Blood in bags and vials

Photo by Daniel Gay

Red blood cell (RBC) transfusions do not increase the risk of a serious intestinal disorder in very low-birth-weight (VLBW) infants, according to a study published in JAMA.

Past research has suggested RBC transfusions increase the risk of necrotizing enterocolitis (NEC) among VLBW infants.

But other studies have shown no association between transfusions and NEC or suggested transfusions actually have a protective effect.

So researchers set out to determine whether RBC transfusions or severe anemia were associated with the rate of NEC among VLBW infants. The results suggested a significant association for severe anemia but not RBC transfusion.

To conduct this study, Ravi M. Patel, MD, of the Emory University School of Medicine in Atlanta, Georgia, and his colleagues assessed 598 VLBW infants from 3 neonatal intensive care units in Atlanta.

The team followed the infants for 90 days or until they were discharged from the hospital, transferred to a non-study-affiliated hospital, or died (whichever came first).

Forty-four (7.4%) infants developed NEC, and 32 (5.4%) died (of any cause). Roughly half of the infants (n=319, 53%) received RBC transfusions (n=1430).

The unadjusted cumulative incidence of NEC at week 8 was 9.9% in infants who received transfusions and 4.6% in those who did not.

However, in multivariable analysis, exposure to RBC transfusion in a given week was not significantly related to the rate of NEC. The hazard ratio was 0.44 (P=0.09).

On the other hand, the rate of NEC was significantly higher among infants with severe anemia in a given week than in those without severe anemia. The hazard ratio was 5.99 (P=0.001).

The researchers said these results suggest preventing severe anemia may be more clinically important than minimizing the use of RBC transfusion as a strategy to decrease the risk of NEC in VLBW infants.

However, such a strategy might impact other important neonatal outcomes, so further study is needed.

Blood in bags and vials

Photo by Daniel Gay

Red blood cell (RBC) transfusions do not increase the risk of a serious intestinal disorder in very low-birth-weight (VLBW) infants, according to a study published in JAMA.

Past research has suggested RBC transfusions increase the risk of necrotizing enterocolitis (NEC) among VLBW infants.

But other studies have shown no association between transfusions and NEC or suggested transfusions actually have a protective effect.

So researchers set out to determine whether RBC transfusions or severe anemia were associated with the rate of NEC among VLBW infants. The results suggested a significant association for severe anemia but not RBC transfusion.

To conduct this study, Ravi M. Patel, MD, of the Emory University School of Medicine in Atlanta, Georgia, and his colleagues assessed 598 VLBW infants from 3 neonatal intensive care units in Atlanta.

The team followed the infants for 90 days or until they were discharged from the hospital, transferred to a non-study-affiliated hospital, or died (whichever came first).

Forty-four (7.4%) infants developed NEC, and 32 (5.4%) died (of any cause). Roughly half of the infants (n=319, 53%) received RBC transfusions (n=1430).

The unadjusted cumulative incidence of NEC at week 8 was 9.9% in infants who received transfusions and 4.6% in those who did not.

However, in multivariable analysis, exposure to RBC transfusion in a given week was not significantly related to the rate of NEC. The hazard ratio was 0.44 (P=0.09).

On the other hand, the rate of NEC was significantly higher among infants with severe anemia in a given week than in those without severe anemia. The hazard ratio was 5.99 (P=0.001).

The researchers said these results suggest preventing severe anemia may be more clinically important than minimizing the use of RBC transfusion as a strategy to decrease the risk of NEC in VLBW infants.

However, such a strategy might impact other important neonatal outcomes, so further study is needed.

Blood in bags and vials

Photo by Daniel Gay

Red blood cell (RBC) transfusions do not increase the risk of a serious intestinal disorder in very low-birth-weight (VLBW) infants, according to a study published in JAMA.

Past research has suggested RBC transfusions increase the risk of necrotizing enterocolitis (NEC) among VLBW infants.

But other studies have shown no association between transfusions and NEC or suggested transfusions actually have a protective effect.

So researchers set out to determine whether RBC transfusions or severe anemia were associated with the rate of NEC among VLBW infants. The results suggested a significant association for severe anemia but not RBC transfusion.

To conduct this study, Ravi M. Patel, MD, of the Emory University School of Medicine in Atlanta, Georgia, and his colleagues assessed 598 VLBW infants from 3 neonatal intensive care units in Atlanta.

The team followed the infants for 90 days or until they were discharged from the hospital, transferred to a non-study-affiliated hospital, or died (whichever came first).

Forty-four (7.4%) infants developed NEC, and 32 (5.4%) died (of any cause). Roughly half of the infants (n=319, 53%) received RBC transfusions (n=1430).

The unadjusted cumulative incidence of NEC at week 8 was 9.9% in infants who received transfusions and 4.6% in those who did not.

However, in multivariable analysis, exposure to RBC transfusion in a given week was not significantly related to the rate of NEC. The hazard ratio was 0.44 (P=0.09).

On the other hand, the rate of NEC was significantly higher among infants with severe anemia in a given week than in those without severe anemia. The hazard ratio was 5.99 (P=0.001).

The researchers said these results suggest preventing severe anemia may be more clinically important than minimizing the use of RBC transfusion as a strategy to decrease the risk of NEC in VLBW infants.

However, such a strategy might impact other important neonatal outcomes, so further study is needed.

Early in 2015, SHM published the updated edition of the “Key Principles and Characteristics of an Effective Hospital Medicine Group,” which is a free download via the SHM website. Every hospitalist group should use this comprehensive list of attributes as one important frame of reference to guide ongoing improvement efforts and long-range planning.

In this column and the next two, I’ll split the difference between the very brief list of top success factors for hospitalist groups I wrote about in my March 2011 column and the very comprehensive “Key Characteristics” document. I think these attributes are among the most important to support a high-performing group, yet they are sometimes overlooked or implemented poorly. They are of roughly equal importance and are listed in no particular order.

Deliberately Cultivating a Culture (or Mindset) of Practice Ownership

It’s easy for hospitalists to think of themselves as employees who just work shifts but have no need or opportunity to attend to the bigger picture of the practice or the hospital in which they operate. After all, being a good doctor for your patients is an awfully big job itself, and lots of recruitment ads tell you doctoring is all that will be expected of you. Someone else will handle everything necessary to ensure your practice is successful.

This line of thinking will limit the success of your group.

Your group will perform much better and you’re likely to find your career much more rewarding if you and your hospitalist colleagues think of yourselves as owning your practice and take an active role in managing it. You’ll still need others to manage day-to-day business affairs, but at least a portion of the hospitalists in the group should be actively involved in planning and making decisions about the group’s operations and future evolution.

I encounter hospitalist groups that have become convinced they don’t even have the opportunity to shape or influence their practice. “No one ever listens,” they say. “The hospital executives just do what they want regardless of what we say.” But in nearly every case, that is an exaggeration. Most administrative leaders desperately want hospitalist engagement and thoughtful participation in planning and decision making.

I wrote additional thoughts about the importance of a culture, or mindset, of practice ownership in August 2008. The print version of that column included a short list of questions you could ask yourself to assess whether your own group has such a culture, but it is missing from the web version and can be found at nelsonflores.com/html/quiz.html.

A Formal System of Group ‘Governance’

So many hospitalist groups rely almost entirely on consensus to make decisions. This might work well enough for a very small group (e.g., four or five doctors), but for large groups, it means just one or two dissenters can block a decision and nothing much gets done.

Disagreements about practice operations and future direction are common, so every group should commit to writing some method of how votes will be taken in the absence of consensus. For example, the group might be divided about whether to adopt unit-based assignments or change the hours of an evening (“swing”) shift, and a formal vote might be the only way to make a decision. It’s best if you have decided in advance issues such as what constitutes a quorum, who is eligible to vote, and whether the winning vote requires a simple or super-majority. And a formalized system of voting helps support a culture ownership.

I wrote about this originally in December 2007 and provided sample bylaws your group could modify as needed. Of course, you should keep in mind that if you are indeed employed by a larger entity such as a hospital or staffing company, you don’t have the ability to make all decisions by a vote of the group. Pay raises, staff additions, and similar decisions require support of the employer, and while a vote in support of them might influence what actually happens, it still requires the support of the employer. But there are lots of things, like the work schedule, system of allocating patients across providers, etc., that are usually best made by the group itself, and sometimes they might come down to a vote of the group.

Never Stop Recruiting and Ensure Hospitalists Themselves Are Actively Engaged in Recruiting

I wrote about recruiting originally in July 2008 when there was a shortage of hospitalists everywhere. Since then, the supply of doctors seeking work as a hospitalist has caught up with demand in many major metropolitan areas like Minneapolis and Washington, D.C.

But outside of large markets—that is, in most of the country—demand for hospitalists still far exceeds supply, and groups face ongoing staffing deficits that come with the need for existing doctors to work extra shifts and use locum tenens or other forms of temporary staffing. The potential excess supply of hospitalists in major markets may eventually trickle out and ease the shortages elsewhere, but that hasn’t happened in a big way yet. So for these places, it is crucial to devote a lot of energy and resources to recruiting.

A vital component of successful recruiting is participation in the effort by the hospitalists themselves. I think the best mindset for the hospitalists is to think of themselves as leading recruitment efforts assisted by recruiters rather than the other way around. For example, the lead hospitalist or some other designated doctor should try to respond by phone (if that’s impractical, then respond by email) to every reasonable inquiry from a new candidate within 24 hours and serve as the candidate’s principle point of communication throughout the recruitment process. The recruiter can handle details of things like arranging travel for an interview, but a hospitalist in the group should be the main source of information regarding things like the work schedule, patient volume, compensation, etc. And a hospitalist should serve as the main host during a candidate’s on-site interview.

More to Come …

Next month, I’ll address things like a written policy and procedure manual, clear reporting relationships for the hospitalist group, and roles for advanced practice clinicians (NPs and PAs). TH

Early in 2015, SHM published the updated edition of the “Key Principles and Characteristics of an Effective Hospital Medicine Group,” which is a free download via the SHM website. Every hospitalist group should use this comprehensive list of attributes as one important frame of reference to guide ongoing improvement efforts and long-range planning.

In this column and the next two, I’ll split the difference between the very brief list of top success factors for hospitalist groups I wrote about in my March 2011 column and the very comprehensive “Key Characteristics” document. I think these attributes are among the most important to support a high-performing group, yet they are sometimes overlooked or implemented poorly. They are of roughly equal importance and are listed in no particular order.

Deliberately Cultivating a Culture (or Mindset) of Practice Ownership

It’s easy for hospitalists to think of themselves as employees who just work shifts but have no need or opportunity to attend to the bigger picture of the practice or the hospital in which they operate. After all, being a good doctor for your patients is an awfully big job itself, and lots of recruitment ads tell you doctoring is all that will be expected of you. Someone else will handle everything necessary to ensure your practice is successful.

This line of thinking will limit the success of your group.

Your group will perform much better and you’re likely to find your career much more rewarding if you and your hospitalist colleagues think of yourselves as owning your practice and take an active role in managing it. You’ll still need others to manage day-to-day business affairs, but at least a portion of the hospitalists in the group should be actively involved in planning and making decisions about the group’s operations and future evolution.

I encounter hospitalist groups that have become convinced they don’t even have the opportunity to shape or influence their practice. “No one ever listens,” they say. “The hospital executives just do what they want regardless of what we say.” But in nearly every case, that is an exaggeration. Most administrative leaders desperately want hospitalist engagement and thoughtful participation in planning and decision making.

I wrote additional thoughts about the importance of a culture, or mindset, of practice ownership in August 2008. The print version of that column included a short list of questions you could ask yourself to assess whether your own group has such a culture, but it is missing from the web version and can be found at nelsonflores.com/html/quiz.html.

A Formal System of Group ‘Governance’

So many hospitalist groups rely almost entirely on consensus to make decisions. This might work well enough for a very small group (e.g., four or five doctors), but for large groups, it means just one or two dissenters can block a decision and nothing much gets done.

Disagreements about practice operations and future direction are common, so every group should commit to writing some method of how votes will be taken in the absence of consensus. For example, the group might be divided about whether to adopt unit-based assignments or change the hours of an evening (“swing”) shift, and a formal vote might be the only way to make a decision. It’s best if you have decided in advance issues such as what constitutes a quorum, who is eligible to vote, and whether the winning vote requires a simple or super-majority. And a formalized system of voting helps support a culture ownership.

I wrote about this originally in December 2007 and provided sample bylaws your group could modify as needed. Of course, you should keep in mind that if you are indeed employed by a larger entity such as a hospital or staffing company, you don’t have the ability to make all decisions by a vote of the group. Pay raises, staff additions, and similar decisions require support of the employer, and while a vote in support of them might influence what actually happens, it still requires the support of the employer. But there are lots of things, like the work schedule, system of allocating patients across providers, etc., that are usually best made by the group itself, and sometimes they might come down to a vote of the group.

Never Stop Recruiting and Ensure Hospitalists Themselves Are Actively Engaged in Recruiting

I wrote about recruiting originally in July 2008 when there was a shortage of hospitalists everywhere. Since then, the supply of doctors seeking work as a hospitalist has caught up with demand in many major metropolitan areas like Minneapolis and Washington, D.C.

But outside of large markets—that is, in most of the country—demand for hospitalists still far exceeds supply, and groups face ongoing staffing deficits that come with the need for existing doctors to work extra shifts and use locum tenens or other forms of temporary staffing. The potential excess supply of hospitalists in major markets may eventually trickle out and ease the shortages elsewhere, but that hasn’t happened in a big way yet. So for these places, it is crucial to devote a lot of energy and resources to recruiting.

A vital component of successful recruiting is participation in the effort by the hospitalists themselves. I think the best mindset for the hospitalists is to think of themselves as leading recruitment efforts assisted by recruiters rather than the other way around. For example, the lead hospitalist or some other designated doctor should try to respond by phone (if that’s impractical, then respond by email) to every reasonable inquiry from a new candidate within 24 hours and serve as the candidate’s principle point of communication throughout the recruitment process. The recruiter can handle details of things like arranging travel for an interview, but a hospitalist in the group should be the main source of information regarding things like the work schedule, patient volume, compensation, etc. And a hospitalist should serve as the main host during a candidate’s on-site interview.

More to Come …

Next month, I’ll address things like a written policy and procedure manual, clear reporting relationships for the hospitalist group, and roles for advanced practice clinicians (NPs and PAs). TH

Early in 2015, SHM published the updated edition of the “Key Principles and Characteristics of an Effective Hospital Medicine Group,” which is a free download via the SHM website. Every hospitalist group should use this comprehensive list of attributes as one important frame of reference to guide ongoing improvement efforts and long-range planning.

In this column and the next two, I’ll split the difference between the very brief list of top success factors for hospitalist groups I wrote about in my March 2011 column and the very comprehensive “Key Characteristics” document. I think these attributes are among the most important to support a high-performing group, yet they are sometimes overlooked or implemented poorly. They are of roughly equal importance and are listed in no particular order.

Deliberately Cultivating a Culture (or Mindset) of Practice Ownership

It’s easy for hospitalists to think of themselves as employees who just work shifts but have no need or opportunity to attend to the bigger picture of the practice or the hospital in which they operate. After all, being a good doctor for your patients is an awfully big job itself, and lots of recruitment ads tell you doctoring is all that will be expected of you. Someone else will handle everything necessary to ensure your practice is successful.

This line of thinking will limit the success of your group.

Your group will perform much better and you’re likely to find your career much more rewarding if you and your hospitalist colleagues think of yourselves as owning your practice and take an active role in managing it. You’ll still need others to manage day-to-day business affairs, but at least a portion of the hospitalists in the group should be actively involved in planning and making decisions about the group’s operations and future evolution.

I encounter hospitalist groups that have become convinced they don’t even have the opportunity to shape or influence their practice. “No one ever listens,” they say. “The hospital executives just do what they want regardless of what we say.” But in nearly every case, that is an exaggeration. Most administrative leaders desperately want hospitalist engagement and thoughtful participation in planning and decision making.

I wrote additional thoughts about the importance of a culture, or mindset, of practice ownership in August 2008. The print version of that column included a short list of questions you could ask yourself to assess whether your own group has such a culture, but it is missing from the web version and can be found at nelsonflores.com/html/quiz.html.

A Formal System of Group ‘Governance’

So many hospitalist groups rely almost entirely on consensus to make decisions. This might work well enough for a very small group (e.g., four or five doctors), but for large groups, it means just one or two dissenters can block a decision and nothing much gets done.

Disagreements about practice operations and future direction are common, so every group should commit to writing some method of how votes will be taken in the absence of consensus. For example, the group might be divided about whether to adopt unit-based assignments or change the hours of an evening (“swing”) shift, and a formal vote might be the only way to make a decision. It’s best if you have decided in advance issues such as what constitutes a quorum, who is eligible to vote, and whether the winning vote requires a simple or super-majority. And a formalized system of voting helps support a culture ownership.

I wrote about this originally in December 2007 and provided sample bylaws your group could modify as needed. Of course, you should keep in mind that if you are indeed employed by a larger entity such as a hospital or staffing company, you don’t have the ability to make all decisions by a vote of the group. Pay raises, staff additions, and similar decisions require support of the employer, and while a vote in support of them might influence what actually happens, it still requires the support of the employer. But there are lots of things, like the work schedule, system of allocating patients across providers, etc., that are usually best made by the group itself, and sometimes they might come down to a vote of the group.

Never Stop Recruiting and Ensure Hospitalists Themselves Are Actively Engaged in Recruiting

I wrote about recruiting originally in July 2008 when there was a shortage of hospitalists everywhere. Since then, the supply of doctors seeking work as a hospitalist has caught up with demand in many major metropolitan areas like Minneapolis and Washington, D.C.

But outside of large markets—that is, in most of the country—demand for hospitalists still far exceeds supply, and groups face ongoing staffing deficits that come with the need for existing doctors to work extra shifts and use locum tenens or other forms of temporary staffing. The potential excess supply of hospitalists in major markets may eventually trickle out and ease the shortages elsewhere, but that hasn’t happened in a big way yet. So for these places, it is crucial to devote a lot of energy and resources to recruiting.

A vital component of successful recruiting is participation in the effort by the hospitalists themselves. I think the best mindset for the hospitalists is to think of themselves as leading recruitment efforts assisted by recruiters rather than the other way around. For example, the lead hospitalist or some other designated doctor should try to respond by phone (if that’s impractical, then respond by email) to every reasonable inquiry from a new candidate within 24 hours and serve as the candidate’s principle point of communication throughout the recruitment process. The recruiter can handle details of things like arranging travel for an interview, but a hospitalist in the group should be the main source of information regarding things like the work schedule, patient volume, compensation, etc. And a hospitalist should serve as the main host during a candidate’s on-site interview.

More to Come …

Next month, I’ll address things like a written policy and procedure manual, clear reporting relationships for the hospitalist group, and roles for advanced practice clinicians (NPs and PAs). TH

NEW YORK (Reuters Health) - Opioid modulation with the combination of buprenorphine and samidorphan (ALKS 5461) improves symptoms in patients whose depression has not responded adequately to antidepressant treatment, researchers report.

"If the findings are confirmed in phase 3 studies, ALKS 5461 could be used as an augmenting agent in patients not responding to standard antidepressant therapies as an alternative to the atypical antipsychotic agents currently approved for the treatment of this population," Dr. Maurizio Fava, from Massachusetts General Hospital and Harvard Medical School, Boston, told Reuters Health by email.

Buprenorphine is a mu- and kappa-opioid partial agonist, and samidorphan blocks the mu agonist effects of buprenorphine associated with its abuse and addictive potential. A growing body of evidence implicates dysregulation of the endogenous mu- and kappa-opioid system in mood disorders.

Dr. Fava and colleagues at 31 sites in the U.S. used a sequential parallel comparison design to investigate the efficacy of buprenorphine/samidorphan (2 mg/2 mg or 8 mg/8 mg) in 142 patients with major depression inadequately responsive to antidepressant therapy.

At the end of four weeks of treatment, patients in the ALKS 5461 2 mg/2 mg group showed significantly greater improvements in Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impression severity scores, compared with patients in the placebo group. The ALKS 5461 8 mg/8 mg group showed smaller, nonsignificant improvements.

"The overall effect sizes for the 2/2 dosage were 0.50 for HAM-D and 0.54 for MADRS," the researchers noted. "The result compares favorably with results from a meta-analysis of 14 studies with atypical antipsychotics as adjunctive therapy for major depression, with reported effect sizes of 0.35 to 0.48 for individual drugs."

Treatment response rates according to HAM-D and MADRS (at least 50% reduction in scores) were highest with ALKS 5461 2 mg/2 mg treatment group, according to the February 12 onlinereport in the American Journal of Psychiatry.

Two patients (1.6%) in the placebo group and 17 patients (19.3%) in the ALKS 5461 groups discontinued because of treatment-emergent adverse events, but there was no evidence of opioid withdrawal in any patient.

"When depressed patients do not respond to standard monoamine-based therapies for depression, consider the use of an augmenting agent that modulates other systems, such as the opioid one," Dr. Fava concluded.

Dr. Jeffrey F. Scherrer, from Saint Louis University School of Medicine, St. Louis, Missouri, recently examined the association between opioid use and increased depression rates. He told Reuters Health by email, "Our analysis of opioid use and depression did not include buprenorphine among the opioid exposure variable. Therefore, it is difficult to extrapolate our results to a trial of buprenorphine/samidorphan and major depression."

"As the authors noted, the clinical trial was of short duration and the risks of depression that we have observed appears to be greatest among those patients remaining on opioids for more than 90 days," he explained. "Additional work is currently being done to determine if some opioid medications have a greater depressogenic effect than others, which further limits direct comparison of our findings to the current study."

"I will say that it is unlikely for oxycodone, codeine, and hydrocodone (which together account for more than 90% of prescribed opioids) would help depressed patients and be more likely to worsen their depression with chronic treatment," Dr. Scherrer concluded.

Alkermes sponsored the trial, employed seven coauthors, and had various relationships with the other four coauthors.

NEW YORK (Reuters Health) - Opioid modulation with the combination of buprenorphine and samidorphan (ALKS 5461) improves symptoms in patients whose depression has not responded adequately to antidepressant treatment, researchers report.

"If the findings are confirmed in phase 3 studies, ALKS 5461 could be used as an augmenting agent in patients not responding to standard antidepressant therapies as an alternative to the atypical antipsychotic agents currently approved for the treatment of this population," Dr. Maurizio Fava, from Massachusetts General Hospital and Harvard Medical School, Boston, told Reuters Health by email.

Buprenorphine is a mu- and kappa-opioid partial agonist, and samidorphan blocks the mu agonist effects of buprenorphine associated with its abuse and addictive potential. A growing body of evidence implicates dysregulation of the endogenous mu- and kappa-opioid system in mood disorders.

Dr. Fava and colleagues at 31 sites in the U.S. used a sequential parallel comparison design to investigate the efficacy of buprenorphine/samidorphan (2 mg/2 mg or 8 mg/8 mg) in 142 patients with major depression inadequately responsive to antidepressant therapy.

At the end of four weeks of treatment, patients in the ALKS 5461 2 mg/2 mg group showed significantly greater improvements in Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impression severity scores, compared with patients in the placebo group. The ALKS 5461 8 mg/8 mg group showed smaller, nonsignificant improvements.

"The overall effect sizes for the 2/2 dosage were 0.50 for HAM-D and 0.54 for MADRS," the researchers noted. "The result compares favorably with results from a meta-analysis of 14 studies with atypical antipsychotics as adjunctive therapy for major depression, with reported effect sizes of 0.35 to 0.48 for individual drugs."

Treatment response rates according to HAM-D and MADRS (at least 50% reduction in scores) were highest with ALKS 5461 2 mg/2 mg treatment group, according to the February 12 onlinereport in the American Journal of Psychiatry.

Two patients (1.6%) in the placebo group and 17 patients (19.3%) in the ALKS 5461 groups discontinued because of treatment-emergent adverse events, but there was no evidence of opioid withdrawal in any patient.

"When depressed patients do not respond to standard monoamine-based therapies for depression, consider the use of an augmenting agent that modulates other systems, such as the opioid one," Dr. Fava concluded.

Dr. Jeffrey F. Scherrer, from Saint Louis University School of Medicine, St. Louis, Missouri, recently examined the association between opioid use and increased depression rates. He told Reuters Health by email, "Our analysis of opioid use and depression did not include buprenorphine among the opioid exposure variable. Therefore, it is difficult to extrapolate our results to a trial of buprenorphine/samidorphan and major depression."

"As the authors noted, the clinical trial was of short duration and the risks of depression that we have observed appears to be greatest among those patients remaining on opioids for more than 90 days," he explained. "Additional work is currently being done to determine if some opioid medications have a greater depressogenic effect than others, which further limits direct comparison of our findings to the current study."

"I will say that it is unlikely for oxycodone, codeine, and hydrocodone (which together account for more than 90% of prescribed opioids) would help depressed patients and be more likely to worsen their depression with chronic treatment," Dr. Scherrer concluded.

Alkermes sponsored the trial, employed seven coauthors, and had various relationships with the other four coauthors.

NEW YORK (Reuters Health) - Opioid modulation with the combination of buprenorphine and samidorphan (ALKS 5461) improves symptoms in patients whose depression has not responded adequately to antidepressant treatment, researchers report.

"If the findings are confirmed in phase 3 studies, ALKS 5461 could be used as an augmenting agent in patients not responding to standard antidepressant therapies as an alternative to the atypical antipsychotic agents currently approved for the treatment of this population," Dr. Maurizio Fava, from Massachusetts General Hospital and Harvard Medical School, Boston, told Reuters Health by email.

Buprenorphine is a mu- and kappa-opioid partial agonist, and samidorphan blocks the mu agonist effects of buprenorphine associated with its abuse and addictive potential. A growing body of evidence implicates dysregulation of the endogenous mu- and kappa-opioid system in mood disorders.

Dr. Fava and colleagues at 31 sites in the U.S. used a sequential parallel comparison design to investigate the efficacy of buprenorphine/samidorphan (2 mg/2 mg or 8 mg/8 mg) in 142 patients with major depression inadequately responsive to antidepressant therapy.

At the end of four weeks of treatment, patients in the ALKS 5461 2 mg/2 mg group showed significantly greater improvements in Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impression severity scores, compared with patients in the placebo group. The ALKS 5461 8 mg/8 mg group showed smaller, nonsignificant improvements.

"The overall effect sizes for the 2/2 dosage were 0.50 for HAM-D and 0.54 for MADRS," the researchers noted. "The result compares favorably with results from a meta-analysis of 14 studies with atypical antipsychotics as adjunctive therapy for major depression, with reported effect sizes of 0.35 to 0.48 for individual drugs."

Treatment response rates according to HAM-D and MADRS (at least 50% reduction in scores) were highest with ALKS 5461 2 mg/2 mg treatment group, according to the February 12 onlinereport in the American Journal of Psychiatry.

Two patients (1.6%) in the placebo group and 17 patients (19.3%) in the ALKS 5461 groups discontinued because of treatment-emergent adverse events, but there was no evidence of opioid withdrawal in any patient.

"When depressed patients do not respond to standard monoamine-based therapies for depression, consider the use of an augmenting agent that modulates other systems, such as the opioid one," Dr. Fava concluded.

Dr. Jeffrey F. Scherrer, from Saint Louis University School of Medicine, St. Louis, Missouri, recently examined the association between opioid use and increased depression rates. He told Reuters Health by email, "Our analysis of opioid use and depression did not include buprenorphine among the opioid exposure variable. Therefore, it is difficult to extrapolate our results to a trial of buprenorphine/samidorphan and major depression."

"As the authors noted, the clinical trial was of short duration and the risks of depression that we have observed appears to be greatest among those patients remaining on opioids for more than 90 days," he explained. "Additional work is currently being done to determine if some opioid medications have a greater depressogenic effect than others, which further limits direct comparison of our findings to the current study."

"I will say that it is unlikely for oxycodone, codeine, and hydrocodone (which together account for more than 90% of prescribed opioids) would help depressed patients and be more likely to worsen their depression with chronic treatment," Dr. Scherrer concluded.

Alkermes sponsored the trial, employed seven coauthors, and had various relationships with the other four coauthors.

Researchers in the lab

Photo by Rhoda Baer

Research published in The Journal of Clinical Investigation has revealed a potential therapeutic target for an aggressive form of acute myeloid leukemia (AML).

Investigators studied AML characterized by overexpression of the gene meningioma-1 (MN1), which is not a druggable target.

The team found that MN1 overexpression induces aggressive AML that is dependent on a gene expression program controlled by 2 histone methyltransferases.

And 1 of these histone methyltransferases can be targeted by drugs currently in clinical development.

To make these discoveries, the investigators forced expression of MN1 in mice, which induced AML, and looked for changes in other genes. They found that MN1 overexpression prompted the activation of genes already linked to AML development—HoxA9 and Meis1.

HoxA9 and Meis1 are key targets of the histone methyltransferases Mll1 and Dot1l. It turned out that Mll1 and Dotl1 are essential for creating the environment MN1 needs to cause AML.

“In mice, we put MN1 in first, leading to AML,” explained study author Kathrin Bernt, MD, of the University of Colorado Anschutz Medical Campus.

“Then, we knocked out these chromatin-regulating molecules, Mll1 or Dot1l. When we did that, the leukemia collapsed.”

The investigators also studied samples from AML patients and found that samples with overexpression of MN1 and HOXA9 were sensitive to the DOT1L inhibitor EPZ004777. The drug induced dose-dependent decreases in cell growth and the fraction of cycling cells, as well as an increase in apoptosis.

Anticancer agents targeting DOT1L are already in clinical trials. One such inhibitor, EPZ-5676, is being tested in a phase 1 trial of pediatric patients with aggressive leukemias (NCT02141828).

“The existing trial targets patients with rearrangements in the gene MLL1,” Dr Bernt noted. “Our study shows another subset of patients that may benefit from this or other therapies aimed at DOT1L inhibition—namely, patients with MN1 overexpression.”

Dr Bernt added, however, that the investigators must still determine the cutoff of MN1 overexpression at which AML is susceptible to DOT1L inhibition.

“Overexpression exists along a spectrum,” she explained. “At what degree of MN1 overexpression does it become clinically significant?”

Researchers in the lab

Photo by Rhoda Baer

Research published in The Journal of Clinical Investigation has revealed a potential therapeutic target for an aggressive form of acute myeloid leukemia (AML).

Investigators studied AML characterized by overexpression of the gene meningioma-1 (MN1), which is not a druggable target.

The team found that MN1 overexpression induces aggressive AML that is dependent on a gene expression program controlled by 2 histone methyltransferases.

And 1 of these histone methyltransferases can be targeted by drugs currently in clinical development.

To make these discoveries, the investigators forced expression of MN1 in mice, which induced AML, and looked for changes in other genes. They found that MN1 overexpression prompted the activation of genes already linked to AML development—HoxA9 and Meis1.

HoxA9 and Meis1 are key targets of the histone methyltransferases Mll1 and Dot1l. It turned out that Mll1 and Dotl1 are essential for creating the environment MN1 needs to cause AML.

“In mice, we put MN1 in first, leading to AML,” explained study author Kathrin Bernt, MD, of the University of Colorado Anschutz Medical Campus.

“Then, we knocked out these chromatin-regulating molecules, Mll1 or Dot1l. When we did that, the leukemia collapsed.”

The investigators also studied samples from AML patients and found that samples with overexpression of MN1 and HOXA9 were sensitive to the DOT1L inhibitor EPZ004777. The drug induced dose-dependent decreases in cell growth and the fraction of cycling cells, as well as an increase in apoptosis.

Anticancer agents targeting DOT1L are already in clinical trials. One such inhibitor, EPZ-5676, is being tested in a phase 1 trial of pediatric patients with aggressive leukemias (NCT02141828).

“The existing trial targets patients with rearrangements in the gene MLL1,” Dr Bernt noted. “Our study shows another subset of patients that may benefit from this or other therapies aimed at DOT1L inhibition—namely, patients with MN1 overexpression.”

Dr Bernt added, however, that the investigators must still determine the cutoff of MN1 overexpression at which AML is susceptible to DOT1L inhibition.

“Overexpression exists along a spectrum,” she explained. “At what degree of MN1 overexpression does it become clinically significant?”

Researchers in the lab

Photo by Rhoda Baer

Research published in The Journal of Clinical Investigation has revealed a potential therapeutic target for an aggressive form of acute myeloid leukemia (AML).

Investigators studied AML characterized by overexpression of the gene meningioma-1 (MN1), which is not a druggable target.

The team found that MN1 overexpression induces aggressive AML that is dependent on a gene expression program controlled by 2 histone methyltransferases.

And 1 of these histone methyltransferases can be targeted by drugs currently in clinical development.

To make these discoveries, the investigators forced expression of MN1 in mice, which induced AML, and looked for changes in other genes. They found that MN1 overexpression prompted the activation of genes already linked to AML development—HoxA9 and Meis1.

HoxA9 and Meis1 are key targets of the histone methyltransferases Mll1 and Dot1l. It turned out that Mll1 and Dotl1 are essential for creating the environment MN1 needs to cause AML.

“In mice, we put MN1 in first, leading to AML,” explained study author Kathrin Bernt, MD, of the University of Colorado Anschutz Medical Campus.

“Then, we knocked out these chromatin-regulating molecules, Mll1 or Dot1l. When we did that, the leukemia collapsed.”

The investigators also studied samples from AML patients and found that samples with overexpression of MN1 and HOXA9 were sensitive to the DOT1L inhibitor EPZ004777. The drug induced dose-dependent decreases in cell growth and the fraction of cycling cells, as well as an increase in apoptosis.

Anticancer agents targeting DOT1L are already in clinical trials. One such inhibitor, EPZ-5676, is being tested in a phase 1 trial of pediatric patients with aggressive leukemias (NCT02141828).

“The existing trial targets patients with rearrangements in the gene MLL1,” Dr Bernt noted. “Our study shows another subset of patients that may benefit from this or other therapies aimed at DOT1L inhibition—namely, patients with MN1 overexpression.”

Dr Bernt added, however, that the investigators must still determine the cutoff of MN1 overexpression at which AML is susceptible to DOT1L inhibition.

“Overexpression exists along a spectrum,” she explained. “At what degree of MN1 overexpression does it become clinically significant?”

Red blood cells

The European Commission (EC) has granted marketing authorization for ferric maltol (Feraccru) to treat iron-deficiency anemia in adults with inflammatory bowel disease (IBD).

The product can now be marketed for this indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.

The company developing the drug, Shield Therapeutics, said it will begin a roll-out of commercialization in the coming months.

Feraccru contains iron in a stable ferric state as a complex with a trimaltol ligand—ferric maltol. It is formulated as 30 mg of ferric iron in a hard gelatin capsule.

The complex is designed to provide iron for uptake across the intestinal wall and transfer to the iron transport and storage proteins—transferrin and ferritin, respectively. Feraccru dissociates on uptake from the gastrointestinal tract, and ferric maltol itself does not appear to enter the systemic circulation.

Phase 3 trials

The EC’s approval of ferric maltol is based on results of 2 phase 3 studies—AEGIS 1 and AEGIS 2. The results of these studies were published in Inflammatory Bowel Diseases in March 2015.

Together, the trials included 128 adult patients with IBD (ulcerative colitis and Crohn’s disease), iron-deficiency anemia, and recorded intolerance of ferrous sulphate. They were randomized to receive either 30 mg of ferric maltol twice a day or a matched placebo capsule for 12 weeks.

The primary efficacy endpoint was the change in hemoglobin (Hb) levels from baseline to week 12. The mean improvement in Hb in the ferric maltol group compared to the placebo group was 2.25 g/dL (P<0.0001).

The absolute mean Hb concentration improved from 11.00 g/dL at baseline to 13.20 g/dL at week 12 in the ferric maltol group. In the placebo group, the mean Hb values were similar at baseline and week 12—11.10 g/dL and 11.20 g/dL, respectively.

The incidence of treatment-emergent adverse events (AEs) was 58% in the ferric maltol group and 72% in the placebo group. However, not all of these events were considered treatment-related.

AEs that were considered treatment-related occurred in 25% of ferric maltol-treated patients and 11.7% of placebo-treated patients. The most common treatment-related AEs in the ferric maltol group were abdominal pain, constipation, and flatulence—each occurring in 6.7% of patients.

“The phase 3 clinical studies clearly demonstrated Feraccru’s effectiveness,” said Andreas Stallmach, MD, of University Clinic Jena in Germany.

“[T]his pan-European marketing authorization gives treating physicians like myself the opportunity to fulfill an important and currently unmet need for patients who are unable to tolerate other oral products, as Feraccru could provide an oral alternative to intravenous iron infusion.’’

Red blood cells

The European Commission (EC) has granted marketing authorization for ferric maltol (Feraccru) to treat iron-deficiency anemia in adults with inflammatory bowel disease (IBD).

The product can now be marketed for this indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.

The company developing the drug, Shield Therapeutics, said it will begin a roll-out of commercialization in the coming months.

Feraccru contains iron in a stable ferric state as a complex with a trimaltol ligand—ferric maltol. It is formulated as 30 mg of ferric iron in a hard gelatin capsule.

The complex is designed to provide iron for uptake across the intestinal wall and transfer to the iron transport and storage proteins—transferrin and ferritin, respectively. Feraccru dissociates on uptake from the gastrointestinal tract, and ferric maltol itself does not appear to enter the systemic circulation.

Phase 3 trials

The EC’s approval of ferric maltol is based on results of 2 phase 3 studies—AEGIS 1 and AEGIS 2. The results of these studies were published in Inflammatory Bowel Diseases in March 2015.

Together, the trials included 128 adult patients with IBD (ulcerative colitis and Crohn’s disease), iron-deficiency anemia, and recorded intolerance of ferrous sulphate. They were randomized to receive either 30 mg of ferric maltol twice a day or a matched placebo capsule for 12 weeks.

The primary efficacy endpoint was the change in hemoglobin (Hb) levels from baseline to week 12. The mean improvement in Hb in the ferric maltol group compared to the placebo group was 2.25 g/dL (P<0.0001).

The absolute mean Hb concentration improved from 11.00 g/dL at baseline to 13.20 g/dL at week 12 in the ferric maltol group. In the placebo group, the mean Hb values were similar at baseline and week 12—11.10 g/dL and 11.20 g/dL, respectively.

The incidence of treatment-emergent adverse events (AEs) was 58% in the ferric maltol group and 72% in the placebo group. However, not all of these events were considered treatment-related.

AEs that were considered treatment-related occurred in 25% of ferric maltol-treated patients and 11.7% of placebo-treated patients. The most common treatment-related AEs in the ferric maltol group were abdominal pain, constipation, and flatulence—each occurring in 6.7% of patients.

“The phase 3 clinical studies clearly demonstrated Feraccru’s effectiveness,” said Andreas Stallmach, MD, of University Clinic Jena in Germany.

“[T]his pan-European marketing authorization gives treating physicians like myself the opportunity to fulfill an important and currently unmet need for patients who are unable to tolerate other oral products, as Feraccru could provide an oral alternative to intravenous iron infusion.’’

Red blood cells

The European Commission (EC) has granted marketing authorization for ferric maltol (Feraccru) to treat iron-deficiency anemia in adults with inflammatory bowel disease (IBD).

The product can now be marketed for this indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.

The company developing the drug, Shield Therapeutics, said it will begin a roll-out of commercialization in the coming months.

Feraccru contains iron in a stable ferric state as a complex with a trimaltol ligand—ferric maltol. It is formulated as 30 mg of ferric iron in a hard gelatin capsule.

The complex is designed to provide iron for uptake across the intestinal wall and transfer to the iron transport and storage proteins—transferrin and ferritin, respectively. Feraccru dissociates on uptake from the gastrointestinal tract, and ferric maltol itself does not appear to enter the systemic circulation.

Phase 3 trials

The EC’s approval of ferric maltol is based on results of 2 phase 3 studies—AEGIS 1 and AEGIS 2. The results of these studies were published in Inflammatory Bowel Diseases in March 2015.

Together, the trials included 128 adult patients with IBD (ulcerative colitis and Crohn’s disease), iron-deficiency anemia, and recorded intolerance of ferrous sulphate. They were randomized to receive either 30 mg of ferric maltol twice a day or a matched placebo capsule for 12 weeks.

The primary efficacy endpoint was the change in hemoglobin (Hb) levels from baseline to week 12. The mean improvement in Hb in the ferric maltol group compared to the placebo group was 2.25 g/dL (P<0.0001).

The absolute mean Hb concentration improved from 11.00 g/dL at baseline to 13.20 g/dL at week 12 in the ferric maltol group. In the placebo group, the mean Hb values were similar at baseline and week 12—11.10 g/dL and 11.20 g/dL, respectively.

The incidence of treatment-emergent adverse events (AEs) was 58% in the ferric maltol group and 72% in the placebo group. However, not all of these events were considered treatment-related.

AEs that were considered treatment-related occurred in 25% of ferric maltol-treated patients and 11.7% of placebo-treated patients. The most common treatment-related AEs in the ferric maltol group were abdominal pain, constipation, and flatulence—each occurring in 6.7% of patients.

“The phase 3 clinical studies clearly demonstrated Feraccru’s effectiveness,” said Andreas Stallmach, MD, of University Clinic Jena in Germany.

“[T]his pan-European marketing authorization gives treating physicians like myself the opportunity to fulfill an important and currently unmet need for patients who are unable to tolerate other oral products, as Feraccru could provide an oral alternative to intravenous iron infusion.’’

Cells infected with

Plasmodium vivax

Image by Mae Melvin

Results of a phase 1 trial suggest a vaccine candidate does not prevent Plasmodium vivax malaria.

The vaccine, VMP001/AS01_B, did not prevent malaria in any of the 30 subjects tested, although it did significantly delay parasitemia in 59% of subjects.

Lieutenant Colonel Jason W. Bennett, of the Walter Reed Army Institute

of Research (WRAIR) in Silver Spring, Maryland, and his colleagues reported these results in PLOS Neglected Tropical Diseases.

The vaccine antigen VMP001 is an Escherichia coli-produced, synthetic, chimeric, recombinant protein that incorporates the 3 major domains of circumsporozoite protein but is distinct from the native molecule. The VMP001 antigen was adjuvanted with AS01_B, a proprietary liposome-based adjuvant system from GlaxoSmithKline.

For this phase 1 study, the investigators tested VMP001/AS01_B in 30 healthy volunteers. The subjects received 3 intramuscular injections of VMP001 at 15 μg (n=10), 30 μg (n=10), or 60 μg (n=10), respectively, all formulated in 500 μL of AS01_B at each immunization.

Fourteen days after the third immunization, the subjects were exposed to mosquitoes carrying P vivax. Six non-vaccinated control subjects were exposed to the mosquitoes as well.

The investigators said VMP001/AS01_B was well tolerated and generated robust immune responses. However, it did not protect the subjects from malaria infection.

Still, the vaccine induced a “small but significant” delay in time to parasitemia in 59% of vaccinated subjects, when compared to controls.

Colonel Robert Paris, director of the US Military Malaria Research Program at WRAIR, believes the investigators can use the results of this study to design a better vaccine for P vivax malaria.

“Findings from the analysis of the immune response of vaccinated subjects have given us clues to improve vaccine candidates,” he said. “[S]tudies are now underway at WRAIR to develop next-generation vivax vaccines.”

Cells infected with

Plasmodium vivax

Image by Mae Melvin

Results of a phase 1 trial suggest a vaccine candidate does not prevent Plasmodium vivax malaria.

The vaccine, VMP001/AS01_B, did not prevent malaria in any of the 30 subjects tested, although it did significantly delay parasitemia in 59% of subjects.

Lieutenant Colonel Jason W. Bennett, of the Walter Reed Army Institute

of Research (WRAIR) in Silver Spring, Maryland, and his colleagues reported these results in PLOS Neglected Tropical Diseases.

The vaccine antigen VMP001 is an Escherichia coli-produced, synthetic, chimeric, recombinant protein that incorporates the 3 major domains of circumsporozoite protein but is distinct from the native molecule. The VMP001 antigen was adjuvanted with AS01_B, a proprietary liposome-based adjuvant system from GlaxoSmithKline.

For this phase 1 study, the investigators tested VMP001/AS01_B in 30 healthy volunteers. The subjects received 3 intramuscular injections of VMP001 at 15 μg (n=10), 30 μg (n=10), or 60 μg (n=10), respectively, all formulated in 500 μL of AS01_B at each immunization.

Fourteen days after the third immunization, the subjects were exposed to mosquitoes carrying P vivax. Six non-vaccinated control subjects were exposed to the mosquitoes as well.

The investigators said VMP001/AS01_B was well tolerated and generated robust immune responses. However, it did not protect the subjects from malaria infection.

Still, the vaccine induced a “small but significant” delay in time to parasitemia in 59% of vaccinated subjects, when compared to controls.

Colonel Robert Paris, director of the US Military Malaria Research Program at WRAIR, believes the investigators can use the results of this study to design a better vaccine for P vivax malaria.

“Findings from the analysis of the immune response of vaccinated subjects have given us clues to improve vaccine candidates,” he said. “[S]tudies are now underway at WRAIR to develop next-generation vivax vaccines.”

Cells infected with

Plasmodium vivax

Image by Mae Melvin

Results of a phase 1 trial suggest a vaccine candidate does not prevent Plasmodium vivax malaria.

The vaccine, VMP001/AS01_B, did not prevent malaria in any of the 30 subjects tested, although it did significantly delay parasitemia in 59% of subjects.

Lieutenant Colonel Jason W. Bennett, of the Walter Reed Army Institute

of Research (WRAIR) in Silver Spring, Maryland, and his colleagues reported these results in PLOS Neglected Tropical Diseases.

The vaccine antigen VMP001 is an Escherichia coli-produced, synthetic, chimeric, recombinant protein that incorporates the 3 major domains of circumsporozoite protein but is distinct from the native molecule. The VMP001 antigen was adjuvanted with AS01_B, a proprietary liposome-based adjuvant system from GlaxoSmithKline.

For this phase 1 study, the investigators tested VMP001/AS01_B in 30 healthy volunteers. The subjects received 3 intramuscular injections of VMP001 at 15 μg (n=10), 30 μg (n=10), or 60 μg (n=10), respectively, all formulated in 500 μL of AS01_B at each immunization.

Fourteen days after the third immunization, the subjects were exposed to mosquitoes carrying P vivax. Six non-vaccinated control subjects were exposed to the mosquitoes as well.

The investigators said VMP001/AS01_B was well tolerated and generated robust immune responses. However, it did not protect the subjects from malaria infection.

Still, the vaccine induced a “small but significant” delay in time to parasitemia in 59% of vaccinated subjects, when compared to controls.

Colonel Robert Paris, director of the US Military Malaria Research Program at WRAIR, believes the investigators can use the results of this study to design a better vaccine for P vivax malaria.

“Findings from the analysis of the immune response of vaccinated subjects have given us clues to improve vaccine candidates,” he said. “[S]tudies are now underway at WRAIR to develop next-generation vivax vaccines.”

Clinical question: Does acetazolamide decrease the duration of mechanical ventilation for patients with chronic obstructive pulmonary disease and metabolic alkalosis?

Bottom line: Although acetazolamide effectively decreased the levels of serum bicarbonate and the number of days with metabolic alkalosis in critically ill patients with chronic obstructive pulmonary disease (COPD) on mechanical ventilation, it did not produce a statistically significant difference in the duration of mechanical ventilation. However, this lack of statistical significance may have been due to an underpowered study. (LOE = 1b-)

Reference: Faisy C, Meziani F, Planquette B, et al, for the DIABOLO Investigators. Effect of acetazolamide vs placebo on duration of invasive mechanical ventilation among patients with chronic obstructive pulmonary disease. JAMA 2016;315(5):480-488.

Study design: Randomized controlled trial (double-blinded)

Funding source: Industry + govt

Allocation: Concealed

Setting: Inpatient (ICU only)

Synopsis:

Acetazolamide is used as a respiratory stimulant for patients with COPD and metabolic alkalosis because of its ability to reduce serum bicarbonate, which may lead to a rise in minute ventilation. However, its clinical benefit has not been demonstrated previously in controlled trials.

Using concealed allocation, these investigators randomized patients with COPD who required invasive mechanical ventilation to receive either acetazolamide 500 mg intravenously twice daily (1000 mg if loop diuretics were also prescribed) or matching placebo up to 28 days. Only those patients found to have pure or mixed metabolic alkalosis received the treatment. The intention-to-treat population consisted of 380 patients and baseline characteristics were similar in both groups. The use of acetazolamide led to decreased levels of serum bicarbonate and fewer days with metabolic alkalosis but did not improve respiratory parameters such as respiratory rate, tidal volume, or minute ventilation.

For the primary outcome of duration of mechanical ventilation, the magnitude of the difference between the 2 groups was large, suggesting a clinically important effect, but the difference did not reach statistical significance (between-group difference -16 hours with acetazolamide; 95% CI -36.5 to 4.0 hours). The lack of statistical significance may be due to an underpowered study because of fewer-than-expected patients who received the treatment (more than 20% of patients in each group did not receive the assigned treatment because of lack of metabolic alkalosis or temporary contraindications) and a shorter-than-anticipated duration of mechanical ventilation in the placebo group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question: Does acetazolamide decrease the duration of mechanical ventilation for patients with chronic obstructive pulmonary disease and metabolic alkalosis?

Bottom line: Although acetazolamide effectively decreased the levels of serum bicarbonate and the number of days with metabolic alkalosis in critically ill patients with chronic obstructive pulmonary disease (COPD) on mechanical ventilation, it did not produce a statistically significant difference in the duration of mechanical ventilation. However, this lack of statistical significance may have been due to an underpowered study. (LOE = 1b-)

Reference: Faisy C, Meziani F, Planquette B, et al, for the DIABOLO Investigators. Effect of acetazolamide vs placebo on duration of invasive mechanical ventilation among patients with chronic obstructive pulmonary disease. JAMA 2016;315(5):480-488.

Study design: Randomized controlled trial (double-blinded)

Funding source: Industry + govt

Allocation: Concealed

Setting: Inpatient (ICU only)

Synopsis:

Acetazolamide is used as a respiratory stimulant for patients with COPD and metabolic alkalosis because of its ability to reduce serum bicarbonate, which may lead to a rise in minute ventilation. However, its clinical benefit has not been demonstrated previously in controlled trials.

Using concealed allocation, these investigators randomized patients with COPD who required invasive mechanical ventilation to receive either acetazolamide 500 mg intravenously twice daily (1000 mg if loop diuretics were also prescribed) or matching placebo up to 28 days. Only those patients found to have pure or mixed metabolic alkalosis received the treatment. The intention-to-treat population consisted of 380 patients and baseline characteristics were similar in both groups. The use of acetazolamide led to decreased levels of serum bicarbonate and fewer days with metabolic alkalosis but did not improve respiratory parameters such as respiratory rate, tidal volume, or minute ventilation.

For the primary outcome of duration of mechanical ventilation, the magnitude of the difference between the 2 groups was large, suggesting a clinically important effect, but the difference did not reach statistical significance (between-group difference -16 hours with acetazolamide; 95% CI -36.5 to 4.0 hours). The lack of statistical significance may be due to an underpowered study because of fewer-than-expected patients who received the treatment (more than 20% of patients in each group did not receive the assigned treatment because of lack of metabolic alkalosis or temporary contraindications) and a shorter-than-anticipated duration of mechanical ventilation in the placebo group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question: Does acetazolamide decrease the duration of mechanical ventilation for patients with chronic obstructive pulmonary disease and metabolic alkalosis?

Bottom line: Although acetazolamide effectively decreased the levels of serum bicarbonate and the number of days with metabolic alkalosis in critically ill patients with chronic obstructive pulmonary disease (COPD) on mechanical ventilation, it did not produce a statistically significant difference in the duration of mechanical ventilation. However, this lack of statistical significance may have been due to an underpowered study. (LOE = 1b-)

Reference: Faisy C, Meziani F, Planquette B, et al, for the DIABOLO Investigators. Effect of acetazolamide vs placebo on duration of invasive mechanical ventilation among patients with chronic obstructive pulmonary disease. JAMA 2016;315(5):480-488.

Study design: Randomized controlled trial (double-blinded)

Funding source: Industry + govt

Allocation: Concealed

Setting: Inpatient (ICU only)

Synopsis:

Acetazolamide is used as a respiratory stimulant for patients with COPD and metabolic alkalosis because of its ability to reduce serum bicarbonate, which may lead to a rise in minute ventilation. However, its clinical benefit has not been demonstrated previously in controlled trials.

Using concealed allocation, these investigators randomized patients with COPD who required invasive mechanical ventilation to receive either acetazolamide 500 mg intravenously twice daily (1000 mg if loop diuretics were also prescribed) or matching placebo up to 28 days. Only those patients found to have pure or mixed metabolic alkalosis received the treatment. The intention-to-treat population consisted of 380 patients and baseline characteristics were similar in both groups. The use of acetazolamide led to decreased levels of serum bicarbonate and fewer days with metabolic alkalosis but did not improve respiratory parameters such as respiratory rate, tidal volume, or minute ventilation.

For the primary outcome of duration of mechanical ventilation, the magnitude of the difference between the 2 groups was large, suggesting a clinically important effect, but the difference did not reach statistical significance (between-group difference -16 hours with acetazolamide; 95% CI -36.5 to 4.0 hours). The lack of statistical significance may be due to an underpowered study because of fewer-than-expected patients who received the treatment (more than 20% of patients in each group did not receive the assigned treatment because of lack of metabolic alkalosis or temporary contraindications) and a shorter-than-anticipated duration of mechanical ventilation in the placebo group.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question: Is tamsulosin effective in the management of distal ureteric stones?

Bottom line: Tamsulosin promotes stone passage of ureteric stones that are 5 mm to 10 mm. You would need to treat 5 patients with tamsulosin to cause the expulsion of one such stone. Stones smaller than 5 mm have a high rate of spontaneous passage without any intervention. (LOE = 1b-)

Reference: Furyk JS, Chu K, Banks C et al. Distal ureteric stones and tamsulosin: a double-blind, placebo-controlled, randomized, multicenter trial. Ann Emerg Med 2016;67(1):86-95.

Study design: Randomized controlled trial (double-blinded)

Funding source: Foundation

Allocation: Concealed

Setting: Outpatient (primary care)

Synopsis: These authors recruited adult patients who presented to the emergency department with symptoms and imaging consistent with distal ureteric stones. Patients with fever, hypotension, stones larger than 10 mm, or kidney disease were excluded. Using concealed allocation, the investigators randomized the patients to receive either tamsulosin 0.4 mg daily or matching placebo for 28 days or until stone passage. The 2 groups had similar baseline characteristics and analysis was by intention to treat.

The primary outcome was stone expulsion as confirmed by computed tomography (CT) and time to stone expulsion was defined by self-reported passage of stone or 48-hour pain-free period. Compliance to the study medications was poor in both groups, and almost one-fifth of the patients did not have follow-up imaging. Of the approximately 80% of patients in each group who underwent follow-up CT, there was no difference in the percentage of patients with passed stones (87% in the tamsulosin group vs 82% in the placebo group; P = .22). In the subset of patients with larger stones (5 mm -10 mm), the tamsulosin group had a significantly higher rate of stone passage than the placebo group (83% vs 61%; P = .03). There were no significant differences detected in time to stone passage, pain, analgesia requirements, need for urological intervention, or adverse events.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question: Is tamsulosin effective in the management of distal ureteric stones?

Bottom line: Tamsulosin promotes stone passage of ureteric stones that are 5 mm to 10 mm. You would need to treat 5 patients with tamsulosin to cause the expulsion of one such stone. Stones smaller than 5 mm have a high rate of spontaneous passage without any intervention. (LOE = 1b-)

Reference: Furyk JS, Chu K, Banks C et al. Distal ureteric stones and tamsulosin: a double-blind, placebo-controlled, randomized, multicenter trial. Ann Emerg Med 2016;67(1):86-95.

Study design: Randomized controlled trial (double-blinded)

Funding source: Foundation

Allocation: Concealed

Setting: Outpatient (primary care)

Synopsis: These authors recruited adult patients who presented to the emergency department with symptoms and imaging consistent with distal ureteric stones. Patients with fever, hypotension, stones larger than 10 mm, or kidney disease were excluded. Using concealed allocation, the investigators randomized the patients to receive either tamsulosin 0.4 mg daily or matching placebo for 28 days or until stone passage. The 2 groups had similar baseline characteristics and analysis was by intention to treat.

The primary outcome was stone expulsion as confirmed by computed tomography (CT) and time to stone expulsion was defined by self-reported passage of stone or 48-hour pain-free period. Compliance to the study medications was poor in both groups, and almost one-fifth of the patients did not have follow-up imaging. Of the approximately 80% of patients in each group who underwent follow-up CT, there was no difference in the percentage of patients with passed stones (87% in the tamsulosin group vs 82% in the placebo group; P = .22). In the subset of patients with larger stones (5 mm -10 mm), the tamsulosin group had a significantly higher rate of stone passage than the placebo group (83% vs 61%; P = .03). There were no significant differences detected in time to stone passage, pain, analgesia requirements, need for urological intervention, or adverse events.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question: Is tamsulosin effective in the management of distal ureteric stones?

Bottom line: Tamsulosin promotes stone passage of ureteric stones that are 5 mm to 10 mm. You would need to treat 5 patients with tamsulosin to cause the expulsion of one such stone. Stones smaller than 5 mm have a high rate of spontaneous passage without any intervention. (LOE = 1b-)

Reference: Furyk JS, Chu K, Banks C et al. Distal ureteric stones and tamsulosin: a double-blind, placebo-controlled, randomized, multicenter trial. Ann Emerg Med 2016;67(1):86-95.

Study design: Randomized controlled trial (double-blinded)

Funding source: Foundation

Allocation: Concealed

Setting: Outpatient (primary care)

Synopsis: These authors recruited adult patients who presented to the emergency department with symptoms and imaging consistent with distal ureteric stones. Patients with fever, hypotension, stones larger than 10 mm, or kidney disease were excluded. Using concealed allocation, the investigators randomized the patients to receive either tamsulosin 0.4 mg daily or matching placebo for 28 days or until stone passage. The 2 groups had similar baseline characteristics and analysis was by intention to treat.

The primary outcome was stone expulsion as confirmed by computed tomography (CT) and time to stone expulsion was defined by self-reported passage of stone or 48-hour pain-free period. Compliance to the study medications was poor in both groups, and almost one-fifth of the patients did not have follow-up imaging. Of the approximately 80% of patients in each group who underwent follow-up CT, there was no difference in the percentage of patients with passed stones (87% in the tamsulosin group vs 82% in the placebo group; P = .22). In the subset of patients with larger stones (5 mm -10 mm), the tamsulosin group had a significantly higher rate of stone passage than the placebo group (83% vs 61%; P = .03). There were no significant differences detected in time to stone passage, pain, analgesia requirements, need for urological intervention, or adverse events.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Embattled scope maker Olympus Corp., already under federal investigation for its role in superbug outbreaks, has agreed to pay $646 million to resolve criminal and civil probes into illegal kickbacks and bribes to doctors and hospitals.

Federal prosecutors said Tuesday that the company’s settlement is the largest ever for violations of the U.S. anti-kickback law. A portion of the company’s payout, $22.8 million, will resolve foreign bribery allegations in Latin America.

U.S. investigators said the company’s “greed-fueled kickback scheme” from 2006 to 2011 used grants, consulting deals, trips to Japan, lavish gifts, and free equipment to induce influential doctors to order more Olympus devices at prominent hospitals and keep out competitors.

After a key doctor for a Midwest hospital system took a week-long trip to Japan and received a company grant, an Olympus vice president wrote an internal email in 2006 that said, “We have received all of the orders expected and have kept (a competitor) completely out of the (Midwestern hospital) system. Hooray!”

The federal complaint against Olympus mentioned similar scenarios at a prominent California institution and a New York medical center, but the exact names were redacted.

The violations produced about $600 million in sales and $230 million in gross profits for Olympus, federal officials said.

Federal prosecutors credited the help of a former compliance officer at Olympus, John Slowik, who filed a whistle-blower case against the company under seal in 2010.

Olympus agreed to a corporate-integrity agreement and the appointment of an independent monitor.

“Olympus leadership acknowledges the company’s responsibility for the past conduct, which does not represent the values of Olympus or its employees,” Nacho Abia, chief executive of the Olympus Corp. of the Americas unit in Center Valley, Pa., said in a statement. “Olympus is committed to complying with all laws and regulations and to adhering to our own rigorous code of conduct.”

Olympus has come under fire for failing to alert U.S. regulators and hospitals sooner about the risks of infection from its duodenoscopes, a gastrointestinal scope that has proven difficult to clean of dangerous bacteria because of its intricate design.

A Senate investigation released in January identified 19 scope-related outbreaks at U.S. medical centers during 2012-2015 that sickened nearly 200 patients with drug-resistant infections.

Olympus announced in January it would recall its duodenoscopes nationwide and make repairs to improve patient safety. The company controls 85% of the U.S. market for gastrointestinal scopes.

Last year, the Tokyo company disclosed it had received a subpoena from federal prosecutors in March 2015 seeking “information relating to duodenoscopes that Olympus manufactures and sells.”

This article was originally published by Kaiser Health News, a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.

Embattled scope maker Olympus Corp., already under federal investigation for its role in superbug outbreaks, has agreed to pay $646 million to resolve criminal and civil probes into illegal kickbacks and bribes to doctors and hospitals.

Federal prosecutors said Tuesday that the company’s settlement is the largest ever for violations of the U.S. anti-kickback law. A portion of the company’s payout, $22.8 million, will resolve foreign bribery allegations in Latin America.

U.S. investigators said the company’s “greed-fueled kickback scheme” from 2006 to 2011 used grants, consulting deals, trips to Japan, lavish gifts, and free equipment to induce influential doctors to order more Olympus devices at prominent hospitals and keep out competitors.

After a key doctor for a Midwest hospital system took a week-long trip to Japan and received a company grant, an Olympus vice president wrote an internal email in 2006 that said, “We have received all of the orders expected and have kept (a competitor) completely out of the (Midwestern hospital) system. Hooray!”

The federal complaint against Olympus mentioned similar scenarios at a prominent California institution and a New York medical center, but the exact names were redacted.

The violations produced about $600 million in sales and $230 million in gross profits for Olympus, federal officials said.

Federal prosecutors credited the help of a former compliance officer at Olympus, John Slowik, who filed a whistle-blower case against the company under seal in 2010.

Olympus agreed to a corporate-integrity agreement and the appointment of an independent monitor.

“Olympus leadership acknowledges the company’s responsibility for the past conduct, which does not represent the values of Olympus or its employees,” Nacho Abia, chief executive of the Olympus Corp. of the Americas unit in Center Valley, Pa., said in a statement. “Olympus is committed to complying with all laws and regulations and to adhering to our own rigorous code of conduct.”

Olympus has come under fire for failing to alert U.S. regulators and hospitals sooner about the risks of infection from its duodenoscopes, a gastrointestinal scope that has proven difficult to clean of dangerous bacteria because of its intricate design.

A Senate investigation released in January identified 19 scope-related outbreaks at U.S. medical centers during 2012-2015 that sickened nearly 200 patients with drug-resistant infections.

Olympus announced in January it would recall its duodenoscopes nationwide and make repairs to improve patient safety. The company controls 85% of the U.S. market for gastrointestinal scopes.

Last year, the Tokyo company disclosed it had received a subpoena from federal prosecutors in March 2015 seeking “information relating to duodenoscopes that Olympus manufactures and sells.”

This article was originally published by Kaiser Health News, a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.

Embattled scope maker Olympus Corp., already under federal investigation for its role in superbug outbreaks, has agreed to pay $646 million to resolve criminal and civil probes into illegal kickbacks and bribes to doctors and hospitals.

Federal prosecutors said Tuesday that the company’s settlement is the largest ever for violations of the U.S. anti-kickback law. A portion of the company’s payout, $22.8 million, will resolve foreign bribery allegations in Latin America.

U.S. investigators said the company’s “greed-fueled kickback scheme” from 2006 to 2011 used grants, consulting deals, trips to Japan, lavish gifts, and free equipment to induce influential doctors to order more Olympus devices at prominent hospitals and keep out competitors.

After a key doctor for a Midwest hospital system took a week-long trip to Japan and received a company grant, an Olympus vice president wrote an internal email in 2006 that said, “We have received all of the orders expected and have kept (a competitor) completely out of the (Midwestern hospital) system. Hooray!”

The federal complaint against Olympus mentioned similar scenarios at a prominent California institution and a New York medical center, but the exact names were redacted.

The violations produced about $600 million in sales and $230 million in gross profits for Olympus, federal officials said.

Federal prosecutors credited the help of a former compliance officer at Olympus, John Slowik, who filed a whistle-blower case against the company under seal in 2010.

Olympus agreed to a corporate-integrity agreement and the appointment of an independent monitor.

“Olympus leadership acknowledges the company’s responsibility for the past conduct, which does not represent the values of Olympus or its employees,” Nacho Abia, chief executive of the Olympus Corp. of the Americas unit in Center Valley, Pa., said in a statement. “Olympus is committed to complying with all laws and regulations and to adhering to our own rigorous code of conduct.”

Olympus has come under fire for failing to alert U.S. regulators and hospitals sooner about the risks of infection from its duodenoscopes, a gastrointestinal scope that has proven difficult to clean of dangerous bacteria because of its intricate design.

A Senate investigation released in January identified 19 scope-related outbreaks at U.S. medical centers during 2012-2015 that sickened nearly 200 patients with drug-resistant infections.

Olympus announced in January it would recall its duodenoscopes nationwide and make repairs to improve patient safety. The company controls 85% of the U.S. market for gastrointestinal scopes.

Last year, the Tokyo company disclosed it had received a subpoena from federal prosecutors in March 2015 seeking “information relating to duodenoscopes that Olympus manufactures and sells.”

This article was originally published by Kaiser Health News, a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.

AGA Legacy Society members are showing their gratitude for what funding and research has brought to our specialty by giving back.

Legacy Society members are the most generous individual donors to the AGA Research Foundation. Members of the AGA Legacy Society provide tax-deductible gifts to the AGA Research Foundation of $25,000 or more (payable over 5 years) or $50,000 or more in a planned gift, such as a bequest.

The AGA Research Foundation’s mission is to raise funds to support young researchers in gastroenterology and hepatology. Richard M. Peek, Jr., M.D., AGAF, Legacy Society member said, “I have a huge appreciation for the AGA Research Foundation, because they were the first foundation that really took a chance on my research. Today, I am proud to be a donor myself because I know it is making a difference [for] yet another young investigator.”

Donors who make gifts at the Legacy Society level before DDW will receive an invitation to the annual Benefactors’ Dinner at The Don Room and Terrace at El Cortez in San Diego. Individuals interested in learning more about Legacy Society membership may contact Stacey Hinton Tuneski, Senior Director of Development at [email protected] or via phone (301) 222-4005.

A celebration of research support

Beginning with a memorable gathering at the United States Library of Congress in 2007, the Benefactors’ Dinner has welcomed members of the AGA Legacy Society and other AGA dignitaries to special locations nationwide. The Don Room and Terrace at El Cortez will be the location of the 2016 AGA Research Foundation Benefactors’ Dinner during DDW in San Diego. Guests will enjoy a wonderful evening in the historic setting that has hosted dignitaries since 1927. Members of the AGA Legacy Society will be among the distinguished honorees at the annual event.

AGA Legacy Society members are showing their gratitude for what funding and research has brought to our specialty by giving back.

Legacy Society members are the most generous individual donors to the AGA Research Foundation. Members of the AGA Legacy Society provide tax-deductible gifts to the AGA Research Foundation of $25,000 or more (payable over 5 years) or $50,000 or more in a planned gift, such as a bequest.

The AGA Research Foundation’s mission is to raise funds to support young researchers in gastroenterology and hepatology. Richard M. Peek, Jr., M.D., AGAF, Legacy Society member said, “I have a huge appreciation for the AGA Research Foundation, because they were the first foundation that really took a chance on my research. Today, I am proud to be a donor myself because I know it is making a difference [for] yet another young investigator.”

Donors who make gifts at the Legacy Society level before DDW will receive an invitation to the annual Benefactors’ Dinner at The Don Room and Terrace at El Cortez in San Diego. Individuals interested in learning more about Legacy Society membership may contact Stacey Hinton Tuneski, Senior Director of Development at [email protected] or via phone (301) 222-4005.

A celebration of research support

Beginning with a memorable gathering at the United States Library of Congress in 2007, the Benefactors’ Dinner has welcomed members of the AGA Legacy Society and other AGA dignitaries to special locations nationwide. The Don Room and Terrace at El Cortez will be the location of the 2016 AGA Research Foundation Benefactors’ Dinner during DDW in San Diego. Guests will enjoy a wonderful evening in the historic setting that has hosted dignitaries since 1927. Members of the AGA Legacy Society will be among the distinguished honorees at the annual event.

AGA Legacy Society members are showing their gratitude for what funding and research has brought to our specialty by giving back.

Legacy Society members are the most generous individual donors to the AGA Research Foundation. Members of the AGA Legacy Society provide tax-deductible gifts to the AGA Research Foundation of $25,000 or more (payable over 5 years) or $50,000 or more in a planned gift, such as a bequest.

The AGA Research Foundation’s mission is to raise funds to support young researchers in gastroenterology and hepatology. Richard M. Peek, Jr., M.D., AGAF, Legacy Society member said, “I have a huge appreciation for the AGA Research Foundation, because they were the first foundation that really took a chance on my research. Today, I am proud to be a donor myself because I know it is making a difference [for] yet another young investigator.”

Donors who make gifts at the Legacy Society level before DDW will receive an invitation to the annual Benefactors’ Dinner at The Don Room and Terrace at El Cortez in San Diego. Individuals interested in learning more about Legacy Society membership may contact Stacey Hinton Tuneski, Senior Director of Development at [email protected] or via phone (301) 222-4005.

A celebration of research support

Beginning with a memorable gathering at the United States Library of Congress in 2007, the Benefactors’ Dinner has welcomed members of the AGA Legacy Society and other AGA dignitaries to special locations nationwide. The Don Room and Terrace at El Cortez will be the location of the 2016 AGA Research Foundation Benefactors’ Dinner during DDW in San Diego. Guests will enjoy a wonderful evening in the historic setting that has hosted dignitaries since 1927. Members of the AGA Legacy Society will be among the distinguished honorees at the annual event.