Talking to your patients about PPIs

AGA has developed talking points about research released associating PPIs with dementia, chronic kidney disease, and the latest research associating PPI use with all-cause mortality. These resources can help you educate your patients on the data and on the risks and benefits of using PPIs in their care.

• • PPIs and dementia: http://www.gastro.org/news_items/2017/07/20/how-to-talk-with-your-patients-about-ppis-and-dementia.
• • PPIs and chronic kidney disease: http://www.gastro.org/news_items/how-to-talk-with-patients-about-ppis-and-chronic-kidney-disease.
• • PPIs and all-cause mortality: http://www.gastro.org/news_items/a-guide-to-conversations-about-the-latest-ppi-research-results.

Talking to your colleagues about PPIs

AGA members have been discussing this new data linking PPIs to death. Weigh in by visiting the AGA Community, www.community.gastro.org.

Talking to your patients about PPIs

AGA has developed talking points about research released associating PPIs with dementia, chronic kidney disease, and the latest research associating PPI use with all-cause mortality. These resources can help you educate your patients on the data and on the risks and benefits of using PPIs in their care.

• • PPIs and dementia: http://www.gastro.org/news_items/2017/07/20/how-to-talk-with-your-patients-about-ppis-and-dementia.
• • PPIs and chronic kidney disease: http://www.gastro.org/news_items/how-to-talk-with-patients-about-ppis-and-chronic-kidney-disease.
• • PPIs and all-cause mortality: http://www.gastro.org/news_items/a-guide-to-conversations-about-the-latest-ppi-research-results.

Talking to your colleagues about PPIs

AGA members have been discussing this new data linking PPIs to death. Weigh in by visiting the AGA Community, www.community.gastro.org.

Talking to your patients about PPIs

AGA has developed talking points about research released associating PPIs with dementia, chronic kidney disease, and the latest research associating PPI use with all-cause mortality. These resources can help you educate your patients on the data and on the risks and benefits of using PPIs in their care.

• • PPIs and dementia: http://www.gastro.org/news_items/2017/07/20/how-to-talk-with-your-patients-about-ppis-and-dementia.
• • PPIs and chronic kidney disease: http://www.gastro.org/news_items/how-to-talk-with-patients-about-ppis-and-chronic-kidney-disease.
• • PPIs and all-cause mortality: http://www.gastro.org/news_items/a-guide-to-conversations-about-the-latest-ppi-research-results.

Talking to your colleagues about PPIs

AGA members have been discussing this new data linking PPIs to death. Weigh in by visiting the AGA Community, www.community.gastro.org.

In 2017, eligible clinicians can use the AGA Clinical Guidelines app — through attestation of its use — to meet your 2017 CMS Merit-based Incentive Payment System (MIPS) pick your pace requirements as one way to try to avoid a payment penalty in 2019. The AGA Clinical Guidelines app has also been proposed by CMS as a 2018 Improvement Activity under MIPS.

How do you attest for 2017?

First, search for and download the AGA Clinical Guidelines app via the Apple App Store or Google Play.

After actively using the AGA Clinical Guidelines app, you will be able, in the near future, to go to the CMS Enterprise Portal to attest that you have met the 2017 MIPS improvement activity participation requirement. AGA will let you know when the portal opens.

CMS lowered the cost performance category to 0% in the 2017 pick your pace year and gave clinicians three reporting options under MIPS.

• Option one: Report to MIPS for a full 90-day period or full year on quality, improvement activities, and advancing care information, and maximize the chance to qualify for positive payment adjustments.
• Option two: Report less than a year, but for the full 90-day period on one quality measure, more than one improvement activity, or more than the required measures in advancing care information to avoid penalties and receive a possible positive update.
• Option three: Report one quality measure, one improvement activity, or report measures of advancing care information to avoid penalty.

Advanced Alternative Payment Models are another way to participate in MACRA in 2017.

What are improvement activities?

The MIPS pathway under the Medicare Access and CHIP Reauthorization Act (MACRA), uses quality and cost data to determine your payment, and replaces the previous framework that included the Medicare EHR Incentive Program, the Physician Quality Reporting System and the Value-Based Payment Modifier program. Physicians participating in MIPS will be scored on four categories:

• Quality.
• Advancing care information.
• Improvement activities.
• Cost.

The AGA Clinical Guidelines app is one way to satisfy participation in the improvement activities category.

[email protected]

In 2017, eligible clinicians can use the AGA Clinical Guidelines app — through attestation of its use — to meet your 2017 CMS Merit-based Incentive Payment System (MIPS) pick your pace requirements as one way to try to avoid a payment penalty in 2019. The AGA Clinical Guidelines app has also been proposed by CMS as a 2018 Improvement Activity under MIPS.

How do you attest for 2017?

First, search for and download the AGA Clinical Guidelines app via the Apple App Store or Google Play.

After actively using the AGA Clinical Guidelines app, you will be able, in the near future, to go to the CMS Enterprise Portal to attest that you have met the 2017 MIPS improvement activity participation requirement. AGA will let you know when the portal opens.

CMS lowered the cost performance category to 0% in the 2017 pick your pace year and gave clinicians three reporting options under MIPS.

• Option one: Report to MIPS for a full 90-day period or full year on quality, improvement activities, and advancing care information, and maximize the chance to qualify for positive payment adjustments.
• Option two: Report less than a year, but for the full 90-day period on one quality measure, more than one improvement activity, or more than the required measures in advancing care information to avoid penalties and receive a possible positive update.
• Option three: Report one quality measure, one improvement activity, or report measures of advancing care information to avoid penalty.

Advanced Alternative Payment Models are another way to participate in MACRA in 2017.

What are improvement activities?

The MIPS pathway under the Medicare Access and CHIP Reauthorization Act (MACRA), uses quality and cost data to determine your payment, and replaces the previous framework that included the Medicare EHR Incentive Program, the Physician Quality Reporting System and the Value-Based Payment Modifier program. Physicians participating in MIPS will be scored on four categories:

• Quality.
• Advancing care information.
• Improvement activities.
• Cost.

The AGA Clinical Guidelines app is one way to satisfy participation in the improvement activities category.

[email protected]

In 2017, eligible clinicians can use the AGA Clinical Guidelines app — through attestation of its use — to meet your 2017 CMS Merit-based Incentive Payment System (MIPS) pick your pace requirements as one way to try to avoid a payment penalty in 2019. The AGA Clinical Guidelines app has also been proposed by CMS as a 2018 Improvement Activity under MIPS.

How do you attest for 2017?

First, search for and download the AGA Clinical Guidelines app via the Apple App Store or Google Play.

After actively using the AGA Clinical Guidelines app, you will be able, in the near future, to go to the CMS Enterprise Portal to attest that you have met the 2017 MIPS improvement activity participation requirement. AGA will let you know when the portal opens.

CMS lowered the cost performance category to 0% in the 2017 pick your pace year and gave clinicians three reporting options under MIPS.

• Option one: Report to MIPS for a full 90-day period or full year on quality, improvement activities, and advancing care information, and maximize the chance to qualify for positive payment adjustments.
• Option two: Report less than a year, but for the full 90-day period on one quality measure, more than one improvement activity, or more than the required measures in advancing care information to avoid penalties and receive a possible positive update.
• Option three: Report one quality measure, one improvement activity, or report measures of advancing care information to avoid penalty.

Advanced Alternative Payment Models are another way to participate in MACRA in 2017.

What are improvement activities?

The MIPS pathway under the Medicare Access and CHIP Reauthorization Act (MACRA), uses quality and cost data to determine your payment, and replaces the previous framework that included the Medicare EHR Incentive Program, the Physician Quality Reporting System and the Value-Based Payment Modifier program. Physicians participating in MIPS will be scored on four categories:

• Quality.
• Advancing care information.
• Improvement activities.
• Cost.

The AGA Clinical Guidelines app is one way to satisfy participation in the improvement activities category.

[email protected]

AGA is proud to share that the AGA Future Leaders Program has been recognized with the 2017 Power of A Silver Award from the American Society of Association Executives. The Power of A Awards recognize a select number of organizations annually for innovative and effective programs that have a positive impact. The Power of A Awards are the association industry’s highest honor.

The AGA Future Leaders Program, which launched in March 2015, provides a pathway for selected participants to develop the leadership skills necessary to serve AGA. The 1.5-year program provides opportunities for participants to network, connect with mentors, develop leadership skills, and learn about AGA’s governance and operations while advancing their careers and supporting the profession. During the program, participants work on creating fresh and innovative projects to support AGA and the field.

The AGA Future Leaders Program’s commitment to encouraging innovation and building the GI workforce are key reasons it was recognized with this prestigious award.

Please join us in congratulating all of the AGA Future Leaders Program participants, mentors, program chairs, and staff for their part in this accomplishment. To learn more about this program, visit the AGA Future Leaders Program web page, http://www.gastro.org/about/initiatives/aga-future-leaders-program.
 

[email protected]

AGA is proud to share that the AGA Future Leaders Program has been recognized with the 2017 Power of A Silver Award from the American Society of Association Executives. The Power of A Awards recognize a select number of organizations annually for innovative and effective programs that have a positive impact. The Power of A Awards are the association industry’s highest honor.

The AGA Future Leaders Program, which launched in March 2015, provides a pathway for selected participants to develop the leadership skills necessary to serve AGA. The 1.5-year program provides opportunities for participants to network, connect with mentors, develop leadership skills, and learn about AGA’s governance and operations while advancing their careers and supporting the profession. During the program, participants work on creating fresh and innovative projects to support AGA and the field.

The AGA Future Leaders Program’s commitment to encouraging innovation and building the GI workforce are key reasons it was recognized with this prestigious award.

Please join us in congratulating all of the AGA Future Leaders Program participants, mentors, program chairs, and staff for their part in this accomplishment. To learn more about this program, visit the AGA Future Leaders Program web page, http://www.gastro.org/about/initiatives/aga-future-leaders-program.
 

[email protected]

AGA is proud to share that the AGA Future Leaders Program has been recognized with the 2017 Power of A Silver Award from the American Society of Association Executives. The Power of A Awards recognize a select number of organizations annually for innovative and effective programs that have a positive impact. The Power of A Awards are the association industry’s highest honor.

The AGA Future Leaders Program, which launched in March 2015, provides a pathway for selected participants to develop the leadership skills necessary to serve AGA. The 1.5-year program provides opportunities for participants to network, connect with mentors, develop leadership skills, and learn about AGA’s governance and operations while advancing their careers and supporting the profession. During the program, participants work on creating fresh and innovative projects to support AGA and the field.

The AGA Future Leaders Program’s commitment to encouraging innovation and building the GI workforce are key reasons it was recognized with this prestigious award.

Please join us in congratulating all of the AGA Future Leaders Program participants, mentors, program chairs, and staff for their part in this accomplishment. To learn more about this program, visit the AGA Future Leaders Program web page, http://www.gastro.org/about/initiatives/aga-future-leaders-program.
 

[email protected]

Pediatric News welcomes Lenore Jarvis MD, MEd, to its editorial advisory board.

Dr. Jarvis is a pediatric emergency medicine physician at Children’s National Health System, and assistant professor of pediatrics at George Washington University, both in Washington.

Pediatric News welcomes Lenore Jarvis MD, MEd, to its editorial advisory board.

Dr. Jarvis is a pediatric emergency medicine physician at Children’s National Health System, and assistant professor of pediatrics at George Washington University, both in Washington.

Pediatric News welcomes Lenore Jarvis MD, MEd, to its editorial advisory board.

Dr. Jarvis is a pediatric emergency medicine physician at Children’s National Health System, and assistant professor of pediatrics at George Washington University, both in Washington.

NEW YORK – Targeted interventions aimed at reducing patient readmission after bariatric surgery at a high-volume academic medical center led to a 61% overall decrease year over year. The center also saw a substantial reduction in readmissions linked to the top three factors of readmission identified by the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program, as well as a precipitous drop in the revisional surgery readmission rate.

“Our center, like so many others, has quarterly meetings in accordance with the MBSAQIP to look at our data. And this led to recognition of some common reasons for readmission,” said Chetan V. Aher, MD, a general surgeon at the department of surgery at Vanderbilt University Medical Center in Nashville, Tenn. Oral (PO) intolerance, dehydration, and nonemergent abdominal pain were the top reasons flagged by the MBSAQIP registry data at the medical center. Dr. Aher and his colleagues moved to focus on postoperative diet, administration of medications, management of patients who return to the hospital after surgery, and optimal staffing.

“Notably, the readmission rate for revisional procedures decreased by a whopping 90%,” Dr. Aher said. “I think a lot of these targeted interventions just really helped these patients who were at a higher risk to begin with to be readmitted.”

New dietary dos and don’ts

“We changed our postoperative diet,” Dr. Aher said. Instead of a soft food diet a couple of days after surgery, the full liquid diet was extended to 3 weeks post surgery.

The clinicians also implemented what they called a ‘no MEALS’ policy, which stands for no Meat, Eggs And Leftovers. “We were having problems with meat, although tender fish was okay, and some other things that went down easily,” Dr. Aher said at the American College of Surgeons Quality and Safety Conference. “We had some complaints about no eggs after surgery. A lot of patients love eggs,” he added. But they recommended avoiding eggs for 1 month after bariatric surgery to avoid nausea.

“Avoiding leftovers was also a big deal for patients,” Dr. Aher said. But patients who microwaved leftovers would “then come into the hospital with problems.”

Medication modifications

Another frequent cause of nausea was a “terrible and off-putting” taste when crushed tablets or medication capsules were added to the patient’s diet. Changing how patients took their medication “was a big help.” At the same time, there was a large institutional effort at Vanderbilt to start providing discharge medications in the hospital to increase postoperative compliance. “Bariatric surgery was one of the pilot programs for this,” Dr. Aher said. Discharge medications were filled by the pharmacy at Vanderbilt and delivered to the patient’s room, and a pharmacist or pharmacy intern explained how to use them. Compliance on medications increased, which may in turn have had an impact on readmissions.

Changes to patient management

Dr. Aher and his colleagues also changed where they treated patients who returned with problems. “Previously, when patients called in, the clinic diverted them to the emergency room. We stopped doing that, and increased our capacity to see these patients in the clinic instead.” This led to an increase in use of IV hydration in the clinic.

A meeting attendee asked if providing this service led to any problems with clinic capacity.

“Sometimes,” Dr. Aher said. “We don’t have a huge number of patients coming in for IV hydration, but when we had two come in on the same day, it did take up a couple of exam rooms.” To address this, the clinicians found other space in the clinic that would offer privacy for patients while not tying up exam rooms.

In addition, the clinic expanded nurse practitioner availability to 5 days a week to make the discharge process more consistent. “Of course, as we rolled all these things out, we made sure our educational material was updated accordingly,” Dr. Aher said.

The study demonstrates that a collaborative team effort and targeted interventions can result in a significant reduction in readmissions, Dr. Aher said. “Regular quality focused meetings are really important to facilitate recognition of various areas for improvement, especially in a high-volume center. Introducing an MBSAQIP registry serves as an excellent tool to effect these changes,” he said.

Dr. Aher had no relevant financial disclosures.

NEW YORK – Targeted interventions aimed at reducing patient readmission after bariatric surgery at a high-volume academic medical center led to a 61% overall decrease year over year. The center also saw a substantial reduction in readmissions linked to the top three factors of readmission identified by the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program, as well as a precipitous drop in the revisional surgery readmission rate.

“Our center, like so many others, has quarterly meetings in accordance with the MBSAQIP to look at our data. And this led to recognition of some common reasons for readmission,” said Chetan V. Aher, MD, a general surgeon at the department of surgery at Vanderbilt University Medical Center in Nashville, Tenn. Oral (PO) intolerance, dehydration, and nonemergent abdominal pain were the top reasons flagged by the MBSAQIP registry data at the medical center. Dr. Aher and his colleagues moved to focus on postoperative diet, administration of medications, management of patients who return to the hospital after surgery, and optimal staffing.

“Notably, the readmission rate for revisional procedures decreased by a whopping 90%,” Dr. Aher said. “I think a lot of these targeted interventions just really helped these patients who were at a higher risk to begin with to be readmitted.”

New dietary dos and don’ts

“We changed our postoperative diet,” Dr. Aher said. Instead of a soft food diet a couple of days after surgery, the full liquid diet was extended to 3 weeks post surgery.

The clinicians also implemented what they called a ‘no MEALS’ policy, which stands for no Meat, Eggs And Leftovers. “We were having problems with meat, although tender fish was okay, and some other things that went down easily,” Dr. Aher said at the American College of Surgeons Quality and Safety Conference. “We had some complaints about no eggs after surgery. A lot of patients love eggs,” he added. But they recommended avoiding eggs for 1 month after bariatric surgery to avoid nausea.

“Avoiding leftovers was also a big deal for patients,” Dr. Aher said. But patients who microwaved leftovers would “then come into the hospital with problems.”

Medication modifications

Another frequent cause of nausea was a “terrible and off-putting” taste when crushed tablets or medication capsules were added to the patient’s diet. Changing how patients took their medication “was a big help.” At the same time, there was a large institutional effort at Vanderbilt to start providing discharge medications in the hospital to increase postoperative compliance. “Bariatric surgery was one of the pilot programs for this,” Dr. Aher said. Discharge medications were filled by the pharmacy at Vanderbilt and delivered to the patient’s room, and a pharmacist or pharmacy intern explained how to use them. Compliance on medications increased, which may in turn have had an impact on readmissions.

Changes to patient management

Dr. Aher and his colleagues also changed where they treated patients who returned with problems. “Previously, when patients called in, the clinic diverted them to the emergency room. We stopped doing that, and increased our capacity to see these patients in the clinic instead.” This led to an increase in use of IV hydration in the clinic.

A meeting attendee asked if providing this service led to any problems with clinic capacity.

“Sometimes,” Dr. Aher said. “We don’t have a huge number of patients coming in for IV hydration, but when we had two come in on the same day, it did take up a couple of exam rooms.” To address this, the clinicians found other space in the clinic that would offer privacy for patients while not tying up exam rooms.

In addition, the clinic expanded nurse practitioner availability to 5 days a week to make the discharge process more consistent. “Of course, as we rolled all these things out, we made sure our educational material was updated accordingly,” Dr. Aher said.

The study demonstrates that a collaborative team effort and targeted interventions can result in a significant reduction in readmissions, Dr. Aher said. “Regular quality focused meetings are really important to facilitate recognition of various areas for improvement, especially in a high-volume center. Introducing an MBSAQIP registry serves as an excellent tool to effect these changes,” he said.

Dr. Aher had no relevant financial disclosures.

NEW YORK – Targeted interventions aimed at reducing patient readmission after bariatric surgery at a high-volume academic medical center led to a 61% overall decrease year over year. The center also saw a substantial reduction in readmissions linked to the top three factors of readmission identified by the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program, as well as a precipitous drop in the revisional surgery readmission rate.

“Our center, like so many others, has quarterly meetings in accordance with the MBSAQIP to look at our data. And this led to recognition of some common reasons for readmission,” said Chetan V. Aher, MD, a general surgeon at the department of surgery at Vanderbilt University Medical Center in Nashville, Tenn. Oral (PO) intolerance, dehydration, and nonemergent abdominal pain were the top reasons flagged by the MBSAQIP registry data at the medical center. Dr. Aher and his colleagues moved to focus on postoperative diet, administration of medications, management of patients who return to the hospital after surgery, and optimal staffing.

“Notably, the readmission rate for revisional procedures decreased by a whopping 90%,” Dr. Aher said. “I think a lot of these targeted interventions just really helped these patients who were at a higher risk to begin with to be readmitted.”

New dietary dos and don’ts

“We changed our postoperative diet,” Dr. Aher said. Instead of a soft food diet a couple of days after surgery, the full liquid diet was extended to 3 weeks post surgery.

The clinicians also implemented what they called a ‘no MEALS’ policy, which stands for no Meat, Eggs And Leftovers. “We were having problems with meat, although tender fish was okay, and some other things that went down easily,” Dr. Aher said at the American College of Surgeons Quality and Safety Conference. “We had some complaints about no eggs after surgery. A lot of patients love eggs,” he added. But they recommended avoiding eggs for 1 month after bariatric surgery to avoid nausea.

“Avoiding leftovers was also a big deal for patients,” Dr. Aher said. But patients who microwaved leftovers would “then come into the hospital with problems.”

Medication modifications

Another frequent cause of nausea was a “terrible and off-putting” taste when crushed tablets or medication capsules were added to the patient’s diet. Changing how patients took their medication “was a big help.” At the same time, there was a large institutional effort at Vanderbilt to start providing discharge medications in the hospital to increase postoperative compliance. “Bariatric surgery was one of the pilot programs for this,” Dr. Aher said. Discharge medications were filled by the pharmacy at Vanderbilt and delivered to the patient’s room, and a pharmacist or pharmacy intern explained how to use them. Compliance on medications increased, which may in turn have had an impact on readmissions.

Changes to patient management

Dr. Aher and his colleagues also changed where they treated patients who returned with problems. “Previously, when patients called in, the clinic diverted them to the emergency room. We stopped doing that, and increased our capacity to see these patients in the clinic instead.” This led to an increase in use of IV hydration in the clinic.

A meeting attendee asked if providing this service led to any problems with clinic capacity.

“Sometimes,” Dr. Aher said. “We don’t have a huge number of patients coming in for IV hydration, but when we had two come in on the same day, it did take up a couple of exam rooms.” To address this, the clinicians found other space in the clinic that would offer privacy for patients while not tying up exam rooms.

In addition, the clinic expanded nurse practitioner availability to 5 days a week to make the discharge process more consistent. “Of course, as we rolled all these things out, we made sure our educational material was updated accordingly,” Dr. Aher said.

The study demonstrates that a collaborative team effort and targeted interventions can result in a significant reduction in readmissions, Dr. Aher said. “Regular quality focused meetings are really important to facilitate recognition of various areas for improvement, especially in a high-volume center. Introducing an MBSAQIP registry serves as an excellent tool to effect these changes,” he said.

Dr. Aher had no relevant financial disclosures.

Background

Hospital-acquired pneumonia (HAP) is defined as pneumonia that develops 48 hours or more after admission that was not present on admission; and ventilator-associated pneumonia (VAP) is pneumonia that develops 48 hours or more after endotracheal intubation.

HAP and VAP are common afflictions in hospitalized patients, accounting for nearly one-quarter of all hospital-acquired infections. They confer mortality rates of 24%-50%, increasing to nearly 75% if caused by resistant organisms.^1,2 Given the high prevalence and significant mortality associated with these types of pneumonia, diagnosis and treatment are essential. Treatment must be balanced against potential unintended consequences of antibiotic use including Clostridium difficile infections and the promotion of resistant bacteria caused by poor antibiotic stewardship.

Given the frequency with which HAP and VAP occur, and the need for equipoise with antibiotic use, it is essential that all practicing clinicians have an evidence-based construct for the diagnosis and treatment of HAP and VAP.
 

Guideline updates

In 2016, the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) reconvened after 11 years to update their recommendations for the treatment of HAP and VAP.² The decision to update their recommendations was based on the availability of new evidence regarding the diagnosis and treatment of these conditions.

Methods for Diagnosis: The use of semi-quantitative, noninvasive sampling of respiratory cultures is preferred for HAP and VAP, rather than empiric treatment or quantitative cultures (i.e., bronchoalveolar lavage, protected-specimen brush and blind bronchial sampling).

Initial antibiotic choice: For HAP and VAP, clinicians should include therapy targeting S. aureus, Pseudomonas aeruginosa, and other gram-negative bacilli. Therapy for methicillin-resistant S. aureus should be included if patients are at high risk for death (i.e., septic shock or ventilated patients) or if local drug-resistant prevalence is greater than 10%-20%. Similarly, two antipseudomonal antibiotics should be used only with empiric therapy if the patient is at high risk for mortality or local drug-resistant prevalence is greater than 10%.

Duration of therapy: HAP and VAP should be treated for 7 days with regimens that are tailored to culture data when available, assuming there has been appropriate clinical response. Procalcitonin may be paired with clinical judgment when considering antibiotic discontinuation.

Guideline analysis

There are several notable differences between the 2016 IDSA/ATS guidelines and the 2005 guidelines.³ The earlier guidelines recommended strong consideration of invasive respiratory cultures such as bronchoalveolar lavage or protected-specimen brush sampling for HAP/VAP. It is now recommended that only noninvasive cultures be performed in most clinical scenarios.

Takeaways

When considering the diagnosis of HAP and VAP, clinicians should be aware that the category of HCAP has been removed from current guidelines, and methods for microbiological diagnosis have been simplified.⁷ In addition, initial antibiotic selection should rely on institution-specific antibiograms and local resistance patterns when available. Recommended duration of therapy has been shortened, and should not include aminoglycosides.

Finally, antibiotic stewardship is the responsibility of each clinician and de-escalation of therapy for HAP and VAP should be guided by available respiratory cultures.
 

Dr. Hippensteel is a pulmonologist in Aurora, Colo. Dr. Sippel is visiting associate professor of clinical practice, medicine-pulmonary sciences & critical care at the University of Colorado School of Medicine.

References

1. Masterton R, Galloway A, French G, Street M, Armstrong J, Brown E, Cleverley J, Dilworth P, Fry C, Gascoigne A. Guidelines for the management of hospital-acquired pneumonia in the UK: report of the working party on hospital-acquired pneumonia of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother. 2008;62(1):5-34.

2. Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano LM, O’grady NP, Bartlett JG, Carratalà J. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016:ciw353.

3. Society AT, America IDSo. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171(4):388-416.

4. Dalhoff K, Abele-Horn M, Andreas S, Bauer T, von Baum H, Deja M, Ewig S, Gastmeier P, Gatermann S, Gerlach H. Epidemiology, diagnosis, and treatment of adult patients with nosocomial pneumonia. S-3 Guideline of the German Society for Anaesthesiology and Intensive Care Medicine, the German Society for Infectious Diseases, the German Society for Hygiene and Microbiology, the German Respiratory Society and the Paul-Ehrlich-Society for Chemotherapy. Pneumologie (Stuttgart, Germany). 2012;66(12):707-65.

5. Rotstein C, Evans G, Born A, Grossman R, Light RB, Magder S, McTaggart B, Weiss K, Zhanel GG. Clinical practice guidelines for hospital-acquired pneumonia and ventilator-associated pneumonia in adults. Canadian Journal of Infectious Diseases and Medical Microbiology. 2008;19(1):19-53.

6. Coffin SE, Klompas M, Classen D, Arias KM, Podgorny K, Anderson DJ, Burstin H, Calfee DP, Dubberke ER, Fraser V. Strategies to prevent ventilator-associated pneumonia in acute care hospitals. Infect Control Hosp Epidemiol. 2008;29(S1):S31-S40.

7. Tablan OC, Anderson LJ, Besser R, Bridges C, Hajjeh R. Guidelines for preventing healthcare-associated pneumonia, 2003. MMWR. 2004;53(RR-3):1-36.

Background

Hospital-acquired pneumonia (HAP) is defined as pneumonia that develops 48 hours or more after admission that was not present on admission; and ventilator-associated pneumonia (VAP) is pneumonia that develops 48 hours or more after endotracheal intubation.

HAP and VAP are common afflictions in hospitalized patients, accounting for nearly one-quarter of all hospital-acquired infections. They confer mortality rates of 24%-50%, increasing to nearly 75% if caused by resistant organisms.^1,2 Given the high prevalence and significant mortality associated with these types of pneumonia, diagnosis and treatment are essential. Treatment must be balanced against potential unintended consequences of antibiotic use including Clostridium difficile infections and the promotion of resistant bacteria caused by poor antibiotic stewardship.

Given the frequency with which HAP and VAP occur, and the need for equipoise with antibiotic use, it is essential that all practicing clinicians have an evidence-based construct for the diagnosis and treatment of HAP and VAP.
 

Guideline updates

In 2016, the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) reconvened after 11 years to update their recommendations for the treatment of HAP and VAP.² The decision to update their recommendations was based on the availability of new evidence regarding the diagnosis and treatment of these conditions.

Methods for Diagnosis: The use of semi-quantitative, noninvasive sampling of respiratory cultures is preferred for HAP and VAP, rather than empiric treatment or quantitative cultures (i.e., bronchoalveolar lavage, protected-specimen brush and blind bronchial sampling).

Initial antibiotic choice: For HAP and VAP, clinicians should include therapy targeting S. aureus, Pseudomonas aeruginosa, and other gram-negative bacilli. Therapy for methicillin-resistant S. aureus should be included if patients are at high risk for death (i.e., septic shock or ventilated patients) or if local drug-resistant prevalence is greater than 10%-20%. Similarly, two antipseudomonal antibiotics should be used only with empiric therapy if the patient is at high risk for mortality or local drug-resistant prevalence is greater than 10%.

Duration of therapy: HAP and VAP should be treated for 7 days with regimens that are tailored to culture data when available, assuming there has been appropriate clinical response. Procalcitonin may be paired with clinical judgment when considering antibiotic discontinuation.

Guideline analysis

There are several notable differences between the 2016 IDSA/ATS guidelines and the 2005 guidelines.³ The earlier guidelines recommended strong consideration of invasive respiratory cultures such as bronchoalveolar lavage or protected-specimen brush sampling for HAP/VAP. It is now recommended that only noninvasive cultures be performed in most clinical scenarios.

Takeaways

When considering the diagnosis of HAP and VAP, clinicians should be aware that the category of HCAP has been removed from current guidelines, and methods for microbiological diagnosis have been simplified.⁷ In addition, initial antibiotic selection should rely on institution-specific antibiograms and local resistance patterns when available. Recommended duration of therapy has been shortened, and should not include aminoglycosides.

Finally, antibiotic stewardship is the responsibility of each clinician and de-escalation of therapy for HAP and VAP should be guided by available respiratory cultures.
 

Dr. Hippensteel is a pulmonologist in Aurora, Colo. Dr. Sippel is visiting associate professor of clinical practice, medicine-pulmonary sciences & critical care at the University of Colorado School of Medicine.

References

1. Masterton R, Galloway A, French G, Street M, Armstrong J, Brown E, Cleverley J, Dilworth P, Fry C, Gascoigne A. Guidelines for the management of hospital-acquired pneumonia in the UK: report of the working party on hospital-acquired pneumonia of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother. 2008;62(1):5-34.

2. Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano LM, O’grady NP, Bartlett JG, Carratalà J. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016:ciw353.

3. Society AT, America IDSo. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171(4):388-416.

4. Dalhoff K, Abele-Horn M, Andreas S, Bauer T, von Baum H, Deja M, Ewig S, Gastmeier P, Gatermann S, Gerlach H. Epidemiology, diagnosis, and treatment of adult patients with nosocomial pneumonia. S-3 Guideline of the German Society for Anaesthesiology and Intensive Care Medicine, the German Society for Infectious Diseases, the German Society for Hygiene and Microbiology, the German Respiratory Society and the Paul-Ehrlich-Society for Chemotherapy. Pneumologie (Stuttgart, Germany). 2012;66(12):707-65.

5. Rotstein C, Evans G, Born A, Grossman R, Light RB, Magder S, McTaggart B, Weiss K, Zhanel GG. Clinical practice guidelines for hospital-acquired pneumonia and ventilator-associated pneumonia in adults. Canadian Journal of Infectious Diseases and Medical Microbiology. 2008;19(1):19-53.

6. Coffin SE, Klompas M, Classen D, Arias KM, Podgorny K, Anderson DJ, Burstin H, Calfee DP, Dubberke ER, Fraser V. Strategies to prevent ventilator-associated pneumonia in acute care hospitals. Infect Control Hosp Epidemiol. 2008;29(S1):S31-S40.

7. Tablan OC, Anderson LJ, Besser R, Bridges C, Hajjeh R. Guidelines for preventing healthcare-associated pneumonia, 2003. MMWR. 2004;53(RR-3):1-36.

Background

Hospital-acquired pneumonia (HAP) is defined as pneumonia that develops 48 hours or more after admission that was not present on admission; and ventilator-associated pneumonia (VAP) is pneumonia that develops 48 hours or more after endotracheal intubation.

HAP and VAP are common afflictions in hospitalized patients, accounting for nearly one-quarter of all hospital-acquired infections. They confer mortality rates of 24%-50%, increasing to nearly 75% if caused by resistant organisms.^1,2 Given the high prevalence and significant mortality associated with these types of pneumonia, diagnosis and treatment are essential. Treatment must be balanced against potential unintended consequences of antibiotic use including Clostridium difficile infections and the promotion of resistant bacteria caused by poor antibiotic stewardship.

Given the frequency with which HAP and VAP occur, and the need for equipoise with antibiotic use, it is essential that all practicing clinicians have an evidence-based construct for the diagnosis and treatment of HAP and VAP.
 

Guideline updates

In 2016, the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) reconvened after 11 years to update their recommendations for the treatment of HAP and VAP.² The decision to update their recommendations was based on the availability of new evidence regarding the diagnosis and treatment of these conditions.

Methods for Diagnosis: The use of semi-quantitative, noninvasive sampling of respiratory cultures is preferred for HAP and VAP, rather than empiric treatment or quantitative cultures (i.e., bronchoalveolar lavage, protected-specimen brush and blind bronchial sampling).

Initial antibiotic choice: For HAP and VAP, clinicians should include therapy targeting S. aureus, Pseudomonas aeruginosa, and other gram-negative bacilli. Therapy for methicillin-resistant S. aureus should be included if patients are at high risk for death (i.e., septic shock or ventilated patients) or if local drug-resistant prevalence is greater than 10%-20%. Similarly, two antipseudomonal antibiotics should be used only with empiric therapy if the patient is at high risk for mortality or local drug-resistant prevalence is greater than 10%.

Duration of therapy: HAP and VAP should be treated for 7 days with regimens that are tailored to culture data when available, assuming there has been appropriate clinical response. Procalcitonin may be paired with clinical judgment when considering antibiotic discontinuation.

Guideline analysis

There are several notable differences between the 2016 IDSA/ATS guidelines and the 2005 guidelines.³ The earlier guidelines recommended strong consideration of invasive respiratory cultures such as bronchoalveolar lavage or protected-specimen brush sampling for HAP/VAP. It is now recommended that only noninvasive cultures be performed in most clinical scenarios.

Takeaways

When considering the diagnosis of HAP and VAP, clinicians should be aware that the category of HCAP has been removed from current guidelines, and methods for microbiological diagnosis have been simplified.⁷ In addition, initial antibiotic selection should rely on institution-specific antibiograms and local resistance patterns when available. Recommended duration of therapy has been shortened, and should not include aminoglycosides.

Finally, antibiotic stewardship is the responsibility of each clinician and de-escalation of therapy for HAP and VAP should be guided by available respiratory cultures.
 

Dr. Hippensteel is a pulmonologist in Aurora, Colo. Dr. Sippel is visiting associate professor of clinical practice, medicine-pulmonary sciences & critical care at the University of Colorado School of Medicine.

References

1. Masterton R, Galloway A, French G, Street M, Armstrong J, Brown E, Cleverley J, Dilworth P, Fry C, Gascoigne A. Guidelines for the management of hospital-acquired pneumonia in the UK: report of the working party on hospital-acquired pneumonia of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother. 2008;62(1):5-34.

2. Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano LM, O’grady NP, Bartlett JG, Carratalà J. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016:ciw353.

3. Society AT, America IDSo. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171(4):388-416.

4. Dalhoff K, Abele-Horn M, Andreas S, Bauer T, von Baum H, Deja M, Ewig S, Gastmeier P, Gatermann S, Gerlach H. Epidemiology, diagnosis, and treatment of adult patients with nosocomial pneumonia. S-3 Guideline of the German Society for Anaesthesiology and Intensive Care Medicine, the German Society for Infectious Diseases, the German Society for Hygiene and Microbiology, the German Respiratory Society and the Paul-Ehrlich-Society for Chemotherapy. Pneumologie (Stuttgart, Germany). 2012;66(12):707-65.

5. Rotstein C, Evans G, Born A, Grossman R, Light RB, Magder S, McTaggart B, Weiss K, Zhanel GG. Clinical practice guidelines for hospital-acquired pneumonia and ventilator-associated pneumonia in adults. Canadian Journal of Infectious Diseases and Medical Microbiology. 2008;19(1):19-53.

6. Coffin SE, Klompas M, Classen D, Arias KM, Podgorny K, Anderson DJ, Burstin H, Calfee DP, Dubberke ER, Fraser V. Strategies to prevent ventilator-associated pneumonia in acute care hospitals. Infect Control Hosp Epidemiol. 2008;29(S1):S31-S40.

7. Tablan OC, Anderson LJ, Besser R, Bridges C, Hajjeh R. Guidelines for preventing healthcare-associated pneumonia, 2003. MMWR. 2004;53(RR-3):1-36.

We already know quite a lot about how brachial blood pressure (BP) varies by day and time—might chronology also influence arterial occlusion pressure? To their knowledge, say researchers from the University of Mississippi and National Institute of Fitness and Sports in Kanoya, Japan, no study has examined that. They hypothesized that arterial occlusion measurements would oscillate in a pattern that mimicked diurnal variation in brachial systolic blood pressure (bSBP)—specifically, that the measurements would be higher in the evening than in the morning.

In their study of 22 participants, the researchers conducted 4 testing sessions, at 8 am and 6 pm, 48 hours apart. They measured arm circumference, bSBP, and bSBP at rest. They measured arterial occlusion pressure using a cuff inflated on the proximal portion of the upper arm, with a Doppler probe placed over the radial artery.

Pressure varied not only between days but within a day. They found significant difference between morning on day 1 and all other visits, although they say that may have been due to anxiousness during the first visit. But they also found a time effect for morning day 2 compared with all other visits. On day 1 there were no differences from morning to evening; on day 2, occlusion pressure increased from morning to evening.

“The interrelationship between the oscillating nature of different variables is extremely difficult to study,” the researchers say, “and makes it hard to ascertain the rhythm of one physiological variable in the absence of others, due to the inability to isolate variables from temporal progression.” To get the most accurate readings, they advise taking multiple measurements.

We already know quite a lot about how brachial blood pressure (BP) varies by day and time—might chronology also influence arterial occlusion pressure? To their knowledge, say researchers from the University of Mississippi and National Institute of Fitness and Sports in Kanoya, Japan, no study has examined that. They hypothesized that arterial occlusion measurements would oscillate in a pattern that mimicked diurnal variation in brachial systolic blood pressure (bSBP)—specifically, that the measurements would be higher in the evening than in the morning.

In their study of 22 participants, the researchers conducted 4 testing sessions, at 8 am and 6 pm, 48 hours apart. They measured arm circumference, bSBP, and bSBP at rest. They measured arterial occlusion pressure using a cuff inflated on the proximal portion of the upper arm, with a Doppler probe placed over the radial artery.

Pressure varied not only between days but within a day. They found significant difference between morning on day 1 and all other visits, although they say that may have been due to anxiousness during the first visit. But they also found a time effect for morning day 2 compared with all other visits. On day 1 there were no differences from morning to evening; on day 2, occlusion pressure increased from morning to evening.

“The interrelationship between the oscillating nature of different variables is extremely difficult to study,” the researchers say, “and makes it hard to ascertain the rhythm of one physiological variable in the absence of others, due to the inability to isolate variables from temporal progression.” To get the most accurate readings, they advise taking multiple measurements.

We already know quite a lot about how brachial blood pressure (BP) varies by day and time—might chronology also influence arterial occlusion pressure? To their knowledge, say researchers from the University of Mississippi and National Institute of Fitness and Sports in Kanoya, Japan, no study has examined that. They hypothesized that arterial occlusion measurements would oscillate in a pattern that mimicked diurnal variation in brachial systolic blood pressure (bSBP)—specifically, that the measurements would be higher in the evening than in the morning.

In their study of 22 participants, the researchers conducted 4 testing sessions, at 8 am and 6 pm, 48 hours apart. They measured arm circumference, bSBP, and bSBP at rest. They measured arterial occlusion pressure using a cuff inflated on the proximal portion of the upper arm, with a Doppler probe placed over the radial artery.

Pressure varied not only between days but within a day. They found significant difference between morning on day 1 and all other visits, although they say that may have been due to anxiousness during the first visit. But they also found a time effect for morning day 2 compared with all other visits. On day 1 there were no differences from morning to evening; on day 2, occlusion pressure increased from morning to evening.

“The interrelationship between the oscillating nature of different variables is extremely difficult to study,” the researchers say, “and makes it hard to ascertain the rhythm of one physiological variable in the absence of others, due to the inability to isolate variables from temporal progression.” To get the most accurate readings, they advise taking multiple measurements.

Exsanguination—bleeding to death—is the most common cause of potentially survivable death among wounded military. But a caulk gun–like device loaded with foam could extend valuable time to trauma patients and provide a “bridge to surgery,” says Leigh Anne Alexander, product manager for the U.S. Army Medical Materiel Agency (USAMMA). The foam is intended to stop massive intracavitary abdominal bleeding until the patient can get surgical care. 

The device contains expandable foam that is injected into the patient. Two separate chemicals, when mixed, cause the foam to swell rapidly to about 35 times its original volume. It expands around the internal organs and can be left inside the patient for up to 3 hours.

The USAMMA, a subordinate organization of the U.S. Army Medical Research and Materiel Command, is supporting a “pivotal” clinical trial to test the safety and effectiveness of the device, which received an Investigational Device Exemption earlier this year from the FDA. The clinical trial will start in 2018.

Exsanguination—bleeding to death—is the most common cause of potentially survivable death among wounded military. But a caulk gun–like device loaded with foam could extend valuable time to trauma patients and provide a “bridge to surgery,” says Leigh Anne Alexander, product manager for the U.S. Army Medical Materiel Agency (USAMMA). The foam is intended to stop massive intracavitary abdominal bleeding until the patient can get surgical care. 

The device contains expandable foam that is injected into the patient. Two separate chemicals, when mixed, cause the foam to swell rapidly to about 35 times its original volume. It expands around the internal organs and can be left inside the patient for up to 3 hours.

The USAMMA, a subordinate organization of the U.S. Army Medical Research and Materiel Command, is supporting a “pivotal” clinical trial to test the safety and effectiveness of the device, which received an Investigational Device Exemption earlier this year from the FDA. The clinical trial will start in 2018.

Exsanguination—bleeding to death—is the most common cause of potentially survivable death among wounded military. But a caulk gun–like device loaded with foam could extend valuable time to trauma patients and provide a “bridge to surgery,” says Leigh Anne Alexander, product manager for the U.S. Army Medical Materiel Agency (USAMMA). The foam is intended to stop massive intracavitary abdominal bleeding until the patient can get surgical care. 

The device contains expandable foam that is injected into the patient. Two separate chemicals, when mixed, cause the foam to swell rapidly to about 35 times its original volume. It expands around the internal organs and can be left inside the patient for up to 3 hours.

The USAMMA, a subordinate organization of the U.S. Army Medical Research and Materiel Command, is supporting a “pivotal” clinical trial to test the safety and effectiveness of the device, which received an Investigational Device Exemption earlier this year from the FDA. The clinical trial will start in 2018.

Hematopoietic stem cells in the bone marrow

New research suggests the classical yet contested “tree” model of hematopoiesis is accurate.

In this model, the tree trunk is composed of hematopoietic stem cells (HSCs), and the branches consist of various progenitor cells that give rise to a number of distinct cell types.

Because previous research raised doubts about this model, investigators set out to track hematopoiesis more effectively than ever before.

The team used a “random generator” to label HSCs with genetic barcodes, and this allowed them to trace which cell types arise from an HSC.

Hans-Reimer Rodewald, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg, and his colleagues described this research in Nature.

“Genetic barcodes have been developed and applied before, but they were based on methods that can also change cellular properties,” Dr Rodewald said. “Our barcodes are different. They can be induced tissue-specifically and directly in the genome of mice–without influencing the animals’ physiological development.”

The basis of the new technology is the Cre/loxP system that is used to rearrange or remove specially labeled DNA segments.

The investigators bred mice whose genomes exhibit the basic elements of the barcode. At a selected site, where no genes are encoded, it contains 9 DNA fragments from a plant called Arabidopsis thaliana. These elements are flanked by 10 genetic cutting sites called IoxP sites.

By administering a pharmacological agent, the matching molecular scissors, called “Cre,” can be activated in the animals’ HSCs. Then, code elements are randomly rearranged or cut out.

“This genetic, random DNA barcode generator can generate up to 1.8 million genetic barcodes, and we can identify the codes that arise only once in an experiment,” said study author Thomas Höfer, PhD, also of DKFZ.

When these specially labeled HSCs divide and mature, the barcodes are preserved.

The investigators performed comprehensive barcode analyses in order to trace an individual blood cell back to the HSC from which it originated.

These analyses revealed 2 large developmental branches “growing” from the HSC “tree trunk.” In one branch, T cells and B cells develop. In the other, red blood cells and other white blood cells, such as granulocytes and monocytes, form.

“Our findings show that the classical model of a hierarchical developmental tree that starts from multipotent stem cells holds true for hematopoiesis,” Dr Rodewald said.

He and his colleagues believe their genetic barcode system can be used for purposes other than studying blood cell development. In the future, it might be used for experimentally tracing the origin of leukemias and other cancers.

Hematopoietic stem cells in the bone marrow

New research suggests the classical yet contested “tree” model of hematopoiesis is accurate.

In this model, the tree trunk is composed of hematopoietic stem cells (HSCs), and the branches consist of various progenitor cells that give rise to a number of distinct cell types.

Because previous research raised doubts about this model, investigators set out to track hematopoiesis more effectively than ever before.

The team used a “random generator” to label HSCs with genetic barcodes, and this allowed them to trace which cell types arise from an HSC.

Hans-Reimer Rodewald, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg, and his colleagues described this research in Nature.

“Genetic barcodes have been developed and applied before, but they were based on methods that can also change cellular properties,” Dr Rodewald said. “Our barcodes are different. They can be induced tissue-specifically and directly in the genome of mice–without influencing the animals’ physiological development.”

The basis of the new technology is the Cre/loxP system that is used to rearrange or remove specially labeled DNA segments.

The investigators bred mice whose genomes exhibit the basic elements of the barcode. At a selected site, where no genes are encoded, it contains 9 DNA fragments from a plant called Arabidopsis thaliana. These elements are flanked by 10 genetic cutting sites called IoxP sites.

By administering a pharmacological agent, the matching molecular scissors, called “Cre,” can be activated in the animals’ HSCs. Then, code elements are randomly rearranged or cut out.

“This genetic, random DNA barcode generator can generate up to 1.8 million genetic barcodes, and we can identify the codes that arise only once in an experiment,” said study author Thomas Höfer, PhD, also of DKFZ.

When these specially labeled HSCs divide and mature, the barcodes are preserved.

The investigators performed comprehensive barcode analyses in order to trace an individual blood cell back to the HSC from which it originated.

These analyses revealed 2 large developmental branches “growing” from the HSC “tree trunk.” In one branch, T cells and B cells develop. In the other, red blood cells and other white blood cells, such as granulocytes and monocytes, form.

“Our findings show that the classical model of a hierarchical developmental tree that starts from multipotent stem cells holds true for hematopoiesis,” Dr Rodewald said.

He and his colleagues believe their genetic barcode system can be used for purposes other than studying blood cell development. In the future, it might be used for experimentally tracing the origin of leukemias and other cancers.

Hematopoietic stem cells in the bone marrow

New research suggests the classical yet contested “tree” model of hematopoiesis is accurate.

In this model, the tree trunk is composed of hematopoietic stem cells (HSCs), and the branches consist of various progenitor cells that give rise to a number of distinct cell types.

Because previous research raised doubts about this model, investigators set out to track hematopoiesis more effectively than ever before.

The team used a “random generator” to label HSCs with genetic barcodes, and this allowed them to trace which cell types arise from an HSC.

Hans-Reimer Rodewald, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg, and his colleagues described this research in Nature.

“Genetic barcodes have been developed and applied before, but they were based on methods that can also change cellular properties,” Dr Rodewald said. “Our barcodes are different. They can be induced tissue-specifically and directly in the genome of mice–without influencing the animals’ physiological development.”

The basis of the new technology is the Cre/loxP system that is used to rearrange or remove specially labeled DNA segments.

The investigators bred mice whose genomes exhibit the basic elements of the barcode. At a selected site, where no genes are encoded, it contains 9 DNA fragments from a plant called Arabidopsis thaliana. These elements are flanked by 10 genetic cutting sites called IoxP sites.

By administering a pharmacological agent, the matching molecular scissors, called “Cre,” can be activated in the animals’ HSCs. Then, code elements are randomly rearranged or cut out.

“This genetic, random DNA barcode generator can generate up to 1.8 million genetic barcodes, and we can identify the codes that arise only once in an experiment,” said study author Thomas Höfer, PhD, also of DKFZ.

When these specially labeled HSCs divide and mature, the barcodes are preserved.

The investigators performed comprehensive barcode analyses in order to trace an individual blood cell back to the HSC from which it originated.

These analyses revealed 2 large developmental branches “growing” from the HSC “tree trunk.” In one branch, T cells and B cells develop. In the other, red blood cells and other white blood cells, such as granulocytes and monocytes, form.

“Our findings show that the classical model of a hierarchical developmental tree that starts from multipotent stem cells holds true for hematopoiesis,” Dr Rodewald said.

He and his colleagues believe their genetic barcode system can be used for purposes other than studying blood cell development. In the future, it might be used for experimentally tracing the origin of leukemias and other cancers.

Image by Ed Uthman

An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.

PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.

Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.

Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.

These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.

“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.

“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”

With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.

The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.

Results in NHL

The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.

PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.

PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.

Results in MM

The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.

Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.

On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).

PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).

The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).

The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).

Results in AML

The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.

They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).

PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).

PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.

The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.

The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.

Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.

“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”

PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.

Image by Ed Uthman

An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.

PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.

Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.

Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.

These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.

“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.

“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”

With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.

The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.

Results in NHL

The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.

PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.

PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.

Results in MM

The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.

Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.

On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).

PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).

The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).

The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).

Results in AML

The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.

They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).

PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).

PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.

The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.

The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.

Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.

“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”

PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.

Image by Ed Uthman

An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.

PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.

Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.

Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.

These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.

“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.

“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”

With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.

The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.

Results in NHL

The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.

PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.

PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.

Results in MM

The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.

Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.

On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).

PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).

The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).

The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).

Results in AML

The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.

They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).

PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).

PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.

The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.

The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.

Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.

“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”

PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.