Novel oral anticoagulants introduced since October 2010 have been adopted into clinical practice rapidly, and within 2.5 years were prescribed for more than 60% of patients with newly diagnosed atrial fibrillation, according to a report published online in the American Journal of Medicine.

Further, the new drugs are being prescribed for a different patient population from that indicated by the clinical trials on which Food and Drug Administration (FDA) approval was based. Specifically, dabigatran, rivaroxaban, and apixaban are selectively prescribed for younger, healthier men who have high incomes and reside in wealthier communities, reported Dr. Nihar R. Desai of the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.

In what they described as the first study to evaluate real-world use of all novel anticoagulants, researchers found that the rapid uptake of the drugs as first-line therapy for atrial fibrillation (AF) was accompanied by a marked decline in the use of warfarin. The difference in total costs between the generic warfarin and the proprietary dabigatran, rivaroxaban, or apixaban totaled $900 per patient during the first 6 months alone, which "translates into billions of dollars at the national level."

This has important economic implications for patients, payers, and the health care system. The impending FDA approval of new factor Xa inhibitors such as edoxaban and betrixaban will likely further complicate the picture, the researchers said.

The researchers analyzed nationwide medical and prescription claims data for 6,893 adults covered by Aetna who had newly diagnosed nonvalvular AF and were prescribed an oral anticoagulant between October 2010 and June 2013. The direct thrombin inhibitor dabigatran was approved in October 2010, and the factor Xa inhibitors rivaroxaban and apixaban were approved in November 2011 and December 2012.

During the study period, these patients filled 45,472 prescriptions for oral anticoagulants: 57.7% for warfarin, 32.8% for dabigatran, 9.3% for rivaroxaban, and 0.1% for apixaban. However, these figures don’t reflect the trend over time in which prescriptions for the newer agents rapidly displaced those for warfarin. Within 1 year of appearing on the market, dabigatran was equally likely to be prescribed as warfarin was for new AF patients. Its use as a first-line therapy dropped considerably a year later, after reports of excess rates of myocardial infarction and serious and fatal bleeding events in patients taking dabigatran. But at that point rivaroxaban had been introduced, and it soon overtook both dabigatran and warfarin as first-line therapy for AF. (Apixaban accounted for 2% of new anticoagulant prescriptions as of 6 months after it was approved, which is the most recent date for which such statistics were available.)

Simultaneously, the costs of oral anticoagulants rose dramatically, with the new agents accounting for 98% of that escalation. It is estimated that insurers spend $5.82 million every month for all agents combined, and that warfarin accounts for only $0.43 million of that. Similarly, patient out-of-pocket spending for all oral anticoagulants combined was estimated to be $1.3 million per month, with warfarin accounting for $3,844 of that total.

Viewed from another perspective, the average combined patient and insurer spending for anticoagulants during the first 6 months of therapy for warfarin was $122, dabigatran $1,053, and rivaroxaban $1,084. "This represents a difference of more than $900 per patient," said Dr. Desai, who is also at the Center for Outcomes Research and Evaluation, Yale-New Haven Health Services, and his associates.

The greatest benefit from novel anticoagulants is among patients at the highest risk for stroke or systemic embolization, as measured by higher scores on CHADS (Congestive Heart Failure, Hypertension, Age of 75 years or more, Diabetes Mellitus, and Stroke) and HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol) assessments. This is also the patient population targeted in the clinical trials that formed the basis for FDA approval.

But in this study, 46% of patients with low CHADS and HAS-BLED scores were initially prescribed the novel anticoagulants, compared with 26% of those with high scores. "For every 1-point increase in CHADS, patients were 20% less likely to receive a novel anticoagulant. Similarly, for every 1-point increase in HAS-BLED, patients were 18% less likely to receive a novel anticoagulant.

"In addition, women were 24% less likely to be initiated on a novel oral anticoagulant as compared with men. [And] there was a significant, stepwise increase in the likelihood of receiving a novel agent with progressively increasing neighborhood household income, compared with a median household income of $50,000 or less," the investigators said (Amer. J. Med. 2014 May 20 [doi: 10.1016/j.amjmed.2014.05.013]).

"These findings point to the need to conduct ongoing surveillance of the adoption of new agents into clinical practice, as well as the need for robust, real-world comparative-effectiveness analyses of these medications, to enable patients and providers to make informed decisions about their relative benefit, safety, and cost-effectiveness," Dr. Desai and his associates said.

This study was funded by an unrestricted research grant from CVS Caremark. Dr. Desai’s associates reported ties to CVS Caremark and Aetna.

Novel oral anticoagulants introduced since October 2010 have been adopted into clinical practice rapidly, and within 2.5 years were prescribed for more than 60% of patients with newly diagnosed atrial fibrillation, according to a report published online in the American Journal of Medicine.

Further, the new drugs are being prescribed for a different patient population from that indicated by the clinical trials on which Food and Drug Administration (FDA) approval was based. Specifically, dabigatran, rivaroxaban, and apixaban are selectively prescribed for younger, healthier men who have high incomes and reside in wealthier communities, reported Dr. Nihar R. Desai of the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.

In what they described as the first study to evaluate real-world use of all novel anticoagulants, researchers found that the rapid uptake of the drugs as first-line therapy for atrial fibrillation (AF) was accompanied by a marked decline in the use of warfarin. The difference in total costs between the generic warfarin and the proprietary dabigatran, rivaroxaban, or apixaban totaled $900 per patient during the first 6 months alone, which "translates into billions of dollars at the national level."

This has important economic implications for patients, payers, and the health care system. The impending FDA approval of new factor Xa inhibitors such as edoxaban and betrixaban will likely further complicate the picture, the researchers said.

The researchers analyzed nationwide medical and prescription claims data for 6,893 adults covered by Aetna who had newly diagnosed nonvalvular AF and were prescribed an oral anticoagulant between October 2010 and June 2013. The direct thrombin inhibitor dabigatran was approved in October 2010, and the factor Xa inhibitors rivaroxaban and apixaban were approved in November 2011 and December 2012.

During the study period, these patients filled 45,472 prescriptions for oral anticoagulants: 57.7% for warfarin, 32.8% for dabigatran, 9.3% for rivaroxaban, and 0.1% for apixaban. However, these figures don’t reflect the trend over time in which prescriptions for the newer agents rapidly displaced those for warfarin. Within 1 year of appearing on the market, dabigatran was equally likely to be prescribed as warfarin was for new AF patients. Its use as a first-line therapy dropped considerably a year later, after reports of excess rates of myocardial infarction and serious and fatal bleeding events in patients taking dabigatran. But at that point rivaroxaban had been introduced, and it soon overtook both dabigatran and warfarin as first-line therapy for AF. (Apixaban accounted for 2% of new anticoagulant prescriptions as of 6 months after it was approved, which is the most recent date for which such statistics were available.)

Simultaneously, the costs of oral anticoagulants rose dramatically, with the new agents accounting for 98% of that escalation. It is estimated that insurers spend $5.82 million every month for all agents combined, and that warfarin accounts for only $0.43 million of that. Similarly, patient out-of-pocket spending for all oral anticoagulants combined was estimated to be $1.3 million per month, with warfarin accounting for $3,844 of that total.

Viewed from another perspective, the average combined patient and insurer spending for anticoagulants during the first 6 months of therapy for warfarin was $122, dabigatran $1,053, and rivaroxaban $1,084. "This represents a difference of more than $900 per patient," said Dr. Desai, who is also at the Center for Outcomes Research and Evaluation, Yale-New Haven Health Services, and his associates.

The greatest benefit from novel anticoagulants is among patients at the highest risk for stroke or systemic embolization, as measured by higher scores on CHADS (Congestive Heart Failure, Hypertension, Age of 75 years or more, Diabetes Mellitus, and Stroke) and HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol) assessments. This is also the patient population targeted in the clinical trials that formed the basis for FDA approval.

But in this study, 46% of patients with low CHADS and HAS-BLED scores were initially prescribed the novel anticoagulants, compared with 26% of those with high scores. "For every 1-point increase in CHADS, patients were 20% less likely to receive a novel anticoagulant. Similarly, for every 1-point increase in HAS-BLED, patients were 18% less likely to receive a novel anticoagulant.

"In addition, women were 24% less likely to be initiated on a novel oral anticoagulant as compared with men. [And] there was a significant, stepwise increase in the likelihood of receiving a novel agent with progressively increasing neighborhood household income, compared with a median household income of $50,000 or less," the investigators said (Amer. J. Med. 2014 May 20 [doi: 10.1016/j.amjmed.2014.05.013]).

"These findings point to the need to conduct ongoing surveillance of the adoption of new agents into clinical practice, as well as the need for robust, real-world comparative-effectiveness analyses of these medications, to enable patients and providers to make informed decisions about their relative benefit, safety, and cost-effectiveness," Dr. Desai and his associates said.

This study was funded by an unrestricted research grant from CVS Caremark. Dr. Desai’s associates reported ties to CVS Caremark and Aetna.

Novel oral anticoagulants introduced since October 2010 have been adopted into clinical practice rapidly, and within 2.5 years were prescribed for more than 60% of patients with newly diagnosed atrial fibrillation, according to a report published online in the American Journal of Medicine.

Further, the new drugs are being prescribed for a different patient population from that indicated by the clinical trials on which Food and Drug Administration (FDA) approval was based. Specifically, dabigatran, rivaroxaban, and apixaban are selectively prescribed for younger, healthier men who have high incomes and reside in wealthier communities, reported Dr. Nihar R. Desai of the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.

In what they described as the first study to evaluate real-world use of all novel anticoagulants, researchers found that the rapid uptake of the drugs as first-line therapy for atrial fibrillation (AF) was accompanied by a marked decline in the use of warfarin. The difference in total costs between the generic warfarin and the proprietary dabigatran, rivaroxaban, or apixaban totaled $900 per patient during the first 6 months alone, which "translates into billions of dollars at the national level."

This has important economic implications for patients, payers, and the health care system. The impending FDA approval of new factor Xa inhibitors such as edoxaban and betrixaban will likely further complicate the picture, the researchers said.

The researchers analyzed nationwide medical and prescription claims data for 6,893 adults covered by Aetna who had newly diagnosed nonvalvular AF and were prescribed an oral anticoagulant between October 2010 and June 2013. The direct thrombin inhibitor dabigatran was approved in October 2010, and the factor Xa inhibitors rivaroxaban and apixaban were approved in November 2011 and December 2012.

During the study period, these patients filled 45,472 prescriptions for oral anticoagulants: 57.7% for warfarin, 32.8% for dabigatran, 9.3% for rivaroxaban, and 0.1% for apixaban. However, these figures don’t reflect the trend over time in which prescriptions for the newer agents rapidly displaced those for warfarin. Within 1 year of appearing on the market, dabigatran was equally likely to be prescribed as warfarin was for new AF patients. Its use as a first-line therapy dropped considerably a year later, after reports of excess rates of myocardial infarction and serious and fatal bleeding events in patients taking dabigatran. But at that point rivaroxaban had been introduced, and it soon overtook both dabigatran and warfarin as first-line therapy for AF. (Apixaban accounted for 2% of new anticoagulant prescriptions as of 6 months after it was approved, which is the most recent date for which such statistics were available.)

Simultaneously, the costs of oral anticoagulants rose dramatically, with the new agents accounting for 98% of that escalation. It is estimated that insurers spend $5.82 million every month for all agents combined, and that warfarin accounts for only $0.43 million of that. Similarly, patient out-of-pocket spending for all oral anticoagulants combined was estimated to be $1.3 million per month, with warfarin accounting for $3,844 of that total.

Viewed from another perspective, the average combined patient and insurer spending for anticoagulants during the first 6 months of therapy for warfarin was $122, dabigatran $1,053, and rivaroxaban $1,084. "This represents a difference of more than $900 per patient," said Dr. Desai, who is also at the Center for Outcomes Research and Evaluation, Yale-New Haven Health Services, and his associates.

The greatest benefit from novel anticoagulants is among patients at the highest risk for stroke or systemic embolization, as measured by higher scores on CHADS (Congestive Heart Failure, Hypertension, Age of 75 years or more, Diabetes Mellitus, and Stroke) and HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol) assessments. This is also the patient population targeted in the clinical trials that formed the basis for FDA approval.

But in this study, 46% of patients with low CHADS and HAS-BLED scores were initially prescribed the novel anticoagulants, compared with 26% of those with high scores. "For every 1-point increase in CHADS, patients were 20% less likely to receive a novel anticoagulant. Similarly, for every 1-point increase in HAS-BLED, patients were 18% less likely to receive a novel anticoagulant.

"In addition, women were 24% less likely to be initiated on a novel oral anticoagulant as compared with men. [And] there was a significant, stepwise increase in the likelihood of receiving a novel agent with progressively increasing neighborhood household income, compared with a median household income of $50,000 or less," the investigators said (Amer. J. Med. 2014 May 20 [doi: 10.1016/j.amjmed.2014.05.013]).

"These findings point to the need to conduct ongoing surveillance of the adoption of new agents into clinical practice, as well as the need for robust, real-world comparative-effectiveness analyses of these medications, to enable patients and providers to make informed decisions about their relative benefit, safety, and cost-effectiveness," Dr. Desai and his associates said.

This study was funded by an unrestricted research grant from CVS Caremark. Dr. Desai’s associates reported ties to CVS Caremark and Aetna.

Sedimented red blood cells

An experimental drug designed to help regulate the blood’s iron supply may be a viable treatment option for inflammation-induced anemia, according to a study published in Blood.

The only current treatment strategy for this type of anemia involves targeting the underlying disease or infection.

However, recent research has sought to explore additional options for patients whose inflammation is difficult to control or when the cause of inflammation is unknown.

A hepcidin inhibitor called lexaptepid pegol (lexaptepid) has demonstrated efficacy in treating inflammation-induced anemia in animal studies. Lexaptepid inactivates hepcidin, thereby maintaining the transport of iron to the bloodstream.

To evaluate lexaptepid’s potential in humans, investigators caused inflammation-induced anemia in 24 healthy male adults and randomized them to receive lexaptepid or placebo.

Subjects received a low dose of Escherichia coli endotoxin to induce controlled inflammation and received either lexaptepid or placebo 30 minutes later.

After 9 hours, serum iron had decreased by 8.3±9.0 μmol/L in controls but increased by 15.9±9.8 μmol/L in lexaptepid-treated subjects (P<0.0001).

In addition to evaluating whether lexaptepid interfered with hepcidin production, the researchers also sought to determine whether the drug influenced the immune response.

Results suggested it did not. Treated subjects and controls alike experienced flu-like symptoms, increased body temperature and white blood cell counts, and higher concentrations of inflammatory and signaling proteins.

“It is quite encouraging that lexaptepid helped maintain appropriate levels of iron in the bloodstream of healthy volunteers without compromising the immune response,” said lead study author Lucas van Eijk, MD, of Radboud University Medical Center in Nijmegen, The Netherlands.

“We are hopeful that, with further study, this first-of-its-kind therapy could significantly improve quality of life for patients suffering from chronic illnesses.”

Results of a phase 2 study testing lexaptepid in anemic cancer patients were presented at the AACR Annual Meeting 2014.

Sedimented red blood cells

An experimental drug designed to help regulate the blood’s iron supply may be a viable treatment option for inflammation-induced anemia, according to a study published in Blood.

The only current treatment strategy for this type of anemia involves targeting the underlying disease or infection.

However, recent research has sought to explore additional options for patients whose inflammation is difficult to control or when the cause of inflammation is unknown.

A hepcidin inhibitor called lexaptepid pegol (lexaptepid) has demonstrated efficacy in treating inflammation-induced anemia in animal studies. Lexaptepid inactivates hepcidin, thereby maintaining the transport of iron to the bloodstream.

To evaluate lexaptepid’s potential in humans, investigators caused inflammation-induced anemia in 24 healthy male adults and randomized them to receive lexaptepid or placebo.

Subjects received a low dose of Escherichia coli endotoxin to induce controlled inflammation and received either lexaptepid or placebo 30 minutes later.

After 9 hours, serum iron had decreased by 8.3±9.0 μmol/L in controls but increased by 15.9±9.8 μmol/L in lexaptepid-treated subjects (P<0.0001).

In addition to evaluating whether lexaptepid interfered with hepcidin production, the researchers also sought to determine whether the drug influenced the immune response.

Results suggested it did not. Treated subjects and controls alike experienced flu-like symptoms, increased body temperature and white blood cell counts, and higher concentrations of inflammatory and signaling proteins.

“It is quite encouraging that lexaptepid helped maintain appropriate levels of iron in the bloodstream of healthy volunteers without compromising the immune response,” said lead study author Lucas van Eijk, MD, of Radboud University Medical Center in Nijmegen, The Netherlands.

“We are hopeful that, with further study, this first-of-its-kind therapy could significantly improve quality of life for patients suffering from chronic illnesses.”

Results of a phase 2 study testing lexaptepid in anemic cancer patients were presented at the AACR Annual Meeting 2014.

Sedimented red blood cells

An experimental drug designed to help regulate the blood’s iron supply may be a viable treatment option for inflammation-induced anemia, according to a study published in Blood.

The only current treatment strategy for this type of anemia involves targeting the underlying disease or infection.

However, recent research has sought to explore additional options for patients whose inflammation is difficult to control or when the cause of inflammation is unknown.

A hepcidin inhibitor called lexaptepid pegol (lexaptepid) has demonstrated efficacy in treating inflammation-induced anemia in animal studies. Lexaptepid inactivates hepcidin, thereby maintaining the transport of iron to the bloodstream.

To evaluate lexaptepid’s potential in humans, investigators caused inflammation-induced anemia in 24 healthy male adults and randomized them to receive lexaptepid or placebo.

Subjects received a low dose of Escherichia coli endotoxin to induce controlled inflammation and received either lexaptepid or placebo 30 minutes later.

After 9 hours, serum iron had decreased by 8.3±9.0 μmol/L in controls but increased by 15.9±9.8 μmol/L in lexaptepid-treated subjects (P<0.0001).

In addition to evaluating whether lexaptepid interfered with hepcidin production, the researchers also sought to determine whether the drug influenced the immune response.

Results suggested it did not. Treated subjects and controls alike experienced flu-like symptoms, increased body temperature and white blood cell counts, and higher concentrations of inflammatory and signaling proteins.

“It is quite encouraging that lexaptepid helped maintain appropriate levels of iron in the bloodstream of healthy volunteers without compromising the immune response,” said lead study author Lucas van Eijk, MD, of Radboud University Medical Center in Nijmegen, The Netherlands.

“We are hopeful that, with further study, this first-of-its-kind therapy could significantly improve quality of life for patients suffering from chronic illnesses.”

Results of a phase 2 study testing lexaptepid in anemic cancer patients were presented at the AACR Annual Meeting 2014.

Ugandan children

Credit: Malayaka house

Children repeatedly infected with malaria have been known to become asymptomatic, and researchers have found evidence suggesting a subset of γδ T cells play a role in this phenomenon.

Studying young children in Uganda, the team discovered that repeated malaria infection was associated with the loss and dysfunction of Vδ2+ γδ T cells.

This appeared to facilitate immunological tolerance of the malaria parasite and, therefore, a reduction in clinical symptoms.

“These inflammatory immune cells are depleted in children with repeated malaria exposure, and those that remain behave differently than the same cell types in children who have not previously been infected,” said Prasanna Jagannathan, MD, of the University of California, San Francisco (UCSF).

He and his colleagues reported these findings in Science Translational Medicine.

The researchers collected data on malaria infections, disease symptoms, and immune responses in 78 children who were monitored from infancy as part of a research collaboration between UCSF and Makarere University in Kampala, Africa. The study was conducted in Tororo, Uganda.

At 1 year of age, all children showed clinical symptoms of malaria with each infection. At 4 years, fewer than 10% were symptom-free upon infection. But 1 year later, more than 20% were symptom-free when infected.

The researchers found that repeated malaria infection was associated with the loss and dysfunction of Vδ2+ γδ T cells. They observed a decrease in cell proliferation and in the production of inflammatory cytokines (IFN-γ and TNF-α) in response to malaria antigens.

Repeated malaria infection was also associated with the upregulation of immunoregulatory pathways—increased expression of genes such as HAVCR2, FCRL6, LYN, BATF, and B3GAT1—that dampen the immune response.

Children with these characteristics were less likely than their peers to exhibit clinical symptoms upon subsequent malaria infection.

So it seems the depletion of Vδ2+ γδ T cells is beneficial in some ways and detrimental in others, said Margaret Feeney, MD, of UCSF. Individuals may no longer suffer symptoms, but they might not clear the parasite and could remain infectious.

Although this discovery has not provided a disease-fighting strategy as of yet, it does point to further avenues of study, according to Dr Feeney.

“We want to understand whether this is a generalizable phenomenon that also occurs among those who are first exposed to malaria as adults and in regions where malaria incidence is lower,” she said.

Dr Feeney speculates that malaria infection, by reshaping immune responses, might influence a person’s susceptibility to, and protection from, other infectious diseases.

Ugandan children

Credit: Malayaka house

Children repeatedly infected with malaria have been known to become asymptomatic, and researchers have found evidence suggesting a subset of γδ T cells play a role in this phenomenon.

Studying young children in Uganda, the team discovered that repeated malaria infection was associated with the loss and dysfunction of Vδ2+ γδ T cells.

This appeared to facilitate immunological tolerance of the malaria parasite and, therefore, a reduction in clinical symptoms.

“These inflammatory immune cells are depleted in children with repeated malaria exposure, and those that remain behave differently than the same cell types in children who have not previously been infected,” said Prasanna Jagannathan, MD, of the University of California, San Francisco (UCSF).

He and his colleagues reported these findings in Science Translational Medicine.

The researchers collected data on malaria infections, disease symptoms, and immune responses in 78 children who were monitored from infancy as part of a research collaboration between UCSF and Makarere University in Kampala, Africa. The study was conducted in Tororo, Uganda.

At 1 year of age, all children showed clinical symptoms of malaria with each infection. At 4 years, fewer than 10% were symptom-free upon infection. But 1 year later, more than 20% were symptom-free when infected.

The researchers found that repeated malaria infection was associated with the loss and dysfunction of Vδ2+ γδ T cells. They observed a decrease in cell proliferation and in the production of inflammatory cytokines (IFN-γ and TNF-α) in response to malaria antigens.

Repeated malaria infection was also associated with the upregulation of immunoregulatory pathways—increased expression of genes such as HAVCR2, FCRL6, LYN, BATF, and B3GAT1—that dampen the immune response.

Children with these characteristics were less likely than their peers to exhibit clinical symptoms upon subsequent malaria infection.

So it seems the depletion of Vδ2+ γδ T cells is beneficial in some ways and detrimental in others, said Margaret Feeney, MD, of UCSF. Individuals may no longer suffer symptoms, but they might not clear the parasite and could remain infectious.

Although this discovery has not provided a disease-fighting strategy as of yet, it does point to further avenues of study, according to Dr Feeney.

“We want to understand whether this is a generalizable phenomenon that also occurs among those who are first exposed to malaria as adults and in regions where malaria incidence is lower,” she said.

Dr Feeney speculates that malaria infection, by reshaping immune responses, might influence a person’s susceptibility to, and protection from, other infectious diseases.

Ugandan children

Credit: Malayaka house

Children repeatedly infected with malaria have been known to become asymptomatic, and researchers have found evidence suggesting a subset of γδ T cells play a role in this phenomenon.

Studying young children in Uganda, the team discovered that repeated malaria infection was associated with the loss and dysfunction of Vδ2+ γδ T cells.

This appeared to facilitate immunological tolerance of the malaria parasite and, therefore, a reduction in clinical symptoms.

“These inflammatory immune cells are depleted in children with repeated malaria exposure, and those that remain behave differently than the same cell types in children who have not previously been infected,” said Prasanna Jagannathan, MD, of the University of California, San Francisco (UCSF).

He and his colleagues reported these findings in Science Translational Medicine.

The researchers collected data on malaria infections, disease symptoms, and immune responses in 78 children who were monitored from infancy as part of a research collaboration between UCSF and Makarere University in Kampala, Africa. The study was conducted in Tororo, Uganda.

At 1 year of age, all children showed clinical symptoms of malaria with each infection. At 4 years, fewer than 10% were symptom-free upon infection. But 1 year later, more than 20% were symptom-free when infected.

The researchers found that repeated malaria infection was associated with the loss and dysfunction of Vδ2+ γδ T cells. They observed a decrease in cell proliferation and in the production of inflammatory cytokines (IFN-γ and TNF-α) in response to malaria antigens.

Repeated malaria infection was also associated with the upregulation of immunoregulatory pathways—increased expression of genes such as HAVCR2, FCRL6, LYN, BATF, and B3GAT1—that dampen the immune response.

Children with these characteristics were less likely than their peers to exhibit clinical symptoms upon subsequent malaria infection.

So it seems the depletion of Vδ2+ γδ T cells is beneficial in some ways and detrimental in others, said Margaret Feeney, MD, of UCSF. Individuals may no longer suffer symptoms, but they might not clear the parasite and could remain infectious.

Although this discovery has not provided a disease-fighting strategy as of yet, it does point to further avenues of study, according to Dr Feeney.

“We want to understand whether this is a generalizable phenomenon that also occurs among those who are first exposed to malaria as adults and in regions where malaria incidence is lower,” she said.

Dr Feeney speculates that malaria infection, by reshaping immune responses, might influence a person’s susceptibility to, and protection from, other infectious diseases.

Drug release in a cancer cell

Credit: PNAS

A new type of nanoparticle (NP) could aid the diagnosis and treatment of cancers, according to research published in Nature Communications.

Built on an easy-to-make polymer, these particles can be used as contrast agents to light up tumors for MRI and PET scans or to deliver chemotherapy and other treatments to cancer cells.

Furthermore, in vivo experiments showed the particles are biocompatible and elicit minimal side effects.

“These are amazingly useful particles,” said study author Yuanpei Li, PhD, of the UC Davis Comprehensive Cancer Center in Sacramento, California.

“As a contrast agent, they make tumors easier to see on MRI and other scans. We can also use them as vehicles to deliver chemotherapy directly to tumors, apply light to make the nanoparticles release singlet oxygen (photodynamic therapy), or use a laser to heat them (photothermal therapy)—all proven ways to destroy tumors.”

These NPs are built on a porphyrin/cholic acid polymer. Porphyrins are common organic compounds, and cholic acid is produced by the liver.

To further stabilize the particles, the researchers added the amino acid cysteine (creating CNPs), which prevents them from prematurely releasing their therapeutic payload when exposed to blood proteins and other barriers.

Therapeutic applications

The researchers tested the CNPs, both in vitro and in vivo, for a wide range of tasks. On the therapeutic side, the particles effectively transported anticancer drugs, such as doxorubicin.

CNPs carrying doxorubicin provided excellent cancer control in animals, with minimal side effects.

Even when kept in the blood for many hours, CNPs only released small amounts of the drug. However, when exposed to light or agents such as glutathione, they readily released their payloads.

The researchers showed that, when exposed to a single wavelength of light, the CNPs could generate heat or produce singlet oxygen to destroy tumor cells.

Imaging applications

CNPs offer a number of advantages to enhance imaging, according to the researchers. The particles readily chelate imaging agents and can remain in the body for long periods.

In animal studies, CNPs largely accumulated in tumors, rather than in normal tissue. So they dramatically enhanced tumor contrast for MRI and may also be promising for PET-MRI scans, the researchers said.

“These particles can combine imaging and therapeutics,” Dr Li noted. “We could potentially use them to simultaneously deliver treatment and monitor treatment efficacy.”

The researchers are now conducting additional preclinical studies with the CNPs. If all goes well, they will proceed to human trials. In the meantime, the team is excited about these capabilities.

“This is the first nanoparticle to perform so many different jobs,” Dr Li said. “From delivering chemo, photodynamic, and photothermal therapies, to enhancing diagnostic imaging, it’s the complete package.”

Drug release in a cancer cell

Credit: PNAS

A new type of nanoparticle (NP) could aid the diagnosis and treatment of cancers, according to research published in Nature Communications.

Built on an easy-to-make polymer, these particles can be used as contrast agents to light up tumors for MRI and PET scans or to deliver chemotherapy and other treatments to cancer cells.

Furthermore, in vivo experiments showed the particles are biocompatible and elicit minimal side effects.

“These are amazingly useful particles,” said study author Yuanpei Li, PhD, of the UC Davis Comprehensive Cancer Center in Sacramento, California.

“As a contrast agent, they make tumors easier to see on MRI and other scans. We can also use them as vehicles to deliver chemotherapy directly to tumors, apply light to make the nanoparticles release singlet oxygen (photodynamic therapy), or use a laser to heat them (photothermal therapy)—all proven ways to destroy tumors.”

These NPs are built on a porphyrin/cholic acid polymer. Porphyrins are common organic compounds, and cholic acid is produced by the liver.

To further stabilize the particles, the researchers added the amino acid cysteine (creating CNPs), which prevents them from prematurely releasing their therapeutic payload when exposed to blood proteins and other barriers.

Therapeutic applications

The researchers tested the CNPs, both in vitro and in vivo, for a wide range of tasks. On the therapeutic side, the particles effectively transported anticancer drugs, such as doxorubicin.

CNPs carrying doxorubicin provided excellent cancer control in animals, with minimal side effects.

Even when kept in the blood for many hours, CNPs only released small amounts of the drug. However, when exposed to light or agents such as glutathione, they readily released their payloads.

The researchers showed that, when exposed to a single wavelength of light, the CNPs could generate heat or produce singlet oxygen to destroy tumor cells.

Imaging applications

CNPs offer a number of advantages to enhance imaging, according to the researchers. The particles readily chelate imaging agents and can remain in the body for long periods.

In animal studies, CNPs largely accumulated in tumors, rather than in normal tissue. So they dramatically enhanced tumor contrast for MRI and may also be promising for PET-MRI scans, the researchers said.

“These particles can combine imaging and therapeutics,” Dr Li noted. “We could potentially use them to simultaneously deliver treatment and monitor treatment efficacy.”

The researchers are now conducting additional preclinical studies with the CNPs. If all goes well, they will proceed to human trials. In the meantime, the team is excited about these capabilities.

“This is the first nanoparticle to perform so many different jobs,” Dr Li said. “From delivering chemo, photodynamic, and photothermal therapies, to enhancing diagnostic imaging, it’s the complete package.”

Drug release in a cancer cell

Credit: PNAS

A new type of nanoparticle (NP) could aid the diagnosis and treatment of cancers, according to research published in Nature Communications.

Built on an easy-to-make polymer, these particles can be used as contrast agents to light up tumors for MRI and PET scans or to deliver chemotherapy and other treatments to cancer cells.

Furthermore, in vivo experiments showed the particles are biocompatible and elicit minimal side effects.

“These are amazingly useful particles,” said study author Yuanpei Li, PhD, of the UC Davis Comprehensive Cancer Center in Sacramento, California.

“As a contrast agent, they make tumors easier to see on MRI and other scans. We can also use them as vehicles to deliver chemotherapy directly to tumors, apply light to make the nanoparticles release singlet oxygen (photodynamic therapy), or use a laser to heat them (photothermal therapy)—all proven ways to destroy tumors.”

These NPs are built on a porphyrin/cholic acid polymer. Porphyrins are common organic compounds, and cholic acid is produced by the liver.

To further stabilize the particles, the researchers added the amino acid cysteine (creating CNPs), which prevents them from prematurely releasing their therapeutic payload when exposed to blood proteins and other barriers.

Therapeutic applications

The researchers tested the CNPs, both in vitro and in vivo, for a wide range of tasks. On the therapeutic side, the particles effectively transported anticancer drugs, such as doxorubicin.

CNPs carrying doxorubicin provided excellent cancer control in animals, with minimal side effects.

Even when kept in the blood for many hours, CNPs only released small amounts of the drug. However, when exposed to light or agents such as glutathione, they readily released their payloads.

The researchers showed that, when exposed to a single wavelength of light, the CNPs could generate heat or produce singlet oxygen to destroy tumor cells.

Imaging applications

CNPs offer a number of advantages to enhance imaging, according to the researchers. The particles readily chelate imaging agents and can remain in the body for long periods.

In animal studies, CNPs largely accumulated in tumors, rather than in normal tissue. So they dramatically enhanced tumor contrast for MRI and may also be promising for PET-MRI scans, the researchers said.

“These particles can combine imaging and therapeutics,” Dr Li noted. “We could potentially use them to simultaneously deliver treatment and monitor treatment efficacy.”

The researchers are now conducting additional preclinical studies with the CNPs. If all goes well, they will proceed to human trials. In the meantime, the team is excited about these capabilities.

“This is the first nanoparticle to perform so many different jobs,” Dr Li said. “From delivering chemo, photodynamic, and photothermal therapies, to enhancing diagnostic imaging, it’s the complete package.”

Lab mouse

Investigators at the Japanese research institute RIKEN have failed to create STAP (stimulus-triggered acquisition of pluripotency) cells in the experiments they’ve conducted thus far.

However, the group plans to continue its attempts to replicate the STAP cell phenomenon—inducing pluripotency in somatic cells by exposing them to stress—until next March.

So far, the group has failed to create STAP cells by exposing cells from newborn C57BL/6 mice to a low-pH environment.

Going forward, the researchers plan to conduct their experiments in another mouse strain. They also intend to alter the methods of stressing the cells.

RIKEN investigator Haruko Obokata, PhD, and her colleagues initially reported the STAP cell phenomenon in an article and a letter published in Nature last January.

Not long after the papers were published, members of the scientific community began to question the validity of the research. They voiced concerns about published images, possible plagiarism, and an inability to replicate the experiments described.

So RIKEN launched an investigation, ultimately concluding that Dr Obokata was guilty of misconduct, and some of her colleagues—including the recently deceased Yoshiki Sasai, MD, PhD—were guilty of negligence.

RIKEN also called for the papers to be retracted, and, in July, they were.

Throughout these proceedings, Dr Obokata insisted the STAP cell phenomenon is real. To investigate this claim, RIKEN organized a group of researchers to recreate Dr Obokata’s experiments.

The group has performed 22 experiments using different types of stress and cells from different tissues in C57BL/6 mice, but they have not reproduced the STAP cell phenomenon described in the Nature papers. (A report on these attempts is available in Japanese.)

Still, the investigators are continuing with their experiments and hope to have definitive results by March.

Lab mouse

Investigators at the Japanese research institute RIKEN have failed to create STAP (stimulus-triggered acquisition of pluripotency) cells in the experiments they’ve conducted thus far.

However, the group plans to continue its attempts to replicate the STAP cell phenomenon—inducing pluripotency in somatic cells by exposing them to stress—until next March.

So far, the group has failed to create STAP cells by exposing cells from newborn C57BL/6 mice to a low-pH environment.

Going forward, the researchers plan to conduct their experiments in another mouse strain. They also intend to alter the methods of stressing the cells.

RIKEN investigator Haruko Obokata, PhD, and her colleagues initially reported the STAP cell phenomenon in an article and a letter published in Nature last January.

Not long after the papers were published, members of the scientific community began to question the validity of the research. They voiced concerns about published images, possible plagiarism, and an inability to replicate the experiments described.

So RIKEN launched an investigation, ultimately concluding that Dr Obokata was guilty of misconduct, and some of her colleagues—including the recently deceased Yoshiki Sasai, MD, PhD—were guilty of negligence.

RIKEN also called for the papers to be retracted, and, in July, they were.

Throughout these proceedings, Dr Obokata insisted the STAP cell phenomenon is real. To investigate this claim, RIKEN organized a group of researchers to recreate Dr Obokata’s experiments.

The group has performed 22 experiments using different types of stress and cells from different tissues in C57BL/6 mice, but they have not reproduced the STAP cell phenomenon described in the Nature papers. (A report on these attempts is available in Japanese.)

Still, the investigators are continuing with their experiments and hope to have definitive results by March.

Lab mouse

Investigators at the Japanese research institute RIKEN have failed to create STAP (stimulus-triggered acquisition of pluripotency) cells in the experiments they’ve conducted thus far.

However, the group plans to continue its attempts to replicate the STAP cell phenomenon—inducing pluripotency in somatic cells by exposing them to stress—until next March.

So far, the group has failed to create STAP cells by exposing cells from newborn C57BL/6 mice to a low-pH environment.

Going forward, the researchers plan to conduct their experiments in another mouse strain. They also intend to alter the methods of stressing the cells.

RIKEN investigator Haruko Obokata, PhD, and her colleagues initially reported the STAP cell phenomenon in an article and a letter published in Nature last January.

Not long after the papers were published, members of the scientific community began to question the validity of the research. They voiced concerns about published images, possible plagiarism, and an inability to replicate the experiments described.

So RIKEN launched an investigation, ultimately concluding that Dr Obokata was guilty of misconduct, and some of her colleagues—including the recently deceased Yoshiki Sasai, MD, PhD—were guilty of negligence.

RIKEN also called for the papers to be retracted, and, in July, they were.

Throughout these proceedings, Dr Obokata insisted the STAP cell phenomenon is real. To investigate this claim, RIKEN organized a group of researchers to recreate Dr Obokata’s experiments.

The group has performed 22 experiments using different types of stress and cells from different tissues in C57BL/6 mice, but they have not reproduced the STAP cell phenomenon described in the Nature papers. (A report on these attempts is available in Japanese.)

Still, the investigators are continuing with their experiments and hope to have definitive results by March.

A surgical hospitalist program that's been shown to improve clinical outcomes and reduce inpatient length of stay (LOS) in a non-trauma setting is replicable across the country, says the author of a recent study.

Published in the Journal of the American College of Surgeons, the study reports that a team of surgeons dedicated solely to acute-care surgeries at Sutter Medical Center in Sacramento, Calif., decreased patients' LOS (6.5 days to 5.7 days, P<0.0016), hospital costs ($12,009 to $8306, P<0.0001), and overall complications (21% to 12%, P<0.0001).

Readmissions also "showed a downward trend" but not enough to be statistically significant. The retrospective review looked at the five-year period from 2007 to 2011, which represented the year before the service was initiated and the subsequent four years in which it was practiced.

"By decreasing variation, we improved outcomes and we improved efficiencies," says study author Leon Owens, MD, FACS, president and chief executive officer of the Sacramento-based Surgical Affiliates Management Group, which provided the surgical coverage for Sutter Medical Center. "So we wound up saving money and taking better care of patients. We succeeded because of the uniformity of how we approached the problems and because our team of surgeons is dedicated to doing these surgeries. They do not additionally need to do an elective surgery or deal with other distractions at their office."

Dr. Owens says he believes a well-managed team of acute-care surgeons can improve patient care at any institution that chooses to institute a similar program. "It's not only the brilliance of our doctors but the methodology," he adds. "Our doctors are bright and good, but if you get group-oriented, team-willing, competent surgeons, I believe this is reproducible. We believe this is going to be a common practice across the country. It's just a matter of time to get there." TH

Visit our website for more information on surgical hospitalists.

A surgical hospitalist program that's been shown to improve clinical outcomes and reduce inpatient length of stay (LOS) in a non-trauma setting is replicable across the country, says the author of a recent study.

Published in the Journal of the American College of Surgeons, the study reports that a team of surgeons dedicated solely to acute-care surgeries at Sutter Medical Center in Sacramento, Calif., decreased patients' LOS (6.5 days to 5.7 days, P<0.0016), hospital costs ($12,009 to $8306, P<0.0001), and overall complications (21% to 12%, P<0.0001).

Readmissions also "showed a downward trend" but not enough to be statistically significant. The retrospective review looked at the five-year period from 2007 to 2011, which represented the year before the service was initiated and the subsequent four years in which it was practiced.

"By decreasing variation, we improved outcomes and we improved efficiencies," says study author Leon Owens, MD, FACS, president and chief executive officer of the Sacramento-based Surgical Affiliates Management Group, which provided the surgical coverage for Sutter Medical Center. "So we wound up saving money and taking better care of patients. We succeeded because of the uniformity of how we approached the problems and because our team of surgeons is dedicated to doing these surgeries. They do not additionally need to do an elective surgery or deal with other distractions at their office."

Dr. Owens says he believes a well-managed team of acute-care surgeons can improve patient care at any institution that chooses to institute a similar program. "It's not only the brilliance of our doctors but the methodology," he adds. "Our doctors are bright and good, but if you get group-oriented, team-willing, competent surgeons, I believe this is reproducible. We believe this is going to be a common practice across the country. It's just a matter of time to get there." TH

Visit our website for more information on surgical hospitalists.

A surgical hospitalist program that's been shown to improve clinical outcomes and reduce inpatient length of stay (LOS) in a non-trauma setting is replicable across the country, says the author of a recent study.

Published in the Journal of the American College of Surgeons, the study reports that a team of surgeons dedicated solely to acute-care surgeries at Sutter Medical Center in Sacramento, Calif., decreased patients' LOS (6.5 days to 5.7 days, P<0.0016), hospital costs ($12,009 to $8306, P<0.0001), and overall complications (21% to 12%, P<0.0001).

Readmissions also "showed a downward trend" but not enough to be statistically significant. The retrospective review looked at the five-year period from 2007 to 2011, which represented the year before the service was initiated and the subsequent four years in which it was practiced.

"By decreasing variation, we improved outcomes and we improved efficiencies," says study author Leon Owens, MD, FACS, president and chief executive officer of the Sacramento-based Surgical Affiliates Management Group, which provided the surgical coverage for Sutter Medical Center. "So we wound up saving money and taking better care of patients. We succeeded because of the uniformity of how we approached the problems and because our team of surgeons is dedicated to doing these surgeries. They do not additionally need to do an elective surgery or deal with other distractions at their office."

Dr. Owens says he believes a well-managed team of acute-care surgeons can improve patient care at any institution that chooses to institute a similar program. "It's not only the brilliance of our doctors but the methodology," he adds. "Our doctors are bright and good, but if you get group-oriented, team-willing, competent surgeons, I believe this is reproducible. We believe this is going to be a common practice across the country. It's just a matter of time to get there." TH

Visit our website for more information on surgical hospitalists.

Clinical question: Which risk factors are key in the development of non-leg deep vein thromboses (NLDVTs), and what are the expected clinical sequelae from these events?

Background: Critically ill patients are at increased risk of venous thrombosis. Despite adherence to recommended daily thromboprophylaxis, many patients will develop a venous thrombosis in a vein other than the lower extremity. The association between NLDVT and pulmonary embolism (PE) or death is less clearly identified.

Study design: The PROphylaxis for ThromboEmbolism in Critical Care Trial (PROTECT), a multicenter, randomized, blinded, and concealed prospective cohort study occurring between May 2006 and June 2010.

Setting: Sixty-seven international secondary and tertiary care ICUs in both academic and community settings.

Synopsis: Researchers enrolled 3,746 ICU patients in a randomized controlled trial of dalteparin versus standard heparin for thromboprophylaxis. Of these patients, 84 (2.2%) developed a NLDVT. These thromboses were more likely to be deep and located proximally.

Risk factors were assessed using five selected variables: APACHE (acute physiology and chronic health evaluation), BMI, malignancy, and treatment with vasopressors or statins. Outside of indwelling upper extremity central venous catheters, cancer was the only independent predictor of NLDVT.

Compared to patients without any VTE, those with NLDVT were more likely to develop PE (14.9% versus 1.9%) and have longer ICU stays (19 versus nine days). On average, one in seven patients with NLDVT developed PE during the hospital stay. Despite the association with PE, NLDVT was not associated with an increased ICU mortality in an adjusted model. However, the PROTECT trial may have been underpowered to detect a difference. Additional limitations of the study included a relatively small total number of NLDVTs and a lack of standardized screening protocols for both NLDVT and PE.

Bottom line: Despite universal heparin thromboprophylaxis, many medical-surgical critically ill patients may develop NLDVT, placing them at higher risk for longer ICU stays and PE. TH

Citation: Lamontagne F, McIntyre L, Dodek P, et al. Nonleg venous thrombosis in critically ill adults: a nested prospective cohort study. JAMA Intern Med. 2014;174(5):689-696.

Clinical question: Which risk factors are key in the development of non-leg deep vein thromboses (NLDVTs), and what are the expected clinical sequelae from these events?

Background: Critically ill patients are at increased risk of venous thrombosis. Despite adherence to recommended daily thromboprophylaxis, many patients will develop a venous thrombosis in a vein other than the lower extremity. The association between NLDVT and pulmonary embolism (PE) or death is less clearly identified.

Study design: The PROphylaxis for ThromboEmbolism in Critical Care Trial (PROTECT), a multicenter, randomized, blinded, and concealed prospective cohort study occurring between May 2006 and June 2010.

Setting: Sixty-seven international secondary and tertiary care ICUs in both academic and community settings.

Synopsis: Researchers enrolled 3,746 ICU patients in a randomized controlled trial of dalteparin versus standard heparin for thromboprophylaxis. Of these patients, 84 (2.2%) developed a NLDVT. These thromboses were more likely to be deep and located proximally.

Risk factors were assessed using five selected variables: APACHE (acute physiology and chronic health evaluation), BMI, malignancy, and treatment with vasopressors or statins. Outside of indwelling upper extremity central venous catheters, cancer was the only independent predictor of NLDVT.

Compared to patients without any VTE, those with NLDVT were more likely to develop PE (14.9% versus 1.9%) and have longer ICU stays (19 versus nine days). On average, one in seven patients with NLDVT developed PE during the hospital stay. Despite the association with PE, NLDVT was not associated with an increased ICU mortality in an adjusted model. However, the PROTECT trial may have been underpowered to detect a difference. Additional limitations of the study included a relatively small total number of NLDVTs and a lack of standardized screening protocols for both NLDVT and PE.

Bottom line: Despite universal heparin thromboprophylaxis, many medical-surgical critically ill patients may develop NLDVT, placing them at higher risk for longer ICU stays and PE. TH

Citation: Lamontagne F, McIntyre L, Dodek P, et al. Nonleg venous thrombosis in critically ill adults: a nested prospective cohort study. JAMA Intern Med. 2014;174(5):689-696.

Clinical question: Which risk factors are key in the development of non-leg deep vein thromboses (NLDVTs), and what are the expected clinical sequelae from these events?

Background: Critically ill patients are at increased risk of venous thrombosis. Despite adherence to recommended daily thromboprophylaxis, many patients will develop a venous thrombosis in a vein other than the lower extremity. The association between NLDVT and pulmonary embolism (PE) or death is less clearly identified.

Study design: The PROphylaxis for ThromboEmbolism in Critical Care Trial (PROTECT), a multicenter, randomized, blinded, and concealed prospective cohort study occurring between May 2006 and June 2010.

Setting: Sixty-seven international secondary and tertiary care ICUs in both academic and community settings.

Synopsis: Researchers enrolled 3,746 ICU patients in a randomized controlled trial of dalteparin versus standard heparin for thromboprophylaxis. Of these patients, 84 (2.2%) developed a NLDVT. These thromboses were more likely to be deep and located proximally.

Risk factors were assessed using five selected variables: APACHE (acute physiology and chronic health evaluation), BMI, malignancy, and treatment with vasopressors or statins. Outside of indwelling upper extremity central venous catheters, cancer was the only independent predictor of NLDVT.

Compared to patients without any VTE, those with NLDVT were more likely to develop PE (14.9% versus 1.9%) and have longer ICU stays (19 versus nine days). On average, one in seven patients with NLDVT developed PE during the hospital stay. Despite the association with PE, NLDVT was not associated with an increased ICU mortality in an adjusted model. However, the PROTECT trial may have been underpowered to detect a difference. Additional limitations of the study included a relatively small total number of NLDVTs and a lack of standardized screening protocols for both NLDVT and PE.

Bottom line: Despite universal heparin thromboprophylaxis, many medical-surgical critically ill patients may develop NLDVT, placing them at higher risk for longer ICU stays and PE. TH

Citation: Lamontagne F, McIntyre L, Dodek P, et al. Nonleg venous thrombosis in critically ill adults: a nested prospective cohort study. JAMA Intern Med. 2014;174(5):689-696.

WASHINGTON – The use of D-cycloserine has promise as a way to augment the beneficial effects of virtual reality therapy of posttraumatic stress disorder, results of two recently published studies show. The results were discussed during a symposium at the annual convention of the American Psychological Association.

In one study of Iraq and Afghanistan veterans, the use of D-cycloserine (DCS) did not provide an advantage overall, compared with alprazolam or placebo. However, DCS was associated with favorable effects on cortisol and startle reactivity, compared with the other two groups, said one of the authors, Tanja Jovanovic, Ph.D. In another trial, a small proof-of concept study, the PTSD remission rate 6 months after treatment was almost 70% among those treated with a combination of virtual reality (VR) therapy and DCS, compared with 17% among those treated with VR therapy and placebo.

DCS, an NMDA (N-methyl-D-aspartate)-receptor partial agonist approved as an antibacterial by the Food and Drug Administration, has been found to enhance exposure therapy for conditions that include social anxiety and acrophobia in previous studies. NMDA also has been found to facilitate extinction learning in animal studies, said Dr. Jovanovic director of the neurophysiology laboratory at the Grady Trauma Project at Emory University, Atlanta.

In the study, 156 veterans of the Iraq and Afghanistan wars were randomized to treatment with DCS (50 mg), alprazolam (0.25 mg), or placebo plus five sessions of virtual reality exposure therapy (after an introductory VR session). Assessments of patients – which included evaluation of PTSD symptoms, psychophysiologic responses, and cortisol reactivity – were performed before treatment and 3, 6, and 12 months after treatment. Monitoring included placing electrodes under the eye to measure the contraction of the eye blink muscle and skin conductance testing during exposure to the VR scenes (two convoy explosion scenes and a city scene), said Dr. Jovanovic, one of the authors of the study, which was published in June (Am. J. Psychiatry 2014;171:640-8).

After five series of VR treatment, PTSD symptoms significantly decreased in all three groups after treatment, based on changes on the Clinician-Administered PTSD Scale (CAPS) score, but the greatest degree of reduction in symptoms at 12 months was observed in the DCS group, she said. Those treated with DCS "showed the biggest decline and actually maintained those gains at 6 months, which we did not see with the other groups."

In addition, those treated with DCS had a reduction in cortisol and startle reactivity that was greater than the changes observed in the two other groups. The magnitude of startle reactivity at baseline was related to the change in the CAPS score 6 months later, "so those gains they are maintaining at 6 months are predicted by their initial response to the virtual reality session pretreatment ... the more reactive, the better they got," Dr. Jovanovic reported.

The same also was true for skin conductance findings: The more reactive they were at baseline in this measure, the more improved the patients were at follow-up, but this association was only evident in the DCS-treated patients, Dr. Jovanovic said.

Measurements of cortisol levels before exposure to the VR scenes, immediately afterward, and 15 minutes afterward determined that cortisol reactivity was attenuated with treatment. Cortisol reactivity significantly dropped in all three groups, from before treatment to the 6-month follow-up but was the lowest in the DCS-treated patients. In the alprazolam-treated group, the higher the cortisol reactivity was before treatment, the worse the outcomes were with treatment, the reverse of what was seen with other psychophysiological measures, she added.

During the same symposium on the use of VR in the treatment of PTSD, JoAnn Difede, Ph.D., professor of psychiatry, Cornell University, New York, described the use of DCS "as a cognitive enhancer" for treatment of people with PTSD related to the World Trade Center attacks in 2001. "We see this as very promising," she said.

In one double-blind, proof-of-concept study, 25 people with PTSD were randomized to DCS (100 mg) or placebo administered 90 minutes before weekly sessions of VR therapy, timed so that plasma concentrations would peak during the session. In the placebo group, 3 dropped out, but none of the 13 patients in the DCS group dropped out (Neuropsychopharmacology 2014; 39:1052-8).

Six months after treatment, 9 of the 13 patients (69%) in the DCS group were in remission, compared with 2 of the 12 (17%) on placebo plus VR exposure. Remission was defined as a CAPS total score of 20 or less, and minimal or no impairment in social, occupational, and other important areas of function, as judged by an independent blinded assessor.

Dr. Difede, also director of the program for anxiety and traumatic stress studies at New York-Presbyterian Hospital, said the two groups began to diverge at the third session, and those who received DCS continued to improve 6 months later. A post-hoc analysis identified a "drastic improvement" in anger and sleep among those treated with DCS, a finding that she and her associates plan to look at more closely. The study presented by Dr. Jovanovic was funded by the National Institute of Mental Health. Dr. Difede received partial funding support from DeWitt-Wallace Fund of the New York Community Trust. The trust was not involved in the design, data collection, or in any other aspects of the study.

[email protected]

WASHINGTON – The use of D-cycloserine has promise as a way to augment the beneficial effects of virtual reality therapy of posttraumatic stress disorder, results of two recently published studies show. The results were discussed during a symposium at the annual convention of the American Psychological Association.

In one study of Iraq and Afghanistan veterans, the use of D-cycloserine (DCS) did not provide an advantage overall, compared with alprazolam or placebo. However, DCS was associated with favorable effects on cortisol and startle reactivity, compared with the other two groups, said one of the authors, Tanja Jovanovic, Ph.D. In another trial, a small proof-of concept study, the PTSD remission rate 6 months after treatment was almost 70% among those treated with a combination of virtual reality (VR) therapy and DCS, compared with 17% among those treated with VR therapy and placebo.

DCS, an NMDA (N-methyl-D-aspartate)-receptor partial agonist approved as an antibacterial by the Food and Drug Administration, has been found to enhance exposure therapy for conditions that include social anxiety and acrophobia in previous studies. NMDA also has been found to facilitate extinction learning in animal studies, said Dr. Jovanovic director of the neurophysiology laboratory at the Grady Trauma Project at Emory University, Atlanta.

In the study, 156 veterans of the Iraq and Afghanistan wars were randomized to treatment with DCS (50 mg), alprazolam (0.25 mg), or placebo plus five sessions of virtual reality exposure therapy (after an introductory VR session). Assessments of patients – which included evaluation of PTSD symptoms, psychophysiologic responses, and cortisol reactivity – were performed before treatment and 3, 6, and 12 months after treatment. Monitoring included placing electrodes under the eye to measure the contraction of the eye blink muscle and skin conductance testing during exposure to the VR scenes (two convoy explosion scenes and a city scene), said Dr. Jovanovic, one of the authors of the study, which was published in June (Am. J. Psychiatry 2014;171:640-8).

After five series of VR treatment, PTSD symptoms significantly decreased in all three groups after treatment, based on changes on the Clinician-Administered PTSD Scale (CAPS) score, but the greatest degree of reduction in symptoms at 12 months was observed in the DCS group, she said. Those treated with DCS "showed the biggest decline and actually maintained those gains at 6 months, which we did not see with the other groups."

In addition, those treated with DCS had a reduction in cortisol and startle reactivity that was greater than the changes observed in the two other groups. The magnitude of startle reactivity at baseline was related to the change in the CAPS score 6 months later, "so those gains they are maintaining at 6 months are predicted by their initial response to the virtual reality session pretreatment ... the more reactive, the better they got," Dr. Jovanovic reported.

The same also was true for skin conductance findings: The more reactive they were at baseline in this measure, the more improved the patients were at follow-up, but this association was only evident in the DCS-treated patients, Dr. Jovanovic said.

Measurements of cortisol levels before exposure to the VR scenes, immediately afterward, and 15 minutes afterward determined that cortisol reactivity was attenuated with treatment. Cortisol reactivity significantly dropped in all three groups, from before treatment to the 6-month follow-up but was the lowest in the DCS-treated patients. In the alprazolam-treated group, the higher the cortisol reactivity was before treatment, the worse the outcomes were with treatment, the reverse of what was seen with other psychophysiological measures, she added.

During the same symposium on the use of VR in the treatment of PTSD, JoAnn Difede, Ph.D., professor of psychiatry, Cornell University, New York, described the use of DCS "as a cognitive enhancer" for treatment of people with PTSD related to the World Trade Center attacks in 2001. "We see this as very promising," she said.

In one double-blind, proof-of-concept study, 25 people with PTSD were randomized to DCS (100 mg) or placebo administered 90 minutes before weekly sessions of VR therapy, timed so that plasma concentrations would peak during the session. In the placebo group, 3 dropped out, but none of the 13 patients in the DCS group dropped out (Neuropsychopharmacology 2014; 39:1052-8).

Six months after treatment, 9 of the 13 patients (69%) in the DCS group were in remission, compared with 2 of the 12 (17%) on placebo plus VR exposure. Remission was defined as a CAPS total score of 20 or less, and minimal or no impairment in social, occupational, and other important areas of function, as judged by an independent blinded assessor.

Dr. Difede, also director of the program for anxiety and traumatic stress studies at New York-Presbyterian Hospital, said the two groups began to diverge at the third session, and those who received DCS continued to improve 6 months later. A post-hoc analysis identified a "drastic improvement" in anger and sleep among those treated with DCS, a finding that she and her associates plan to look at more closely. The study presented by Dr. Jovanovic was funded by the National Institute of Mental Health. Dr. Difede received partial funding support from DeWitt-Wallace Fund of the New York Community Trust. The trust was not involved in the design, data collection, or in any other aspects of the study.

[email protected]

WASHINGTON – The use of D-cycloserine has promise as a way to augment the beneficial effects of virtual reality therapy of posttraumatic stress disorder, results of two recently published studies show. The results were discussed during a symposium at the annual convention of the American Psychological Association.

In one study of Iraq and Afghanistan veterans, the use of D-cycloserine (DCS) did not provide an advantage overall, compared with alprazolam or placebo. However, DCS was associated with favorable effects on cortisol and startle reactivity, compared with the other two groups, said one of the authors, Tanja Jovanovic, Ph.D. In another trial, a small proof-of concept study, the PTSD remission rate 6 months after treatment was almost 70% among those treated with a combination of virtual reality (VR) therapy and DCS, compared with 17% among those treated with VR therapy and placebo.

DCS, an NMDA (N-methyl-D-aspartate)-receptor partial agonist approved as an antibacterial by the Food and Drug Administration, has been found to enhance exposure therapy for conditions that include social anxiety and acrophobia in previous studies. NMDA also has been found to facilitate extinction learning in animal studies, said Dr. Jovanovic director of the neurophysiology laboratory at the Grady Trauma Project at Emory University, Atlanta.

In the study, 156 veterans of the Iraq and Afghanistan wars were randomized to treatment with DCS (50 mg), alprazolam (0.25 mg), or placebo plus five sessions of virtual reality exposure therapy (after an introductory VR session). Assessments of patients – which included evaluation of PTSD symptoms, psychophysiologic responses, and cortisol reactivity – were performed before treatment and 3, 6, and 12 months after treatment. Monitoring included placing electrodes under the eye to measure the contraction of the eye blink muscle and skin conductance testing during exposure to the VR scenes (two convoy explosion scenes and a city scene), said Dr. Jovanovic, one of the authors of the study, which was published in June (Am. J. Psychiatry 2014;171:640-8).

After five series of VR treatment, PTSD symptoms significantly decreased in all three groups after treatment, based on changes on the Clinician-Administered PTSD Scale (CAPS) score, but the greatest degree of reduction in symptoms at 12 months was observed in the DCS group, she said. Those treated with DCS "showed the biggest decline and actually maintained those gains at 6 months, which we did not see with the other groups."

In addition, those treated with DCS had a reduction in cortisol and startle reactivity that was greater than the changes observed in the two other groups. The magnitude of startle reactivity at baseline was related to the change in the CAPS score 6 months later, "so those gains they are maintaining at 6 months are predicted by their initial response to the virtual reality session pretreatment ... the more reactive, the better they got," Dr. Jovanovic reported.

The same also was true for skin conductance findings: The more reactive they were at baseline in this measure, the more improved the patients were at follow-up, but this association was only evident in the DCS-treated patients, Dr. Jovanovic said.

Measurements of cortisol levels before exposure to the VR scenes, immediately afterward, and 15 minutes afterward determined that cortisol reactivity was attenuated with treatment. Cortisol reactivity significantly dropped in all three groups, from before treatment to the 6-month follow-up but was the lowest in the DCS-treated patients. In the alprazolam-treated group, the higher the cortisol reactivity was before treatment, the worse the outcomes were with treatment, the reverse of what was seen with other psychophysiological measures, she added.

During the same symposium on the use of VR in the treatment of PTSD, JoAnn Difede, Ph.D., professor of psychiatry, Cornell University, New York, described the use of DCS "as a cognitive enhancer" for treatment of people with PTSD related to the World Trade Center attacks in 2001. "We see this as very promising," she said.

In one double-blind, proof-of-concept study, 25 people with PTSD were randomized to DCS (100 mg) or placebo administered 90 minutes before weekly sessions of VR therapy, timed so that plasma concentrations would peak during the session. In the placebo group, 3 dropped out, but none of the 13 patients in the DCS group dropped out (Neuropsychopharmacology 2014; 39:1052-8).

Six months after treatment, 9 of the 13 patients (69%) in the DCS group were in remission, compared with 2 of the 12 (17%) on placebo plus VR exposure. Remission was defined as a CAPS total score of 20 or less, and minimal or no impairment in social, occupational, and other important areas of function, as judged by an independent blinded assessor.

Dr. Difede, also director of the program for anxiety and traumatic stress studies at New York-Presbyterian Hospital, said the two groups began to diverge at the third session, and those who received DCS continued to improve 6 months later. A post-hoc analysis identified a "drastic improvement" in anger and sleep among those treated with DCS, a finding that she and her associates plan to look at more closely. The study presented by Dr. Jovanovic was funded by the National Institute of Mental Health. Dr. Difede received partial funding support from DeWitt-Wallace Fund of the New York Community Trust. The trust was not involved in the design, data collection, or in any other aspects of the study.

[email protected]

In this comprehensive educational video we review appropriate patient positioning for laparoscopic and robotic surgery to prevent postoperative neuropathies that can be experienced with gynecologic surgery. We also include a case-based review of injuries specific to the brachial plexus, ulnar nerve, and femoral nerve.

Our technique involves the use of a bed sheet, an egg crate foam mattress pad, and boot-type stirrups. We recommend setting up the operating room table to facilitate tucking of the patient’s arms and to prevent slippage of the patient when she is placed in steep Trendelenburg. For all steps involved, see the video.

Tips for setting up the operating room bed include: 

• Use of a single bed sheet placed across the head of a bare table with an egg crate foam mattress pad over the sheet to prevent the need for strapping the patient to the bed or the use of shoulder braces to prevent slippage.
• For low dorsal lithotomy positioning, flex the patient’s hips with a trunk-to-thigh angle of approximately 170°, and never more than 180°.
• For arm tucking, remove the arm boards and excess egg crate foam from the patient’s side and placecushioning over the elbow and the wrist. Keep the patient’s hand pronated when tucking and do not allow the arm to hang over the side of the bed.
• If the patient is obese, support the tucked arm by placing the arm boards beneath the arm parallel to the bed.

Next month we continue our series on surgical techniques with a video on why choosing the proper colpotomy cup is critical for successful minimally invasive hysterectomy.

Vidyard Video

Will you be joining me at the AAGL Global Congress on Minimally Invasive Gynecology in Vancouver this November? Safe patient positioning for minimally invasive surgery and other exciting topics will be discussed. Visit www.aagl.org/globalcongress for more information.
—Dr. Arnold Advincula, AAGL 2014 Scientific Program Chair

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In this comprehensive educational video we review appropriate patient positioning for laparoscopic and robotic surgery to prevent postoperative neuropathies that can be experienced with gynecologic surgery. We also include a case-based review of injuries specific to the brachial plexus, ulnar nerve, and femoral nerve.

Our technique involves the use of a bed sheet, an egg crate foam mattress pad, and boot-type stirrups. We recommend setting up the operating room table to facilitate tucking of the patient’s arms and to prevent slippage of the patient when she is placed in steep Trendelenburg. For all steps involved, see the video.

Tips for setting up the operating room bed include: 

• Use of a single bed sheet placed across the head of a bare table with an egg crate foam mattress pad over the sheet to prevent the need for strapping the patient to the bed or the use of shoulder braces to prevent slippage.
• For low dorsal lithotomy positioning, flex the patient’s hips with a trunk-to-thigh angle of approximately 170°, and never more than 180°.
• For arm tucking, remove the arm boards and excess egg crate foam from the patient’s side and placecushioning over the elbow and the wrist. Keep the patient’s hand pronated when tucking and do not allow the arm to hang over the side of the bed.
• If the patient is obese, support the tucked arm by placing the arm boards beneath the arm parallel to the bed.

Next month we continue our series on surgical techniques with a video on why choosing the proper colpotomy cup is critical for successful minimally invasive hysterectomy.

Vidyard Video

Will you be joining me at the AAGL Global Congress on Minimally Invasive Gynecology in Vancouver this November? Safe patient positioning for minimally invasive surgery and other exciting topics will be discussed. Visit www.aagl.org/globalcongress for more information.
—Dr. Arnold Advincula, AAGL 2014 Scientific Program Chair

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In this comprehensive educational video we review appropriate patient positioning for laparoscopic and robotic surgery to prevent postoperative neuropathies that can be experienced with gynecologic surgery. We also include a case-based review of injuries specific to the brachial plexus, ulnar nerve, and femoral nerve.

Our technique involves the use of a bed sheet, an egg crate foam mattress pad, and boot-type stirrups. We recommend setting up the operating room table to facilitate tucking of the patient’s arms and to prevent slippage of the patient when she is placed in steep Trendelenburg. For all steps involved, see the video.

Tips for setting up the operating room bed include: 

• Use of a single bed sheet placed across the head of a bare table with an egg crate foam mattress pad over the sheet to prevent the need for strapping the patient to the bed or the use of shoulder braces to prevent slippage.
• For low dorsal lithotomy positioning, flex the patient’s hips with a trunk-to-thigh angle of approximately 170°, and never more than 180°.
• For arm tucking, remove the arm boards and excess egg crate foam from the patient’s side and placecushioning over the elbow and the wrist. Keep the patient’s hand pronated when tucking and do not allow the arm to hang over the side of the bed.
• If the patient is obese, support the tucked arm by placing the arm boards beneath the arm parallel to the bed.

Next month we continue our series on surgical techniques with a video on why choosing the proper colpotomy cup is critical for successful minimally invasive hysterectomy.

Vidyard Video

Will you be joining me at the AAGL Global Congress on Minimally Invasive Gynecology in Vancouver this November? Safe patient positioning for minimally invasive surgery and other exciting topics will be discussed. Visit www.aagl.org/globalcongress for more information.
—Dr. Arnold Advincula, AAGL 2014 Scientific Program Chair

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Isolated high systolic blood pressure is strongly associated with risk for intracerebral hemorrhage, subarachnoid hemorrhage, and stable angina, whereas isolated high diastolic blood pressure is associated with risk for abdominal aortic aneurysm, according to findings published in the Lancet.

The observations debunk widespread assumptions that isolated systolic and diastolic blood pressures are similarly and consistently associated with cardiovascular diseases, wrote Dr. Eleni Rapsomaniki and associates of the Farr Institute of Health Informatics Research in London (Lancet 2014;383:1899-1911).

©American Heart Association

"Our data support the possibility that blood pressure functions through different underlying biological mechanisms for different diseases," the researchers wrote. These data can be considered when counseling patients.

The results "also emphasize the limitations of existing blood pressure–lowering strategies," they added. Better implementation of existing blood pressure–lowering treatments and better management of other cardiovascular risk factors as part of global risk estimation could help to mitigate excess risk.

The researchers studied 1.25 million patients, aged 30 years or older, who had no previous history of cardiovascular disease. Baseline blood pressures were recorded during primary care consultations. Patients were classified as having hypertension with a baseline blood pressure reading of 140/90 mm Hg or greater, a previous diagnosis of hypertension, or repeat prescriptions for blood pressure–lowering medications.

Isolated systolic hypertension was defined as a value of 140 mm Hg or higher with a diastolic level of lower than 90 mm Hg. Isolated diastolic hypertension was defined as systolic blood pressure of less than 140 mm Hg and a diastolic level of 90 mm Hg or higher.

Endpoints were defined as the initial presentation of any of 12 cardiovascular diseases.

The primary analysis reported associations of outcomes with a 20/10 mm Hg increase in systolic/diastolic blood pressure by age group (30-59 years, 60-79 years, and 80 years or older), and estimated risks and years of life lost associated with hypertension for the index ages of 30, 60, and 80 years. The secondary analysis reported associations of blood pressure with cardiovascular outcomes, after adjusting for smoking status, diabetes, cholesterol, body mass index, and baseline treatment with hypertension drugs.

Isolated systolic hypertension was strongly associated with intracerebral hemorrhage (hazard ratio, 1.44; 95% confidence interval, 1.32-1.58), subarachnoid hemorrhage (HR, 1.43; CI, 1.25-1.63), and stable angina (HR, 1.41; CI, 1.36-1.46).

Isolated diastolic hypertension was associated with abdominal aortic aneurysm (HR, 1.45; 95% CI, 1.34-1.56).

Peripheral arterial disease had the strongest association with pulse pressure (HR, 1.23; CI, 1.20-1.27).

The lifetime risk of total cardiovascular disease at 30 years of age was 63.3% in people with hypertension and 46·1% in those with healthy blood pressure, with stable and unstable angina as the most frequent outcomes. The mean number of cardiovascular disease–free life years lost in those with hypertension was 5 years at 30 years of age, 3.4 years at 60 years, and 1.6 years at 80 years.

The study was funded by the National Institute for Health Research, the Wellcome Trust, the Medical Research Council Prognosis Research Strategy Partnership, and numerous other sources. The researchers had no competing interests.

[email protected]

Isolated high systolic blood pressure is strongly associated with risk for intracerebral hemorrhage, subarachnoid hemorrhage, and stable angina, whereas isolated high diastolic blood pressure is associated with risk for abdominal aortic aneurysm, according to findings published in the Lancet.

The observations debunk widespread assumptions that isolated systolic and diastolic blood pressures are similarly and consistently associated with cardiovascular diseases, wrote Dr. Eleni Rapsomaniki and associates of the Farr Institute of Health Informatics Research in London (Lancet 2014;383:1899-1911).

©American Heart Association

"Our data support the possibility that blood pressure functions through different underlying biological mechanisms for different diseases," the researchers wrote. These data can be considered when counseling patients.

The results "also emphasize the limitations of existing blood pressure–lowering strategies," they added. Better implementation of existing blood pressure–lowering treatments and better management of other cardiovascular risk factors as part of global risk estimation could help to mitigate excess risk.

The researchers studied 1.25 million patients, aged 30 years or older, who had no previous history of cardiovascular disease. Baseline blood pressures were recorded during primary care consultations. Patients were classified as having hypertension with a baseline blood pressure reading of 140/90 mm Hg or greater, a previous diagnosis of hypertension, or repeat prescriptions for blood pressure–lowering medications.

Isolated systolic hypertension was defined as a value of 140 mm Hg or higher with a diastolic level of lower than 90 mm Hg. Isolated diastolic hypertension was defined as systolic blood pressure of less than 140 mm Hg and a diastolic level of 90 mm Hg or higher.

Endpoints were defined as the initial presentation of any of 12 cardiovascular diseases.

The primary analysis reported associations of outcomes with a 20/10 mm Hg increase in systolic/diastolic blood pressure by age group (30-59 years, 60-79 years, and 80 years or older), and estimated risks and years of life lost associated with hypertension for the index ages of 30, 60, and 80 years. The secondary analysis reported associations of blood pressure with cardiovascular outcomes, after adjusting for smoking status, diabetes, cholesterol, body mass index, and baseline treatment with hypertension drugs.

Isolated systolic hypertension was strongly associated with intracerebral hemorrhage (hazard ratio, 1.44; 95% confidence interval, 1.32-1.58), subarachnoid hemorrhage (HR, 1.43; CI, 1.25-1.63), and stable angina (HR, 1.41; CI, 1.36-1.46).

Isolated diastolic hypertension was associated with abdominal aortic aneurysm (HR, 1.45; 95% CI, 1.34-1.56).

Peripheral arterial disease had the strongest association with pulse pressure (HR, 1.23; CI, 1.20-1.27).

The lifetime risk of total cardiovascular disease at 30 years of age was 63.3% in people with hypertension and 46·1% in those with healthy blood pressure, with stable and unstable angina as the most frequent outcomes. The mean number of cardiovascular disease–free life years lost in those with hypertension was 5 years at 30 years of age, 3.4 years at 60 years, and 1.6 years at 80 years.

The study was funded by the National Institute for Health Research, the Wellcome Trust, the Medical Research Council Prognosis Research Strategy Partnership, and numerous other sources. The researchers had no competing interests.

[email protected]

Isolated high systolic blood pressure is strongly associated with risk for intracerebral hemorrhage, subarachnoid hemorrhage, and stable angina, whereas isolated high diastolic blood pressure is associated with risk for abdominal aortic aneurysm, according to findings published in the Lancet.

The observations debunk widespread assumptions that isolated systolic and diastolic blood pressures are similarly and consistently associated with cardiovascular diseases, wrote Dr. Eleni Rapsomaniki and associates of the Farr Institute of Health Informatics Research in London (Lancet 2014;383:1899-1911).

©American Heart Association

"Our data support the possibility that blood pressure functions through different underlying biological mechanisms for different diseases," the researchers wrote. These data can be considered when counseling patients.

The results "also emphasize the limitations of existing blood pressure–lowering strategies," they added. Better implementation of existing blood pressure–lowering treatments and better management of other cardiovascular risk factors as part of global risk estimation could help to mitigate excess risk.

The researchers studied 1.25 million patients, aged 30 years or older, who had no previous history of cardiovascular disease. Baseline blood pressures were recorded during primary care consultations. Patients were classified as having hypertension with a baseline blood pressure reading of 140/90 mm Hg or greater, a previous diagnosis of hypertension, or repeat prescriptions for blood pressure–lowering medications.

Isolated systolic hypertension was defined as a value of 140 mm Hg or higher with a diastolic level of lower than 90 mm Hg. Isolated diastolic hypertension was defined as systolic blood pressure of less than 140 mm Hg and a diastolic level of 90 mm Hg or higher.

Endpoints were defined as the initial presentation of any of 12 cardiovascular diseases.

The primary analysis reported associations of outcomes with a 20/10 mm Hg increase in systolic/diastolic blood pressure by age group (30-59 years, 60-79 years, and 80 years or older), and estimated risks and years of life lost associated with hypertension for the index ages of 30, 60, and 80 years. The secondary analysis reported associations of blood pressure with cardiovascular outcomes, after adjusting for smoking status, diabetes, cholesterol, body mass index, and baseline treatment with hypertension drugs.

Isolated systolic hypertension was strongly associated with intracerebral hemorrhage (hazard ratio, 1.44; 95% confidence interval, 1.32-1.58), subarachnoid hemorrhage (HR, 1.43; CI, 1.25-1.63), and stable angina (HR, 1.41; CI, 1.36-1.46).

Isolated diastolic hypertension was associated with abdominal aortic aneurysm (HR, 1.45; 95% CI, 1.34-1.56).

Peripheral arterial disease had the strongest association with pulse pressure (HR, 1.23; CI, 1.20-1.27).

The lifetime risk of total cardiovascular disease at 30 years of age was 63.3% in people with hypertension and 46·1% in those with healthy blood pressure, with stable and unstable angina as the most frequent outcomes. The mean number of cardiovascular disease–free life years lost in those with hypertension was 5 years at 30 years of age, 3.4 years at 60 years, and 1.6 years at 80 years.

The study was funded by the National Institute for Health Research, the Wellcome Trust, the Medical Research Council Prognosis Research Strategy Partnership, and numerous other sources. The researchers had no competing interests.

[email protected]