A hospitalist and SHM Public Policy Committee member is hopeful that SHM's recently released position paper recommending changes to the way the "observation status" designation is used for admitted hospital patients will help improve patient care.

The increasing use of the Centers for Medicare & Medicaid Services' (CMS) patient observation status designation—which grew 88% from 2006 to 2012—has frustrated hospitalists. Under the rule, patients are ineligible for skilled-nursing facility (SNF) care, may not claim insurance coverage for some medications, and may face uncertain cost-sharing and other financial liabilities for their hospitalization.

SHM outlined its concerns about the policy and suggested solutions in the report titled "The Observation Status Problem: Impact and Recommendations for Change."

CMS has attempted to address the issue by creating the "two-midnight rule." The report notes, however, that amid confusion on the application of the "two-midnight rule," Medicare auditing and enforcement have been pushed back several times, most recently to March 31, 2015.

"We still are unclear about what patient vulnerability is under this," says SHM Public Policy Committee member Ann Sheehy, MD, MS, FHM, a hospitalist at the University of Wisconsin School of Medicine and Public Health in Madison, who testified before Congress last May on observation status and other Medicare policies.

"We know that patients can't get SNF coverage when they're under observation," Dr. Sheehy says. "We know that patients are subject to unlimited co-pays when they're under observation, as opposed to when they're hospitalized as inpatients under Medicare Part A, which has a one-time deductible."

The SHM white paper outlines both short- and long-term fixes to the policy. In the near term, SHM recommends:

• Educating providers and patients on the purpose of observation status and raising confidence in when and how it should be applied;

• Changing SNF coverage rules to ensure patients’ eligibility; and

• Reforming the Medicare Recovery Audit Contractor program to improve RAC performance and reduce unintended pressures on admission decisions.

In the long term, the report suggests creating modifiers for diagnosis-related group (DRG) payments to assign to patients needing lower-acuity services, as well as crafting a list of DRGs to assign to patients needing short periods of inpatient care.

"The policy overall is very frustrating," Dr. Sheehy adds. "We hope that any rule change that comes out will address the core problems of observation so that patients can get the care they need with fair and appropriate insurance coverage." TH

Visit our website for more information about patient observation status.

A hospitalist and SHM Public Policy Committee member is hopeful that SHM's recently released position paper recommending changes to the way the "observation status" designation is used for admitted hospital patients will help improve patient care.

The increasing use of the Centers for Medicare & Medicaid Services' (CMS) patient observation status designation—which grew 88% from 2006 to 2012—has frustrated hospitalists. Under the rule, patients are ineligible for skilled-nursing facility (SNF) care, may not claim insurance coverage for some medications, and may face uncertain cost-sharing and other financial liabilities for their hospitalization.

SHM outlined its concerns about the policy and suggested solutions in the report titled "The Observation Status Problem: Impact and Recommendations for Change."

CMS has attempted to address the issue by creating the "two-midnight rule." The report notes, however, that amid confusion on the application of the "two-midnight rule," Medicare auditing and enforcement have been pushed back several times, most recently to March 31, 2015.

"We still are unclear about what patient vulnerability is under this," says SHM Public Policy Committee member Ann Sheehy, MD, MS, FHM, a hospitalist at the University of Wisconsin School of Medicine and Public Health in Madison, who testified before Congress last May on observation status and other Medicare policies.

"We know that patients can't get SNF coverage when they're under observation," Dr. Sheehy says. "We know that patients are subject to unlimited co-pays when they're under observation, as opposed to when they're hospitalized as inpatients under Medicare Part A, which has a one-time deductible."

The SHM white paper outlines both short- and long-term fixes to the policy. In the near term, SHM recommends:

• Educating providers and patients on the purpose of observation status and raising confidence in when and how it should be applied;

• Changing SNF coverage rules to ensure patients’ eligibility; and

• Reforming the Medicare Recovery Audit Contractor program to improve RAC performance and reduce unintended pressures on admission decisions.

In the long term, the report suggests creating modifiers for diagnosis-related group (DRG) payments to assign to patients needing lower-acuity services, as well as crafting a list of DRGs to assign to patients needing short periods of inpatient care.

"The policy overall is very frustrating," Dr. Sheehy adds. "We hope that any rule change that comes out will address the core problems of observation so that patients can get the care they need with fair and appropriate insurance coverage." TH

Visit our website for more information about patient observation status.

A hospitalist and SHM Public Policy Committee member is hopeful that SHM's recently released position paper recommending changes to the way the "observation status" designation is used for admitted hospital patients will help improve patient care.

The increasing use of the Centers for Medicare & Medicaid Services' (CMS) patient observation status designation—which grew 88% from 2006 to 2012—has frustrated hospitalists. Under the rule, patients are ineligible for skilled-nursing facility (SNF) care, may not claim insurance coverage for some medications, and may face uncertain cost-sharing and other financial liabilities for their hospitalization.

SHM outlined its concerns about the policy and suggested solutions in the report titled "The Observation Status Problem: Impact and Recommendations for Change."

CMS has attempted to address the issue by creating the "two-midnight rule." The report notes, however, that amid confusion on the application of the "two-midnight rule," Medicare auditing and enforcement have been pushed back several times, most recently to March 31, 2015.

"We still are unclear about what patient vulnerability is under this," says SHM Public Policy Committee member Ann Sheehy, MD, MS, FHM, a hospitalist at the University of Wisconsin School of Medicine and Public Health in Madison, who testified before Congress last May on observation status and other Medicare policies.

"We know that patients can't get SNF coverage when they're under observation," Dr. Sheehy says. "We know that patients are subject to unlimited co-pays when they're under observation, as opposed to when they're hospitalized as inpatients under Medicare Part A, which has a one-time deductible."

The SHM white paper outlines both short- and long-term fixes to the policy. In the near term, SHM recommends:

• Educating providers and patients on the purpose of observation status and raising confidence in when and how it should be applied;

• Changing SNF coverage rules to ensure patients’ eligibility; and

• Reforming the Medicare Recovery Audit Contractor program to improve RAC performance and reduce unintended pressures on admission decisions.

In the long term, the report suggests creating modifiers for diagnosis-related group (DRG) payments to assign to patients needing lower-acuity services, as well as crafting a list of DRGs to assign to patients needing short periods of inpatient care.

"The policy overall is very frustrating," Dr. Sheehy adds. "We hope that any rule change that comes out will address the core problems of observation so that patients can get the care they need with fair and appropriate insurance coverage." TH

Visit our website for more information about patient observation status.

In a Senate subcommittee hearing last month, a panel of patient safety experts and physicians raised concerns about the problem of preventable medical errors, which they say can be linked to more than 1,000 patient deaths per day.

For their part, SHM Public Policy Committee member Bradley Flansbaum, DO, MPH, FHM, says hospitalists should demand that their hospitals report better data on patient outcomes.

"When you talk about a patient death, you're talking about the efforts of an entire hospital going into the death or survival of that patient," says Dr. Flansbaum, a hospitalist at Lenox Hill Hospital in New York. "If you ask, 'Where did something go wrong?' just looking at the mortality rate doesn't help. What service are you inquiring about? How can you get clean data that’s also useful to the clinician?"

In his testimony before the Subcommittee on Primary Health and Aging, hospitalist Ashish Jha, MD, MPH, referenced a landmark 1999 report from the Institute of Medicine (IOM), "To Err Is Human: Building a Safer Health System," [PDF] which estimated that between 44,000 and 98,000 deaths in the U.S. each year can be attributed to preventable medical errors.

Since the IOM report was published, little has been done to change the systems of care delivery that can lead providers to make errors, said Dr. Jha, an internist at the VA Boston Healthcare System and professor of health policy and management at the Harvard School of Public Health in Boston.

"When a physician orders the wrong medication because two drugs might sound alike, or when a patient develops a central-line infection because a rushed surgeon didn't use proper sterile technique, we now understand that we need to focus on the system that produced the errors," Dr. Jha told Senate subcommittee members.

Both Dr. Jha and panelist Peter Pronovost, MD, PhD, FCCM, senior vice president for patient safety and quality at Johns Hopkins Medicine in Baltimore, said the Centers for Disease Control and Prevention should expand its National Nosocomial Infections Surveillance Program to collect and report data on medical errors.

Several other speakers said hospitals should be mandated to publicly report medical errors.

"Public disclosure is a critical element to preventing these events from happening," said panelist Lisa McGiffert, director of the Consumers Union Safe Patient Project in Austin, Texas. "It informs people about healthcare outcomes and motivates healthcare providers to do more to prevent errors." TH

Visit our website for more information on the impact of medical errors.

In a Senate subcommittee hearing last month, a panel of patient safety experts and physicians raised concerns about the problem of preventable medical errors, which they say can be linked to more than 1,000 patient deaths per day.

For their part, SHM Public Policy Committee member Bradley Flansbaum, DO, MPH, FHM, says hospitalists should demand that their hospitals report better data on patient outcomes.

"When you talk about a patient death, you're talking about the efforts of an entire hospital going into the death or survival of that patient," says Dr. Flansbaum, a hospitalist at Lenox Hill Hospital in New York. "If you ask, 'Where did something go wrong?' just looking at the mortality rate doesn't help. What service are you inquiring about? How can you get clean data that’s also useful to the clinician?"

In his testimony before the Subcommittee on Primary Health and Aging, hospitalist Ashish Jha, MD, MPH, referenced a landmark 1999 report from the Institute of Medicine (IOM), "To Err Is Human: Building a Safer Health System," [PDF] which estimated that between 44,000 and 98,000 deaths in the U.S. each year can be attributed to preventable medical errors.

Since the IOM report was published, little has been done to change the systems of care delivery that can lead providers to make errors, said Dr. Jha, an internist at the VA Boston Healthcare System and professor of health policy and management at the Harvard School of Public Health in Boston.

"When a physician orders the wrong medication because two drugs might sound alike, or when a patient develops a central-line infection because a rushed surgeon didn't use proper sterile technique, we now understand that we need to focus on the system that produced the errors," Dr. Jha told Senate subcommittee members.

Both Dr. Jha and panelist Peter Pronovost, MD, PhD, FCCM, senior vice president for patient safety and quality at Johns Hopkins Medicine in Baltimore, said the Centers for Disease Control and Prevention should expand its National Nosocomial Infections Surveillance Program to collect and report data on medical errors.

Several other speakers said hospitals should be mandated to publicly report medical errors.

"Public disclosure is a critical element to preventing these events from happening," said panelist Lisa McGiffert, director of the Consumers Union Safe Patient Project in Austin, Texas. "It informs people about healthcare outcomes and motivates healthcare providers to do more to prevent errors." TH

Visit our website for more information on the impact of medical errors.

In a Senate subcommittee hearing last month, a panel of patient safety experts and physicians raised concerns about the problem of preventable medical errors, which they say can be linked to more than 1,000 patient deaths per day.

For their part, SHM Public Policy Committee member Bradley Flansbaum, DO, MPH, FHM, says hospitalists should demand that their hospitals report better data on patient outcomes.

"When you talk about a patient death, you're talking about the efforts of an entire hospital going into the death or survival of that patient," says Dr. Flansbaum, a hospitalist at Lenox Hill Hospital in New York. "If you ask, 'Where did something go wrong?' just looking at the mortality rate doesn't help. What service are you inquiring about? How can you get clean data that’s also useful to the clinician?"

In his testimony before the Subcommittee on Primary Health and Aging, hospitalist Ashish Jha, MD, MPH, referenced a landmark 1999 report from the Institute of Medicine (IOM), "To Err Is Human: Building a Safer Health System," [PDF] which estimated that between 44,000 and 98,000 deaths in the U.S. each year can be attributed to preventable medical errors.

Since the IOM report was published, little has been done to change the systems of care delivery that can lead providers to make errors, said Dr. Jha, an internist at the VA Boston Healthcare System and professor of health policy and management at the Harvard School of Public Health in Boston.

"When a physician orders the wrong medication because two drugs might sound alike, or when a patient develops a central-line infection because a rushed surgeon didn't use proper sterile technique, we now understand that we need to focus on the system that produced the errors," Dr. Jha told Senate subcommittee members.

Both Dr. Jha and panelist Peter Pronovost, MD, PhD, FCCM, senior vice president for patient safety and quality at Johns Hopkins Medicine in Baltimore, said the Centers for Disease Control and Prevention should expand its National Nosocomial Infections Surveillance Program to collect and report data on medical errors.

Several other speakers said hospitals should be mandated to publicly report medical errors.

"Public disclosure is a critical element to preventing these events from happening," said panelist Lisa McGiffert, director of the Consumers Union Safe Patient Project in Austin, Texas. "It informs people about healthcare outcomes and motivates healthcare providers to do more to prevent errors." TH

Visit our website for more information on the impact of medical errors.

A majority of general surgery residents seriously consider dropping out of their training, with female residents more likely to consider quitting, a new study in JAMA Surgery reveals.

According to a survey, 58.0% of the 288 respondents "seriously considered leaving training." The most frequent reasons cited for wanting to quit training were sleep deprivation on a specific rotation (50%), an undesirable future lifestyle (47%), and excessive work hours on a specific rotation (41.4%). Survey results were published online July 30 in JAMA Surgery (2014 [doi:10.1001/jamasurg.2014.935]).

© Maridav / iStockphoto.com

Factors cited that ultimately keep general surgery residents from ending training are support from family or significant other (65%), support from other residents (63.5%), and perception of being better rested (58.9%).

"We believe that our survey findings highlight the fact that a desire to leave training may not be affected by job rigor alone but rather [by] program-specific or rotation-specific factors or dissatisfaction with a future career in general surgery," the report states. Dr. Edward Gifford of the department of surgery, University of California, Los Angeles, Medical Center, is the report’s lead author.

In addressing the factors that led to consideration for leaving training, the authors noted that "a potential remedy may be to identify those high work-hour rotations and modify them accordingly," though lifestyle concerns may be harder to address as practicing surgeons "continue to experience high levels of work-home conflicts and burnout."

For women specifically, another issue is "the paucity of female mentors in academic surgery," the report states. "Striving to increase the number of female faculty members within training programs and refining the mentor-mentee relationship with incoming residents may improve the outlook and productivity of future female surgeons."

Overall, while men’s thoughts of quitting decreased as their residency progressed, women’s considerations remained persistent. The report cites previous studies that reported that men and women view general surgery careers differently, including that it was not a welcoming career because of lifestyle challenges, particularly if the woman had children, limited flexible training, and lack of role models.

"These findings may explain why women in our survey continued to consider leaving residency throughout the duration of training and underscores the importance of supporting female residents through the difficult balance between motherhood and professional life," the report states.

The study was approved by the human subjects committee of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles. The authors reported no conflicts of interest.

A majority of general surgery residents seriously consider dropping out of their training, with female residents more likely to consider quitting, a new study in JAMA Surgery reveals.

According to a survey, 58.0% of the 288 respondents "seriously considered leaving training." The most frequent reasons cited for wanting to quit training were sleep deprivation on a specific rotation (50%), an undesirable future lifestyle (47%), and excessive work hours on a specific rotation (41.4%). Survey results were published online July 30 in JAMA Surgery (2014 [doi:10.1001/jamasurg.2014.935]).

© Maridav / iStockphoto.com

Factors cited that ultimately keep general surgery residents from ending training are support from family or significant other (65%), support from other residents (63.5%), and perception of being better rested (58.9%).

"We believe that our survey findings highlight the fact that a desire to leave training may not be affected by job rigor alone but rather [by] program-specific or rotation-specific factors or dissatisfaction with a future career in general surgery," the report states. Dr. Edward Gifford of the department of surgery, University of California, Los Angeles, Medical Center, is the report’s lead author.

In addressing the factors that led to consideration for leaving training, the authors noted that "a potential remedy may be to identify those high work-hour rotations and modify them accordingly," though lifestyle concerns may be harder to address as practicing surgeons "continue to experience high levels of work-home conflicts and burnout."

For women specifically, another issue is "the paucity of female mentors in academic surgery," the report states. "Striving to increase the number of female faculty members within training programs and refining the mentor-mentee relationship with incoming residents may improve the outlook and productivity of future female surgeons."

Overall, while men’s thoughts of quitting decreased as their residency progressed, women’s considerations remained persistent. The report cites previous studies that reported that men and women view general surgery careers differently, including that it was not a welcoming career because of lifestyle challenges, particularly if the woman had children, limited flexible training, and lack of role models.

"These findings may explain why women in our survey continued to consider leaving residency throughout the duration of training and underscores the importance of supporting female residents through the difficult balance between motherhood and professional life," the report states.

The study was approved by the human subjects committee of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles. The authors reported no conflicts of interest.

A majority of general surgery residents seriously consider dropping out of their training, with female residents more likely to consider quitting, a new study in JAMA Surgery reveals.

According to a survey, 58.0% of the 288 respondents "seriously considered leaving training." The most frequent reasons cited for wanting to quit training were sleep deprivation on a specific rotation (50%), an undesirable future lifestyle (47%), and excessive work hours on a specific rotation (41.4%). Survey results were published online July 30 in JAMA Surgery (2014 [doi:10.1001/jamasurg.2014.935]).

© Maridav / iStockphoto.com

Factors cited that ultimately keep general surgery residents from ending training are support from family or significant other (65%), support from other residents (63.5%), and perception of being better rested (58.9%).

"We believe that our survey findings highlight the fact that a desire to leave training may not be affected by job rigor alone but rather [by] program-specific or rotation-specific factors or dissatisfaction with a future career in general surgery," the report states. Dr. Edward Gifford of the department of surgery, University of California, Los Angeles, Medical Center, is the report’s lead author.

In addressing the factors that led to consideration for leaving training, the authors noted that "a potential remedy may be to identify those high work-hour rotations and modify them accordingly," though lifestyle concerns may be harder to address as practicing surgeons "continue to experience high levels of work-home conflicts and burnout."

For women specifically, another issue is "the paucity of female mentors in academic surgery," the report states. "Striving to increase the number of female faculty members within training programs and refining the mentor-mentee relationship with incoming residents may improve the outlook and productivity of future female surgeons."

Overall, while men’s thoughts of quitting decreased as their residency progressed, women’s considerations remained persistent. The report cites previous studies that reported that men and women view general surgery careers differently, including that it was not a welcoming career because of lifestyle challenges, particularly if the woman had children, limited flexible training, and lack of role models.

"These findings may explain why women in our survey continued to consider leaving residency throughout the duration of training and underscores the importance of supporting female residents through the difficult balance between motherhood and professional life," the report states.

The study was approved by the human subjects committee of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles. The authors reported no conflicts of interest.

An estimated 42 million (18.1%) of the U.S. adult population continues to smoke cigarettes. Effective treatments exist for patients who are willing to avail themselves of such assistance. Varenicline is one of the most effective medications that we have to combat tobacco dependence. However, it doesn’t work for everybody, and questions have remained about how safe and effective it is to combine varenicline with other smoking cessation therapies such as nicotine replacement therapy.

Varenicline binds to a specific nicotine receptor, thereby partially agonizing and blocking it. The result is decreased cravings for tobacco and increased smoking quit rates. Data from early studies conducted by our group suggested that nicotine replacement therapy (NRT) combined with varenicline was safe, but questions remained about its efficacy.

One group of researchers conducted a multicenter clinical trial evaluating the efficacy of combining varenicline and the nicotine patch for increasing smoking cessation rates. Smokers were eligible if they smoked at least 10 cigarettes per day, reported F.N. Coenraad, from the Stellenbosch University, Cape Town, South Africa, and associates. Participants were randomized to active 15-mg nicotine patches or placebo patches started 2 weeks before the target quit date. All participants received varenicline for a total of 14 weeks with a 1-week ramp-up and a 1-week taper. Use of the varenicline in combination with the nicotine patch resulted in increased rates of continuous abstinence from smoking at 12 weeks (no smoking from weeks 9 to 12: 55.4% vs. 40.9%; odds ratio, 1.85; 95% confidence interval, 1.19-2.89; P = .007) and at 24 weeks (no smoking from weeks 9 to 24: 49% vs. 32.6%; OR, 1.98; 95% CI, 1.25-3.14; P = .004) (JAMA 2014;312:155-61).

This is a fantastic study answering a lingering question in tobacco control. But what is the theoretical underpinning by which this combination works? Isn’t the NRT blocked by the varenicline? It is possible that the varenicline incompletely saturates the nicotine receptors, which are additionally saturated by the supplemented nicotine. The varenicline effect is mediated through the alpha-4 beta-2 nicotinic receptor, and it is also possible that nicotine binds to nicotine receptor types that varenicline does not bind to, which decreases withdrawal symptoms.

We aren’t exactly sure how this might be working, but a near doubling of the odds of quitting is not to be disregarded. We are also not sure whether the effect holds when one uses other types of NRT such as the nicotine inhaler, nicotine lozenge, nicotine nasal spray, and nicotine gum. In practice, I tend to lean toward a combination of varenicline with the nicotine inhaler since the inhaler can help with some of the behavioral aspects of smoking while the varenicline does its heavy lifting.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author. Dr. Ebbert reports receiving research support from Pfizer, manufacturer of varenicline and the nicotine inhaler, and consulting fees from GlaxoSmithKline, manufacturer of the nicotine patch. The opinions expressed in this article should not be used to diagnose or treat any medical condition, nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician.

An estimated 42 million (18.1%) of the U.S. adult population continues to smoke cigarettes. Effective treatments exist for patients who are willing to avail themselves of such assistance. Varenicline is one of the most effective medications that we have to combat tobacco dependence. However, it doesn’t work for everybody, and questions have remained about how safe and effective it is to combine varenicline with other smoking cessation therapies such as nicotine replacement therapy.

Varenicline binds to a specific nicotine receptor, thereby partially agonizing and blocking it. The result is decreased cravings for tobacco and increased smoking quit rates. Data from early studies conducted by our group suggested that nicotine replacement therapy (NRT) combined with varenicline was safe, but questions remained about its efficacy.

One group of researchers conducted a multicenter clinical trial evaluating the efficacy of combining varenicline and the nicotine patch for increasing smoking cessation rates. Smokers were eligible if they smoked at least 10 cigarettes per day, reported F.N. Coenraad, from the Stellenbosch University, Cape Town, South Africa, and associates. Participants were randomized to active 15-mg nicotine patches or placebo patches started 2 weeks before the target quit date. All participants received varenicline for a total of 14 weeks with a 1-week ramp-up and a 1-week taper. Use of the varenicline in combination with the nicotine patch resulted in increased rates of continuous abstinence from smoking at 12 weeks (no smoking from weeks 9 to 12: 55.4% vs. 40.9%; odds ratio, 1.85; 95% confidence interval, 1.19-2.89; P = .007) and at 24 weeks (no smoking from weeks 9 to 24: 49% vs. 32.6%; OR, 1.98; 95% CI, 1.25-3.14; P = .004) (JAMA 2014;312:155-61).

This is a fantastic study answering a lingering question in tobacco control. But what is the theoretical underpinning by which this combination works? Isn’t the NRT blocked by the varenicline? It is possible that the varenicline incompletely saturates the nicotine receptors, which are additionally saturated by the supplemented nicotine. The varenicline effect is mediated through the alpha-4 beta-2 nicotinic receptor, and it is also possible that nicotine binds to nicotine receptor types that varenicline does not bind to, which decreases withdrawal symptoms.

We aren’t exactly sure how this might be working, but a near doubling of the odds of quitting is not to be disregarded. We are also not sure whether the effect holds when one uses other types of NRT such as the nicotine inhaler, nicotine lozenge, nicotine nasal spray, and nicotine gum. In practice, I tend to lean toward a combination of varenicline with the nicotine inhaler since the inhaler can help with some of the behavioral aspects of smoking while the varenicline does its heavy lifting.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author. Dr. Ebbert reports receiving research support from Pfizer, manufacturer of varenicline and the nicotine inhaler, and consulting fees from GlaxoSmithKline, manufacturer of the nicotine patch. The opinions expressed in this article should not be used to diagnose or treat any medical condition, nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician.

An estimated 42 million (18.1%) of the U.S. adult population continues to smoke cigarettes. Effective treatments exist for patients who are willing to avail themselves of such assistance. Varenicline is one of the most effective medications that we have to combat tobacco dependence. However, it doesn’t work for everybody, and questions have remained about how safe and effective it is to combine varenicline with other smoking cessation therapies such as nicotine replacement therapy.

Varenicline binds to a specific nicotine receptor, thereby partially agonizing and blocking it. The result is decreased cravings for tobacco and increased smoking quit rates. Data from early studies conducted by our group suggested that nicotine replacement therapy (NRT) combined with varenicline was safe, but questions remained about its efficacy.

One group of researchers conducted a multicenter clinical trial evaluating the efficacy of combining varenicline and the nicotine patch for increasing smoking cessation rates. Smokers were eligible if they smoked at least 10 cigarettes per day, reported F.N. Coenraad, from the Stellenbosch University, Cape Town, South Africa, and associates. Participants were randomized to active 15-mg nicotine patches or placebo patches started 2 weeks before the target quit date. All participants received varenicline for a total of 14 weeks with a 1-week ramp-up and a 1-week taper. Use of the varenicline in combination with the nicotine patch resulted in increased rates of continuous abstinence from smoking at 12 weeks (no smoking from weeks 9 to 12: 55.4% vs. 40.9%; odds ratio, 1.85; 95% confidence interval, 1.19-2.89; P = .007) and at 24 weeks (no smoking from weeks 9 to 24: 49% vs. 32.6%; OR, 1.98; 95% CI, 1.25-3.14; P = .004) (JAMA 2014;312:155-61).

This is a fantastic study answering a lingering question in tobacco control. But what is the theoretical underpinning by which this combination works? Isn’t the NRT blocked by the varenicline? It is possible that the varenicline incompletely saturates the nicotine receptors, which are additionally saturated by the supplemented nicotine. The varenicline effect is mediated through the alpha-4 beta-2 nicotinic receptor, and it is also possible that nicotine binds to nicotine receptor types that varenicline does not bind to, which decreases withdrawal symptoms.

We aren’t exactly sure how this might be working, but a near doubling of the odds of quitting is not to be disregarded. We are also not sure whether the effect holds when one uses other types of NRT such as the nicotine inhaler, nicotine lozenge, nicotine nasal spray, and nicotine gum. In practice, I tend to lean toward a combination of varenicline with the nicotine inhaler since the inhaler can help with some of the behavioral aspects of smoking while the varenicline does its heavy lifting.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author. Dr. Ebbert reports receiving research support from Pfizer, manufacturer of varenicline and the nicotine inhaler, and consulting fees from GlaxoSmithKline, manufacturer of the nicotine patch. The opinions expressed in this article should not be used to diagnose or treat any medical condition, nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician.

A device that preserves less-than-ideal donor lungs until they are cleared for transplantation has been approved, the Food and Drug Administration announced on Aug. 12.

The ex vivo perfusion device preserves donated lungs that initially do not meet all the criteria for a transplantable lung. The device does this by warming the donor lung to "near normal body temperature," continuously flushing the lung with a sterile solution, and ventilating the lungs, "which oxygenates the cells and makes it possible for the transplant team to examine the lungs’ airways with a bronchoscope," according to the FDA statement.

Courtesy XVIVO Perfusion

The lungs can remain in the machine for up to 4 hours, providing time for the transplant team to evaluate the lungs to determine if they meet the criteria; donor lungs that meet the criteria are then transplanted into a patient.

The device, the XVIVO Perfusion System (XPS) with STEEN Solution, is manufactured by XVIVO Perfusion.

"With this approval, there may be more lungs available for transplant, which could allow more people with end stage lung disease who have exhausted all other treatment options to be able to receive a lung transplant," Christy Foreman, director of the Office of Device Evaluation in the FDA’s Center for Devices and Radiological Health, Silver Spring, Md., said in the statement.

About one in five donor lungs meet the standard transplantation criteria. In the United States, 1,754 lung transplants were performed in 2012 and 1,616 potential recipients were on the lung transplant waiting list at the end of 2012, according to the FDA.

In two studies, outcomes for lung-transplant recipients were similar among those who received a donor lung preserved with the device and those who received donor lungs that were considered ideal and were preserved in cold storage. "Both trials showed that recipients of the ideal and non-ideal lungs had similar survival rates up to 12 months after transplant and similar rates of organ rejection," the FDA statement said.

The manufacturer is required to conduct a long-term study of the effects of the device as a condition of approval.

[email protected]

A device that preserves less-than-ideal donor lungs until they are cleared for transplantation has been approved, the Food and Drug Administration announced on Aug. 12.

The ex vivo perfusion device preserves donated lungs that initially do not meet all the criteria for a transplantable lung. The device does this by warming the donor lung to "near normal body temperature," continuously flushing the lung with a sterile solution, and ventilating the lungs, "which oxygenates the cells and makes it possible for the transplant team to examine the lungs’ airways with a bronchoscope," according to the FDA statement.

Courtesy XVIVO Perfusion

The lungs can remain in the machine for up to 4 hours, providing time for the transplant team to evaluate the lungs to determine if they meet the criteria; donor lungs that meet the criteria are then transplanted into a patient.

The device, the XVIVO Perfusion System (XPS) with STEEN Solution, is manufactured by XVIVO Perfusion.

"With this approval, there may be more lungs available for transplant, which could allow more people with end stage lung disease who have exhausted all other treatment options to be able to receive a lung transplant," Christy Foreman, director of the Office of Device Evaluation in the FDA’s Center for Devices and Radiological Health, Silver Spring, Md., said in the statement.

About one in five donor lungs meet the standard transplantation criteria. In the United States, 1,754 lung transplants were performed in 2012 and 1,616 potential recipients were on the lung transplant waiting list at the end of 2012, according to the FDA.

In two studies, outcomes for lung-transplant recipients were similar among those who received a donor lung preserved with the device and those who received donor lungs that were considered ideal and were preserved in cold storage. "Both trials showed that recipients of the ideal and non-ideal lungs had similar survival rates up to 12 months after transplant and similar rates of organ rejection," the FDA statement said.

The manufacturer is required to conduct a long-term study of the effects of the device as a condition of approval.

[email protected]

A device that preserves less-than-ideal donor lungs until they are cleared for transplantation has been approved, the Food and Drug Administration announced on Aug. 12.

The ex vivo perfusion device preserves donated lungs that initially do not meet all the criteria for a transplantable lung. The device does this by warming the donor lung to "near normal body temperature," continuously flushing the lung with a sterile solution, and ventilating the lungs, "which oxygenates the cells and makes it possible for the transplant team to examine the lungs’ airways with a bronchoscope," according to the FDA statement.

Courtesy XVIVO Perfusion

The lungs can remain in the machine for up to 4 hours, providing time for the transplant team to evaluate the lungs to determine if they meet the criteria; donor lungs that meet the criteria are then transplanted into a patient.

The device, the XVIVO Perfusion System (XPS) with STEEN Solution, is manufactured by XVIVO Perfusion.

"With this approval, there may be more lungs available for transplant, which could allow more people with end stage lung disease who have exhausted all other treatment options to be able to receive a lung transplant," Christy Foreman, director of the Office of Device Evaluation in the FDA’s Center for Devices and Radiological Health, Silver Spring, Md., said in the statement.

About one in five donor lungs meet the standard transplantation criteria. In the United States, 1,754 lung transplants were performed in 2012 and 1,616 potential recipients were on the lung transplant waiting list at the end of 2012, according to the FDA.

In two studies, outcomes for lung-transplant recipients were similar among those who received a donor lung preserved with the device and those who received donor lungs that were considered ideal and were preserved in cold storage. "Both trials showed that recipients of the ideal and non-ideal lungs had similar survival rates up to 12 months after transplant and similar rates of organ rejection," the FDA statement said.

The manufacturer is required to conduct a long-term study of the effects of the device as a condition of approval.

[email protected]

Blood for transfusion

Credit: UAB Hospital

Results of a retrospective study suggest an antifibrinolytic agent can significantly reduce the need for blood transfusions after surgery, without increasing the risk of complications.

The agent, tranexamic acid, has been shown to reduce blood loss during or shortly after major joint surgery, but safety concerns remain because large-scale effectiveness studies are lacking.

So researchers set out to evaluate tranexamic acid in a large sample of surgical patients.

The team recounted their efforts in BMJ.

Stavros Memtsoudis, MD, PhD, of the Hospital for Special Surgery in New York, New York, and his colleagues analyzed data from 872,416 patients who underwent total hip or knee replacement procedures at 510 US hospitals between 2006 and 2012.

The researchers compared patients who received tranexamic acid (at 1000 mg,

2000 mg, or 3000 mg) on the day of surgery to patients who did not. The team adjusted their analysis for factors such as patient age and sex, hospital size and location, the type of procedure, and the anesthesia used.

Results showed that use of tranexamic acid was associated with an up to 69% reduction in the need for blood transfusions. Overall, the rate of allogeneic or autologous transfusion was 7.7% among patients who received tranexamic acid and 20.1% among those who did not (P<0.01).

Tranexamic acid use was also linked to a decreased risk of all complications (1.9% vs 2.6%, P<0.001),  thromboembolic events (0.6% vs 0.8%, P=0.0057), the need for mechanical ventilation (0.1% vs 0.2%, P=0.0003), and admission to an intensive care unit (3.1% vs 7.5%, P<0.001).

The median length of hospital stay was the same for treated and untreated patients—3 days. But the median cost of hospital stay was lower among tranexamic acid-treated patients—$14,890 vs $15,110 (P<0.001).

A tranexamic acid dose of 2000 mg appeared to have the best effectiveness and safety profile. But the researchers said additional studies are needed to establish optimal dosing schemes and assess subgroup-specific effectiveness and safety.

Blood for transfusion

Credit: UAB Hospital

Results of a retrospective study suggest an antifibrinolytic agent can significantly reduce the need for blood transfusions after surgery, without increasing the risk of complications.

The agent, tranexamic acid, has been shown to reduce blood loss during or shortly after major joint surgery, but safety concerns remain because large-scale effectiveness studies are lacking.

So researchers set out to evaluate tranexamic acid in a large sample of surgical patients.

The team recounted their efforts in BMJ.

Stavros Memtsoudis, MD, PhD, of the Hospital for Special Surgery in New York, New York, and his colleagues analyzed data from 872,416 patients who underwent total hip or knee replacement procedures at 510 US hospitals between 2006 and 2012.

The researchers compared patients who received tranexamic acid (at 1000 mg,

2000 mg, or 3000 mg) on the day of surgery to patients who did not. The team adjusted their analysis for factors such as patient age and sex, hospital size and location, the type of procedure, and the anesthesia used.

Results showed that use of tranexamic acid was associated with an up to 69% reduction in the need for blood transfusions. Overall, the rate of allogeneic or autologous transfusion was 7.7% among patients who received tranexamic acid and 20.1% among those who did not (P<0.01).

Tranexamic acid use was also linked to a decreased risk of all complications (1.9% vs 2.6%, P<0.001),  thromboembolic events (0.6% vs 0.8%, P=0.0057), the need for mechanical ventilation (0.1% vs 0.2%, P=0.0003), and admission to an intensive care unit (3.1% vs 7.5%, P<0.001).

The median length of hospital stay was the same for treated and untreated patients—3 days. But the median cost of hospital stay was lower among tranexamic acid-treated patients—$14,890 vs $15,110 (P<0.001).

A tranexamic acid dose of 2000 mg appeared to have the best effectiveness and safety profile. But the researchers said additional studies are needed to establish optimal dosing schemes and assess subgroup-specific effectiveness and safety.

Blood for transfusion

Credit: UAB Hospital

Results of a retrospective study suggest an antifibrinolytic agent can significantly reduce the need for blood transfusions after surgery, without increasing the risk of complications.

The agent, tranexamic acid, has been shown to reduce blood loss during or shortly after major joint surgery, but safety concerns remain because large-scale effectiveness studies are lacking.

So researchers set out to evaluate tranexamic acid in a large sample of surgical patients.

The team recounted their efforts in BMJ.

Stavros Memtsoudis, MD, PhD, of the Hospital for Special Surgery in New York, New York, and his colleagues analyzed data from 872,416 patients who underwent total hip or knee replacement procedures at 510 US hospitals between 2006 and 2012.

The researchers compared patients who received tranexamic acid (at 1000 mg,

2000 mg, or 3000 mg) on the day of surgery to patients who did not. The team adjusted their analysis for factors such as patient age and sex, hospital size and location, the type of procedure, and the anesthesia used.

Results showed that use of tranexamic acid was associated with an up to 69% reduction in the need for blood transfusions. Overall, the rate of allogeneic or autologous transfusion was 7.7% among patients who received tranexamic acid and 20.1% among those who did not (P<0.01).

Tranexamic acid use was also linked to a decreased risk of all complications (1.9% vs 2.6%, P<0.001),  thromboembolic events (0.6% vs 0.8%, P=0.0057), the need for mechanical ventilation (0.1% vs 0.2%, P=0.0003), and admission to an intensive care unit (3.1% vs 7.5%, P<0.001).

The median length of hospital stay was the same for treated and untreated patients—3 days. But the median cost of hospital stay was lower among tranexamic acid-treated patients—$14,890 vs $15,110 (P<0.001).

A tranexamic acid dose of 2000 mg appeared to have the best effectiveness and safety profile. But the researchers said additional studies are needed to establish optimal dosing schemes and assess subgroup-specific effectiveness and safety.

Burkitt lymphoma

Credit: Ed Uthman

A small molecule can disrupt the interactions between MYC and its binding partner MAX in MYC-driven cancers, according to research published in PNAS.

The molecule, KJ-Pyr-9, inhibited MYC-induced oncogenic transformation in cell culture but had little to no effect on the oncogenic activity of several unrelated oncoproteins.

KJ-Pyr-9 preferentially interfered with proliferation in a range of cells that overexpressed MYC, including leukemia and lymphoma cells.

In vivo, the molecule inhibited the growth of MYC-amplified human cancer cells.

“We finally hit a home run with this—maybe a grand slam,” said study author Kim Janda, PhD, of The Scripps Research Institute in La Jolla, California.

For years, MYC has challenged researchers seeking to disrupt its activity in cancer cells.

“At room temperature or body temperature, MYC without any binding partners is random and constantly shifting,” said study author Jonathan Ross Hart, PhD, also of The Scripps Research Institute. “It’s like a piece of spaghetti.”

So instead of designing a compound to target the structure of MYC, the researchers tested a range of compounds from a library to see if any could disrupt the interactions between MYC and other proteins important in cell proliferation. One did—the small molecule KJ-Pyr-9.

To further investigate, the researchers ran tests in a variety of cell lines, including chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, Burkitt lymphoma, and solid tumors. And they tested KJ-Pyr-9 in mouse models of breast cancer.

The experiments showed that MYC-dependent cells die if treated with KJ-Pyr-9. In fact, a dose of KJ-Pyr-9 made it seem as if MYC was not present at all.

When mice with MYC-dependent tumors received KJ-Pyr-9, the tumors showed no growth after 31 days, compared with significant tumor growth in untreated mice.

Dr Janda said he hopes further research will reveal exactly how KJ-Pyr-9 interacts with MYC and how the compound can more effectively reach tumor cells.

Burkitt lymphoma

Credit: Ed Uthman

A small molecule can disrupt the interactions between MYC and its binding partner MAX in MYC-driven cancers, according to research published in PNAS.

The molecule, KJ-Pyr-9, inhibited MYC-induced oncogenic transformation in cell culture but had little to no effect on the oncogenic activity of several unrelated oncoproteins.

KJ-Pyr-9 preferentially interfered with proliferation in a range of cells that overexpressed MYC, including leukemia and lymphoma cells.

In vivo, the molecule inhibited the growth of MYC-amplified human cancer cells.

“We finally hit a home run with this—maybe a grand slam,” said study author Kim Janda, PhD, of The Scripps Research Institute in La Jolla, California.

For years, MYC has challenged researchers seeking to disrupt its activity in cancer cells.

“At room temperature or body temperature, MYC without any binding partners is random and constantly shifting,” said study author Jonathan Ross Hart, PhD, also of The Scripps Research Institute. “It’s like a piece of spaghetti.”

So instead of designing a compound to target the structure of MYC, the researchers tested a range of compounds from a library to see if any could disrupt the interactions between MYC and other proteins important in cell proliferation. One did—the small molecule KJ-Pyr-9.

To further investigate, the researchers ran tests in a variety of cell lines, including chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, Burkitt lymphoma, and solid tumors. And they tested KJ-Pyr-9 in mouse models of breast cancer.

The experiments showed that MYC-dependent cells die if treated with KJ-Pyr-9. In fact, a dose of KJ-Pyr-9 made it seem as if MYC was not present at all.

When mice with MYC-dependent tumors received KJ-Pyr-9, the tumors showed no growth after 31 days, compared with significant tumor growth in untreated mice.

Dr Janda said he hopes further research will reveal exactly how KJ-Pyr-9 interacts with MYC and how the compound can more effectively reach tumor cells.

Burkitt lymphoma

Credit: Ed Uthman

A small molecule can disrupt the interactions between MYC and its binding partner MAX in MYC-driven cancers, according to research published in PNAS.

The molecule, KJ-Pyr-9, inhibited MYC-induced oncogenic transformation in cell culture but had little to no effect on the oncogenic activity of several unrelated oncoproteins.

KJ-Pyr-9 preferentially interfered with proliferation in a range of cells that overexpressed MYC, including leukemia and lymphoma cells.

In vivo, the molecule inhibited the growth of MYC-amplified human cancer cells.

“We finally hit a home run with this—maybe a grand slam,” said study author Kim Janda, PhD, of The Scripps Research Institute in La Jolla, California.

For years, MYC has challenged researchers seeking to disrupt its activity in cancer cells.

“At room temperature or body temperature, MYC without any binding partners is random and constantly shifting,” said study author Jonathan Ross Hart, PhD, also of The Scripps Research Institute. “It’s like a piece of spaghetti.”

So instead of designing a compound to target the structure of MYC, the researchers tested a range of compounds from a library to see if any could disrupt the interactions between MYC and other proteins important in cell proliferation. One did—the small molecule KJ-Pyr-9.

To further investigate, the researchers ran tests in a variety of cell lines, including chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, Burkitt lymphoma, and solid tumors. And they tested KJ-Pyr-9 in mouse models of breast cancer.

The experiments showed that MYC-dependent cells die if treated with KJ-Pyr-9. In fact, a dose of KJ-Pyr-9 made it seem as if MYC was not present at all.

When mice with MYC-dependent tumors received KJ-Pyr-9, the tumors showed no growth after 31 days, compared with significant tumor growth in untreated mice.

Dr Janda said he hopes further research will reveal exactly how KJ-Pyr-9 interacts with MYC and how the compound can more effectively reach tumor cells.

Plasmodium sporozoite

Credit: Ute Frevert

and Margaret Shear

In a new study, genetically altered viruses produced long-lasting antimalaria antibodies in mice and protected many of them from the disease.

The approach, known as vector immunoprophylaxis (VIP), produced antibodies against the Plasmodium falciparum circumsporozoite protein (CSP) and prevented malaria infection in 10% to 100% of mice, depending on the dose and type of viral vector used.

Researchers recounted these results in PNAS.

“We need better ways to fight malaria,” said study author Gary Ketner, PhD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. “And our research suggests [VIP] could be a promising approach.”

To test the approach, Dr Ketner and his colleagues constructed adeno-associated virus (AAV) vectors encoding human immunoglobulin G (hIgG) specific for the P falciparum CSP central repeat by inserting the variable regions of mouse monoclonal antibodies (mAbs) 2A10 and 2C11 into the hIgG framework of the VIP expression plasmid.

The team then injected mice with 1 x 10¹¹ genome copies (GC) of 2A10-AAV, 2C11-AAV, b12-AAV (which protects against HIV), or with buffer.

Within a week, the AAV-transduced mice expressed hIgG at 50 μg/mL to 500 μg/mL in serum. The expression increased until about the 4-week mark, when it reached 1000 μg/mL in some mice.

The mice that received 2A10-AAV or 2C11-AAV expressed antibodies that bound recombinant CSP and recognized whole P falciparum sporozoites. The b12-AAV-transduced mice and buffer-transduced mice did not.

In all AAV-transduced mice, serum antibody concentrations plateaued at 4 to 8 weeks and remained at that level through the end of the study, which was 52 weeks after transduction.

At the 8-week mark, the researchers tested the efficacy of VIP. They introduced—either intravenously or through a mosquito-bite challenge—transgenic Plasmodium berghei rodent sporozoites that incorporate the P falciparum target of the antibody in their CSP.

In the intravenously challenged group, 70% of 2A10-AAV-transduced mice were protected from malaria. In the mosquito-bite-challenged group, 60% of 2A10-AAV-transduced mice and 30% of 2C11-AAV-transduced mice were protected from malaria.

Role of dose and antibody level

To examine the effects of vector dose on mAb production and malaria protection, the researchers compared varying doses of 2A10-AAV to b12-AAV. They tested mice transduced with 3 x 10¹¹ GC of b12-AAV or doses of 2A10-AAV ranging from 3 x 10⁹ GC to 3 x 10¹¹ GC.

The team conducted a mosquito-bite challenge at 11 weeks after transduction. And they found that 70% of the mice that received the highest AAV dose (1 x 10¹¹ GC) were protected, as were 40% of mice that received 3 x 10¹⁰ GC and 10% of mice that received 1 x 10¹⁰ GC.

All mice transduced with 3 x 10⁹ GC were parasitemic by day 7, and all b12-AAV mice were parasitemic by day 6. There was a signficant correlation between 2A10 antibody concentration and day to parasitemia.

In a subset of mice that produced higher levels of antibodies, the antimalaria protection was 100%. These mice expressed CSP-specific mAb 2A10 at 1 mg/mL or more.

So it seems the protection from malaria is dose-dependent, said study author Cailin Deal, PhD, of the Ragon Institute of MGH, MIT and Harvard in Cambridge, Massachusetts.

“Of course, we don’t know what the human dosage would be,” she added, “but it’s conceivable that the right dosage could completely protect against malaria.”

Plasmodium sporozoite

Credit: Ute Frevert

and Margaret Shear

In a new study, genetically altered viruses produced long-lasting antimalaria antibodies in mice and protected many of them from the disease.

The approach, known as vector immunoprophylaxis (VIP), produced antibodies against the Plasmodium falciparum circumsporozoite protein (CSP) and prevented malaria infection in 10% to 100% of mice, depending on the dose and type of viral vector used.

Researchers recounted these results in PNAS.

“We need better ways to fight malaria,” said study author Gary Ketner, PhD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. “And our research suggests [VIP] could be a promising approach.”

To test the approach, Dr Ketner and his colleagues constructed adeno-associated virus (AAV) vectors encoding human immunoglobulin G (hIgG) specific for the P falciparum CSP central repeat by inserting the variable regions of mouse monoclonal antibodies (mAbs) 2A10 and 2C11 into the hIgG framework of the VIP expression plasmid.

The team then injected mice with 1 x 10¹¹ genome copies (GC) of 2A10-AAV, 2C11-AAV, b12-AAV (which protects against HIV), or with buffer.

Within a week, the AAV-transduced mice expressed hIgG at 50 μg/mL to 500 μg/mL in serum. The expression increased until about the 4-week mark, when it reached 1000 μg/mL in some mice.

The mice that received 2A10-AAV or 2C11-AAV expressed antibodies that bound recombinant CSP and recognized whole P falciparum sporozoites. The b12-AAV-transduced mice and buffer-transduced mice did not.

In all AAV-transduced mice, serum antibody concentrations plateaued at 4 to 8 weeks and remained at that level through the end of the study, which was 52 weeks after transduction.

At the 8-week mark, the researchers tested the efficacy of VIP. They introduced—either intravenously or through a mosquito-bite challenge—transgenic Plasmodium berghei rodent sporozoites that incorporate the P falciparum target of the antibody in their CSP.

In the intravenously challenged group, 70% of 2A10-AAV-transduced mice were protected from malaria. In the mosquito-bite-challenged group, 60% of 2A10-AAV-transduced mice and 30% of 2C11-AAV-transduced mice were protected from malaria.

Role of dose and antibody level

To examine the effects of vector dose on mAb production and malaria protection, the researchers compared varying doses of 2A10-AAV to b12-AAV. They tested mice transduced with 3 x 10¹¹ GC of b12-AAV or doses of 2A10-AAV ranging from 3 x 10⁹ GC to 3 x 10¹¹ GC.

The team conducted a mosquito-bite challenge at 11 weeks after transduction. And they found that 70% of the mice that received the highest AAV dose (1 x 10¹¹ GC) were protected, as were 40% of mice that received 3 x 10¹⁰ GC and 10% of mice that received 1 x 10¹⁰ GC.

All mice transduced with 3 x 10⁹ GC were parasitemic by day 7, and all b12-AAV mice were parasitemic by day 6. There was a signficant correlation between 2A10 antibody concentration and day to parasitemia.

In a subset of mice that produced higher levels of antibodies, the antimalaria protection was 100%. These mice expressed CSP-specific mAb 2A10 at 1 mg/mL or more.

So it seems the protection from malaria is dose-dependent, said study author Cailin Deal, PhD, of the Ragon Institute of MGH, MIT and Harvard in Cambridge, Massachusetts.

“Of course, we don’t know what the human dosage would be,” she added, “but it’s conceivable that the right dosage could completely protect against malaria.”

Plasmodium sporozoite

Credit: Ute Frevert

and Margaret Shear

In a new study, genetically altered viruses produced long-lasting antimalaria antibodies in mice and protected many of them from the disease.

The approach, known as vector immunoprophylaxis (VIP), produced antibodies against the Plasmodium falciparum circumsporozoite protein (CSP) and prevented malaria infection in 10% to 100% of mice, depending on the dose and type of viral vector used.

Researchers recounted these results in PNAS.

“We need better ways to fight malaria,” said study author Gary Ketner, PhD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. “And our research suggests [VIP] could be a promising approach.”

To test the approach, Dr Ketner and his colleagues constructed adeno-associated virus (AAV) vectors encoding human immunoglobulin G (hIgG) specific for the P falciparum CSP central repeat by inserting the variable regions of mouse monoclonal antibodies (mAbs) 2A10 and 2C11 into the hIgG framework of the VIP expression plasmid.

The team then injected mice with 1 x 10¹¹ genome copies (GC) of 2A10-AAV, 2C11-AAV, b12-AAV (which protects against HIV), or with buffer.

Within a week, the AAV-transduced mice expressed hIgG at 50 μg/mL to 500 μg/mL in serum. The expression increased until about the 4-week mark, when it reached 1000 μg/mL in some mice.

The mice that received 2A10-AAV or 2C11-AAV expressed antibodies that bound recombinant CSP and recognized whole P falciparum sporozoites. The b12-AAV-transduced mice and buffer-transduced mice did not.

In all AAV-transduced mice, serum antibody concentrations plateaued at 4 to 8 weeks and remained at that level through the end of the study, which was 52 weeks after transduction.

At the 8-week mark, the researchers tested the efficacy of VIP. They introduced—either intravenously or through a mosquito-bite challenge—transgenic Plasmodium berghei rodent sporozoites that incorporate the P falciparum target of the antibody in their CSP.

In the intravenously challenged group, 70% of 2A10-AAV-transduced mice were protected from malaria. In the mosquito-bite-challenged group, 60% of 2A10-AAV-transduced mice and 30% of 2C11-AAV-transduced mice were protected from malaria.

Role of dose and antibody level

To examine the effects of vector dose on mAb production and malaria protection, the researchers compared varying doses of 2A10-AAV to b12-AAV. They tested mice transduced with 3 x 10¹¹ GC of b12-AAV or doses of 2A10-AAV ranging from 3 x 10⁹ GC to 3 x 10¹¹ GC.

The team conducted a mosquito-bite challenge at 11 weeks after transduction. And they found that 70% of the mice that received the highest AAV dose (1 x 10¹¹ GC) were protected, as were 40% of mice that received 3 x 10¹⁰ GC and 10% of mice that received 1 x 10¹⁰ GC.

All mice transduced with 3 x 10⁹ GC were parasitemic by day 7, and all b12-AAV mice were parasitemic by day 6. There was a signficant correlation between 2A10 antibody concentration and day to parasitemia.

In a subset of mice that produced higher levels of antibodies, the antimalaria protection was 100%. These mice expressed CSP-specific mAb 2A10 at 1 mg/mL or more.

So it seems the protection from malaria is dose-dependent, said study author Cailin Deal, PhD, of the Ragon Institute of MGH, MIT and Harvard in Cambridge, Massachusetts.

“Of course, we don’t know what the human dosage would be,” she added, “but it’s conceivable that the right dosage could completely protect against malaria.”

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan designation for the histone deacetylase (HDAC) inhibitor mocetinostat to treat diffuse large B-cell lymphoma (DLBCL). The drug already had orphan designation as a treatment for myelodysplastic syndrome (MDS).

The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders affecting fewer than 200,000 people in the US.

Orphan designation provides the drug’s developer, Mirati Therapeutics, Inc., with certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

Mocetinostat works by reversing aberrant acetylation resulting from mutations in histone acetyltransferases (HATs).

The drug is being developed as a single-agent treatment for patients with DLBCL or bladder cancer characterized by HAT mutations that Mirati believes are critical in the pathogenesis and progression of these cancers.

“We have identified genetic alterations in histone acetylation pathways (CREBBP and EP300) in approximately one-third of DLBCL and bladder tumors,” said Charles Baum, MD, PhD, president and CEO of Mirati.

He added that nonclinical tumor models with these mutations have proven responsive to mocetinostat, so  Mirati predicts the HDAC inhibitor will halt tumor progression and reduce tumor burden in patients.

Mocetinostat is also under investigation in phase 2 studies in combination with azacitidine (Vidaza) as a treatment for intermediate- and high-risk MDS.

Mocetinostat previously demonstrated activity, as well as toxicity, in patients with Hodgkin lymphoma.

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan designation for the histone deacetylase (HDAC) inhibitor mocetinostat to treat diffuse large B-cell lymphoma (DLBCL). The drug already had orphan designation as a treatment for myelodysplastic syndrome (MDS).

The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders affecting fewer than 200,000 people in the US.

Orphan designation provides the drug’s developer, Mirati Therapeutics, Inc., with certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

Mocetinostat works by reversing aberrant acetylation resulting from mutations in histone acetyltransferases (HATs).

The drug is being developed as a single-agent treatment for patients with DLBCL or bladder cancer characterized by HAT mutations that Mirati believes are critical in the pathogenesis and progression of these cancers.

“We have identified genetic alterations in histone acetylation pathways (CREBBP and EP300) in approximately one-third of DLBCL and bladder tumors,” said Charles Baum, MD, PhD, president and CEO of Mirati.

He added that nonclinical tumor models with these mutations have proven responsive to mocetinostat, so  Mirati predicts the HDAC inhibitor will halt tumor progression and reduce tumor burden in patients.

Mocetinostat is also under investigation in phase 2 studies in combination with azacitidine (Vidaza) as a treatment for intermediate- and high-risk MDS.

Mocetinostat previously demonstrated activity, as well as toxicity, in patients with Hodgkin lymphoma.

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan designation for the histone deacetylase (HDAC) inhibitor mocetinostat to treat diffuse large B-cell lymphoma (DLBCL). The drug already had orphan designation as a treatment for myelodysplastic syndrome (MDS).

The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders affecting fewer than 200,000 people in the US.

Orphan designation provides the drug’s developer, Mirati Therapeutics, Inc., with certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

Mocetinostat works by reversing aberrant acetylation resulting from mutations in histone acetyltransferases (HATs).

The drug is being developed as a single-agent treatment for patients with DLBCL or bladder cancer characterized by HAT mutations that Mirati believes are critical in the pathogenesis and progression of these cancers.

“We have identified genetic alterations in histone acetylation pathways (CREBBP and EP300) in approximately one-third of DLBCL and bladder tumors,” said Charles Baum, MD, PhD, president and CEO of Mirati.

He added that nonclinical tumor models with these mutations have proven responsive to mocetinostat, so  Mirati predicts the HDAC inhibitor will halt tumor progression and reduce tumor burden in patients.

Mocetinostat is also under investigation in phase 2 studies in combination with azacitidine (Vidaza) as a treatment for intermediate- and high-risk MDS.

Mocetinostat previously demonstrated activity, as well as toxicity, in patients with Hodgkin lymphoma.