Q1: ANSWER: E

Critique

The incidence of bacterial infections in patients with cirrhosis with and without ascites who are admitted to the hospital with an upper GI bleed is 45% and studies have shown that the use of short-term (less than 7 days) prophylactic antibiotics is associated with lower rates of bacterial infections and lower risk for bleeding and death. Nadolol, a noncardioselective beta-blocker, is not helpful in active bleeding from gastric fundic varices. Imaging studies are the second step in the management of the patient to look for splenic vein thrombosis as a cause for fundic gastric varices. In cases where isolated gastric fundic varices are due to splenic vein thrombosis the treatment would be surgical referral for splenectomy.

References

1. Chavez-Tapia N.C., Barrientos-Gutierrez T., Tellez-Avila F.I., et al. Antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding. Cochrane Database Syst Rev. 2010;Sep 8:CD002907.
2. Hou M.C., Lin H.C., Liu T.T., et al. Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial. Hepatology. 2004;39:746-53.
3. Rimola A., García-Tsao G., Navasa M., et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol. 2000 Jan;32:142-53.

Q1: ANSWER: E

Critique

The incidence of bacterial infections in patients with cirrhosis with and without ascites who are admitted to the hospital with an upper GI bleed is 45% and studies have shown that the use of short-term (less than 7 days) prophylactic antibiotics is associated with lower rates of bacterial infections and lower risk for bleeding and death. Nadolol, a noncardioselective beta-blocker, is not helpful in active bleeding from gastric fundic varices. Imaging studies are the second step in the management of the patient to look for splenic vein thrombosis as a cause for fundic gastric varices. In cases where isolated gastric fundic varices are due to splenic vein thrombosis the treatment would be surgical referral for splenectomy.

References

1. Chavez-Tapia N.C., Barrientos-Gutierrez T., Tellez-Avila F.I., et al. Antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding. Cochrane Database Syst Rev. 2010;Sep 8:CD002907.
2. Hou M.C., Lin H.C., Liu T.T., et al. Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial. Hepatology. 2004;39:746-53.
3. Rimola A., García-Tsao G., Navasa M., et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol. 2000 Jan;32:142-53.

Q1: ANSWER: E

Critique

The incidence of bacterial infections in patients with cirrhosis with and without ascites who are admitted to the hospital with an upper GI bleed is 45% and studies have shown that the use of short-term (less than 7 days) prophylactic antibiotics is associated with lower rates of bacterial infections and lower risk for bleeding and death. Nadolol, a noncardioselective beta-blocker, is not helpful in active bleeding from gastric fundic varices. Imaging studies are the second step in the management of the patient to look for splenic vein thrombosis as a cause for fundic gastric varices. In cases where isolated gastric fundic varices are due to splenic vein thrombosis the treatment would be surgical referral for splenectomy.

References

1. Chavez-Tapia N.C., Barrientos-Gutierrez T., Tellez-Avila F.I., et al. Antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding. Cochrane Database Syst Rev. 2010;Sep 8:CD002907.
2. Hou M.C., Lin H.C., Liu T.T., et al. Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial. Hepatology. 2004;39:746-53.
3. Rimola A., García-Tsao G., Navasa M., et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol. 2000 Jan;32:142-53.

Many breakthroughs have been achieved through gastroenterological and hepatological research over the past century, forming the basis of the modern medical practice. As the charitable arm of the American Gastroenterological Association (AGA), the AGA Research Foundation contributes to this tradition of discovery to combat the continued loss of life and suffering brought on by digestive diseases.

The AGA Research Foundation is committed to closing the gap in research funding. The foundation serves the physicians and scientists who research, diagnose, prevent, and treat diseases of the gastrointestinal tract and liver and serves the patients whose lives and well-being depend on AGA’s members.

“This award is an invaluable asset to the start of my career in the field of pediatric gastroenterology and eosinophilic esophagitis research. It will foster continual growth in my research proficiency during my early years as a young physician-scientist,” said Dr. Edaire Cheng, UT Southwestern Medical Center, 2013 Research Scholar Award recipient.

“I have the great opportunity to pursue my research endeavors with protected time and resources. I also aim to encourage other young physicians to the field of gastroenterology and participation in research. The AGA Research Foundation has been extremely supportive of my work.”

The Foundation’s impact

• More than 863 scientists have been awarded grants.

• 90% of investigators who received an AGA Research Scholar Award (RSA) over the past 10 years have stayed in gastroenterology and hepatology research.

• Over 85% of AGA-funded researchers in the past 10 years received NIH funding subsequent to their AGA award with over 50% receiving $1 million or more in NIH grant support.

The AGA Research Foundation provides a key source of funding at a critical juncture in a young researcher’s career. Help provide critical funding to young researchers today by making a donation to the AGA Research Foundation on the foundation’s website or by mail to 4930 Del Ray Avenue, Bethesda, MD 20814.

Many breakthroughs have been achieved through gastroenterological and hepatological research over the past century, forming the basis of the modern medical practice. As the charitable arm of the American Gastroenterological Association (AGA), the AGA Research Foundation contributes to this tradition of discovery to combat the continued loss of life and suffering brought on by digestive diseases.

The AGA Research Foundation is committed to closing the gap in research funding. The foundation serves the physicians and scientists who research, diagnose, prevent, and treat diseases of the gastrointestinal tract and liver and serves the patients whose lives and well-being depend on AGA’s members.

“This award is an invaluable asset to the start of my career in the field of pediatric gastroenterology and eosinophilic esophagitis research. It will foster continual growth in my research proficiency during my early years as a young physician-scientist,” said Dr. Edaire Cheng, UT Southwestern Medical Center, 2013 Research Scholar Award recipient.

“I have the great opportunity to pursue my research endeavors with protected time and resources. I also aim to encourage other young physicians to the field of gastroenterology and participation in research. The AGA Research Foundation has been extremely supportive of my work.”

The Foundation’s impact

• More than 863 scientists have been awarded grants.

• 90% of investigators who received an AGA Research Scholar Award (RSA) over the past 10 years have stayed in gastroenterology and hepatology research.

• Over 85% of AGA-funded researchers in the past 10 years received NIH funding subsequent to their AGA award with over 50% receiving $1 million or more in NIH grant support.

The AGA Research Foundation provides a key source of funding at a critical juncture in a young researcher’s career. Help provide critical funding to young researchers today by making a donation to the AGA Research Foundation on the foundation’s website or by mail to 4930 Del Ray Avenue, Bethesda, MD 20814.

Many breakthroughs have been achieved through gastroenterological and hepatological research over the past century, forming the basis of the modern medical practice. As the charitable arm of the American Gastroenterological Association (AGA), the AGA Research Foundation contributes to this tradition of discovery to combat the continued loss of life and suffering brought on by digestive diseases.

The AGA Research Foundation is committed to closing the gap in research funding. The foundation serves the physicians and scientists who research, diagnose, prevent, and treat diseases of the gastrointestinal tract and liver and serves the patients whose lives and well-being depend on AGA’s members.

“This award is an invaluable asset to the start of my career in the field of pediatric gastroenterology and eosinophilic esophagitis research. It will foster continual growth in my research proficiency during my early years as a young physician-scientist,” said Dr. Edaire Cheng, UT Southwestern Medical Center, 2013 Research Scholar Award recipient.

“I have the great opportunity to pursue my research endeavors with protected time and resources. I also aim to encourage other young physicians to the field of gastroenterology and participation in research. The AGA Research Foundation has been extremely supportive of my work.”

The Foundation’s impact

• More than 863 scientists have been awarded grants.

• 90% of investigators who received an AGA Research Scholar Award (RSA) over the past 10 years have stayed in gastroenterology and hepatology research.

• Over 85% of AGA-funded researchers in the past 10 years received NIH funding subsequent to their AGA award with over 50% receiving $1 million or more in NIH grant support.

The AGA Research Foundation provides a key source of funding at a critical juncture in a young researcher’s career. Help provide critical funding to young researchers today by making a donation to the AGA Research Foundation on the foundation’s website or by mail to 4930 Del Ray Avenue, Bethesda, MD 20814.

The use of oral fluconazole during pregnancy significantly raises the risk of spontaneous abortion, according to a report published online Jan. 5 in JAMA.

In a nationwide cohort study in Denmark involving more than 1.4 million pregnancies that occurred from 1997-2013, oral fluconazole increased the risk of spontaneous abortion from 7-22 weeks gestation, compared with no exposure to fluconazole and with exposure to a topical azole.

The drug did not raise the risk of stillbirth significantly in this study, “but this outcome was relatively rare and the results were therefore imprecise,” wrote Ditte Molgaard-Nielsen of the department of epidemiology research, Statens Serum Institut, Copenhagen, and associates.

Creatas Images

The study findings indicate that “cautious prescribing of oral fluconazole in pregnancy may be advisable,” at least until more data regarding this association become available.

Pregnant women are at increased risk for candidiasis because of hormonal changes, and the prevalence of the infection is estimated to be 10% among pregnant women in the U.S. Intravaginal topical azoles are considered first-line treatment during pregnancy, but oral fluconazole can be used instead if the patient prefers it, in recurrent cases, or if symptoms are severe.

Long-term, high-dose oral fluconazole is associated with distinct craniofacial and skeletal birth defects, and most safety studies have focused on the possible teratogenic effects of the lower doses typically used during pregnancy. Only two epidemiologic studies to date have assessed a possible association with spontaneous abortion and stillbirth, and both “may not have had sufficient power to detect even a moderately increased risk,” the investigators wrote.

To examine a possible association between oral fluconazole use and spontaneous abortion (pregnancy loss at 7-22 gestational weeks) or stillbirth (pregnancy loss at 23 weeks or later), the investigators analyzed data in a national registry of all births, stillbirths, spontaneous abortions, induced abortions, ectopic pregnancies, cases of hydatidiform mole, and all other abnormal products of gestation. They correlated this with data in registries of all hospitalizations and all prescriptions filled in Denmark, focusing on the period from 1997-2013.

There were 3,315 pregnancies in which the mother received oral fluconazole during weeks 7-22, and these were matched for propensity score and maternal age with 13,246 control pregnancies. A total of 147 spontaneous abortions occurred in the exposed group and 563 in the control group. Exposure to oral fluconazole significantly increased the risk of spontaneous abortion, with a hazard ratio (HR) of 1.48, the investigators found (JAMA. 2016 Jan;315(1):58-67. doi: 10.1001/jama.2015.17844). In a further analysis that controlled for confounding by underlying disease (vaginal candidiasis), pregnancies exposed to oral fluconazole were at significantly higher risk of spontaneous abortion compared with both pregnancies exposed to topical azoles (HR, 1.62) and those exposed to pivmecillinam (HR, 1.44).

In addition, there were 5,382 pregnancies in which the mother received oral fluconazole during weeks 23 onward, and these were matched with 21,506 control pregnancies. A total of 21 stillbirths occurred in the exposed group and 77 in the control group. The hazard ratio for stillbirth in exposed pregnancies, compared with control pregnancies, was 1.32, which was not statistically significant. However, this result should be interpreted with caution because of the small numbers in these categories, the investigators wrote.

The use of oral fluconazole during pregnancy significantly raises the risk of spontaneous abortion, according to a report published online Jan. 5 in JAMA.

In a nationwide cohort study in Denmark involving more than 1.4 million pregnancies that occurred from 1997-2013, oral fluconazole increased the risk of spontaneous abortion from 7-22 weeks gestation, compared with no exposure to fluconazole and with exposure to a topical azole.

The drug did not raise the risk of stillbirth significantly in this study, “but this outcome was relatively rare and the results were therefore imprecise,” wrote Ditte Molgaard-Nielsen of the department of epidemiology research, Statens Serum Institut, Copenhagen, and associates.

Creatas Images

The study findings indicate that “cautious prescribing of oral fluconazole in pregnancy may be advisable,” at least until more data regarding this association become available.

Pregnant women are at increased risk for candidiasis because of hormonal changes, and the prevalence of the infection is estimated to be 10% among pregnant women in the U.S. Intravaginal topical azoles are considered first-line treatment during pregnancy, but oral fluconazole can be used instead if the patient prefers it, in recurrent cases, or if symptoms are severe.

Long-term, high-dose oral fluconazole is associated with distinct craniofacial and skeletal birth defects, and most safety studies have focused on the possible teratogenic effects of the lower doses typically used during pregnancy. Only two epidemiologic studies to date have assessed a possible association with spontaneous abortion and stillbirth, and both “may not have had sufficient power to detect even a moderately increased risk,” the investigators wrote.

To examine a possible association between oral fluconazole use and spontaneous abortion (pregnancy loss at 7-22 gestational weeks) or stillbirth (pregnancy loss at 23 weeks or later), the investigators analyzed data in a national registry of all births, stillbirths, spontaneous abortions, induced abortions, ectopic pregnancies, cases of hydatidiform mole, and all other abnormal products of gestation. They correlated this with data in registries of all hospitalizations and all prescriptions filled in Denmark, focusing on the period from 1997-2013.

There were 3,315 pregnancies in which the mother received oral fluconazole during weeks 7-22, and these were matched for propensity score and maternal age with 13,246 control pregnancies. A total of 147 spontaneous abortions occurred in the exposed group and 563 in the control group. Exposure to oral fluconazole significantly increased the risk of spontaneous abortion, with a hazard ratio (HR) of 1.48, the investigators found (JAMA. 2016 Jan;315(1):58-67. doi: 10.1001/jama.2015.17844). In a further analysis that controlled for confounding by underlying disease (vaginal candidiasis), pregnancies exposed to oral fluconazole were at significantly higher risk of spontaneous abortion compared with both pregnancies exposed to topical azoles (HR, 1.62) and those exposed to pivmecillinam (HR, 1.44).

In addition, there were 5,382 pregnancies in which the mother received oral fluconazole during weeks 23 onward, and these were matched with 21,506 control pregnancies. A total of 21 stillbirths occurred in the exposed group and 77 in the control group. The hazard ratio for stillbirth in exposed pregnancies, compared with control pregnancies, was 1.32, which was not statistically significant. However, this result should be interpreted with caution because of the small numbers in these categories, the investigators wrote.

The use of oral fluconazole during pregnancy significantly raises the risk of spontaneous abortion, according to a report published online Jan. 5 in JAMA.

In a nationwide cohort study in Denmark involving more than 1.4 million pregnancies that occurred from 1997-2013, oral fluconazole increased the risk of spontaneous abortion from 7-22 weeks gestation, compared with no exposure to fluconazole and with exposure to a topical azole.

The drug did not raise the risk of stillbirth significantly in this study, “but this outcome was relatively rare and the results were therefore imprecise,” wrote Ditte Molgaard-Nielsen of the department of epidemiology research, Statens Serum Institut, Copenhagen, and associates.

Creatas Images

The study findings indicate that “cautious prescribing of oral fluconazole in pregnancy may be advisable,” at least until more data regarding this association become available.

Pregnant women are at increased risk for candidiasis because of hormonal changes, and the prevalence of the infection is estimated to be 10% among pregnant women in the U.S. Intravaginal topical azoles are considered first-line treatment during pregnancy, but oral fluconazole can be used instead if the patient prefers it, in recurrent cases, or if symptoms are severe.

Long-term, high-dose oral fluconazole is associated with distinct craniofacial and skeletal birth defects, and most safety studies have focused on the possible teratogenic effects of the lower doses typically used during pregnancy. Only two epidemiologic studies to date have assessed a possible association with spontaneous abortion and stillbirth, and both “may not have had sufficient power to detect even a moderately increased risk,” the investigators wrote.

To examine a possible association between oral fluconazole use and spontaneous abortion (pregnancy loss at 7-22 gestational weeks) or stillbirth (pregnancy loss at 23 weeks or later), the investigators analyzed data in a national registry of all births, stillbirths, spontaneous abortions, induced abortions, ectopic pregnancies, cases of hydatidiform mole, and all other abnormal products of gestation. They correlated this with data in registries of all hospitalizations and all prescriptions filled in Denmark, focusing on the period from 1997-2013.

There were 3,315 pregnancies in which the mother received oral fluconazole during weeks 7-22, and these were matched for propensity score and maternal age with 13,246 control pregnancies. A total of 147 spontaneous abortions occurred in the exposed group and 563 in the control group. Exposure to oral fluconazole significantly increased the risk of spontaneous abortion, with a hazard ratio (HR) of 1.48, the investigators found (JAMA. 2016 Jan;315(1):58-67. doi: 10.1001/jama.2015.17844). In a further analysis that controlled for confounding by underlying disease (vaginal candidiasis), pregnancies exposed to oral fluconazole were at significantly higher risk of spontaneous abortion compared with both pregnancies exposed to topical azoles (HR, 1.62) and those exposed to pivmecillinam (HR, 1.44).

In addition, there were 5,382 pregnancies in which the mother received oral fluconazole during weeks 23 onward, and these were matched with 21,506 control pregnancies. A total of 21 stillbirths occurred in the exposed group and 77 in the control group. The hazard ratio for stillbirth in exposed pregnancies, compared with control pregnancies, was 1.32, which was not statistically significant. However, this result should be interpreted with caution because of the small numbers in these categories, the investigators wrote.

Space is truly a magical place, enchanting philosophers, scientists, artists and dreamers. From ancient civilizations that found pantheons of gods among the stars, to novelist Andy Weir’s visionary tale of human efforts to colonize Mars recently portrayed in the movie “The Martian,” to George Lucas’ epic drama between Jedis and Sith lords in “Star Wars,” it is clear that space draws humanity to push the frontiers of science and technology – or maybe just draws us to the box office.

Nonetheless, in this day and age there are astronauts and cosmonauts who have colonized lower earth orbit (LEO) on the International Space Station (ISS), in a situation quite similar to that of the station Arthur C. Clark envisioned in his 1968 science fiction novel, “2001: A Space Odyssey.”

Unfortunately, human physiology, which has evolved in and grown accustomed to Earth’s gravity, is completely altered in space where there is either no gravity effect or different gravitational pulls result from different planetary bodies. Because of this unique medical anomaly, the ISS is a platform for research of interest to a forward-thinking vascular specialist.

Dr. Richard Hughson, from the University of Waterloo in Waterloo, Ontario, is researching vascular aging in spaceflight crew members. His work is a part of the Schlegel-University of Waterloo Research Institute for Aging, where he is theme leader/chair of vascular aging and brain health and holds the Schlegel Research Chair in that discipline.

Dr. Hughson is supported by the Canadian Space Agency (CSA) and Canadian Institute for Health Research (CIHR) He discussed his research in a recent audio interview (http://cihr-irsc.gc.ca/e/49523.html).

Observations have demonstrated that short-duration and extended spaceflight missions may simulate accelerated vascular aging in some of these highly fit individuals traveling to space. Specifically, spaceflight crew members have been shown to have difficulty controlling a rise in their blood pressure, perhaps secondary to the loss of Earth’s gravity, but rather in the inherent cephalad fluid shift (as blood no longer pools in the legs). In addition, significant postflight postural hypotension and physical deconditioning with resultant sarcopenia and osteopenia are known to occur.

Dr. Hughson has shown through ultrasonography that the carotid arteries of spaceflight crew members are considerably stiffer compared to their preflight arteries and that they appear to have “aged the equivalent of 20-30 years in stiffness.” The ramifications of this type of research on the study of the normal earthbound vascular aging processes are under investigation.

To counteract the effects of vascular aging and physical deconditioning in space, physical activity is key; however, the 30 minutes per day allotted to busy astronauts amid their responsibilities is just not cutting it, according to Dr. Hughson. Missions are being extended for longer periods of time, leading to serious physical consequences, For example, American astronaut Scott Kelly’s year in space will certainly result in considerable accelerated aging in his arterial system. Thus, it becomes increasingly necessary to understand and prevent the vascular aging process in astronauts, future spaceflight crew members, and perhaps one day those seeking to colonize the Moon, Mars, and beyond.

When colonization time arrives, space agencies certainly should be in the market for well-qualified vascular specialists.

Perhaps great job opportunities await those in our profession who will be brave enough to leave Earth’s cradle.

Dr Drudi is a vascular surgery resident at McGill University, Montreal.

Space is truly a magical place, enchanting philosophers, scientists, artists and dreamers. From ancient civilizations that found pantheons of gods among the stars, to novelist Andy Weir’s visionary tale of human efforts to colonize Mars recently portrayed in the movie “The Martian,” to George Lucas’ epic drama between Jedis and Sith lords in “Star Wars,” it is clear that space draws humanity to push the frontiers of science and technology – or maybe just draws us to the box office.

Nonetheless, in this day and age there are astronauts and cosmonauts who have colonized lower earth orbit (LEO) on the International Space Station (ISS), in a situation quite similar to that of the station Arthur C. Clark envisioned in his 1968 science fiction novel, “2001: A Space Odyssey.”

Unfortunately, human physiology, which has evolved in and grown accustomed to Earth’s gravity, is completely altered in space where there is either no gravity effect or different gravitational pulls result from different planetary bodies. Because of this unique medical anomaly, the ISS is a platform for research of interest to a forward-thinking vascular specialist.

Dr. Richard Hughson, from the University of Waterloo in Waterloo, Ontario, is researching vascular aging in spaceflight crew members. His work is a part of the Schlegel-University of Waterloo Research Institute for Aging, where he is theme leader/chair of vascular aging and brain health and holds the Schlegel Research Chair in that discipline.

Dr. Hughson is supported by the Canadian Space Agency (CSA) and Canadian Institute for Health Research (CIHR) He discussed his research in a recent audio interview (http://cihr-irsc.gc.ca/e/49523.html).

Observations have demonstrated that short-duration and extended spaceflight missions may simulate accelerated vascular aging in some of these highly fit individuals traveling to space. Specifically, spaceflight crew members have been shown to have difficulty controlling a rise in their blood pressure, perhaps secondary to the loss of Earth’s gravity, but rather in the inherent cephalad fluid shift (as blood no longer pools in the legs). In addition, significant postflight postural hypotension and physical deconditioning with resultant sarcopenia and osteopenia are known to occur.

Dr. Hughson has shown through ultrasonography that the carotid arteries of spaceflight crew members are considerably stiffer compared to their preflight arteries and that they appear to have “aged the equivalent of 20-30 years in stiffness.” The ramifications of this type of research on the study of the normal earthbound vascular aging processes are under investigation.

To counteract the effects of vascular aging and physical deconditioning in space, physical activity is key; however, the 30 minutes per day allotted to busy astronauts amid their responsibilities is just not cutting it, according to Dr. Hughson. Missions are being extended for longer periods of time, leading to serious physical consequences, For example, American astronaut Scott Kelly’s year in space will certainly result in considerable accelerated aging in his arterial system. Thus, it becomes increasingly necessary to understand and prevent the vascular aging process in astronauts, future spaceflight crew members, and perhaps one day those seeking to colonize the Moon, Mars, and beyond.

When colonization time arrives, space agencies certainly should be in the market for well-qualified vascular specialists.

Perhaps great job opportunities await those in our profession who will be brave enough to leave Earth’s cradle.

Dr Drudi is a vascular surgery resident at McGill University, Montreal.

Space is truly a magical place, enchanting philosophers, scientists, artists and dreamers. From ancient civilizations that found pantheons of gods among the stars, to novelist Andy Weir’s visionary tale of human efforts to colonize Mars recently portrayed in the movie “The Martian,” to George Lucas’ epic drama between Jedis and Sith lords in “Star Wars,” it is clear that space draws humanity to push the frontiers of science and technology – or maybe just draws us to the box office.

Nonetheless, in this day and age there are astronauts and cosmonauts who have colonized lower earth orbit (LEO) on the International Space Station (ISS), in a situation quite similar to that of the station Arthur C. Clark envisioned in his 1968 science fiction novel, “2001: A Space Odyssey.”

Unfortunately, human physiology, which has evolved in and grown accustomed to Earth’s gravity, is completely altered in space where there is either no gravity effect or different gravitational pulls result from different planetary bodies. Because of this unique medical anomaly, the ISS is a platform for research of interest to a forward-thinking vascular specialist.

Dr. Richard Hughson, from the University of Waterloo in Waterloo, Ontario, is researching vascular aging in spaceflight crew members. His work is a part of the Schlegel-University of Waterloo Research Institute for Aging, where he is theme leader/chair of vascular aging and brain health and holds the Schlegel Research Chair in that discipline.

Dr. Hughson is supported by the Canadian Space Agency (CSA) and Canadian Institute for Health Research (CIHR) He discussed his research in a recent audio interview (http://cihr-irsc.gc.ca/e/49523.html).

Observations have demonstrated that short-duration and extended spaceflight missions may simulate accelerated vascular aging in some of these highly fit individuals traveling to space. Specifically, spaceflight crew members have been shown to have difficulty controlling a rise in their blood pressure, perhaps secondary to the loss of Earth’s gravity, but rather in the inherent cephalad fluid shift (as blood no longer pools in the legs). In addition, significant postflight postural hypotension and physical deconditioning with resultant sarcopenia and osteopenia are known to occur.

Dr. Hughson has shown through ultrasonography that the carotid arteries of spaceflight crew members are considerably stiffer compared to their preflight arteries and that they appear to have “aged the equivalent of 20-30 years in stiffness.” The ramifications of this type of research on the study of the normal earthbound vascular aging processes are under investigation.

To counteract the effects of vascular aging and physical deconditioning in space, physical activity is key; however, the 30 minutes per day allotted to busy astronauts amid their responsibilities is just not cutting it, according to Dr. Hughson. Missions are being extended for longer periods of time, leading to serious physical consequences, For example, American astronaut Scott Kelly’s year in space will certainly result in considerable accelerated aging in his arterial system. Thus, it becomes increasingly necessary to understand and prevent the vascular aging process in astronauts, future spaceflight crew members, and perhaps one day those seeking to colonize the Moon, Mars, and beyond.

When colonization time arrives, space agencies certainly should be in the market for well-qualified vascular specialists.

Perhaps great job opportunities await those in our profession who will be brave enough to leave Earth’s cradle.

Dr Drudi is a vascular surgery resident at McGill University, Montreal.

Methyl aminolevulinate plus photodynamic therapy shows promise as a treatment for severe acne vulgaris, according to a U.S. study published in the British Journal of Dermatology.

Dr. David M. Pariser of Eastern Virginia Medical School, Norfolk, and his associates conducted the randomized double-blind, vehicle-controlled trial of photodynamic therapy (PDT) with methyl aminolevulinate (MAL) as a photosensitizer in 153 males and females aged 12-35 years with severe facial acne. Inclusion criteria comprised an Investigator Global Assessment (IGA) rating score of 4, 20-100 noninflammatory lesions, and 25-75 inflammatory lesions with no more than three nodules (Br J Dermatol. 2015 December. doi: 10.1111/bjd.14345).

Participants received topical MAL 80 mg/g (100) or vehicle cream (53) and PDT every 2 weeks for four treatments, and were evaluated at each treatment and at 12 weeks. The MAL or vehicle cream was applied and covered for 1.5 hours, followed by PDT (635 nm of red light for a total dose of 37 J/cm²). Most completed the study (85% in MAL group and 91% in vehicle group).

Those in the MAL PDT group demonstrated a significant reduction in inflammatory lesions based on the percentage change at 12 weeks (a mean reduction of 37.3% vs. 16.2%; P = .003), and absolute change (a mean reduction of 15.6 lesions vs. 7.8; P = .006). However, the reduction in noninflammatory lesions was not significantly different between the two groups (a mean reduction of 11.8 lesions among those on MAL PDT vs. 10.7 with vehicle PDT) .

The rates of treatment success, defined as improvement of 2 or more IGA grades at 12 weeks, were higher among those in the MAL PDT group (44% vs. 26.4%; OR, 3.24; P = .013).

Pain scores were higher during PDT for the MAL group and remained similar with subsequent treatments. The MAL treatment was discontinued in six participants because of pain and PDT was paused briefly in 15 participants. More participants in the MAL group reported moderate erythema after the first PDT session (46% versus 15%) and three reported severe erythema.

The most commonly reported adverse events in the MAL treatment group were a sensation of skin burning and pain, mostly mild to moderate, lasting a median of 3 days. Further, 12% of those in the MAL group withdrew secondary to adverse events.

“This large, controlled randomized clinical study shows the potential of PDT using 80 mg/g MAL cream for treatment of severe acne” in patients aged 12 years and older, with all skin types, the authors concluded, noting that more follow-up data are needed on the duration of treatment response and long-term effect on scarring. “Severe acne has limited therapeutic options with problematic side effects and bacterial resistance and 80 mg/g MAL PDT could be an alternative approach with improved tolerability for these patients,” they added.

The authors noted that for severe cases of acne, treatment is limited, and while oral isotretinoin is often used, it is teratogenic, has side effects, and is associated with reimbursement difficulties.

Dr. Pariser and two colleagues disclosed receiving honoraria from Photocure ASA, which markets MAL as Visonac. The company funded the study. 

Methyl aminolevulinate plus photodynamic therapy shows promise as a treatment for severe acne vulgaris, according to a U.S. study published in the British Journal of Dermatology.

Dr. David M. Pariser of Eastern Virginia Medical School, Norfolk, and his associates conducted the randomized double-blind, vehicle-controlled trial of photodynamic therapy (PDT) with methyl aminolevulinate (MAL) as a photosensitizer in 153 males and females aged 12-35 years with severe facial acne. Inclusion criteria comprised an Investigator Global Assessment (IGA) rating score of 4, 20-100 noninflammatory lesions, and 25-75 inflammatory lesions with no more than three nodules (Br J Dermatol. 2015 December. doi: 10.1111/bjd.14345).

Participants received topical MAL 80 mg/g (100) or vehicle cream (53) and PDT every 2 weeks for four treatments, and were evaluated at each treatment and at 12 weeks. The MAL or vehicle cream was applied and covered for 1.5 hours, followed by PDT (635 nm of red light for a total dose of 37 J/cm²). Most completed the study (85% in MAL group and 91% in vehicle group).

Those in the MAL PDT group demonstrated a significant reduction in inflammatory lesions based on the percentage change at 12 weeks (a mean reduction of 37.3% vs. 16.2%; P = .003), and absolute change (a mean reduction of 15.6 lesions vs. 7.8; P = .006). However, the reduction in noninflammatory lesions was not significantly different between the two groups (a mean reduction of 11.8 lesions among those on MAL PDT vs. 10.7 with vehicle PDT) .

The rates of treatment success, defined as improvement of 2 or more IGA grades at 12 weeks, were higher among those in the MAL PDT group (44% vs. 26.4%; OR, 3.24; P = .013).

Pain scores were higher during PDT for the MAL group and remained similar with subsequent treatments. The MAL treatment was discontinued in six participants because of pain and PDT was paused briefly in 15 participants. More participants in the MAL group reported moderate erythema after the first PDT session (46% versus 15%) and three reported severe erythema.

The most commonly reported adverse events in the MAL treatment group were a sensation of skin burning and pain, mostly mild to moderate, lasting a median of 3 days. Further, 12% of those in the MAL group withdrew secondary to adverse events.

“This large, controlled randomized clinical study shows the potential of PDT using 80 mg/g MAL cream for treatment of severe acne” in patients aged 12 years and older, with all skin types, the authors concluded, noting that more follow-up data are needed on the duration of treatment response and long-term effect on scarring. “Severe acne has limited therapeutic options with problematic side effects and bacterial resistance and 80 mg/g MAL PDT could be an alternative approach with improved tolerability for these patients,” they added.

The authors noted that for severe cases of acne, treatment is limited, and while oral isotretinoin is often used, it is teratogenic, has side effects, and is associated with reimbursement difficulties.

Dr. Pariser and two colleagues disclosed receiving honoraria from Photocure ASA, which markets MAL as Visonac. The company funded the study. 

Methyl aminolevulinate plus photodynamic therapy shows promise as a treatment for severe acne vulgaris, according to a U.S. study published in the British Journal of Dermatology.

Dr. David M. Pariser of Eastern Virginia Medical School, Norfolk, and his associates conducted the randomized double-blind, vehicle-controlled trial of photodynamic therapy (PDT) with methyl aminolevulinate (MAL) as a photosensitizer in 153 males and females aged 12-35 years with severe facial acne. Inclusion criteria comprised an Investigator Global Assessment (IGA) rating score of 4, 20-100 noninflammatory lesions, and 25-75 inflammatory lesions with no more than three nodules (Br J Dermatol. 2015 December. doi: 10.1111/bjd.14345).

Participants received topical MAL 80 mg/g (100) or vehicle cream (53) and PDT every 2 weeks for four treatments, and were evaluated at each treatment and at 12 weeks. The MAL or vehicle cream was applied and covered for 1.5 hours, followed by PDT (635 nm of red light for a total dose of 37 J/cm²). Most completed the study (85% in MAL group and 91% in vehicle group).

Those in the MAL PDT group demonstrated a significant reduction in inflammatory lesions based on the percentage change at 12 weeks (a mean reduction of 37.3% vs. 16.2%; P = .003), and absolute change (a mean reduction of 15.6 lesions vs. 7.8; P = .006). However, the reduction in noninflammatory lesions was not significantly different between the two groups (a mean reduction of 11.8 lesions among those on MAL PDT vs. 10.7 with vehicle PDT) .

The rates of treatment success, defined as improvement of 2 or more IGA grades at 12 weeks, were higher among those in the MAL PDT group (44% vs. 26.4%; OR, 3.24; P = .013).

Pain scores were higher during PDT for the MAL group and remained similar with subsequent treatments. The MAL treatment was discontinued in six participants because of pain and PDT was paused briefly in 15 participants. More participants in the MAL group reported moderate erythema after the first PDT session (46% versus 15%) and three reported severe erythema.

The most commonly reported adverse events in the MAL treatment group were a sensation of skin burning and pain, mostly mild to moderate, lasting a median of 3 days. Further, 12% of those in the MAL group withdrew secondary to adverse events.

“This large, controlled randomized clinical study shows the potential of PDT using 80 mg/g MAL cream for treatment of severe acne” in patients aged 12 years and older, with all skin types, the authors concluded, noting that more follow-up data are needed on the duration of treatment response and long-term effect on scarring. “Severe acne has limited therapeutic options with problematic side effects and bacterial resistance and 80 mg/g MAL PDT could be an alternative approach with improved tolerability for these patients,” they added.

The authors noted that for severe cases of acne, treatment is limited, and while oral isotretinoin is often used, it is teratogenic, has side effects, and is associated with reimbursement difficulties.

Dr. Pariser and two colleagues disclosed receiving honoraria from Photocure ASA, which markets MAL as Visonac. The company funded the study. 

 

 

Micrograph showing FL

 

Mutations in the RRAGC gene appear to be an “excellent candidate for therapeutic targeting” in follicular lymphoma (FL), according to investigators.

They analyzed mutations found in tumors with multiple relapses of FL without transformation to diffuse large B-cell lymphoma.

And they found that one commonly mutated gene encodes the protein RagC, which is essential for activating the amino-acid sensing mTORC1 pathway.

Although mutations in genes in the mTORC1 pathway have been associated with various cancers, this is the first time a genetic mutation in any of the 4 Rag proteins has been identified in malignancy.

“One of the mutations that we have identified allows follicular lymphoma tumors to turn on growth signals regardless of whether nutrients are available, thereby evading normal restrictions on its growth,” said study author Jessica Okosun, MB BChir, PhD, of Barts Cancer Institute at Queen Mary University of London in the UK.

“Remarkably, the mutations we have discovered have not been seen in other cancer types. However, drugs that directly target this nutrient-sensing mechanism are currently used to treat other types of cancer and may benefit patients with follicular lymphoma.”

Dr Okosun and her colleagues reported these findings in a letter to Nature Genetics.

In experiments with cell lines, the investigators found that expression of the mutated RagC proteins activate mTORC1 signaling in the absence of amino acids and increase binding to an important part of the mTORC1 complex, consistent with the established role of RagC in the mTORC1 pathway.

Because this research was performed exclusively in cell lines, the investigators have not yet deciphered the mutations’ mechanistic effect in patients. However, study author Rachel Wolfson, of the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology in Cambridge, Massachusetts, said there are clues to the mutations’ significance.

“mTORC1 is linked to cell growth, so it is not surprising that activation of the pathway could lead to some growth advantage for cancer cells,” Wolfson said. “But it leads to an interesting question: When is it a proliferative advantage versus a disadvantage to no longer be able to accurately sense amino acid levels? That is something we would need to investigate further, likely in vivo.”

The investigators would also like to know how the drug rapamycin affects FL with RagC mutations. Rapamycin binds to mTORC1 and inhibits its activity. If the drug interferes with mTORC1 dysregulation caused by RagC mutations, perhaps the drug could be used in FL treatment.

“If so, maybe these RagC mutations could be used as biomarkers to predict sensitivity to rapamycin treatment in follicular lymphoma patients,” Wolfson said. “That would be very exciting, and it’s something that should be investigated further.”

 

 

Micrograph showing FL

 

Mutations in the RRAGC gene appear to be an “excellent candidate for therapeutic targeting” in follicular lymphoma (FL), according to investigators.

They analyzed mutations found in tumors with multiple relapses of FL without transformation to diffuse large B-cell lymphoma.

And they found that one commonly mutated gene encodes the protein RagC, which is essential for activating the amino-acid sensing mTORC1 pathway.

Although mutations in genes in the mTORC1 pathway have been associated with various cancers, this is the first time a genetic mutation in any of the 4 Rag proteins has been identified in malignancy.

“One of the mutations that we have identified allows follicular lymphoma tumors to turn on growth signals regardless of whether nutrients are available, thereby evading normal restrictions on its growth,” said study author Jessica Okosun, MB BChir, PhD, of Barts Cancer Institute at Queen Mary University of London in the UK.

“Remarkably, the mutations we have discovered have not been seen in other cancer types. However, drugs that directly target this nutrient-sensing mechanism are currently used to treat other types of cancer and may benefit patients with follicular lymphoma.”

Dr Okosun and her colleagues reported these findings in a letter to Nature Genetics.

In experiments with cell lines, the investigators found that expression of the mutated RagC proteins activate mTORC1 signaling in the absence of amino acids and increase binding to an important part of the mTORC1 complex, consistent with the established role of RagC in the mTORC1 pathway.

Because this research was performed exclusively in cell lines, the investigators have not yet deciphered the mutations’ mechanistic effect in patients. However, study author Rachel Wolfson, of the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology in Cambridge, Massachusetts, said there are clues to the mutations’ significance.

“mTORC1 is linked to cell growth, so it is not surprising that activation of the pathway could lead to some growth advantage for cancer cells,” Wolfson said. “But it leads to an interesting question: When is it a proliferative advantage versus a disadvantage to no longer be able to accurately sense amino acid levels? That is something we would need to investigate further, likely in vivo.”

The investigators would also like to know how the drug rapamycin affects FL with RagC mutations. Rapamycin binds to mTORC1 and inhibits its activity. If the drug interferes with mTORC1 dysregulation caused by RagC mutations, perhaps the drug could be used in FL treatment.

“If so, maybe these RagC mutations could be used as biomarkers to predict sensitivity to rapamycin treatment in follicular lymphoma patients,” Wolfson said. “That would be very exciting, and it’s something that should be investigated further.”

 

 

Micrograph showing FL

 

Mutations in the RRAGC gene appear to be an “excellent candidate for therapeutic targeting” in follicular lymphoma (FL), according to investigators.

They analyzed mutations found in tumors with multiple relapses of FL without transformation to diffuse large B-cell lymphoma.

And they found that one commonly mutated gene encodes the protein RagC, which is essential for activating the amino-acid sensing mTORC1 pathway.

Although mutations in genes in the mTORC1 pathway have been associated with various cancers, this is the first time a genetic mutation in any of the 4 Rag proteins has been identified in malignancy.

“One of the mutations that we have identified allows follicular lymphoma tumors to turn on growth signals regardless of whether nutrients are available, thereby evading normal restrictions on its growth,” said study author Jessica Okosun, MB BChir, PhD, of Barts Cancer Institute at Queen Mary University of London in the UK.

“Remarkably, the mutations we have discovered have not been seen in other cancer types. However, drugs that directly target this nutrient-sensing mechanism are currently used to treat other types of cancer and may benefit patients with follicular lymphoma.”

Dr Okosun and her colleagues reported these findings in a letter to Nature Genetics.

In experiments with cell lines, the investigators found that expression of the mutated RagC proteins activate mTORC1 signaling in the absence of amino acids and increase binding to an important part of the mTORC1 complex, consistent with the established role of RagC in the mTORC1 pathway.

Because this research was performed exclusively in cell lines, the investigators have not yet deciphered the mutations’ mechanistic effect in patients. However, study author Rachel Wolfson, of the Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology in Cambridge, Massachusetts, said there are clues to the mutations’ significance.

“mTORC1 is linked to cell growth, so it is not surprising that activation of the pathway could lead to some growth advantage for cancer cells,” Wolfson said. “But it leads to an interesting question: When is it a proliferative advantage versus a disadvantage to no longer be able to accurately sense amino acid levels? That is something we would need to investigate further, likely in vivo.”

The investigators would also like to know how the drug rapamycin affects FL with RagC mutations. Rapamycin binds to mTORC1 and inhibits its activity. If the drug interferes with mTORC1 dysregulation caused by RagC mutations, perhaps the drug could be used in FL treatment.

“If so, maybe these RagC mutations could be used as biomarkers to predict sensitivity to rapamycin treatment in follicular lymphoma patients,” Wolfson said. “That would be very exciting, and it’s something that should be investigated further.”

Researcher in the lab

Photo by Bill Branson

Two new studies suggest biomedical research may be hindered by poor reporting and a lack of transparency.

In one study, researchers analyzed more than 400 biomedical science articles and found the papers rarely provided full protocol information, complete data, and the necessary level of transparency to verify or replicate the work.

In the other study, researchers analyzed more than 500 preclinical experiments and found that most didn’t contain sufficient information on the animals used.

Both studies were published in PLOS Biology.

For the first study, Shareen Iqbal, PhD, of Emory University in Atlanta, Georgia, and her colleagues analyzed papers published between 2000 and 2014.

The team set out to determine the extent to which researchers report key information necessary for properly evaluating and replicating published research, including availability of protocols, data, and the frequency of published novel or replication studies.

Out of 441 articles drawn from across the biomedical literature, only 1 paper provided a full protocol, and none of the papers made all the data available. The majority of studies didn’t state funding or conflicts of interest, and replication studies were very rare.

Dr Iqbal and her colleagues said they hope their study will further sensitize scientists, funders, journals, and other science-related stakeholders about the need to improve these indicators.

For the second study, Ulrich Dirnagl, MD, of Charité Universitätsmedizin in Berlin, Germany, and his colleagues examined 100 papers describing preclinical research on stroke and cancer. These papers contained accounts of 316 experiments on infarct volume and 206 experiments on tumor shrinkage.

The vast majority of the reports didn’t contain sufficient information on how many animals were used in the experiments. What’s more, in many papers, animals “vanished” over the course of the study.

Using a computer model, the researchers simulated the effects of such animal loss on the validity of the experiments. They found that the more animals lost or removed, the shakier or more biased the experimental conclusions.

“The study began with an attempt to look at the robustness of findings in a handful of preclinical papers, but the sheer number of missing animals stopped us in our tracks,” said author Constance Holman, a graduate student at Charité Universitätsmedizin.

Researchers from both studies believe their findings add to the list of concerns about bias and reporting in research, but the results also establish ways in which research can become more transparent and potentially more reproducible.

Researcher in the lab

Photo by Bill Branson

Two new studies suggest biomedical research may be hindered by poor reporting and a lack of transparency.

In one study, researchers analyzed more than 400 biomedical science articles and found the papers rarely provided full protocol information, complete data, and the necessary level of transparency to verify or replicate the work.

In the other study, researchers analyzed more than 500 preclinical experiments and found that most didn’t contain sufficient information on the animals used.

Both studies were published in PLOS Biology.

For the first study, Shareen Iqbal, PhD, of Emory University in Atlanta, Georgia, and her colleagues analyzed papers published between 2000 and 2014.

The team set out to determine the extent to which researchers report key information necessary for properly evaluating and replicating published research, including availability of protocols, data, and the frequency of published novel or replication studies.

Out of 441 articles drawn from across the biomedical literature, only 1 paper provided a full protocol, and none of the papers made all the data available. The majority of studies didn’t state funding or conflicts of interest, and replication studies were very rare.

Dr Iqbal and her colleagues said they hope their study will further sensitize scientists, funders, journals, and other science-related stakeholders about the need to improve these indicators.

For the second study, Ulrich Dirnagl, MD, of Charité Universitätsmedizin in Berlin, Germany, and his colleagues examined 100 papers describing preclinical research on stroke and cancer. These papers contained accounts of 316 experiments on infarct volume and 206 experiments on tumor shrinkage.

The vast majority of the reports didn’t contain sufficient information on how many animals were used in the experiments. What’s more, in many papers, animals “vanished” over the course of the study.

Using a computer model, the researchers simulated the effects of such animal loss on the validity of the experiments. They found that the more animals lost or removed, the shakier or more biased the experimental conclusions.

“The study began with an attempt to look at the robustness of findings in a handful of preclinical papers, but the sheer number of missing animals stopped us in our tracks,” said author Constance Holman, a graduate student at Charité Universitätsmedizin.

Researchers from both studies believe their findings add to the list of concerns about bias and reporting in research, but the results also establish ways in which research can become more transparent and potentially more reproducible.

Researcher in the lab

Photo by Bill Branson

Two new studies suggest biomedical research may be hindered by poor reporting and a lack of transparency.

In one study, researchers analyzed more than 400 biomedical science articles and found the papers rarely provided full protocol information, complete data, and the necessary level of transparency to verify or replicate the work.

In the other study, researchers analyzed more than 500 preclinical experiments and found that most didn’t contain sufficient information on the animals used.

Both studies were published in PLOS Biology.

For the first study, Shareen Iqbal, PhD, of Emory University in Atlanta, Georgia, and her colleagues analyzed papers published between 2000 and 2014.

The team set out to determine the extent to which researchers report key information necessary for properly evaluating and replicating published research, including availability of protocols, data, and the frequency of published novel or replication studies.

Out of 441 articles drawn from across the biomedical literature, only 1 paper provided a full protocol, and none of the papers made all the data available. The majority of studies didn’t state funding or conflicts of interest, and replication studies were very rare.

Dr Iqbal and her colleagues said they hope their study will further sensitize scientists, funders, journals, and other science-related stakeholders about the need to improve these indicators.

For the second study, Ulrich Dirnagl, MD, of Charité Universitätsmedizin in Berlin, Germany, and his colleagues examined 100 papers describing preclinical research on stroke and cancer. These papers contained accounts of 316 experiments on infarct volume and 206 experiments on tumor shrinkage.

The vast majority of the reports didn’t contain sufficient information on how many animals were used in the experiments. What’s more, in many papers, animals “vanished” over the course of the study.

Using a computer model, the researchers simulated the effects of such animal loss on the validity of the experiments. They found that the more animals lost or removed, the shakier or more biased the experimental conclusions.

“The study began with an attempt to look at the robustness of findings in a handful of preclinical papers, but the sheer number of missing animals stopped us in our tracks,” said author Constance Holman, a graduate student at Charité Universitätsmedizin.

Researchers from both studies believe their findings add to the list of concerns about bias and reporting in research, but the results also establish ways in which research can become more transparent and potentially more reproducible.

Sickled and normal

red blood cells

Image by Graham Beards

The US Food and Drug Administration (FDA) has granted orphan drug designation for the small molecule GBT440 to treat patients with sickle cell disease (SCD).

GBT440 is being developed as a potentially disease-modifying therapy for SCD. The drug works by increasing hemoglobin’s affinity for oxygen.

Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the drug may be capable of modifying the progression of SCD.

“Receiving orphan drug designation, along with the previously announced fast track designation, are important milestones in our regulatory strategy for GBT440 and highlight the FDA’s agreement that the SCD community faces a critical need for new treatments,” said Ted W. Love, MD, chief executive officer of Global Blood Therapeutics, Inc., the company developing GBT440.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US. The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

The FDA grants fast track designation to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need. Through the fast track program, a drug may be eligible for priority review and rolling review, and the company developing the drug may receive additional help from the FDA to expedite development.

GBT440 trial

Early results from an ongoing phase 1/2 study of GBT440 were presented at the 2015 ASH Annual Meeting last month (abstract 542*).

The trial, which includes healthy subjects and patients with SCD, is being conducted in 2 parts: part A (single-dose administration) and part B (multiple-dose administration, daily for 15 days in healthy subjects and 28 days in SCD patients).

As of November 20, 2015, 8 SCD patients completed part A, and 30 SCD patients had either completed or were ongoing in part B.

Of the 30 SCD patients, 16 patients completed 700 mg daily dosing and follow-up (12 on GBT440 and 4 on placebo), and 14 patients completed or were ongoing at 500 mg daily dosing and follow-up (10 on GBT440 and 4 on placebo). A cohort of SCD patients on 1000 mg per day for 28 days is currently enrolling.

Thus far, GBT440 treatment has conferred several improvements from baseline to day 28.

Hemoglobin increases were evident by day 4 of treatment. And the researchers observed absolute hemoglobin increases of 0.5 and 0.7 g/dL with GBT440 at 500 and 700 mg, respectively, compared with a 0.1 g/dL decrease with placebo.

The median reticulocyte count decreased by 31% and 37% with GBT440 at 500 and 700 mg, respectively, compared with a 7% increase with placebo, indicating that the hemoglobin rise is due to decreased hemolysis.

Median erythropoietin levels decreased by 9 and 18 mU/mL with GBT440 at 500 and 700 mg, respectively, compared with an increase of 28 mU/mL with placebo.

Median unconjugated bilirubin levels decrease by 31% and 43% with GBT440 at 500 mg and 700 mg, respectively, compared with an increase of 2% with placebo.

Median lactate dehydrogenase levels decreased by 20% and 12% with GBT440 at 500 and 700 mg, respectively, compared with a decrease of 7% with placebo.

Median sickle cell counts decreased by 56% and 46% with GBT440 at 500 and 700 mg, respectively, compared with a 14% increase with placebo.

The researchers noted high inter- and intra-patient variability in circulating sickle cell counts.

They said inflammatory soluble adhesion molecules for the 700 mg dose cohort showed promising trends in improvement. The median P-selectin decreased 19%, compared with an increase of 20% with placebo. And the median ICAM-1 decreased 6%, compared with an increase of 33% in placebo. Data for the 500 mg dose cohort has not yet been analyzed.

The researchers said pharmacokinetic data demonstrated linear and dose-proportional properties, with a half-life amenable to once-daily dosing.

And GBT440 was well tolerated over the 28 days of dosing. None of the SCD patients discontinued GBT440. The most common adverse event was headache, and there have been no serious adverse events thought to be drug-related.

“We continue to believe that GBT440 has the potential to become the first mechanism-based and disease-modifying therapeutic for this grievous disease and look forward to sharing full results from our phase 1/2 trial and potentially initiating a pivotal trial in adult patients with SCD in 2016,” Dr Love said.

*Data in the abstract differ from the presentation.

Sickled and normal

red blood cells

Image by Graham Beards

The US Food and Drug Administration (FDA) has granted orphan drug designation for the small molecule GBT440 to treat patients with sickle cell disease (SCD).

GBT440 is being developed as a potentially disease-modifying therapy for SCD. The drug works by increasing hemoglobin’s affinity for oxygen.

Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the drug may be capable of modifying the progression of SCD.

“Receiving orphan drug designation, along with the previously announced fast track designation, are important milestones in our regulatory strategy for GBT440 and highlight the FDA’s agreement that the SCD community faces a critical need for new treatments,” said Ted W. Love, MD, chief executive officer of Global Blood Therapeutics, Inc., the company developing GBT440.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US. The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

The FDA grants fast track designation to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need. Through the fast track program, a drug may be eligible for priority review and rolling review, and the company developing the drug may receive additional help from the FDA to expedite development.

GBT440 trial

Early results from an ongoing phase 1/2 study of GBT440 were presented at the 2015 ASH Annual Meeting last month (abstract 542*).

The trial, which includes healthy subjects and patients with SCD, is being conducted in 2 parts: part A (single-dose administration) and part B (multiple-dose administration, daily for 15 days in healthy subjects and 28 days in SCD patients).

As of November 20, 2015, 8 SCD patients completed part A, and 30 SCD patients had either completed or were ongoing in part B.

Of the 30 SCD patients, 16 patients completed 700 mg daily dosing and follow-up (12 on GBT440 and 4 on placebo), and 14 patients completed or were ongoing at 500 mg daily dosing and follow-up (10 on GBT440 and 4 on placebo). A cohort of SCD patients on 1000 mg per day for 28 days is currently enrolling.

Thus far, GBT440 treatment has conferred several improvements from baseline to day 28.

Hemoglobin increases were evident by day 4 of treatment. And the researchers observed absolute hemoglobin increases of 0.5 and 0.7 g/dL with GBT440 at 500 and 700 mg, respectively, compared with a 0.1 g/dL decrease with placebo.

The median reticulocyte count decreased by 31% and 37% with GBT440 at 500 and 700 mg, respectively, compared with a 7% increase with placebo, indicating that the hemoglobin rise is due to decreased hemolysis.

Median erythropoietin levels decreased by 9 and 18 mU/mL with GBT440 at 500 and 700 mg, respectively, compared with an increase of 28 mU/mL with placebo.

Median unconjugated bilirubin levels decrease by 31% and 43% with GBT440 at 500 mg and 700 mg, respectively, compared with an increase of 2% with placebo.

Median lactate dehydrogenase levels decreased by 20% and 12% with GBT440 at 500 and 700 mg, respectively, compared with a decrease of 7% with placebo.

Median sickle cell counts decreased by 56% and 46% with GBT440 at 500 and 700 mg, respectively, compared with a 14% increase with placebo.

The researchers noted high inter- and intra-patient variability in circulating sickle cell counts.

They said inflammatory soluble adhesion molecules for the 700 mg dose cohort showed promising trends in improvement. The median P-selectin decreased 19%, compared with an increase of 20% with placebo. And the median ICAM-1 decreased 6%, compared with an increase of 33% in placebo. Data for the 500 mg dose cohort has not yet been analyzed.

The researchers said pharmacokinetic data demonstrated linear and dose-proportional properties, with a half-life amenable to once-daily dosing.

And GBT440 was well tolerated over the 28 days of dosing. None of the SCD patients discontinued GBT440. The most common adverse event was headache, and there have been no serious adverse events thought to be drug-related.

“We continue to believe that GBT440 has the potential to become the first mechanism-based and disease-modifying therapeutic for this grievous disease and look forward to sharing full results from our phase 1/2 trial and potentially initiating a pivotal trial in adult patients with SCD in 2016,” Dr Love said.

*Data in the abstract differ from the presentation.

Sickled and normal

red blood cells

Image by Graham Beards

The US Food and Drug Administration (FDA) has granted orphan drug designation for the small molecule GBT440 to treat patients with sickle cell disease (SCD).

GBT440 is being developed as a potentially disease-modifying therapy for SCD. The drug works by increasing hemoglobin’s affinity for oxygen.

Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the drug may be capable of modifying the progression of SCD.

“Receiving orphan drug designation, along with the previously announced fast track designation, are important milestones in our regulatory strategy for GBT440 and highlight the FDA’s agreement that the SCD community faces a critical need for new treatments,” said Ted W. Love, MD, chief executive officer of Global Blood Therapeutics, Inc., the company developing GBT440.

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US. The designation provides the drug’s sponsor with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.

The FDA grants fast track designation to facilitate and expedite the development and review of new drugs intended to treat serious or life-threatening conditions and address unmet medical need. Through the fast track program, a drug may be eligible for priority review and rolling review, and the company developing the drug may receive additional help from the FDA to expedite development.

GBT440 trial

Early results from an ongoing phase 1/2 study of GBT440 were presented at the 2015 ASH Annual Meeting last month (abstract 542*).

The trial, which includes healthy subjects and patients with SCD, is being conducted in 2 parts: part A (single-dose administration) and part B (multiple-dose administration, daily for 15 days in healthy subjects and 28 days in SCD patients).

As of November 20, 2015, 8 SCD patients completed part A, and 30 SCD patients had either completed or were ongoing in part B.

Of the 30 SCD patients, 16 patients completed 700 mg daily dosing and follow-up (12 on GBT440 and 4 on placebo), and 14 patients completed or were ongoing at 500 mg daily dosing and follow-up (10 on GBT440 and 4 on placebo). A cohort of SCD patients on 1000 mg per day for 28 days is currently enrolling.

Thus far, GBT440 treatment has conferred several improvements from baseline to day 28.

Hemoglobin increases were evident by day 4 of treatment. And the researchers observed absolute hemoglobin increases of 0.5 and 0.7 g/dL with GBT440 at 500 and 700 mg, respectively, compared with a 0.1 g/dL decrease with placebo.

The median reticulocyte count decreased by 31% and 37% with GBT440 at 500 and 700 mg, respectively, compared with a 7% increase with placebo, indicating that the hemoglobin rise is due to decreased hemolysis.

Median erythropoietin levels decreased by 9 and 18 mU/mL with GBT440 at 500 and 700 mg, respectively, compared with an increase of 28 mU/mL with placebo.

Median unconjugated bilirubin levels decrease by 31% and 43% with GBT440 at 500 mg and 700 mg, respectively, compared with an increase of 2% with placebo.

Median lactate dehydrogenase levels decreased by 20% and 12% with GBT440 at 500 and 700 mg, respectively, compared with a decrease of 7% with placebo.

Median sickle cell counts decreased by 56% and 46% with GBT440 at 500 and 700 mg, respectively, compared with a 14% increase with placebo.

The researchers noted high inter- and intra-patient variability in circulating sickle cell counts.

They said inflammatory soluble adhesion molecules for the 700 mg dose cohort showed promising trends in improvement. The median P-selectin decreased 19%, compared with an increase of 20% with placebo. And the median ICAM-1 decreased 6%, compared with an increase of 33% in placebo. Data for the 500 mg dose cohort has not yet been analyzed.

The researchers said pharmacokinetic data demonstrated linear and dose-proportional properties, with a half-life amenable to once-daily dosing.

And GBT440 was well tolerated over the 28 days of dosing. None of the SCD patients discontinued GBT440. The most common adverse event was headache, and there have been no serious adverse events thought to be drug-related.

“We continue to believe that GBT440 has the potential to become the first mechanism-based and disease-modifying therapeutic for this grievous disease and look forward to sharing full results from our phase 1/2 trial and potentially initiating a pivotal trial in adult patients with SCD in 2016,” Dr Love said.

*Data in the abstract differ from the presentation.

Doctor with clipboard

Doctors may convey racial bias with their body language, according to research published in The Journal of Pain and Symptom Management.

In this small study, a group of physicians, most of whom were white males, gave less compassionate nonverbal cues when interacting with black actors portraying seriously ill patients than when interacting with white actors portraying seriously ill patients.

“Although we found that physicians said the same things to their black and white patients, communication is not just the spoken word. It also involves nonverbal cues, such as eye contact, body positioning, and touch,” said study author Amber Barnato, MD, of the University of Pittsburg in Pennsylvania.

“Poor nonverbal communication—something the physician may not even be aware he or she is doing—could explain why many black patients perceive discrimination in the healthcare setting.”

For this study, Dr Barnato and her colleagues recruited 33 hospital-based attending emergency medicine physicians, hospitalists, and intensivists from Allegheny County, Pennsylvania, and put them in realistic simulations where actors portrayed dying black and white patients accompanied by a family member.

The actors portrayed comparable medical conditions—plummeting vital signs related to either metastatic gastric or pancreatic cancer—and read from matching scripts. The physicians were unaware of what the trial was testing.

The majority of the physicians were white men, so the researchers could not derive any statistically significant conclusions about whether a physician’s race impacted his or her actions.

Physicians were scored on a point system for both their verbal and nonverbal communication skills when interacting with the patient and family member. The physicians averaged 7% lower scores for their nonverbal interactions with the black patients than with the white patients.

“When explaining what was happening and what the next steps for care could be, with the white patients, the physicians were more likely to stand right at the patient’s bedside and touch them in a sympathetic manner,” Dr Barnato said.

She explained that something as simple as a physician staying near the door and holding a binder in front of his body could be perceived by the patient and family as defensive or disengaged. This could lead to a cascade of misunderstandings that result in patients and their families requesting extraordinary life-saving measures because they don’t trust the doctor has their best interests in mind when suggesting gentler, end-of-life care options.

“When you survey people in the community about their feelings on end-of-life care, blacks are only slightly more likely than whites to say they want aggressive, life-sustaining measures when terminally ill,” Dr Barnato said.

“However, blacks are much more likely than whites to request such care when they are faced with making the decision in the hospital. Body language is a significant tool in building trust—or mistrust—and physicians need to ensure that their body language isn’t contributing to that decision.”

“To help black patients and their families feel welcome and encouraged to be partners in medical decision-making, it is critical that doctors be aware of their verbal and nonverbal communication and any unintentional biases.”

Doctor with clipboard

Doctors may convey racial bias with their body language, according to research published in The Journal of Pain and Symptom Management.

In this small study, a group of physicians, most of whom were white males, gave less compassionate nonverbal cues when interacting with black actors portraying seriously ill patients than when interacting with white actors portraying seriously ill patients.

“Although we found that physicians said the same things to their black and white patients, communication is not just the spoken word. It also involves nonverbal cues, such as eye contact, body positioning, and touch,” said study author Amber Barnato, MD, of the University of Pittsburg in Pennsylvania.

“Poor nonverbal communication—something the physician may not even be aware he or she is doing—could explain why many black patients perceive discrimination in the healthcare setting.”

For this study, Dr Barnato and her colleagues recruited 33 hospital-based attending emergency medicine physicians, hospitalists, and intensivists from Allegheny County, Pennsylvania, and put them in realistic simulations where actors portrayed dying black and white patients accompanied by a family member.

The actors portrayed comparable medical conditions—plummeting vital signs related to either metastatic gastric or pancreatic cancer—and read from matching scripts. The physicians were unaware of what the trial was testing.

The majority of the physicians were white men, so the researchers could not derive any statistically significant conclusions about whether a physician’s race impacted his or her actions.

Physicians were scored on a point system for both their verbal and nonverbal communication skills when interacting with the patient and family member. The physicians averaged 7% lower scores for their nonverbal interactions with the black patients than with the white patients.

“When explaining what was happening and what the next steps for care could be, with the white patients, the physicians were more likely to stand right at the patient’s bedside and touch them in a sympathetic manner,” Dr Barnato said.

She explained that something as simple as a physician staying near the door and holding a binder in front of his body could be perceived by the patient and family as defensive or disengaged. This could lead to a cascade of misunderstandings that result in patients and their families requesting extraordinary life-saving measures because they don’t trust the doctor has their best interests in mind when suggesting gentler, end-of-life care options.

“When you survey people in the community about their feelings on end-of-life care, blacks are only slightly more likely than whites to say they want aggressive, life-sustaining measures when terminally ill,” Dr Barnato said.

“However, blacks are much more likely than whites to request such care when they are faced with making the decision in the hospital. Body language is a significant tool in building trust—or mistrust—and physicians need to ensure that their body language isn’t contributing to that decision.”

“To help black patients and their families feel welcome and encouraged to be partners in medical decision-making, it is critical that doctors be aware of their verbal and nonverbal communication and any unintentional biases.”

Doctor with clipboard

Doctors may convey racial bias with their body language, according to research published in The Journal of Pain and Symptom Management.

In this small study, a group of physicians, most of whom were white males, gave less compassionate nonverbal cues when interacting with black actors portraying seriously ill patients than when interacting with white actors portraying seriously ill patients.

“Although we found that physicians said the same things to their black and white patients, communication is not just the spoken word. It also involves nonverbal cues, such as eye contact, body positioning, and touch,” said study author Amber Barnato, MD, of the University of Pittsburg in Pennsylvania.

“Poor nonverbal communication—something the physician may not even be aware he or she is doing—could explain why many black patients perceive discrimination in the healthcare setting.”

For this study, Dr Barnato and her colleagues recruited 33 hospital-based attending emergency medicine physicians, hospitalists, and intensivists from Allegheny County, Pennsylvania, and put them in realistic simulations where actors portrayed dying black and white patients accompanied by a family member.

The actors portrayed comparable medical conditions—plummeting vital signs related to either metastatic gastric or pancreatic cancer—and read from matching scripts. The physicians were unaware of what the trial was testing.

The majority of the physicians were white men, so the researchers could not derive any statistically significant conclusions about whether a physician’s race impacted his or her actions.

Physicians were scored on a point system for both their verbal and nonverbal communication skills when interacting with the patient and family member. The physicians averaged 7% lower scores for their nonverbal interactions with the black patients than with the white patients.

“When explaining what was happening and what the next steps for care could be, with the white patients, the physicians were more likely to stand right at the patient’s bedside and touch them in a sympathetic manner,” Dr Barnato said.

She explained that something as simple as a physician staying near the door and holding a binder in front of his body could be perceived by the patient and family as defensive or disengaged. This could lead to a cascade of misunderstandings that result in patients and their families requesting extraordinary life-saving measures because they don’t trust the doctor has their best interests in mind when suggesting gentler, end-of-life care options.

“When you survey people in the community about their feelings on end-of-life care, blacks are only slightly more likely than whites to say they want aggressive, life-sustaining measures when terminally ill,” Dr Barnato said.

“However, blacks are much more likely than whites to request such care when they are faced with making the decision in the hospital. Body language is a significant tool in building trust—or mistrust—and physicians need to ensure that their body language isn’t contributing to that decision.”

“To help black patients and their families feel welcome and encouraged to be partners in medical decision-making, it is critical that doctors be aware of their verbal and nonverbal communication and any unintentional biases.”

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Click here to download the PDF.

Click here to download the PDF.