A retrospective study of nearly 1.5 million patients over the course of 44 years showed no evidence to support the claim that neurodegenerative disorders can be transmitted between individuals through blood transfusions.

“Given that the neurodegenerative diseases on the dementia spectrum are relatively common, the misfolded proteins in affected persons have a wide tissue distribution, and the diseases may have a protracted prediagnostic course, potential transmission through transfusion could have important public health implications,” explained study authors led by Gustaf Edgren, MD, PhD, of the Karolinska Institute in Stockholm.

©Hemera/Thinkstock.com

The retrospective cohort study analyzed data on 1,465,845 patients listed in nationwide transfusion registers, all of whom had undergone transfusions between 1968 and 2012 in Sweden, or during 1981-2012 in Denmark. The investigators looked for transfusions in which the donor had a diagnosis – either before or after the transfusion – of Alzheimer’s disease, Parkinson’s disease, or amyotrophic lateral sclerosis, and compared them with transfusions involving two healthy control groups. Creutzfeldt-Jakob disease was not included in the analysis (Ann Intern Med. 2016 Jun 28. doi: 10.7326/M15-2421).

All transfusion recipients were followed from 180 days after the transfusion date in order to minimize the risk of including a patient who had a neurodegenerative disorder that was present but not registered at the time of the transfusion. Follow-ups lasted until either the first diagnosis of a neurodegenerative disorder, death, emigration, or the end of the trial period on Dec. 31, 2012.

If a donor had received a diagnosis of a neurodegenerative disorder within 20 years of the transfusion, all recipients from said donor were considered to be exposed. “The maximum latency of 20 years was used as a compromise between allowing a long preclinical phase – during which donors may still be infectious – and avoiding classifying clearly healthy donors as potentially infectious,” the authors wrote.

Only 42,254 (2.9%) of subjects were deemed to be exposed to a neurodegenerative disorder based on their blood transfusion donor. However, there was no evidence of any increased risk of dementia of any type from exposure to blood from affected donors in any of the recipients over the course of the follow-up period (hazard ratio, 1.04; 95% confidence interval, 0.99-1.09), and similar results were obtained individually for Alzheimer’s disease and Parkinson’s disease. As a control measure, the investigators also tested for hepatitis C transmission before and after transfusions, and were “as expected, readily able to detect transmission of viral hepatitis,” despite finding no traces of neurodegenerative conditions.

“Despite accumulating scientific support for horizontal transmissibility of a range of disorders in the neurodegenerative spectrum through various methods of inoculation in animal models and of variant Creutzfeldt-Jakob disease from human and animal model data, this study provides evidence against blood transfusion as an important route of transmission of neurodegenerative diseases between humans,” the authors concluded.

The authors also added that “given that the study was based on the entire computerized blood banking history in two countries with several decades of follow-up, more comprehensive data are unlikely to be available in the foreseeable future.”

Funding for the study was provided by the Swedish Research Council, the Swedish Heart-Lung Foundation, the Swedish Society for Medical Research, and the Danish Council for Independent Research. One coauthor reported receiving a grant from the Danish Council for Independent Research, and another reported receiving grants from the Swedish Research Council and the Swedish Heart-Lung Foundation during the conduct of the study. No other authors reported any relevant financial disclosures.

[email protected]

A retrospective study of nearly 1.5 million patients over the course of 44 years showed no evidence to support the claim that neurodegenerative disorders can be transmitted between individuals through blood transfusions.

“Given that the neurodegenerative diseases on the dementia spectrum are relatively common, the misfolded proteins in affected persons have a wide tissue distribution, and the diseases may have a protracted prediagnostic course, potential transmission through transfusion could have important public health implications,” explained study authors led by Gustaf Edgren, MD, PhD, of the Karolinska Institute in Stockholm.

©Hemera/Thinkstock.com

The retrospective cohort study analyzed data on 1,465,845 patients listed in nationwide transfusion registers, all of whom had undergone transfusions between 1968 and 2012 in Sweden, or during 1981-2012 in Denmark. The investigators looked for transfusions in which the donor had a diagnosis – either before or after the transfusion – of Alzheimer’s disease, Parkinson’s disease, or amyotrophic lateral sclerosis, and compared them with transfusions involving two healthy control groups. Creutzfeldt-Jakob disease was not included in the analysis (Ann Intern Med. 2016 Jun 28. doi: 10.7326/M15-2421).

All transfusion recipients were followed from 180 days after the transfusion date in order to minimize the risk of including a patient who had a neurodegenerative disorder that was present but not registered at the time of the transfusion. Follow-ups lasted until either the first diagnosis of a neurodegenerative disorder, death, emigration, or the end of the trial period on Dec. 31, 2012.

If a donor had received a diagnosis of a neurodegenerative disorder within 20 years of the transfusion, all recipients from said donor were considered to be exposed. “The maximum latency of 20 years was used as a compromise between allowing a long preclinical phase – during which donors may still be infectious – and avoiding classifying clearly healthy donors as potentially infectious,” the authors wrote.

Only 42,254 (2.9%) of subjects were deemed to be exposed to a neurodegenerative disorder based on their blood transfusion donor. However, there was no evidence of any increased risk of dementia of any type from exposure to blood from affected donors in any of the recipients over the course of the follow-up period (hazard ratio, 1.04; 95% confidence interval, 0.99-1.09), and similar results were obtained individually for Alzheimer’s disease and Parkinson’s disease. As a control measure, the investigators also tested for hepatitis C transmission before and after transfusions, and were “as expected, readily able to detect transmission of viral hepatitis,” despite finding no traces of neurodegenerative conditions.

“Despite accumulating scientific support for horizontal transmissibility of a range of disorders in the neurodegenerative spectrum through various methods of inoculation in animal models and of variant Creutzfeldt-Jakob disease from human and animal model data, this study provides evidence against blood transfusion as an important route of transmission of neurodegenerative diseases between humans,” the authors concluded.

The authors also added that “given that the study was based on the entire computerized blood banking history in two countries with several decades of follow-up, more comprehensive data are unlikely to be available in the foreseeable future.”

Funding for the study was provided by the Swedish Research Council, the Swedish Heart-Lung Foundation, the Swedish Society for Medical Research, and the Danish Council for Independent Research. One coauthor reported receiving a grant from the Danish Council for Independent Research, and another reported receiving grants from the Swedish Research Council and the Swedish Heart-Lung Foundation during the conduct of the study. No other authors reported any relevant financial disclosures.

[email protected]

A retrospective study of nearly 1.5 million patients over the course of 44 years showed no evidence to support the claim that neurodegenerative disorders can be transmitted between individuals through blood transfusions.

“Given that the neurodegenerative diseases on the dementia spectrum are relatively common, the misfolded proteins in affected persons have a wide tissue distribution, and the diseases may have a protracted prediagnostic course, potential transmission through transfusion could have important public health implications,” explained study authors led by Gustaf Edgren, MD, PhD, of the Karolinska Institute in Stockholm.

©Hemera/Thinkstock.com

The retrospective cohort study analyzed data on 1,465,845 patients listed in nationwide transfusion registers, all of whom had undergone transfusions between 1968 and 2012 in Sweden, or during 1981-2012 in Denmark. The investigators looked for transfusions in which the donor had a diagnosis – either before or after the transfusion – of Alzheimer’s disease, Parkinson’s disease, or amyotrophic lateral sclerosis, and compared them with transfusions involving two healthy control groups. Creutzfeldt-Jakob disease was not included in the analysis (Ann Intern Med. 2016 Jun 28. doi: 10.7326/M15-2421).

All transfusion recipients were followed from 180 days after the transfusion date in order to minimize the risk of including a patient who had a neurodegenerative disorder that was present but not registered at the time of the transfusion. Follow-ups lasted until either the first diagnosis of a neurodegenerative disorder, death, emigration, or the end of the trial period on Dec. 31, 2012.

If a donor had received a diagnosis of a neurodegenerative disorder within 20 years of the transfusion, all recipients from said donor were considered to be exposed. “The maximum latency of 20 years was used as a compromise between allowing a long preclinical phase – during which donors may still be infectious – and avoiding classifying clearly healthy donors as potentially infectious,” the authors wrote.

Only 42,254 (2.9%) of subjects were deemed to be exposed to a neurodegenerative disorder based on their blood transfusion donor. However, there was no evidence of any increased risk of dementia of any type from exposure to blood from affected donors in any of the recipients over the course of the follow-up period (hazard ratio, 1.04; 95% confidence interval, 0.99-1.09), and similar results were obtained individually for Alzheimer’s disease and Parkinson’s disease. As a control measure, the investigators also tested for hepatitis C transmission before and after transfusions, and were “as expected, readily able to detect transmission of viral hepatitis,” despite finding no traces of neurodegenerative conditions.

“Despite accumulating scientific support for horizontal transmissibility of a range of disorders in the neurodegenerative spectrum through various methods of inoculation in animal models and of variant Creutzfeldt-Jakob disease from human and animal model data, this study provides evidence against blood transfusion as an important route of transmission of neurodegenerative diseases between humans,” the authors concluded.

The authors also added that “given that the study was based on the entire computerized blood banking history in two countries with several decades of follow-up, more comprehensive data are unlikely to be available in the foreseeable future.”

Funding for the study was provided by the Swedish Research Council, the Swedish Heart-Lung Foundation, the Swedish Society for Medical Research, and the Danish Council for Independent Research. One coauthor reported receiving a grant from the Danish Council for Independent Research, and another reported receiving grants from the Swedish Research Council and the Swedish Heart-Lung Foundation during the conduct of the study. No other authors reported any relevant financial disclosures.

[email protected]

Clinical question: Which medications are most safe and effective at managing type 2 diabetes?

Background: Patients and practitioners need an updated review of the evidence to select the optimal medication for type 2 diabetes management.

Study design: Systematic review.

Synopsis: The authors reviewed 179 trials and 25 observational studies. When comparing metformin to sulfonylureas, metformin was associated with less cardiovascular mortality.

However, when trying to make comparisons based on all-cause mortality or microvascular complications, the evidence is limited. Improvements in hemoglobin A1c levels are similar when comparing different monotherapy options, and low blood sugar was most common with sulfonylureas. The short duration of many trials limits the ability to provide better data on long-term outcomes.

Bottom line: Metformin remains the first-line agent for type 2 diabetes management.

Citation: Maruthur NM, Tseng E, Hutfless S, et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systemic review and meta-analysis. Ann Intern Med. 2016;164(1):740-751.

Short Take

Patients Discharge Readiness May Not Be Adequately Assessed and/or Addressed During Hospitalization

Prospective observational study found unresolved barriers to discharge were common in at least 90% of patients. Patients frequently cited issues including unresolved pain, lack of understanding around discharge plans, and ability to provide self-care.

Citation: Harrison JD, Greysen RS, Jacolbia R, Nguyen A, Auerbach AD. Not ready, not set…discharge: patient-reported barriers to discharge readiness at an academic medical center [published online ahead of print April 15, 2016]. J Hosp Med. doi:10.1002/jhm.2591.

Clinical question: Which medications are most safe and effective at managing type 2 diabetes?

Background: Patients and practitioners need an updated review of the evidence to select the optimal medication for type 2 diabetes management.

Study design: Systematic review.

Synopsis: The authors reviewed 179 trials and 25 observational studies. When comparing metformin to sulfonylureas, metformin was associated with less cardiovascular mortality.

However, when trying to make comparisons based on all-cause mortality or microvascular complications, the evidence is limited. Improvements in hemoglobin A1c levels are similar when comparing different monotherapy options, and low blood sugar was most common with sulfonylureas. The short duration of many trials limits the ability to provide better data on long-term outcomes.

Bottom line: Metformin remains the first-line agent for type 2 diabetes management.

Citation: Maruthur NM, Tseng E, Hutfless S, et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systemic review and meta-analysis. Ann Intern Med. 2016;164(1):740-751.

Short Take

Patients Discharge Readiness May Not Be Adequately Assessed and/or Addressed During Hospitalization

Prospective observational study found unresolved barriers to discharge were common in at least 90% of patients. Patients frequently cited issues including unresolved pain, lack of understanding around discharge plans, and ability to provide self-care.

Citation: Harrison JD, Greysen RS, Jacolbia R, Nguyen A, Auerbach AD. Not ready, not set…discharge: patient-reported barriers to discharge readiness at an academic medical center [published online ahead of print April 15, 2016]. J Hosp Med. doi:10.1002/jhm.2591.

Clinical question: Which medications are most safe and effective at managing type 2 diabetes?

Background: Patients and practitioners need an updated review of the evidence to select the optimal medication for type 2 diabetes management.

Study design: Systematic review.

Synopsis: The authors reviewed 179 trials and 25 observational studies. When comparing metformin to sulfonylureas, metformin was associated with less cardiovascular mortality.

However, when trying to make comparisons based on all-cause mortality or microvascular complications, the evidence is limited. Improvements in hemoglobin A1c levels are similar when comparing different monotherapy options, and low blood sugar was most common with sulfonylureas. The short duration of many trials limits the ability to provide better data on long-term outcomes.

Bottom line: Metformin remains the first-line agent for type 2 diabetes management.

Citation: Maruthur NM, Tseng E, Hutfless S, et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systemic review and meta-analysis. Ann Intern Med. 2016;164(1):740-751.

Short Take

Patients Discharge Readiness May Not Be Adequately Assessed and/or Addressed During Hospitalization

Prospective observational study found unresolved barriers to discharge were common in at least 90% of patients. Patients frequently cited issues including unresolved pain, lack of understanding around discharge plans, and ability to provide self-care.

Citation: Harrison JD, Greysen RS, Jacolbia R, Nguyen A, Auerbach AD. Not ready, not set…discharge: patient-reported barriers to discharge readiness at an academic medical center [published online ahead of print April 15, 2016]. J Hosp Med. doi:10.1002/jhm.2591.

Clinical question: What is the prognosis of patients who have a TIA or minor stroke?

Background: Prior studies had estimated the risk in the three months following a TIA or minor stroke of having a stroke or acute coronary syndrome (ACS) as 12% to 20%, but this may not reflect the risk of modern patients receiving the current standards of care.

Study design: Prospective observational registry of patients with recent TIA or minor stroke.

Setting: International, including 21 countries.

Synopsis: Adults with recent TIA or minor stroke were included in this multi-center, international registry, and one-year outcomes were reported. At one year, the Kaplan-Meier estimated event rate for the combined outcome of stroke, ACS, or death from cardiovascular causes was 6.2%. The risk of the cardiovascular events was found to be lower than previously reported, suggesting an improvement in outcomes with current interventions. Elevated ABCD2 score, infarction seen on brain imaging, and large-artery atherosclerosis were each associated with higher risk.

Bottom line: Elevated ABCD2 score, brain imaging findings, and large-artery atherosclerosis suggest increased risk for recurrent stroke.

Citation: Amarenco P, Lavallée PC, Labreuche J, et al. One-year risk of stroke after transient ischemic attack or minor stroke. N Engl J Med. 2016;374(16):1533-1542.

Clinical question: What is the prognosis of patients who have a TIA or minor stroke?

Background: Prior studies had estimated the risk in the three months following a TIA or minor stroke of having a stroke or acute coronary syndrome (ACS) as 12% to 20%, but this may not reflect the risk of modern patients receiving the current standards of care.

Study design: Prospective observational registry of patients with recent TIA or minor stroke.

Setting: International, including 21 countries.

Synopsis: Adults with recent TIA or minor stroke were included in this multi-center, international registry, and one-year outcomes were reported. At one year, the Kaplan-Meier estimated event rate for the combined outcome of stroke, ACS, or death from cardiovascular causes was 6.2%. The risk of the cardiovascular events was found to be lower than previously reported, suggesting an improvement in outcomes with current interventions. Elevated ABCD2 score, infarction seen on brain imaging, and large-artery atherosclerosis were each associated with higher risk.

Bottom line: Elevated ABCD2 score, brain imaging findings, and large-artery atherosclerosis suggest increased risk for recurrent stroke.

Citation: Amarenco P, Lavallée PC, Labreuche J, et al. One-year risk of stroke after transient ischemic attack or minor stroke. N Engl J Med. 2016;374(16):1533-1542.

Clinical question: What is the prognosis of patients who have a TIA or minor stroke?

Background: Prior studies had estimated the risk in the three months following a TIA or minor stroke of having a stroke or acute coronary syndrome (ACS) as 12% to 20%, but this may not reflect the risk of modern patients receiving the current standards of care.

Study design: Prospective observational registry of patients with recent TIA or minor stroke.

Setting: International, including 21 countries.

Synopsis: Adults with recent TIA or minor stroke were included in this multi-center, international registry, and one-year outcomes were reported. At one year, the Kaplan-Meier estimated event rate for the combined outcome of stroke, ACS, or death from cardiovascular causes was 6.2%. The risk of the cardiovascular events was found to be lower than previously reported, suggesting an improvement in outcomes with current interventions. Elevated ABCD2 score, infarction seen on brain imaging, and large-artery atherosclerosis were each associated with higher risk.

Bottom line: Elevated ABCD2 score, brain imaging findings, and large-artery atherosclerosis suggest increased risk for recurrent stroke.

Citation: Amarenco P, Lavallée PC, Labreuche J, et al. One-year risk of stroke after transient ischemic attack or minor stroke. N Engl J Med. 2016;374(16):1533-1542.

Micrograph showing CMV

Image by Ed Uthman

Research published in PLOS Pathogens suggests that emetine, a drug once used to treat amebiasis and induce vomiting in cases of poisoning, may also halt replication of cytomegalovirus (CMV).

Although there are drugs available to treat CMV, they can cause serious toxicity.

Furthermore, resistant strains of CMV can emerge, creating “a desperate need for other ways to control this virus,” according to Ravit Boger, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

Dr Boger and her colleagues decided to search for drugs to treat CMV by screening 1280 pharmacologically active compounds already approved by the US Food and Drug Administration.

The researchers found a “hit” with emetine, a drug that was used in the past to treat amebiasis before other drugs took its place decades ago.

Results showed that emetine can inhibit CMV at much lower doses than those used for amebiasis, and less frequent doses might be effective for CMV inhibition as well.

In vitro and in vivo tests showed that very low doses of emetine significantly reduced viral replication—75 nm in vitro and 0.1 mg/kg in mice.

Furthermore, with a half-life of 35 hours, the drug exerted its effects over a sustained period, effectively inhibiting virus replication at 14 days after 3 doses.

Additional investigation revealed that emetine’s action against CMV was due to its effects on proteins that control the cell cycle.

Dr Boger cautioned that there is a long way to go before emetine or similar agents can be considered for the treatment of CMV.

“But if further research affirms its potential value, emetine might eventually be used in patients who don’t respond to approved anti-CMV drugs, alone or in combination with these,” she said.

Dr Boger and her colleagues also believe that gaining a better understanding of emetine’s activity in cells could lead to the discovery of new drugs that take advantage of the same or similar pathways.

Micrograph showing CMV

Image by Ed Uthman

Research published in PLOS Pathogens suggests that emetine, a drug once used to treat amebiasis and induce vomiting in cases of poisoning, may also halt replication of cytomegalovirus (CMV).

Although there are drugs available to treat CMV, they can cause serious toxicity.

Furthermore, resistant strains of CMV can emerge, creating “a desperate need for other ways to control this virus,” according to Ravit Boger, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

Dr Boger and her colleagues decided to search for drugs to treat CMV by screening 1280 pharmacologically active compounds already approved by the US Food and Drug Administration.

The researchers found a “hit” with emetine, a drug that was used in the past to treat amebiasis before other drugs took its place decades ago.

Results showed that emetine can inhibit CMV at much lower doses than those used for amebiasis, and less frequent doses might be effective for CMV inhibition as well.

In vitro and in vivo tests showed that very low doses of emetine significantly reduced viral replication—75 nm in vitro and 0.1 mg/kg in mice.

Furthermore, with a half-life of 35 hours, the drug exerted its effects over a sustained period, effectively inhibiting virus replication at 14 days after 3 doses.

Additional investigation revealed that emetine’s action against CMV was due to its effects on proteins that control the cell cycle.

Dr Boger cautioned that there is a long way to go before emetine or similar agents can be considered for the treatment of CMV.

“But if further research affirms its potential value, emetine might eventually be used in patients who don’t respond to approved anti-CMV drugs, alone or in combination with these,” she said.

Dr Boger and her colleagues also believe that gaining a better understanding of emetine’s activity in cells could lead to the discovery of new drugs that take advantage of the same or similar pathways.

Micrograph showing CMV

Image by Ed Uthman

Research published in PLOS Pathogens suggests that emetine, a drug once used to treat amebiasis and induce vomiting in cases of poisoning, may also halt replication of cytomegalovirus (CMV).

Although there are drugs available to treat CMV, they can cause serious toxicity.

Furthermore, resistant strains of CMV can emerge, creating “a desperate need for other ways to control this virus,” according to Ravit Boger, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

Dr Boger and her colleagues decided to search for drugs to treat CMV by screening 1280 pharmacologically active compounds already approved by the US Food and Drug Administration.

The researchers found a “hit” with emetine, a drug that was used in the past to treat amebiasis before other drugs took its place decades ago.

Results showed that emetine can inhibit CMV at much lower doses than those used for amebiasis, and less frequent doses might be effective for CMV inhibition as well.

In vitro and in vivo tests showed that very low doses of emetine significantly reduced viral replication—75 nm in vitro and 0.1 mg/kg in mice.

Furthermore, with a half-life of 35 hours, the drug exerted its effects over a sustained period, effectively inhibiting virus replication at 14 days after 3 doses.

Additional investigation revealed that emetine’s action against CMV was due to its effects on proteins that control the cell cycle.

Dr Boger cautioned that there is a long way to go before emetine or similar agents can be considered for the treatment of CMV.

“But if further research affirms its potential value, emetine might eventually be used in patients who don’t respond to approved anti-CMV drugs, alone or in combination with these,” she said.

Dr Boger and her colleagues also believe that gaining a better understanding of emetine’s activity in cells could lead to the discovery of new drugs that take advantage of the same or similar pathways.

Red blood cells

Researchers have created a computer model that shows how tiny slits in the spleen prevent old, diseased, or misshapen red blood cells from re-entering the bloodstream.

The team says the model can be used to study the spleen’s role in controlling diseases that affect the size and structure of red blood cells—such as sickle cell anemia, thalassemia, and malaria—and to develop new diagnostics and therapeutics for these diseases.

The researchers described the model in PNAS.

Previous studies have shown that part of the spleen’s filtration process relies on having red blood cells squeeze through tiny slits between the endothelial cells that line the spleen’s blood vessels. These “interendothelial slits” are no larger than 1.2 µm tall, 4 µm wide, and 1.9 µm deep.

More rigid and misshapen blood cells might not be able to pass through these narrow passages. And this process cannot be observed in vivo because of the minute size of the slits.

In order to “see” how the interendothelial slits regulate red blood cell circulation, the researchers created a computer simulation based on dissipative particle dynamics, a modeling method.

Their model allowed the team to determine the range of cell sizes and shapes that could fit through the slits. The range closely mirrored the range of sizes and shapes for healthy red blood cells, indicating that only healthy cells should be able to pass through the slits.

“The computational and analytical models from this work, along with a variety of experimental observations, point to a more detailed picture of how the physiology of the human spleen likely influences several key geometrical characteristics of red blood cells,” said study author Subra Suresh, ScD, of Carnegie Mellon University in Pittsburgh, Pennsylvania.

“They also offer better understanding of how the circulatory bottleneck for the red blood cell in the spleen could affect a variety of acute and chronic disease states arising from hereditary disorders, human cancers, and infectious diseases, with implications for therapeutic interventions and drug efficacy assays.”

In addition to giving researchers a better picture of how the spleen functions, the findings provide new insights into drug treatments.

A class of drugs currently in development for treating malaria alters the shape of red blood cells infected with malaria, theoretically preventing them from passing through interendothelial slits. One such drug, spiroindoline KAE609, is in clinical trials.

The researchers’ results might also explain why artemisinin-based antimalarial drugs, which stiffen healthy and malaria-infected red blood cells, can lead to severe anemia.

Red blood cells

Researchers have created a computer model that shows how tiny slits in the spleen prevent old, diseased, or misshapen red blood cells from re-entering the bloodstream.

The team says the model can be used to study the spleen’s role in controlling diseases that affect the size and structure of red blood cells—such as sickle cell anemia, thalassemia, and malaria—and to develop new diagnostics and therapeutics for these diseases.

The researchers described the model in PNAS.

Previous studies have shown that part of the spleen’s filtration process relies on having red blood cells squeeze through tiny slits between the endothelial cells that line the spleen’s blood vessels. These “interendothelial slits” are no larger than 1.2 µm tall, 4 µm wide, and 1.9 µm deep.

More rigid and misshapen blood cells might not be able to pass through these narrow passages. And this process cannot be observed in vivo because of the minute size of the slits.

In order to “see” how the interendothelial slits regulate red blood cell circulation, the researchers created a computer simulation based on dissipative particle dynamics, a modeling method.

Their model allowed the team to determine the range of cell sizes and shapes that could fit through the slits. The range closely mirrored the range of sizes and shapes for healthy red blood cells, indicating that only healthy cells should be able to pass through the slits.

“The computational and analytical models from this work, along with a variety of experimental observations, point to a more detailed picture of how the physiology of the human spleen likely influences several key geometrical characteristics of red blood cells,” said study author Subra Suresh, ScD, of Carnegie Mellon University in Pittsburgh, Pennsylvania.

“They also offer better understanding of how the circulatory bottleneck for the red blood cell in the spleen could affect a variety of acute and chronic disease states arising from hereditary disorders, human cancers, and infectious diseases, with implications for therapeutic interventions and drug efficacy assays.”

In addition to giving researchers a better picture of how the spleen functions, the findings provide new insights into drug treatments.

A class of drugs currently in development for treating malaria alters the shape of red blood cells infected with malaria, theoretically preventing them from passing through interendothelial slits. One such drug, spiroindoline KAE609, is in clinical trials.

The researchers’ results might also explain why artemisinin-based antimalarial drugs, which stiffen healthy and malaria-infected red blood cells, can lead to severe anemia.

Red blood cells

Researchers have created a computer model that shows how tiny slits in the spleen prevent old, diseased, or misshapen red blood cells from re-entering the bloodstream.

The team says the model can be used to study the spleen’s role in controlling diseases that affect the size and structure of red blood cells—such as sickle cell anemia, thalassemia, and malaria—and to develop new diagnostics and therapeutics for these diseases.

The researchers described the model in PNAS.

Previous studies have shown that part of the spleen’s filtration process relies on having red blood cells squeeze through tiny slits between the endothelial cells that line the spleen’s blood vessels. These “interendothelial slits” are no larger than 1.2 µm tall, 4 µm wide, and 1.9 µm deep.

More rigid and misshapen blood cells might not be able to pass through these narrow passages. And this process cannot be observed in vivo because of the minute size of the slits.

In order to “see” how the interendothelial slits regulate red blood cell circulation, the researchers created a computer simulation based on dissipative particle dynamics, a modeling method.

Their model allowed the team to determine the range of cell sizes and shapes that could fit through the slits. The range closely mirrored the range of sizes and shapes for healthy red blood cells, indicating that only healthy cells should be able to pass through the slits.

“The computational and analytical models from this work, along with a variety of experimental observations, point to a more detailed picture of how the physiology of the human spleen likely influences several key geometrical characteristics of red blood cells,” said study author Subra Suresh, ScD, of Carnegie Mellon University in Pittsburgh, Pennsylvania.

“They also offer better understanding of how the circulatory bottleneck for the red blood cell in the spleen could affect a variety of acute and chronic disease states arising from hereditary disorders, human cancers, and infectious diseases, with implications for therapeutic interventions and drug efficacy assays.”

In addition to giving researchers a better picture of how the spleen functions, the findings provide new insights into drug treatments.

A class of drugs currently in development for treating malaria alters the shape of red blood cells infected with malaria, theoretically preventing them from passing through interendothelial slits. One such drug, spiroindoline KAE609, is in clinical trials.

The researchers’ results might also explain why artemisinin-based antimalarial drugs, which stiffen healthy and malaria-infected red blood cells, can lead to severe anemia.

T cells

Image courtesy of NIAID

Results of a phase 1 study suggest that chimeric antigen receptor T cells specific for the κ light chain (κ.CAR T cells) can produce responses in patients with relapsed or refractory B-cell malignancies, largely without side effects.

The therapy induced complete and partial responses in some patients with non-Hodgkin lymphoma (NHL), and it allowed other patients with chronic lymphocytic leukemia (CLL) or multiple myeloma (MM) to maintain stable disease.

There was 1 adverse event considered possibly related to the treatment.

The researchers reported these results in The Journal of Clinical Investigation.

The κ.CAR T cells were designed to recognize κ-restricted cells and spare normal B cells expressing the nontargeted λ light chain.

“We reasoned that targeting the light chain expressed by malignant B cells should efficiently kill tumor cells while sparing normal B cells expressing the other type of light chain,” said study author Carlos Ramos, MD, of Baylor College of Medicine in Houston, Texas.

He and his colleagues tested the κ.CAR T cells in 16 patients with relapsed or refractory κ+ NHL (n=7), CLL (n=2), or MM (n=7).

The team isolated T cells from these patients and modified the cells so they could target the κ light chain on the surface of malignant B cells. The modified T cells were infused back into the patients, and each patient was monitored for disease progression and side effects.

Eleven patients stopped receiving other treatments at least 4 weeks prior to T-cell infusion. Six patients without lymphopenia received cyclophosphamide at 12.5 mg/kg 4 days before κ.CAR T-cell infusion (0.2×10⁸ to 2×10⁸ κ.CAR T cells/m²).

“We found the treatment to be feasible and safe at all the dose levels studied,” Dr Ramos said.

One MM patient had grade 3 lymphopenia that was deemed possibly related to treatment, but none of the other adverse events were thought to result from the κ.CAR T cells.

Two patients with NHL achieved a complete response to treatment, 1 lasting more than 32 months and the other lasting 6 weeks. A third NHL patient had a partial response lasting 3 months, and a CLL patient had stable disease lasting 6 weeks.

Five of the 7 MM patients had stable disease, 3 lasting 6 weeks, 1 lasting 17 months, and 1 lasting 24 months.

“Our approach, although we are still optimizing it, offers a new possibility for patients in whom other treatments have not been successful,” Dr Ramos concluded.

T cells

Image courtesy of NIAID

Results of a phase 1 study suggest that chimeric antigen receptor T cells specific for the κ light chain (κ.CAR T cells) can produce responses in patients with relapsed or refractory B-cell malignancies, largely without side effects.

The therapy induced complete and partial responses in some patients with non-Hodgkin lymphoma (NHL), and it allowed other patients with chronic lymphocytic leukemia (CLL) or multiple myeloma (MM) to maintain stable disease.

There was 1 adverse event considered possibly related to the treatment.

The researchers reported these results in The Journal of Clinical Investigation.

The κ.CAR T cells were designed to recognize κ-restricted cells and spare normal B cells expressing the nontargeted λ light chain.

“We reasoned that targeting the light chain expressed by malignant B cells should efficiently kill tumor cells while sparing normal B cells expressing the other type of light chain,” said study author Carlos Ramos, MD, of Baylor College of Medicine in Houston, Texas.

He and his colleagues tested the κ.CAR T cells in 16 patients with relapsed or refractory κ+ NHL (n=7), CLL (n=2), or MM (n=7).

The team isolated T cells from these patients and modified the cells so they could target the κ light chain on the surface of malignant B cells. The modified T cells were infused back into the patients, and each patient was monitored for disease progression and side effects.

Eleven patients stopped receiving other treatments at least 4 weeks prior to T-cell infusion. Six patients without lymphopenia received cyclophosphamide at 12.5 mg/kg 4 days before κ.CAR T-cell infusion (0.2×10⁸ to 2×10⁸ κ.CAR T cells/m²).

“We found the treatment to be feasible and safe at all the dose levels studied,” Dr Ramos said.

One MM patient had grade 3 lymphopenia that was deemed possibly related to treatment, but none of the other adverse events were thought to result from the κ.CAR T cells.

Two patients with NHL achieved a complete response to treatment, 1 lasting more than 32 months and the other lasting 6 weeks. A third NHL patient had a partial response lasting 3 months, and a CLL patient had stable disease lasting 6 weeks.

Five of the 7 MM patients had stable disease, 3 lasting 6 weeks, 1 lasting 17 months, and 1 lasting 24 months.

“Our approach, although we are still optimizing it, offers a new possibility for patients in whom other treatments have not been successful,” Dr Ramos concluded.

T cells

Image courtesy of NIAID

Results of a phase 1 study suggest that chimeric antigen receptor T cells specific for the κ light chain (κ.CAR T cells) can produce responses in patients with relapsed or refractory B-cell malignancies, largely without side effects.

The therapy induced complete and partial responses in some patients with non-Hodgkin lymphoma (NHL), and it allowed other patients with chronic lymphocytic leukemia (CLL) or multiple myeloma (MM) to maintain stable disease.

There was 1 adverse event considered possibly related to the treatment.

The researchers reported these results in The Journal of Clinical Investigation.

The κ.CAR T cells were designed to recognize κ-restricted cells and spare normal B cells expressing the nontargeted λ light chain.

“We reasoned that targeting the light chain expressed by malignant B cells should efficiently kill tumor cells while sparing normal B cells expressing the other type of light chain,” said study author Carlos Ramos, MD, of Baylor College of Medicine in Houston, Texas.

He and his colleagues tested the κ.CAR T cells in 16 patients with relapsed or refractory κ+ NHL (n=7), CLL (n=2), or MM (n=7).

The team isolated T cells from these patients and modified the cells so they could target the κ light chain on the surface of malignant B cells. The modified T cells were infused back into the patients, and each patient was monitored for disease progression and side effects.

Eleven patients stopped receiving other treatments at least 4 weeks prior to T-cell infusion. Six patients without lymphopenia received cyclophosphamide at 12.5 mg/kg 4 days before κ.CAR T-cell infusion (0.2×10⁸ to 2×10⁸ κ.CAR T cells/m²).

“We found the treatment to be feasible and safe at all the dose levels studied,” Dr Ramos said.

One MM patient had grade 3 lymphopenia that was deemed possibly related to treatment, but none of the other adverse events were thought to result from the κ.CAR T cells.

Two patients with NHL achieved a complete response to treatment, 1 lasting more than 32 months and the other lasting 6 weeks. A third NHL patient had a partial response lasting 3 months, and a CLL patient had stable disease lasting 6 weeks.

Five of the 7 MM patients had stable disease, 3 lasting 6 weeks, 1 lasting 17 months, and 1 lasting 24 months.

“Our approach, although we are still optimizing it, offers a new possibility for patients in whom other treatments have not been successful,” Dr Ramos concluded.

Daratumumab (Darzalex)

Photo courtesy of Janssen

Health Canada has granted conditional approval, or a Notice of Compliance with Conditions (NOC/c), for daratumumab (Darzalex), a monoclonal antibody (mAb) targeting CD38.

The mAb is now approved to treat patients with multiple myeloma (MM) who have received at least 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or MM patients who are refractory to both a PI and an IMiD.

An NOC/c is authorization to market a drug with the condition that the sponsor—in this case, Janssen Inc.—undertake additional studies to verify a clinical benefit.

The NOC/c policy is designed to provide access to:

• Drugs that can treat serious, life-threatening, or severely debilitating diseases
• Drugs that can treat conditions for which no drug is currently marketed in Canada
• Drugs that provide a significant increase in efficacy or significant decrease in risk when compared to existing drugs marketed in Canada.

Studies of daratumumab

The NOC/c for daratumumab was based on a review of data from the phase 2 SIRIUS study, the phase 1/2 GEN501 study, and additional supportive studies.

The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.

The results suggested daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%. Most adverse events in this study were grade 1 or 2, although serious events did occur.

The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 patients received the drug at 16 mg/kg.

Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.

Findings from a combined efficacy analysis of the GEN501 and SIRIUS trials demonstrated that, after a mean follow-up of 14.8 months, the estimated median overall survival for patients who received single-agent daratumumab at 16 mg/kg was 20 months.

Five phase 3 clinical studies with daratumumab in MM patients—in relapsed and frontline settings—are ongoing. Additional studies are ongoing or planned to assess the mAb’s potential in other malignant and pre-malignant diseases in which CD38 is expressed.

Janssen has exclusive worldwide rights to the development, manufacturing, and commercialization of daratumumab for all potential indications. The company licensed daratumumab from Genmab A/S in August 2012.

Daratumumab (Darzalex)

Photo courtesy of Janssen

Health Canada has granted conditional approval, or a Notice of Compliance with Conditions (NOC/c), for daratumumab (Darzalex), a monoclonal antibody (mAb) targeting CD38.

The mAb is now approved to treat patients with multiple myeloma (MM) who have received at least 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or MM patients who are refractory to both a PI and an IMiD.

An NOC/c is authorization to market a drug with the condition that the sponsor—in this case, Janssen Inc.—undertake additional studies to verify a clinical benefit.

The NOC/c policy is designed to provide access to:

• Drugs that can treat serious, life-threatening, or severely debilitating diseases
• Drugs that can treat conditions for which no drug is currently marketed in Canada
• Drugs that provide a significant increase in efficacy or significant decrease in risk when compared to existing drugs marketed in Canada.

Studies of daratumumab

The NOC/c for daratumumab was based on a review of data from the phase 2 SIRIUS study, the phase 1/2 GEN501 study, and additional supportive studies.

The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.

The results suggested daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%. Most adverse events in this study were grade 1 or 2, although serious events did occur.

The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 patients received the drug at 16 mg/kg.

Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.

Findings from a combined efficacy analysis of the GEN501 and SIRIUS trials demonstrated that, after a mean follow-up of 14.8 months, the estimated median overall survival for patients who received single-agent daratumumab at 16 mg/kg was 20 months.

Five phase 3 clinical studies with daratumumab in MM patients—in relapsed and frontline settings—are ongoing. Additional studies are ongoing or planned to assess the mAb’s potential in other malignant and pre-malignant diseases in which CD38 is expressed.

Janssen has exclusive worldwide rights to the development, manufacturing, and commercialization of daratumumab for all potential indications. The company licensed daratumumab from Genmab A/S in August 2012.

Daratumumab (Darzalex)

Photo courtesy of Janssen

Health Canada has granted conditional approval, or a Notice of Compliance with Conditions (NOC/c), for daratumumab (Darzalex), a monoclonal antibody (mAb) targeting CD38.

The mAb is now approved to treat patients with multiple myeloma (MM) who have received at least 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or MM patients who are refractory to both a PI and an IMiD.

An NOC/c is authorization to market a drug with the condition that the sponsor—in this case, Janssen Inc.—undertake additional studies to verify a clinical benefit.

The NOC/c policy is designed to provide access to:

• Drugs that can treat serious, life-threatening, or severely debilitating diseases
• Drugs that can treat conditions for which no drug is currently marketed in Canada
• Drugs that provide a significant increase in efficacy or significant decrease in risk when compared to existing drugs marketed in Canada.

Studies of daratumumab

The NOC/c for daratumumab was based on a review of data from the phase 2 SIRIUS study, the phase 1/2 GEN501 study, and additional supportive studies.

The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.

The results suggested daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%. Most adverse events in this study were grade 1 or 2, although serious events did occur.

The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 patients received the drug at 16 mg/kg.

Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.

Findings from a combined efficacy analysis of the GEN501 and SIRIUS trials demonstrated that, after a mean follow-up of 14.8 months, the estimated median overall survival for patients who received single-agent daratumumab at 16 mg/kg was 20 months.

Five phase 3 clinical studies with daratumumab in MM patients—in relapsed and frontline settings—are ongoing. Additional studies are ongoing or planned to assess the mAb’s potential in other malignant and pre-malignant diseases in which CD38 is expressed.

Janssen has exclusive worldwide rights to the development, manufacturing, and commercialization of daratumumab for all potential indications. The company licensed daratumumab from Genmab A/S in August 2012.

Click here to access the July 2016 Digital Edition. 

Table of Contents

• What is the VA? The Largest Educator of Health Care Professionals in the U.S.
• The Relationship Between Sustained Gripping and the Development of Carpal Tunnel Syndrome
• Efficacy and Safety Outcomes for Patients Taking Warfarin Who Were Switched From Face-to-Face to Telephone Anticoagulation Clinic
• The Most Expensive Drug in the World: To Continue or Discontinue, That Is the Question
• The Unique Value of Externships to Nursing Education and Health Care Organizations
• The Cost of Oncology Drugs: A Pharmacy Perspective, Part 2
• Diabetic Peripheral Neuropathy: The Learning Curve
• Let’s Dance: A Holistic Approach to Treating Veterans With Posttraumatic Stress Disorder

Click here to access the July 2016 Digital Edition. 

Table of Contents

• What is the VA? The Largest Educator of Health Care Professionals in the U.S.
• The Relationship Between Sustained Gripping and the Development of Carpal Tunnel Syndrome
• Efficacy and Safety Outcomes for Patients Taking Warfarin Who Were Switched From Face-to-Face to Telephone Anticoagulation Clinic
• The Most Expensive Drug in the World: To Continue or Discontinue, That Is the Question
• The Unique Value of Externships to Nursing Education and Health Care Organizations
• The Cost of Oncology Drugs: A Pharmacy Perspective, Part 2
• Diabetic Peripheral Neuropathy: The Learning Curve
• Let’s Dance: A Holistic Approach to Treating Veterans With Posttraumatic Stress Disorder

Click here to access the July 2016 Digital Edition. 

Table of Contents

• What is the VA? The Largest Educator of Health Care Professionals in the U.S.
• The Relationship Between Sustained Gripping and the Development of Carpal Tunnel Syndrome
• Efficacy and Safety Outcomes for Patients Taking Warfarin Who Were Switched From Face-to-Face to Telephone Anticoagulation Clinic
• The Most Expensive Drug in the World: To Continue or Discontinue, That Is the Question
• The Unique Value of Externships to Nursing Education and Health Care Organizations
• The Cost of Oncology Drugs: A Pharmacy Perspective, Part 2
• Diabetic Peripheral Neuropathy: The Learning Curve
• Let’s Dance: A Holistic Approach to Treating Veterans With Posttraumatic Stress Disorder

Adults with irritable bowel syndrome (IBS) who underwent psychotherapy improved more than about 75% of controls, and the effect “remained significant and medium in magnitude” for at least 6-12 months, according to a meta-analysis of 41 randomized, controlled trials reported in the July issue of Clinical Gastroenterology and Hepatology.

The finding “is particularly noteworthy because of the typically recurrent, persistent nature of IBS symptoms,” said Kelsey Laird, a doctoral student of clinical psychology at Vanderbilt University in Nashville, Tenn., together with her associates there. “Future research is needed to compare the longevity of treatment effects for psychotherapy with pharmacologic therapies, such as antidepressants,” they added. “Although it is beyond the scope of this review, it is also important to consider the mechanisms by which psychotherapies improve GI symptoms and to determine the ‘active ingredients’ responsible for this effect.”

©MacXever/Thinkstock

Up to 16% of individuals in the United States have IBS, and treating it costs anywhere from $950 million to $1.35 billion per year, the researchers noted. Other meta-analyses found psychotherapy about as effective as antidepressants for treating IBS-related GI symptoms over the short term, but its long-term efficacy was unknown, they added. Therefore, they searched PubMed, PsycINFO, Science Direct, and ProQuest through Aug. 15, 2015, identifying randomized controlled trials of psychological therapy and active or nonactive comparators. Psychotherapy included not only traditional psychodynamic and cognitive-behavioral therapies, but also mind-body approaches, such as relaxation training, biofeedback, and yoga, “which can be conceptualized as mindful movement,” Ms. Laird and her associates said. Comparators included support groups, education, sham treatments for hypnosis or biofeedback, online discussion forums, enhanced medical care, treatment as usual, symptom monitoring, and being wait-listed for psychological treatment (Clin Gastroenterol Hepatol. 2016 Jan 21. doi: 10.1016/j.cgh.2015.11.020). The 41 trials included 2,290 patients, comprising 1,183 assigned to the psychological modalities and 1,107 assigned to the various comparators. Taken together, the psychological modalities were associated with greater improvements in GI symptoms immediately after treatment, as compared with the grouped comparators. The Cohen’s d value was 0.69 (95% confidence interval, 0.52-0.86; P less than .001), indicating a medium effect size, the researchers said. Moreover, Cohen’s d values were 0.76 and 0.73, respectively, at short-term follow-up (1-6 months) and long-term follow-up (6-12 months). “On average, individuals who received psychotherapy had a greater reduction in GI symptoms after treatment than 75% of individuals assigned to a control condition,” the researchers concluded.

Effect sizes were similar among cognitive, cognitive-behavioral, and relaxation and hypnosis interventions, and between interventions delivered online and in person, the investigators also reported. Furthermore, longer durations or sessions of psychotherapy did not appear to further improve symptoms.

Study limitations included substantial variability between trials, and the fact that none of the 41 trials could be seen as having a low risk of bias in every domain assessed, the investigators said. “This was partially a result of the difficulty in blinding participants in psychological trials,” they noted. “However, even after excluding this domain, only nine trials were rated as low risk of bias in all remaining domains. Future studies should follow the CONSORT guidelines for [randomized controlled trials], use [intention-to-treat] designs, use active control conditions to control for nonspecific treatment effects, and assess treatment credibility and expectancy.”

The authors reported no funding sources and had no disclosures.

Adults with irritable bowel syndrome (IBS) who underwent psychotherapy improved more than about 75% of controls, and the effect “remained significant and medium in magnitude” for at least 6-12 months, according to a meta-analysis of 41 randomized, controlled trials reported in the July issue of Clinical Gastroenterology and Hepatology.

The finding “is particularly noteworthy because of the typically recurrent, persistent nature of IBS symptoms,” said Kelsey Laird, a doctoral student of clinical psychology at Vanderbilt University in Nashville, Tenn., together with her associates there. “Future research is needed to compare the longevity of treatment effects for psychotherapy with pharmacologic therapies, such as antidepressants,” they added. “Although it is beyond the scope of this review, it is also important to consider the mechanisms by which psychotherapies improve GI symptoms and to determine the ‘active ingredients’ responsible for this effect.”

©MacXever/Thinkstock

Up to 16% of individuals in the United States have IBS, and treating it costs anywhere from $950 million to $1.35 billion per year, the researchers noted. Other meta-analyses found psychotherapy about as effective as antidepressants for treating IBS-related GI symptoms over the short term, but its long-term efficacy was unknown, they added. Therefore, they searched PubMed, PsycINFO, Science Direct, and ProQuest through Aug. 15, 2015, identifying randomized controlled trials of psychological therapy and active or nonactive comparators. Psychotherapy included not only traditional psychodynamic and cognitive-behavioral therapies, but also mind-body approaches, such as relaxation training, biofeedback, and yoga, “which can be conceptualized as mindful movement,” Ms. Laird and her associates said. Comparators included support groups, education, sham treatments for hypnosis or biofeedback, online discussion forums, enhanced medical care, treatment as usual, symptom monitoring, and being wait-listed for psychological treatment (Clin Gastroenterol Hepatol. 2016 Jan 21. doi: 10.1016/j.cgh.2015.11.020). The 41 trials included 2,290 patients, comprising 1,183 assigned to the psychological modalities and 1,107 assigned to the various comparators. Taken together, the psychological modalities were associated with greater improvements in GI symptoms immediately after treatment, as compared with the grouped comparators. The Cohen’s d value was 0.69 (95% confidence interval, 0.52-0.86; P less than .001), indicating a medium effect size, the researchers said. Moreover, Cohen’s d values were 0.76 and 0.73, respectively, at short-term follow-up (1-6 months) and long-term follow-up (6-12 months). “On average, individuals who received psychotherapy had a greater reduction in GI symptoms after treatment than 75% of individuals assigned to a control condition,” the researchers concluded.

Effect sizes were similar among cognitive, cognitive-behavioral, and relaxation and hypnosis interventions, and between interventions delivered online and in person, the investigators also reported. Furthermore, longer durations or sessions of psychotherapy did not appear to further improve symptoms.

Study limitations included substantial variability between trials, and the fact that none of the 41 trials could be seen as having a low risk of bias in every domain assessed, the investigators said. “This was partially a result of the difficulty in blinding participants in psychological trials,” they noted. “However, even after excluding this domain, only nine trials were rated as low risk of bias in all remaining domains. Future studies should follow the CONSORT guidelines for [randomized controlled trials], use [intention-to-treat] designs, use active control conditions to control for nonspecific treatment effects, and assess treatment credibility and expectancy.”

The authors reported no funding sources and had no disclosures.

Adults with irritable bowel syndrome (IBS) who underwent psychotherapy improved more than about 75% of controls, and the effect “remained significant and medium in magnitude” for at least 6-12 months, according to a meta-analysis of 41 randomized, controlled trials reported in the July issue of Clinical Gastroenterology and Hepatology.

The finding “is particularly noteworthy because of the typically recurrent, persistent nature of IBS symptoms,” said Kelsey Laird, a doctoral student of clinical psychology at Vanderbilt University in Nashville, Tenn., together with her associates there. “Future research is needed to compare the longevity of treatment effects for psychotherapy with pharmacologic therapies, such as antidepressants,” they added. “Although it is beyond the scope of this review, it is also important to consider the mechanisms by which psychotherapies improve GI symptoms and to determine the ‘active ingredients’ responsible for this effect.”

©MacXever/Thinkstock

Up to 16% of individuals in the United States have IBS, and treating it costs anywhere from $950 million to $1.35 billion per year, the researchers noted. Other meta-analyses found psychotherapy about as effective as antidepressants for treating IBS-related GI symptoms over the short term, but its long-term efficacy was unknown, they added. Therefore, they searched PubMed, PsycINFO, Science Direct, and ProQuest through Aug. 15, 2015, identifying randomized controlled trials of psychological therapy and active or nonactive comparators. Psychotherapy included not only traditional psychodynamic and cognitive-behavioral therapies, but also mind-body approaches, such as relaxation training, biofeedback, and yoga, “which can be conceptualized as mindful movement,” Ms. Laird and her associates said. Comparators included support groups, education, sham treatments for hypnosis or biofeedback, online discussion forums, enhanced medical care, treatment as usual, symptom monitoring, and being wait-listed for psychological treatment (Clin Gastroenterol Hepatol. 2016 Jan 21. doi: 10.1016/j.cgh.2015.11.020). The 41 trials included 2,290 patients, comprising 1,183 assigned to the psychological modalities and 1,107 assigned to the various comparators. Taken together, the psychological modalities were associated with greater improvements in GI symptoms immediately after treatment, as compared with the grouped comparators. The Cohen’s d value was 0.69 (95% confidence interval, 0.52-0.86; P less than .001), indicating a medium effect size, the researchers said. Moreover, Cohen’s d values were 0.76 and 0.73, respectively, at short-term follow-up (1-6 months) and long-term follow-up (6-12 months). “On average, individuals who received psychotherapy had a greater reduction in GI symptoms after treatment than 75% of individuals assigned to a control condition,” the researchers concluded.

Effect sizes were similar among cognitive, cognitive-behavioral, and relaxation and hypnosis interventions, and between interventions delivered online and in person, the investigators also reported. Furthermore, longer durations or sessions of psychotherapy did not appear to further improve symptoms.

Study limitations included substantial variability between trials, and the fact that none of the 41 trials could be seen as having a low risk of bias in every domain assessed, the investigators said. “This was partially a result of the difficulty in blinding participants in psychological trials,” they noted. “However, even after excluding this domain, only nine trials were rated as low risk of bias in all remaining domains. Future studies should follow the CONSORT guidelines for [randomized controlled trials], use [intention-to-treat] designs, use active control conditions to control for nonspecific treatment effects, and assess treatment credibility and expectancy.”

The authors reported no funding sources and had no disclosures.

Integrins that bind arginine-glycine-aspartic acid (RGD) activated stellate cells in the pancreas, inducing pancreatic fibrogenesis in mice, researchers reported in the July issue of Cellular and Molecular Gastroenterology and Hepatology.

“Small-molecule antagonists of this interaction might be developed for the treatment of pancreatic fibrotic diseases,” wrote Dr. Barbara Ulmasov and her associates at Saint Louis University.

Cytokine transforming growth factor beta, or TGFB, plays a “central” role in the activation of pancreatic stellate cells and the promotion of fibrogenesis, both in the pancreas and in other organs, the investigators noted. Because latent TGFB is “abundantly present” in the pancreas and most other tissues, it might be more important to control the activation of TGFB than its expression, they added. Studies of other organs have shown that TGFB is activated when integrins of the av family bind the RGD sequence, but no one had determined whether this was true for pancreatic fibrogenesis, Dr. Ulmasov and her associates asserted (Cell Mol Gastroenterol Hepatol. 2016 Mar 16. doi: 10.1016/j.jcmgh.2016.03.004).

Therefore, they repeatedly injected female C57BL/6 mice with cerulein to induce pancreatic fibrogenesis, and gave a group of control mice sterile saline instead. The mice then received continuous infusions of a small molecule called CWHM-12, which is an antagonist of RGD-integrin that is known to prevent both pulmonary and hepatic fibrosis in mice. After euthanizing the mice, the researchers measured pancreatic parenchymal atrophy, fibrosis, and activation of pancreatic stellate cells. They also studied TGFB activation in an established line of pancreatic stellate cells from rats.

Pancreatic stellate cells expressed messenger RNAs encoding RGD-binding integrins, the investigators found. The mice that received cerulein had higher levels of these integrins than the mice that received saline, and the cerulein group also had more disrupted acinar cell architecture, tubular complexes, and infiltrations of inflammatory cells. Mice that received prophylactic CWHM-12 had only somewhat less acinar cell loss and atrophy than the control mice, and had similar levels of inflammatory cell infiltration, but had “dramatically” lower levels of pancreatic fibrosis, the researchers said. Even if mice received CWHM-12 several days after starting cerulein, they still had less fibrosis and activation of TGFB than if they received saline, they noted.

The established line of pancreatic stellate cells “could robustly activate endogenously produced TGFB,” the investigators also reported. Furthermore, CWHM-12 “potently blocked TGFB activation,” unlike the control compound. Taken together, the findings illustrate the “critical role of RGD-binding integrins in chronic pancreatitis, and the promising potential to arrest or possibly even reverse pancreatic fibrosis using a pharmacologic approach to inhibiting integrin-mediated TGFB activation,” the researchers concluded.

The National Pancreas Foundation and the Frank R. Burton Memorial Fund supported the study. Dr. Ulmasov had no disclosures. Three coinvestigators reported being consultants and/or holding equity in Integrin Therapeutics, Nimbus Therapeutics, Bristol-Myers Squibb, Janssen, Mitsubishi Tanabe, Conatus, and Scholar Rock.

Integrins that bind arginine-glycine-aspartic acid (RGD) activated stellate cells in the pancreas, inducing pancreatic fibrogenesis in mice, researchers reported in the July issue of Cellular and Molecular Gastroenterology and Hepatology.

“Small-molecule antagonists of this interaction might be developed for the treatment of pancreatic fibrotic diseases,” wrote Dr. Barbara Ulmasov and her associates at Saint Louis University.

Cytokine transforming growth factor beta, or TGFB, plays a “central” role in the activation of pancreatic stellate cells and the promotion of fibrogenesis, both in the pancreas and in other organs, the investigators noted. Because latent TGFB is “abundantly present” in the pancreas and most other tissues, it might be more important to control the activation of TGFB than its expression, they added. Studies of other organs have shown that TGFB is activated when integrins of the av family bind the RGD sequence, but no one had determined whether this was true for pancreatic fibrogenesis, Dr. Ulmasov and her associates asserted (Cell Mol Gastroenterol Hepatol. 2016 Mar 16. doi: 10.1016/j.jcmgh.2016.03.004).

Therefore, they repeatedly injected female C57BL/6 mice with cerulein to induce pancreatic fibrogenesis, and gave a group of control mice sterile saline instead. The mice then received continuous infusions of a small molecule called CWHM-12, which is an antagonist of RGD-integrin that is known to prevent both pulmonary and hepatic fibrosis in mice. After euthanizing the mice, the researchers measured pancreatic parenchymal atrophy, fibrosis, and activation of pancreatic stellate cells. They also studied TGFB activation in an established line of pancreatic stellate cells from rats.

Pancreatic stellate cells expressed messenger RNAs encoding RGD-binding integrins, the investigators found. The mice that received cerulein had higher levels of these integrins than the mice that received saline, and the cerulein group also had more disrupted acinar cell architecture, tubular complexes, and infiltrations of inflammatory cells. Mice that received prophylactic CWHM-12 had only somewhat less acinar cell loss and atrophy than the control mice, and had similar levels of inflammatory cell infiltration, but had “dramatically” lower levels of pancreatic fibrosis, the researchers said. Even if mice received CWHM-12 several days after starting cerulein, they still had less fibrosis and activation of TGFB than if they received saline, they noted.

The established line of pancreatic stellate cells “could robustly activate endogenously produced TGFB,” the investigators also reported. Furthermore, CWHM-12 “potently blocked TGFB activation,” unlike the control compound. Taken together, the findings illustrate the “critical role of RGD-binding integrins in chronic pancreatitis, and the promising potential to arrest or possibly even reverse pancreatic fibrosis using a pharmacologic approach to inhibiting integrin-mediated TGFB activation,” the researchers concluded.

The National Pancreas Foundation and the Frank R. Burton Memorial Fund supported the study. Dr. Ulmasov had no disclosures. Three coinvestigators reported being consultants and/or holding equity in Integrin Therapeutics, Nimbus Therapeutics, Bristol-Myers Squibb, Janssen, Mitsubishi Tanabe, Conatus, and Scholar Rock.

Integrins that bind arginine-glycine-aspartic acid (RGD) activated stellate cells in the pancreas, inducing pancreatic fibrogenesis in mice, researchers reported in the July issue of Cellular and Molecular Gastroenterology and Hepatology.

“Small-molecule antagonists of this interaction might be developed for the treatment of pancreatic fibrotic diseases,” wrote Dr. Barbara Ulmasov and her associates at Saint Louis University.

Cytokine transforming growth factor beta, or TGFB, plays a “central” role in the activation of pancreatic stellate cells and the promotion of fibrogenesis, both in the pancreas and in other organs, the investigators noted. Because latent TGFB is “abundantly present” in the pancreas and most other tissues, it might be more important to control the activation of TGFB than its expression, they added. Studies of other organs have shown that TGFB is activated when integrins of the av family bind the RGD sequence, but no one had determined whether this was true for pancreatic fibrogenesis, Dr. Ulmasov and her associates asserted (Cell Mol Gastroenterol Hepatol. 2016 Mar 16. doi: 10.1016/j.jcmgh.2016.03.004).

Therefore, they repeatedly injected female C57BL/6 mice with cerulein to induce pancreatic fibrogenesis, and gave a group of control mice sterile saline instead. The mice then received continuous infusions of a small molecule called CWHM-12, which is an antagonist of RGD-integrin that is known to prevent both pulmonary and hepatic fibrosis in mice. After euthanizing the mice, the researchers measured pancreatic parenchymal atrophy, fibrosis, and activation of pancreatic stellate cells. They also studied TGFB activation in an established line of pancreatic stellate cells from rats.

Pancreatic stellate cells expressed messenger RNAs encoding RGD-binding integrins, the investigators found. The mice that received cerulein had higher levels of these integrins than the mice that received saline, and the cerulein group also had more disrupted acinar cell architecture, tubular complexes, and infiltrations of inflammatory cells. Mice that received prophylactic CWHM-12 had only somewhat less acinar cell loss and atrophy than the control mice, and had similar levels of inflammatory cell infiltration, but had “dramatically” lower levels of pancreatic fibrosis, the researchers said. Even if mice received CWHM-12 several days after starting cerulein, they still had less fibrosis and activation of TGFB than if they received saline, they noted.

The established line of pancreatic stellate cells “could robustly activate endogenously produced TGFB,” the investigators also reported. Furthermore, CWHM-12 “potently blocked TGFB activation,” unlike the control compound. Taken together, the findings illustrate the “critical role of RGD-binding integrins in chronic pancreatitis, and the promising potential to arrest or possibly even reverse pancreatic fibrosis using a pharmacologic approach to inhibiting integrin-mediated TGFB activation,” the researchers concluded.

The National Pancreas Foundation and the Frank R. Burton Memorial Fund supported the study. Dr. Ulmasov had no disclosures. Three coinvestigators reported being consultants and/or holding equity in Integrin Therapeutics, Nimbus Therapeutics, Bristol-Myers Squibb, Janssen, Mitsubishi Tanabe, Conatus, and Scholar Rock.