The nanoparticles

Credit: Jonathan Lovell

A new type of nanoparticle can be used with 6 different imaging techniques, according to research published in Advanced Materials.

Investigators found they could detect these nanoparticles via CT and PET scans, as well as photoacoustic, fluorescence, upconversion, and Cerenkov luminescence imaging.

A machine capable of performing all 6 imaging techniques at once has not yet been invented, to the researchers’ knowledge.

But they hope the creation of their nanoparticles and related work will spur the development of such technology.

That way, patients could receive a single injection of the nanoparticles and have several types of imaging done, which would provide a clearer picture of organs and tissues than a single imaging method alone.

For instance, when the investigators used their nanoparticles to examine the lymph nodes of mice, they found that CT and PET scans provided the

deepest tissue penetration, while the photoacoustic imaging showed blood vessel details the first 2 techniques missed.

“This nanoparticle may open the door for new ‘hypermodal’ imaging systems that allow a lot of new information to be obtained using just one contrast agent,” said study author Jonathan Lovell, PhD, of the University of Buffalo in New York.

“Once such systems are developed, a patient could theoretically go in for one scan with one machine instead of multiple scans with multiple machines.”

Dr Lovell and his colleagues designed their nanoparticles to have 2 components: a core that glows blue when struck by near-infrared light and an outer fabric of porphyrin-phospholipids (PoP) that wraps around the core.

Each part has unique characteristics that make it ideal for certain types of imaging.

The core, initially designed for upconversion imaging, is made from sodium, ytterbium, fluorine, yttrium, and thulium. The ytterbium is dense in electrons—a property that facilitates detection by CT scans.

The PoP wrapper has biophotonic qualities that make it a great match for fluorescence and photoacoustic imagining. The PoP layer is also adept at attracting copper, which is used in PET and Cerenkov luminescence imaging.

“Combining these 2 biocompatible components into a single nanoparticle could give tomorrow’s doctors a powerful new tool for medical imaging,” said Paras Prasad, PhD, also of the University of Buffalo.

“More studies would have to be done to determine whether the nanoparticle is safe to use for such purposes, but it does not contain toxic metals, such as cadmium, that are known to pose potential risks and are found in some other nanoparticles.”

“Another advantage of this core/shell imaging contrast agent is that it could enable biomedical imaging at multiple scales, from single-molecule to cell imaging, as well as from vascular and organ imaging to whole-body bioimaging,” added Guanying Chen, PhD, of the University of Buffalo and Harbin Institute of Technology in China.

Dr Lovell said the next step for this research is to explore additional uses for the technology.

For example, it might be possible to attach a targeting molecule to the PoP surface that would enable cancer cells to take up the particles, something that photoacoustic and fluorescence imaging can detect due to the properties of the smart PoP coating. This would enable doctors to better see where tumors begin and end.

The nanoparticles

Credit: Jonathan Lovell

A new type of nanoparticle can be used with 6 different imaging techniques, according to research published in Advanced Materials.

Investigators found they could detect these nanoparticles via CT and PET scans, as well as photoacoustic, fluorescence, upconversion, and Cerenkov luminescence imaging.

A machine capable of performing all 6 imaging techniques at once has not yet been invented, to the researchers’ knowledge.

But they hope the creation of their nanoparticles and related work will spur the development of such technology.

That way, patients could receive a single injection of the nanoparticles and have several types of imaging done, which would provide a clearer picture of organs and tissues than a single imaging method alone.

For instance, when the investigators used their nanoparticles to examine the lymph nodes of mice, they found that CT and PET scans provided the

deepest tissue penetration, while the photoacoustic imaging showed blood vessel details the first 2 techniques missed.

“This nanoparticle may open the door for new ‘hypermodal’ imaging systems that allow a lot of new information to be obtained using just one contrast agent,” said study author Jonathan Lovell, PhD, of the University of Buffalo in New York.

“Once such systems are developed, a patient could theoretically go in for one scan with one machine instead of multiple scans with multiple machines.”

Dr Lovell and his colleagues designed their nanoparticles to have 2 components: a core that glows blue when struck by near-infrared light and an outer fabric of porphyrin-phospholipids (PoP) that wraps around the core.

Each part has unique characteristics that make it ideal for certain types of imaging.

The core, initially designed for upconversion imaging, is made from sodium, ytterbium, fluorine, yttrium, and thulium. The ytterbium is dense in electrons—a property that facilitates detection by CT scans.

The PoP wrapper has biophotonic qualities that make it a great match for fluorescence and photoacoustic imagining. The PoP layer is also adept at attracting copper, which is used in PET and Cerenkov luminescence imaging.

“Combining these 2 biocompatible components into a single nanoparticle could give tomorrow’s doctors a powerful new tool for medical imaging,” said Paras Prasad, PhD, also of the University of Buffalo.

“More studies would have to be done to determine whether the nanoparticle is safe to use for such purposes, but it does not contain toxic metals, such as cadmium, that are known to pose potential risks and are found in some other nanoparticles.”

“Another advantage of this core/shell imaging contrast agent is that it could enable biomedical imaging at multiple scales, from single-molecule to cell imaging, as well as from vascular and organ imaging to whole-body bioimaging,” added Guanying Chen, PhD, of the University of Buffalo and Harbin Institute of Technology in China.

Dr Lovell said the next step for this research is to explore additional uses for the technology.

For example, it might be possible to attach a targeting molecule to the PoP surface that would enable cancer cells to take up the particles, something that photoacoustic and fluorescence imaging can detect due to the properties of the smart PoP coating. This would enable doctors to better see where tumors begin and end.

The nanoparticles

Credit: Jonathan Lovell

A new type of nanoparticle can be used with 6 different imaging techniques, according to research published in Advanced Materials.

Investigators found they could detect these nanoparticles via CT and PET scans, as well as photoacoustic, fluorescence, upconversion, and Cerenkov luminescence imaging.

A machine capable of performing all 6 imaging techniques at once has not yet been invented, to the researchers’ knowledge.

But they hope the creation of their nanoparticles and related work will spur the development of such technology.

That way, patients could receive a single injection of the nanoparticles and have several types of imaging done, which would provide a clearer picture of organs and tissues than a single imaging method alone.

For instance, when the investigators used their nanoparticles to examine the lymph nodes of mice, they found that CT and PET scans provided the

deepest tissue penetration, while the photoacoustic imaging showed blood vessel details the first 2 techniques missed.

“This nanoparticle may open the door for new ‘hypermodal’ imaging systems that allow a lot of new information to be obtained using just one contrast agent,” said study author Jonathan Lovell, PhD, of the University of Buffalo in New York.

“Once such systems are developed, a patient could theoretically go in for one scan with one machine instead of multiple scans with multiple machines.”

Dr Lovell and his colleagues designed their nanoparticles to have 2 components: a core that glows blue when struck by near-infrared light and an outer fabric of porphyrin-phospholipids (PoP) that wraps around the core.

Each part has unique characteristics that make it ideal for certain types of imaging.

The core, initially designed for upconversion imaging, is made from sodium, ytterbium, fluorine, yttrium, and thulium. The ytterbium is dense in electrons—a property that facilitates detection by CT scans.

The PoP wrapper has biophotonic qualities that make it a great match for fluorescence and photoacoustic imagining. The PoP layer is also adept at attracting copper, which is used in PET and Cerenkov luminescence imaging.

“Combining these 2 biocompatible components into a single nanoparticle could give tomorrow’s doctors a powerful new tool for medical imaging,” said Paras Prasad, PhD, also of the University of Buffalo.

“More studies would have to be done to determine whether the nanoparticle is safe to use for such purposes, but it does not contain toxic metals, such as cadmium, that are known to pose potential risks and are found in some other nanoparticles.”

“Another advantage of this core/shell imaging contrast agent is that it could enable biomedical imaging at multiple scales, from single-molecule to cell imaging, as well as from vascular and organ imaging to whole-body bioimaging,” added Guanying Chen, PhD, of the University of Buffalo and Harbin Institute of Technology in China.

Dr Lovell said the next step for this research is to explore additional uses for the technology.

For example, it might be possible to attach a targeting molecule to the PoP surface that would enable cancer cells to take up the particles, something that photoacoustic and fluorescence imaging can detect due to the properties of the smart PoP coating. This would enable doctors to better see where tumors begin and end.

Blood smear showing

Plasmodium falciparum

Credit: CDC/Mae Melvin

Researchers say they’ve uncovered the complex genetic architecture that enables the malaria parasite Plasmodium falciparum to develop resistance to the antimalarial drug artemisinin.

The team found evidence to suggest that 20 mutations in a single gene work with background mutations in 4 other genes to promote resistance.

The group believes their findings, published in Nature Genetics, could help improve early detection of emerging artemisinin resistance.

To make their discovery, the researchers analyzed 1612 samples from subjects at 15 locations in Southeast Asia and Africa. The team performed P falciparum genome sequencing and genotype calling at more than 600,000 single-nucleotide polymorphism positions on all samples.

The work revealed 20 mutations in the kelch13 gene, a known artemisinin resistance marker, that appear to work in concert with a set of background mutations in 4 other genes—fd, arps10, mdr2, and crt—to support artemisinin resistance.

“Our findings suggest that these background mutations emerged with limited impact on artemisinin resistance—until mutations occurred in the kelch13 gene,” said Roberto Amato, PhD, of the Wellcome Trust Sanger Institute in Oxford, UK.

“It’s similar to what we see with precancerous cells, which accumulate genetic changes but only become malignant when they acquire critical driver mutations that kick off growth.”

The variety of kelch13 mutations associated with artemisinin resistance makes it difficult to use this gene alone as a marker for genetic surveillance.

Monitoring parasite populations for a specific genetic background—in this case, a fixed set of 4 well-defined mutations in fd, arps10, mdr2, and crt—could allow researchers to assess the likelihood of new resistance-causing mutations emerging in different locations, helping to target high-risk regions before resistant parasites take hold.

“We are at a pivotal point for malaria control,” said Nick Day, MBBS, of the Mahidol-Oxford Tropical Medicine Research Unit (MORU) in Bangkok, Thailand.

“While malaria deaths have been halved, this progress is at risk if artemisinin ceases to be effective. We need to use every tool at our disposal to protect this drug. Monitoring parasites for background mutations could provide an early warning system to identify areas at risk for artemisinin resistance.”

The researchers also uncovered new clues about how artemisinin resistance has evolved in Southeast Asia. By comparing parasites from Cambodia, Vietnam, Laos, Thailand, Myanmar, and Bangladesh, the team found that the distribution of different kelch13 mutations is localized within relatively well-defined geographical areas.

Although artemisinin-resistant parasites appear to have migrated across national borders, this only happened on a limited scale. In fact, the most widespread kelch13 mutation, C580Y, seems to have emerged independently on several occasions.

Parasites along the Thailand-Myanmar border appear to have acquired C580Y separately from those in Cambodia and Vietnam. But parasite populations in both regions possess the genetic background mutations, even though they are clearly genetically distinct.

“We don’t yet know the role of these background mutations,” said Olivo Miotto, PhD, also of MORU. “Some may not affect drug resistance directly but, rather, provide an environment where drug-resistance mutations are tolerated.”

“Since kelch13 has hardly changed in 50 million years of Plasmodium evolution, we can assume that this gene is essential to parasite survival. Therefore, kelch13 mutations may severely handicap mutant parasites, compromising their survival unless some other change can counteract this negative effect.”

Mutations in the kelch13 gene were present, yet rare, in Africa. But they weren’t associated with artemisinin resistance and lacked the genetic background present in artemisinin-resistant parasites in Southeast Asia. This provides some reassurance for public health authorities working to prevent the spread of artemisinin resistance to Africa, where most malaria deaths occur.

“These data serve as a reminder of how crucial surveillance and elimination programs are,” said Dominic Kwiatkowski, MBBS, of the Wellcome Trust Sanger Institute.

“At present, artemisinin resistance appears to be largely confined to Southeast Asia, but the situation might change as the parasite population continues to evolve. By linking genomic data with clinical data, we’re developing a better understanding of the multiple genetic factors involved in the emergence of resistance, and that is starting to provide vital clues about how to prevent its spread.”

Blood smear showing

Plasmodium falciparum

Credit: CDC/Mae Melvin

Researchers say they’ve uncovered the complex genetic architecture that enables the malaria parasite Plasmodium falciparum to develop resistance to the antimalarial drug artemisinin.

The team found evidence to suggest that 20 mutations in a single gene work with background mutations in 4 other genes to promote resistance.

The group believes their findings, published in Nature Genetics, could help improve early detection of emerging artemisinin resistance.

To make their discovery, the researchers analyzed 1612 samples from subjects at 15 locations in Southeast Asia and Africa. The team performed P falciparum genome sequencing and genotype calling at more than 600,000 single-nucleotide polymorphism positions on all samples.

The work revealed 20 mutations in the kelch13 gene, a known artemisinin resistance marker, that appear to work in concert with a set of background mutations in 4 other genes—fd, arps10, mdr2, and crt—to support artemisinin resistance.

“Our findings suggest that these background mutations emerged with limited impact on artemisinin resistance—until mutations occurred in the kelch13 gene,” said Roberto Amato, PhD, of the Wellcome Trust Sanger Institute in Oxford, UK.

“It’s similar to what we see with precancerous cells, which accumulate genetic changes but only become malignant when they acquire critical driver mutations that kick off growth.”

The variety of kelch13 mutations associated with artemisinin resistance makes it difficult to use this gene alone as a marker for genetic surveillance.

Monitoring parasite populations for a specific genetic background—in this case, a fixed set of 4 well-defined mutations in fd, arps10, mdr2, and crt—could allow researchers to assess the likelihood of new resistance-causing mutations emerging in different locations, helping to target high-risk regions before resistant parasites take hold.

“We are at a pivotal point for malaria control,” said Nick Day, MBBS, of the Mahidol-Oxford Tropical Medicine Research Unit (MORU) in Bangkok, Thailand.

“While malaria deaths have been halved, this progress is at risk if artemisinin ceases to be effective. We need to use every tool at our disposal to protect this drug. Monitoring parasites for background mutations could provide an early warning system to identify areas at risk for artemisinin resistance.”

The researchers also uncovered new clues about how artemisinin resistance has evolved in Southeast Asia. By comparing parasites from Cambodia, Vietnam, Laos, Thailand, Myanmar, and Bangladesh, the team found that the distribution of different kelch13 mutations is localized within relatively well-defined geographical areas.

Although artemisinin-resistant parasites appear to have migrated across national borders, this only happened on a limited scale. In fact, the most widespread kelch13 mutation, C580Y, seems to have emerged independently on several occasions.

Parasites along the Thailand-Myanmar border appear to have acquired C580Y separately from those in Cambodia and Vietnam. But parasite populations in both regions possess the genetic background mutations, even though they are clearly genetically distinct.

“We don’t yet know the role of these background mutations,” said Olivo Miotto, PhD, also of MORU. “Some may not affect drug resistance directly but, rather, provide an environment where drug-resistance mutations are tolerated.”

“Since kelch13 has hardly changed in 50 million years of Plasmodium evolution, we can assume that this gene is essential to parasite survival. Therefore, kelch13 mutations may severely handicap mutant parasites, compromising their survival unless some other change can counteract this negative effect.”

Mutations in the kelch13 gene were present, yet rare, in Africa. But they weren’t associated with artemisinin resistance and lacked the genetic background present in artemisinin-resistant parasites in Southeast Asia. This provides some reassurance for public health authorities working to prevent the spread of artemisinin resistance to Africa, where most malaria deaths occur.

“These data serve as a reminder of how crucial surveillance and elimination programs are,” said Dominic Kwiatkowski, MBBS, of the Wellcome Trust Sanger Institute.

“At present, artemisinin resistance appears to be largely confined to Southeast Asia, but the situation might change as the parasite population continues to evolve. By linking genomic data with clinical data, we’re developing a better understanding of the multiple genetic factors involved in the emergence of resistance, and that is starting to provide vital clues about how to prevent its spread.”

Blood smear showing

Plasmodium falciparum

Credit: CDC/Mae Melvin

Researchers say they’ve uncovered the complex genetic architecture that enables the malaria parasite Plasmodium falciparum to develop resistance to the antimalarial drug artemisinin.

The team found evidence to suggest that 20 mutations in a single gene work with background mutations in 4 other genes to promote resistance.

The group believes their findings, published in Nature Genetics, could help improve early detection of emerging artemisinin resistance.

To make their discovery, the researchers analyzed 1612 samples from subjects at 15 locations in Southeast Asia and Africa. The team performed P falciparum genome sequencing and genotype calling at more than 600,000 single-nucleotide polymorphism positions on all samples.

The work revealed 20 mutations in the kelch13 gene, a known artemisinin resistance marker, that appear to work in concert with a set of background mutations in 4 other genes—fd, arps10, mdr2, and crt—to support artemisinin resistance.

“Our findings suggest that these background mutations emerged with limited impact on artemisinin resistance—until mutations occurred in the kelch13 gene,” said Roberto Amato, PhD, of the Wellcome Trust Sanger Institute in Oxford, UK.

“It’s similar to what we see with precancerous cells, which accumulate genetic changes but only become malignant when they acquire critical driver mutations that kick off growth.”

The variety of kelch13 mutations associated with artemisinin resistance makes it difficult to use this gene alone as a marker for genetic surveillance.

Monitoring parasite populations for a specific genetic background—in this case, a fixed set of 4 well-defined mutations in fd, arps10, mdr2, and crt—could allow researchers to assess the likelihood of new resistance-causing mutations emerging in different locations, helping to target high-risk regions before resistant parasites take hold.

“We are at a pivotal point for malaria control,” said Nick Day, MBBS, of the Mahidol-Oxford Tropical Medicine Research Unit (MORU) in Bangkok, Thailand.

“While malaria deaths have been halved, this progress is at risk if artemisinin ceases to be effective. We need to use every tool at our disposal to protect this drug. Monitoring parasites for background mutations could provide an early warning system to identify areas at risk for artemisinin resistance.”

The researchers also uncovered new clues about how artemisinin resistance has evolved in Southeast Asia. By comparing parasites from Cambodia, Vietnam, Laos, Thailand, Myanmar, and Bangladesh, the team found that the distribution of different kelch13 mutations is localized within relatively well-defined geographical areas.

Although artemisinin-resistant parasites appear to have migrated across national borders, this only happened on a limited scale. In fact, the most widespread kelch13 mutation, C580Y, seems to have emerged independently on several occasions.

Parasites along the Thailand-Myanmar border appear to have acquired C580Y separately from those in Cambodia and Vietnam. But parasite populations in both regions possess the genetic background mutations, even though they are clearly genetically distinct.

“We don’t yet know the role of these background mutations,” said Olivo Miotto, PhD, also of MORU. “Some may not affect drug resistance directly but, rather, provide an environment where drug-resistance mutations are tolerated.”

“Since kelch13 has hardly changed in 50 million years of Plasmodium evolution, we can assume that this gene is essential to parasite survival. Therefore, kelch13 mutations may severely handicap mutant parasites, compromising their survival unless some other change can counteract this negative effect.”

Mutations in the kelch13 gene were present, yet rare, in Africa. But they weren’t associated with artemisinin resistance and lacked the genetic background present in artemisinin-resistant parasites in Southeast Asia. This provides some reassurance for public health authorities working to prevent the spread of artemisinin resistance to Africa, where most malaria deaths occur.

“These data serve as a reminder of how crucial surveillance and elimination programs are,” said Dominic Kwiatkowski, MBBS, of the Wellcome Trust Sanger Institute.

“At present, artemisinin resistance appears to be largely confined to Southeast Asia, but the situation might change as the parasite population continues to evolve. By linking genomic data with clinical data, we’re developing a better understanding of the multiple genetic factors involved in the emergence of resistance, and that is starting to provide vital clues about how to prevent its spread.”

One day in 1986, a medical school classmate handed Dr. Robert P. Bright a gun that she intended to use to kill herself. She asked him to hold on to it for her and to keep quiet about her sense of hopelessness.

“She didn’t want anybody in the medical school to know; it was all hidden and hush-hushed,” recalled Dr. Bright, who is now a psychiatrist at the Mayo Clinic, Scottsdale, Ariz. “I was trying to juggle that with the issue of safety.”

He honored his classmate’s request for confidentiality, but he sought advice from the medical school dean about what to do. Before long, his classmate sought help from a psychiatrist and got better with medication and psychotherapy. “It turned out well, thank goodness,” Dr. Bright said.

Similar stories of despair among medical students and physicians don’t always end well. The American Foundation for Suicide Prevention estimates that 300-400 U.S. physicians commit suicide each year, about one per day. Suicide deaths are 250%-400% higher among female physicians, compared with women in other professions, and 70% higher among male physicians, compared with men in other professions. Major depression is a common risk factor, along with bipolar disorder and substance abuse.

Depression and other mood disorders may be underrecognized and inadequately treated in physicians because they may be reluctant to seek treatment, may attempt to diagnose and treat themselves, or may seek and receive “VIP treatment” from health care providers, according to a review article coauthored by Dr. Bright (Current Psych. 2011;10:16-30).

“Physicians struggling with these things are very much in the closet about it,” he said. “It’s a sad reflection on the stigma that’s still in our country that people can’t come forth and say, ‘I’m struggling with depression or anxiety.’ ”

Researchers led by Dr. Katherine J. Gold at the University of Michigan used data from the National Violent Death Reporting System to evaluate suicide among physicians and found that job stressors “may impact physician identity and be a particular risk factor for which more attention is warranted” (Gen. Hosp. Psychiatry 2013;35:45-9).

Work dissatisfaction sent Dr. Pamela Wible into a tailspin early in her career. In 2004 she found herself in a suicidal state for about 6 weeks, “I stayed at home, crying myself into my pillow and I never sought help from my colleagues,” recalled Dr. Wible, a family physician in Eugene, Ore., who currently leads training sessions in medical student and physician suicide prevention. “I was not depressed before entering the medical profession, but [I had developed] constant thoughts of ‘Can I just disappear? What’s the easiest way to do this?’ I got to a place of complete surrender but I didn’t have the gun. I didn’t have the stockpile of pills. I didn’t have a follow-through on the plan.”

Instead of taking her own life, she “had an epiphany” and changed the way she practiced medicine. She said that owning her own clinic empowered her to “become the doctor I had originally described on my personal statement when I entered medical school.”

According to Dr. Charles F. Reynolds III, a psychiatrist at the University of Pittsburgh, reluctance to seek treatment can also be driven by concerns about the amount of time that treatment could take.

“As physicians, we often don’t appropriately take care of ourselves when it comes to issues like depression,” said Dr. Reynolds, who also directs the National Institute of Mental Health–sponsored Center of Excellence in the Prevention and Treatment of Late Life Mood Disorders. “We may still see it as a character weakness rather than as a medical illness that can be diagnosed and appropriately treated. Concerns about privacy also figure into the concerns of some physicians as well.”

Practicing in a rural area or small community can also be an obstacle to treatment, not only because of limited access to psychiatrists, but because the “patient” may be the only physician in town.

“As much as there’s stigma for everybody being voluntarily or involuntarily admitted [for suicidal ideation], it’s a little different when you’re a provider within the hospital where you’re seeking care,” Dr. Bright noted.

He said that if he had the opportunity to counsel physicians experiencing suicidal thoughts, he would “remind them of the medical nature of depression, that the brain is just another organ and the organ is not making chemicals just like the pancreas doesn’t make insulin in diabetes,” he said. “I’d also encourage them to get the treatment that they need. I would encourage compassion for themselves that they would give to anybody else in the same situation.”

He said that he would advise them to find a mental health provider “that they trust with confidentiality, and to reach out to other people for support. I would also let them know about the physician assistance programs that are available. There’s one through Vanderbilt (the Vanderbilt Center for Professional Health) and several others that specialize in working with physicians who are struggling with mental health or substance abuse or disruptive behavior.”

Dr. Reynolds’ core message to distressed physicians is that “you’re a better doctor for your patients, and a better father or mother for your family, if you’re taking good care of yourself,” he said. “It’s hard for you to take care of your patients if you’re not also taking care of yourself, if you’re burning out. Get help. Treatment works.”

Dr. Christine Moutier, chief medical officer of the American Foundation for Suicide Prevention, added that troubled physicians “should feel no shame for the fact that they’re in distress. Any of us can get there through a whole variety of different pathways that life presents. There’s science and data to support this experience as commonplace and having underpinnings that are of no fault to anyone. That’s the reality.”

Dr. Wible, who has lost several colleagues and physician friends to suicide, said that she hopes for a more transparent discussion of the topic by the medical profession. She presented on the topic at the 2014 annual scientific assembly of the American Academy of Family Physicians.

“The talk before mine was on Ebola, and every seat was taken” in the 900-seat room. When it came time for her presentation, “I maybe had 100 people in the room. Now, are physicians more likely to die from Ebola or from suicide? We are in a state of denial. If we don’t talk about suicide, we will continue to lose one or two medical students or doctors every day. The sooner we talk about this and connect with each other outside of a PowerPoint presentation, the sooner we’re going to solve this.”

After a physician in a large clinical department at the University of Pittsburgh took his own life several years ago, the chair of that department invited Dr. Reynolds to speak with his staff. The meeting “was primarily educational in nature, so we talked about the topic, to try to destigmatize and to educate people about the need for appropriate help-seeking,” recalled Dr. Reynolds, who is a former president of the American College of Psychiatrists. “If the leadership of a medical institution appropriately sanctions help-seeking behavior and treatment of mental disorders like depression, that’s going to make it okay for people to reach out and seek help rather than pushing it under the rug, so to speak. If the leadership says ‘this is a key thing and we don’t think you can function adequately as a medical student or as a physician if you’re not taking appropriate care of yourself,’ that helps to shift the culture.”

The ripple effect of that kind of message from health care administrators can’t be underestimated, said Dr. Moutier, who helped launch a suicide and depression awareness program at the University of California, San Diego (Acad. Med. 2012;87:320-6). She encouraged health care leaders to stage periodic grand rounds and lectures for their medical staff about physician well-being, burnout, and the risk of suicide. “If the leader is uncomfortable talking about these things, that’s a sign they should get a little education for themselves about [these topics],” she said.

Dr. Reynolds noted that certain state medical licensure boards including those for Arkansas and Pennsylvania have incorporated destigmatizing language into relicensure exams. “Some of them previously would ask questions such as whether the applicants had a history of a mental disorder like depression,” he said. “What you’re beginning to see now increasingly is that the state medical board will ask more generic questions, like ‘Do you have any conditions that would interfere with the practice of your specialty in medicine?’ This is a good thing.”

He said that he is optimistic about future of physician well-being, noting that the University of Pittsburgh and other medical schools have incorporated wellness principles into first-year curriculum. “We underscore the importance of students becoming sensitive to one another, learning how to recognize depression in each other and creating a culture in which students can encourage each other to engage in appropriate help-seeking,” Dr. Reynolds explained. “I think we are witnessing a shift in the culture of institutional medicine as we bring along new generations of physicians who are better educated about mental disorders and their treatment and issues related to suicide as we reach out to students, make counseling services available to them, educate them about these issues. That supports a cultural shift that gradually erodes the issue of stigma that has so long plagued appropriate help-seeking in medical institutions.”

Still, Dr. Wible said that she worries about the disaffected colleagues who reach out to her almost every day. “Just yesterday I got an e-mail from a physician in Oklahoma who told me they just lost three physicians to suicide in 1 month who were on probation with the medical board,” she said. “These are not defective physicians. These people need to be helped.”

Dr. Wible said that she favors holding periodic panel discussions on the topics of depression and physician suicide for medical students and physicians alike. “Let other physicians who’ve been depressed and suicidal sit in front of the room on the first week of medical school, or in a hospital once in a while, mandatory, where you listen to other well-respected physicians say, ‘yeah. I cried myself to sleep after I lost this patient,’ or ‘I had suicidal thoughts during a malpractice case.’ There are lots of reasons why physicians could be sad. They need to start talking about it publicly. Other medical students and physicians would then feel comfortable to raise their hands in the audience and say, ‘I felt the same way.’ ”

Suggested resources for help

American Foundation for Suicide Prevention (www.afsp.org/).

24-hour crisis line: 1-800-273-TALK (8255).

In 2008 the AFSP released a documentary about the problem of physician depression and suicide titled “Struggling in Silence,” which aired on public television stations nationwide and is available on DVD for $24.99.

Center for Patient and Professional Advocacy (www.mc.vanderbilt.edu/centers/cppa/index.php)

Depression and Bipolar Support Alliance (www.dbsalliance.org).

Federation of State Physician Health Programs Inc. (www.fsphp.org).

Vanderbilt Center for Professional Health (www.mc.vanderbilt.edu/cph).

The Mayo Clinic Program on Physician Well-Being (http://www.mayo.edu/research/centers-programs/physician-well-being-program/overview).

ePhysicianHealth.com, a program of the Ontario Medical Association (http://php.oma.org/ePhysicianHealth.html)

The Academic Medicine Handbook: A Guide to Achievement and Fulfillment for Academic Faculty, New York: Springer, 2013 (http://www.springer.com/medicine/internal/book/978-1-4614-5692-6)

[email protected]

On Twitter @dougbrunk

One day in 1986, a medical school classmate handed Dr. Robert P. Bright a gun that she intended to use to kill herself. She asked him to hold on to it for her and to keep quiet about her sense of hopelessness.

“She didn’t want anybody in the medical school to know; it was all hidden and hush-hushed,” recalled Dr. Bright, who is now a psychiatrist at the Mayo Clinic, Scottsdale, Ariz. “I was trying to juggle that with the issue of safety.”

He honored his classmate’s request for confidentiality, but he sought advice from the medical school dean about what to do. Before long, his classmate sought help from a psychiatrist and got better with medication and psychotherapy. “It turned out well, thank goodness,” Dr. Bright said.

Similar stories of despair among medical students and physicians don’t always end well. The American Foundation for Suicide Prevention estimates that 300-400 U.S. physicians commit suicide each year, about one per day. Suicide deaths are 250%-400% higher among female physicians, compared with women in other professions, and 70% higher among male physicians, compared with men in other professions. Major depression is a common risk factor, along with bipolar disorder and substance abuse.

Depression and other mood disorders may be underrecognized and inadequately treated in physicians because they may be reluctant to seek treatment, may attempt to diagnose and treat themselves, or may seek and receive “VIP treatment” from health care providers, according to a review article coauthored by Dr. Bright (Current Psych. 2011;10:16-30).

“Physicians struggling with these things are very much in the closet about it,” he said. “It’s a sad reflection on the stigma that’s still in our country that people can’t come forth and say, ‘I’m struggling with depression or anxiety.’ ”

Researchers led by Dr. Katherine J. Gold at the University of Michigan used data from the National Violent Death Reporting System to evaluate suicide among physicians and found that job stressors “may impact physician identity and be a particular risk factor for which more attention is warranted” (Gen. Hosp. Psychiatry 2013;35:45-9).

Work dissatisfaction sent Dr. Pamela Wible into a tailspin early in her career. In 2004 she found herself in a suicidal state for about 6 weeks, “I stayed at home, crying myself into my pillow and I never sought help from my colleagues,” recalled Dr. Wible, a family physician in Eugene, Ore., who currently leads training sessions in medical student and physician suicide prevention. “I was not depressed before entering the medical profession, but [I had developed] constant thoughts of ‘Can I just disappear? What’s the easiest way to do this?’ I got to a place of complete surrender but I didn’t have the gun. I didn’t have the stockpile of pills. I didn’t have a follow-through on the plan.”

Instead of taking her own life, she “had an epiphany” and changed the way she practiced medicine. She said that owning her own clinic empowered her to “become the doctor I had originally described on my personal statement when I entered medical school.”

According to Dr. Charles F. Reynolds III, a psychiatrist at the University of Pittsburgh, reluctance to seek treatment can also be driven by concerns about the amount of time that treatment could take.

“As physicians, we often don’t appropriately take care of ourselves when it comes to issues like depression,” said Dr. Reynolds, who also directs the National Institute of Mental Health–sponsored Center of Excellence in the Prevention and Treatment of Late Life Mood Disorders. “We may still see it as a character weakness rather than as a medical illness that can be diagnosed and appropriately treated. Concerns about privacy also figure into the concerns of some physicians as well.”

Practicing in a rural area or small community can also be an obstacle to treatment, not only because of limited access to psychiatrists, but because the “patient” may be the only physician in town.

“As much as there’s stigma for everybody being voluntarily or involuntarily admitted [for suicidal ideation], it’s a little different when you’re a provider within the hospital where you’re seeking care,” Dr. Bright noted.

He said that if he had the opportunity to counsel physicians experiencing suicidal thoughts, he would “remind them of the medical nature of depression, that the brain is just another organ and the organ is not making chemicals just like the pancreas doesn’t make insulin in diabetes,” he said. “I’d also encourage them to get the treatment that they need. I would encourage compassion for themselves that they would give to anybody else in the same situation.”

He said that he would advise them to find a mental health provider “that they trust with confidentiality, and to reach out to other people for support. I would also let them know about the physician assistance programs that are available. There’s one through Vanderbilt (the Vanderbilt Center for Professional Health) and several others that specialize in working with physicians who are struggling with mental health or substance abuse or disruptive behavior.”

Dr. Reynolds’ core message to distressed physicians is that “you’re a better doctor for your patients, and a better father or mother for your family, if you’re taking good care of yourself,” he said. “It’s hard for you to take care of your patients if you’re not also taking care of yourself, if you’re burning out. Get help. Treatment works.”

Dr. Christine Moutier, chief medical officer of the American Foundation for Suicide Prevention, added that troubled physicians “should feel no shame for the fact that they’re in distress. Any of us can get there through a whole variety of different pathways that life presents. There’s science and data to support this experience as commonplace and having underpinnings that are of no fault to anyone. That’s the reality.”

Dr. Wible, who has lost several colleagues and physician friends to suicide, said that she hopes for a more transparent discussion of the topic by the medical profession. She presented on the topic at the 2014 annual scientific assembly of the American Academy of Family Physicians.

“The talk before mine was on Ebola, and every seat was taken” in the 900-seat room. When it came time for her presentation, “I maybe had 100 people in the room. Now, are physicians more likely to die from Ebola or from suicide? We are in a state of denial. If we don’t talk about suicide, we will continue to lose one or two medical students or doctors every day. The sooner we talk about this and connect with each other outside of a PowerPoint presentation, the sooner we’re going to solve this.”

After a physician in a large clinical department at the University of Pittsburgh took his own life several years ago, the chair of that department invited Dr. Reynolds to speak with his staff. The meeting “was primarily educational in nature, so we talked about the topic, to try to destigmatize and to educate people about the need for appropriate help-seeking,” recalled Dr. Reynolds, who is a former president of the American College of Psychiatrists. “If the leadership of a medical institution appropriately sanctions help-seeking behavior and treatment of mental disorders like depression, that’s going to make it okay for people to reach out and seek help rather than pushing it under the rug, so to speak. If the leadership says ‘this is a key thing and we don’t think you can function adequately as a medical student or as a physician if you’re not taking appropriate care of yourself,’ that helps to shift the culture.”

The ripple effect of that kind of message from health care administrators can’t be underestimated, said Dr. Moutier, who helped launch a suicide and depression awareness program at the University of California, San Diego (Acad. Med. 2012;87:320-6). She encouraged health care leaders to stage periodic grand rounds and lectures for their medical staff about physician well-being, burnout, and the risk of suicide. “If the leader is uncomfortable talking about these things, that’s a sign they should get a little education for themselves about [these topics],” she said.

Dr. Reynolds noted that certain state medical licensure boards including those for Arkansas and Pennsylvania have incorporated destigmatizing language into relicensure exams. “Some of them previously would ask questions such as whether the applicants had a history of a mental disorder like depression,” he said. “What you’re beginning to see now increasingly is that the state medical board will ask more generic questions, like ‘Do you have any conditions that would interfere with the practice of your specialty in medicine?’ This is a good thing.”

He said that he is optimistic about future of physician well-being, noting that the University of Pittsburgh and other medical schools have incorporated wellness principles into first-year curriculum. “We underscore the importance of students becoming sensitive to one another, learning how to recognize depression in each other and creating a culture in which students can encourage each other to engage in appropriate help-seeking,” Dr. Reynolds explained. “I think we are witnessing a shift in the culture of institutional medicine as we bring along new generations of physicians who are better educated about mental disorders and their treatment and issues related to suicide as we reach out to students, make counseling services available to them, educate them about these issues. That supports a cultural shift that gradually erodes the issue of stigma that has so long plagued appropriate help-seeking in medical institutions.”

Still, Dr. Wible said that she worries about the disaffected colleagues who reach out to her almost every day. “Just yesterday I got an e-mail from a physician in Oklahoma who told me they just lost three physicians to suicide in 1 month who were on probation with the medical board,” she said. “These are not defective physicians. These people need to be helped.”

Dr. Wible said that she favors holding periodic panel discussions on the topics of depression and physician suicide for medical students and physicians alike. “Let other physicians who’ve been depressed and suicidal sit in front of the room on the first week of medical school, or in a hospital once in a while, mandatory, where you listen to other well-respected physicians say, ‘yeah. I cried myself to sleep after I lost this patient,’ or ‘I had suicidal thoughts during a malpractice case.’ There are lots of reasons why physicians could be sad. They need to start talking about it publicly. Other medical students and physicians would then feel comfortable to raise their hands in the audience and say, ‘I felt the same way.’ ”

Suggested resources for help

American Foundation for Suicide Prevention (www.afsp.org/).

24-hour crisis line: 1-800-273-TALK (8255).

In 2008 the AFSP released a documentary about the problem of physician depression and suicide titled “Struggling in Silence,” which aired on public television stations nationwide and is available on DVD for $24.99.

Center for Patient and Professional Advocacy (www.mc.vanderbilt.edu/centers/cppa/index.php)

Depression and Bipolar Support Alliance (www.dbsalliance.org).

Federation of State Physician Health Programs Inc. (www.fsphp.org).

Vanderbilt Center for Professional Health (www.mc.vanderbilt.edu/cph).

The Mayo Clinic Program on Physician Well-Being (http://www.mayo.edu/research/centers-programs/physician-well-being-program/overview).

ePhysicianHealth.com, a program of the Ontario Medical Association (http://php.oma.org/ePhysicianHealth.html)

The Academic Medicine Handbook: A Guide to Achievement and Fulfillment for Academic Faculty, New York: Springer, 2013 (http://www.springer.com/medicine/internal/book/978-1-4614-5692-6)

[email protected]

On Twitter @dougbrunk

One day in 1986, a medical school classmate handed Dr. Robert P. Bright a gun that she intended to use to kill herself. She asked him to hold on to it for her and to keep quiet about her sense of hopelessness.

“She didn’t want anybody in the medical school to know; it was all hidden and hush-hushed,” recalled Dr. Bright, who is now a psychiatrist at the Mayo Clinic, Scottsdale, Ariz. “I was trying to juggle that with the issue of safety.”

He honored his classmate’s request for confidentiality, but he sought advice from the medical school dean about what to do. Before long, his classmate sought help from a psychiatrist and got better with medication and psychotherapy. “It turned out well, thank goodness,” Dr. Bright said.

Similar stories of despair among medical students and physicians don’t always end well. The American Foundation for Suicide Prevention estimates that 300-400 U.S. physicians commit suicide each year, about one per day. Suicide deaths are 250%-400% higher among female physicians, compared with women in other professions, and 70% higher among male physicians, compared with men in other professions. Major depression is a common risk factor, along with bipolar disorder and substance abuse.

Depression and other mood disorders may be underrecognized and inadequately treated in physicians because they may be reluctant to seek treatment, may attempt to diagnose and treat themselves, or may seek and receive “VIP treatment” from health care providers, according to a review article coauthored by Dr. Bright (Current Psych. 2011;10:16-30).

“Physicians struggling with these things are very much in the closet about it,” he said. “It’s a sad reflection on the stigma that’s still in our country that people can’t come forth and say, ‘I’m struggling with depression or anxiety.’ ”

Researchers led by Dr. Katherine J. Gold at the University of Michigan used data from the National Violent Death Reporting System to evaluate suicide among physicians and found that job stressors “may impact physician identity and be a particular risk factor for which more attention is warranted” (Gen. Hosp. Psychiatry 2013;35:45-9).

Work dissatisfaction sent Dr. Pamela Wible into a tailspin early in her career. In 2004 she found herself in a suicidal state for about 6 weeks, “I stayed at home, crying myself into my pillow and I never sought help from my colleagues,” recalled Dr. Wible, a family physician in Eugene, Ore., who currently leads training sessions in medical student and physician suicide prevention. “I was not depressed before entering the medical profession, but [I had developed] constant thoughts of ‘Can I just disappear? What’s the easiest way to do this?’ I got to a place of complete surrender but I didn’t have the gun. I didn’t have the stockpile of pills. I didn’t have a follow-through on the plan.”

Instead of taking her own life, she “had an epiphany” and changed the way she practiced medicine. She said that owning her own clinic empowered her to “become the doctor I had originally described on my personal statement when I entered medical school.”

According to Dr. Charles F. Reynolds III, a psychiatrist at the University of Pittsburgh, reluctance to seek treatment can also be driven by concerns about the amount of time that treatment could take.

“As physicians, we often don’t appropriately take care of ourselves when it comes to issues like depression,” said Dr. Reynolds, who also directs the National Institute of Mental Health–sponsored Center of Excellence in the Prevention and Treatment of Late Life Mood Disorders. “We may still see it as a character weakness rather than as a medical illness that can be diagnosed and appropriately treated. Concerns about privacy also figure into the concerns of some physicians as well.”

Practicing in a rural area or small community can also be an obstacle to treatment, not only because of limited access to psychiatrists, but because the “patient” may be the only physician in town.

“As much as there’s stigma for everybody being voluntarily or involuntarily admitted [for suicidal ideation], it’s a little different when you’re a provider within the hospital where you’re seeking care,” Dr. Bright noted.

He said that if he had the opportunity to counsel physicians experiencing suicidal thoughts, he would “remind them of the medical nature of depression, that the brain is just another organ and the organ is not making chemicals just like the pancreas doesn’t make insulin in diabetes,” he said. “I’d also encourage them to get the treatment that they need. I would encourage compassion for themselves that they would give to anybody else in the same situation.”

He said that he would advise them to find a mental health provider “that they trust with confidentiality, and to reach out to other people for support. I would also let them know about the physician assistance programs that are available. There’s one through Vanderbilt (the Vanderbilt Center for Professional Health) and several others that specialize in working with physicians who are struggling with mental health or substance abuse or disruptive behavior.”

Dr. Reynolds’ core message to distressed physicians is that “you’re a better doctor for your patients, and a better father or mother for your family, if you’re taking good care of yourself,” he said. “It’s hard for you to take care of your patients if you’re not also taking care of yourself, if you’re burning out. Get help. Treatment works.”

Dr. Christine Moutier, chief medical officer of the American Foundation for Suicide Prevention, added that troubled physicians “should feel no shame for the fact that they’re in distress. Any of us can get there through a whole variety of different pathways that life presents. There’s science and data to support this experience as commonplace and having underpinnings that are of no fault to anyone. That’s the reality.”

Dr. Wible, who has lost several colleagues and physician friends to suicide, said that she hopes for a more transparent discussion of the topic by the medical profession. She presented on the topic at the 2014 annual scientific assembly of the American Academy of Family Physicians.

“The talk before mine was on Ebola, and every seat was taken” in the 900-seat room. When it came time for her presentation, “I maybe had 100 people in the room. Now, are physicians more likely to die from Ebola or from suicide? We are in a state of denial. If we don’t talk about suicide, we will continue to lose one or two medical students or doctors every day. The sooner we talk about this and connect with each other outside of a PowerPoint presentation, the sooner we’re going to solve this.”

After a physician in a large clinical department at the University of Pittsburgh took his own life several years ago, the chair of that department invited Dr. Reynolds to speak with his staff. The meeting “was primarily educational in nature, so we talked about the topic, to try to destigmatize and to educate people about the need for appropriate help-seeking,” recalled Dr. Reynolds, who is a former president of the American College of Psychiatrists. “If the leadership of a medical institution appropriately sanctions help-seeking behavior and treatment of mental disorders like depression, that’s going to make it okay for people to reach out and seek help rather than pushing it under the rug, so to speak. If the leadership says ‘this is a key thing and we don’t think you can function adequately as a medical student or as a physician if you’re not taking appropriate care of yourself,’ that helps to shift the culture.”

The ripple effect of that kind of message from health care administrators can’t be underestimated, said Dr. Moutier, who helped launch a suicide and depression awareness program at the University of California, San Diego (Acad. Med. 2012;87:320-6). She encouraged health care leaders to stage periodic grand rounds and lectures for their medical staff about physician well-being, burnout, and the risk of suicide. “If the leader is uncomfortable talking about these things, that’s a sign they should get a little education for themselves about [these topics],” she said.

Dr. Reynolds noted that certain state medical licensure boards including those for Arkansas and Pennsylvania have incorporated destigmatizing language into relicensure exams. “Some of them previously would ask questions such as whether the applicants had a history of a mental disorder like depression,” he said. “What you’re beginning to see now increasingly is that the state medical board will ask more generic questions, like ‘Do you have any conditions that would interfere with the practice of your specialty in medicine?’ This is a good thing.”

He said that he is optimistic about future of physician well-being, noting that the University of Pittsburgh and other medical schools have incorporated wellness principles into first-year curriculum. “We underscore the importance of students becoming sensitive to one another, learning how to recognize depression in each other and creating a culture in which students can encourage each other to engage in appropriate help-seeking,” Dr. Reynolds explained. “I think we are witnessing a shift in the culture of institutional medicine as we bring along new generations of physicians who are better educated about mental disorders and their treatment and issues related to suicide as we reach out to students, make counseling services available to them, educate them about these issues. That supports a cultural shift that gradually erodes the issue of stigma that has so long plagued appropriate help-seeking in medical institutions.”

Still, Dr. Wible said that she worries about the disaffected colleagues who reach out to her almost every day. “Just yesterday I got an e-mail from a physician in Oklahoma who told me they just lost three physicians to suicide in 1 month who were on probation with the medical board,” she said. “These are not defective physicians. These people need to be helped.”

Dr. Wible said that she favors holding periodic panel discussions on the topics of depression and physician suicide for medical students and physicians alike. “Let other physicians who’ve been depressed and suicidal sit in front of the room on the first week of medical school, or in a hospital once in a while, mandatory, where you listen to other well-respected physicians say, ‘yeah. I cried myself to sleep after I lost this patient,’ or ‘I had suicidal thoughts during a malpractice case.’ There are lots of reasons why physicians could be sad. They need to start talking about it publicly. Other medical students and physicians would then feel comfortable to raise their hands in the audience and say, ‘I felt the same way.’ ”

Suggested resources for help

American Foundation for Suicide Prevention (www.afsp.org/).

24-hour crisis line: 1-800-273-TALK (8255).

In 2008 the AFSP released a documentary about the problem of physician depression and suicide titled “Struggling in Silence,” which aired on public television stations nationwide and is available on DVD for $24.99.

Center for Patient and Professional Advocacy (www.mc.vanderbilt.edu/centers/cppa/index.php)

Depression and Bipolar Support Alliance (www.dbsalliance.org).

Federation of State Physician Health Programs Inc. (www.fsphp.org).

Vanderbilt Center for Professional Health (www.mc.vanderbilt.edu/cph).

The Mayo Clinic Program on Physician Well-Being (http://www.mayo.edu/research/centers-programs/physician-well-being-program/overview).

ePhysicianHealth.com, a program of the Ontario Medical Association (http://php.oma.org/ePhysicianHealth.html)

The Academic Medicine Handbook: A Guide to Achievement and Fulfillment for Academic Faculty, New York: Springer, 2013 (http://www.springer.com/medicine/internal/book/978-1-4614-5692-6)

[email protected]

On Twitter @dougbrunk

Four months ago, this 23-year-old man developed a lesion on his right shoulder. It appeared, as he recalls, over the course of a week and has subsequently grown. The lesion, which is now rather large, bleeds copiously with minor trauma. It causes only modest discomfort to the patient but considerable worry to his family.

The lesion was originally tiny and tag-like; the patient initially mistook it for a tick and tried to pull it off. Not only did that fail to work, it also seemed to irritate the lesion. At that point, it started to swell, eventually transforming into the lesion he presents with today.

The patient’s history is otherwise uneventful, and he reports taking no medications. He has had minimal sun exposure but says he tans easily when he does get some sun.

EXAMINATION
The lesion, measuring 5 mm x 2.5 mm, is a dark red and pedunculated papule on the crown of the right shoulder. It looks edematous and feels firm. The patient has otherwise unremarkable type IV skin.

Shave biopsy is performed, using a double-edged razor to make a shallow concave defect under the lesion. The wound is cauterized.

What is the diagnosis?

DISCUSSION
The pathology report confirmed the clinical suspicion of pyogenic granuloma, which, ironically, is neither pyogenic nor granulomatous. The condition acquired this name more than 100 years ago, based on assumptions about its origin. Microscopic examination revealed the highly vascular nature of these lesions, showing a field full of circles that represented the truncated ends of bundles of capillaries and venules. Although they are also called lobular capillary hemangiomas, the term pyogenic granuloma (PG) is still more commonly used.

PGs commonly manifest in the patient’s second or third decade of life, typically on extremities, chest, and nipples. This patient’s story is typical: His lesion began as a tag or wart that he then traumatized, creating a situation in which the body attempts (in vain) to heal the wound. Undisturbed, nearly all PGs would eventually wither and resolve with minimal scarring; however, that process is prolonged when the patient fails to “leave it alone.” (This is especially true in the case of young children.)

While this presentation is characteristic, there are other circumstances in which PGs develop. One is as a consequence of taking certain medications (eg, retinoids, antiretrovirals, and certain chemotherapy drugs). PGs are also commonly seen in the oral cavity of pregnant women in the third trimester and on the end of the umbilical stump in many newborns. Ingrown toenails are another common site; PGs will appear as glistening red, friable buttons of vascular tissue in the perionychial skin adjacent to the affected portion of the nail.

Shave biopsy is standard in such cases, not only to produce a cure but also to establish, via pathologic examination of the tissue, the correct diagnosis. (Nodular melanoma is the most prominent item in the differential; to miss that diagnosis would have dire consequences.) In terms of treatment, mere cautery or cryotherapy will not work and excision is seldom necessary. A deep shave will capture the entire lesion; if any remains, electrodessication and curettage will take care of it. Prior to such procedures, the patient (and family) needs to understand that scarring and pigment loss will occur.

In cases associated with medications or with ingrown toenails, the “cure” would be to withdraw the offending medications—although this is not always advisable for other, obvious reasons.

TAKE-HOME LEARNING POINTS
• Pyogenic granulomas (PG) have nothing to do with infection, nor are they truly granulomatous.

• PGs bleed readily with minor trauma and are often swollen and occasionally painful.

• PGs appear to represent, in most cases, the body’s frustrated attempt to heal a wound, most often a prick or pinch of a pre-existing lesion (eg, tag or mole).

• PGs are also seen in other contexts, such as with use of certain medications or in association with pregnancy.

• If treatment is attempted, the resulting specimen must be submitted for pathologic examination, since other lesions can mimic PGs (of most concern, nodular melanoma).

Four months ago, this 23-year-old man developed a lesion on his right shoulder. It appeared, as he recalls, over the course of a week and has subsequently grown. The lesion, which is now rather large, bleeds copiously with minor trauma. It causes only modest discomfort to the patient but considerable worry to his family.

The lesion was originally tiny and tag-like; the patient initially mistook it for a tick and tried to pull it off. Not only did that fail to work, it also seemed to irritate the lesion. At that point, it started to swell, eventually transforming into the lesion he presents with today.

The patient’s history is otherwise uneventful, and he reports taking no medications. He has had minimal sun exposure but says he tans easily when he does get some sun.

EXAMINATION
The lesion, measuring 5 mm x 2.5 mm, is a dark red and pedunculated papule on the crown of the right shoulder. It looks edematous and feels firm. The patient has otherwise unremarkable type IV skin.

Shave biopsy is performed, using a double-edged razor to make a shallow concave defect under the lesion. The wound is cauterized.

What is the diagnosis?

DISCUSSION
The pathology report confirmed the clinical suspicion of pyogenic granuloma, which, ironically, is neither pyogenic nor granulomatous. The condition acquired this name more than 100 years ago, based on assumptions about its origin. Microscopic examination revealed the highly vascular nature of these lesions, showing a field full of circles that represented the truncated ends of bundles of capillaries and venules. Although they are also called lobular capillary hemangiomas, the term pyogenic granuloma (PG) is still more commonly used.

PGs commonly manifest in the patient’s second or third decade of life, typically on extremities, chest, and nipples. This patient’s story is typical: His lesion began as a tag or wart that he then traumatized, creating a situation in which the body attempts (in vain) to heal the wound. Undisturbed, nearly all PGs would eventually wither and resolve with minimal scarring; however, that process is prolonged when the patient fails to “leave it alone.” (This is especially true in the case of young children.)

While this presentation is characteristic, there are other circumstances in which PGs develop. One is as a consequence of taking certain medications (eg, retinoids, antiretrovirals, and certain chemotherapy drugs). PGs are also commonly seen in the oral cavity of pregnant women in the third trimester and on the end of the umbilical stump in many newborns. Ingrown toenails are another common site; PGs will appear as glistening red, friable buttons of vascular tissue in the perionychial skin adjacent to the affected portion of the nail.

Shave biopsy is standard in such cases, not only to produce a cure but also to establish, via pathologic examination of the tissue, the correct diagnosis. (Nodular melanoma is the most prominent item in the differential; to miss that diagnosis would have dire consequences.) In terms of treatment, mere cautery or cryotherapy will not work and excision is seldom necessary. A deep shave will capture the entire lesion; if any remains, electrodessication and curettage will take care of it. Prior to such procedures, the patient (and family) needs to understand that scarring and pigment loss will occur.

In cases associated with medications or with ingrown toenails, the “cure” would be to withdraw the offending medications—although this is not always advisable for other, obvious reasons.

TAKE-HOME LEARNING POINTS
• Pyogenic granulomas (PG) have nothing to do with infection, nor are they truly granulomatous.

• PGs bleed readily with minor trauma and are often swollen and occasionally painful.

• PGs appear to represent, in most cases, the body’s frustrated attempt to heal a wound, most often a prick or pinch of a pre-existing lesion (eg, tag or mole).

• PGs are also seen in other contexts, such as with use of certain medications or in association with pregnancy.

• If treatment is attempted, the resulting specimen must be submitted for pathologic examination, since other lesions can mimic PGs (of most concern, nodular melanoma).

Four months ago, this 23-year-old man developed a lesion on his right shoulder. It appeared, as he recalls, over the course of a week and has subsequently grown. The lesion, which is now rather large, bleeds copiously with minor trauma. It causes only modest discomfort to the patient but considerable worry to his family.

The lesion was originally tiny and tag-like; the patient initially mistook it for a tick and tried to pull it off. Not only did that fail to work, it also seemed to irritate the lesion. At that point, it started to swell, eventually transforming into the lesion he presents with today.

The patient’s history is otherwise uneventful, and he reports taking no medications. He has had minimal sun exposure but says he tans easily when he does get some sun.

EXAMINATION
The lesion, measuring 5 mm x 2.5 mm, is a dark red and pedunculated papule on the crown of the right shoulder. It looks edematous and feels firm. The patient has otherwise unremarkable type IV skin.

Shave biopsy is performed, using a double-edged razor to make a shallow concave defect under the lesion. The wound is cauterized.

What is the diagnosis?

DISCUSSION
The pathology report confirmed the clinical suspicion of pyogenic granuloma, which, ironically, is neither pyogenic nor granulomatous. The condition acquired this name more than 100 years ago, based on assumptions about its origin. Microscopic examination revealed the highly vascular nature of these lesions, showing a field full of circles that represented the truncated ends of bundles of capillaries and venules. Although they are also called lobular capillary hemangiomas, the term pyogenic granuloma (PG) is still more commonly used.

PGs commonly manifest in the patient’s second or third decade of life, typically on extremities, chest, and nipples. This patient’s story is typical: His lesion began as a tag or wart that he then traumatized, creating a situation in which the body attempts (in vain) to heal the wound. Undisturbed, nearly all PGs would eventually wither and resolve with minimal scarring; however, that process is prolonged when the patient fails to “leave it alone.” (This is especially true in the case of young children.)

While this presentation is characteristic, there are other circumstances in which PGs develop. One is as a consequence of taking certain medications (eg, retinoids, antiretrovirals, and certain chemotherapy drugs). PGs are also commonly seen in the oral cavity of pregnant women in the third trimester and on the end of the umbilical stump in many newborns. Ingrown toenails are another common site; PGs will appear as glistening red, friable buttons of vascular tissue in the perionychial skin adjacent to the affected portion of the nail.

Shave biopsy is standard in such cases, not only to produce a cure but also to establish, via pathologic examination of the tissue, the correct diagnosis. (Nodular melanoma is the most prominent item in the differential; to miss that diagnosis would have dire consequences.) In terms of treatment, mere cautery or cryotherapy will not work and excision is seldom necessary. A deep shave will capture the entire lesion; if any remains, electrodessication and curettage will take care of it. Prior to such procedures, the patient (and family) needs to understand that scarring and pigment loss will occur.

In cases associated with medications or with ingrown toenails, the “cure” would be to withdraw the offending medications—although this is not always advisable for other, obvious reasons.

TAKE-HOME LEARNING POINTS
• Pyogenic granulomas (PG) have nothing to do with infection, nor are they truly granulomatous.

• PGs bleed readily with minor trauma and are often swollen and occasionally painful.

• PGs appear to represent, in most cases, the body’s frustrated attempt to heal a wound, most often a prick or pinch of a pre-existing lesion (eg, tag or mole).

• PGs are also seen in other contexts, such as with use of certain medications or in association with pregnancy.

• If treatment is attempted, the resulting specimen must be submitted for pathologic examination, since other lesions can mimic PGs (of most concern, nodular melanoma).

Hematopoietic stem cells

in the bone marrow

Two new studies have revealed elements that are key to hematopoietic stem and progenitor cell (HSPC) mobilization.

In one study, investigators discovered that elevated levels of the peptide hormone angiotensin II increases HSPC mobilization in the context of vasculopathy and sickle cell disease (SCD).

In the other study, researchers found that p62, an autophagy regulator and signal organizer, is required to maintain HSPC retention in the bone marrow.

Jose Cancelas, MD, PhD, of the University of Cincinnati College of Medicine in Ohio, is the corresponding author on both studies.

In the first paper, published in Nature Communications, Dr Cancelas and his colleagues noted that patients with vasculopathies have an increase in circulating HSPCs.

“This phenomenon may represent a stress response contributing to vascular damage repair,” he said. “So the question becomes, how can we learn from these patients?”

Using mouse models of vasculopathy and vasculopathy-associated SCD, Dr Cancelas and his colleagues showed that acute and chronic elevated levels of angiotensin II resulted in an increased pool of HSPCs.

And when the researchers administered anti-angiotensin therapy, the pool of HSPCs decreased in mice and humans with SCD.

“These results indicate a new role for angiotensin in hematopoietic stem and progenitor cell trafficking under pathological conditions and define the hematopoietic consequences of anti-angiotensin therapy in vascular disease and sickle cell disease,” Dr Cancelas said.

“Every year, millions of patients receive anti-angiotensin therapies due to the harmful effects associated with chronic hyperangiotensinemia in cardiac, renal, or liver failure. Our study shows that this anti-angiotensin therapy modulates the levels of circulating stem cells and progenitors.”

In the second paper, published in Cell Reports, Dr Cancelas and his colleagues examined the role that p62 plays in HSPC mobilization.

The investigators found that, when p62 is lost in osteoblasts, mice develop a condition similar to osteoporosis in humans.

The osteoblasts cannot degrade inflammatory signals coming from macrophages. And as a consequence, the deficient osteoblasts secrete inflammatory signals that impair the retention of HSPCs in the bone marrow and allow their escape to the circulation.

Specifically, the team found that macrophages activate osteoblastic NF-kB, which results in osteopenia and HSPC egress. And p62 negatively regulates osteoblastic NF-kB activation.

Dr Cancelas noted that patients with inflammatory diseases often have osteopenia. So this research may provide insight into that phenomenon and help explain why patients with chronic inflammatory diseases have higher levels of circulating HSPCs.

Hematopoietic stem cells

in the bone marrow

Two new studies have revealed elements that are key to hematopoietic stem and progenitor cell (HSPC) mobilization.

In one study, investigators discovered that elevated levels of the peptide hormone angiotensin II increases HSPC mobilization in the context of vasculopathy and sickle cell disease (SCD).

In the other study, researchers found that p62, an autophagy regulator and signal organizer, is required to maintain HSPC retention in the bone marrow.

Jose Cancelas, MD, PhD, of the University of Cincinnati College of Medicine in Ohio, is the corresponding author on both studies.

In the first paper, published in Nature Communications, Dr Cancelas and his colleagues noted that patients with vasculopathies have an increase in circulating HSPCs.

“This phenomenon may represent a stress response contributing to vascular damage repair,” he said. “So the question becomes, how can we learn from these patients?”

Using mouse models of vasculopathy and vasculopathy-associated SCD, Dr Cancelas and his colleagues showed that acute and chronic elevated levels of angiotensin II resulted in an increased pool of HSPCs.

And when the researchers administered anti-angiotensin therapy, the pool of HSPCs decreased in mice and humans with SCD.

“These results indicate a new role for angiotensin in hematopoietic stem and progenitor cell trafficking under pathological conditions and define the hematopoietic consequences of anti-angiotensin therapy in vascular disease and sickle cell disease,” Dr Cancelas said.

“Every year, millions of patients receive anti-angiotensin therapies due to the harmful effects associated with chronic hyperangiotensinemia in cardiac, renal, or liver failure. Our study shows that this anti-angiotensin therapy modulates the levels of circulating stem cells and progenitors.”

In the second paper, published in Cell Reports, Dr Cancelas and his colleagues examined the role that p62 plays in HSPC mobilization.

The investigators found that, when p62 is lost in osteoblasts, mice develop a condition similar to osteoporosis in humans.

The osteoblasts cannot degrade inflammatory signals coming from macrophages. And as a consequence, the deficient osteoblasts secrete inflammatory signals that impair the retention of HSPCs in the bone marrow and allow their escape to the circulation.

Specifically, the team found that macrophages activate osteoblastic NF-kB, which results in osteopenia and HSPC egress. And p62 negatively regulates osteoblastic NF-kB activation.

Dr Cancelas noted that patients with inflammatory diseases often have osteopenia. So this research may provide insight into that phenomenon and help explain why patients with chronic inflammatory diseases have higher levels of circulating HSPCs.

Hematopoietic stem cells

in the bone marrow

Two new studies have revealed elements that are key to hematopoietic stem and progenitor cell (HSPC) mobilization.

In one study, investigators discovered that elevated levels of the peptide hormone angiotensin II increases HSPC mobilization in the context of vasculopathy and sickle cell disease (SCD).

In the other study, researchers found that p62, an autophagy regulator and signal organizer, is required to maintain HSPC retention in the bone marrow.

Jose Cancelas, MD, PhD, of the University of Cincinnati College of Medicine in Ohio, is the corresponding author on both studies.

In the first paper, published in Nature Communications, Dr Cancelas and his colleagues noted that patients with vasculopathies have an increase in circulating HSPCs.

“This phenomenon may represent a stress response contributing to vascular damage repair,” he said. “So the question becomes, how can we learn from these patients?”

Using mouse models of vasculopathy and vasculopathy-associated SCD, Dr Cancelas and his colleagues showed that acute and chronic elevated levels of angiotensin II resulted in an increased pool of HSPCs.

And when the researchers administered anti-angiotensin therapy, the pool of HSPCs decreased in mice and humans with SCD.

“These results indicate a new role for angiotensin in hematopoietic stem and progenitor cell trafficking under pathological conditions and define the hematopoietic consequences of anti-angiotensin therapy in vascular disease and sickle cell disease,” Dr Cancelas said.

“Every year, millions of patients receive anti-angiotensin therapies due to the harmful effects associated with chronic hyperangiotensinemia in cardiac, renal, or liver failure. Our study shows that this anti-angiotensin therapy modulates the levels of circulating stem cells and progenitors.”

In the second paper, published in Cell Reports, Dr Cancelas and his colleagues examined the role that p62 plays in HSPC mobilization.

The investigators found that, when p62 is lost in osteoblasts, mice develop a condition similar to osteoporosis in humans.

The osteoblasts cannot degrade inflammatory signals coming from macrophages. And as a consequence, the deficient osteoblasts secrete inflammatory signals that impair the retention of HSPCs in the bone marrow and allow their escape to the circulation.

Specifically, the team found that macrophages activate osteoblastic NF-kB, which results in osteopenia and HSPC egress. And p62 negatively regulates osteoblastic NF-kB activation.

Dr Cancelas noted that patients with inflammatory diseases often have osteopenia. So this research may provide insight into that phenomenon and help explain why patients with chronic inflammatory diseases have higher levels of circulating HSPCs.

Patient consults pharmacist

Credit: Rhoda Baer

The European Commission (EC) has concluded that ponatinib (Iclusig) should continue to be prescribed in accordance with its already approved indications.

After trial results suggested the drug poses an increased risk of thrombotic events, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) conducted a review of available ponatinib data.

Results of that review suggested the benefits of ponatinib outweigh the risks. So the committee said the drug should be prescribed as indicated.

The EMA’s Committee for Medicinal Products for Human Use (CHMP) recently endorsed this recommendation, and, now, the EC has followed suit. The EC’s decision is legally binding.

Ponatinib is approved in the European Union to treat adults with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia who are resistant to dasatinib or nilotinib, who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.

The drug is also approved to treat adults with Philadelphia-chromosome positive acute lymphoblastic leukemia who are resistant to dasatinib, who cannot tolerate dasatinib and subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.

In October 2013, extended follow-up data from the PACE trial revealed that ponatinib-treated patients had a higher incidence of arterial and venous thrombotic events than was observed when the drug first gained approval. So one ponatinib trial was discontinued, and the rest were placed on partial clinical hold.

Soon after, ponatinib was pulled from the US market. The drug ultimately returned to the marketplace with new recommendations designed to decrease the risk of thrombotic events.

The EMA also revised its recommendations for ponatinib—discouraging use of the drug in certain patients, providing advice for managing comorbidities, and suggesting patient monitoring—but kept the drug on the market.

In October 2014, the PRAC concluded its 11-month review of ponatinib data, confirming that the benefit-risk profile of the drug was favorable in its approved indications and recommending that the indications remain unchanged.

However, the PRAC also said the risk of vascular occlusive events with ponatinib is likely dose-related. So the committee recommended that healthcare professionals monitor ponatinib-treated patients and consider dose reductions or discontinuing the drug in certain patients.

The CHMP endorsed these recommendations, and, now, the EC has as well. This is a legally binding decision for ponatinib to continue to be prescribed in Europe in accordance with its already approved indications.

Ponatinib is being developed by ARIAD Pharmaceuticals, Inc.

Patient consults pharmacist

Credit: Rhoda Baer

The European Commission (EC) has concluded that ponatinib (Iclusig) should continue to be prescribed in accordance with its already approved indications.

After trial results suggested the drug poses an increased risk of thrombotic events, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) conducted a review of available ponatinib data.

Results of that review suggested the benefits of ponatinib outweigh the risks. So the committee said the drug should be prescribed as indicated.

The EMA’s Committee for Medicinal Products for Human Use (CHMP) recently endorsed this recommendation, and, now, the EC has followed suit. The EC’s decision is legally binding.

Ponatinib is approved in the European Union to treat adults with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia who are resistant to dasatinib or nilotinib, who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.

The drug is also approved to treat adults with Philadelphia-chromosome positive acute lymphoblastic leukemia who are resistant to dasatinib, who cannot tolerate dasatinib and subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.

In October 2013, extended follow-up data from the PACE trial revealed that ponatinib-treated patients had a higher incidence of arterial and venous thrombotic events than was observed when the drug first gained approval. So one ponatinib trial was discontinued, and the rest were placed on partial clinical hold.

Soon after, ponatinib was pulled from the US market. The drug ultimately returned to the marketplace with new recommendations designed to decrease the risk of thrombotic events.

The EMA also revised its recommendations for ponatinib—discouraging use of the drug in certain patients, providing advice for managing comorbidities, and suggesting patient monitoring—but kept the drug on the market.

In October 2014, the PRAC concluded its 11-month review of ponatinib data, confirming that the benefit-risk profile of the drug was favorable in its approved indications and recommending that the indications remain unchanged.

However, the PRAC also said the risk of vascular occlusive events with ponatinib is likely dose-related. So the committee recommended that healthcare professionals monitor ponatinib-treated patients and consider dose reductions or discontinuing the drug in certain patients.

The CHMP endorsed these recommendations, and, now, the EC has as well. This is a legally binding decision for ponatinib to continue to be prescribed in Europe in accordance with its already approved indications.

Ponatinib is being developed by ARIAD Pharmaceuticals, Inc.

Patient consults pharmacist

Credit: Rhoda Baer

The European Commission (EC) has concluded that ponatinib (Iclusig) should continue to be prescribed in accordance with its already approved indications.

After trial results suggested the drug poses an increased risk of thrombotic events, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) conducted a review of available ponatinib data.

Results of that review suggested the benefits of ponatinib outweigh the risks. So the committee said the drug should be prescribed as indicated.

The EMA’s Committee for Medicinal Products for Human Use (CHMP) recently endorsed this recommendation, and, now, the EC has followed suit. The EC’s decision is legally binding.

Ponatinib is approved in the European Union to treat adults with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia who are resistant to dasatinib or nilotinib, who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.

The drug is also approved to treat adults with Philadelphia-chromosome positive acute lymphoblastic leukemia who are resistant to dasatinib, who cannot tolerate dasatinib and subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.

In October 2013, extended follow-up data from the PACE trial revealed that ponatinib-treated patients had a higher incidence of arterial and venous thrombotic events than was observed when the drug first gained approval. So one ponatinib trial was discontinued, and the rest were placed on partial clinical hold.

Soon after, ponatinib was pulled from the US market. The drug ultimately returned to the marketplace with new recommendations designed to decrease the risk of thrombotic events.

The EMA also revised its recommendations for ponatinib—discouraging use of the drug in certain patients, providing advice for managing comorbidities, and suggesting patient monitoring—but kept the drug on the market.

In October 2014, the PRAC concluded its 11-month review of ponatinib data, confirming that the benefit-risk profile of the drug was favorable in its approved indications and recommending that the indications remain unchanged.

However, the PRAC also said the risk of vascular occlusive events with ponatinib is likely dose-related. So the committee recommended that healthcare professionals monitor ponatinib-treated patients and consider dose reductions or discontinuing the drug in certain patients.

The CHMP endorsed these recommendations, and, now, the EC has as well. This is a legally binding decision for ponatinib to continue to be prescribed in Europe in accordance with its already approved indications.

Ponatinib is being developed by ARIAD Pharmaceuticals, Inc.

Child receives malaria vaccine

Credit: Caitlin Kleiboer

New research suggests that combining the use of malaria vaccines and insecticide-treated bed nets may actually increase the incidence of malaria.

The researchers used a mathematical model of malaria transmission to examine potential interactions between vaccines and bed nets.

They found that using insecticide-treated bed nets along with pre-erythrocytic vaccines (PEVs) or blood-stage vaccines (BSVs) increased the number of malaria cases.

However, using bed nets in conjunction with transmission-blocking vaccines (TBVs) resulted in fewer cases of malaria and increased the probability of eliminating the disease.

“The joint use of bed nets and vaccines will not always lead to consistent increases in the efficacy of malaria control,” said study author Mercedes Pascual, PhD, of the University of Michigan in Ann Arbor.

“Specifically, our study suggests that the combined use of some malaria vaccines with bed nets can lead to increased morbidity and mortality in older age classes.”

Dr Pascual and her colleagues described this research in Proceedings of the National Academy of Sciences.

The team noted that the malaria vaccine candidates currently under development fall into 3 categories, each focusing on a different stage of the malaria life cycle.

PEVs aim to reduce the chances that a person will be infected when bitten by a disease-carrying mosquito. BSVs don’t block infection but try to reduce the level of disease severity and the number of fatalities.

And TBVs don’t protect vaccinated individuals against infection or illness, but they prevent mosquitoes from spreading the disease to others after biting a vaccinated person.

Dr Pascual and her colleagues found that using bed nets in communities treated with BSVs can increase levels of morbidity—to levels even higher than those expected in the absence of nets. Furthermore, BSVs can’t promote malaria elimination on their own.

PEVs can promote malaria elimination, but the researchers found regions of decreased morbidity when PEV vaccination levels were low and increased morbidity when PEV vaccination levels were high.

This suggests that higher levels of PEV coverage and bed net use could result in malaria elimination, but it would involve crossing a peak of enhanced morbidity.

Finally, the researchers found that using bed nets in communities treated with TBVs always leads to significant decreases in morbidity and increases the probability of malaria elimination.

“Ironically, the vaccines that work best with bed nets are the ones that do not protect the vaccinated host—the bed net does that—but instead block transmission of malaria in mosquitoes that have found an opportunity to bite vaccinated hosts,” said study author Yael Artzy-Randrup, PhD, of the University of Amsterdam in The Netherlands.

Unraveling the interactions between bed nets and vaccines is especially challenging due to the complex and transient nature of malaria immunity, the researchers noted.

A child’s first malaria infection can result in severe, sometimes fatal, illness. If the child survives, he or she will gain partial immunity that reduces the risk of severe illness in the future.

Additional bites from infected mosquitoes can help the child retain that immunity, which would otherwise wane after 1 to 2 years. But the combination of bed nets and certain vaccines can undermine that natural immunity.

“This complexity is at the heart of why it has been so hard to develop any sort of malaria vaccine,” said study author Andrew Dobson, DPhil, of Princeton University in New Jersey.

Child receives malaria vaccine

Credit: Caitlin Kleiboer

New research suggests that combining the use of malaria vaccines and insecticide-treated bed nets may actually increase the incidence of malaria.

The researchers used a mathematical model of malaria transmission to examine potential interactions between vaccines and bed nets.

They found that using insecticide-treated bed nets along with pre-erythrocytic vaccines (PEVs) or blood-stage vaccines (BSVs) increased the number of malaria cases.

However, using bed nets in conjunction with transmission-blocking vaccines (TBVs) resulted in fewer cases of malaria and increased the probability of eliminating the disease.

“The joint use of bed nets and vaccines will not always lead to consistent increases in the efficacy of malaria control,” said study author Mercedes Pascual, PhD, of the University of Michigan in Ann Arbor.

“Specifically, our study suggests that the combined use of some malaria vaccines with bed nets can lead to increased morbidity and mortality in older age classes.”

Dr Pascual and her colleagues described this research in Proceedings of the National Academy of Sciences.

The team noted that the malaria vaccine candidates currently under development fall into 3 categories, each focusing on a different stage of the malaria life cycle.

PEVs aim to reduce the chances that a person will be infected when bitten by a disease-carrying mosquito. BSVs don’t block infection but try to reduce the level of disease severity and the number of fatalities.

And TBVs don’t protect vaccinated individuals against infection or illness, but they prevent mosquitoes from spreading the disease to others after biting a vaccinated person.

Dr Pascual and her colleagues found that using bed nets in communities treated with BSVs can increase levels of morbidity—to levels even higher than those expected in the absence of nets. Furthermore, BSVs can’t promote malaria elimination on their own.

PEVs can promote malaria elimination, but the researchers found regions of decreased morbidity when PEV vaccination levels were low and increased morbidity when PEV vaccination levels were high.

This suggests that higher levels of PEV coverage and bed net use could result in malaria elimination, but it would involve crossing a peak of enhanced morbidity.

Finally, the researchers found that using bed nets in communities treated with TBVs always leads to significant decreases in morbidity and increases the probability of malaria elimination.

“Ironically, the vaccines that work best with bed nets are the ones that do not protect the vaccinated host—the bed net does that—but instead block transmission of malaria in mosquitoes that have found an opportunity to bite vaccinated hosts,” said study author Yael Artzy-Randrup, PhD, of the University of Amsterdam in The Netherlands.

Unraveling the interactions between bed nets and vaccines is especially challenging due to the complex and transient nature of malaria immunity, the researchers noted.

A child’s first malaria infection can result in severe, sometimes fatal, illness. If the child survives, he or she will gain partial immunity that reduces the risk of severe illness in the future.

Additional bites from infected mosquitoes can help the child retain that immunity, which would otherwise wane after 1 to 2 years. But the combination of bed nets and certain vaccines can undermine that natural immunity.

“This complexity is at the heart of why it has been so hard to develop any sort of malaria vaccine,” said study author Andrew Dobson, DPhil, of Princeton University in New Jersey.

Child receives malaria vaccine

Credit: Caitlin Kleiboer

New research suggests that combining the use of malaria vaccines and insecticide-treated bed nets may actually increase the incidence of malaria.

The researchers used a mathematical model of malaria transmission to examine potential interactions between vaccines and bed nets.

They found that using insecticide-treated bed nets along with pre-erythrocytic vaccines (PEVs) or blood-stage vaccines (BSVs) increased the number of malaria cases.

However, using bed nets in conjunction with transmission-blocking vaccines (TBVs) resulted in fewer cases of malaria and increased the probability of eliminating the disease.

“The joint use of bed nets and vaccines will not always lead to consistent increases in the efficacy of malaria control,” said study author Mercedes Pascual, PhD, of the University of Michigan in Ann Arbor.

“Specifically, our study suggests that the combined use of some malaria vaccines with bed nets can lead to increased morbidity and mortality in older age classes.”

Dr Pascual and her colleagues described this research in Proceedings of the National Academy of Sciences.

The team noted that the malaria vaccine candidates currently under development fall into 3 categories, each focusing on a different stage of the malaria life cycle.

PEVs aim to reduce the chances that a person will be infected when bitten by a disease-carrying mosquito. BSVs don’t block infection but try to reduce the level of disease severity and the number of fatalities.

And TBVs don’t protect vaccinated individuals against infection or illness, but they prevent mosquitoes from spreading the disease to others after biting a vaccinated person.

Dr Pascual and her colleagues found that using bed nets in communities treated with BSVs can increase levels of morbidity—to levels even higher than those expected in the absence of nets. Furthermore, BSVs can’t promote malaria elimination on their own.

PEVs can promote malaria elimination, but the researchers found regions of decreased morbidity when PEV vaccination levels were low and increased morbidity when PEV vaccination levels were high.

This suggests that higher levels of PEV coverage and bed net use could result in malaria elimination, but it would involve crossing a peak of enhanced morbidity.

Finally, the researchers found that using bed nets in communities treated with TBVs always leads to significant decreases in morbidity and increases the probability of malaria elimination.

“Ironically, the vaccines that work best with bed nets are the ones that do not protect the vaccinated host—the bed net does that—but instead block transmission of malaria in mosquitoes that have found an opportunity to bite vaccinated hosts,” said study author Yael Artzy-Randrup, PhD, of the University of Amsterdam in The Netherlands.

Unraveling the interactions between bed nets and vaccines is especially challenging due to the complex and transient nature of malaria immunity, the researchers noted.

A child’s first malaria infection can result in severe, sometimes fatal, illness. If the child survives, he or she will gain partial immunity that reduces the risk of severe illness in the future.

Additional bites from infected mosquitoes can help the child retain that immunity, which would otherwise wane after 1 to 2 years. But the combination of bed nets and certain vaccines can undermine that natural immunity.

“This complexity is at the heart of why it has been so hard to develop any sort of malaria vaccine,” said study author Andrew Dobson, DPhil, of Princeton University in New Jersey.

Patients who develop HCV infections after liver transplant may respond to a 24-week course of sofosbuvir and ribavirin, Dr. Michael Charlton, of the Mayo Clinic in Rochester, Minn., and his colleagues reported.

The researchers enrolled and treated 40 liver transplant patients with compensated recurrent HCV infection of any genotype; 83% had HCV genotype 1, 40% had cirrhosis (based on biopsy), and 88% had been previously treated with interferon. All patients received 24 weeks of sofosbuvir 400 mg daily and ribavirin starting at 400 mg daily, which was adjusted according to creatinine clearance and hemoglobin values, the researchers said in the January 2015 issue of Gastroenterology.

After 12 weeks, 28 of 40 had a sustained virologic response (70%; 90% confidence interval: 56%−82%). Relapse accounted for all cases of virologic failure. No patients had detectable viral resistance during or after treatment.

Click here to read the study: http://www.ncbi.nlm.nih.gov/pubmed/25304641

Patients who develop HCV infections after liver transplant may respond to a 24-week course of sofosbuvir and ribavirin, Dr. Michael Charlton, of the Mayo Clinic in Rochester, Minn., and his colleagues reported.

The researchers enrolled and treated 40 liver transplant patients with compensated recurrent HCV infection of any genotype; 83% had HCV genotype 1, 40% had cirrhosis (based on biopsy), and 88% had been previously treated with interferon. All patients received 24 weeks of sofosbuvir 400 mg daily and ribavirin starting at 400 mg daily, which was adjusted according to creatinine clearance and hemoglobin values, the researchers said in the January 2015 issue of Gastroenterology.

After 12 weeks, 28 of 40 had a sustained virologic response (70%; 90% confidence interval: 56%−82%). Relapse accounted for all cases of virologic failure. No patients had detectable viral resistance during or after treatment.

Click here to read the study: http://www.ncbi.nlm.nih.gov/pubmed/25304641

Patients who develop HCV infections after liver transplant may respond to a 24-week course of sofosbuvir and ribavirin, Dr. Michael Charlton, of the Mayo Clinic in Rochester, Minn., and his colleagues reported.

The researchers enrolled and treated 40 liver transplant patients with compensated recurrent HCV infection of any genotype; 83% had HCV genotype 1, 40% had cirrhosis (based on biopsy), and 88% had been previously treated with interferon. All patients received 24 weeks of sofosbuvir 400 mg daily and ribavirin starting at 400 mg daily, which was adjusted according to creatinine clearance and hemoglobin values, the researchers said in the January 2015 issue of Gastroenterology.

After 12 weeks, 28 of 40 had a sustained virologic response (70%; 90% confidence interval: 56%−82%). Relapse accounted for all cases of virologic failure. No patients had detectable viral resistance during or after treatment.

Click here to read the study: http://www.ncbi.nlm.nih.gov/pubmed/25304641

Sofosbuvir and ribavirin given before liver transplantation prevented most cases of post-transplant HCV recurrence, according to Dr. Michael P. Curry, of Beth Israel Deaconess Medical Center, Boston, and his colleagues.

Up to 48 weeks of sofosbuvir (400 mg) and ribavirin were given to hepatocellular carcinoma patients on organ transplant waitlists. The patients had HCV of any genotype and cirrhosis (Child–Turcotte–Pugh score of 7 or less). The primary end point of the study (ClinicalTrials.gov: NCT01559844) was the proportion of 43 patients who had HCV-RNA levels of less than 25 IU/ml at transplant and at 12 weeks after transplant.

Of the 43 patients, 30 (70%) had a post-transplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died, the researchers reported in the January issue of Gastroenterology.

Click here to read the entire article: http://www.gastrojournal.org/article/S0016-5085%2814%2901145-7/fulltext

Sofosbuvir and ribavirin given before liver transplantation prevented most cases of post-transplant HCV recurrence, according to Dr. Michael P. Curry, of Beth Israel Deaconess Medical Center, Boston, and his colleagues.

Up to 48 weeks of sofosbuvir (400 mg) and ribavirin were given to hepatocellular carcinoma patients on organ transplant waitlists. The patients had HCV of any genotype and cirrhosis (Child–Turcotte–Pugh score of 7 or less). The primary end point of the study (ClinicalTrials.gov: NCT01559844) was the proportion of 43 patients who had HCV-RNA levels of less than 25 IU/ml at transplant and at 12 weeks after transplant.

Of the 43 patients, 30 (70%) had a post-transplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died, the researchers reported in the January issue of Gastroenterology.

Click here to read the entire article: http://www.gastrojournal.org/article/S0016-5085%2814%2901145-7/fulltext

Sofosbuvir and ribavirin given before liver transplantation prevented most cases of post-transplant HCV recurrence, according to Dr. Michael P. Curry, of Beth Israel Deaconess Medical Center, Boston, and his colleagues.

Up to 48 weeks of sofosbuvir (400 mg) and ribavirin were given to hepatocellular carcinoma patients on organ transplant waitlists. The patients had HCV of any genotype and cirrhosis (Child–Turcotte–Pugh score of 7 or less). The primary end point of the study (ClinicalTrials.gov: NCT01559844) was the proportion of 43 patients who had HCV-RNA levels of less than 25 IU/ml at transplant and at 12 weeks after transplant.

Of the 43 patients, 30 (70%) had a post-transplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died, the researchers reported in the January issue of Gastroenterology.

Click here to read the entire article: http://www.gastrojournal.org/article/S0016-5085%2814%2901145-7/fulltext