BRAF inhibitor (BRAFi) combined with MEK inhibitor (MEKi) are used to treat melanomas harboring (V600E) mutation. While response is high, the majority of them relapsed. We found novel mechanisms to treat BRAFi resistant (BR) patients.

Five BR cells were established from known BRAF mutant cell lines A375, MEL-1220, A2058, UACC-62, and SKMEL28 by long-term exposure to BRAFi. These BR cells are hypersensitive to ADI-PEG20, an enzyme which degrades arginine to citrulline. ADI-PEG20 treatment resulted in 10-30% increase in apoptosis (Annexin V/PI) in BR cells compared to their paternal cells. The mechanisms involved are as follows: All BR cells express very low levels or do not express argininosuccinate synthetase (ASS, a key enzyme to generate arginine from citrulline) and also have attenuated glucose uptake. Thus, these BR cells rely primarily on exogenous arginine. Importantly, their ability to undergo autophagy upon nutritional stress is also impaired. The underlying mechanism for low levels of ASS is due to diminished c-Myc expression,a positive regulator for ASS. Additionally, AMPK-α 1, which governed autophagy and glucose uptake, was attenuated in BR cells. Overexpression of AMPK-α 1 using plasmid transfection in A2058BR and MEL-1220BR cells rescued 8-28% ADI-PEG20-induced apoptosis and enhanced autophagosome formation. Conversely, knockdown of AMPK-α 1 significantly enhanced ADI-PEG20-reduced cell viability in A2058 and MEL-1220 cells through attenuation of autophagy and glucose uptake. This is evidenced by decreased GLUT1 and LC3-II expression, and low activity of 2-NBDG uptake seen in BR cells. BMR (BRAF and MEK inhibitor) resistant cells also shared similar biochemical changes. Immunohistochemical staining further confirmed lower levels of ASS and AMPK-α 1 in A2058BR, BMR and in tumor tissues from 10 BR patients relative to their parental counterparts (average H-scores of ASS and AMPK in parental tissues vs. BR tissues are 58.2 vs. 7.8, and 146 vs. 78.3, respectively, P < 0.03). Importantly, these findings also apply to cell lines and tumor samples from patients who failed both BRAF and MEK inhibitor.

In summary, our data suggest that attenuated AMPK-α 1 mediated autophagy and glucose uptake and decreased c-Myc mediated ASS re-expression sensitize BR cells to arginine deprivation, and can be used as salvage therapy for BR patients.

Supported by 1RO1CA152197 and VA Merit Review BLR&D11860649.

BRAF inhibitor (BRAFi) combined with MEK inhibitor (MEKi) are used to treat melanomas harboring (V600E) mutation. While response is high, the majority of them relapsed. We found novel mechanisms to treat BRAFi resistant (BR) patients.

Five BR cells were established from known BRAF mutant cell lines A375, MEL-1220, A2058, UACC-62, and SKMEL28 by long-term exposure to BRAFi. These BR cells are hypersensitive to ADI-PEG20, an enzyme which degrades arginine to citrulline. ADI-PEG20 treatment resulted in 10-30% increase in apoptosis (Annexin V/PI) in BR cells compared to their paternal cells. The mechanisms involved are as follows: All BR cells express very low levels or do not express argininosuccinate synthetase (ASS, a key enzyme to generate arginine from citrulline) and also have attenuated glucose uptake. Thus, these BR cells rely primarily on exogenous arginine. Importantly, their ability to undergo autophagy upon nutritional stress is also impaired. The underlying mechanism for low levels of ASS is due to diminished c-Myc expression,a positive regulator for ASS. Additionally, AMPK-α 1, which governed autophagy and glucose uptake, was attenuated in BR cells. Overexpression of AMPK-α 1 using plasmid transfection in A2058BR and MEL-1220BR cells rescued 8-28% ADI-PEG20-induced apoptosis and enhanced autophagosome formation. Conversely, knockdown of AMPK-α 1 significantly enhanced ADI-PEG20-reduced cell viability in A2058 and MEL-1220 cells through attenuation of autophagy and glucose uptake. This is evidenced by decreased GLUT1 and LC3-II expression, and low activity of 2-NBDG uptake seen in BR cells. BMR (BRAF and MEK inhibitor) resistant cells also shared similar biochemical changes. Immunohistochemical staining further confirmed lower levels of ASS and AMPK-α 1 in A2058BR, BMR and in tumor tissues from 10 BR patients relative to their parental counterparts (average H-scores of ASS and AMPK in parental tissues vs. BR tissues are 58.2 vs. 7.8, and 146 vs. 78.3, respectively, P < 0.03). Importantly, these findings also apply to cell lines and tumor samples from patients who failed both BRAF and MEK inhibitor.

In summary, our data suggest that attenuated AMPK-α 1 mediated autophagy and glucose uptake and decreased c-Myc mediated ASS re-expression sensitize BR cells to arginine deprivation, and can be used as salvage therapy for BR patients.

Supported by 1RO1CA152197 and VA Merit Review BLR&D11860649.

BRAF inhibitor (BRAFi) combined with MEK inhibitor (MEKi) are used to treat melanomas harboring (V600E) mutation. While response is high, the majority of them relapsed. We found novel mechanisms to treat BRAFi resistant (BR) patients.

Five BR cells were established from known BRAF mutant cell lines A375, MEL-1220, A2058, UACC-62, and SKMEL28 by long-term exposure to BRAFi. These BR cells are hypersensitive to ADI-PEG20, an enzyme which degrades arginine to citrulline. ADI-PEG20 treatment resulted in 10-30% increase in apoptosis (Annexin V/PI) in BR cells compared to their paternal cells. The mechanisms involved are as follows: All BR cells express very low levels or do not express argininosuccinate synthetase (ASS, a key enzyme to generate arginine from citrulline) and also have attenuated glucose uptake. Thus, these BR cells rely primarily on exogenous arginine. Importantly, their ability to undergo autophagy upon nutritional stress is also impaired. The underlying mechanism for low levels of ASS is due to diminished c-Myc expression,a positive regulator for ASS. Additionally, AMPK-α 1, which governed autophagy and glucose uptake, was attenuated in BR cells. Overexpression of AMPK-α 1 using plasmid transfection in A2058BR and MEL-1220BR cells rescued 8-28% ADI-PEG20-induced apoptosis and enhanced autophagosome formation. Conversely, knockdown of AMPK-α 1 significantly enhanced ADI-PEG20-reduced cell viability in A2058 and MEL-1220 cells through attenuation of autophagy and glucose uptake. This is evidenced by decreased GLUT1 and LC3-II expression, and low activity of 2-NBDG uptake seen in BR cells. BMR (BRAF and MEK inhibitor) resistant cells also shared similar biochemical changes. Immunohistochemical staining further confirmed lower levels of ASS and AMPK-α 1 in A2058BR, BMR and in tumor tissues from 10 BR patients relative to their parental counterparts (average H-scores of ASS and AMPK in parental tissues vs. BR tissues are 58.2 vs. 7.8, and 146 vs. 78.3, respectively, P < 0.03). Importantly, these findings also apply to cell lines and tumor samples from patients who failed both BRAF and MEK inhibitor.

In summary, our data suggest that attenuated AMPK-α 1 mediated autophagy and glucose uptake and decreased c-Myc mediated ASS re-expression sensitize BR cells to arginine deprivation, and can be used as salvage therapy for BR patients.

Supported by 1RO1CA152197 and VA Merit Review BLR&D11860649.

Here are 5 articles in the August issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Women With BRCA1 Mutations at Higher Risk for Endometrial Cancers

To take the posttest, go to: http://bit.ly/2t6SPIY
Expires June 30, 2017

VITALSKey clinical point: Clinicians may wish to discuss the option of hysterectomy at the time of salpingo-oophorectomy in women with deleterious BRCA1 mutations.
Major finding: Among women with BRCA1 but not BRCA2 mutations there was increased risk for serous/serous-like endometrial carcinomas.
Data source: Prospective multicenter follow-up study of 1,083 women with BRCA mutations who underwent salpingo-oophorectomy without hysterectomy.
Disclosures: The study was supported by grants from the Department of Defense, National Institutes of Health, and public and private foundations. Coauthor Robert Soslow, MD, disclosed consulting for EMD Serono. No others reported conflicts of interest. The editorialists reported no conflicts of interest related to the study.

2. Cochrane Review: Topical Steroid—Vitamin D Combo Best for Scalp Psoriasis

To take the posttest, go to: http://bit.ly/2sIyLNI
Expires July 14, 2017

VITALSKey clinical point: The combination of a topical steroid and topical vitamin D is marginally better but with a similar safety profile to steroids alone as a treatment for psoriasis on the scalp.
Major finding: The combination of a topical steroid and vitamin D showed a small but statistically significant advantage over steroids alone, and a greater advantage over vitamin D alone.
Data source: A systematic review of 59 randomized controlled studies in 11,561 patients.
Disclosures: The study was supported by the Universidade Federal de São Paulo, Brazil; the Universidade Federal do Rio Grande do Norte, Brazil; and the National Institute for Health Research, United Kingdom. Six authors and one clinical referee declared speakers' fees, research grants, and funding from the pharmaceutical industry. One author had no conflicts of interest to disclose.

3. Study Finds Emergence of Azithromycin-resistant Gonorrhea

To take the posttest, go to: http://bit.ly/2u1nMmb
Expires July 16, 2017

VITALSKey clinical point:Resistance to azithromycin is emerging among patients diagnosed with gonorrhea.
Major finding: Among patients with gonorrhea, resistance to azithromycin increased from 0.6% in 2013 to 2.5% in 2014, predominantly in the Midwest.
Data source: An analysis of 5,093 Neisseria gonorrhoeae isolates from 27 clinics as part of the CDC's Gonococcal Isolate Surveillance Project.
Disclosures: The researchers had no financial disclosures.

4. Statins Improve Ovarian Cancer Survival

To take the posttest, go to: http://bit.ly/2t6swCF
Expires June 16, 2017

VITALSKey clinical point: The risk of all-cause mortality in ovarian cancer patients on statin therapy was reduced by one-third.
Major finding: Mean survival in a large cohort of women with stage III ovarian cancer was 5.8 months longer among those on statin therapy.
Data source: A retrospective study of 1,510 women diagnosed with epithelial ovarian cancer during 2007-2009.
Disclosures: Dr. Vogel reported having no financial conflicts regarding this study, conducted without commercial support.

5. Common Surgeries Linked to Chronic Opioid Use Among Opioid-naive Patients

To take the posttest, go to: http://bit.ly/2ub9fFg
Expires June 18, 2017

VITALSKey clinical point: Common surgeries increase the risk of chronic opioid use in opioid-naive adults, especially among those using antidepressants or benzodiazepines before their operations, and those with substance abuse histories.
Major finding: After adjustment for potential confounders, knee replacement increased the risk fivefold; open cholecystectomy almost fourfold; and total hip replacement and simple mastectomy almost threefold.
Data source: Insurance claims of more than 18 million people.
Disclosures: The authors had no disclosures. The work was funded in part by the Foundation for Anesthesia Education and Research and the Anesthesia Quality Institute. Claims data came from MarketScan (Truven Health Analytics).

Here are 5 articles in the August issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Women With BRCA1 Mutations at Higher Risk for Endometrial Cancers

To take the posttest, go to: http://bit.ly/2t6SPIY
Expires June 30, 2017

VITALSKey clinical point: Clinicians may wish to discuss the option of hysterectomy at the time of salpingo-oophorectomy in women with deleterious BRCA1 mutations.
Major finding: Among women with BRCA1 but not BRCA2 mutations there was increased risk for serous/serous-like endometrial carcinomas.
Data source: Prospective multicenter follow-up study of 1,083 women with BRCA mutations who underwent salpingo-oophorectomy without hysterectomy.
Disclosures: The study was supported by grants from the Department of Defense, National Institutes of Health, and public and private foundations. Coauthor Robert Soslow, MD, disclosed consulting for EMD Serono. No others reported conflicts of interest. The editorialists reported no conflicts of interest related to the study.

2. Cochrane Review: Topical Steroid—Vitamin D Combo Best for Scalp Psoriasis

To take the posttest, go to: http://bit.ly/2sIyLNI
Expires July 14, 2017

VITALSKey clinical point: The combination of a topical steroid and topical vitamin D is marginally better but with a similar safety profile to steroids alone as a treatment for psoriasis on the scalp.
Major finding: The combination of a topical steroid and vitamin D showed a small but statistically significant advantage over steroids alone, and a greater advantage over vitamin D alone.
Data source: A systematic review of 59 randomized controlled studies in 11,561 patients.
Disclosures: The study was supported by the Universidade Federal de São Paulo, Brazil; the Universidade Federal do Rio Grande do Norte, Brazil; and the National Institute for Health Research, United Kingdom. Six authors and one clinical referee declared speakers' fees, research grants, and funding from the pharmaceutical industry. One author had no conflicts of interest to disclose.

3. Study Finds Emergence of Azithromycin-resistant Gonorrhea

To take the posttest, go to: http://bit.ly/2u1nMmb
Expires July 16, 2017

VITALSKey clinical point:Resistance to azithromycin is emerging among patients diagnosed with gonorrhea.
Major finding: Among patients with gonorrhea, resistance to azithromycin increased from 0.6% in 2013 to 2.5% in 2014, predominantly in the Midwest.
Data source: An analysis of 5,093 Neisseria gonorrhoeae isolates from 27 clinics as part of the CDC's Gonococcal Isolate Surveillance Project.
Disclosures: The researchers had no financial disclosures.

4. Statins Improve Ovarian Cancer Survival

To take the posttest, go to: http://bit.ly/2t6swCF
Expires June 16, 2017

VITALSKey clinical point: The risk of all-cause mortality in ovarian cancer patients on statin therapy was reduced by one-third.
Major finding: Mean survival in a large cohort of women with stage III ovarian cancer was 5.8 months longer among those on statin therapy.
Data source: A retrospective study of 1,510 women diagnosed with epithelial ovarian cancer during 2007-2009.
Disclosures: Dr. Vogel reported having no financial conflicts regarding this study, conducted without commercial support.

5. Common Surgeries Linked to Chronic Opioid Use Among Opioid-naive Patients

To take the posttest, go to: http://bit.ly/2ub9fFg
Expires June 18, 2017

VITALSKey clinical point: Common surgeries increase the risk of chronic opioid use in opioid-naive adults, especially among those using antidepressants or benzodiazepines before their operations, and those with substance abuse histories.
Major finding: After adjustment for potential confounders, knee replacement increased the risk fivefold; open cholecystectomy almost fourfold; and total hip replacement and simple mastectomy almost threefold.
Data source: Insurance claims of more than 18 million people.
Disclosures: The authors had no disclosures. The work was funded in part by the Foundation for Anesthesia Education and Research and the Anesthesia Quality Institute. Claims data came from MarketScan (Truven Health Analytics).

Here are 5 articles in the August issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Women With BRCA1 Mutations at Higher Risk for Endometrial Cancers

To take the posttest, go to: http://bit.ly/2t6SPIY
Expires June 30, 2017

VITALSKey clinical point: Clinicians may wish to discuss the option of hysterectomy at the time of salpingo-oophorectomy in women with deleterious BRCA1 mutations.
Major finding: Among women with BRCA1 but not BRCA2 mutations there was increased risk for serous/serous-like endometrial carcinomas.
Data source: Prospective multicenter follow-up study of 1,083 women with BRCA mutations who underwent salpingo-oophorectomy without hysterectomy.
Disclosures: The study was supported by grants from the Department of Defense, National Institutes of Health, and public and private foundations. Coauthor Robert Soslow, MD, disclosed consulting for EMD Serono. No others reported conflicts of interest. The editorialists reported no conflicts of interest related to the study.

2. Cochrane Review: Topical Steroid—Vitamin D Combo Best for Scalp Psoriasis

To take the posttest, go to: http://bit.ly/2sIyLNI
Expires July 14, 2017

VITALSKey clinical point: The combination of a topical steroid and topical vitamin D is marginally better but with a similar safety profile to steroids alone as a treatment for psoriasis on the scalp.
Major finding: The combination of a topical steroid and vitamin D showed a small but statistically significant advantage over steroids alone, and a greater advantage over vitamin D alone.
Data source: A systematic review of 59 randomized controlled studies in 11,561 patients.
Disclosures: The study was supported by the Universidade Federal de São Paulo, Brazil; the Universidade Federal do Rio Grande do Norte, Brazil; and the National Institute for Health Research, United Kingdom. Six authors and one clinical referee declared speakers' fees, research grants, and funding from the pharmaceutical industry. One author had no conflicts of interest to disclose.

3. Study Finds Emergence of Azithromycin-resistant Gonorrhea

To take the posttest, go to: http://bit.ly/2u1nMmb
Expires July 16, 2017

VITALSKey clinical point:Resistance to azithromycin is emerging among patients diagnosed with gonorrhea.
Major finding: Among patients with gonorrhea, resistance to azithromycin increased from 0.6% in 2013 to 2.5% in 2014, predominantly in the Midwest.
Data source: An analysis of 5,093 Neisseria gonorrhoeae isolates from 27 clinics as part of the CDC's Gonococcal Isolate Surveillance Project.
Disclosures: The researchers had no financial disclosures.

4. Statins Improve Ovarian Cancer Survival

To take the posttest, go to: http://bit.ly/2t6swCF
Expires June 16, 2017

VITALSKey clinical point: The risk of all-cause mortality in ovarian cancer patients on statin therapy was reduced by one-third.
Major finding: Mean survival in a large cohort of women with stage III ovarian cancer was 5.8 months longer among those on statin therapy.
Data source: A retrospective study of 1,510 women diagnosed with epithelial ovarian cancer during 2007-2009.
Disclosures: Dr. Vogel reported having no financial conflicts regarding this study, conducted without commercial support.

5. Common Surgeries Linked to Chronic Opioid Use Among Opioid-naive Patients

To take the posttest, go to: http://bit.ly/2ub9fFg
Expires June 18, 2017

VITALSKey clinical point: Common surgeries increase the risk of chronic opioid use in opioid-naive adults, especially among those using antidepressants or benzodiazepines before their operations, and those with substance abuse histories.
Major finding: After adjustment for potential confounders, knee replacement increased the risk fivefold; open cholecystectomy almost fourfold; and total hip replacement and simple mastectomy almost threefold.
Data source: Insurance claims of more than 18 million people.
Disclosures: The authors had no disclosures. The work was funded in part by the Foundation for Anesthesia Education and Research and the Anesthesia Quality Institute. Claims data came from MarketScan (Truven Health Analytics).

“Increasingly, we are not having faculty who are going up for promotion and reliably running into challenges around mentorship, national reputation, and having a network outside of their local hospital that is critical for advancement,” says lead author Ethan Cumbler, MD, FHM, FACP, of the Department of Medicine at the University of Colorado School of Medicine. “Hospital medicine as a movement is built on a foundation of innovation, and so as a specialty, we have a mandate to not only innovate but to disseminate those innovations.”

The model of the visiting professorship described in the paper takes midcareer academic hospitalists and provides an infrastructure for reciprocal faculty exchanges. This provides a forum to increase professional networks.

“We found that both junior faculty and our visiting professors saw value in advancing those goals,” Dr. Cumbler says. “We also saw evidence of the spread of ideas and new shared scholarship derived from having these reciprocal visits.”

This has model relevance for nonacademic hospitals, too. For example, it’d be useful for hospital medicine groups to share ideas with one another, Dr. Cumbler says.

“This is a simple structure, but it’s just like a small pebble thrown into a large body of water can create ripples which affect distant shores—sometimes it’s very simple concepts that are worth pursuing,” he says.

Reference

1. Cumbler E, Herzke C, Smalligan R, Glasheen JJ, O’Malley C, Pierce JR Jr. Visiting professorship in hospital medicine: an innovative twist for a growing specialty [published online ahead of print June 23, 2016]. J Hosp Med. doi:10.1002/jhm.2625.

“Increasingly, we are not having faculty who are going up for promotion and reliably running into challenges around mentorship, national reputation, and having a network outside of their local hospital that is critical for advancement,” says lead author Ethan Cumbler, MD, FHM, FACP, of the Department of Medicine at the University of Colorado School of Medicine. “Hospital medicine as a movement is built on a foundation of innovation, and so as a specialty, we have a mandate to not only innovate but to disseminate those innovations.”

The model of the visiting professorship described in the paper takes midcareer academic hospitalists and provides an infrastructure for reciprocal faculty exchanges. This provides a forum to increase professional networks.

“We found that both junior faculty and our visiting professors saw value in advancing those goals,” Dr. Cumbler says. “We also saw evidence of the spread of ideas and new shared scholarship derived from having these reciprocal visits.”

This has model relevance for nonacademic hospitals, too. For example, it’d be useful for hospital medicine groups to share ideas with one another, Dr. Cumbler says.

“This is a simple structure, but it’s just like a small pebble thrown into a large body of water can create ripples which affect distant shores—sometimes it’s very simple concepts that are worth pursuing,” he says.

Reference

1. Cumbler E, Herzke C, Smalligan R, Glasheen JJ, O’Malley C, Pierce JR Jr. Visiting professorship in hospital medicine: an innovative twist for a growing specialty [published online ahead of print June 23, 2016]. J Hosp Med. doi:10.1002/jhm.2625.

“Increasingly, we are not having faculty who are going up for promotion and reliably running into challenges around mentorship, national reputation, and having a network outside of their local hospital that is critical for advancement,” says lead author Ethan Cumbler, MD, FHM, FACP, of the Department of Medicine at the University of Colorado School of Medicine. “Hospital medicine as a movement is built on a foundation of innovation, and so as a specialty, we have a mandate to not only innovate but to disseminate those innovations.”

The model of the visiting professorship described in the paper takes midcareer academic hospitalists and provides an infrastructure for reciprocal faculty exchanges. This provides a forum to increase professional networks.

“We found that both junior faculty and our visiting professors saw value in advancing those goals,” Dr. Cumbler says. “We also saw evidence of the spread of ideas and new shared scholarship derived from having these reciprocal visits.”

This has model relevance for nonacademic hospitals, too. For example, it’d be useful for hospital medicine groups to share ideas with one another, Dr. Cumbler says.

“This is a simple structure, but it’s just like a small pebble thrown into a large body of water can create ripples which affect distant shores—sometimes it’s very simple concepts that are worth pursuing,” he says.

Reference

1. Cumbler E, Herzke C, Smalligan R, Glasheen JJ, O’Malley C, Pierce JR Jr. Visiting professorship in hospital medicine: an innovative twist for a growing specialty [published online ahead of print June 23, 2016]. J Hosp Med. doi:10.1002/jhm.2625.

PAs are highly educated, trusted health care providers who lead patient-centered medical teams. Trained as experts in general medicine, we often pursue multiple specialties over the course of our careers—typically in three or four. PAs can decide to work in surgery, emergency care, orthopedics, oncology, pediatrics, dermatology, and many other areas. Moving among and between specialties is a hallmark of our profession. Unfortunately, a new proposal would alter how PAs are tested in order to maintain their certification—and, in 20 states, potentially jeopardize their license to practice.

The National Commission on Certification of PAs (NCCPA) has proposed significant changes to how PAs are recertified by requiring multiple exams, including a proctored, closed-book exam in a specialty area and two or three take-home exams during every 10-year recertification cycle. The proposal would in effect force PAs to choose a specialty and as a result undermine their ability to fill care gaps in hospitals, health systems, and communities.

The new requirements are cumbersome and unnecessary. PAs already undergo rigorous medical training and have initial licensing requirements that are similar to those of our physician, nurse practitioner, and pharmacist colleagues—none of whom are required to retest. PAs must graduate from an accredited program and take a test in general medicine in order to be licensed and certified in the first place. Throughout their careers, they have to complete extensive continuing medical education (CME). They also practice in clinical settings that continually inform and enhance their experience and base of knowledge.

Additional testing would take valuable time away from patients and could even discourage PAs from staying in a profession that is in high demand. More to the point, NCCPA has pursued its proposal even though studies have shown that recertification testing is not related to improvements in patient outcomes or safety.

AAPA recently received a message from longtime PA Peter Schuman, who is as passionate about patient care as he is leery of NCCPA’s recertification plan. “[NCCPA has] no significant, scientifically valid evidence to support their claims. I can honestly say that their testing requirements have not helped me care for patients better or become more knowledgeable in my field of practice/expertise one bit,” he wrote. “The PANRE is a waste of time and effort and is a source of great stress, taking time away from my patients, practice, and family. Enough is enough, NCCPA!”

The AAPA board has reached out to NCCPA and still hopes that it will engage in substantive discussions. Given the seriousness of our concerns, however, the AAPA Board voted recently to take steps toward the creation of an alternative certifying body for PAs. This vote came after careful deliberation and in response to the concerns of the thousands of professionals that AAPA represents. The decision was not made lightly and it reflects the priority of PAs to put patient care ahead of unnecessary testing.

AAPA is not alone in its opposition to recertification testing. A growing number of medical associations, including the American Medical Association (AMA), reject it as unnecessary and overly burdensome. AMA has rightly identified these exams as high-stakes tests because, it said, “failure to pass can result in a physician’s loss of privileges or employment.” Every PA would face similar consequences and, in 20 states, put their license at risk. At least 19 state medical associations have adopted similar resolutions in opposition to unnecessary retesting.

To be clear, AAPA does not oppose initial testing for certification and licensing and embraces the value of an exam in the licensing process. AAPA also strongly supports extensive CME and the benefits it provides.

We have not yet decided whether to establish a new certification organization. But we do know that there is no reason PAs should be singled out for additional testing when the extra requirement does not help patients and when other medical professionals are not required to do the same. Let PAs focus on patient care, not unwarranted test-taking. 

PAs are highly educated, trusted health care providers who lead patient-centered medical teams. Trained as experts in general medicine, we often pursue multiple specialties over the course of our careers—typically in three or four. PAs can decide to work in surgery, emergency care, orthopedics, oncology, pediatrics, dermatology, and many other areas. Moving among and between specialties is a hallmark of our profession. Unfortunately, a new proposal would alter how PAs are tested in order to maintain their certification—and, in 20 states, potentially jeopardize their license to practice.

The National Commission on Certification of PAs (NCCPA) has proposed significant changes to how PAs are recertified by requiring multiple exams, including a proctored, closed-book exam in a specialty area and two or three take-home exams during every 10-year recertification cycle. The proposal would in effect force PAs to choose a specialty and as a result undermine their ability to fill care gaps in hospitals, health systems, and communities.

The new requirements are cumbersome and unnecessary. PAs already undergo rigorous medical training and have initial licensing requirements that are similar to those of our physician, nurse practitioner, and pharmacist colleagues—none of whom are required to retest. PAs must graduate from an accredited program and take a test in general medicine in order to be licensed and certified in the first place. Throughout their careers, they have to complete extensive continuing medical education (CME). They also practice in clinical settings that continually inform and enhance their experience and base of knowledge.

Additional testing would take valuable time away from patients and could even discourage PAs from staying in a profession that is in high demand. More to the point, NCCPA has pursued its proposal even though studies have shown that recertification testing is not related to improvements in patient outcomes or safety.

AAPA recently received a message from longtime PA Peter Schuman, who is as passionate about patient care as he is leery of NCCPA’s recertification plan. “[NCCPA has] no significant, scientifically valid evidence to support their claims. I can honestly say that their testing requirements have not helped me care for patients better or become more knowledgeable in my field of practice/expertise one bit,” he wrote. “The PANRE is a waste of time and effort and is a source of great stress, taking time away from my patients, practice, and family. Enough is enough, NCCPA!”

The AAPA board has reached out to NCCPA and still hopes that it will engage in substantive discussions. Given the seriousness of our concerns, however, the AAPA Board voted recently to take steps toward the creation of an alternative certifying body for PAs. This vote came after careful deliberation and in response to the concerns of the thousands of professionals that AAPA represents. The decision was not made lightly and it reflects the priority of PAs to put patient care ahead of unnecessary testing.

AAPA is not alone in its opposition to recertification testing. A growing number of medical associations, including the American Medical Association (AMA), reject it as unnecessary and overly burdensome. AMA has rightly identified these exams as high-stakes tests because, it said, “failure to pass can result in a physician’s loss of privileges or employment.” Every PA would face similar consequences and, in 20 states, put their license at risk. At least 19 state medical associations have adopted similar resolutions in opposition to unnecessary retesting.

To be clear, AAPA does not oppose initial testing for certification and licensing and embraces the value of an exam in the licensing process. AAPA also strongly supports extensive CME and the benefits it provides.

We have not yet decided whether to establish a new certification organization. But we do know that there is no reason PAs should be singled out for additional testing when the extra requirement does not help patients and when other medical professionals are not required to do the same. Let PAs focus on patient care, not unwarranted test-taking. 

PAs are highly educated, trusted health care providers who lead patient-centered medical teams. Trained as experts in general medicine, we often pursue multiple specialties over the course of our careers—typically in three or four. PAs can decide to work in surgery, emergency care, orthopedics, oncology, pediatrics, dermatology, and many other areas. Moving among and between specialties is a hallmark of our profession. Unfortunately, a new proposal would alter how PAs are tested in order to maintain their certification—and, in 20 states, potentially jeopardize their license to practice.

The National Commission on Certification of PAs (NCCPA) has proposed significant changes to how PAs are recertified by requiring multiple exams, including a proctored, closed-book exam in a specialty area and two or three take-home exams during every 10-year recertification cycle. The proposal would in effect force PAs to choose a specialty and as a result undermine their ability to fill care gaps in hospitals, health systems, and communities.

The new requirements are cumbersome and unnecessary. PAs already undergo rigorous medical training and have initial licensing requirements that are similar to those of our physician, nurse practitioner, and pharmacist colleagues—none of whom are required to retest. PAs must graduate from an accredited program and take a test in general medicine in order to be licensed and certified in the first place. Throughout their careers, they have to complete extensive continuing medical education (CME). They also practice in clinical settings that continually inform and enhance their experience and base of knowledge.

Additional testing would take valuable time away from patients and could even discourage PAs from staying in a profession that is in high demand. More to the point, NCCPA has pursued its proposal even though studies have shown that recertification testing is not related to improvements in patient outcomes or safety.

AAPA recently received a message from longtime PA Peter Schuman, who is as passionate about patient care as he is leery of NCCPA’s recertification plan. “[NCCPA has] no significant, scientifically valid evidence to support their claims. I can honestly say that their testing requirements have not helped me care for patients better or become more knowledgeable in my field of practice/expertise one bit,” he wrote. “The PANRE is a waste of time and effort and is a source of great stress, taking time away from my patients, practice, and family. Enough is enough, NCCPA!”

The AAPA board has reached out to NCCPA and still hopes that it will engage in substantive discussions. Given the seriousness of our concerns, however, the AAPA Board voted recently to take steps toward the creation of an alternative certifying body for PAs. This vote came after careful deliberation and in response to the concerns of the thousands of professionals that AAPA represents. The decision was not made lightly and it reflects the priority of PAs to put patient care ahead of unnecessary testing.

AAPA is not alone in its opposition to recertification testing. A growing number of medical associations, including the American Medical Association (AMA), reject it as unnecessary and overly burdensome. AMA has rightly identified these exams as high-stakes tests because, it said, “failure to pass can result in a physician’s loss of privileges or employment.” Every PA would face similar consequences and, in 20 states, put their license at risk. At least 19 state medical associations have adopted similar resolutions in opposition to unnecessary retesting.

To be clear, AAPA does not oppose initial testing for certification and licensing and embraces the value of an exam in the licensing process. AAPA also strongly supports extensive CME and the benefits it provides.

We have not yet decided whether to establish a new certification organization. But we do know that there is no reason PAs should be singled out for additional testing when the extra requirement does not help patients and when other medical professionals are not required to do the same. Let PAs focus on patient care, not unwarranted test-taking. 

Rivaroxaban tablets

ROME—Preliminary results from the ANNEXA-4 study suggest that andexanet alfa, an investigational antidote to factor Xa inhibitors, can be effective in patients with acute major bleeding.

The drug reversed the anticoagulant effects of rivaroxaban, apixaban, and enoxaparin in this study, providing “excellent” or “good” hemostatic efficacy in 79% of patients over 12 hours.

Thrombotic events occurred in 18% of patients, and 15% died during the 30-day follow-up period.

According to investigators, these events occurred within the range expected in this patient population, given the severity of their bleeding, their underlying thrombotic risk, and the low percentage of patients who restarted anticoagulant therapy following their bleeding episode.

Stuart J. Connolly, MD, of McMaster University in Hamilton, Ontario, Canada, presented results from  ANNEXA-4 at ESC Congress 2016 (abstract 5718).

Results were also published in NEJM. The study was funded by Portola Pharmaceuticals Inc.

Patients and treatment

The preliminary analysis of the phase 3/4 ANNEXA-4 trial included 67 patients. All of these patients were evaluated for safety, and 47 were evaluated for efficacy. The mean age of both populations was 77.1, and slightly more than half of the patients were male.

All patients received andexanet alfa given as a bolus dose over 30 minutes, followed by a 2-hour infusion. Patients received a low or high dose depending on which factor Xa inhibitor they received and the time they received it. The patients were evaluated for 30 days following andexanet alfa administration.

The co-primary efficacy endpoints are the percent change in anti-factor Xa activity at 2 hours and the assessment of hemostasis over 12 hours following the infusion. Hemostatic efficacy is assessed by an independent endpoint adjudication committee as excellent, good, or poor/none.

Efficacy

“In this preliminary analysis, [andexanet alfa] was effective in rapidly reversing anti-factor Xa inhibitor activity and restoring normal blood clotting in real-world patients with factor Xa inhibitor-related bleeding,” Dr Connolly said.

Of the 47 patients evaluable for efficacy, 32 were receiving an anticoagulant due to atrial fibrillation, 12 had venous thromboembolism (VTE), and 3 had both atrial fibrillation and VTE.

Twenty-six patients were receiving rivaroxaban, 20 were receiving apixaban, and 1 was receiving enoxaparin. Twenty-five patients had gastrointestinal bleeding, 20 had intracranial bleeding, and 2 had bleeding at other sites.

Forty-two patients received a low dose of andexanet alfa, and 5 received a high dose. The mean time from presentation to the emergency department and the administration of the andexanet alfa bolus was 4.8 ± 1.8 hours.

After the bolus, the median anti-factor Xa activity decreased by 89% from baseline among patients receiving rivaroxaban and by 93% among those receiving apixaban. At the end of the 2-hour infusion, the decrease from baseline was 86% and 92%, respectively.

Twelve hours after the infusion ended, the median anti-factor Xa activity had decreased 64% from baseline among patients receiving rivaroxaban and 31% among those receiving apixaban.

Overall, at 12 hours, clinical hemostasis was rated excellent or good in 79% of patients. Hemostatic efficacy was rated as excellent or good in 81% of the patients on rivaroxaban, 75% of the patients on apixaban, and in the 1 patient on edoxaban.

Safety

Of the 67 patients in the safety population, 47 were receiving an anticoagulant due to atrial fibrillation, 15 had VTE, and 5 had both atrial fibrillation and VTE.

Thirty-two patients were receiving rivaroxaban, 31 were receiving apixaban, and 4 were receiving edoxaban. Thirty-eight patients had gastrointestinal bleeding, 28 had intracranial bleeding, and 6 had bleeding at other sites.

There were no infusion reactions, no antibodies to factors Xa or X, and no neutralizing antibodies to andexanet alfa.

Twelve patients (18%) experienced thrombotic events—1 with myocardial infarction, 5 with stroke, 7 with deep-vein thrombosis, and 1 with pulmonary embolism. (Some patients had more than 1 event.)

“This rate of events is not unexpected, considering the thrombotic potential of the patients and the fact that, in most of them, anticoagulation was discontinued at the time of bleeding and not restarted,” Dr Connolly said.

Four patients had a thrombotic event within 3 days of andexanet alfa treatment, and the rest occurred between 4 days and 30 days.

Eighteen patients (27%) resumed anticoagulant therapy within 30 days. One of the 12 patients with a thrombotic event restarted anticoagulation at a therapeutic dose before the event. One other patient received prophylactic doses of enoxaparin before developing a deep-vein thrombosis.

There were 10 deaths (15%), 6 due to cardiovascular events.

Andexanet alfa development

Andexanet alfa is being developed as a reversal agent for apixaban, rivaroxaban, edoxaban, and enoxaparin. Andexanet alfa is intended to be used when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.

The drug is under review by the US Food and Drug Administration (FDA) and the European Medicines Agency. The FDA recently issued a complete response letter regarding the biologics license application for andexanet alfa.

Portola said it plans to meet with the FDA as soon as possible to resolve the outstanding questions in the letter and determine the appropriate next steps.

Rivaroxaban tablets

ROME—Preliminary results from the ANNEXA-4 study suggest that andexanet alfa, an investigational antidote to factor Xa inhibitors, can be effective in patients with acute major bleeding.

The drug reversed the anticoagulant effects of rivaroxaban, apixaban, and enoxaparin in this study, providing “excellent” or “good” hemostatic efficacy in 79% of patients over 12 hours.

Thrombotic events occurred in 18% of patients, and 15% died during the 30-day follow-up period.

According to investigators, these events occurred within the range expected in this patient population, given the severity of their bleeding, their underlying thrombotic risk, and the low percentage of patients who restarted anticoagulant therapy following their bleeding episode.

Stuart J. Connolly, MD, of McMaster University in Hamilton, Ontario, Canada, presented results from  ANNEXA-4 at ESC Congress 2016 (abstract 5718).

Results were also published in NEJM. The study was funded by Portola Pharmaceuticals Inc.

Patients and treatment

The preliminary analysis of the phase 3/4 ANNEXA-4 trial included 67 patients. All of these patients were evaluated for safety, and 47 were evaluated for efficacy. The mean age of both populations was 77.1, and slightly more than half of the patients were male.

All patients received andexanet alfa given as a bolus dose over 30 minutes, followed by a 2-hour infusion. Patients received a low or high dose depending on which factor Xa inhibitor they received and the time they received it. The patients were evaluated for 30 days following andexanet alfa administration.

The co-primary efficacy endpoints are the percent change in anti-factor Xa activity at 2 hours and the assessment of hemostasis over 12 hours following the infusion. Hemostatic efficacy is assessed by an independent endpoint adjudication committee as excellent, good, or poor/none.

Efficacy

“In this preliminary analysis, [andexanet alfa] was effective in rapidly reversing anti-factor Xa inhibitor activity and restoring normal blood clotting in real-world patients with factor Xa inhibitor-related bleeding,” Dr Connolly said.

Of the 47 patients evaluable for efficacy, 32 were receiving an anticoagulant due to atrial fibrillation, 12 had venous thromboembolism (VTE), and 3 had both atrial fibrillation and VTE.

Twenty-six patients were receiving rivaroxaban, 20 were receiving apixaban, and 1 was receiving enoxaparin. Twenty-five patients had gastrointestinal bleeding, 20 had intracranial bleeding, and 2 had bleeding at other sites.

Forty-two patients received a low dose of andexanet alfa, and 5 received a high dose. The mean time from presentation to the emergency department and the administration of the andexanet alfa bolus was 4.8 ± 1.8 hours.

After the bolus, the median anti-factor Xa activity decreased by 89% from baseline among patients receiving rivaroxaban and by 93% among those receiving apixaban. At the end of the 2-hour infusion, the decrease from baseline was 86% and 92%, respectively.

Twelve hours after the infusion ended, the median anti-factor Xa activity had decreased 64% from baseline among patients receiving rivaroxaban and 31% among those receiving apixaban.

Overall, at 12 hours, clinical hemostasis was rated excellent or good in 79% of patients. Hemostatic efficacy was rated as excellent or good in 81% of the patients on rivaroxaban, 75% of the patients on apixaban, and in the 1 patient on edoxaban.

Safety

Of the 67 patients in the safety population, 47 were receiving an anticoagulant due to atrial fibrillation, 15 had VTE, and 5 had both atrial fibrillation and VTE.

Thirty-two patients were receiving rivaroxaban, 31 were receiving apixaban, and 4 were receiving edoxaban. Thirty-eight patients had gastrointestinal bleeding, 28 had intracranial bleeding, and 6 had bleeding at other sites.

There were no infusion reactions, no antibodies to factors Xa or X, and no neutralizing antibodies to andexanet alfa.

Twelve patients (18%) experienced thrombotic events—1 with myocardial infarction, 5 with stroke, 7 with deep-vein thrombosis, and 1 with pulmonary embolism. (Some patients had more than 1 event.)

“This rate of events is not unexpected, considering the thrombotic potential of the patients and the fact that, in most of them, anticoagulation was discontinued at the time of bleeding and not restarted,” Dr Connolly said.

Four patients had a thrombotic event within 3 days of andexanet alfa treatment, and the rest occurred between 4 days and 30 days.

Eighteen patients (27%) resumed anticoagulant therapy within 30 days. One of the 12 patients with a thrombotic event restarted anticoagulation at a therapeutic dose before the event. One other patient received prophylactic doses of enoxaparin before developing a deep-vein thrombosis.

There were 10 deaths (15%), 6 due to cardiovascular events.

Andexanet alfa development

Andexanet alfa is being developed as a reversal agent for apixaban, rivaroxaban, edoxaban, and enoxaparin. Andexanet alfa is intended to be used when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.

The drug is under review by the US Food and Drug Administration (FDA) and the European Medicines Agency. The FDA recently issued a complete response letter regarding the biologics license application for andexanet alfa.

Portola said it plans to meet with the FDA as soon as possible to resolve the outstanding questions in the letter and determine the appropriate next steps.

Rivaroxaban tablets

ROME—Preliminary results from the ANNEXA-4 study suggest that andexanet alfa, an investigational antidote to factor Xa inhibitors, can be effective in patients with acute major bleeding.

The drug reversed the anticoagulant effects of rivaroxaban, apixaban, and enoxaparin in this study, providing “excellent” or “good” hemostatic efficacy in 79% of patients over 12 hours.

Thrombotic events occurred in 18% of patients, and 15% died during the 30-day follow-up period.

According to investigators, these events occurred within the range expected in this patient population, given the severity of their bleeding, their underlying thrombotic risk, and the low percentage of patients who restarted anticoagulant therapy following their bleeding episode.

Stuart J. Connolly, MD, of McMaster University in Hamilton, Ontario, Canada, presented results from  ANNEXA-4 at ESC Congress 2016 (abstract 5718).

Results were also published in NEJM. The study was funded by Portola Pharmaceuticals Inc.

Patients and treatment

The preliminary analysis of the phase 3/4 ANNEXA-4 trial included 67 patients. All of these patients were evaluated for safety, and 47 were evaluated for efficacy. The mean age of both populations was 77.1, and slightly more than half of the patients were male.

All patients received andexanet alfa given as a bolus dose over 30 minutes, followed by a 2-hour infusion. Patients received a low or high dose depending on which factor Xa inhibitor they received and the time they received it. The patients were evaluated for 30 days following andexanet alfa administration.

The co-primary efficacy endpoints are the percent change in anti-factor Xa activity at 2 hours and the assessment of hemostasis over 12 hours following the infusion. Hemostatic efficacy is assessed by an independent endpoint adjudication committee as excellent, good, or poor/none.

Efficacy

“In this preliminary analysis, [andexanet alfa] was effective in rapidly reversing anti-factor Xa inhibitor activity and restoring normal blood clotting in real-world patients with factor Xa inhibitor-related bleeding,” Dr Connolly said.

Of the 47 patients evaluable for efficacy, 32 were receiving an anticoagulant due to atrial fibrillation, 12 had venous thromboembolism (VTE), and 3 had both atrial fibrillation and VTE.

Twenty-six patients were receiving rivaroxaban, 20 were receiving apixaban, and 1 was receiving enoxaparin. Twenty-five patients had gastrointestinal bleeding, 20 had intracranial bleeding, and 2 had bleeding at other sites.

Forty-two patients received a low dose of andexanet alfa, and 5 received a high dose. The mean time from presentation to the emergency department and the administration of the andexanet alfa bolus was 4.8 ± 1.8 hours.

After the bolus, the median anti-factor Xa activity decreased by 89% from baseline among patients receiving rivaroxaban and by 93% among those receiving apixaban. At the end of the 2-hour infusion, the decrease from baseline was 86% and 92%, respectively.

Twelve hours after the infusion ended, the median anti-factor Xa activity had decreased 64% from baseline among patients receiving rivaroxaban and 31% among those receiving apixaban.

Overall, at 12 hours, clinical hemostasis was rated excellent or good in 79% of patients. Hemostatic efficacy was rated as excellent or good in 81% of the patients on rivaroxaban, 75% of the patients on apixaban, and in the 1 patient on edoxaban.

Safety

Of the 67 patients in the safety population, 47 were receiving an anticoagulant due to atrial fibrillation, 15 had VTE, and 5 had both atrial fibrillation and VTE.

Thirty-two patients were receiving rivaroxaban, 31 were receiving apixaban, and 4 were receiving edoxaban. Thirty-eight patients had gastrointestinal bleeding, 28 had intracranial bleeding, and 6 had bleeding at other sites.

There were no infusion reactions, no antibodies to factors Xa or X, and no neutralizing antibodies to andexanet alfa.

Twelve patients (18%) experienced thrombotic events—1 with myocardial infarction, 5 with stroke, 7 with deep-vein thrombosis, and 1 with pulmonary embolism. (Some patients had more than 1 event.)

“This rate of events is not unexpected, considering the thrombotic potential of the patients and the fact that, in most of them, anticoagulation was discontinued at the time of bleeding and not restarted,” Dr Connolly said.

Four patients had a thrombotic event within 3 days of andexanet alfa treatment, and the rest occurred between 4 days and 30 days.

Eighteen patients (27%) resumed anticoagulant therapy within 30 days. One of the 12 patients with a thrombotic event restarted anticoagulation at a therapeutic dose before the event. One other patient received prophylactic doses of enoxaparin before developing a deep-vein thrombosis.

There were 10 deaths (15%), 6 due to cardiovascular events.

Andexanet alfa development

Andexanet alfa is being developed as a reversal agent for apixaban, rivaroxaban, edoxaban, and enoxaparin. Andexanet alfa is intended to be used when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.

The drug is under review by the US Food and Drug Administration (FDA) and the European Medicines Agency. The FDA recently issued a complete response letter regarding the biologics license application for andexanet alfa.

Portola said it plans to meet with the FDA as soon as possible to resolve the outstanding questions in the letter and determine the appropriate next steps.

Ticagrelor tablets

Photo courtesy of AstraZeneca

ROME—The antiplatelet drugs prasugrel and ticagrelor produce similar early results in patients with acute myocardial infarction (AMI) treated with percutaneous coronary intervention (PCI), according to PRAGUE-18, the first randomized, head-to-head comparison of the drugs.

“Our findings confirm previous indirect—non-randomized—comparisons of these 2 drugs, based on analyses of various registries,” said study investigator Petr Widimsky MD, DSc, of Charles University in Prague, Czech Republic.

“Thus, both drugs are very effective and safe and significantly contribute to the excellent outcomes of patients with acute myocardial infarction in modern cardiology.”

Dr Widimsky presented results from PRAGUE-18 at ESC Congress 2016 (abstract 5028). This was an investigator-initiated study, so there was no industry support.

The trial included 1230 AMI patients who were randomized to receive prasugrel (n=634) or ticagrelor (n=596) prior to PCI. There were no significant differences in baseline characteristics between the treatment arms.

Randomization took place immediately after a patient’s arrival to the PCI center. Patients received prasugrel at 60 mg, followed by 10 mg per day (5 mg per day if they were older than 75 or weighed less than 60 kg) for 1 year. Patients received ticagrelor at 180 mg, followed by 90 mg twice a day for 1 year.

The study’s primary endpoint was the occurrence of death, re-infarction, urgent target vessel revascularization, stroke, prolonged hospitalization, or serious bleeding requiring transfusion at 7 days (or discharge if earlier).

The trial was halted prematurely, after an interim analysis showed no significant difference in the rate of the primary endpoint between the prasugrel and ticagrelor arms—4.0% and 4.1%, respectively (odds ratio=0.98, P=0.939).

Likewise, there was no significant difference between the treatment arms for any of the components of the primary endpoint.

The key secondary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, and stroke within 30 days. There was no significant difference in the rate of this endpoint between the prasugrel and ticagrelor arms—2.7% and 2.5%, respectively (odds ratio=1.06, P=0.864).

“This study did not show any difference between ticagrelor and prasugrel in the early phase of acute myocardial infarction treated by primary PCI,” Dr Widimsky concluded.

He and his colleagues are planning the final follow-up of this study at 1 year, which will be completed in 2017.

Ticagrelor tablets

Photo courtesy of AstraZeneca

ROME—The antiplatelet drugs prasugrel and ticagrelor produce similar early results in patients with acute myocardial infarction (AMI) treated with percutaneous coronary intervention (PCI), according to PRAGUE-18, the first randomized, head-to-head comparison of the drugs.

“Our findings confirm previous indirect—non-randomized—comparisons of these 2 drugs, based on analyses of various registries,” said study investigator Petr Widimsky MD, DSc, of Charles University in Prague, Czech Republic.

“Thus, both drugs are very effective and safe and significantly contribute to the excellent outcomes of patients with acute myocardial infarction in modern cardiology.”

Dr Widimsky presented results from PRAGUE-18 at ESC Congress 2016 (abstract 5028). This was an investigator-initiated study, so there was no industry support.

The trial included 1230 AMI patients who were randomized to receive prasugrel (n=634) or ticagrelor (n=596) prior to PCI. There were no significant differences in baseline characteristics between the treatment arms.

Randomization took place immediately after a patient’s arrival to the PCI center. Patients received prasugrel at 60 mg, followed by 10 mg per day (5 mg per day if they were older than 75 or weighed less than 60 kg) for 1 year. Patients received ticagrelor at 180 mg, followed by 90 mg twice a day for 1 year.

The study’s primary endpoint was the occurrence of death, re-infarction, urgent target vessel revascularization, stroke, prolonged hospitalization, or serious bleeding requiring transfusion at 7 days (or discharge if earlier).

The trial was halted prematurely, after an interim analysis showed no significant difference in the rate of the primary endpoint between the prasugrel and ticagrelor arms—4.0% and 4.1%, respectively (odds ratio=0.98, P=0.939).

Likewise, there was no significant difference between the treatment arms for any of the components of the primary endpoint.

The key secondary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, and stroke within 30 days. There was no significant difference in the rate of this endpoint between the prasugrel and ticagrelor arms—2.7% and 2.5%, respectively (odds ratio=1.06, P=0.864).

“This study did not show any difference between ticagrelor and prasugrel in the early phase of acute myocardial infarction treated by primary PCI,” Dr Widimsky concluded.

He and his colleagues are planning the final follow-up of this study at 1 year, which will be completed in 2017.

Ticagrelor tablets

Photo courtesy of AstraZeneca

ROME—The antiplatelet drugs prasugrel and ticagrelor produce similar early results in patients with acute myocardial infarction (AMI) treated with percutaneous coronary intervention (PCI), according to PRAGUE-18, the first randomized, head-to-head comparison of the drugs.

“Our findings confirm previous indirect—non-randomized—comparisons of these 2 drugs, based on analyses of various registries,” said study investigator Petr Widimsky MD, DSc, of Charles University in Prague, Czech Republic.

“Thus, both drugs are very effective and safe and significantly contribute to the excellent outcomes of patients with acute myocardial infarction in modern cardiology.”

Dr Widimsky presented results from PRAGUE-18 at ESC Congress 2016 (abstract 5028). This was an investigator-initiated study, so there was no industry support.

The trial included 1230 AMI patients who were randomized to receive prasugrel (n=634) or ticagrelor (n=596) prior to PCI. There were no significant differences in baseline characteristics between the treatment arms.

Randomization took place immediately after a patient’s arrival to the PCI center. Patients received prasugrel at 60 mg, followed by 10 mg per day (5 mg per day if they were older than 75 or weighed less than 60 kg) for 1 year. Patients received ticagrelor at 180 mg, followed by 90 mg twice a day for 1 year.

The study’s primary endpoint was the occurrence of death, re-infarction, urgent target vessel revascularization, stroke, prolonged hospitalization, or serious bleeding requiring transfusion at 7 days (or discharge if earlier).

The trial was halted prematurely, after an interim analysis showed no significant difference in the rate of the primary endpoint between the prasugrel and ticagrelor arms—4.0% and 4.1%, respectively (odds ratio=0.98, P=0.939).

Likewise, there was no significant difference between the treatment arms for any of the components of the primary endpoint.

The key secondary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, and stroke within 30 days. There was no significant difference in the rate of this endpoint between the prasugrel and ticagrelor arms—2.7% and 2.5%, respectively (odds ratio=1.06, P=0.864).

“This study did not show any difference between ticagrelor and prasugrel in the early phase of acute myocardial infarction treated by primary PCI,” Dr Widimsky concluded.

He and his colleagues are planning the final follow-up of this study at 1 year, which will be completed in 2017.

Ofatumumab (Arzerra)

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved the use of ofatumumab (Arzerra®) in combination with fludarabine and cyclophosphamide to treat patients with relapsed chronic lymphocytic leukemia (CLL).

Ofatumumab was previously approved by the FDA for use in combination with chlorambucil to treat previously untreated CLL patients who cannot receive fludarabine-based therapy, as monotherapy for CLL that is refractory to fludarabine and alemtuzumab, and as maintenance therapy for patients who are in complete or partial response after receiving at least 2 lines of therapy for recurrent or progressive CLL.

Ofatumumab is a monoclonal antibody designed to target CD20.

The drug’s prescribing information includes a boxed warning noting that hepatitis B virus reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab. In some cases, this results in fulminant hepatitis, hepatic failure, and death.

The boxed warning also states that progressive multifocal leukoencephalopathy, resulting in death, can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab.

Ofatumumab is marketed under a collaboration agreement between Genmab and Novartis.

COMPLEMENT 2 trial

The FDA’s latest approval for ofatumumab is based on results of the phase 3 COMPLEMENT 2 trial. Novartis reported top-line results from this study in April.

The trial enrolled 365 patients with relapsed CLL. The patients were randomized 1:1 to receive up to 6 cycles of ofatumumab in combination with fludarabine and cyclophosphamide or up to 6 cycles of fludarabine and cyclophosphamide alone.

The primary endpoint was progression-free survival, as assessed by an independent review committee.

The median progression-free survival was 28.9 months for patients receiving ofatumumab plus fludarabine and cyclophosphamide, compared to 18.8 months for patients receiving fludarabine and cyclophosphamide alone (hazard ratio=0.67, P=0.0032).

Novartis said the safety profile observed in this study was consistent with other trials of ofatumumab, and no new safety signals were observed.

Ofatumumab (Arzerra)

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved the use of ofatumumab (Arzerra®) in combination with fludarabine and cyclophosphamide to treat patients with relapsed chronic lymphocytic leukemia (CLL).

Ofatumumab was previously approved by the FDA for use in combination with chlorambucil to treat previously untreated CLL patients who cannot receive fludarabine-based therapy, as monotherapy for CLL that is refractory to fludarabine and alemtuzumab, and as maintenance therapy for patients who are in complete or partial response after receiving at least 2 lines of therapy for recurrent or progressive CLL.

Ofatumumab is a monoclonal antibody designed to target CD20.

The drug’s prescribing information includes a boxed warning noting that hepatitis B virus reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab. In some cases, this results in fulminant hepatitis, hepatic failure, and death.

The boxed warning also states that progressive multifocal leukoencephalopathy, resulting in death, can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab.

Ofatumumab is marketed under a collaboration agreement between Genmab and Novartis.

COMPLEMENT 2 trial

The FDA’s latest approval for ofatumumab is based on results of the phase 3 COMPLEMENT 2 trial. Novartis reported top-line results from this study in April.

The trial enrolled 365 patients with relapsed CLL. The patients were randomized 1:1 to receive up to 6 cycles of ofatumumab in combination with fludarabine and cyclophosphamide or up to 6 cycles of fludarabine and cyclophosphamide alone.

The primary endpoint was progression-free survival, as assessed by an independent review committee.

The median progression-free survival was 28.9 months for patients receiving ofatumumab plus fludarabine and cyclophosphamide, compared to 18.8 months for patients receiving fludarabine and cyclophosphamide alone (hazard ratio=0.67, P=0.0032).

Novartis said the safety profile observed in this study was consistent with other trials of ofatumumab, and no new safety signals were observed.

Ofatumumab (Arzerra)

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved the use of ofatumumab (Arzerra®) in combination with fludarabine and cyclophosphamide to treat patients with relapsed chronic lymphocytic leukemia (CLL).

Ofatumumab was previously approved by the FDA for use in combination with chlorambucil to treat previously untreated CLL patients who cannot receive fludarabine-based therapy, as monotherapy for CLL that is refractory to fludarabine and alemtuzumab, and as maintenance therapy for patients who are in complete or partial response after receiving at least 2 lines of therapy for recurrent or progressive CLL.

Ofatumumab is a monoclonal antibody designed to target CD20.

The drug’s prescribing information includes a boxed warning noting that hepatitis B virus reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab. In some cases, this results in fulminant hepatitis, hepatic failure, and death.

The boxed warning also states that progressive multifocal leukoencephalopathy, resulting in death, can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab.

Ofatumumab is marketed under a collaboration agreement between Genmab and Novartis.

COMPLEMENT 2 trial

The FDA’s latest approval for ofatumumab is based on results of the phase 3 COMPLEMENT 2 trial. Novartis reported top-line results from this study in April.

The trial enrolled 365 patients with relapsed CLL. The patients were randomized 1:1 to receive up to 6 cycles of ofatumumab in combination with fludarabine and cyclophosphamide or up to 6 cycles of fludarabine and cyclophosphamide alone.

The primary endpoint was progression-free survival, as assessed by an independent review committee.

The median progression-free survival was 28.9 months for patients receiving ofatumumab plus fludarabine and cyclophosphamide, compared to 18.8 months for patients receiving fludarabine and cyclophosphamide alone (hazard ratio=0.67, P=0.0032).

Novartis said the safety profile observed in this study was consistent with other trials of ofatumumab, and no new safety signals were observed.

Blood in bags and vials

Photo by Daniel Gay

Results of preclinical research may explain why people with blood type O often get more severely ill from cholera than people with other blood types.

The study suggests that, in people with blood type O, cholera toxin hyperactivates a key signaling molecule in intestinal cells.

And high levels of that molecule, cyclic adenosine monophosphate (cAMP), lead to excretion of electrolytes and water—in other words, diarrhea.

“We have shown that blood type influences how strongly cholera toxin activates intestinal cells, leading to diarrhea,” said study author James Fleckenstein, MD, of Washington University School of Medicine in Saint Louis, Missouri.

Dr Fleckenstein and his colleagues reported these findings in The American Journal of Tropical Medicine and Hygiene.

Cholera is caused by Vibrio cholerae, a bacterium that infects cells of the small intestine.

Epidemiologists first noticed 4 decades ago that people with blood type O were more likely to be hospitalized for cholera than people with other blood types, but the reasons for the difference had never been determined.

Although the blood group antigens—A, B, AB, and O—are best known for their presence on red blood cells, they also are found on the surface of many other cell types, including the cells that line the intestine.

To find out what effect cholera toxin has on intestinal cells carrying different blood group antigens, Dr Fleckenstein and his colleagues used clusters of intestinal epithelial stem cells, called enteroids, that can be grown in the lab and differentiated into mature intestinal cells.

The researchers treated 4 groups of enteroids with cholera toxin—2 derived from people with blood type A and 2 from people with blood type O—and measured the amount of cAMP inside the cells. Enteroids from the other 2 blood types—B and AB—were not available at the time the study was done.

The researchers found that levels of cAMP were roughly twice as high in the cells with the type O antigen than in the cells with type A antigen, suggesting that people with type O antigen who were exposed to cholera toxin would suffer more severe diarrhea.

“It is well-established that high levels of this molecule lead to diarrhea, so we’re making the assumption that higher levels lead to even more diarrhea,” said study author F. Matthew Kuhlmann, MD, of Washington University School of Medicine.

“Unfortunately, we have no way directly to link the responses to the volume of diarrhea and, therefore, the severity of disease.”

The researchers confirmed their enteroid results in an intestinal cell line originally derived from a person with blood type A. The cell line was modified to produce the type O antigen instead.

The team found that cholera toxin induced roughly double the amount of cAMP in cells with type O antigen than in those with type A.

Dr Fleckenstein said the researchers are not sure why cholera toxin induces different responses in cells with different blood group antigens on their surfaces.

“The cholera toxin is known to bind weakly to the ABO antigens, so they may be acting as decoys to draw the toxin away from its true target,” Dr Fleckenstein said. “It may be that the type O antigen just isn’t as good of a decoy as the type A antigen.”

Blood in bags and vials

Photo by Daniel Gay

Results of preclinical research may explain why people with blood type O often get more severely ill from cholera than people with other blood types.

The study suggests that, in people with blood type O, cholera toxin hyperactivates a key signaling molecule in intestinal cells.

And high levels of that molecule, cyclic adenosine monophosphate (cAMP), lead to excretion of electrolytes and water—in other words, diarrhea.

“We have shown that blood type influences how strongly cholera toxin activates intestinal cells, leading to diarrhea,” said study author James Fleckenstein, MD, of Washington University School of Medicine in Saint Louis, Missouri.

Dr Fleckenstein and his colleagues reported these findings in The American Journal of Tropical Medicine and Hygiene.

Cholera is caused by Vibrio cholerae, a bacterium that infects cells of the small intestine.

Epidemiologists first noticed 4 decades ago that people with blood type O were more likely to be hospitalized for cholera than people with other blood types, but the reasons for the difference had never been determined.

Although the blood group antigens—A, B, AB, and O—are best known for their presence on red blood cells, they also are found on the surface of many other cell types, including the cells that line the intestine.

To find out what effect cholera toxin has on intestinal cells carrying different blood group antigens, Dr Fleckenstein and his colleagues used clusters of intestinal epithelial stem cells, called enteroids, that can be grown in the lab and differentiated into mature intestinal cells.

The researchers treated 4 groups of enteroids with cholera toxin—2 derived from people with blood type A and 2 from people with blood type O—and measured the amount of cAMP inside the cells. Enteroids from the other 2 blood types—B and AB—were not available at the time the study was done.

The researchers found that levels of cAMP were roughly twice as high in the cells with the type O antigen than in the cells with type A antigen, suggesting that people with type O antigen who were exposed to cholera toxin would suffer more severe diarrhea.

“It is well-established that high levels of this molecule lead to diarrhea, so we’re making the assumption that higher levels lead to even more diarrhea,” said study author F. Matthew Kuhlmann, MD, of Washington University School of Medicine.

“Unfortunately, we have no way directly to link the responses to the volume of diarrhea and, therefore, the severity of disease.”

The researchers confirmed their enteroid results in an intestinal cell line originally derived from a person with blood type A. The cell line was modified to produce the type O antigen instead.

The team found that cholera toxin induced roughly double the amount of cAMP in cells with type O antigen than in those with type A.

Dr Fleckenstein said the researchers are not sure why cholera toxin induces different responses in cells with different blood group antigens on their surfaces.

“The cholera toxin is known to bind weakly to the ABO antigens, so they may be acting as decoys to draw the toxin away from its true target,” Dr Fleckenstein said. “It may be that the type O antigen just isn’t as good of a decoy as the type A antigen.”

Blood in bags and vials

Photo by Daniel Gay

Results of preclinical research may explain why people with blood type O often get more severely ill from cholera than people with other blood types.

The study suggests that, in people with blood type O, cholera toxin hyperactivates a key signaling molecule in intestinal cells.

And high levels of that molecule, cyclic adenosine monophosphate (cAMP), lead to excretion of electrolytes and water—in other words, diarrhea.

“We have shown that blood type influences how strongly cholera toxin activates intestinal cells, leading to diarrhea,” said study author James Fleckenstein, MD, of Washington University School of Medicine in Saint Louis, Missouri.

Dr Fleckenstein and his colleagues reported these findings in The American Journal of Tropical Medicine and Hygiene.

Cholera is caused by Vibrio cholerae, a bacterium that infects cells of the small intestine.

Epidemiologists first noticed 4 decades ago that people with blood type O were more likely to be hospitalized for cholera than people with other blood types, but the reasons for the difference had never been determined.

Although the blood group antigens—A, B, AB, and O—are best known for their presence on red blood cells, they also are found on the surface of many other cell types, including the cells that line the intestine.

To find out what effect cholera toxin has on intestinal cells carrying different blood group antigens, Dr Fleckenstein and his colleagues used clusters of intestinal epithelial stem cells, called enteroids, that can be grown in the lab and differentiated into mature intestinal cells.

The researchers treated 4 groups of enteroids with cholera toxin—2 derived from people with blood type A and 2 from people with blood type O—and measured the amount of cAMP inside the cells. Enteroids from the other 2 blood types—B and AB—were not available at the time the study was done.

The researchers found that levels of cAMP were roughly twice as high in the cells with the type O antigen than in the cells with type A antigen, suggesting that people with type O antigen who were exposed to cholera toxin would suffer more severe diarrhea.

“It is well-established that high levels of this molecule lead to diarrhea, so we’re making the assumption that higher levels lead to even more diarrhea,” said study author F. Matthew Kuhlmann, MD, of Washington University School of Medicine.

“Unfortunately, we have no way directly to link the responses to the volume of diarrhea and, therefore, the severity of disease.”

The researchers confirmed their enteroid results in an intestinal cell line originally derived from a person with blood type A. The cell line was modified to produce the type O antigen instead.

The team found that cholera toxin induced roughly double the amount of cAMP in cells with type O antigen than in those with type A.

Dr Fleckenstein said the researchers are not sure why cholera toxin induces different responses in cells with different blood group antigens on their surfaces.

“The cholera toxin is known to bind weakly to the ABO antigens, so they may be acting as decoys to draw the toxin away from its true target,” Dr Fleckenstein said. “It may be that the type O antigen just isn’t as good of a decoy as the type A antigen.”

Purpose: The purpose of this study is to determine the efficacy of inhibition of mitochondrial antioxidant defense against mesothelioma and whether the cyclin-dependent kinase 4 (CDK4) inhibitor palbociclib sensitizes mesothelioma cells to inhibition of mitochondrial antioxidant defense.

Background: Mesothelioma is a highly fatal cancer with limited therapeutic options. Low expression of the endogenous CDK4 inhibitor p16INK4A has been demonstrated in up to 90% of mesothelioma tumors. CDK4 has also been demonstrated to activate manganese superoxide dismutase, which can decrease superoxide levels in cells and may make them less susceptible to induction of apoptosis. Downregulation of the key mitochondrial antioxidant protein, thioredoxin 2 (Trx2) has been demonstrated to increase reactive oxygen species production in mesothelioma cells resulting in reduced mesothelioma tumor growth. Gentian violet has been demonstrated to result in decreased expression of Trx2, a key mitochondrial antioxidant protein. The goal of this project is to determine whether concomitant targeting of the cell cycle and mitochondrial antioxidant pathways lead to improved efficacy against mesothelioma.

Methods: Mesothelioma cells were treated with compound or control and proliferation was evaluated using Cell Counting Kit 8 (Dojindo). For immunoblotting experiments, detection was performed using enhanced chemiluminescence. Apoptosis was detected via Cell Death Detection ELISAPLUS (Sigma-Aldrich). All experiments were done in duplicate or triplicate.

Data Analysis: IC50 curves were fitted via Origin software.

Results: Previously, we have demonstrated that palbociclib inhibits mesothelioma cell proliferation, inhibits retinoblastoma protein (Rb) phosphorylation, and results in cell cycle arrest. Mesothelioma cells in culture were treated with palbociclib and gentian violet alone and in combination. After 72h incubation with gentian violet, decreased cell proliferation was observed for 3 separate cell lines (IC50 = 365 nM, 870 nM, and 920 nM, respectively). Incubation with gentian violet for 24h resulted in decreased expression of Trx2 in all cell lines and also induced apoptosis in all cell lines. Gentian violetsensitized mesothelioma cells to palbociclib in a cell proliferation assay.

Implications: Gentian violet resulted in a significant decrease in mesothelioma cell proliferation. Palbociclib also sensitizes mesothelioma cells to gentian violet. Further investigation of this combination approach may demonstrate these combinations are useful for mesothelioma treatment.

Purpose: The purpose of this study is to determine the efficacy of inhibition of mitochondrial antioxidant defense against mesothelioma and whether the cyclin-dependent kinase 4 (CDK4) inhibitor palbociclib sensitizes mesothelioma cells to inhibition of mitochondrial antioxidant defense.

Background: Mesothelioma is a highly fatal cancer with limited therapeutic options. Low expression of the endogenous CDK4 inhibitor p16INK4A has been demonstrated in up to 90% of mesothelioma tumors. CDK4 has also been demonstrated to activate manganese superoxide dismutase, which can decrease superoxide levels in cells and may make them less susceptible to induction of apoptosis. Downregulation of the key mitochondrial antioxidant protein, thioredoxin 2 (Trx2) has been demonstrated to increase reactive oxygen species production in mesothelioma cells resulting in reduced mesothelioma tumor growth. Gentian violet has been demonstrated to result in decreased expression of Trx2, a key mitochondrial antioxidant protein. The goal of this project is to determine whether concomitant targeting of the cell cycle and mitochondrial antioxidant pathways lead to improved efficacy against mesothelioma.

Methods: Mesothelioma cells were treated with compound or control and proliferation was evaluated using Cell Counting Kit 8 (Dojindo). For immunoblotting experiments, detection was performed using enhanced chemiluminescence. Apoptosis was detected via Cell Death Detection ELISAPLUS (Sigma-Aldrich). All experiments were done in duplicate or triplicate.

Data Analysis: IC50 curves were fitted via Origin software.

Results: Previously, we have demonstrated that palbociclib inhibits mesothelioma cell proliferation, inhibits retinoblastoma protein (Rb) phosphorylation, and results in cell cycle arrest. Mesothelioma cells in culture were treated with palbociclib and gentian violet alone and in combination. After 72h incubation with gentian violet, decreased cell proliferation was observed for 3 separate cell lines (IC50 = 365 nM, 870 nM, and 920 nM, respectively). Incubation with gentian violet for 24h resulted in decreased expression of Trx2 in all cell lines and also induced apoptosis in all cell lines. Gentian violetsensitized mesothelioma cells to palbociclib in a cell proliferation assay.

Implications: Gentian violet resulted in a significant decrease in mesothelioma cell proliferation. Palbociclib also sensitizes mesothelioma cells to gentian violet. Further investigation of this combination approach may demonstrate these combinations are useful for mesothelioma treatment.

Purpose: The purpose of this study is to determine the efficacy of inhibition of mitochondrial antioxidant defense against mesothelioma and whether the cyclin-dependent kinase 4 (CDK4) inhibitor palbociclib sensitizes mesothelioma cells to inhibition of mitochondrial antioxidant defense.

Background: Mesothelioma is a highly fatal cancer with limited therapeutic options. Low expression of the endogenous CDK4 inhibitor p16INK4A has been demonstrated in up to 90% of mesothelioma tumors. CDK4 has also been demonstrated to activate manganese superoxide dismutase, which can decrease superoxide levels in cells and may make them less susceptible to induction of apoptosis. Downregulation of the key mitochondrial antioxidant protein, thioredoxin 2 (Trx2) has been demonstrated to increase reactive oxygen species production in mesothelioma cells resulting in reduced mesothelioma tumor growth. Gentian violet has been demonstrated to result in decreased expression of Trx2, a key mitochondrial antioxidant protein. The goal of this project is to determine whether concomitant targeting of the cell cycle and mitochondrial antioxidant pathways lead to improved efficacy against mesothelioma.

Methods: Mesothelioma cells were treated with compound or control and proliferation was evaluated using Cell Counting Kit 8 (Dojindo). For immunoblotting experiments, detection was performed using enhanced chemiluminescence. Apoptosis was detected via Cell Death Detection ELISAPLUS (Sigma-Aldrich). All experiments were done in duplicate or triplicate.

Data Analysis: IC50 curves were fitted via Origin software.

Results: Previously, we have demonstrated that palbociclib inhibits mesothelioma cell proliferation, inhibits retinoblastoma protein (Rb) phosphorylation, and results in cell cycle arrest. Mesothelioma cells in culture were treated with palbociclib and gentian violet alone and in combination. After 72h incubation with gentian violet, decreased cell proliferation was observed for 3 separate cell lines (IC50 = 365 nM, 870 nM, and 920 nM, respectively). Incubation with gentian violet for 24h resulted in decreased expression of Trx2 in all cell lines and also induced apoptosis in all cell lines. Gentian violetsensitized mesothelioma cells to palbociclib in a cell proliferation assay.

Implications: Gentian violet resulted in a significant decrease in mesothelioma cell proliferation. Palbociclib also sensitizes mesothelioma cells to gentian violet. Further investigation of this combination approach may demonstrate these combinations are useful for mesothelioma treatment.

Click here to access the September 2016 Digital Edition. 

Table of Contents

• Finally, Some Good News!
• Emerging Cataract Surgery Practice Patterns in the VHA
• Medication List Discrepancies and Therapeutic Duplications Among Dual Use Veterans
• Laboring in the Shadow of the Media: Care and Perceptions of Care in the VA
• Providing Quality Epilepsy Care for Veterans
• Is It All in the Eye of the Beholder? Comparing Pulmonologists’ and Radiologists’ Performance
• Angiomyomatous Hamartoma With Unexplained Hepatosplenomegaly
• Veteran Perceptions, Interest, and Use of Complementary and Alternative Medicine

Click here to access the September 2016 Digital Edition. 

Table of Contents

• Finally, Some Good News!
• Emerging Cataract Surgery Practice Patterns in the VHA
• Medication List Discrepancies and Therapeutic Duplications Among Dual Use Veterans
• Laboring in the Shadow of the Media: Care and Perceptions of Care in the VA
• Providing Quality Epilepsy Care for Veterans
• Is It All in the Eye of the Beholder? Comparing Pulmonologists’ and Radiologists’ Performance
• Angiomyomatous Hamartoma With Unexplained Hepatosplenomegaly
• Veteran Perceptions, Interest, and Use of Complementary and Alternative Medicine

Click here to access the September 2016 Digital Edition. 

Table of Contents

• Finally, Some Good News!
• Emerging Cataract Surgery Practice Patterns in the VHA
• Medication List Discrepancies and Therapeutic Duplications Among Dual Use Veterans
• Laboring in the Shadow of the Media: Care and Perceptions of Care in the VA
• Providing Quality Epilepsy Care for Veterans
• Is It All in the Eye of the Beholder? Comparing Pulmonologists’ and Radiologists’ Performance
• Angiomyomatous Hamartoma With Unexplained Hepatosplenomegaly
• Veteran Perceptions, Interest, and Use of Complementary and Alternative Medicine