work at any other hospital without another extension/addendum to current visa status, even in cases where a physician had time off and would like to offer services at another facility. It is a well-known fact that hospitalist teams are understaffed and try to bring on per-diem staff to fill holes in schedules. The majority of hospitalists are working week-on/week-off schedules, and with an expedited pathway to a green card they would be able to work in different hospitals. They would also be able to move to remote places, or “doctor deserts,” and offer their services, helping to ensure the quality and safety of patient care to which all Americans are entitled.
In 2016 alone, around 1,500 H-1B visas were filed for hospitalist physicians.7 Each hospitalist has an average of 15 patient encounters per day, and for 1,500 physicians that amounts to about 4 million patient encounters annually.8 These data account for only new 2016 visa-holding physicians, and do not account for already approved or renewed visas. It would be very challenging to count the number of patient encounters by hospitalists who are on a visa, but 1 billion patient encounters is not overestimating. Recent studies show that quality of care provided by IMGs is not inferior to that of U.S. medical graduates. The study showed that patients cared for by IMGs have lesser mortality, compared with those cared by U.S. medical graduates.9
In this era of hospital medicine, hospitalists are focusing not only on clinical aspects of patient care but also on efficacy, quality of care, and patient safety and satisfaction, and they are working with the Centers for Medicare & Medicaid Services to develop cost-cutting programs to save billions of dollars in health care expenses. This is the primary reason a majority of hospitals are focused on developing a hospitalist track, and encouraging hospitalists to pursue leadership roles in managing hospitals effectively.
The U.S. health care system is starved for hospitalists and primary care physicians, and IMGs will continue to play a pivotal role. Yet IMGs must deal with shifting trends in immigration policy, and in some recent instances immigrant physicians have been asked to leave the U.S. because of immigration reforms.10,11 We would like the Society of Hospital Medicine to take a stand on behalf of IMG hospitalists and ask the U.S. Department of Labor and Homeland Security for an expedited permanent residency pathway for IMG hospitalists. We are certain that our request will get a fair hearing, as the former U.S. surgeon general was a hospitalist and, indeed, an immigrant.
Dr. Medarametla is medical director, Intermediate Care Unit, Baystate Medical Center, Springfield, Mass., and assistant professor of medicine, University of Massachusetts Medical School. Dr. Pamerla is a hospitalist at Wilson Medical Center, Wilson, N.C.
References
1. Educational Commission for Foreign Medical Graduates; ECFMG 2015 Annual Report. April 2016 http://www.ecfmg.org/resources/ECFMG-2015-annual-report.pdf.
2. Pinsky WW. The Importance of International Medical Graduates in the United States. Ann Intern Med. 2017. doi: 10.7326/M17-0505.
3. Hart LG, Skillman SM, Fordyce M, et al. International medical graduate physicians in the United States: changes since 1981. Health Aff. 2007 July/August;26(4):1159-69.
4. Goodfellow A1, Ulloa JG, Dowling PT, et al. Predictors of Primary Care Physician Practice Location in Underserved Urban or Rural Areas in the United States: A Systematic Literature Review. Acad Med. 2016 Sep;91(9):1313-21.
5. https://www.uscis.gov/working-united-states/temporary-workers/h-1b-specialty-occupations-and-fashion-models/h-1b-fiscal-year-fy-2018-cap-season#count
6. https://www.graphiq.com/vlp/bCIqXCpVqF7
7. http://www.myvisajobs.com/Reports/2017-H1B-Visa-Category.aspx?T=JT&P=2
8. Steven M Harris: http://www.the-hospitalist.org/hospitalist/article/125455/appropriate-patient-census-hospital-medicines-holy-grail
9. Tsugawa Y, Jena AB, Orav EJ, Jha AK. Quality of care delivered by general internists in US hospitals who graduated from foreign versus US medical schools: observational study. BMJ. 2017;356:j273.
10. https://www.propublica.org/article/cleveland-clinic-doctor-forced-to-leave-country-after-trump-order
11. http://www.houstonchronicle.com/news/houston-texas/houston/article/Houston-immigrant-doctors-given-24-hours-to-leave-11040259.php
International medical graduates (IMGs) have been playing a crucial role in clinician staffing needs for U.S. hospitals, especially in hospital medicine and internal medicine. According to a study, IMGs comprise 25% of the total U.S. physician workforce and 36% of internists.1,2 According to data from the 2008 Today’s Hospitalist Compensation & Career Survey, 32% of practicing hospitalists are IMGs.3
Many IMGs come to work in the U.S. via one of three paths. Just like all roads lead to Rome, all visas lead to a permanent residency pathway, eventually based on the country of origin and number of years waiting. The first path is a green card – cases where IMGs were on a visa and within a certain amount of time they received a green card. The second path is J-1 visa waivers for physicians who trained in the U.S. under a J-1 Visa. Typically, physicians on J-1 Visa waivers need to provide their services for a minimum of 3 years working in underserved areas – where there’s a shortage of health professionals – before they can apply for permanent residency.
The third and most popular path is the H-1B visa, which hospitalists traditionally use as a springboard to apply for permanent residency. Studies have shown that IMGs are more likely to practice medicine in rural and underserved areas. In many instances, physicians end up working in these areas for long periods of time.4
The Department of Homeland Security has considered creating another visa pathway for the technology industry, whereby an alien graduating from a U.S. university with an advanced degree in a STEM (Science, Technology, Engineering, and Math) course of study would receive a new visa and pathway to permanent residency. We believe hospitalists and other physicians should also have an expedited pathway to permanent residency. This step benefits both the U.S. health care system and hospitalists in many ways. It increases hospitalists’ portability and flexibility with schedules. With a traditional H-1B visa, hospitalists are bound to work with the one hospital/system that sponsors the H-1B, and would not be able to work at any other hospital without another extension/addendum to current visa status, even in cases where a physician had time off and would like to offer services at another facility. It is a well-known fact that hospitalist teams are understaffed and try to bring on per-diem staff to fill holes in schedules. The majority of hospitalists are working week-on/week-off schedules, and with an expedited pathway to a green card they would be able to work in different hospitals. They would also be able to move to remote places, or “doctor deserts,” and offer their services, helping to ensure the quality and safety of patient care to which all Americans are entitled.
In 2016 alone, around 1,500 H-1B visas were filed for hospitalist physicians.7 Each hospitalist has an average of 15 patient encounters per day, and for 1,500 physicians that amounts to about 4 million patient encounters annually.8 These data account for only new 2016 visa-holding physicians, and do not account for already approved or renewed visas. It would be very challenging to count the number of patient encounters by hospitalists who are on a visa, but 1 billion patient encounters is not overestimating. Recent studies show that quality of care provided by IMGs is not inferior to that of U.S. medical graduates. The study showed that patients cared for by IMGs have lesser mortality, compared with those cared by U.S. medical graduates.9
In this era of hospital medicine, hospitalists are focusing not only on clinical aspects of patient care but also on efficacy, quality of care, and patient safety and satisfaction, and they are working with the Centers for Medicare & Medicaid Services to develop cost-cutting programs to save billions of dollars in health care expenses. This is the primary reason a majority of hospitals are focused on developing a hospitalist track, and encouraging hospitalists to pursue leadership roles in managing hospitals effectively.
The U.S. health care system is starved for hospitalists and primary care physicians, and IMGs will continue to play a pivotal role. Yet IMGs must deal with shifting trends in immigration policy, and in some recent instances immigrant physicians have been asked to leave the U.S. because of immigration reforms.10,11 We would like the Society of Hospital Medicine to take a stand on behalf of IMG hospitalists and ask the U.S. Department of Labor and Homeland Security for an expedited permanent residency pathway for IMG hospitalists. We are certain that our request will get a fair hearing, as the former U.S. surgeon general was a hospitalist and, indeed, an immigrant.
Dr. Medarametla is medical director, Intermediate Care Unit, Baystate Medical Center, Springfield, Mass., and assistant professor of medicine, University of Massachusetts Medical School. Dr. Pamerla is a hospitalist at Wilson Medical Center, Wilson, N.C.
References
1. Educational Commission for Foreign Medical Graduates; ECFMG 2015 Annual Report. April 2016 http://www.ecfmg.org/resources/ECFMG-2015-annual-report.pdf.
2. Pinsky WW. The Importance of International Medical Graduates in the United States. Ann Intern Med. 2017. doi: 10.7326/M17-0505.
3. Hart LG, Skillman SM, Fordyce M, et al. International medical graduate physicians in the United States: changes since 1981. Health Aff. 2007 July/August;26(4):1159-69.
4. Goodfellow A1, Ulloa JG, Dowling PT, et al. Predictors of Primary Care Physician Practice Location in Underserved Urban or Rural Areas in the United States: A Systematic Literature Review. Acad Med. 2016 Sep;91(9):1313-21.
5. https://www.uscis.gov/working-united-states/temporary-workers/h-1b-specialty-occupations-and-fashion-models/h-1b-fiscal-year-fy-2018-cap-season#count
6. https://www.graphiq.com/vlp/bCIqXCpVqF7
7. http://www.myvisajobs.com/Reports/2017-H1B-Visa-Category.aspx?T=JT&P=2
8. Steven M Harris: http://www.the-hospitalist.org/hospitalist/article/125455/appropriate-patient-census-hospital-medicines-holy-grail
9. Tsugawa Y, Jena AB, Orav EJ, Jha AK. Quality of care delivered by general internists in US hospitals who graduated from foreign versus US medical schools: observational study. BMJ. 2017;356:j273.
10. https://www.propublica.org/article/cleveland-clinic-doctor-forced-to-leave-country-after-trump-order
11. http://www.houstonchronicle.com/news/houston-texas/houston/article/Houston-immigrant-doctors-given-24-hours-to-leave-11040259.php
International medical graduates (IMGs) have been playing a crucial role in clinician staffing needs for U.S. hospitals, especially in hospital medicine and internal medicine. According to a study, IMGs comprise 25% of the total U.S. physician workforce and 36% of internists.1,2 According to data from the 2008 Today’s Hospitalist Compensation & Career Survey, 32% of practicing hospitalists are IMGs.3
Many IMGs come to work in the U.S. via one of three paths. Just like all roads lead to Rome, all visas lead to a permanent residency pathway, eventually based on the country of origin and number of years waiting. The first path is a green card – cases where IMGs were on a visa and within a certain amount of time they received a green card. The second path is J-1 visa waivers for physicians who trained in the U.S. under a J-1 Visa. Typically, physicians on J-1 Visa waivers need to provide their services for a minimum of 3 years working in underserved areas – where there’s a shortage of health professionals – before they can apply for permanent residency.
The third and most popular path is the H-1B visa, which hospitalists traditionally use as a springboard to apply for permanent residency. Studies have shown that IMGs are more likely to practice medicine in rural and underserved areas. In many instances, physicians end up working in these areas for long periods of time.4
The Department of Homeland Security has considered creating another visa pathway for the technology industry, whereby an alien graduating from a U.S. university with an advanced degree in a STEM (Science, Technology, Engineering, and Math) course of study would receive a new visa and pathway to permanent residency. We believe hospitalists and other physicians should also have an expedited pathway to permanent residency. This step benefits both the U.S. health care system and hospitalists in many ways. It increases hospitalists’ portability and flexibility with schedules. With a traditional H-1B visa, hospitalists are bound to work with the one hospital/system that sponsors the H-1B, and would not be able to work at any other hospital without another extension/addendum to current visa status, even in cases where a physician had time off and would like to offer services at another facility. It is a well-known fact that hospitalist teams are understaffed and try to bring on per-diem staff to fill holes in schedules. The majority of hospitalists are working week-on/week-off schedules, and with an expedited pathway to a green card they would be able to work in different hospitals. They would also be able to move to remote places, or “doctor deserts,” and offer their services, helping to ensure the quality and safety of patient care to which all Americans are entitled.
In 2016 alone, around 1,500 H-1B visas were filed for hospitalist physicians.7 Each hospitalist has an average of 15 patient encounters per day, and for 1,500 physicians that amounts to about 4 million patient encounters annually.8 These data account for only new 2016 visa-holding physicians, and do not account for already approved or renewed visas. It would be very challenging to count the number of patient encounters by hospitalists who are on a visa, but 1 billion patient encounters is not overestimating. Recent studies show that quality of care provided by IMGs is not inferior to that of U.S. medical graduates. The study showed that patients cared for by IMGs have lesser mortality, compared with those cared by U.S. medical graduates.9
In this era of hospital medicine, hospitalists are focusing not only on clinical aspects of patient care but also on efficacy, quality of care, and patient safety and satisfaction, and they are working with the Centers for Medicare & Medicaid Services to develop cost-cutting programs to save billions of dollars in health care expenses. This is the primary reason a majority of hospitals are focused on developing a hospitalist track, and encouraging hospitalists to pursue leadership roles in managing hospitals effectively.
The U.S. health care system is starved for hospitalists and primary care physicians, and IMGs will continue to play a pivotal role. Yet IMGs must deal with shifting trends in immigration policy, and in some recent instances immigrant physicians have been asked to leave the U.S. because of immigration reforms.10,11 We would like the Society of Hospital Medicine to take a stand on behalf of IMG hospitalists and ask the U.S. Department of Labor and Homeland Security for an expedited permanent residency pathway for IMG hospitalists. We are certain that our request will get a fair hearing, as the former U.S. surgeon general was a hospitalist and, indeed, an immigrant.
Dr. Medarametla is medical director, Intermediate Care Unit, Baystate Medical Center, Springfield, Mass., and assistant professor of medicine, University of Massachusetts Medical School. Dr. Pamerla is a hospitalist at Wilson Medical Center, Wilson, N.C.
References
1. Educational Commission for Foreign Medical Graduates; ECFMG 2015 Annual Report. April 2016 http://www.ecfmg.org/resources/ECFMG-2015-annual-report.pdf.
2. Pinsky WW. The Importance of International Medical Graduates in the United States. Ann Intern Med. 2017. doi: 10.7326/M17-0505.
3. Hart LG, Skillman SM, Fordyce M, et al. International medical graduate physicians in the United States: changes since 1981. Health Aff. 2007 July/August;26(4):1159-69.
4. Goodfellow A1, Ulloa JG, Dowling PT, et al. Predictors of Primary Care Physician Practice Location in Underserved Urban or Rural Areas in the United States: A Systematic Literature Review. Acad Med. 2016 Sep;91(9):1313-21.
5. https://www.uscis.gov/working-united-states/temporary-workers/h-1b-specialty-occupations-and-fashion-models/h-1b-fiscal-year-fy-2018-cap-season#count
6. https://www.graphiq.com/vlp/bCIqXCpVqF7
7. http://www.myvisajobs.com/Reports/2017-H1B-Visa-Category.aspx?T=JT&P=2
8. Steven M Harris: http://www.the-hospitalist.org/hospitalist/article/125455/appropriate-patient-census-hospital-medicines-holy-grail
9. Tsugawa Y, Jena AB, Orav EJ, Jha AK. Quality of care delivered by general internists in US hospitals who graduated from foreign versus US medical schools: observational study. BMJ. 2017;356:j273.
10. https://www.propublica.org/article/cleveland-clinic-doctor-forced-to-leave-country-after-trump-order
11. http://www.houstonchronicle.com/news/houston-texas/houston/article/Houston-immigrant-doctors-given-24-hours-to-leave-11040259.php
Be alert for embezzlement
I can almost hear you saying it now: “Here’s a column I can skip! Embezzlement has never been a problem in this office.” Unfortunately, theft from within is way more common in medical offices than most of us suppose – and it often occurs in full view of physicians who are convinced that it cannot happen to them. Most embezzlers are not particularly skillful, nor very good at covering their tracks. But their transgressions can go undetected for years, simply because no one is watching.
A friend’s experience was all too typical: His bookkeeper wrote sizable checks to herself, disguising them in the ledger as payments to vendors commonly used by his practice. Since she also balanced the checkbook, she got away with it for a long time. “It wasn’t at all clever,” he told me, “and I’m embarrassed to admit that it happened to me.” Is it happening to you, too? You won’t know unless you look.
Detecting fraud is an inexact science; there is no textbook approach that one can follow, but a few simple measures will uncover or prevent a large percentage of dishonest behavior:
• Hire honest employees. Check applicants’ references; find out if they are really as good as they look on paper. And for a few dollars, you can screen prospective employees on one of several public information websites to see if they have a criminal record, or have been sued (or are suing others). My columns on hiring and background checks can be found at http://www.mdedge.com/edermatologynews/managing-your-practice.
• Minimize opportunities for dishonesty. Theft and embezzlement are usually products of opportunity; there are many ways to minimize those opportunities. No one person should be in charge of the entire bookkeeping process. The person who enters charges should be different from the one who enters payments. The employee who writes the checks should not balance the checkbook, and so on. Internal audits should be done on a regular basis, and all employees should know that. Your accountant can help with this.
• Reconcile receipts and cash daily. The most common form of embezzlement is simply taking cash out of the till. In a typical scenario, a patient pays a $15 copay in cash; the receptionist records the payment as $5 and pockets the rest. Make sure a receipt is generated for every cash transaction, and that someone other than the person accepting cash reconciles the receipts and the cash daily.
• Insist on separate accounting duties. Another common scam – the one to which my friend fell victim – is false invoices: You think you are paying for supplies and services, but the money is going to an employee. Once again, separation of duties is the key to prevention. One employee should enter invoices into the data system, another should issue the check or make the electronic transfer, and a third should match invoices to goods and services received.
• Verify expense reports. False expense reports are another common form of fraud. When an employee asks for reimbursement of expenses, make sure they are real.
• Safeguard your computers. A major downside of computerization is the facilitation of embezzlement. Data are usually concentrated in one place, accounts can be accessed from remote workstations or off-premises servers, and a paper trail is often eliminated. Your computer vendor should be aware of this, and should have safeguards built into your system. Ask about them. If they aren’t there, ask why.
• Look for “red flags.” Do you have an employee who refuses to take vacations, because someone else will have to look at the books? Does someone insist on approving or entering expenses that are another employee’s responsibility, “just to be nice”? Is an employee suddenly living beyond his or her means?
• Consider bonding your employees. Dishonesty bonds are relatively inexpensive, and you will be assured of some measure of recovery should your safeguards fail. In addition, the mere knowledge that your staff is bonded will frighten off many dishonest applicants.
• Keep in mind that office personnel are not the only ones susceptible to temptation. A colleague recently told me about a per diem physician in his employ who conspired with a receptionist to keep fees collected for cosmetic neurotoxin and filler procedures “off the books,” then split the proceeds among themselves.
Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected]
I can almost hear you saying it now: “Here’s a column I can skip! Embezzlement has never been a problem in this office.” Unfortunately, theft from within is way more common in medical offices than most of us suppose – and it often occurs in full view of physicians who are convinced that it cannot happen to them. Most embezzlers are not particularly skillful, nor very good at covering their tracks. But their transgressions can go undetected for years, simply because no one is watching.
A friend’s experience was all too typical: His bookkeeper wrote sizable checks to herself, disguising them in the ledger as payments to vendors commonly used by his practice. Since she also balanced the checkbook, she got away with it for a long time. “It wasn’t at all clever,” he told me, “and I’m embarrassed to admit that it happened to me.” Is it happening to you, too? You won’t know unless you look.
Detecting fraud is an inexact science; there is no textbook approach that one can follow, but a few simple measures will uncover or prevent a large percentage of dishonest behavior:
• Hire honest employees. Check applicants’ references; find out if they are really as good as they look on paper. And for a few dollars, you can screen prospective employees on one of several public information websites to see if they have a criminal record, or have been sued (or are suing others). My columns on hiring and background checks can be found at http://www.mdedge.com/edermatologynews/managing-your-practice.
• Minimize opportunities for dishonesty. Theft and embezzlement are usually products of opportunity; there are many ways to minimize those opportunities. No one person should be in charge of the entire bookkeeping process. The person who enters charges should be different from the one who enters payments. The employee who writes the checks should not balance the checkbook, and so on. Internal audits should be done on a regular basis, and all employees should know that. Your accountant can help with this.
• Reconcile receipts and cash daily. The most common form of embezzlement is simply taking cash out of the till. In a typical scenario, a patient pays a $15 copay in cash; the receptionist records the payment as $5 and pockets the rest. Make sure a receipt is generated for every cash transaction, and that someone other than the person accepting cash reconciles the receipts and the cash daily.
• Insist on separate accounting duties. Another common scam – the one to which my friend fell victim – is false invoices: You think you are paying for supplies and services, but the money is going to an employee. Once again, separation of duties is the key to prevention. One employee should enter invoices into the data system, another should issue the check or make the electronic transfer, and a third should match invoices to goods and services received.
• Verify expense reports. False expense reports are another common form of fraud. When an employee asks for reimbursement of expenses, make sure they are real.
• Safeguard your computers. A major downside of computerization is the facilitation of embezzlement. Data are usually concentrated in one place, accounts can be accessed from remote workstations or off-premises servers, and a paper trail is often eliminated. Your computer vendor should be aware of this, and should have safeguards built into your system. Ask about them. If they aren’t there, ask why.
• Look for “red flags.” Do you have an employee who refuses to take vacations, because someone else will have to look at the books? Does someone insist on approving or entering expenses that are another employee’s responsibility, “just to be nice”? Is an employee suddenly living beyond his or her means?
• Consider bonding your employees. Dishonesty bonds are relatively inexpensive, and you will be assured of some measure of recovery should your safeguards fail. In addition, the mere knowledge that your staff is bonded will frighten off many dishonest applicants.
• Keep in mind that office personnel are not the only ones susceptible to temptation. A colleague recently told me about a per diem physician in his employ who conspired with a receptionist to keep fees collected for cosmetic neurotoxin and filler procedures “off the books,” then split the proceeds among themselves.
Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected]
I can almost hear you saying it now: “Here’s a column I can skip! Embezzlement has never been a problem in this office.” Unfortunately, theft from within is way more common in medical offices than most of us suppose – and it often occurs in full view of physicians who are convinced that it cannot happen to them. Most embezzlers are not particularly skillful, nor very good at covering their tracks. But their transgressions can go undetected for years, simply because no one is watching.
A friend’s experience was all too typical: His bookkeeper wrote sizable checks to herself, disguising them in the ledger as payments to vendors commonly used by his practice. Since she also balanced the checkbook, she got away with it for a long time. “It wasn’t at all clever,” he told me, “and I’m embarrassed to admit that it happened to me.” Is it happening to you, too? You won’t know unless you look.
Detecting fraud is an inexact science; there is no textbook approach that one can follow, but a few simple measures will uncover or prevent a large percentage of dishonest behavior:
• Hire honest employees. Check applicants’ references; find out if they are really as good as they look on paper. And for a few dollars, you can screen prospective employees on one of several public information websites to see if they have a criminal record, or have been sued (or are suing others). My columns on hiring and background checks can be found at http://www.mdedge.com/edermatologynews/managing-your-practice.
• Minimize opportunities for dishonesty. Theft and embezzlement are usually products of opportunity; there are many ways to minimize those opportunities. No one person should be in charge of the entire bookkeeping process. The person who enters charges should be different from the one who enters payments. The employee who writes the checks should not balance the checkbook, and so on. Internal audits should be done on a regular basis, and all employees should know that. Your accountant can help with this.
• Reconcile receipts and cash daily. The most common form of embezzlement is simply taking cash out of the till. In a typical scenario, a patient pays a $15 copay in cash; the receptionist records the payment as $5 and pockets the rest. Make sure a receipt is generated for every cash transaction, and that someone other than the person accepting cash reconciles the receipts and the cash daily.
• Insist on separate accounting duties. Another common scam – the one to which my friend fell victim – is false invoices: You think you are paying for supplies and services, but the money is going to an employee. Once again, separation of duties is the key to prevention. One employee should enter invoices into the data system, another should issue the check or make the electronic transfer, and a third should match invoices to goods and services received.
• Verify expense reports. False expense reports are another common form of fraud. When an employee asks for reimbursement of expenses, make sure they are real.
• Safeguard your computers. A major downside of computerization is the facilitation of embezzlement. Data are usually concentrated in one place, accounts can be accessed from remote workstations or off-premises servers, and a paper trail is often eliminated. Your computer vendor should be aware of this, and should have safeguards built into your system. Ask about them. If they aren’t there, ask why.
• Look for “red flags.” Do you have an employee who refuses to take vacations, because someone else will have to look at the books? Does someone insist on approving or entering expenses that are another employee’s responsibility, “just to be nice”? Is an employee suddenly living beyond his or her means?
• Consider bonding your employees. Dishonesty bonds are relatively inexpensive, and you will be assured of some measure of recovery should your safeguards fail. In addition, the mere knowledge that your staff is bonded will frighten off many dishonest applicants.
• Keep in mind that office personnel are not the only ones susceptible to temptation. A colleague recently told me about a per diem physician in his employ who conspired with a receptionist to keep fees collected for cosmetic neurotoxin and filler procedures “off the books,” then split the proceeds among themselves.
Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected]
Calculating the Risk of Parkinson-Related Cognitive Deficits
Currently, treatments for Parkinson disease are only effective in improving motor deficits. But the loss of cognitive abilities is just as devastating. About 25% of patients also experience cognitive deficits that impair function. One problem in developing treatments, however, is that patients with cognitive effects vary widely. Being able to predict the chance that someone with Parkinson disease will develop cognitive deficits could be a useful tool, say researchers from Brigham and Women’s Hospital in Boston, Massachusetts, who conducted a study partly funded by the National Institute Neurological Disorders and Stroke. They think they might have created just the tool: a computer-based risk calculator.
The researchers combined data from 3,200 patients with Parkinson disease, representing more than 25,000 individual clinical assessments. They evaluated 7 known clinical and genetic risk factors associated with developing dementia, then used the information to build the risk calculator.
“By allowing clinical researchers to identify and select only patients at high risk for developing dementia, this tool could help in the design of ‘smarter’ trials that require a manageable number of participating patients,” said Clemens Scherzer, MD, the lead investigator.
By improving clinical trial design, the risk calculator could first help in the discovery of new treatments, the researchers say, then help determine which patients would benefit most from those treatments. “Prediction is the first step,” said Dr. Scherzer. “Prevention is the ultimate goal, preventing a dismal prognosis from ever happening.”
Currently, treatments for Parkinson disease are only effective in improving motor deficits. But the loss of cognitive abilities is just as devastating. About 25% of patients also experience cognitive deficits that impair function. One problem in developing treatments, however, is that patients with cognitive effects vary widely. Being able to predict the chance that someone with Parkinson disease will develop cognitive deficits could be a useful tool, say researchers from Brigham and Women’s Hospital in Boston, Massachusetts, who conducted a study partly funded by the National Institute Neurological Disorders and Stroke. They think they might have created just the tool: a computer-based risk calculator.
The researchers combined data from 3,200 patients with Parkinson disease, representing more than 25,000 individual clinical assessments. They evaluated 7 known clinical and genetic risk factors associated with developing dementia, then used the information to build the risk calculator.
“By allowing clinical researchers to identify and select only patients at high risk for developing dementia, this tool could help in the design of ‘smarter’ trials that require a manageable number of participating patients,” said Clemens Scherzer, MD, the lead investigator.
By improving clinical trial design, the risk calculator could first help in the discovery of new treatments, the researchers say, then help determine which patients would benefit most from those treatments. “Prediction is the first step,” said Dr. Scherzer. “Prevention is the ultimate goal, preventing a dismal prognosis from ever happening.”
Currently, treatments for Parkinson disease are only effective in improving motor deficits. But the loss of cognitive abilities is just as devastating. About 25% of patients also experience cognitive deficits that impair function. One problem in developing treatments, however, is that patients with cognitive effects vary widely. Being able to predict the chance that someone with Parkinson disease will develop cognitive deficits could be a useful tool, say researchers from Brigham and Women’s Hospital in Boston, Massachusetts, who conducted a study partly funded by the National Institute Neurological Disorders and Stroke. They think they might have created just the tool: a computer-based risk calculator.
The researchers combined data from 3,200 patients with Parkinson disease, representing more than 25,000 individual clinical assessments. They evaluated 7 known clinical and genetic risk factors associated with developing dementia, then used the information to build the risk calculator.
“By allowing clinical researchers to identify and select only patients at high risk for developing dementia, this tool could help in the design of ‘smarter’ trials that require a manageable number of participating patients,” said Clemens Scherzer, MD, the lead investigator.
By improving clinical trial design, the risk calculator could first help in the discovery of new treatments, the researchers say, then help determine which patients would benefit most from those treatments. “Prediction is the first step,” said Dr. Scherzer. “Prevention is the ultimate goal, preventing a dismal prognosis from ever happening.”
Lenalidomide maintenance prolongs PFS, OS in MM
Lenalidomide maintenance can be considered a standard of care for multiple myeloma (MM) patients who have undergone hematopoietic stem cell transplant (HSCT), according to researchers.
A meta-analysis of data from 3 trials showed that lenalidomide maintenance extended both progression-free survival (PFS) and overall survival (OS) in these patients.
Philip L. McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, New York, and his colleagues reported results of the analysis in the Journal of Clinical Oncology.
The researchers analyzed data from 3 large, randomized trials conducted in the US, France, and Italy. The studies included patients with newly diagnosed MM who underwent autologous HSCT and then received continuous lenalidomide (n=605) or no maintenance/placebo (n=603).
Patient demographics and disease-related characteristics were generally balanced between the treatment groups.
The mean duration of maintenance was 28 months (range, 0-108) in the lenalidomide group and 22 months (range, 0-86) in the control group.
Fewer patients in the lenalidomide group (52.6%) started second-line anti-MM therapy than patients in the control group (70.8%). And the time to second-line anti-MM treatment was longer with lenalidomide than with control (hazard ratio [HR]=0.57; 95% CI, 0.49 to 0.66).
PFS and OS
Patients who received lenalidomide maintenance had significantly longer PFS and OS than patients in the control group.
The median PFS was 52.8 months and 23.5 months, respectively (HR=0.48; 95% CI, 0.41 to 0.55).
The median OS was not reached in the lenalidomide group and was 86.0 months in the control group (HR=0.75; 95% CI, 0.63 to 0.90; P=0.001),
At a median follow-up of 79.5 months, the OS rate was 64% in the lenalidomide group and 54% in the control group. The 7-year OS rates were 62% and 50%, respectively.
Safety
Safety data were not available for the Italian study. In the other 2 studies, 29.1% of patients in the lenalidomide group had treatment-emergent adverse events that led to discontinuation, as did 12.2% of patients in the control group.
Treatment-emergent adverse events leading to treatment discontinuation (in the lenalidomide and control groups, respectively) included neutropenia (2.3% vs 0.2%), thrombocytopenia (1.7% vs 1.1%), general disorders and administration site conditions (4.7% vs 1.5%), neoplasms (4.3% vs 1.0%), skin and subcutaneous tissue disorders (3.4% vs 1.9%), nervous system disorders (3.4% vs 1.7%), gastrointestinal disorders (3.4% vs 0.2%), infections and infestations (1.7% vs 0.8%), and musculoskeletal and connective tissue disorders (1.1% and 1.3%).
There was a higher frequency of second primary malignancies (SPMs) in the lenalidomide group than in the control group.
The incidence of hematologic SPMs occurring before disease progression was 5.3% and 0.8%, respectively. The incidence before and after progression was 6.1% and 2.8%, respectively.
The incidence of solid tumor SPMs occurring before disease progression was 5.8% and 2.0%, respectively. The incidence before and after progression was 7.3% and 4.2%, respectively.
“With this complete and mature data from 3 large, multinational studies, we now have clear evidence that ongoing treatment with lenalidomide can prevent disease progression and extend survival in patients with multiple myeloma who’ve received a stem cell transplant,” Dr McCarthy said.
“All the investigators wish to express enormous gratitude to the patients who took part in these trials. Many others will benefit from their role in this research.” 
Lenalidomide maintenance can be considered a standard of care for multiple myeloma (MM) patients who have undergone hematopoietic stem cell transplant (HSCT), according to researchers.
A meta-analysis of data from 3 trials showed that lenalidomide maintenance extended both progression-free survival (PFS) and overall survival (OS) in these patients.
Philip L. McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, New York, and his colleagues reported results of the analysis in the Journal of Clinical Oncology.
The researchers analyzed data from 3 large, randomized trials conducted in the US, France, and Italy. The studies included patients with newly diagnosed MM who underwent autologous HSCT and then received continuous lenalidomide (n=605) or no maintenance/placebo (n=603).
Patient demographics and disease-related characteristics were generally balanced between the treatment groups.
The mean duration of maintenance was 28 months (range, 0-108) in the lenalidomide group and 22 months (range, 0-86) in the control group.
Fewer patients in the lenalidomide group (52.6%) started second-line anti-MM therapy than patients in the control group (70.8%). And the time to second-line anti-MM treatment was longer with lenalidomide than with control (hazard ratio [HR]=0.57; 95% CI, 0.49 to 0.66).
PFS and OS
Patients who received lenalidomide maintenance had significantly longer PFS and OS than patients in the control group.
The median PFS was 52.8 months and 23.5 months, respectively (HR=0.48; 95% CI, 0.41 to 0.55).
The median OS was not reached in the lenalidomide group and was 86.0 months in the control group (HR=0.75; 95% CI, 0.63 to 0.90; P=0.001),
At a median follow-up of 79.5 months, the OS rate was 64% in the lenalidomide group and 54% in the control group. The 7-year OS rates were 62% and 50%, respectively.
Safety
Safety data were not available for the Italian study. In the other 2 studies, 29.1% of patients in the lenalidomide group had treatment-emergent adverse events that led to discontinuation, as did 12.2% of patients in the control group.
Treatment-emergent adverse events leading to treatment discontinuation (in the lenalidomide and control groups, respectively) included neutropenia (2.3% vs 0.2%), thrombocytopenia (1.7% vs 1.1%), general disorders and administration site conditions (4.7% vs 1.5%), neoplasms (4.3% vs 1.0%), skin and subcutaneous tissue disorders (3.4% vs 1.9%), nervous system disorders (3.4% vs 1.7%), gastrointestinal disorders (3.4% vs 0.2%), infections and infestations (1.7% vs 0.8%), and musculoskeletal and connective tissue disorders (1.1% and 1.3%).
There was a higher frequency of second primary malignancies (SPMs) in the lenalidomide group than in the control group.
The incidence of hematologic SPMs occurring before disease progression was 5.3% and 0.8%, respectively. The incidence before and after progression was 6.1% and 2.8%, respectively.
The incidence of solid tumor SPMs occurring before disease progression was 5.8% and 2.0%, respectively. The incidence before and after progression was 7.3% and 4.2%, respectively.
“With this complete and mature data from 3 large, multinational studies, we now have clear evidence that ongoing treatment with lenalidomide can prevent disease progression and extend survival in patients with multiple myeloma who’ve received a stem cell transplant,” Dr McCarthy said.
“All the investigators wish to express enormous gratitude to the patients who took part in these trials. Many others will benefit from their role in this research.”
Lenalidomide maintenance can be considered a standard of care for multiple myeloma (MM) patients who have undergone hematopoietic stem cell transplant (HSCT), according to researchers.
A meta-analysis of data from 3 trials showed that lenalidomide maintenance extended both progression-free survival (PFS) and overall survival (OS) in these patients.
Philip L. McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, New York, and his colleagues reported results of the analysis in the Journal of Clinical Oncology.
The researchers analyzed data from 3 large, randomized trials conducted in the US, France, and Italy. The studies included patients with newly diagnosed MM who underwent autologous HSCT and then received continuous lenalidomide (n=605) or no maintenance/placebo (n=603).
Patient demographics and disease-related characteristics were generally balanced between the treatment groups.
The mean duration of maintenance was 28 months (range, 0-108) in the lenalidomide group and 22 months (range, 0-86) in the control group.
Fewer patients in the lenalidomide group (52.6%) started second-line anti-MM therapy than patients in the control group (70.8%). And the time to second-line anti-MM treatment was longer with lenalidomide than with control (hazard ratio [HR]=0.57; 95% CI, 0.49 to 0.66).
PFS and OS
Patients who received lenalidomide maintenance had significantly longer PFS and OS than patients in the control group.
The median PFS was 52.8 months and 23.5 months, respectively (HR=0.48; 95% CI, 0.41 to 0.55).
The median OS was not reached in the lenalidomide group and was 86.0 months in the control group (HR=0.75; 95% CI, 0.63 to 0.90; P=0.001),
At a median follow-up of 79.5 months, the OS rate was 64% in the lenalidomide group and 54% in the control group. The 7-year OS rates were 62% and 50%, respectively.
Safety
Safety data were not available for the Italian study. In the other 2 studies, 29.1% of patients in the lenalidomide group had treatment-emergent adverse events that led to discontinuation, as did 12.2% of patients in the control group.
Treatment-emergent adverse events leading to treatment discontinuation (in the lenalidomide and control groups, respectively) included neutropenia (2.3% vs 0.2%), thrombocytopenia (1.7% vs 1.1%), general disorders and administration site conditions (4.7% vs 1.5%), neoplasms (4.3% vs 1.0%), skin and subcutaneous tissue disorders (3.4% vs 1.9%), nervous system disorders (3.4% vs 1.7%), gastrointestinal disorders (3.4% vs 0.2%), infections and infestations (1.7% vs 0.8%), and musculoskeletal and connective tissue disorders (1.1% and 1.3%).
There was a higher frequency of second primary malignancies (SPMs) in the lenalidomide group than in the control group.
The incidence of hematologic SPMs occurring before disease progression was 5.3% and 0.8%, respectively. The incidence before and after progression was 6.1% and 2.8%, respectively.
The incidence of solid tumor SPMs occurring before disease progression was 5.8% and 2.0%, respectively. The incidence before and after progression was 7.3% and 4.2%, respectively.
“With this complete and mature data from 3 large, multinational studies, we now have clear evidence that ongoing treatment with lenalidomide can prevent disease progression and extend survival in patients with multiple myeloma who’ve received a stem cell transplant,” Dr McCarthy said.
“All the investigators wish to express enormous gratitude to the patients who took part in these trials. Many others will benefit from their role in this research.”
Post-approval trials for accelerated drugs fall short
New research has revealed shortcomings of post-approval studies for drugs granted accelerated approval in the US.
Researchers found that, for drugs granted accelerated approval from 2009 to 2013, both pre-approval and post-approval trials had limitations in their design and the endpoints used.
“One might expect accelerated approval confirmatory trials to be much more rigorous than the pre-approval trials,” said study author Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“But we found that there were few differences in these key design features of the trials conducted before or after approval.”
Dr Kesselheim and his colleagues reported these findings in JAMA.
The researchers examined pre- and post-approval clinical trials of drugs granted accelerated approval by the US Food and Drug Administration (FDA) between 2009 and 2013.
During that time, the FDA granted 22 drugs accelerated approval for 24 indications (15 of them for hematologic disorders).
Fourteen of the indications were approved on the basis of single-intervention-group studies that enrolled a median of 132 patients.
The FDA ordered 38 post-approval studies to confirm the safety and efficacy of the drugs.
Three years after the last drug’s approval, half of those studies (n=19) were not complete. Eight (42%) of the incomplete studies were either terminated or delayed by more than 1 year.
For 14 of the 24 indications (58%), results from the post-approval studies were not available after a median of 5 years of follow-up.
Study comparison
Published reports were available for 18 of the 19 completed post-approval studies. The characteristics of these studies did not differ much from the 30 pre-approval studies.
There were no statistically significant differences with regard to median patient enrollment (P=0.17), the use of randomized (P=0.31) or double-blind trials (P=0.17), the use of placebo as a comparator (P=0.17), or the lack of a comparator (P=0.21).
However, there was a significant difference in the use of an active comparator (P=0.02), with more post-approval studies using an active comparator.
The researchers also found that 17 of the 18 post-approval trials still used surrogate measures of effect as primary endpoints.
There was no significant difference between pre- and post-approval trials when it came to the use of disease response (P=0.17) or most other surrogate measures (P=0.21) as the trials’ primary endpoint.
The same was true for overall survival (P=0.20), although significantly more post-approval studies used progression-free survival (P=0.001) as a primary endpoint.
“It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes—or even make them worse,” Dr Kesselheim said.
To address these issues and improve the quality of confirmatory studies, Dr Kesselheim suggested the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies.
He also suggested the agency work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug.
New research has revealed shortcomings of post-approval studies for drugs granted accelerated approval in the US.
Researchers found that, for drugs granted accelerated approval from 2009 to 2013, both pre-approval and post-approval trials had limitations in their design and the endpoints used.
“One might expect accelerated approval confirmatory trials to be much more rigorous than the pre-approval trials,” said study author Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“But we found that there were few differences in these key design features of the trials conducted before or after approval.”
Dr Kesselheim and his colleagues reported these findings in JAMA.
The researchers examined pre- and post-approval clinical trials of drugs granted accelerated approval by the US Food and Drug Administration (FDA) between 2009 and 2013.
During that time, the FDA granted 22 drugs accelerated approval for 24 indications (15 of them for hematologic disorders).
Fourteen of the indications were approved on the basis of single-intervention-group studies that enrolled a median of 132 patients.
The FDA ordered 38 post-approval studies to confirm the safety and efficacy of the drugs.
Three years after the last drug’s approval, half of those studies (n=19) were not complete. Eight (42%) of the incomplete studies were either terminated or delayed by more than 1 year.
For 14 of the 24 indications (58%), results from the post-approval studies were not available after a median of 5 years of follow-up.
Study comparison
Published reports were available for 18 of the 19 completed post-approval studies. The characteristics of these studies did not differ much from the 30 pre-approval studies.
There were no statistically significant differences with regard to median patient enrollment (P=0.17), the use of randomized (P=0.31) or double-blind trials (P=0.17), the use of placebo as a comparator (P=0.17), or the lack of a comparator (P=0.21).
However, there was a significant difference in the use of an active comparator (P=0.02), with more post-approval studies using an active comparator.
The researchers also found that 17 of the 18 post-approval trials still used surrogate measures of effect as primary endpoints.
There was no significant difference between pre- and post-approval trials when it came to the use of disease response (P=0.17) or most other surrogate measures (P=0.21) as the trials’ primary endpoint.
The same was true for overall survival (P=0.20), although significantly more post-approval studies used progression-free survival (P=0.001) as a primary endpoint.
“It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes—or even make them worse,” Dr Kesselheim said.
To address these issues and improve the quality of confirmatory studies, Dr Kesselheim suggested the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies.
He also suggested the agency work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug.
New research has revealed shortcomings of post-approval studies for drugs granted accelerated approval in the US.
Researchers found that, for drugs granted accelerated approval from 2009 to 2013, both pre-approval and post-approval trials had limitations in their design and the endpoints used.
“One might expect accelerated approval confirmatory trials to be much more rigorous than the pre-approval trials,” said study author Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“But we found that there were few differences in these key design features of the trials conducted before or after approval.”
Dr Kesselheim and his colleagues reported these findings in JAMA.
The researchers examined pre- and post-approval clinical trials of drugs granted accelerated approval by the US Food and Drug Administration (FDA) between 2009 and 2013.
During that time, the FDA granted 22 drugs accelerated approval for 24 indications (15 of them for hematologic disorders).
Fourteen of the indications were approved on the basis of single-intervention-group studies that enrolled a median of 132 patients.
The FDA ordered 38 post-approval studies to confirm the safety and efficacy of the drugs.
Three years after the last drug’s approval, half of those studies (n=19) were not complete. Eight (42%) of the incomplete studies were either terminated or delayed by more than 1 year.
For 14 of the 24 indications (58%), results from the post-approval studies were not available after a median of 5 years of follow-up.
Study comparison
Published reports were available for 18 of the 19 completed post-approval studies. The characteristics of these studies did not differ much from the 30 pre-approval studies.
There were no statistically significant differences with regard to median patient enrollment (P=0.17), the use of randomized (P=0.31) or double-blind trials (P=0.17), the use of placebo as a comparator (P=0.17), or the lack of a comparator (P=0.21).
However, there was a significant difference in the use of an active comparator (P=0.02), with more post-approval studies using an active comparator.
The researchers also found that 17 of the 18 post-approval trials still used surrogate measures of effect as primary endpoints.
There was no significant difference between pre- and post-approval trials when it came to the use of disease response (P=0.17) or most other surrogate measures (P=0.21) as the trials’ primary endpoint.
The same was true for overall survival (P=0.20), although significantly more post-approval studies used progression-free survival (P=0.001) as a primary endpoint.
“It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes—or even make them worse,” Dr Kesselheim said.
To address these issues and improve the quality of confirmatory studies, Dr Kesselheim suggested the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies.
He also suggested the agency work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug.
FDA grants drug orphan designation for AML, CMML
The US Food and Drug Administration (FDA) has granted orphan drug designation to H3B-8800 as a treatment for patients with acute myelogenous leukemia (AML) or chronic myelomonocytic leukemia (CMML).
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
About H3B-8800
H3B-8800 is an orally bioavailable small-molecule modulator of wild-type and mutant SF3b complexes. The SF3b complex is a key component of the spliceosome that is found in the cell nucleus and is responsible for the removal of noncoding introns from a transcribed pre-messenger RNA.
Recurrent heterozygous mutations in several core members of the spliceosome (SF3B1, U2AF1, SRSF2, and ZRSR2) have been identified in solid tumor and hematologic malignancies. Mutations in the core spliceosome components lead to aberrant mRNA splicing that may contribute to disease pathogenesis.
Preclinical data have suggested that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in spliceosome-mutant cancer models, including models of AML and CMML. H3B-8800 showed dose-dependent modulation of canonical and aberrant splicing when administered at tolerated doses.
Results from this research were presented at the 2017 AACR Annual Meeting (abstract 1185).
H3B-8800 is currently under investigation in a phase 1 trial of patients with AML, CMML, and myelodysplastic syndromes that may carry mutations in the core spliceosome genes.
H3B-8800 is being developed by H3 Biomedicine Inc.
The US Food and Drug Administration (FDA) has granted orphan drug designation to H3B-8800 as a treatment for patients with acute myelogenous leukemia (AML) or chronic myelomonocytic leukemia (CMML).
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
About H3B-8800
H3B-8800 is an orally bioavailable small-molecule modulator of wild-type and mutant SF3b complexes. The SF3b complex is a key component of the spliceosome that is found in the cell nucleus and is responsible for the removal of noncoding introns from a transcribed pre-messenger RNA.
Recurrent heterozygous mutations in several core members of the spliceosome (SF3B1, U2AF1, SRSF2, and ZRSR2) have been identified in solid tumor and hematologic malignancies. Mutations in the core spliceosome components lead to aberrant mRNA splicing that may contribute to disease pathogenesis.
Preclinical data have suggested that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in spliceosome-mutant cancer models, including models of AML and CMML. H3B-8800 showed dose-dependent modulation of canonical and aberrant splicing when administered at tolerated doses.
Results from this research were presented at the 2017 AACR Annual Meeting (abstract 1185).
H3B-8800 is currently under investigation in a phase 1 trial of patients with AML, CMML, and myelodysplastic syndromes that may carry mutations in the core spliceosome genes.
H3B-8800 is being developed by H3 Biomedicine Inc.
The US Food and Drug Administration (FDA) has granted orphan drug designation to H3B-8800 as a treatment for patients with acute myelogenous leukemia (AML) or chronic myelomonocytic leukemia (CMML).
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
About H3B-8800
H3B-8800 is an orally bioavailable small-molecule modulator of wild-type and mutant SF3b complexes. The SF3b complex is a key component of the spliceosome that is found in the cell nucleus and is responsible for the removal of noncoding introns from a transcribed pre-messenger RNA.
Recurrent heterozygous mutations in several core members of the spliceosome (SF3B1, U2AF1, SRSF2, and ZRSR2) have been identified in solid tumor and hematologic malignancies. Mutations in the core spliceosome components lead to aberrant mRNA splicing that may contribute to disease pathogenesis.
Preclinical data have suggested that H3B-8800 modulates RNA splicing and shows preferential antitumor activity in spliceosome-mutant cancer models, including models of AML and CMML. H3B-8800 showed dose-dependent modulation of canonical and aberrant splicing when administered at tolerated doses.
Results from this research were presented at the 2017 AACR Annual Meeting (abstract 1185).
H3B-8800 is currently under investigation in a phase 1 trial of patients with AML, CMML, and myelodysplastic syndromes that may carry mutations in the core spliceosome genes.
H3B-8800 is being developed by H3 Biomedicine Inc.
FDA allows emergency use of multiplex Zika test
The US Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) for the CII-ArboViroPlex rRT-PCR Test.
It is the first multiplex assay that simultaneously tests for the presence of Zika virus, all serotypes of dengue virus, chikungunya virus, and West Nile virus, as well as a host gene that ensures the accuracy of results.
The EUA does not mean the CII-ArboViroPlex rRT-PCR Test is FDA cleared or approved.
An EUA allows for the use of unapproved medical products in an emergency. The products must be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, or nuclear threat agents, when there are no adequate alternatives.
The EUA for the CII-ArboViroPlex rRT-PCR Test means the test is only authorized as long as circumstances exist to justify the emergency use of in vitro diagnostics for the detection of Zika virus, unless the authorization is terminated or revoked sooner.
About the test
The CII-ArboViroPlex rRT-PCR Test is an assay that detects viral RNA matching Zika virus (ZIKV), dengue virus types 1-4 (DENV), chikungunya virus (CHIKV), and West Nile virus (WNV) with a human housekeeping gene, viral RNA controls, and extraction controls that ensure the integrity of the test from nucleic extraction to the final result.
Named for the 4 arboviruses it targets and the real-time reverse transcription polymerase chain reaction (rRT-PCR) technique it employs, the test can simultaneously detect ZIKV, DENV, CHIKV, and WNV in up to 88 samples of blood in less than 2 hours and ZIKV in urine (collected alongside a patient-matched serum specimen).
The CII-ArboViroPlex rRT-PCR Test was developed by scientists at the Center for Infection and Immunity (CII) at Columbia University’s Mailman School of Public Health in New York, New York. The manufacture of the test will be overseen by CII.
The CII-ArboViroPlex rRT-PCR Test is authorized to be used by laboratories in the US that are certified under the Clinical Laboratory Improvement Amendments of 1988, 42 U.S.C. § 263a, to perform high complexity tests, or by similarly qualified non-US laboratories.
The CII-ArboViroPlex rRT-PCR Test is authorized to be performed with the NucliSENS® easyMag® automated extraction platform (bioMérieux), the RNA UltraSense™ One-Step Quantitative RT-PCR System (Thermo Fisher), and CFX96 Real-Time PCR Detection System (Bio-Rad).
“The ArboViroPlex Test provides an easy and efficient means to simultaneously detect Zika and 3 other mosquito-borne viral infections that may present with similar clinical features,” said Nischay Mishra, of CII.
“The FDA decision to issue the EUA gives clinicians and researchers a powerful tool to diagnose and prevent the spread of Zika,” added W. Ian Lipkin, director of CII.
More information on the CII-ArboViroPlex rRT-PCR Test Virus Kit and other Zika tests granted EUAs can be found on the FDA’s EUA page.
The US Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) for the CII-ArboViroPlex rRT-PCR Test.
It is the first multiplex assay that simultaneously tests for the presence of Zika virus, all serotypes of dengue virus, chikungunya virus, and West Nile virus, as well as a host gene that ensures the accuracy of results.
The EUA does not mean the CII-ArboViroPlex rRT-PCR Test is FDA cleared or approved.
An EUA allows for the use of unapproved medical products in an emergency. The products must be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, or nuclear threat agents, when there are no adequate alternatives.
The EUA for the CII-ArboViroPlex rRT-PCR Test means the test is only authorized as long as circumstances exist to justify the emergency use of in vitro diagnostics for the detection of Zika virus, unless the authorization is terminated or revoked sooner.
About the test
The CII-ArboViroPlex rRT-PCR Test is an assay that detects viral RNA matching Zika virus (ZIKV), dengue virus types 1-4 (DENV), chikungunya virus (CHIKV), and West Nile virus (WNV) with a human housekeeping gene, viral RNA controls, and extraction controls that ensure the integrity of the test from nucleic extraction to the final result.
Named for the 4 arboviruses it targets and the real-time reverse transcription polymerase chain reaction (rRT-PCR) technique it employs, the test can simultaneously detect ZIKV, DENV, CHIKV, and WNV in up to 88 samples of blood in less than 2 hours and ZIKV in urine (collected alongside a patient-matched serum specimen).
The CII-ArboViroPlex rRT-PCR Test was developed by scientists at the Center for Infection and Immunity (CII) at Columbia University’s Mailman School of Public Health in New York, New York. The manufacture of the test will be overseen by CII.
The CII-ArboViroPlex rRT-PCR Test is authorized to be used by laboratories in the US that are certified under the Clinical Laboratory Improvement Amendments of 1988, 42 U.S.C. § 263a, to perform high complexity tests, or by similarly qualified non-US laboratories.
The CII-ArboViroPlex rRT-PCR Test is authorized to be performed with the NucliSENS® easyMag® automated extraction platform (bioMérieux), the RNA UltraSense™ One-Step Quantitative RT-PCR System (Thermo Fisher), and CFX96 Real-Time PCR Detection System (Bio-Rad).
“The ArboViroPlex Test provides an easy and efficient means to simultaneously detect Zika and 3 other mosquito-borne viral infections that may present with similar clinical features,” said Nischay Mishra, of CII.
“The FDA decision to issue the EUA gives clinicians and researchers a powerful tool to diagnose and prevent the spread of Zika,” added W. Ian Lipkin, director of CII.
More information on the CII-ArboViroPlex rRT-PCR Test Virus Kit and other Zika tests granted EUAs can be found on the FDA’s EUA page.
The US Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) for the CII-ArboViroPlex rRT-PCR Test.
It is the first multiplex assay that simultaneously tests for the presence of Zika virus, all serotypes of dengue virus, chikungunya virus, and West Nile virus, as well as a host gene that ensures the accuracy of results.
The EUA does not mean the CII-ArboViroPlex rRT-PCR Test is FDA cleared or approved.
An EUA allows for the use of unapproved medical products in an emergency. The products must be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, or nuclear threat agents, when there are no adequate alternatives.
The EUA for the CII-ArboViroPlex rRT-PCR Test means the test is only authorized as long as circumstances exist to justify the emergency use of in vitro diagnostics for the detection of Zika virus, unless the authorization is terminated or revoked sooner.
About the test
The CII-ArboViroPlex rRT-PCR Test is an assay that detects viral RNA matching Zika virus (ZIKV), dengue virus types 1-4 (DENV), chikungunya virus (CHIKV), and West Nile virus (WNV) with a human housekeeping gene, viral RNA controls, and extraction controls that ensure the integrity of the test from nucleic extraction to the final result.
Named for the 4 arboviruses it targets and the real-time reverse transcription polymerase chain reaction (rRT-PCR) technique it employs, the test can simultaneously detect ZIKV, DENV, CHIKV, and WNV in up to 88 samples of blood in less than 2 hours and ZIKV in urine (collected alongside a patient-matched serum specimen).
The CII-ArboViroPlex rRT-PCR Test was developed by scientists at the Center for Infection and Immunity (CII) at Columbia University’s Mailman School of Public Health in New York, New York. The manufacture of the test will be overseen by CII.
The CII-ArboViroPlex rRT-PCR Test is authorized to be used by laboratories in the US that are certified under the Clinical Laboratory Improvement Amendments of 1988, 42 U.S.C. § 263a, to perform high complexity tests, or by similarly qualified non-US laboratories.
The CII-ArboViroPlex rRT-PCR Test is authorized to be performed with the NucliSENS® easyMag® automated extraction platform (bioMérieux), the RNA UltraSense™ One-Step Quantitative RT-PCR System (Thermo Fisher), and CFX96 Real-Time PCR Detection System (Bio-Rad).
“The ArboViroPlex Test provides an easy and efficient means to simultaneously detect Zika and 3 other mosquito-borne viral infections that may present with similar clinical features,” said Nischay Mishra, of CII.
“The FDA decision to issue the EUA gives clinicians and researchers a powerful tool to diagnose and prevent the spread of Zika,” added W. Ian Lipkin, director of CII.
More information on the CII-ArboViroPlex rRT-PCR Test Virus Kit and other Zika tests granted EUAs can be found on the FDA’s EUA page.
CBO: End of ACA subsidies would mean short-term exit of insurers
Terminating the Affordable Care Act’s cost-sharing reduction payments to insurers would cause a short-term exit by insurers from the individual insurance marketplaces, but the availability of plans is expected to rebound, according to the Congressional Budget Office.
In a new analysis requested by Democratic leadership in the House of Representatives, CBO and staff from the congressional Joint Committee on Taxation (JCT) examined what would happen if the Trump administration announced by the end of August that it would cease to make cost-sharing reduction payments at the end of 2017.
However, insurers would be on the hook to cover the payments no longer provided by the government, which means that “participating insurers would raise premiums of ‘silver’ plans to recover the costs.”
Gross premiums for silver plans “would be 20% higher in 2018 and 25% by 2020,” pushing higher premium tax credits and increasing the federal deficit by $194 billion from 2017 through 2026,” the report states. “Most people would pay net premiums (after accounting for premium tax credits) for nongroup insurance throughout the next decade that were similar to or less than what they would pay otherwise.”
The percentage of people facing a “slight increases” would be higher during the next 2 years, they pointed out.
The number of uninsured would be slightly higher in 2018 (about 1 million more uninsured) but then would be slightly lower starting in 2020 (about 1 million less each year).
Should the administration end cost-sharing reduction payments in 2017, those eligible for tax credits who have annual incomes 200%-400% of the federal poverty level would use their subsidies to purchase either gold or bronze plans, with silver plans going almost exclusively to people eligible for cost-sharing reductions (100%-200% of the poverty line).
Terminating the Affordable Care Act’s cost-sharing reduction payments to insurers would cause a short-term exit by insurers from the individual insurance marketplaces, but the availability of plans is expected to rebound, according to the Congressional Budget Office.
In a new analysis requested by Democratic leadership in the House of Representatives, CBO and staff from the congressional Joint Committee on Taxation (JCT) examined what would happen if the Trump administration announced by the end of August that it would cease to make cost-sharing reduction payments at the end of 2017.
However, insurers would be on the hook to cover the payments no longer provided by the government, which means that “participating insurers would raise premiums of ‘silver’ plans to recover the costs.”
Gross premiums for silver plans “would be 20% higher in 2018 and 25% by 2020,” pushing higher premium tax credits and increasing the federal deficit by $194 billion from 2017 through 2026,” the report states. “Most people would pay net premiums (after accounting for premium tax credits) for nongroup insurance throughout the next decade that were similar to or less than what they would pay otherwise.”
The percentage of people facing a “slight increases” would be higher during the next 2 years, they pointed out.
The number of uninsured would be slightly higher in 2018 (about 1 million more uninsured) but then would be slightly lower starting in 2020 (about 1 million less each year).
Should the administration end cost-sharing reduction payments in 2017, those eligible for tax credits who have annual incomes 200%-400% of the federal poverty level would use their subsidies to purchase either gold or bronze plans, with silver plans going almost exclusively to people eligible for cost-sharing reductions (100%-200% of the poverty line).
Terminating the Affordable Care Act’s cost-sharing reduction payments to insurers would cause a short-term exit by insurers from the individual insurance marketplaces, but the availability of plans is expected to rebound, according to the Congressional Budget Office.
In a new analysis requested by Democratic leadership in the House of Representatives, CBO and staff from the congressional Joint Committee on Taxation (JCT) examined what would happen if the Trump administration announced by the end of August that it would cease to make cost-sharing reduction payments at the end of 2017.
However, insurers would be on the hook to cover the payments no longer provided by the government, which means that “participating insurers would raise premiums of ‘silver’ plans to recover the costs.”
Gross premiums for silver plans “would be 20% higher in 2018 and 25% by 2020,” pushing higher premium tax credits and increasing the federal deficit by $194 billion from 2017 through 2026,” the report states. “Most people would pay net premiums (after accounting for premium tax credits) for nongroup insurance throughout the next decade that were similar to or less than what they would pay otherwise.”
The percentage of people facing a “slight increases” would be higher during the next 2 years, they pointed out.
The number of uninsured would be slightly higher in 2018 (about 1 million more uninsured) but then would be slightly lower starting in 2020 (about 1 million less each year).
Should the administration end cost-sharing reduction payments in 2017, those eligible for tax credits who have annual incomes 200%-400% of the federal poverty level would use their subsidies to purchase either gold or bronze plans, with silver plans going almost exclusively to people eligible for cost-sharing reductions (100%-200% of the poverty line).
Study advances noninvasive prenatal testing for hemophilia
Digital droplet PCR (ddPCR) was an accurate and noninvasive method to detect mutations leading to hemophilia A and B in maternal plasma DNA in 15 at-risk pregnancies of 8 to 42 weeks’ gestation, researchers reported.
Additionally, the researchers showed for the first time that targeted massively parallel sequencing (MPS) accurately detected the clinically important int22h-related inversion mutations in maternal plasma DNA from pregnant hemophilia carriers from three families with the disorder.
As costs of sequencing continue to fall, larger studies of pregnant carriers of F8 int22h-related inversions can help make MPS “an essential part in noninvasive prenatal testing of hemophilia carriers,” Irena Hudecova, PhD, of Li Ka Shing Institute of Health Sciences, Hong Kong, and her associates wrote (Blood. 2017 Jul 20;130[3]:340-7).
Diagnosing hemophilia during pregnancy helps optimize care and allows mothers to make informed decisions about whether to terminate pregnancies. But for male fetuses, invasive testing has been the only option. In a prior small study, researchers used noninvasive microfluidics PCR to detect sequence variants of F8, which encodes factor VIII, and F9, which encodes Factor IX. The assay uses a chip that can accommodate about 9,000 reaction wells, making noninvasive screening much more feasible and affordable. But technical difficulties had precluded detection of int22h-related inversions, the inversion mutations of intron 22 in F8 on chromosome X that affect about half of individuals with severe hemophilia (Blood. 2011 Mar 31;117[13]:3684-91).
For the current study, the researchers first designed family-specific ddPCR assays to test for relevant maternal sequence variants scattered across the F8 and F9 genes. Tests of 15 male singleton fetuses produced three unclassified samples, but no misclassifications.
“Because of the scalability of ddPCR, the protocol performed reliably even in cases with fetal DNA fraction lower than 10%,” the researchers wrote. “When an unclassified result is encountered, one either performs more digital analyses on the sample to accumulate more data points, or when the sample is consumed, one may resort to an additional blood draw, possibly at a later gestational age with higher fetal DNA fraction.”
Next, the investigators used MPS to create detailed fetal haplotype maps of the 7.6-Md region of F8 where int22h-related inversions occur. This approach yielded an “accurate and robust measurement of maternally inherited fetal haplotypes,” they wrote. “Our data suggest it is feasible to apply targeted MPS to interrogate maternally inherited F8 int22h-related inversions, whereas ddPCR [is] an affordable approach for the identification of F8 and F9 sequence variants in maternal plasma.”
The study was funded by the Research Grants Council of the Hong Kong SAR Government and the Vice Chancellor’s One-Off Discretionary Fund of The Chinese University of Hong Kong. Dr. Hudecova reported having no financial disclosures. Several coauthors disclosed patents for plasma nucleic acid analysis and ties to Sequenom, Illumina, Xcelom, and Cirina.
The use of digital droplet PCR for prenatal diagnosis of hemophilia is a major improvement over current invasive methods, such as chorionic villus sampling, amniocentesis, and cordocentesis.
Knowledge of a hemophilia diagnosis before birth provides an opportunity for early hemostatic intervention before procedures such as circumcision are performed, or to prevent morbidity and mortality by cesarean delivery to reduce the risk of intracranial hemorrhage when the birth of a child with severe hemophilia is anticipated. Prenatal testing is also important to ensure hemostatic support for the mother, for whom it may be necessary to prevent bleeding with perinatal anesthesia and/or postpartum bleeding. These prenatal assays depend on knowledge of the mother’s carrier genotype, which is potentially more accurate than factor levels, which may increase with hormone use or the increasing hormone levels of pregnancy and mask carrier diagnosis.
The development of these assays is timely in view of the ongoing My Life, Our Future (MLOF) genome project in hemophilia and underscores the need for carrier testing and genetic counseling of female members from hemophilia kindreds.
Margaret V. Ragni, MD, is with the University of Pittsburgh Medical Center. She reported having no relevant disclosures. These comments are adapted from an accompanying editorial (Blood. 2017 Jul 20;130[3]:240-1).
The use of digital droplet PCR for prenatal diagnosis of hemophilia is a major improvement over current invasive methods, such as chorionic villus sampling, amniocentesis, and cordocentesis.
Knowledge of a hemophilia diagnosis before birth provides an opportunity for early hemostatic intervention before procedures such as circumcision are performed, or to prevent morbidity and mortality by cesarean delivery to reduce the risk of intracranial hemorrhage when the birth of a child with severe hemophilia is anticipated. Prenatal testing is also important to ensure hemostatic support for the mother, for whom it may be necessary to prevent bleeding with perinatal anesthesia and/or postpartum bleeding. These prenatal assays depend on knowledge of the mother’s carrier genotype, which is potentially more accurate than factor levels, which may increase with hormone use or the increasing hormone levels of pregnancy and mask carrier diagnosis.
The development of these assays is timely in view of the ongoing My Life, Our Future (MLOF) genome project in hemophilia and underscores the need for carrier testing and genetic counseling of female members from hemophilia kindreds.
Margaret V. Ragni, MD, is with the University of Pittsburgh Medical Center. She reported having no relevant disclosures. These comments are adapted from an accompanying editorial (Blood. 2017 Jul 20;130[3]:240-1).
The use of digital droplet PCR for prenatal diagnosis of hemophilia is a major improvement over current invasive methods, such as chorionic villus sampling, amniocentesis, and cordocentesis.
Knowledge of a hemophilia diagnosis before birth provides an opportunity for early hemostatic intervention before procedures such as circumcision are performed, or to prevent morbidity and mortality by cesarean delivery to reduce the risk of intracranial hemorrhage when the birth of a child with severe hemophilia is anticipated. Prenatal testing is also important to ensure hemostatic support for the mother, for whom it may be necessary to prevent bleeding with perinatal anesthesia and/or postpartum bleeding. These prenatal assays depend on knowledge of the mother’s carrier genotype, which is potentially more accurate than factor levels, which may increase with hormone use or the increasing hormone levels of pregnancy and mask carrier diagnosis.
The development of these assays is timely in view of the ongoing My Life, Our Future (MLOF) genome project in hemophilia and underscores the need for carrier testing and genetic counseling of female members from hemophilia kindreds.
Margaret V. Ragni, MD, is with the University of Pittsburgh Medical Center. She reported having no relevant disclosures. These comments are adapted from an accompanying editorial (Blood. 2017 Jul 20;130[3]:240-1).
Digital droplet PCR (ddPCR) was an accurate and noninvasive method to detect mutations leading to hemophilia A and B in maternal plasma DNA in 15 at-risk pregnancies of 8 to 42 weeks’ gestation, researchers reported.
Additionally, the researchers showed for the first time that targeted massively parallel sequencing (MPS) accurately detected the clinically important int22h-related inversion mutations in maternal plasma DNA from pregnant hemophilia carriers from three families with the disorder.
As costs of sequencing continue to fall, larger studies of pregnant carriers of F8 int22h-related inversions can help make MPS “an essential part in noninvasive prenatal testing of hemophilia carriers,” Irena Hudecova, PhD, of Li Ka Shing Institute of Health Sciences, Hong Kong, and her associates wrote (Blood. 2017 Jul 20;130[3]:340-7).
Diagnosing hemophilia during pregnancy helps optimize care and allows mothers to make informed decisions about whether to terminate pregnancies. But for male fetuses, invasive testing has been the only option. In a prior small study, researchers used noninvasive microfluidics PCR to detect sequence variants of F8, which encodes factor VIII, and F9, which encodes Factor IX. The assay uses a chip that can accommodate about 9,000 reaction wells, making noninvasive screening much more feasible and affordable. But technical difficulties had precluded detection of int22h-related inversions, the inversion mutations of intron 22 in F8 on chromosome X that affect about half of individuals with severe hemophilia (Blood. 2011 Mar 31;117[13]:3684-91).
For the current study, the researchers first designed family-specific ddPCR assays to test for relevant maternal sequence variants scattered across the F8 and F9 genes. Tests of 15 male singleton fetuses produced three unclassified samples, but no misclassifications.
“Because of the scalability of ddPCR, the protocol performed reliably even in cases with fetal DNA fraction lower than 10%,” the researchers wrote. “When an unclassified result is encountered, one either performs more digital analyses on the sample to accumulate more data points, or when the sample is consumed, one may resort to an additional blood draw, possibly at a later gestational age with higher fetal DNA fraction.”
Next, the investigators used MPS to create detailed fetal haplotype maps of the 7.6-Md region of F8 where int22h-related inversions occur. This approach yielded an “accurate and robust measurement of maternally inherited fetal haplotypes,” they wrote. “Our data suggest it is feasible to apply targeted MPS to interrogate maternally inherited F8 int22h-related inversions, whereas ddPCR [is] an affordable approach for the identification of F8 and F9 sequence variants in maternal plasma.”
The study was funded by the Research Grants Council of the Hong Kong SAR Government and the Vice Chancellor’s One-Off Discretionary Fund of The Chinese University of Hong Kong. Dr. Hudecova reported having no financial disclosures. Several coauthors disclosed patents for plasma nucleic acid analysis and ties to Sequenom, Illumina, Xcelom, and Cirina.
Digital droplet PCR (ddPCR) was an accurate and noninvasive method to detect mutations leading to hemophilia A and B in maternal plasma DNA in 15 at-risk pregnancies of 8 to 42 weeks’ gestation, researchers reported.
Additionally, the researchers showed for the first time that targeted massively parallel sequencing (MPS) accurately detected the clinically important int22h-related inversion mutations in maternal plasma DNA from pregnant hemophilia carriers from three families with the disorder.
As costs of sequencing continue to fall, larger studies of pregnant carriers of F8 int22h-related inversions can help make MPS “an essential part in noninvasive prenatal testing of hemophilia carriers,” Irena Hudecova, PhD, of Li Ka Shing Institute of Health Sciences, Hong Kong, and her associates wrote (Blood. 2017 Jul 20;130[3]:340-7).
Diagnosing hemophilia during pregnancy helps optimize care and allows mothers to make informed decisions about whether to terminate pregnancies. But for male fetuses, invasive testing has been the only option. In a prior small study, researchers used noninvasive microfluidics PCR to detect sequence variants of F8, which encodes factor VIII, and F9, which encodes Factor IX. The assay uses a chip that can accommodate about 9,000 reaction wells, making noninvasive screening much more feasible and affordable. But technical difficulties had precluded detection of int22h-related inversions, the inversion mutations of intron 22 in F8 on chromosome X that affect about half of individuals with severe hemophilia (Blood. 2011 Mar 31;117[13]:3684-91).
For the current study, the researchers first designed family-specific ddPCR assays to test for relevant maternal sequence variants scattered across the F8 and F9 genes. Tests of 15 male singleton fetuses produced three unclassified samples, but no misclassifications.
“Because of the scalability of ddPCR, the protocol performed reliably even in cases with fetal DNA fraction lower than 10%,” the researchers wrote. “When an unclassified result is encountered, one either performs more digital analyses on the sample to accumulate more data points, or when the sample is consumed, one may resort to an additional blood draw, possibly at a later gestational age with higher fetal DNA fraction.”
Next, the investigators used MPS to create detailed fetal haplotype maps of the 7.6-Md region of F8 where int22h-related inversions occur. This approach yielded an “accurate and robust measurement of maternally inherited fetal haplotypes,” they wrote. “Our data suggest it is feasible to apply targeted MPS to interrogate maternally inherited F8 int22h-related inversions, whereas ddPCR [is] an affordable approach for the identification of F8 and F9 sequence variants in maternal plasma.”
The study was funded by the Research Grants Council of the Hong Kong SAR Government and the Vice Chancellor’s One-Off Discretionary Fund of The Chinese University of Hong Kong. Dr. Hudecova reported having no financial disclosures. Several coauthors disclosed patents for plasma nucleic acid analysis and ties to Sequenom, Illumina, Xcelom, and Cirina.
FROM BLOOD
Key clinical point:
Major finding: Digital droplet PCR (ddPCR) detected relevant F8 and F9 gene mutations. Targeted massively parallel sequencing (MPS) determined fetal inheritance of F8 int22h-related inversions, which up to half of individuals with severe hemophilia carry.
Data source: ddPCR of 15 singleton male fetuses from at-risk mothers and MPS of the maternal plasma of pregnant carriers from three hemophilia families.
Disclosures: The study was funded by the Research Grants Council of the Hong Kong SAR Government and the Vice Chancellor’s One-Off Discretionary Fund of The Chinese University of Hong Kong. Dr. Hudecova reported having no financial disclosures. Some of the coauthors disclosed patents for plasma nucleic acid analysis and ties to Sequenom, Illumina, Xcelom, and Cirina.
How many strikes?
(Larissa MacFarquar, Aug. 7 & 14, 2017). It is a very complex question, and one for which there has never been an easy answer, certainly not an answer that can be applied universally. However, my reflex response was “sooner rather than later!”
What prompted my hasty from-the-hip answer is 40-plus years of watching the legal system grind along at a pace that too often fails to take into account the emotional needs of a child’s developing personality. While lawyers file for extensions and wait for slots in dockets bloated with less time-sensitive cases, children float in limbo waiting to hear where their home will be and who will constitute their family.
Even if he is lucky enough to be housed with a single foster home, the odds are that his stays there will be punctuated with returns to his parent as the parent is given one more chance to beat back the demons that have stood in the way of at least an adequate, if not a model, parenthood. The New Yorker article chronicles one such odyssey that spans a mother’s four pregnancies with several fathers.
In the crudest terms, here is the question: “How many strikes does one get before one loses his or her parental rights?” It is a bit easier to make the call when there have been incidents in which a parent’s action or inaction has put the child’s physical health in jeopardy. However, the social workers, physicians, and law enforcement officials who must shoulder the burden of these decisions involving the abusive parent often find themselves in no-win situations. Giving the parent who is suspected of physical abuse having been “just a little heavy handed” one more chance could result in death or life-long impairment.
I suspect the rationale for giving the parent another chance is based on the belief that the biologic family should always be the preferred option; an assumption that can be called into question. While I don’t think these decisions should be made with the strict application of an algorithm, I believe there is more room for evidence-based decision-making. That evidence may not be currently available, but I think we should be asking questions to get that information. For example, for an individual with a specific substance addiction or mental illness with a certain diagnosis, what are the chances of a remedy that will allow that individual to become a functional parent? And how long will it take?
Information like this may be helpful for those folks with the difficult job of deciding when a parent should lose his parental rights in a time course that takes into account the emotional needs of his children.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
(Larissa MacFarquar, Aug. 7 & 14, 2017). It is a very complex question, and one for which there has never been an easy answer, certainly not an answer that can be applied universally. However, my reflex response was “sooner rather than later!”
What prompted my hasty from-the-hip answer is 40-plus years of watching the legal system grind along at a pace that too often fails to take into account the emotional needs of a child’s developing personality. While lawyers file for extensions and wait for slots in dockets bloated with less time-sensitive cases, children float in limbo waiting to hear where their home will be and who will constitute their family.
Even if he is lucky enough to be housed with a single foster home, the odds are that his stays there will be punctuated with returns to his parent as the parent is given one more chance to beat back the demons that have stood in the way of at least an adequate, if not a model, parenthood. The New Yorker article chronicles one such odyssey that spans a mother’s four pregnancies with several fathers.
In the crudest terms, here is the question: “How many strikes does one get before one loses his or her parental rights?” It is a bit easier to make the call when there have been incidents in which a parent’s action or inaction has put the child’s physical health in jeopardy. However, the social workers, physicians, and law enforcement officials who must shoulder the burden of these decisions involving the abusive parent often find themselves in no-win situations. Giving the parent who is suspected of physical abuse having been “just a little heavy handed” one more chance could result in death or life-long impairment.
I suspect the rationale for giving the parent another chance is based on the belief that the biologic family should always be the preferred option; an assumption that can be called into question. While I don’t think these decisions should be made with the strict application of an algorithm, I believe there is more room for evidence-based decision-making. That evidence may not be currently available, but I think we should be asking questions to get that information. For example, for an individual with a specific substance addiction or mental illness with a certain diagnosis, what are the chances of a remedy that will allow that individual to become a functional parent? And how long will it take?
Information like this may be helpful for those folks with the difficult job of deciding when a parent should lose his parental rights in a time course that takes into account the emotional needs of his children.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
(Larissa MacFarquar, Aug. 7 & 14, 2017). It is a very complex question, and one for which there has never been an easy answer, certainly not an answer that can be applied universally. However, my reflex response was “sooner rather than later!”
What prompted my hasty from-the-hip answer is 40-plus years of watching the legal system grind along at a pace that too often fails to take into account the emotional needs of a child’s developing personality. While lawyers file for extensions and wait for slots in dockets bloated with less time-sensitive cases, children float in limbo waiting to hear where their home will be and who will constitute their family.
Even if he is lucky enough to be housed with a single foster home, the odds are that his stays there will be punctuated with returns to his parent as the parent is given one more chance to beat back the demons that have stood in the way of at least an adequate, if not a model, parenthood. The New Yorker article chronicles one such odyssey that spans a mother’s four pregnancies with several fathers.
In the crudest terms, here is the question: “How many strikes does one get before one loses his or her parental rights?” It is a bit easier to make the call when there have been incidents in which a parent’s action or inaction has put the child’s physical health in jeopardy. However, the social workers, physicians, and law enforcement officials who must shoulder the burden of these decisions involving the abusive parent often find themselves in no-win situations. Giving the parent who is suspected of physical abuse having been “just a little heavy handed” one more chance could result in death or life-long impairment.
I suspect the rationale for giving the parent another chance is based on the belief that the biologic family should always be the preferred option; an assumption that can be called into question. While I don’t think these decisions should be made with the strict application of an algorithm, I believe there is more room for evidence-based decision-making. That evidence may not be currently available, but I think we should be asking questions to get that information. For example, for an individual with a specific substance addiction or mental illness with a certain diagnosis, what are the chances of a remedy that will allow that individual to become a functional parent? And how long will it take?
Information like this may be helpful for those folks with the difficult job of deciding when a parent should lose his parental rights in a time course that takes into account the emotional needs of his children.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].