PET scan

Image by Jens Langner

A PET probe known as [¹⁸F]CFA could be used to aid the treatment of leukemias and other cancers, according to research published in PNAS.

Investigators say [¹⁸F]CFA can detect the activity of deoxycytidine kinase (dCK) in humans more effectively than existing probes.

dCK is a rate-limiting enzyme in the cytosolic deoxyribonucleoside salvage pathway and is considered an important therapeutic and PET-imaging target in certain cancers.

Research has shown that dCK is highly expressed in acute leukemia cells and activated lymphocytes. And the enzyme plays an integral role in allowing drugs such as clofarabine, cytarabine, and fludarabine to treat certain leukemias.

“This enzyme is essential for the therapeutic activity of an entire class of anticancer drugs and even for some antiviral drugs,” said study author Caius Radu, MD, of the University of California, Los Angeles.

“It can take an inactive drug and activate it. If you trick a cancer cell or virus to activate the drug, it would be toxic for the cancer cell or viral genome.”

Until recently, PET technology was only able to clearly detect dCK in mice due to the metabolic instability of the available probes and cross-reactivity with a dCK-related enzyme in humans.

However, Dr Radu and his colleagues showed that [¹⁸F]CFA can clearly detect dCK in humans.

The team found that [¹⁸F]CFA accumulation in leukemia cells correlated with dCK expression, and they were able to inhibit [¹⁸F]CFA accumulation with a dCK inhibitor.

Experiments with [¹⁸F]CFA PET/CT in humans showed probe accumulation in tissues with high dCK expression, such as hematopoietic bone marrow and secondary lymphoid organs.

“We are able to clearly see tissues, including tumor tissues, with high dCK activity that we haven’t seen before in humans using any of the other probes previously developed for this enzyme,” Dr Radu said.

He added that, since activated immune cells increase their expression of dCK, [¹⁸F]CFA could also be used to monitor the effectiveness of immunotherapeutic interventions.

The investigators hope to begin clinical trials with [¹⁸F]CFA in the near future.

Dr Radu and his team invented [¹⁸F]CFA and its analogs, which were patented by the University of California and have been licensed to Sofie Biosciences, a company founded by Dr Radu and his team. The University of California also patented additional intellectual property for small-molecule dCK inhibitors.

PET scan

Image by Jens Langner

A PET probe known as [¹⁸F]CFA could be used to aid the treatment of leukemias and other cancers, according to research published in PNAS.

Investigators say [¹⁸F]CFA can detect the activity of deoxycytidine kinase (dCK) in humans more effectively than existing probes.

dCK is a rate-limiting enzyme in the cytosolic deoxyribonucleoside salvage pathway and is considered an important therapeutic and PET-imaging target in certain cancers.

Research has shown that dCK is highly expressed in acute leukemia cells and activated lymphocytes. And the enzyme plays an integral role in allowing drugs such as clofarabine, cytarabine, and fludarabine to treat certain leukemias.

“This enzyme is essential for the therapeutic activity of an entire class of anticancer drugs and even for some antiviral drugs,” said study author Caius Radu, MD, of the University of California, Los Angeles.

“It can take an inactive drug and activate it. If you trick a cancer cell or virus to activate the drug, it would be toxic for the cancer cell or viral genome.”

Until recently, PET technology was only able to clearly detect dCK in mice due to the metabolic instability of the available probes and cross-reactivity with a dCK-related enzyme in humans.

However, Dr Radu and his colleagues showed that [¹⁸F]CFA can clearly detect dCK in humans.

The team found that [¹⁸F]CFA accumulation in leukemia cells correlated with dCK expression, and they were able to inhibit [¹⁸F]CFA accumulation with a dCK inhibitor.

Experiments with [¹⁸F]CFA PET/CT in humans showed probe accumulation in tissues with high dCK expression, such as hematopoietic bone marrow and secondary lymphoid organs.

“We are able to clearly see tissues, including tumor tissues, with high dCK activity that we haven’t seen before in humans using any of the other probes previously developed for this enzyme,” Dr Radu said.

He added that, since activated immune cells increase their expression of dCK, [¹⁸F]CFA could also be used to monitor the effectiveness of immunotherapeutic interventions.

The investigators hope to begin clinical trials with [¹⁸F]CFA in the near future.

Dr Radu and his team invented [¹⁸F]CFA and its analogs, which were patented by the University of California and have been licensed to Sofie Biosciences, a company founded by Dr Radu and his team. The University of California also patented additional intellectual property for small-molecule dCK inhibitors.

PET scan

Image by Jens Langner

A PET probe known as [¹⁸F]CFA could be used to aid the treatment of leukemias and other cancers, according to research published in PNAS.

Investigators say [¹⁸F]CFA can detect the activity of deoxycytidine kinase (dCK) in humans more effectively than existing probes.

dCK is a rate-limiting enzyme in the cytosolic deoxyribonucleoside salvage pathway and is considered an important therapeutic and PET-imaging target in certain cancers.

Research has shown that dCK is highly expressed in acute leukemia cells and activated lymphocytes. And the enzyme plays an integral role in allowing drugs such as clofarabine, cytarabine, and fludarabine to treat certain leukemias.

“This enzyme is essential for the therapeutic activity of an entire class of anticancer drugs and even for some antiviral drugs,” said study author Caius Radu, MD, of the University of California, Los Angeles.

“It can take an inactive drug and activate it. If you trick a cancer cell or virus to activate the drug, it would be toxic for the cancer cell or viral genome.”

Until recently, PET technology was only able to clearly detect dCK in mice due to the metabolic instability of the available probes and cross-reactivity with a dCK-related enzyme in humans.

However, Dr Radu and his colleagues showed that [¹⁸F]CFA can clearly detect dCK in humans.

The team found that [¹⁸F]CFA accumulation in leukemia cells correlated with dCK expression, and they were able to inhibit [¹⁸F]CFA accumulation with a dCK inhibitor.

Experiments with [¹⁸F]CFA PET/CT in humans showed probe accumulation in tissues with high dCK expression, such as hematopoietic bone marrow and secondary lymphoid organs.

“We are able to clearly see tissues, including tumor tissues, with high dCK activity that we haven’t seen before in humans using any of the other probes previously developed for this enzyme,” Dr Radu said.

He added that, since activated immune cells increase their expression of dCK, [¹⁸F]CFA could also be used to monitor the effectiveness of immunotherapeutic interventions.

The investigators hope to begin clinical trials with [¹⁸F]CFA in the near future.

Dr Radu and his team invented [¹⁸F]CFA and its analogs, which were patented by the University of California and have been licensed to Sofie Biosciences, a company founded by Dr Radu and his team. The University of California also patented additional intellectual property for small-molecule dCK inhibitors.

Blood culture positive for

Staphylococcus infection

Photo by Bill Branson

The US Food and Drug Administration (FDA) has granted 510(k) clearance for a blood culture panel that detects sepsis caused by methicillin-resistant Staphylococcus aureus (MRSA) and other Staphylococcus species.

The Staph ID/R Blood Culture Panel is a product of Great Basin Scientific, Inc.

It is an automated, DNA multiplex assay used to identify Staphylococcus species directly from positive blood cultures in about 2 hours.

The panel also detects the mecA gene, a drug-resistance marker that confers resistance to methicillin and other beta-­lactams and creates MRSA.

In addition, the Staph ID/R Blood Culture Panel identifies coagulase-negative staphylococci.

According to the US Centers for Disease Control and Prevention, 20% to 50% of all positive blood cultures are likely false positives due to contamination caused by coagulase-negative staphylococci, many of which are part of the normal flora of human skin and are not dangerous.

The Staph ID/R Blood Culture Panel is run on the Great Basin Analyzer. The company says the assay requires less than a minute of hands-­on time and no results interpretation due to electronic results reporting.

Blood culture positive for

Staphylococcus infection

Photo by Bill Branson

The US Food and Drug Administration (FDA) has granted 510(k) clearance for a blood culture panel that detects sepsis caused by methicillin-resistant Staphylococcus aureus (MRSA) and other Staphylococcus species.

The Staph ID/R Blood Culture Panel is a product of Great Basin Scientific, Inc.

It is an automated, DNA multiplex assay used to identify Staphylococcus species directly from positive blood cultures in about 2 hours.

The panel also detects the mecA gene, a drug-resistance marker that confers resistance to methicillin and other beta-­lactams and creates MRSA.

In addition, the Staph ID/R Blood Culture Panel identifies coagulase-negative staphylococci.

According to the US Centers for Disease Control and Prevention, 20% to 50% of all positive blood cultures are likely false positives due to contamination caused by coagulase-negative staphylococci, many of which are part of the normal flora of human skin and are not dangerous.

The Staph ID/R Blood Culture Panel is run on the Great Basin Analyzer. The company says the assay requires less than a minute of hands-­on time and no results interpretation due to electronic results reporting.

Blood culture positive for

Staphylococcus infection

Photo by Bill Branson

The US Food and Drug Administration (FDA) has granted 510(k) clearance for a blood culture panel that detects sepsis caused by methicillin-resistant Staphylococcus aureus (MRSA) and other Staphylococcus species.

The Staph ID/R Blood Culture Panel is a product of Great Basin Scientific, Inc.

It is an automated, DNA multiplex assay used to identify Staphylococcus species directly from positive blood cultures in about 2 hours.

The panel also detects the mecA gene, a drug-resistance marker that confers resistance to methicillin and other beta-­lactams and creates MRSA.

In addition, the Staph ID/R Blood Culture Panel identifies coagulase-negative staphylococci.

According to the US Centers for Disease Control and Prevention, 20% to 50% of all positive blood cultures are likely false positives due to contamination caused by coagulase-negative staphylococci, many of which are part of the normal flora of human skin and are not dangerous.

The Staph ID/R Blood Culture Panel is run on the Great Basin Analyzer. The company says the assay requires less than a minute of hands-­on time and no results interpretation due to electronic results reporting.

Blood samples

Photo by Graham Colm

A comparison of commercially available blood tests has revealed more variability than expected, according to researchers.

The group compared basic blood tests run by commercial laboratories and found the testing service, type of test, and time of collection all influenced the accuracy of results.

Given that these tests can be used for disease diagnosis or to determine whether a patient’s medication is working, the researchers said this study highlights the importance of knowing the accuracy and variability of blood test results.

“While most of the variability we found was within clinically accepted ranges, there were several cases where inaccurate results would have led to incorrect medical decisions,” said Joel Dudley, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York.

“We hope this study will inspire the biomedical community to take a critical look at all testing variables to ensure that lab results are as robust and reproducible as possible.”

Dr Dudley and his colleagues described this study in the Journal of Clinical Investigation.

The researchers collected peripheral blood samples from 60 healthy adults at 4 separate time points within a 6.5-hour window. The samples were collected in Phoenix, Arizona, at an ambulatory clinic and at retail outlets with point-of-care services.

The team collected 14 samples per subject and used those samples to compare 22 common clinical lab tests conducted at 3 commercial labs. One lab, Theranos, offered blood tests obtained from a finger prick, and the other 2, Quest and LabCorp, required standard venipuncture draws.

More than half of the test results showed significant differences between test providers. Of the 22 tests, 15 (68%) showed significant variability between labs (P<0.002).

Triglyceride levels and red blood cell counts were among the most consistent results, while white blood cell counts and overall cholesterol levels were among the most variable.

Test results from Theranos were flagged by Theranos as abnormal 1.6 times more often than tests from LabCorp or Quest (P<0.0001). The percentages for measurements outside their normal range were 8.3% for LabCorp, 7.5% for Quest, and 12.2% for Theranos.

In addition, the researchers noted that, although they controlled subjects’ eating and physical activity, data from blood samples collected earlier in the day were sometimes significantly different from samples taken from the same subjects later in the day.

There were significant difference between measurements collected at time points 1 and 2 vs time points 3 and 4 for 13 of the 22 tests (P<0.002).

“These testing disparities occurred despite rigorous laboratory certification and proficiency standards designed to ensure consistency,” said study author Eric Schadt, PhD, of Mount Sinai.

“Our results suggest the need for greater transparency in lab technologies and procedures, as well as a much more thorough investigation of biological mechanisms that may contribute to more dynamic levels than we currently understand.”

Blood samples

Photo by Graham Colm

A comparison of commercially available blood tests has revealed more variability than expected, according to researchers.

The group compared basic blood tests run by commercial laboratories and found the testing service, type of test, and time of collection all influenced the accuracy of results.

Given that these tests can be used for disease diagnosis or to determine whether a patient’s medication is working, the researchers said this study highlights the importance of knowing the accuracy and variability of blood test results.

“While most of the variability we found was within clinically accepted ranges, there were several cases where inaccurate results would have led to incorrect medical decisions,” said Joel Dudley, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York.

“We hope this study will inspire the biomedical community to take a critical look at all testing variables to ensure that lab results are as robust and reproducible as possible.”

Dr Dudley and his colleagues described this study in the Journal of Clinical Investigation.

The researchers collected peripheral blood samples from 60 healthy adults at 4 separate time points within a 6.5-hour window. The samples were collected in Phoenix, Arizona, at an ambulatory clinic and at retail outlets with point-of-care services.

The team collected 14 samples per subject and used those samples to compare 22 common clinical lab tests conducted at 3 commercial labs. One lab, Theranos, offered blood tests obtained from a finger prick, and the other 2, Quest and LabCorp, required standard venipuncture draws.

More than half of the test results showed significant differences between test providers. Of the 22 tests, 15 (68%) showed significant variability between labs (P<0.002).

Triglyceride levels and red blood cell counts were among the most consistent results, while white blood cell counts and overall cholesterol levels were among the most variable.

Test results from Theranos were flagged by Theranos as abnormal 1.6 times more often than tests from LabCorp or Quest (P<0.0001). The percentages for measurements outside their normal range were 8.3% for LabCorp, 7.5% for Quest, and 12.2% for Theranos.

In addition, the researchers noted that, although they controlled subjects’ eating and physical activity, data from blood samples collected earlier in the day were sometimes significantly different from samples taken from the same subjects later in the day.

There were significant difference between measurements collected at time points 1 and 2 vs time points 3 and 4 for 13 of the 22 tests (P<0.002).

“These testing disparities occurred despite rigorous laboratory certification and proficiency standards designed to ensure consistency,” said study author Eric Schadt, PhD, of Mount Sinai.

“Our results suggest the need for greater transparency in lab technologies and procedures, as well as a much more thorough investigation of biological mechanisms that may contribute to more dynamic levels than we currently understand.”

Blood samples

Photo by Graham Colm

A comparison of commercially available blood tests has revealed more variability than expected, according to researchers.

The group compared basic blood tests run by commercial laboratories and found the testing service, type of test, and time of collection all influenced the accuracy of results.

Given that these tests can be used for disease diagnosis or to determine whether a patient’s medication is working, the researchers said this study highlights the importance of knowing the accuracy and variability of blood test results.

“While most of the variability we found was within clinically accepted ranges, there were several cases where inaccurate results would have led to incorrect medical decisions,” said Joel Dudley, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York.

“We hope this study will inspire the biomedical community to take a critical look at all testing variables to ensure that lab results are as robust and reproducible as possible.”

Dr Dudley and his colleagues described this study in the Journal of Clinical Investigation.

The researchers collected peripheral blood samples from 60 healthy adults at 4 separate time points within a 6.5-hour window. The samples were collected in Phoenix, Arizona, at an ambulatory clinic and at retail outlets with point-of-care services.

The team collected 14 samples per subject and used those samples to compare 22 common clinical lab tests conducted at 3 commercial labs. One lab, Theranos, offered blood tests obtained from a finger prick, and the other 2, Quest and LabCorp, required standard venipuncture draws.

More than half of the test results showed significant differences between test providers. Of the 22 tests, 15 (68%) showed significant variability between labs (P<0.002).

Triglyceride levels and red blood cell counts were among the most consistent results, while white blood cell counts and overall cholesterol levels were among the most variable.

Test results from Theranos were flagged by Theranos as abnormal 1.6 times more often than tests from LabCorp or Quest (P<0.0001). The percentages for measurements outside their normal range were 8.3% for LabCorp, 7.5% for Quest, and 12.2% for Theranos.

In addition, the researchers noted that, although they controlled subjects’ eating and physical activity, data from blood samples collected earlier in the day were sometimes significantly different from samples taken from the same subjects later in the day.

There were significant difference between measurements collected at time points 1 and 2 vs time points 3 and 4 for 13 of the 22 tests (P<0.002).

“These testing disparities occurred despite rigorous laboratory certification and proficiency standards designed to ensure consistency,” said study author Eric Schadt, PhD, of Mount Sinai.

“Our results suggest the need for greater transparency in lab technologies and procedures, as well as a much more thorough investigation of biological mechanisms that may contribute to more dynamic levels than we currently understand.”

THE CASE

A 45-year-old airman presented to our medical group with acute onset of sharp, positional left lateral chest wall pain that he’d had for 2 days. The pain began after an extreme core body workout. Treatment with ibuprofen 800 mg and local electrical stimulation one day prior provided no benefit. The patient reported the pain to be a 6 out of 10 when still and a 9 to 10 when sitting for more than a few minutes, turning, or taking a medium to deep breath. The patient felt “dangerously distracted by the pain” while driving in for his appointment.

We noted focal left lower lateral intercostal muscle tenderness without trigger point-like thickness or spasm. The patient also had restricted inspiration, secondary to the severe pain, and decreased left lower field breath sounds. His vital signs were normal, as was his cardiac exam.

THE DIAGNOSIS

While awaiting a chest x-ray, the patient was offered and opted to try acupuncture for pain relief. (We have medical acupuncturists on staff.) Analgesics had already been used, but had provided little relief.

We identified 4 acupuncture sites in the ear: 2 were battlefield acupuncture (BFA) points (more on this in a bit) and 2 points were deemed active by a skin conductance point finder (a handheld device that assesses changes in electrical skin resistance at auricular acupuncture points). The left ear points that were treated included the cingulate gyrus (intertragic notch), Shen Men (triangular fossa), and chest and abdomen regional points (antihelix) (FIGURE 1).

Within 15 minutes, the patient reported significant pain relief and was able to inspire deeply without pain. The patient also underwent a chest x-ray, which revealed atelectasis of the left lower lobe (FIGURE 2A) caused by pain-induced hypoventilation.

Because the patient’s pain was so well controlled, he returned to work immediately after the appointment. At the end of his shift 6 hours later he returned, unscheduled, to report pain at a level of one out of 10 and said he was able to breathe normally. In addition, lung auscultation was normal and a repeat chest x-ray revealed that the atelectasis had almost completely resolved (FIGURE 2B). This occurred without medication or other therapy. The pain did not return.

DISCUSSION

Although acupuncture is over 2000 years old, it has been largely disregarded in the United States due to a lack of mainstream evidence supporting its efficacy. Research is hindered by significant variation in approach between providers, the difficulties inherent to blinding patients and providers to treatment vs placebo, and poor insurance coverage and reimbursement.

Acupuncture research is burgeoning. A 2012 meta-analysis concluded that patients receiving acupuncture had less pain than those receiving sham or no acupuncture for several pain conditions. Specifically, scores for back and neck pain, osteoarthritis, and chronic headache were 0.23, 0.16, and 0.15 standard deviations (SDs), respectively, lower for patients receiving acupuncture than for those who got sham acupuncture. The effect sizes for acupuncture patients compared to no acupuncture controls were 0.55, 0.57, and 0.42 respectively (all P<.001).¹

Several theories explain how auricular acupuncture may work. Paul Nogier, MD, noted that the ear is composed of ectodermal, mesodermal, and endodermal tissues, and mapped the “inverted fetus” homunculus in the ear, which corresponds to specific body points.² Functional magnetic resonance imaging has demonstrated increased brain activity in the cingulate gyrus and thalamic regions in response to a painful stimulus, as well as attenuation of this activity after the placement of needles in corresponding auricular cingulate gyrus and thalamus points.³ In addition, research has confirmed that acupuncture raises serum and cerebrospinal levels of endorphins and enkephalins.⁴

Less than 15 minutes after needle placement, our patient reported significant pain relief and was able to inspire deeply without pain.

Battlefield acupuncture (BFA) was developed by Richard Niemtzow, MD, and has been used for acute injuries in the front lines of battle as well as for many health conditions. BFA treats pain using a sequence of 5 predetermined auricular acupuncture points.⁵ Onset and duration of pain relief vary depending on the location and nature of the pathology. We’ve noted that BFA for chronic pain has a shorter duration of benefit and is more likely to need to be repeated.

One randomized pilot study involving 87 patients presenting to the emergency room blinded emergency health care providers to the inclusion of the first 2 BFA points in their otherwise usual care of acute pain patients. Participants in the acupuncture group experienced a 23% reduction in pain before discharge compared to no change in the standard care group (P<.0005).⁶

Our patient. We inserted semi-permanent needles with a needle length of 2 mm into 4 locations on the ear. (These needles can remain in the ear for several days and fall out on their own or they may be removed by pulling the stud ends.) As noted earlier, our patient reported pain relief within 15 minutes and was pain free by the next day.

THE TAKEAWAY

Research confirms that acupuncture raises serum and cerebrospinal levels of endorphins and enkephalins.

Auricular acupuncture can treat acute and chronic pain. As proof, the BFA technique is widely used by health care providers throughout the US military and Department of Veterans Affairs. In this case, the immediate pain relief and x-ray documentation of atelectasis resolution within 6 hours of treatment provide support that auricular acupuncture was beneficial in reversing the cause of this atelectasis, which was pain-induced hypoventilation.

While the acute pain control observed with this patient is not unusual in our experience, what is unusual is the rare visual confirmation of the striking degree of pain reduction possible with auricular acupuncture.

THE CASE

A 45-year-old airman presented to our medical group with acute onset of sharp, positional left lateral chest wall pain that he’d had for 2 days. The pain began after an extreme core body workout. Treatment with ibuprofen 800 mg and local electrical stimulation one day prior provided no benefit. The patient reported the pain to be a 6 out of 10 when still and a 9 to 10 when sitting for more than a few minutes, turning, or taking a medium to deep breath. The patient felt “dangerously distracted by the pain” while driving in for his appointment.

We noted focal left lower lateral intercostal muscle tenderness without trigger point-like thickness or spasm. The patient also had restricted inspiration, secondary to the severe pain, and decreased left lower field breath sounds. His vital signs were normal, as was his cardiac exam.

THE DIAGNOSIS

While awaiting a chest x-ray, the patient was offered and opted to try acupuncture for pain relief. (We have medical acupuncturists on staff.) Analgesics had already been used, but had provided little relief.

We identified 4 acupuncture sites in the ear: 2 were battlefield acupuncture (BFA) points (more on this in a bit) and 2 points were deemed active by a skin conductance point finder (a handheld device that assesses changes in electrical skin resistance at auricular acupuncture points). The left ear points that were treated included the cingulate gyrus (intertragic notch), Shen Men (triangular fossa), and chest and abdomen regional points (antihelix) (FIGURE 1).

Within 15 minutes, the patient reported significant pain relief and was able to inspire deeply without pain. The patient also underwent a chest x-ray, which revealed atelectasis of the left lower lobe (FIGURE 2A) caused by pain-induced hypoventilation.

Because the patient’s pain was so well controlled, he returned to work immediately after the appointment. At the end of his shift 6 hours later he returned, unscheduled, to report pain at a level of one out of 10 and said he was able to breathe normally. In addition, lung auscultation was normal and a repeat chest x-ray revealed that the atelectasis had almost completely resolved (FIGURE 2B). This occurred without medication or other therapy. The pain did not return.

DISCUSSION

Although acupuncture is over 2000 years old, it has been largely disregarded in the United States due to a lack of mainstream evidence supporting its efficacy. Research is hindered by significant variation in approach between providers, the difficulties inherent to blinding patients and providers to treatment vs placebo, and poor insurance coverage and reimbursement.

Acupuncture research is burgeoning. A 2012 meta-analysis concluded that patients receiving acupuncture had less pain than those receiving sham or no acupuncture for several pain conditions. Specifically, scores for back and neck pain, osteoarthritis, and chronic headache were 0.23, 0.16, and 0.15 standard deviations (SDs), respectively, lower for patients receiving acupuncture than for those who got sham acupuncture. The effect sizes for acupuncture patients compared to no acupuncture controls were 0.55, 0.57, and 0.42 respectively (all P<.001).¹

Several theories explain how auricular acupuncture may work. Paul Nogier, MD, noted that the ear is composed of ectodermal, mesodermal, and endodermal tissues, and mapped the “inverted fetus” homunculus in the ear, which corresponds to specific body points.² Functional magnetic resonance imaging has demonstrated increased brain activity in the cingulate gyrus and thalamic regions in response to a painful stimulus, as well as attenuation of this activity after the placement of needles in corresponding auricular cingulate gyrus and thalamus points.³ In addition, research has confirmed that acupuncture raises serum and cerebrospinal levels of endorphins and enkephalins.⁴

Less than 15 minutes after needle placement, our patient reported significant pain relief and was able to inspire deeply without pain.

Battlefield acupuncture (BFA) was developed by Richard Niemtzow, MD, and has been used for acute injuries in the front lines of battle as well as for many health conditions. BFA treats pain using a sequence of 5 predetermined auricular acupuncture points.⁵ Onset and duration of pain relief vary depending on the location and nature of the pathology. We’ve noted that BFA for chronic pain has a shorter duration of benefit and is more likely to need to be repeated.

One randomized pilot study involving 87 patients presenting to the emergency room blinded emergency health care providers to the inclusion of the first 2 BFA points in their otherwise usual care of acute pain patients. Participants in the acupuncture group experienced a 23% reduction in pain before discharge compared to no change in the standard care group (P<.0005).⁶

Our patient. We inserted semi-permanent needles with a needle length of 2 mm into 4 locations on the ear. (These needles can remain in the ear for several days and fall out on their own or they may be removed by pulling the stud ends.) As noted earlier, our patient reported pain relief within 15 minutes and was pain free by the next day.

THE TAKEAWAY

Research confirms that acupuncture raises serum and cerebrospinal levels of endorphins and enkephalins.

Auricular acupuncture can treat acute and chronic pain. As proof, the BFA technique is widely used by health care providers throughout the US military and Department of Veterans Affairs. In this case, the immediate pain relief and x-ray documentation of atelectasis resolution within 6 hours of treatment provide support that auricular acupuncture was beneficial in reversing the cause of this atelectasis, which was pain-induced hypoventilation.

While the acute pain control observed with this patient is not unusual in our experience, what is unusual is the rare visual confirmation of the striking degree of pain reduction possible with auricular acupuncture.

THE CASE

A 45-year-old airman presented to our medical group with acute onset of sharp, positional left lateral chest wall pain that he’d had for 2 days. The pain began after an extreme core body workout. Treatment with ibuprofen 800 mg and local electrical stimulation one day prior provided no benefit. The patient reported the pain to be a 6 out of 10 when still and a 9 to 10 when sitting for more than a few minutes, turning, or taking a medium to deep breath. The patient felt “dangerously distracted by the pain” while driving in for his appointment.

We noted focal left lower lateral intercostal muscle tenderness without trigger point-like thickness or spasm. The patient also had restricted inspiration, secondary to the severe pain, and decreased left lower field breath sounds. His vital signs were normal, as was his cardiac exam.

THE DIAGNOSIS

While awaiting a chest x-ray, the patient was offered and opted to try acupuncture for pain relief. (We have medical acupuncturists on staff.) Analgesics had already been used, but had provided little relief.

We identified 4 acupuncture sites in the ear: 2 were battlefield acupuncture (BFA) points (more on this in a bit) and 2 points were deemed active by a skin conductance point finder (a handheld device that assesses changes in electrical skin resistance at auricular acupuncture points). The left ear points that were treated included the cingulate gyrus (intertragic notch), Shen Men (triangular fossa), and chest and abdomen regional points (antihelix) (FIGURE 1).

Within 15 minutes, the patient reported significant pain relief and was able to inspire deeply without pain. The patient also underwent a chest x-ray, which revealed atelectasis of the left lower lobe (FIGURE 2A) caused by pain-induced hypoventilation.

Because the patient’s pain was so well controlled, he returned to work immediately after the appointment. At the end of his shift 6 hours later he returned, unscheduled, to report pain at a level of one out of 10 and said he was able to breathe normally. In addition, lung auscultation was normal and a repeat chest x-ray revealed that the atelectasis had almost completely resolved (FIGURE 2B). This occurred without medication or other therapy. The pain did not return.

DISCUSSION

Although acupuncture is over 2000 years old, it has been largely disregarded in the United States due to a lack of mainstream evidence supporting its efficacy. Research is hindered by significant variation in approach between providers, the difficulties inherent to blinding patients and providers to treatment vs placebo, and poor insurance coverage and reimbursement.

Acupuncture research is burgeoning. A 2012 meta-analysis concluded that patients receiving acupuncture had less pain than those receiving sham or no acupuncture for several pain conditions. Specifically, scores for back and neck pain, osteoarthritis, and chronic headache were 0.23, 0.16, and 0.15 standard deviations (SDs), respectively, lower for patients receiving acupuncture than for those who got sham acupuncture. The effect sizes for acupuncture patients compared to no acupuncture controls were 0.55, 0.57, and 0.42 respectively (all P<.001).¹

Several theories explain how auricular acupuncture may work. Paul Nogier, MD, noted that the ear is composed of ectodermal, mesodermal, and endodermal tissues, and mapped the “inverted fetus” homunculus in the ear, which corresponds to specific body points.² Functional magnetic resonance imaging has demonstrated increased brain activity in the cingulate gyrus and thalamic regions in response to a painful stimulus, as well as attenuation of this activity after the placement of needles in corresponding auricular cingulate gyrus and thalamus points.³ In addition, research has confirmed that acupuncture raises serum and cerebrospinal levels of endorphins and enkephalins.⁴

Less than 15 minutes after needle placement, our patient reported significant pain relief and was able to inspire deeply without pain.

Battlefield acupuncture (BFA) was developed by Richard Niemtzow, MD, and has been used for acute injuries in the front lines of battle as well as for many health conditions. BFA treats pain using a sequence of 5 predetermined auricular acupuncture points.⁵ Onset and duration of pain relief vary depending on the location and nature of the pathology. We’ve noted that BFA for chronic pain has a shorter duration of benefit and is more likely to need to be repeated.

One randomized pilot study involving 87 patients presenting to the emergency room blinded emergency health care providers to the inclusion of the first 2 BFA points in their otherwise usual care of acute pain patients. Participants in the acupuncture group experienced a 23% reduction in pain before discharge compared to no change in the standard care group (P<.0005).⁶

Our patient. We inserted semi-permanent needles with a needle length of 2 mm into 4 locations on the ear. (These needles can remain in the ear for several days and fall out on their own or they may be removed by pulling the stud ends.) As noted earlier, our patient reported pain relief within 15 minutes and was pain free by the next day.

THE TAKEAWAY

Research confirms that acupuncture raises serum and cerebrospinal levels of endorphins and enkephalins.

Auricular acupuncture can treat acute and chronic pain. As proof, the BFA technique is widely used by health care providers throughout the US military and Department of Veterans Affairs. In this case, the immediate pain relief and x-ray documentation of atelectasis resolution within 6 hours of treatment provide support that auricular acupuncture was beneficial in reversing the cause of this atelectasis, which was pain-induced hypoventilation.

While the acute pain control observed with this patient is not unusual in our experience, what is unusual is the rare visual confirmation of the striking degree of pain reduction possible with auricular acupuncture.

THE CASE

A 16-year-old boy presented to the emergency room (ER) with pain, redness, and swelling of his right upper arm that had been bothering him for 2 days. He was the quarterback of his high school football team, a sport that he’d been playing since he was 8 years old. He indicated that his football training—which involved repetitive throwing with his right arm—had intensified over the previous 2 months.

Prior to the ER visit, the patient was healthy and active with no significant medical history. He’d had no shoulder trauma and there was no family history of any coagulopathies, venous thrombosis, or pulmonary embolism. He denied chest pain, shortness of breath, palpitations, and fever, and said that he did not smoke cigarettes or drink alcohol.

On physical examination, his blood pressure was 118/70 mm Hg and his heart rate was 74 beats per minute. He had nonpitting edema and erythema of his right upper arm. His radial and brachial pulses were strong and equal in both arms. Assessment of neurologic and vascular integrity produced positive Wright’s and Adson’s tests, but a negative Halstead’s test. (For more on these tests, see: Wright’s test, Adson’s test, and Halstead’s test.) The circumference of the patient’s right upper arm was 2.5 cm greater than the left upper arm. The remainder of the physical exam was normal.

THE DIAGNOSIS

A duplex ultrasound of the right upper arm revealed an acute occlusive thrombus in the axillary vein. We started the patient on intravenous heparin. A venogram confirmed thrombosis of the axillary-subclavian vein (FIGURE 1A). Based on the patient’s clinical presentation and the results of the venogram, we diagnosed Paget-Schroetter syndrome. The venogram was followed by thrombolysis with alteplase (FIGURE 1B) and a balloon angioplasty (FIGURE 1C). One week later, a repeat venogram demonstrated partial removal of the thrombus and an area of compression on the inferior aspect of the subclavian vein due to a cervical band (FIGURE 1D).

DISCUSSION

Paget-Schroetter syndrome (PSS), or effort thrombosis of the upper extremities, is defined as spontaneous thrombus in the axillary and subclavian veins that occurs as a consequence of strenuous upper-extremity activity. It is a rare condition with an incidence of one to 2 cases per 100,000 people per year, and represents 1% to 4% of all cases of deep vein thrombosis (DVT).¹

Spontaneous thrombosis of the upper extremities typically presents in young, otherwise healthy individuals. It has been described in athletes who are involved in ball games, games with rackets or clubs, aquatic sports, combatant sports, and in violin players.² The repetitive movements used in these activities can lead to compression of the axillary and subclavian veins by hypertrophied muscles. Repetitive trauma causes intimal damage and thrombogenesis.³

PSS is characterized by the abrupt, spontaneous swelling of the entire arm, cyanosis, and pain that occurs with use or overhead positioning. Enlarged subcutaneous veins are present in the upper arm, around the shoulder, or in the upper anterior chest wall (Urschel’s sign). The classic presentation is acute onset of upper extremity pain and swelling in the dominant arm following a particularly strenuous activity.⁴ A low-grade fever, superficial thrombophlebitis, or neurologic symptoms may coexist. Certain provocative maneuvers can help reproduce the symptoms (TABLE 1^5,6). Complications of PSS include pulmonary embolism, postthrombotic syndrome (pain, heaviness, and swelling), and recurrent thrombosis.⁷

Contrast venography best shows the extent of thrombosis

Duplex ultrasound, with its high sensitivity and specificity, is the initial, noninvasive test of choice (TABLE 2^4,8-11). However, duplex ultrasound has a false-negative rate of 30% because it is highly technician-dependent and can be complicated by acoustic shadows from the clavicle or sternum.⁸

The most direct and definitive means to confirm the diagnosis of PSS is catheter-directed contrast venography.⁹ This method provides complete anatomic information regarding the site and extent of thrombosis, allows definitive evaluation of the collateral venous pathways, and is a necessary step toward the use of thrombolytic therapy. Contrast load, however, contraindicates the procedure in patients with renal failure and in those who are pregnant.

Contrast-enhanced computed tomography (CT) and magnetic resonance angiography (MRA) are also highly sensitive for detecting focal stenosis at the level of the first rib, the presence or absence of enlarged collateral veins, and the chronicity of any thrombus present. However, the usefulness of CT and magnetic resonance venography in initial screening is unclear, due to a lack of randomized controlled trials.

Treatment involves anticoagulants, thrombolytics, and possibly surgery

Prompt use of anticoagulation is indicated in PSS. Initial anticoagulation with low molecular weight unfractionated heparin or a direct thrombin inhibitor followed by warfarin for a minimum of 3 to 6 months is recommended.¹²

Patients treated with anticoagulation alone have a higher incidence of long-term residual symptoms, disability, and recurrent thrombosis.⁷ As a result, a more aggressive approach with the use of thrombolytic therapy is indicated, especially in young, active patients, to minimize long-term consequences. Alteplase or reteplase are used for this purpose. Thrombolysis is less likely to be beneficial if the thrombus is more than 2 weeks old or if there are inflammatory changes in the vein. The use of catheter-directed thrombolysis minimizes the risk of systemic adverse effects and achieves higher clot resolution rates.¹³

Because PSS is caused by compression of the vein, rather than a disorder of blood clotting, there is still a 50% to 70% risk of recurrent thrombosis despite thrombolysis and anticoagulation.¹⁴ Therefore, the most definitive management approach remains surgical treatment. Patients with recent thrombosis who are within the first several weeks of undergoing successful thrombolytic therapy are excellent candidates for surgery. Operative treatment for PSS includes first rib resection, scalene muscle removal, or subclavius muscle removal, along with removal of constricting scar tissue from around the vein.⁷

THE TAKEAWAY

PSS is characterized by upper-extremity DVT resulting from repetitive trauma to the subclavian-axillary vein. Early diagnosis of PSS with contrast venography and prompt use of anticoagulation can effectively restore venous patency, reduce the risk of rethrombosis, and return the patient to normal function. Primary care physicians should be aware of this condition, because delayed recognition in a high-functioning person can be potentially disabling.

Our patient had a first rib resection, partial division of the scalenus anterior and medius muscles, and lysis of the cervical band. Follow-up venography confirmed resolution of thrombosis without any complications. The patient was continued on anticoagulation with warfarin for 3 months.

THE CASE

A 16-year-old boy presented to the emergency room (ER) with pain, redness, and swelling of his right upper arm that had been bothering him for 2 days. He was the quarterback of his high school football team, a sport that he’d been playing since he was 8 years old. He indicated that his football training—which involved repetitive throwing with his right arm—had intensified over the previous 2 months.

Prior to the ER visit, the patient was healthy and active with no significant medical history. He’d had no shoulder trauma and there was no family history of any coagulopathies, venous thrombosis, or pulmonary embolism. He denied chest pain, shortness of breath, palpitations, and fever, and said that he did not smoke cigarettes or drink alcohol.

On physical examination, his blood pressure was 118/70 mm Hg and his heart rate was 74 beats per minute. He had nonpitting edema and erythema of his right upper arm. His radial and brachial pulses were strong and equal in both arms. Assessment of neurologic and vascular integrity produced positive Wright’s and Adson’s tests, but a negative Halstead’s test. (For more on these tests, see: Wright’s test, Adson’s test, and Halstead’s test.) The circumference of the patient’s right upper arm was 2.5 cm greater than the left upper arm. The remainder of the physical exam was normal.

THE DIAGNOSIS

A duplex ultrasound of the right upper arm revealed an acute occlusive thrombus in the axillary vein. We started the patient on intravenous heparin. A venogram confirmed thrombosis of the axillary-subclavian vein (FIGURE 1A). Based on the patient’s clinical presentation and the results of the venogram, we diagnosed Paget-Schroetter syndrome. The venogram was followed by thrombolysis with alteplase (FIGURE 1B) and a balloon angioplasty (FIGURE 1C). One week later, a repeat venogram demonstrated partial removal of the thrombus and an area of compression on the inferior aspect of the subclavian vein due to a cervical band (FIGURE 1D).

DISCUSSION

Paget-Schroetter syndrome (PSS), or effort thrombosis of the upper extremities, is defined as spontaneous thrombus in the axillary and subclavian veins that occurs as a consequence of strenuous upper-extremity activity. It is a rare condition with an incidence of one to 2 cases per 100,000 people per year, and represents 1% to 4% of all cases of deep vein thrombosis (DVT).¹

Spontaneous thrombosis of the upper extremities typically presents in young, otherwise healthy individuals. It has been described in athletes who are involved in ball games, games with rackets or clubs, aquatic sports, combatant sports, and in violin players.² The repetitive movements used in these activities can lead to compression of the axillary and subclavian veins by hypertrophied muscles. Repetitive trauma causes intimal damage and thrombogenesis.³

PSS is characterized by the abrupt, spontaneous swelling of the entire arm, cyanosis, and pain that occurs with use or overhead positioning. Enlarged subcutaneous veins are present in the upper arm, around the shoulder, or in the upper anterior chest wall (Urschel’s sign). The classic presentation is acute onset of upper extremity pain and swelling in the dominant arm following a particularly strenuous activity.⁴ A low-grade fever, superficial thrombophlebitis, or neurologic symptoms may coexist. Certain provocative maneuvers can help reproduce the symptoms (TABLE 1^5,6). Complications of PSS include pulmonary embolism, postthrombotic syndrome (pain, heaviness, and swelling), and recurrent thrombosis.⁷

Contrast venography best shows the extent of thrombosis

Duplex ultrasound, with its high sensitivity and specificity, is the initial, noninvasive test of choice (TABLE 2^4,8-11). However, duplex ultrasound has a false-negative rate of 30% because it is highly technician-dependent and can be complicated by acoustic shadows from the clavicle or sternum.⁸

The most direct and definitive means to confirm the diagnosis of PSS is catheter-directed contrast venography.⁹ This method provides complete anatomic information regarding the site and extent of thrombosis, allows definitive evaluation of the collateral venous pathways, and is a necessary step toward the use of thrombolytic therapy. Contrast load, however, contraindicates the procedure in patients with renal failure and in those who are pregnant.

Contrast-enhanced computed tomography (CT) and magnetic resonance angiography (MRA) are also highly sensitive for detecting focal stenosis at the level of the first rib, the presence or absence of enlarged collateral veins, and the chronicity of any thrombus present. However, the usefulness of CT and magnetic resonance venography in initial screening is unclear, due to a lack of randomized controlled trials.

Treatment involves anticoagulants, thrombolytics, and possibly surgery

Prompt use of anticoagulation is indicated in PSS. Initial anticoagulation with low molecular weight unfractionated heparin or a direct thrombin inhibitor followed by warfarin for a minimum of 3 to 6 months is recommended.¹²

Patients treated with anticoagulation alone have a higher incidence of long-term residual symptoms, disability, and recurrent thrombosis.⁷ As a result, a more aggressive approach with the use of thrombolytic therapy is indicated, especially in young, active patients, to minimize long-term consequences. Alteplase or reteplase are used for this purpose. Thrombolysis is less likely to be beneficial if the thrombus is more than 2 weeks old or if there are inflammatory changes in the vein. The use of catheter-directed thrombolysis minimizes the risk of systemic adverse effects and achieves higher clot resolution rates.¹³

Because PSS is caused by compression of the vein, rather than a disorder of blood clotting, there is still a 50% to 70% risk of recurrent thrombosis despite thrombolysis and anticoagulation.¹⁴ Therefore, the most definitive management approach remains surgical treatment. Patients with recent thrombosis who are within the first several weeks of undergoing successful thrombolytic therapy are excellent candidates for surgery. Operative treatment for PSS includes first rib resection, scalene muscle removal, or subclavius muscle removal, along with removal of constricting scar tissue from around the vein.⁷

THE TAKEAWAY

PSS is characterized by upper-extremity DVT resulting from repetitive trauma to the subclavian-axillary vein. Early diagnosis of PSS with contrast venography and prompt use of anticoagulation can effectively restore venous patency, reduce the risk of rethrombosis, and return the patient to normal function. Primary care physicians should be aware of this condition, because delayed recognition in a high-functioning person can be potentially disabling.

Our patient had a first rib resection, partial division of the scalenus anterior and medius muscles, and lysis of the cervical band. Follow-up venography confirmed resolution of thrombosis without any complications. The patient was continued on anticoagulation with warfarin for 3 months.

THE CASE

A 16-year-old boy presented to the emergency room (ER) with pain, redness, and swelling of his right upper arm that had been bothering him for 2 days. He was the quarterback of his high school football team, a sport that he’d been playing since he was 8 years old. He indicated that his football training—which involved repetitive throwing with his right arm—had intensified over the previous 2 months.

Prior to the ER visit, the patient was healthy and active with no significant medical history. He’d had no shoulder trauma and there was no family history of any coagulopathies, venous thrombosis, or pulmonary embolism. He denied chest pain, shortness of breath, palpitations, and fever, and said that he did not smoke cigarettes or drink alcohol.

On physical examination, his blood pressure was 118/70 mm Hg and his heart rate was 74 beats per minute. He had nonpitting edema and erythema of his right upper arm. His radial and brachial pulses were strong and equal in both arms. Assessment of neurologic and vascular integrity produced positive Wright’s and Adson’s tests, but a negative Halstead’s test. (For more on these tests, see: Wright’s test, Adson’s test, and Halstead’s test.) The circumference of the patient’s right upper arm was 2.5 cm greater than the left upper arm. The remainder of the physical exam was normal.

THE DIAGNOSIS

A duplex ultrasound of the right upper arm revealed an acute occlusive thrombus in the axillary vein. We started the patient on intravenous heparin. A venogram confirmed thrombosis of the axillary-subclavian vein (FIGURE 1A). Based on the patient’s clinical presentation and the results of the venogram, we diagnosed Paget-Schroetter syndrome. The venogram was followed by thrombolysis with alteplase (FIGURE 1B) and a balloon angioplasty (FIGURE 1C). One week later, a repeat venogram demonstrated partial removal of the thrombus and an area of compression on the inferior aspect of the subclavian vein due to a cervical band (FIGURE 1D).

DISCUSSION

Paget-Schroetter syndrome (PSS), or effort thrombosis of the upper extremities, is defined as spontaneous thrombus in the axillary and subclavian veins that occurs as a consequence of strenuous upper-extremity activity. It is a rare condition with an incidence of one to 2 cases per 100,000 people per year, and represents 1% to 4% of all cases of deep vein thrombosis (DVT).¹

Spontaneous thrombosis of the upper extremities typically presents in young, otherwise healthy individuals. It has been described in athletes who are involved in ball games, games with rackets or clubs, aquatic sports, combatant sports, and in violin players.² The repetitive movements used in these activities can lead to compression of the axillary and subclavian veins by hypertrophied muscles. Repetitive trauma causes intimal damage and thrombogenesis.³

PSS is characterized by the abrupt, spontaneous swelling of the entire arm, cyanosis, and pain that occurs with use or overhead positioning. Enlarged subcutaneous veins are present in the upper arm, around the shoulder, or in the upper anterior chest wall (Urschel’s sign). The classic presentation is acute onset of upper extremity pain and swelling in the dominant arm following a particularly strenuous activity.⁴ A low-grade fever, superficial thrombophlebitis, or neurologic symptoms may coexist. Certain provocative maneuvers can help reproduce the symptoms (TABLE 1^5,6). Complications of PSS include pulmonary embolism, postthrombotic syndrome (pain, heaviness, and swelling), and recurrent thrombosis.⁷

Contrast venography best shows the extent of thrombosis

Duplex ultrasound, with its high sensitivity and specificity, is the initial, noninvasive test of choice (TABLE 2^4,8-11). However, duplex ultrasound has a false-negative rate of 30% because it is highly technician-dependent and can be complicated by acoustic shadows from the clavicle or sternum.⁸

The most direct and definitive means to confirm the diagnosis of PSS is catheter-directed contrast venography.⁹ This method provides complete anatomic information regarding the site and extent of thrombosis, allows definitive evaluation of the collateral venous pathways, and is a necessary step toward the use of thrombolytic therapy. Contrast load, however, contraindicates the procedure in patients with renal failure and in those who are pregnant.

Contrast-enhanced computed tomography (CT) and magnetic resonance angiography (MRA) are also highly sensitive for detecting focal stenosis at the level of the first rib, the presence or absence of enlarged collateral veins, and the chronicity of any thrombus present. However, the usefulness of CT and magnetic resonance venography in initial screening is unclear, due to a lack of randomized controlled trials.

Treatment involves anticoagulants, thrombolytics, and possibly surgery

Prompt use of anticoagulation is indicated in PSS. Initial anticoagulation with low molecular weight unfractionated heparin or a direct thrombin inhibitor followed by warfarin for a minimum of 3 to 6 months is recommended.¹²

Patients treated with anticoagulation alone have a higher incidence of long-term residual symptoms, disability, and recurrent thrombosis.⁷ As a result, a more aggressive approach with the use of thrombolytic therapy is indicated, especially in young, active patients, to minimize long-term consequences. Alteplase or reteplase are used for this purpose. Thrombolysis is less likely to be beneficial if the thrombus is more than 2 weeks old or if there are inflammatory changes in the vein. The use of catheter-directed thrombolysis minimizes the risk of systemic adverse effects and achieves higher clot resolution rates.¹³

Because PSS is caused by compression of the vein, rather than a disorder of blood clotting, there is still a 50% to 70% risk of recurrent thrombosis despite thrombolysis and anticoagulation.¹⁴ Therefore, the most definitive management approach remains surgical treatment. Patients with recent thrombosis who are within the first several weeks of undergoing successful thrombolytic therapy are excellent candidates for surgery. Operative treatment for PSS includes first rib resection, scalene muscle removal, or subclavius muscle removal, along with removal of constricting scar tissue from around the vein.⁷

THE TAKEAWAY

PSS is characterized by upper-extremity DVT resulting from repetitive trauma to the subclavian-axillary vein. Early diagnosis of PSS with contrast venography and prompt use of anticoagulation can effectively restore venous patency, reduce the risk of rethrombosis, and return the patient to normal function. Primary care physicians should be aware of this condition, because delayed recognition in a high-functioning person can be potentially disabling.

Our patient had a first rib resection, partial division of the scalenus anterior and medius muscles, and lysis of the cervical band. Follow-up venography confirmed resolution of thrombosis without any complications. The patient was continued on anticoagulation with warfarin for 3 months.

Shorter hospital stay with oral replacement therapy

A 2006 systematic review compared ORT and IVF in 1811 children 0 to 18 years of age with viral gastroenteritis who were treated for failure to rehydrate in both outpatient and inpatient settings (18 randomized controlled trials [RCTs] of poor to moderate quality).¹ The primary outcome was “continued failure to rehydrate,” which varied by study and included persistent vomiting, persistent dehydration, shock, or seizures.

Overall, the risk of failure to rehydrate was 4.9% for ORT and 1.3% for IVF (risk difference [RD]=4%; 95% confidence interval [CI], 1%-7%; number needed to treat [NNT]=25). The length of stay (24-hour observation unit or inpatient hospitalization) was shorter for ORT than IVF (6 studies, 526 patients; weighted mean difference (WMD)= −1.2 days; 95% CI, −2.38 to −0.02). Investigators found no difference in weight gain, hyponatremia, hypernatremia, duration of diarrhea, or total fluid intake at 24 hours.

ORT can be started more quickly than IVF

An RCT conducted in an urban emergency department evaluated ORT and IVF for 4 hours in 72 children ages 8 weeks to 3 years with moderate dehydration from viral gastroenteritis.² This trial was included in the previously described review but evaluated additional outcomes: time required to initiate either ORT or IVF, improvement in symptoms at 2 hours, hospitalization rate, and preference for ORT in the future.

The authors also used a 10-point dehydration scoring system that included: decreased skin elasticity, capillary refill >2 seconds, general appearance, absence of tears, abnormal respirations, dry mucous membranes, sunken eyes, abnormal radial pulse, tachycardia >150 beats per minute, and decreased urine output. Details on the type of ORT or IVF were not reported.

ORT was initiated faster than IVF (mean difference [MD]=21 minutes; 95% CI, 10-32 minutes). No difference in improvement in dehydration scores was observed at 2 hours (ORT 78% vs IVF 80%; MD=1.2%; 95% CI, −20.5% to 18%). Nor was the hospitalization rate significantly different (IVF 48.7% and ORT 30.6%; MD=−18.1%; 95% CI, −40.1% to 4.1%). Most patients preferred to have the same therapy, whether ORT or IVF, with the next episode of gastroenteritis (61.3% vs 51.4%; MD=9.9%; 95% CI, −14 to 34).

Shorter hospital stay with oral replacement therapy

A 2006 systematic review compared ORT and IVF in 1811 children 0 to 18 years of age with viral gastroenteritis who were treated for failure to rehydrate in both outpatient and inpatient settings (18 randomized controlled trials [RCTs] of poor to moderate quality).¹ The primary outcome was “continued failure to rehydrate,” which varied by study and included persistent vomiting, persistent dehydration, shock, or seizures.

Overall, the risk of failure to rehydrate was 4.9% for ORT and 1.3% for IVF (risk difference [RD]=4%; 95% confidence interval [CI], 1%-7%; number needed to treat [NNT]=25). The length of stay (24-hour observation unit or inpatient hospitalization) was shorter for ORT than IVF (6 studies, 526 patients; weighted mean difference (WMD)= −1.2 days; 95% CI, −2.38 to −0.02). Investigators found no difference in weight gain, hyponatremia, hypernatremia, duration of diarrhea, or total fluid intake at 24 hours.

ORT can be started more quickly than IVF

An RCT conducted in an urban emergency department evaluated ORT and IVF for 4 hours in 72 children ages 8 weeks to 3 years with moderate dehydration from viral gastroenteritis.² This trial was included in the previously described review but evaluated additional outcomes: time required to initiate either ORT or IVF, improvement in symptoms at 2 hours, hospitalization rate, and preference for ORT in the future.

The authors also used a 10-point dehydration scoring system that included: decreased skin elasticity, capillary refill >2 seconds, general appearance, absence of tears, abnormal respirations, dry mucous membranes, sunken eyes, abnormal radial pulse, tachycardia >150 beats per minute, and decreased urine output. Details on the type of ORT or IVF were not reported.

ORT was initiated faster than IVF (mean difference [MD]=21 minutes; 95% CI, 10-32 minutes). No difference in improvement in dehydration scores was observed at 2 hours (ORT 78% vs IVF 80%; MD=1.2%; 95% CI, −20.5% to 18%). Nor was the hospitalization rate significantly different (IVF 48.7% and ORT 30.6%; MD=−18.1%; 95% CI, −40.1% to 4.1%). Most patients preferred to have the same therapy, whether ORT or IVF, with the next episode of gastroenteritis (61.3% vs 51.4%; MD=9.9%; 95% CI, −14 to 34).

Shorter hospital stay with oral replacement therapy

A 2006 systematic review compared ORT and IVF in 1811 children 0 to 18 years of age with viral gastroenteritis who were treated for failure to rehydrate in both outpatient and inpatient settings (18 randomized controlled trials [RCTs] of poor to moderate quality).¹ The primary outcome was “continued failure to rehydrate,” which varied by study and included persistent vomiting, persistent dehydration, shock, or seizures.

Overall, the risk of failure to rehydrate was 4.9% for ORT and 1.3% for IVF (risk difference [RD]=4%; 95% confidence interval [CI], 1%-7%; number needed to treat [NNT]=25). The length of stay (24-hour observation unit or inpatient hospitalization) was shorter for ORT than IVF (6 studies, 526 patients; weighted mean difference (WMD)= −1.2 days; 95% CI, −2.38 to −0.02). Investigators found no difference in weight gain, hyponatremia, hypernatremia, duration of diarrhea, or total fluid intake at 24 hours.

ORT can be started more quickly than IVF

An RCT conducted in an urban emergency department evaluated ORT and IVF for 4 hours in 72 children ages 8 weeks to 3 years with moderate dehydration from viral gastroenteritis.² This trial was included in the previously described review but evaluated additional outcomes: time required to initiate either ORT or IVF, improvement in symptoms at 2 hours, hospitalization rate, and preference for ORT in the future.

The authors also used a 10-point dehydration scoring system that included: decreased skin elasticity, capillary refill >2 seconds, general appearance, absence of tears, abnormal respirations, dry mucous membranes, sunken eyes, abnormal radial pulse, tachycardia >150 beats per minute, and decreased urine output. Details on the type of ORT or IVF were not reported.

ORT was initiated faster than IVF (mean difference [MD]=21 minutes; 95% CI, 10-32 minutes). No difference in improvement in dehydration scores was observed at 2 hours (ORT 78% vs IVF 80%; MD=1.2%; 95% CI, −20.5% to 18%). Nor was the hospitalization rate significantly different (IVF 48.7% and ORT 30.6%; MD=−18.1%; 95% CI, −40.1% to 4.1%). Most patients preferred to have the same therapy, whether ORT or IVF, with the next episode of gastroenteritis (61.3% vs 51.4%; MD=9.9%; 95% CI, −14 to 34).

The lack of available treatments that adequately treat Parkinson’s disease psychosis proved to be a big motivating factor for a majority of members of the Food and Drug Administration’s Psychopharmacologic Drugs Advisory Committee, who voted at a meeting March 29 that the benefits of the novel drug pimavanserin outweigh its risks.

The panel voted 12-2 in support of the benefit-to-risk ratio for pimavanserin, a selective 5-hydroxytryptamine_2A (5-HT_2A) inverse agonist that does not affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems, according to its developer, Acadia Pharmaceuticals.

Although Acadia submitted just one positive phase III trial out of a total of four 6-week, randomized, placebo-controlled trials of pimavanserin, committee members voted 12-2 that the company “provided substantial evidence of the effectiveness” of the drug for the treatment of psychosis associated with Parkinsons’s disease (PDP). Another 11-3 vote supported the question of whether pimavanersin’s safety profile was “adequately characterized.”

Results from the single phase III trial conducted in 199 patients with Parkinsons’s disease psychosis (PDP) unequivocally showed that 34 mg/day pimavanserin improved scores on an abbreviated, 9-item version of the 20-item Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions score, called the SAPS-PD. After 6 weeks, SAPS-PD scores declined by a statistically significant 3.1 points or 23.1% on active treatment versus placebo, which was an absolute decrease of about 6 points from baseline. One of the questions brought up by FDA reviewers and panelists was whether the 3.1-point difference (on the SAPS-PD’s 45-point scale) seen between active treatment and placebo was of great enough clinical benefit to outweigh the higher rate of serious adverse events observed with pimavanserin versus placebo across all of the 6-week trials.

Across all four 6-week studies, serious adverse events occurred in 16 (7.9%) of 202 patients who took 34 mg pimavanserin and in 8 (3.5%) of 231 placebo-treated patients. Three deaths occurred in the patients who received pimavanserin, and one in the placebo arms. However, none of the deaths were considered to be a drug-related event, and the deaths were not pathologically unique relative to what is expected in the disease course of patients with PDP. The death of another patient who had received 10 mg pimavanserin in an earlier uncontrolled trial also was reported.

Meanwhile, the drug did not worsen motor symptoms of Parkinson’s disease.

FDA analyses showed that 11 patients would need to be treated in order for 1 patient to have a 50% reduction in the SAPS-PD, which corresponds to “much improvement,” whereas 22 patients would need to be treated for 1 to be harmed with a serious adverse event (SAE). This means that for every two patients who have a 50% reduction in the SAPS-PD, one will have a serious adverse event attributable to pimavanserin. Overall, 37.2% of patients in the pimavanserin arm of the phase III trial had a 50% decline in the SAPS-PD after 6 weeks, compared with 27.8% in the placebo arm.

However, the number needed to harm/number needed to treat ratio for SAEs had wide confidence intervals, and there was a high degree of uncertainty about its magnitude such that the inclusion of just one or two more SAEs would substantially change the ratio, many panelists agreed.

Some panelists voiced concern about pimavanserin being called an antipsychotic, even though it has demonstrated no proof of efficacy in conditions with classical symptoms of psychosis, such as schizophrenia, and worried about its off-label use in patients with other conditions who have psychotic symptoms. They also called for a postmarketing observational study to track the safety of the drug if it is approved.

Pimavanserin’s application received breakthrough drug status from the FDA and was fast tracked, and a decision is expected from the agency by May 1. If approved, pimavanserin would be marketed under the trade name Nuplazid.

[email protected]

The lack of available treatments that adequately treat Parkinson’s disease psychosis proved to be a big motivating factor for a majority of members of the Food and Drug Administration’s Psychopharmacologic Drugs Advisory Committee, who voted at a meeting March 29 that the benefits of the novel drug pimavanserin outweigh its risks.

The panel voted 12-2 in support of the benefit-to-risk ratio for pimavanserin, a selective 5-hydroxytryptamine_2A (5-HT_2A) inverse agonist that does not affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems, according to its developer, Acadia Pharmaceuticals.

Although Acadia submitted just one positive phase III trial out of a total of four 6-week, randomized, placebo-controlled trials of pimavanserin, committee members voted 12-2 that the company “provided substantial evidence of the effectiveness” of the drug for the treatment of psychosis associated with Parkinsons’s disease (PDP). Another 11-3 vote supported the question of whether pimavanersin’s safety profile was “adequately characterized.”

Results from the single phase III trial conducted in 199 patients with Parkinsons’s disease psychosis (PDP) unequivocally showed that 34 mg/day pimavanserin improved scores on an abbreviated, 9-item version of the 20-item Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions score, called the SAPS-PD. After 6 weeks, SAPS-PD scores declined by a statistically significant 3.1 points or 23.1% on active treatment versus placebo, which was an absolute decrease of about 6 points from baseline. One of the questions brought up by FDA reviewers and panelists was whether the 3.1-point difference (on the SAPS-PD’s 45-point scale) seen between active treatment and placebo was of great enough clinical benefit to outweigh the higher rate of serious adverse events observed with pimavanserin versus placebo across all of the 6-week trials.

Across all four 6-week studies, serious adverse events occurred in 16 (7.9%) of 202 patients who took 34 mg pimavanserin and in 8 (3.5%) of 231 placebo-treated patients. Three deaths occurred in the patients who received pimavanserin, and one in the placebo arms. However, none of the deaths were considered to be a drug-related event, and the deaths were not pathologically unique relative to what is expected in the disease course of patients with PDP. The death of another patient who had received 10 mg pimavanserin in an earlier uncontrolled trial also was reported.

Meanwhile, the drug did not worsen motor symptoms of Parkinson’s disease.

FDA analyses showed that 11 patients would need to be treated in order for 1 patient to have a 50% reduction in the SAPS-PD, which corresponds to “much improvement,” whereas 22 patients would need to be treated for 1 to be harmed with a serious adverse event (SAE). This means that for every two patients who have a 50% reduction in the SAPS-PD, one will have a serious adverse event attributable to pimavanserin. Overall, 37.2% of patients in the pimavanserin arm of the phase III trial had a 50% decline in the SAPS-PD after 6 weeks, compared with 27.8% in the placebo arm.

However, the number needed to harm/number needed to treat ratio for SAEs had wide confidence intervals, and there was a high degree of uncertainty about its magnitude such that the inclusion of just one or two more SAEs would substantially change the ratio, many panelists agreed.

Some panelists voiced concern about pimavanserin being called an antipsychotic, even though it has demonstrated no proof of efficacy in conditions with classical symptoms of psychosis, such as schizophrenia, and worried about its off-label use in patients with other conditions who have psychotic symptoms. They also called for a postmarketing observational study to track the safety of the drug if it is approved.

Pimavanserin’s application received breakthrough drug status from the FDA and was fast tracked, and a decision is expected from the agency by May 1. If approved, pimavanserin would be marketed under the trade name Nuplazid.

[email protected]

The lack of available treatments that adequately treat Parkinson’s disease psychosis proved to be a big motivating factor for a majority of members of the Food and Drug Administration’s Psychopharmacologic Drugs Advisory Committee, who voted at a meeting March 29 that the benefits of the novel drug pimavanserin outweigh its risks.

The panel voted 12-2 in support of the benefit-to-risk ratio for pimavanserin, a selective 5-hydroxytryptamine_2A (5-HT_2A) inverse agonist that does not affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems, according to its developer, Acadia Pharmaceuticals.

Although Acadia submitted just one positive phase III trial out of a total of four 6-week, randomized, placebo-controlled trials of pimavanserin, committee members voted 12-2 that the company “provided substantial evidence of the effectiveness” of the drug for the treatment of psychosis associated with Parkinsons’s disease (PDP). Another 11-3 vote supported the question of whether pimavanersin’s safety profile was “adequately characterized.”

Results from the single phase III trial conducted in 199 patients with Parkinsons’s disease psychosis (PDP) unequivocally showed that 34 mg/day pimavanserin improved scores on an abbreviated, 9-item version of the 20-item Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions score, called the SAPS-PD. After 6 weeks, SAPS-PD scores declined by a statistically significant 3.1 points or 23.1% on active treatment versus placebo, which was an absolute decrease of about 6 points from baseline. One of the questions brought up by FDA reviewers and panelists was whether the 3.1-point difference (on the SAPS-PD’s 45-point scale) seen between active treatment and placebo was of great enough clinical benefit to outweigh the higher rate of serious adverse events observed with pimavanserin versus placebo across all of the 6-week trials.

Across all four 6-week studies, serious adverse events occurred in 16 (7.9%) of 202 patients who took 34 mg pimavanserin and in 8 (3.5%) of 231 placebo-treated patients. Three deaths occurred in the patients who received pimavanserin, and one in the placebo arms. However, none of the deaths were considered to be a drug-related event, and the deaths were not pathologically unique relative to what is expected in the disease course of patients with PDP. The death of another patient who had received 10 mg pimavanserin in an earlier uncontrolled trial also was reported.

Meanwhile, the drug did not worsen motor symptoms of Parkinson’s disease.

FDA analyses showed that 11 patients would need to be treated in order for 1 patient to have a 50% reduction in the SAPS-PD, which corresponds to “much improvement,” whereas 22 patients would need to be treated for 1 to be harmed with a serious adverse event (SAE). This means that for every two patients who have a 50% reduction in the SAPS-PD, one will have a serious adverse event attributable to pimavanserin. Overall, 37.2% of patients in the pimavanserin arm of the phase III trial had a 50% decline in the SAPS-PD after 6 weeks, compared with 27.8% in the placebo arm.

However, the number needed to harm/number needed to treat ratio for SAEs had wide confidence intervals, and there was a high degree of uncertainty about its magnitude such that the inclusion of just one or two more SAEs would substantially change the ratio, many panelists agreed.

Some panelists voiced concern about pimavanserin being called an antipsychotic, even though it has demonstrated no proof of efficacy in conditions with classical symptoms of psychosis, such as schizophrenia, and worried about its off-label use in patients with other conditions who have psychotic symptoms. They also called for a postmarketing observational study to track the safety of the drug if it is approved.

Pimavanserin’s application received breakthrough drug status from the FDA and was fast tracked, and a decision is expected from the agency by May 1. If approved, pimavanserin would be marketed under the trade name Nuplazid.

[email protected]

The lack of available treatments that adequately treat Parkinson’s disease psychosis proved to be a big motivating factor for a majority of members of the Food and Drug Administration’s Psychopharmacologic Drugs Advisory Committee, who voted at a meeting March 29 that the benefits of the novel drug pimavanserin outweigh its risks.

The panel voted 12-2 in support of the benefit-to-risk ratio for pimavanserin, a selective 5-hydroxytryptamine_2A (5-HT_2A) inverse agonist that does not affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems, according to its developer, Acadia Pharmaceuticals.

Although Acadia submitted just one positive phase III trial out of a total of four 6-week, randomized, placebo-controlled trials of pimavanserin, committee members voted 12-2 that the company “provided substantial evidence of the effectiveness” of the drug for the treatment of psychosis associated with Parkinsons’s disease (PDP). Another 11-3 vote supported the question of whether pimavanersin’s safety profile was “adequately characterized.”

Results from the single phase III trial conducted in 199 patients with Parkinsons’s disease psychosis (PDP) unequivocally showed that 34 mg/day pimavanserin improved scores on an abbreviated, 9-item version of the 20-item Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions score, called the SAPS-PD. After 6 weeks, SAPS-PD scores declined by a statistically significant 3.1 points or 23.1% on active treatment versus placebo, which was an absolute decrease of about 6 points from baseline. One of the questions brought up by FDA reviewers and panelists was whether the 3.1-point difference (on the SAPS-PD’s 45-point scale) seen between active treatment and placebo was of great enough clinical benefit to outweigh the higher rate of serious adverse events observed with pimavanserin versus placebo across all of the 6-week trials.

Across all four 6-week studies, serious adverse events occurred in 16 (7.9%) of 202 patients who took 34 mg pimavanserin and in 8 (3.5%) of 231 placebo-treated patients. Three deaths occurred in the patients who received pimavanserin, and one in the placebo arms. However, none of the deaths were considered to be a drug-related event, and the deaths were not pathologically unique relative to what is expected in the disease course of patients with PDP. The death of another patient who had received 10 mg pimavanserin in an earlier uncontrolled trial also was reported.

Meanwhile, the drug did not worsen motor symptoms of Parkinson’s disease.

FDA analyses showed that 11 patients would need to be treated in order for 1 patient to have a 50% reduction in the SAPS-PD, which corresponds to “much improvement,” whereas 22 patients would need to be treated for 1 to be harmed with a serious adverse event (SAE). This means that for every two patients who have a 50% reduction in the SAPS-PD, one will have a serious adverse event attributable to pimavanserin. Overall, 37.2% of patients in the pimavanserin arm of the phase III trial had a 50% decline in the SAPS-PD after 6 weeks, compared with 27.8% in the placebo arm.

However, the number needed to harm/number needed to treat ratio for SAEs had wide confidence intervals, and there was a high degree of uncertainty about its magnitude such that the inclusion of just one or two more SAEs would substantially change the ratio, many panelists agreed.

Some panelists voiced concern about pimavanserin being called an antipsychotic, even though it has demonstrated no proof of efficacy in conditions with classical symptoms of psychosis, such as schizophrenia, and worried about its off-label use in patients with other conditions who have psychotic symptoms. They also called for a postmarketing observational study to track the safety of the drug if it is approved.

Pimavanserin’s application received breakthrough drug status from the FDA and was fast tracked, and a decision is expected from the agency by May 1. If approved, pimavanserin would be marketed under the trade name Nuplazid.

[email protected]

The lack of available treatments that adequately treat Parkinson’s disease psychosis proved to be a big motivating factor for a majority of members of the Food and Drug Administration’s Psychopharmacologic Drugs Advisory Committee, who voted at a meeting March 29 that the benefits of the novel drug pimavanserin outweigh its risks.

The panel voted 12-2 in support of the benefit-to-risk ratio for pimavanserin, a selective 5-hydroxytryptamine_2A (5-HT_2A) inverse agonist that does not affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems, according to its developer, Acadia Pharmaceuticals.

Although Acadia submitted just one positive phase III trial out of a total of four 6-week, randomized, placebo-controlled trials of pimavanserin, committee members voted 12-2 that the company “provided substantial evidence of the effectiveness” of the drug for the treatment of psychosis associated with Parkinsons’s disease (PDP). Another 11-3 vote supported the question of whether pimavanersin’s safety profile was “adequately characterized.”

Results from the single phase III trial conducted in 199 patients with Parkinsons’s disease psychosis (PDP) unequivocally showed that 34 mg/day pimavanserin improved scores on an abbreviated, 9-item version of the 20-item Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions score, called the SAPS-PD. After 6 weeks, SAPS-PD scores declined by a statistically significant 3.1 points or 23.1% on active treatment versus placebo, which was an absolute decrease of about 6 points from baseline. One of the questions brought up by FDA reviewers and panelists was whether the 3.1-point difference (on the SAPS-PD’s 45-point scale) seen between active treatment and placebo was of great enough clinical benefit to outweigh the higher rate of serious adverse events observed with pimavanserin versus placebo across all of the 6-week trials.

Across all four 6-week studies, serious adverse events occurred in 16 (7.9%) of 202 patients who took 34 mg pimavanserin and in 8 (3.5%) of 231 placebo-treated patients. Three deaths occurred in the patients who received pimavanserin, and one in the placebo arms. However, none of the deaths were considered to be a drug-related event, and the deaths were not pathologically unique relative to what is expected in the disease course of patients with PDP. The death of another patient who had received 10 mg pimavanserin in an earlier uncontrolled trial also was reported.

Meanwhile, the drug did not worsen motor symptoms of Parkinson’s disease.

FDA analyses showed that 11 patients would need to be treated in order for 1 patient to have a 50% reduction in the SAPS-PD, which corresponds to “much improvement,” whereas 22 patients would need to be treated for 1 to be harmed with a serious adverse event (SAE). This means that for every two patients who have a 50% reduction in the SAPS-PD, one will have a serious adverse event attributable to pimavanserin. Overall, 37.2% of patients in the pimavanserin arm of the phase III trial had a 50% decline in the SAPS-PD after 6 weeks, compared with 27.8% in the placebo arm.

However, the number needed to harm/number needed to treat ratio for SAEs had wide confidence intervals, and there was a high degree of uncertainty about its magnitude such that the inclusion of just one or two more SAEs would substantially change the ratio, many panelists agreed.

Some panelists voiced concern about pimavanserin being called an antipsychotic, even though it has demonstrated no proof of efficacy in conditions with classical symptoms of psychosis, such as schizophrenia, and worried about its off-label use in patients with other conditions who have psychotic symptoms. They also called for a postmarketing observational study to track the safety of the drug if it is approved.

Pimavanserin’s application received breakthrough drug status from the FDA and was fast tracked, and a decision is expected from the agency by May 1. If approved, pimavanserin would be marketed under the trade name Nuplazid.

[email protected]

The lack of available treatments that adequately treat Parkinson’s disease psychosis proved to be a big motivating factor for a majority of members of the Food and Drug Administration’s Psychopharmacologic Drugs Advisory Committee, who voted at a meeting March 29 that the benefits of the novel drug pimavanserin outweigh its risks.

The panel voted 12-2 in support of the benefit-to-risk ratio for pimavanserin, a selective 5-hydroxytryptamine_2A (5-HT_2A) inverse agonist that does not affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems, according to its developer, Acadia Pharmaceuticals.

Although Acadia submitted just one positive phase III trial out of a total of four 6-week, randomized, placebo-controlled trials of pimavanserin, committee members voted 12-2 that the company “provided substantial evidence of the effectiveness” of the drug for the treatment of psychosis associated with Parkinsons’s disease (PDP). Another 11-3 vote supported the question of whether pimavanersin’s safety profile was “adequately characterized.”

Results from the single phase III trial conducted in 199 patients with Parkinsons’s disease psychosis (PDP) unequivocally showed that 34 mg/day pimavanserin improved scores on an abbreviated, 9-item version of the 20-item Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions score, called the SAPS-PD. After 6 weeks, SAPS-PD scores declined by a statistically significant 3.1 points or 23.1% on active treatment versus placebo, which was an absolute decrease of about 6 points from baseline. One of the questions brought up by FDA reviewers and panelists was whether the 3.1-point difference (on the SAPS-PD’s 45-point scale) seen between active treatment and placebo was of great enough clinical benefit to outweigh the higher rate of serious adverse events observed with pimavanserin versus placebo across all of the 6-week trials.

Across all four 6-week studies, serious adverse events occurred in 16 (7.9%) of 202 patients who took 34 mg pimavanserin and in 8 (3.5%) of 231 placebo-treated patients. Three deaths occurred in the patients who received pimavanserin, and one in the placebo arms. However, none of the deaths were considered to be a drug-related event, and the deaths were not pathologically unique relative to what is expected in the disease course of patients with PDP. The death of another patient who had received 10 mg pimavanserin in an earlier uncontrolled trial also was reported.

Meanwhile, the drug did not worsen motor symptoms of Parkinson’s disease.

FDA analyses showed that 11 patients would need to be treated in order for 1 patient to have a 50% reduction in the SAPS-PD, which corresponds to “much improvement,” whereas 22 patients would need to be treated for 1 to be harmed with a serious adverse event (SAE). This means that for every two patients who have a 50% reduction in the SAPS-PD, one will have a serious adverse event attributable to pimavanserin. Overall, 37.2% of patients in the pimavanserin arm of the phase III trial had a 50% decline in the SAPS-PD after 6 weeks, compared with 27.8% in the placebo arm.

However, the number needed to harm/number needed to treat ratio for SAEs had wide confidence intervals, and there was a high degree of uncertainty about its magnitude such that the inclusion of just one or two more SAEs would substantially change the ratio, many panelists agreed.

Some panelists voiced concern about pimavanserin being called an antipsychotic, even though it has demonstrated no proof of efficacy in conditions with classical symptoms of psychosis, such as schizophrenia, and worried about its off-label use in patients with other conditions who have psychotic symptoms. They also called for a postmarketing observational study to track the safety of the drug if it is approved.

Pimavanserin’s application received breakthrough drug status from the FDA and was fast tracked, and a decision is expected from the agency by May 1. If approved, pimavanserin would be marketed under the trade name Nuplazid.

[email protected]

Less than a week after hearing oral arguments, Supreme Court justices have ordered both sides to provide new briefs in a religious freedom case that centers on the federal government’s contraception mandate.

In an unexpected move, the justices on March 29 directed attorneys to file supplemental briefs that propose alternatives to the government’s current accommodation under the mandate. The high court wants to know whether, and how, contraceptive coverage could be obtained by employees of religious nonprofits through the plaintiffs’ health plans in a way that does not require employer involvement.

Gregory Twachtman/ Frontline Medical Media

The request is likely an attempt to avoid a 4-4 ruling in Zubik v. Burwell, while finding a way to spare religious nonprofits from participating in the process of providing birth control coverage, according to analysts.

“The court here is clearly looking to craft a win-win situation; a compromise where no one has to lose,” said Mark Goldfeder, a law professor at Emory University in Atlanta and director of the school’s law and religion student program. “The court is asking for the parties to help craft a process by which the affected employees can get their contraception easily covered, in a way that does not violate their employer’s religious beliefs.”

During oral arguments on March 23, the justices focused much attention on the process of the accommodation and how the arrangement unfolds between employers and the government, said Laurie Sobel, a senior policy analyst for the Henry J. Kaiser Family Foundation who attended the oral arguments.

“The fundamental issue in this case comes down to how the accommodation works,” Ms. Sobel said in an interview. “The petitioners believe the notification is the permission slip that triggers the coverage from the insurance companies. The government’s position is, ‘No, that’s just a notification, and the requirement to provide the coverage comes from the law.’ That came up a lot during arguments.”

The Supreme Court’s more conservative justices, including Justice Samuel A. Alito Jr. and Chief Justice John G. Roberts, were skeptical that the accommodation is the least restrictive means of advancing a compelling interest. The court’s four more liberal justices – particularly the three women on the court – appeared to support the accommodation, said Marci A. Hamilton, a law professor at Yeshiva University, New York, who also attended oral arguments.

Ms. Hamilton wrote a friend-of-the-court brief on behalf of Rep. Bobby Scott (D-Va.) in support of the government.

“[Plaintiffs’ attorney] Paul Clement was very quickly attacked by all three female Supreme Court justices,” Ms. Hamilton said in an interview. “It was really interesting that the female justices clearly took this to heart. They fundamentally identified with the contraceptive issue, and they really dominated the first part of the argument.”

Justice Ruth Bader Ginsburg countered the assertion that under the accommodation, notification by employers is treated by the government as an authorization for contraceptive coverage.

“It’s not an authorization,” Justice Ginsburg said during arguments. “The government, the law,­ the regulation requires it, but it doesn’t matter whether you say, yes or no. And you could say, ‘I fill out the form. I do not authorize. I do not permit.’ It won’t make any difference.”

The ACA’s accommodation clause refers to an exception for organizations that oppose coverage for contraceptives but are not exempted entities, such as churches. The plaintiffs – part of seven consolidated cases that include a Catholic bishop and an order of nuns – argue that the opt-out process put in place by the government makes them complicit in offering contraception coverage indirectly. Forcing them to cooperate with the accommodation violates their rights under the federal Religious Freedom Restoration Act, according to the plaintiffs.

The government contends that the exception does not impose a burden on the groups and that courts should not disregard the interest of employees who may not share their employers’ religious beliefs. The 8th U.S. Circuit Court of Appeals struck down the exception twice, ruling that forcing organizations to offer contraceptive coverage – even indirectly – violates their religious rights. The 8th Circuit’s decisions are at odds with rulings by the 2nd and 5th Circuit courts.

Chief Justice Roberts indicated agreement that the government is attempting to take control of the plaintiff’s health plans and provide coverage against the will of the nonprofit employers, said Mr. Goldfeder.

During arguments, Justice Roberts also made it clear that religious liberty versus reproductive rights is not at the center of the case, noted Mr. Goldfeder, who co-wrote a friend-of-the-court brief for the American Center for Law and Justice in support of the employers. Specifically, Justice Roberts stressed that the case is rooted in the employer’s objection to the government’s mechanism, not to employees receiving contraceptive care.

“The way this case has often been portrayed in the media, it has been about a clash between religious liberty and reproductive rights,” Mr. Goldfeder said in an interview. “As became clear in the arguments today, that is a false dichotomy, and a false narrative.”

Foreshadowing their latest move, justices and attorneys spent ample time arguing over whether an alternative paperwork process could satisfy both parties. Justice Alito asked whether it was possible that patients who do not get contraceptive coverage from their religious nonprofit employer could obtain a free contraceptive-­only policy through the ACA insurance exchanges.

Solicitor General Donald B. Verrilli, Jr. dismissed that proposal.

“It’s not a less restrictive alternative because it has precisely the problem Congress was trying to overcome in the preventive services provision,” he said. “That [proposal] is not equally effective at achieving the government’s interest, because the whole point of this provision is that you get this care from your regular doctor as part of your regular health care without any barriers, including any co­pay barriers.”

The justices have several options in deciding the case, including choosing to rehear arguments at a later date. The Feb. 13 death of Justice Antonin Scalia could also mean a 4-4 split decision. If such a division occurs, the lower court rulings would stand.

“The impact will be that women employed by nonprofits in the 8th Circuit will be denied contraception coverage, but that women in all the other circuits will receive the coverage,” Ms. Hamilton said. “And we’ll be back to not having an answer from the Supreme Court. So all of the machinery that went into play for consideration of this case ... all of the entities that worked on it, will have to repeat itself. It will turn the whole exercise into something of a joke.”

In the two-page order issued March 29, the justices encouraged both parties to suggest ways in which the plaintiffs would have no legal obligation to provide contraceptive coverage, would not have to pay for such coverage, and would not be required to submit any separate notice to insurers, the government, or employees. New briefs are due by April 20.

[email protected]

On Twitter @legal_med

Less than a week after hearing oral arguments, Supreme Court justices have ordered both sides to provide new briefs in a religious freedom case that centers on the federal government’s contraception mandate.

In an unexpected move, the justices on March 29 directed attorneys to file supplemental briefs that propose alternatives to the government’s current accommodation under the mandate. The high court wants to know whether, and how, contraceptive coverage could be obtained by employees of religious nonprofits through the plaintiffs’ health plans in a way that does not require employer involvement.

Gregory Twachtman/ Frontline Medical Media

The request is likely an attempt to avoid a 4-4 ruling in Zubik v. Burwell, while finding a way to spare religious nonprofits from participating in the process of providing birth control coverage, according to analysts.

“The court here is clearly looking to craft a win-win situation; a compromise where no one has to lose,” said Mark Goldfeder, a law professor at Emory University in Atlanta and director of the school’s law and religion student program. “The court is asking for the parties to help craft a process by which the affected employees can get their contraception easily covered, in a way that does not violate their employer’s religious beliefs.”

During oral arguments on March 23, the justices focused much attention on the process of the accommodation and how the arrangement unfolds between employers and the government, said Laurie Sobel, a senior policy analyst for the Henry J. Kaiser Family Foundation who attended the oral arguments.

“The fundamental issue in this case comes down to how the accommodation works,” Ms. Sobel said in an interview. “The petitioners believe the notification is the permission slip that triggers the coverage from the insurance companies. The government’s position is, ‘No, that’s just a notification, and the requirement to provide the coverage comes from the law.’ That came up a lot during arguments.”

The Supreme Court’s more conservative justices, including Justice Samuel A. Alito Jr. and Chief Justice John G. Roberts, were skeptical that the accommodation is the least restrictive means of advancing a compelling interest. The court’s four more liberal justices – particularly the three women on the court – appeared to support the accommodation, said Marci A. Hamilton, a law professor at Yeshiva University, New York, who also attended oral arguments.

Ms. Hamilton wrote a friend-of-the-court brief on behalf of Rep. Bobby Scott (D-Va.) in support of the government.

“[Plaintiffs’ attorney] Paul Clement was very quickly attacked by all three female Supreme Court justices,” Ms. Hamilton said in an interview. “It was really interesting that the female justices clearly took this to heart. They fundamentally identified with the contraceptive issue, and they really dominated the first part of the argument.”

Justice Ruth Bader Ginsburg countered the assertion that under the accommodation, notification by employers is treated by the government as an authorization for contraceptive coverage.

“It’s not an authorization,” Justice Ginsburg said during arguments. “The government, the law,­ the regulation requires it, but it doesn’t matter whether you say, yes or no. And you could say, ‘I fill out the form. I do not authorize. I do not permit.’ It won’t make any difference.”

The ACA’s accommodation clause refers to an exception for organizations that oppose coverage for contraceptives but are not exempted entities, such as churches. The plaintiffs – part of seven consolidated cases that include a Catholic bishop and an order of nuns – argue that the opt-out process put in place by the government makes them complicit in offering contraception coverage indirectly. Forcing them to cooperate with the accommodation violates their rights under the federal Religious Freedom Restoration Act, according to the plaintiffs.

The government contends that the exception does not impose a burden on the groups and that courts should not disregard the interest of employees who may not share their employers’ religious beliefs. The 8th U.S. Circuit Court of Appeals struck down the exception twice, ruling that forcing organizations to offer contraceptive coverage – even indirectly – violates their religious rights. The 8th Circuit’s decisions are at odds with rulings by the 2nd and 5th Circuit courts.

Chief Justice Roberts indicated agreement that the government is attempting to take control of the plaintiff’s health plans and provide coverage against the will of the nonprofit employers, said Mr. Goldfeder.

During arguments, Justice Roberts also made it clear that religious liberty versus reproductive rights is not at the center of the case, noted Mr. Goldfeder, who co-wrote a friend-of-the-court brief for the American Center for Law and Justice in support of the employers. Specifically, Justice Roberts stressed that the case is rooted in the employer’s objection to the government’s mechanism, not to employees receiving contraceptive care.

“The way this case has often been portrayed in the media, it has been about a clash between religious liberty and reproductive rights,” Mr. Goldfeder said in an interview. “As became clear in the arguments today, that is a false dichotomy, and a false narrative.”

Foreshadowing their latest move, justices and attorneys spent ample time arguing over whether an alternative paperwork process could satisfy both parties. Justice Alito asked whether it was possible that patients who do not get contraceptive coverage from their religious nonprofit employer could obtain a free contraceptive-­only policy through the ACA insurance exchanges.

Solicitor General Donald B. Verrilli, Jr. dismissed that proposal.

“It’s not a less restrictive alternative because it has precisely the problem Congress was trying to overcome in the preventive services provision,” he said. “That [proposal] is not equally effective at achieving the government’s interest, because the whole point of this provision is that you get this care from your regular doctor as part of your regular health care without any barriers, including any co­pay barriers.”

The justices have several options in deciding the case, including choosing to rehear arguments at a later date. The Feb. 13 death of Justice Antonin Scalia could also mean a 4-4 split decision. If such a division occurs, the lower court rulings would stand.

“The impact will be that women employed by nonprofits in the 8th Circuit will be denied contraception coverage, but that women in all the other circuits will receive the coverage,” Ms. Hamilton said. “And we’ll be back to not having an answer from the Supreme Court. So all of the machinery that went into play for consideration of this case ... all of the entities that worked on it, will have to repeat itself. It will turn the whole exercise into something of a joke.”

In the two-page order issued March 29, the justices encouraged both parties to suggest ways in which the plaintiffs would have no legal obligation to provide contraceptive coverage, would not have to pay for such coverage, and would not be required to submit any separate notice to insurers, the government, or employees. New briefs are due by April 20.

[email protected]

On Twitter @legal_med

Less than a week after hearing oral arguments, Supreme Court justices have ordered both sides to provide new briefs in a religious freedom case that centers on the federal government’s contraception mandate.

In an unexpected move, the justices on March 29 directed attorneys to file supplemental briefs that propose alternatives to the government’s current accommodation under the mandate. The high court wants to know whether, and how, contraceptive coverage could be obtained by employees of religious nonprofits through the plaintiffs’ health plans in a way that does not require employer involvement.

Gregory Twachtman/ Frontline Medical Media

The request is likely an attempt to avoid a 4-4 ruling in Zubik v. Burwell, while finding a way to spare religious nonprofits from participating in the process of providing birth control coverage, according to analysts.

“The court here is clearly looking to craft a win-win situation; a compromise where no one has to lose,” said Mark Goldfeder, a law professor at Emory University in Atlanta and director of the school’s law and religion student program. “The court is asking for the parties to help craft a process by which the affected employees can get their contraception easily covered, in a way that does not violate their employer’s religious beliefs.”

During oral arguments on March 23, the justices focused much attention on the process of the accommodation and how the arrangement unfolds between employers and the government, said Laurie Sobel, a senior policy analyst for the Henry J. Kaiser Family Foundation who attended the oral arguments.

“The fundamental issue in this case comes down to how the accommodation works,” Ms. Sobel said in an interview. “The petitioners believe the notification is the permission slip that triggers the coverage from the insurance companies. The government’s position is, ‘No, that’s just a notification, and the requirement to provide the coverage comes from the law.’ That came up a lot during arguments.”

The Supreme Court’s more conservative justices, including Justice Samuel A. Alito Jr. and Chief Justice John G. Roberts, were skeptical that the accommodation is the least restrictive means of advancing a compelling interest. The court’s four more liberal justices – particularly the three women on the court – appeared to support the accommodation, said Marci A. Hamilton, a law professor at Yeshiva University, New York, who also attended oral arguments.

Ms. Hamilton wrote a friend-of-the-court brief on behalf of Rep. Bobby Scott (D-Va.) in support of the government.

“[Plaintiffs’ attorney] Paul Clement was very quickly attacked by all three female Supreme Court justices,” Ms. Hamilton said in an interview. “It was really interesting that the female justices clearly took this to heart. They fundamentally identified with the contraceptive issue, and they really dominated the first part of the argument.”

Justice Ruth Bader Ginsburg countered the assertion that under the accommodation, notification by employers is treated by the government as an authorization for contraceptive coverage.

“It’s not an authorization,” Justice Ginsburg said during arguments. “The government, the law,­ the regulation requires it, but it doesn’t matter whether you say, yes or no. And you could say, ‘I fill out the form. I do not authorize. I do not permit.’ It won’t make any difference.”

The ACA’s accommodation clause refers to an exception for organizations that oppose coverage for contraceptives but are not exempted entities, such as churches. The plaintiffs – part of seven consolidated cases that include a Catholic bishop and an order of nuns – argue that the opt-out process put in place by the government makes them complicit in offering contraception coverage indirectly. Forcing them to cooperate with the accommodation violates their rights under the federal Religious Freedom Restoration Act, according to the plaintiffs.

The government contends that the exception does not impose a burden on the groups and that courts should not disregard the interest of employees who may not share their employers’ religious beliefs. The 8th U.S. Circuit Court of Appeals struck down the exception twice, ruling that forcing organizations to offer contraceptive coverage – even indirectly – violates their religious rights. The 8th Circuit’s decisions are at odds with rulings by the 2nd and 5th Circuit courts.

Chief Justice Roberts indicated agreement that the government is attempting to take control of the plaintiff’s health plans and provide coverage against the will of the nonprofit employers, said Mr. Goldfeder.

During arguments, Justice Roberts also made it clear that religious liberty versus reproductive rights is not at the center of the case, noted Mr. Goldfeder, who co-wrote a friend-of-the-court brief for the American Center for Law and Justice in support of the employers. Specifically, Justice Roberts stressed that the case is rooted in the employer’s objection to the government’s mechanism, not to employees receiving contraceptive care.

“The way this case has often been portrayed in the media, it has been about a clash between religious liberty and reproductive rights,” Mr. Goldfeder said in an interview. “As became clear in the arguments today, that is a false dichotomy, and a false narrative.”

Foreshadowing their latest move, justices and attorneys spent ample time arguing over whether an alternative paperwork process could satisfy both parties. Justice Alito asked whether it was possible that patients who do not get contraceptive coverage from their religious nonprofit employer could obtain a free contraceptive-­only policy through the ACA insurance exchanges.

Solicitor General Donald B. Verrilli, Jr. dismissed that proposal.

“It’s not a less restrictive alternative because it has precisely the problem Congress was trying to overcome in the preventive services provision,” he said. “That [proposal] is not equally effective at achieving the government’s interest, because the whole point of this provision is that you get this care from your regular doctor as part of your regular health care without any barriers, including any co­pay barriers.”

The justices have several options in deciding the case, including choosing to rehear arguments at a later date. The Feb. 13 death of Justice Antonin Scalia could also mean a 4-4 split decision. If such a division occurs, the lower court rulings would stand.

“The impact will be that women employed by nonprofits in the 8th Circuit will be denied contraception coverage, but that women in all the other circuits will receive the coverage,” Ms. Hamilton said. “And we’ll be back to not having an answer from the Supreme Court. So all of the machinery that went into play for consideration of this case ... all of the entities that worked on it, will have to repeat itself. It will turn the whole exercise into something of a joke.”

In the two-page order issued March 29, the justices encouraged both parties to suggest ways in which the plaintiffs would have no legal obligation to provide contraceptive coverage, would not have to pay for such coverage, and would not be required to submit any separate notice to insurers, the government, or employees. New briefs are due by April 20.

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Subclinical hyperthyroidism and hypothyroidism are both linked to higher mortality in the elderly, with the greatest mortality increases found in those with thyroid-stimulating hormone (TSH) values above 6.38 mIU/L, according to a retrospective cohort study.

Researchers analyzed medical records from 538 individuals with subclinical hyperthyroidism, 1,956 with subclinical hypothyroidism and 14,946 with normal thyroid-stimulating hormone levels, and found subclinical hyperthyroidism (TSH less than 0.35 mIU/L) was associated with an 80% greater risk of mortality over 10 years of follow-up, compared with normal TSH levels.

The study showed subclinical hypothyroidism (TSH greater than 4.2 mIU/L) was associated with a 68% greater mortality risk, even after adjustment for potential confounders such as age, sex, chronic kidney or lung disease, smoking, and hypertension.

The analysis also showed that when TSH values were stratified into quintiles for both subclinical hyperthyroidism and hypothyroidism, individuals with TSH levels above 6.38 mIU/L had the greatest excess of mortality, compared with other individuals with hypothyroidism, while there were no significant mortality differences between the quintiles in subclinical hyperthyroidism.

“Whether this should lead to less-restricted thyroid hormone replacement in elderly individuals with subclinical hypothyroidism is unclear, but these results certainly serve as preliminary evidence for the requirement for thyroid hormone replacement in the elderly with subclinical hypothyroidism, possibly with a higher thyroid-stimulating hormone threshold value,” wrote Dr. Alon Grossman from the Rabin Medical Center, Petah Tikva, Israel, and coauthors (Am J Med. 2016 Apr;129[4]:423-30).

No conflicts of interest were declared.

Subclinical hyperthyroidism and hypothyroidism are both linked to higher mortality in the elderly, with the greatest mortality increases found in those with thyroid-stimulating hormone (TSH) values above 6.38 mIU/L, according to a retrospective cohort study.

Researchers analyzed medical records from 538 individuals with subclinical hyperthyroidism, 1,956 with subclinical hypothyroidism and 14,946 with normal thyroid-stimulating hormone levels, and found subclinical hyperthyroidism (TSH less than 0.35 mIU/L) was associated with an 80% greater risk of mortality over 10 years of follow-up, compared with normal TSH levels.

The study showed subclinical hypothyroidism (TSH greater than 4.2 mIU/L) was associated with a 68% greater mortality risk, even after adjustment for potential confounders such as age, sex, chronic kidney or lung disease, smoking, and hypertension.

The analysis also showed that when TSH values were stratified into quintiles for both subclinical hyperthyroidism and hypothyroidism, individuals with TSH levels above 6.38 mIU/L had the greatest excess of mortality, compared with other individuals with hypothyroidism, while there were no significant mortality differences between the quintiles in subclinical hyperthyroidism.

“Whether this should lead to less-restricted thyroid hormone replacement in elderly individuals with subclinical hypothyroidism is unclear, but these results certainly serve as preliminary evidence for the requirement for thyroid hormone replacement in the elderly with subclinical hypothyroidism, possibly with a higher thyroid-stimulating hormone threshold value,” wrote Dr. Alon Grossman from the Rabin Medical Center, Petah Tikva, Israel, and coauthors (Am J Med. 2016 Apr;129[4]:423-30).

No conflicts of interest were declared.

Subclinical hyperthyroidism and hypothyroidism are both linked to higher mortality in the elderly, with the greatest mortality increases found in those with thyroid-stimulating hormone (TSH) values above 6.38 mIU/L, according to a retrospective cohort study.

Researchers analyzed medical records from 538 individuals with subclinical hyperthyroidism, 1,956 with subclinical hypothyroidism and 14,946 with normal thyroid-stimulating hormone levels, and found subclinical hyperthyroidism (TSH less than 0.35 mIU/L) was associated with an 80% greater risk of mortality over 10 years of follow-up, compared with normal TSH levels.

The study showed subclinical hypothyroidism (TSH greater than 4.2 mIU/L) was associated with a 68% greater mortality risk, even after adjustment for potential confounders such as age, sex, chronic kidney or lung disease, smoking, and hypertension.

The analysis also showed that when TSH values were stratified into quintiles for both subclinical hyperthyroidism and hypothyroidism, individuals with TSH levels above 6.38 mIU/L had the greatest excess of mortality, compared with other individuals with hypothyroidism, while there were no significant mortality differences between the quintiles in subclinical hyperthyroidism.

“Whether this should lead to less-restricted thyroid hormone replacement in elderly individuals with subclinical hypothyroidism is unclear, but these results certainly serve as preliminary evidence for the requirement for thyroid hormone replacement in the elderly with subclinical hypothyroidism, possibly with a higher thyroid-stimulating hormone threshold value,” wrote Dr. Alon Grossman from the Rabin Medical Center, Petah Tikva, Israel, and coauthors (Am J Med. 2016 Apr;129[4]:423-30).

No conflicts of interest were declared.