Aspergillus fumigatus

WASHINGTON, DC—A new antifungal agent is as effective as an existing drug against invasive mold infection in patients with hematologic disorders, results of a phase 3 trial suggest.

Overall response and all-cause mortality rates were comparable with the newer drug, isavuconazole (ISA), and the existing drug, voriconazole (VRC).

The overall rates of treatment-emergent adverse events were comparable as well, but ISA was associated with a significantly lower incidence of several events.

Kieren Marr, MD, of Johns Hopkins University in Baltimore, Maryland, and her colleagues presented these results in a subset of patients from the SECURE trial at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (poster M-1757).

Patient characteristics and safety outcomes

Of the 433 patients with a hematologic disorder enrolled in the trial, 217 had proven or probable invasive mold infection. The researchers divided patients into 2 groups according to disease: those with acute myeloid leukemia (AML) and those with acute lymphoblastic leukemia (ALL) or other conditions.

In all, 102 patients had AML, and 115 had ALL (n=28) or other conditions, including non-Hodgkin lymphoma (n=19), chronic lymphocytic leukemia (n=15), refractory anemia with excess blasts (n=9), myelodysplastic syndrome (n=8), chronic myeloid leukemia (n=6), and “other” underlying conditions (n=30).

Patients were randomized to receive VRC (n=105) or ISA (N=112). Thirty patients in the ISA arm and 26 in the VRC arm had undergone allogeneic transplant prior to therapy.

The primary outcome was all-cause mortality at day 42. Overall response and safety were secondary endpoints.

The overall rates of treatment-emergent adverse events were similar between ISA and VRC arms. Ninety-seven percent of patients in the ISA arm and 98% of patients in the VRC arm reported at least 1 treatment-emergent adverse event.

However, patients in the ISA arm had significantly fewer (P<0.05) events for the cardiac disorders, eye, psychiatric disorders, renal and urinary, and vascular system organ classes.

Response and mortality

All-cause mortality rates were comparable between the ISA and VRC arms—22% and 24%, respectively—as were overall response rates—39% and 34%, respectively—and complete response rates—13% and 10%, respectively.

All-cause mortality rates among patients with AML were 18% in the ISA arm and 15% in the VRC arm. Overall response rates were 36% and 48%, respectively.

For patients with ALL or other hematologic conditions, all-cause mortality rates were 26% in the ISA arm and 32% in the VRC arm. Overall response rates were 42% and 21%, respectively.

In transplant patients, the all-cause mortality rate was 27% for both the ISA and VRC arms. The overall response rate was 27% for both arms as well.

“These results show the potential of isavuconazole as a potent antifungal in the fight against invasive mold disease,” Dr Marr said.

ISA is an investigational antifungal under development by Astellas and Basilea Pharmaceutica International Ltd. The SECURE trial was funded by Astellas.

The US Food and Drug Administration recently accepted a new drug application seeking approval for ISA for the treatment of invasive aspergillosis and invasive mucormycosis.

Aspergillus fumigatus

WASHINGTON, DC—A new antifungal agent is as effective as an existing drug against invasive mold infection in patients with hematologic disorders, results of a phase 3 trial suggest.

Overall response and all-cause mortality rates were comparable with the newer drug, isavuconazole (ISA), and the existing drug, voriconazole (VRC).

The overall rates of treatment-emergent adverse events were comparable as well, but ISA was associated with a significantly lower incidence of several events.

Kieren Marr, MD, of Johns Hopkins University in Baltimore, Maryland, and her colleagues presented these results in a subset of patients from the SECURE trial at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (poster M-1757).

Patient characteristics and safety outcomes

Of the 433 patients with a hematologic disorder enrolled in the trial, 217 had proven or probable invasive mold infection. The researchers divided patients into 2 groups according to disease: those with acute myeloid leukemia (AML) and those with acute lymphoblastic leukemia (ALL) or other conditions.

In all, 102 patients had AML, and 115 had ALL (n=28) or other conditions, including non-Hodgkin lymphoma (n=19), chronic lymphocytic leukemia (n=15), refractory anemia with excess blasts (n=9), myelodysplastic syndrome (n=8), chronic myeloid leukemia (n=6), and “other” underlying conditions (n=30).

Patients were randomized to receive VRC (n=105) or ISA (N=112). Thirty patients in the ISA arm and 26 in the VRC arm had undergone allogeneic transplant prior to therapy.

The primary outcome was all-cause mortality at day 42. Overall response and safety were secondary endpoints.

The overall rates of treatment-emergent adverse events were similar between ISA and VRC arms. Ninety-seven percent of patients in the ISA arm and 98% of patients in the VRC arm reported at least 1 treatment-emergent adverse event.

However, patients in the ISA arm had significantly fewer (P<0.05) events for the cardiac disorders, eye, psychiatric disorders, renal and urinary, and vascular system organ classes.

Response and mortality

All-cause mortality rates were comparable between the ISA and VRC arms—22% and 24%, respectively—as were overall response rates—39% and 34%, respectively—and complete response rates—13% and 10%, respectively.

All-cause mortality rates among patients with AML were 18% in the ISA arm and 15% in the VRC arm. Overall response rates were 36% and 48%, respectively.

For patients with ALL or other hematologic conditions, all-cause mortality rates were 26% in the ISA arm and 32% in the VRC arm. Overall response rates were 42% and 21%, respectively.

In transplant patients, the all-cause mortality rate was 27% for both the ISA and VRC arms. The overall response rate was 27% for both arms as well.

“These results show the potential of isavuconazole as a potent antifungal in the fight against invasive mold disease,” Dr Marr said.

ISA is an investigational antifungal under development by Astellas and Basilea Pharmaceutica International Ltd. The SECURE trial was funded by Astellas.

The US Food and Drug Administration recently accepted a new drug application seeking approval for ISA for the treatment of invasive aspergillosis and invasive mucormycosis.

Aspergillus fumigatus

WASHINGTON, DC—A new antifungal agent is as effective as an existing drug against invasive mold infection in patients with hematologic disorders, results of a phase 3 trial suggest.

Overall response and all-cause mortality rates were comparable with the newer drug, isavuconazole (ISA), and the existing drug, voriconazole (VRC).

The overall rates of treatment-emergent adverse events were comparable as well, but ISA was associated with a significantly lower incidence of several events.

Kieren Marr, MD, of Johns Hopkins University in Baltimore, Maryland, and her colleagues presented these results in a subset of patients from the SECURE trial at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (poster M-1757).

Patient characteristics and safety outcomes

Of the 433 patients with a hematologic disorder enrolled in the trial, 217 had proven or probable invasive mold infection. The researchers divided patients into 2 groups according to disease: those with acute myeloid leukemia (AML) and those with acute lymphoblastic leukemia (ALL) or other conditions.

In all, 102 patients had AML, and 115 had ALL (n=28) or other conditions, including non-Hodgkin lymphoma (n=19), chronic lymphocytic leukemia (n=15), refractory anemia with excess blasts (n=9), myelodysplastic syndrome (n=8), chronic myeloid leukemia (n=6), and “other” underlying conditions (n=30).

Patients were randomized to receive VRC (n=105) or ISA (N=112). Thirty patients in the ISA arm and 26 in the VRC arm had undergone allogeneic transplant prior to therapy.

The primary outcome was all-cause mortality at day 42. Overall response and safety were secondary endpoints.

The overall rates of treatment-emergent adverse events were similar between ISA and VRC arms. Ninety-seven percent of patients in the ISA arm and 98% of patients in the VRC arm reported at least 1 treatment-emergent adverse event.

However, patients in the ISA arm had significantly fewer (P<0.05) events for the cardiac disorders, eye, psychiatric disorders, renal and urinary, and vascular system organ classes.

Response and mortality

All-cause mortality rates were comparable between the ISA and VRC arms—22% and 24%, respectively—as were overall response rates—39% and 34%, respectively—and complete response rates—13% and 10%, respectively.

All-cause mortality rates among patients with AML were 18% in the ISA arm and 15% in the VRC arm. Overall response rates were 36% and 48%, respectively.

For patients with ALL or other hematologic conditions, all-cause mortality rates were 26% in the ISA arm and 32% in the VRC arm. Overall response rates were 42% and 21%, respectively.

In transplant patients, the all-cause mortality rate was 27% for both the ISA and VRC arms. The overall response rate was 27% for both arms as well.

“These results show the potential of isavuconazole as a potent antifungal in the fight against invasive mold disease,” Dr Marr said.

ISA is an investigational antifungal under development by Astellas and Basilea Pharmaceutica International Ltd. The SECURE trial was funded by Astellas.

The US Food and Drug Administration recently accepted a new drug application seeking approval for ISA for the treatment of invasive aspergillosis and invasive mucormycosis.

Skin biopsy showing GVHD

Credit: PLOS ONE

Results of a retrospective study have revealed factors that appear to increase the risk of vitiligo and alopecia areata (AA) in patients who develop chronic graft-vs-host disease (cGVHD) after a stem cell transplant.

Multivariable analysis suggested that a female donor to male recipient sex mismatch and positive test results for anticardiolipin immunoglobulin G (ACA-IgG) were both significantly associated with vitiligo and/or AA.

This research was published in JAMA Dermatology.

Edward W. Cowen, MD, of the National Cancer Institute in Bethesda, Maryland, and his colleagues conducted the study in 282 adult and pediatric patients with cGVHD.

Fifteen of the patients (5.3%) had vitiligo and/or AA. One patient had only AA, 1 had vitiligo and AA, and the rest had vitiligo alone. The median age of these patients at enrollment was 38 years (range, 9-69 years), and most were male (n=10).

Most patients had received a transplant to treat chronic myelogenous leukemia (n=5) or acute leukemia/myelodysplastic syndrome (n=5). Most patients (n=13) had an HLA-identical donor and received a peripheral blood stem cell transplant (n=9).

Eleven patients had concomitant skin cGVHD at the time of evaluation, and it was most often sclerotic-type cGVHD (n=9).

For the 5 vitiligo patients in whom the onset of skin depigmentation was documented, pigment changes occurred at a median of 41 months (range, 24-84) after transplant.

Depigmentation was classic periorbital, perioral, acrofacial involvement in 6 patients, generalized in 6 patients, and torso-predominant in 2 patients. Trichrome vitiligo was present in 3 patients, and poliosis occurred in 5 patients. In both AA patients, hair loss was localized to the scalp.

The researchers evaluated demographic, clinical, and laboratory data from these patients, and used univariate and multivariable logistic regression analyses to identify risk factors for vitiligo and AA.

Univariate analysis suggested the following factors were significantly associated with vitiligo and/or AA: female donor to male recipient sex mismatch (P=0.003), positive test results for ACA-IgG (P=0.03) or antiparietal antibody (P=0.049), elevated CD19 (P=0.045), and normal or elevated IgG (P=0.02).

However, only positive ACA-IgG results and female donor to male recipient mismatch retained significance in multivariable analysis (P=0.01 and P=0.003, respectively).

The researchers said additional studies are needed to clarify whether these risk factors can lead to a better understanding of the pathomechanisms of cGVHD.

Skin biopsy showing GVHD

Credit: PLOS ONE

Results of a retrospective study have revealed factors that appear to increase the risk of vitiligo and alopecia areata (AA) in patients who develop chronic graft-vs-host disease (cGVHD) after a stem cell transplant.

Multivariable analysis suggested that a female donor to male recipient sex mismatch and positive test results for anticardiolipin immunoglobulin G (ACA-IgG) were both significantly associated with vitiligo and/or AA.

This research was published in JAMA Dermatology.

Edward W. Cowen, MD, of the National Cancer Institute in Bethesda, Maryland, and his colleagues conducted the study in 282 adult and pediatric patients with cGVHD.

Fifteen of the patients (5.3%) had vitiligo and/or AA. One patient had only AA, 1 had vitiligo and AA, and the rest had vitiligo alone. The median age of these patients at enrollment was 38 years (range, 9-69 years), and most were male (n=10).

Most patients had received a transplant to treat chronic myelogenous leukemia (n=5) or acute leukemia/myelodysplastic syndrome (n=5). Most patients (n=13) had an HLA-identical donor and received a peripheral blood stem cell transplant (n=9).

Eleven patients had concomitant skin cGVHD at the time of evaluation, and it was most often sclerotic-type cGVHD (n=9).

For the 5 vitiligo patients in whom the onset of skin depigmentation was documented, pigment changes occurred at a median of 41 months (range, 24-84) after transplant.

Depigmentation was classic periorbital, perioral, acrofacial involvement in 6 patients, generalized in 6 patients, and torso-predominant in 2 patients. Trichrome vitiligo was present in 3 patients, and poliosis occurred in 5 patients. In both AA patients, hair loss was localized to the scalp.

The researchers evaluated demographic, clinical, and laboratory data from these patients, and used univariate and multivariable logistic regression analyses to identify risk factors for vitiligo and AA.

Univariate analysis suggested the following factors were significantly associated with vitiligo and/or AA: female donor to male recipient sex mismatch (P=0.003), positive test results for ACA-IgG (P=0.03) or antiparietal antibody (P=0.049), elevated CD19 (P=0.045), and normal or elevated IgG (P=0.02).

However, only positive ACA-IgG results and female donor to male recipient mismatch retained significance in multivariable analysis (P=0.01 and P=0.003, respectively).

The researchers said additional studies are needed to clarify whether these risk factors can lead to a better understanding of the pathomechanisms of cGVHD.

Skin biopsy showing GVHD

Credit: PLOS ONE

Results of a retrospective study have revealed factors that appear to increase the risk of vitiligo and alopecia areata (AA) in patients who develop chronic graft-vs-host disease (cGVHD) after a stem cell transplant.

Multivariable analysis suggested that a female donor to male recipient sex mismatch and positive test results for anticardiolipin immunoglobulin G (ACA-IgG) were both significantly associated with vitiligo and/or AA.

This research was published in JAMA Dermatology.

Edward W. Cowen, MD, of the National Cancer Institute in Bethesda, Maryland, and his colleagues conducted the study in 282 adult and pediatric patients with cGVHD.

Fifteen of the patients (5.3%) had vitiligo and/or AA. One patient had only AA, 1 had vitiligo and AA, and the rest had vitiligo alone. The median age of these patients at enrollment was 38 years (range, 9-69 years), and most were male (n=10).

Most patients had received a transplant to treat chronic myelogenous leukemia (n=5) or acute leukemia/myelodysplastic syndrome (n=5). Most patients (n=13) had an HLA-identical donor and received a peripheral blood stem cell transplant (n=9).

Eleven patients had concomitant skin cGVHD at the time of evaluation, and it was most often sclerotic-type cGVHD (n=9).

For the 5 vitiligo patients in whom the onset of skin depigmentation was documented, pigment changes occurred at a median of 41 months (range, 24-84) after transplant.

Depigmentation was classic periorbital, perioral, acrofacial involvement in 6 patients, generalized in 6 patients, and torso-predominant in 2 patients. Trichrome vitiligo was present in 3 patients, and poliosis occurred in 5 patients. In both AA patients, hair loss was localized to the scalp.

The researchers evaluated demographic, clinical, and laboratory data from these patients, and used univariate and multivariable logistic regression analyses to identify risk factors for vitiligo and AA.

Univariate analysis suggested the following factors were significantly associated with vitiligo and/or AA: female donor to male recipient sex mismatch (P=0.003), positive test results for ACA-IgG (P=0.03) or antiparietal antibody (P=0.049), elevated CD19 (P=0.045), and normal or elevated IgG (P=0.02).

However, only positive ACA-IgG results and female donor to male recipient mismatch retained significance in multivariable analysis (P=0.01 and P=0.003, respectively).

The researchers said additional studies are needed to clarify whether these risk factors can lead to a better understanding of the pathomechanisms of cGVHD.

Between the ongoing shortage of child psychiatrists, ever-evolving changes in health care policy and medical insurance, and documented increases in the rates of many psychiatric disorders, it can be difficult for pediatricians to define their role in delivering quality mental health care. To get some perspective on these issues, I talked with Dr. Joseph F. Hagan Jr., a pediatrician from Burlington, Vt. Dr. Hagan has been involved in shaping pediatric mental health care policy for years as the former chair of the American Academy of Pediatrics’ (AAP) Committee on the Psychosocial Aspects of Child & Family Health and current member of the Bright Futures Steering Committee. He is also running this year to be the president-elect of the national AAP.

Q: What do you see as some of the key issues affecting child mental health care?

A: One of the things I haven’t heard a lot about is that there are not enough therapists to see children. The system has traditionally been based upon procedures and not on time, and that’s a problem. Therapists get paid less than the shop rate of your local auto mechanic, and of course, anyone who sees children has to talk with schools and parents outside of the session. That’s nonbillable, and we wonder why nobody will see children. Mental health is part of health, and the earlier we invest, the bigger the return. Because our practice was certified as a Family Centered Medical Home and now has access to a Community Health Team, my life has changed because we now have services that we didn’t have before. The problem with screening in the past has been "What if you find something?" Now we have so much more to offer.

Q: How much should a pediatrician really be expected to know and do when it comes to child behavioral problems? Is there a floor of knowledge and skills when it comes to mental health that all pediatricians should attain?

A: I think there definitely is. I would say that this could happen in steps. The AAP’s Taskforce for Mental Health really helped lay this out, but we already knew this. Behavioral and mental health problems can be managed in our offices, and everyone ought to be able to manage the majority of children with attention-deficit/hyperactivity disorder (ADHD), but also those with oppositional defiant disorder, anxiety, and depression. There are certain mental health problems that are part of pediatrics. To refer a standard ADHD child is absurd, because it really is a day-to-day problem that needs to be managed in your primary care medical home. Everybody needs to know how to do that and do it well. It is a chronic illness, and you need to hang in there with these children. That’s the basic floor. I think the floor is extended in being able to identify postpartum depression because we know that’s crucial and to be able to identify families who are really struggling with social determinants of health. This is going to be a big push in the forthcoming edition of Bright Futures. I think you also need to be able to identify anxiety and depression and be able to take the first steps in that. And maybe you should know how to treat them with selective serotonin reuptake inhibitors (SSRIs) if that should become important. I think you also should be able to talk about preventive things and ought to know that there is this thing called CBT (cognitive-behavioral therapy), and which therapists are in town who do CBT. You’ve got to know your community nonmedication options and access them before you decide upon meds.

Q: Psychiatric medications certainly have become even more controversial lately. What advice do you have for pediatricians when they prescribe them?

A: Tell families the expected effects and potential side effects. If you don’t, Dr. Google will. Start low and go slow, but titrate until desired effect of recovery. Remember if you are 100% anxious and miserable, you’ll look and feel great when you’re only 50% anxious, but you’re still only halfway better! It’s also important to discuss with your patient when you start meds, how long you are going to continue them, lest they feel good and stop prematurely.

Q: There are a lot of efforts these days to extend the education of pediatricians and provide consulting back up while the patient remains directly in the care of pediatrician. Do you think those efforts are enough or should we be more focused on providing more psychiatrists and other mental health clinicians that pediatricians can refer to?

A: We need to be able to do this (mental health) work, but part of being successful is having someone to consult with and someone to refer to. Just like with cardiac or GI problems, there are cases we can take care of all by ourselves, cases in which we will need to reach out to a consultant for help, and cases that need referral. Yes, we need more child psychiatrists. Co-located and collaborative care are the best-case scenarios.

More information about mental health care from the American Academy of Pediatrics can be found if you click here.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. He is the author of "Child Temperament: New Thinking About the Boundary between Traits and Illness." Follow him on Twitter @pedipsych.

Between the ongoing shortage of child psychiatrists, ever-evolving changes in health care policy and medical insurance, and documented increases in the rates of many psychiatric disorders, it can be difficult for pediatricians to define their role in delivering quality mental health care. To get some perspective on these issues, I talked with Dr. Joseph F. Hagan Jr., a pediatrician from Burlington, Vt. Dr. Hagan has been involved in shaping pediatric mental health care policy for years as the former chair of the American Academy of Pediatrics’ (AAP) Committee on the Psychosocial Aspects of Child & Family Health and current member of the Bright Futures Steering Committee. He is also running this year to be the president-elect of the national AAP.

Q: What do you see as some of the key issues affecting child mental health care?

A: One of the things I haven’t heard a lot about is that there are not enough therapists to see children. The system has traditionally been based upon procedures and not on time, and that’s a problem. Therapists get paid less than the shop rate of your local auto mechanic, and of course, anyone who sees children has to talk with schools and parents outside of the session. That’s nonbillable, and we wonder why nobody will see children. Mental health is part of health, and the earlier we invest, the bigger the return. Because our practice was certified as a Family Centered Medical Home and now has access to a Community Health Team, my life has changed because we now have services that we didn’t have before. The problem with screening in the past has been "What if you find something?" Now we have so much more to offer.

Q: How much should a pediatrician really be expected to know and do when it comes to child behavioral problems? Is there a floor of knowledge and skills when it comes to mental health that all pediatricians should attain?

A: I think there definitely is. I would say that this could happen in steps. The AAP’s Taskforce for Mental Health really helped lay this out, but we already knew this. Behavioral and mental health problems can be managed in our offices, and everyone ought to be able to manage the majority of children with attention-deficit/hyperactivity disorder (ADHD), but also those with oppositional defiant disorder, anxiety, and depression. There are certain mental health problems that are part of pediatrics. To refer a standard ADHD child is absurd, because it really is a day-to-day problem that needs to be managed in your primary care medical home. Everybody needs to know how to do that and do it well. It is a chronic illness, and you need to hang in there with these children. That’s the basic floor. I think the floor is extended in being able to identify postpartum depression because we know that’s crucial and to be able to identify families who are really struggling with social determinants of health. This is going to be a big push in the forthcoming edition of Bright Futures. I think you also need to be able to identify anxiety and depression and be able to take the first steps in that. And maybe you should know how to treat them with selective serotonin reuptake inhibitors (SSRIs) if that should become important. I think you also should be able to talk about preventive things and ought to know that there is this thing called CBT (cognitive-behavioral therapy), and which therapists are in town who do CBT. You’ve got to know your community nonmedication options and access them before you decide upon meds.

Q: Psychiatric medications certainly have become even more controversial lately. What advice do you have for pediatricians when they prescribe them?

A: Tell families the expected effects and potential side effects. If you don’t, Dr. Google will. Start low and go slow, but titrate until desired effect of recovery. Remember if you are 100% anxious and miserable, you’ll look and feel great when you’re only 50% anxious, but you’re still only halfway better! It’s also important to discuss with your patient when you start meds, how long you are going to continue them, lest they feel good and stop prematurely.

Q: There are a lot of efforts these days to extend the education of pediatricians and provide consulting back up while the patient remains directly in the care of pediatrician. Do you think those efforts are enough or should we be more focused on providing more psychiatrists and other mental health clinicians that pediatricians can refer to?

A: We need to be able to do this (mental health) work, but part of being successful is having someone to consult with and someone to refer to. Just like with cardiac or GI problems, there are cases we can take care of all by ourselves, cases in which we will need to reach out to a consultant for help, and cases that need referral. Yes, we need more child psychiatrists. Co-located and collaborative care are the best-case scenarios.

More information about mental health care from the American Academy of Pediatrics can be found if you click here.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. He is the author of "Child Temperament: New Thinking About the Boundary between Traits and Illness." Follow him on Twitter @pedipsych.

Between the ongoing shortage of child psychiatrists, ever-evolving changes in health care policy and medical insurance, and documented increases in the rates of many psychiatric disorders, it can be difficult for pediatricians to define their role in delivering quality mental health care. To get some perspective on these issues, I talked with Dr. Joseph F. Hagan Jr., a pediatrician from Burlington, Vt. Dr. Hagan has been involved in shaping pediatric mental health care policy for years as the former chair of the American Academy of Pediatrics’ (AAP) Committee on the Psychosocial Aspects of Child & Family Health and current member of the Bright Futures Steering Committee. He is also running this year to be the president-elect of the national AAP.

Q: What do you see as some of the key issues affecting child mental health care?

A: One of the things I haven’t heard a lot about is that there are not enough therapists to see children. The system has traditionally been based upon procedures and not on time, and that’s a problem. Therapists get paid less than the shop rate of your local auto mechanic, and of course, anyone who sees children has to talk with schools and parents outside of the session. That’s nonbillable, and we wonder why nobody will see children. Mental health is part of health, and the earlier we invest, the bigger the return. Because our practice was certified as a Family Centered Medical Home and now has access to a Community Health Team, my life has changed because we now have services that we didn’t have before. The problem with screening in the past has been "What if you find something?" Now we have so much more to offer.

Q: How much should a pediatrician really be expected to know and do when it comes to child behavioral problems? Is there a floor of knowledge and skills when it comes to mental health that all pediatricians should attain?

A: I think there definitely is. I would say that this could happen in steps. The AAP’s Taskforce for Mental Health really helped lay this out, but we already knew this. Behavioral and mental health problems can be managed in our offices, and everyone ought to be able to manage the majority of children with attention-deficit/hyperactivity disorder (ADHD), but also those with oppositional defiant disorder, anxiety, and depression. There are certain mental health problems that are part of pediatrics. To refer a standard ADHD child is absurd, because it really is a day-to-day problem that needs to be managed in your primary care medical home. Everybody needs to know how to do that and do it well. It is a chronic illness, and you need to hang in there with these children. That’s the basic floor. I think the floor is extended in being able to identify postpartum depression because we know that’s crucial and to be able to identify families who are really struggling with social determinants of health. This is going to be a big push in the forthcoming edition of Bright Futures. I think you also need to be able to identify anxiety and depression and be able to take the first steps in that. And maybe you should know how to treat them with selective serotonin reuptake inhibitors (SSRIs) if that should become important. I think you also should be able to talk about preventive things and ought to know that there is this thing called CBT (cognitive-behavioral therapy), and which therapists are in town who do CBT. You’ve got to know your community nonmedication options and access them before you decide upon meds.

Q: Psychiatric medications certainly have become even more controversial lately. What advice do you have for pediatricians when they prescribe them?

A: Tell families the expected effects and potential side effects. If you don’t, Dr. Google will. Start low and go slow, but titrate until desired effect of recovery. Remember if you are 100% anxious and miserable, you’ll look and feel great when you’re only 50% anxious, but you’re still only halfway better! It’s also important to discuss with your patient when you start meds, how long you are going to continue them, lest they feel good and stop prematurely.

Q: There are a lot of efforts these days to extend the education of pediatricians and provide consulting back up while the patient remains directly in the care of pediatrician. Do you think those efforts are enough or should we be more focused on providing more psychiatrists and other mental health clinicians that pediatricians can refer to?

A: We need to be able to do this (mental health) work, but part of being successful is having someone to consult with and someone to refer to. Just like with cardiac or GI problems, there are cases we can take care of all by ourselves, cases in which we will need to reach out to a consultant for help, and cases that need referral. Yes, we need more child psychiatrists. Co-located and collaborative care are the best-case scenarios.

More information about mental health care from the American Academy of Pediatrics can be found if you click here.

Dr. Rettew is an associate professor of psychiatry and pediatrics at the University of Vermont, Burlington. He is the author of "Child Temperament: New Thinking About the Boundary between Traits and Illness." Follow him on Twitter @pedipsych.

SAN FRANCISCO – Dr. Eleftherios (Terry) Mamounas reviews the first day of the annual breast cancer symposium sponsored by the American Society of Clinical Oncology.

Key sessions covered the increasingly complex topic of genetic risk assessment and stirred up the debate about management of ductal carcinoma in situ (DCIS). Dr. Mamounas, professor of surgery at the University of Central Florida and medical director of the comprehensive breast program at the University of Florida Health Cancer Center, both in Orlando, discusses the significance of atypical hyperplasia, including new data suggesting that the fourfold increased risk of developing breast cancer in women with ductal carcinoma in situ (DCIS) is not further worsened by having a family history of DCIS.

Among the top oral presentations, one study suggested that a nomogram helped predict the risk of locoregional recurrence in patients treated for breast cancer using accelerated partial-breast irradiation. Another study examined the effect of hormone receptor status and local treatment on overall survival for patients with early-stage breast cancer.

Dr. Mamounas also discusses his own study, which he presented at the meeting, showing lower rates of locoregional recurrence in patients who have a pathologic complete response to neoadjuvant therapy. He puts the findings in context with tips on how to incorporate pathologic complete response data into clinical practice.

A separate study reported some of the first data on complication rates after unilateral or bilateral mastectomy and reconstruction. Dr. Mamounas wraps up the day’s review by discussing sessions on the effect of luteinizing hormone-releasing hormone agonists during chemotherapy in preserving ovarian function, and on breast cancer prevention, including the use of aromatase inhibitors.

For more of the meeting’s highlights, see our video interviews with Dr. Hope S. Rugo discussing the events of the second and third days of the Breast Cancer Symposium. Dr. Rugo is director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

Dr. Mamounas reported financial associations with Genomic Health, Genentech/Roche, Pfizer, GlaxoSmithKline, Eisai, Celgene, and GE Healthcare.

[email protected]

On Twitter @sherryboschert

SAN FRANCISCO – Dr. Eleftherios (Terry) Mamounas reviews the first day of the annual breast cancer symposium sponsored by the American Society of Clinical Oncology.

Key sessions covered the increasingly complex topic of genetic risk assessment and stirred up the debate about management of ductal carcinoma in situ (DCIS). Dr. Mamounas, professor of surgery at the University of Central Florida and medical director of the comprehensive breast program at the University of Florida Health Cancer Center, both in Orlando, discusses the significance of atypical hyperplasia, including new data suggesting that the fourfold increased risk of developing breast cancer in women with ductal carcinoma in situ (DCIS) is not further worsened by having a family history of DCIS.

Among the top oral presentations, one study suggested that a nomogram helped predict the risk of locoregional recurrence in patients treated for breast cancer using accelerated partial-breast irradiation. Another study examined the effect of hormone receptor status and local treatment on overall survival for patients with early-stage breast cancer.

Dr. Mamounas also discusses his own study, which he presented at the meeting, showing lower rates of locoregional recurrence in patients who have a pathologic complete response to neoadjuvant therapy. He puts the findings in context with tips on how to incorporate pathologic complete response data into clinical practice.

A separate study reported some of the first data on complication rates after unilateral or bilateral mastectomy and reconstruction. Dr. Mamounas wraps up the day’s review by discussing sessions on the effect of luteinizing hormone-releasing hormone agonists during chemotherapy in preserving ovarian function, and on breast cancer prevention, including the use of aromatase inhibitors.

For more of the meeting’s highlights, see our video interviews with Dr. Hope S. Rugo discussing the events of the second and third days of the Breast Cancer Symposium. Dr. Rugo is director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

Dr. Mamounas reported financial associations with Genomic Health, Genentech/Roche, Pfizer, GlaxoSmithKline, Eisai, Celgene, and GE Healthcare.

[email protected]

On Twitter @sherryboschert

SAN FRANCISCO – Dr. Eleftherios (Terry) Mamounas reviews the first day of the annual breast cancer symposium sponsored by the American Society of Clinical Oncology.

Key sessions covered the increasingly complex topic of genetic risk assessment and stirred up the debate about management of ductal carcinoma in situ (DCIS). Dr. Mamounas, professor of surgery at the University of Central Florida and medical director of the comprehensive breast program at the University of Florida Health Cancer Center, both in Orlando, discusses the significance of atypical hyperplasia, including new data suggesting that the fourfold increased risk of developing breast cancer in women with ductal carcinoma in situ (DCIS) is not further worsened by having a family history of DCIS.

Among the top oral presentations, one study suggested that a nomogram helped predict the risk of locoregional recurrence in patients treated for breast cancer using accelerated partial-breast irradiation. Another study examined the effect of hormone receptor status and local treatment on overall survival for patients with early-stage breast cancer.

Dr. Mamounas also discusses his own study, which he presented at the meeting, showing lower rates of locoregional recurrence in patients who have a pathologic complete response to neoadjuvant therapy. He puts the findings in context with tips on how to incorporate pathologic complete response data into clinical practice.

A separate study reported some of the first data on complication rates after unilateral or bilateral mastectomy and reconstruction. Dr. Mamounas wraps up the day’s review by discussing sessions on the effect of luteinizing hormone-releasing hormone agonists during chemotherapy in preserving ovarian function, and on breast cancer prevention, including the use of aromatase inhibitors.

For more of the meeting’s highlights, see our video interviews with Dr. Hope S. Rugo discussing the events of the second and third days of the Breast Cancer Symposium. Dr. Rugo is director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

Dr. Mamounas reported financial associations with Genomic Health, Genentech/Roche, Pfizer, GlaxoSmithKline, Eisai, Celgene, and GE Healthcare.

[email protected]

On Twitter @sherryboschert

Active-duty military personnel, members of the National Guard and reserve, veterans, military families, and health professionals all are provided unique resources for ongoing support when they visit the Real Warriors Campaign at http://www.realwarriors.net, launched by the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury. The public awareness campaign is intended “to promote the processes of building resilience, facilitating recovery, and supporting reintegration of returning service members, veterans, and their families.”

The Active Duty menu addresses broad topics, such as Signs and Symptoms of Combat Stress, Building Resilience, and After Deployment. Additional topics are drilled down for active-duty members of the Army, Navy, Marine Corps, and Air Force.

National Guard and reserve members are provided advice to assist in preparation for deployment, a reintegration guide for communicating with employers and family members, and coping and support.

The Veterans page directs users to resources provided through the VA; meanwhile, health care professionals are directed to TRICARE information, evidence-based treatment guidelines for PTSD and TBI, and original presentations of tools and tips, many of which can be ordered online at no cost.

Active-duty military personnel, members of the National Guard and reserve, veterans, military families, and health professionals all are provided unique resources for ongoing support when they visit the Real Warriors Campaign at http://www.realwarriors.net, launched by the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury. The public awareness campaign is intended “to promote the processes of building resilience, facilitating recovery, and supporting reintegration of returning service members, veterans, and their families.”

The Active Duty menu addresses broad topics, such as Signs and Symptoms of Combat Stress, Building Resilience, and After Deployment. Additional topics are drilled down for active-duty members of the Army, Navy, Marine Corps, and Air Force.

National Guard and reserve members are provided advice to assist in preparation for deployment, a reintegration guide for communicating with employers and family members, and coping and support.

The Veterans page directs users to resources provided through the VA; meanwhile, health care professionals are directed to TRICARE information, evidence-based treatment guidelines for PTSD and TBI, and original presentations of tools and tips, many of which can be ordered online at no cost.

Active-duty military personnel, members of the National Guard and reserve, veterans, military families, and health professionals all are provided unique resources for ongoing support when they visit the Real Warriors Campaign at http://www.realwarriors.net, launched by the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury. The public awareness campaign is intended “to promote the processes of building resilience, facilitating recovery, and supporting reintegration of returning service members, veterans, and their families.”

The Active Duty menu addresses broad topics, such as Signs and Symptoms of Combat Stress, Building Resilience, and After Deployment. Additional topics are drilled down for active-duty members of the Army, Navy, Marine Corps, and Air Force.

National Guard and reserve members are provided advice to assist in preparation for deployment, a reintegration guide for communicating with employers and family members, and coping and support.

The Veterans page directs users to resources provided through the VA; meanwhile, health care professionals are directed to TRICARE information, evidence-based treatment guidelines for PTSD and TBI, and original presentations of tools and tips, many of which can be ordered online at no cost.

Genome testing

Credit: NIGMS

Researchers have identified mutations in microRNAs (miRNAs) that are closely associated with certain global populations and have been implicated in cancers.

The group discovered 31 miRNAs containing variants that occur with different frequencies in African and non-African populations.

Seven of these miRNAs have been linked to the onset, progression, and spread of cancers with known health disparities between patients of European and African descent.

And a variant in one of these miRNAs is associated with a significantly increased risk of non-Hodgkin lymphoma (NHL).

These findings appear in BMC Medical Genomics.

To better understand miRNA diversity across the world, the researchers searched for miRNA variants in the genome sequences of 69 individuals from 14 populations in Europe, Asia, the Americas, and Africa. The samples included genetic material from diverse African populations, including 3 hunter-gatherer populations.

“We wanted to try to see if there was variability in miRNA that hadn’t been identified before,” said study author Renata A. Rawlings-Goss, PhD, of the University of Pennsylvania’s Perelman School of Medicine in Philadelphia.

Overall, the researchers found that miRNA sequences were similar across the populations they sampled. But they did identify 33 novel variants and found that variants in 31 miRNAs were population-differentiated.

The team searched available databases to see which genes these miRNAs were known to inhibit. Their query turned up a large proportion of genes involved in glucose and insulin metabolism, indicating a possible connection between diabetes risk and possessing one of these variants. The search also pointed to effects on genes implicated in cancers.

Specifically, 7 of the population-differentiated miRNAs are currently implicated as cancer biomarkers: hsa-mir-202, hsa-mir-423, hsa-mir-196a-2, hsa-mir-520h, hsa-mir-647, hsa-mir-943, and hsa-mir-1908.

Of particular interest was hsa-mir-202, which contained one of the most highly population-differentiated variants in the dataset and is under investigation as a marker for NHL and early stage breast cancer.

Recent research suggested that a T allele at SNP rs12355840 in hsa-mir-202 helps protect against death from breast cancer by increasing mature hsa-mir-202 expression levels, which leads to downregulation of its gene targets.

On the other hand, diminished expression of mature hsa-mir-202 in subjects harboring at least 1 non-T allele resulted in a significantly elevated risk of NHL (odds ratio=1.83, P=0.008).

Dr Rawlings-Goss and her colleagues found that African/African-American populations had a lower frequency of the T allele compared to European/Asian populations—26% vs 65%, on average. And this suggests decreased baseline expression levels of mature hsa-mir-202 in African populations.

“It’s becoming more and more apparent that miRNAs can have a broad-reaching and global effect on our health and adaptation to disease,” Dr Rawlings-Goss said. “Learning more about differences across populations could be helpful to doing early diagnostics and treating disease across diverse populations.”

Genome testing

Credit: NIGMS

Researchers have identified mutations in microRNAs (miRNAs) that are closely associated with certain global populations and have been implicated in cancers.

The group discovered 31 miRNAs containing variants that occur with different frequencies in African and non-African populations.

Seven of these miRNAs have been linked to the onset, progression, and spread of cancers with known health disparities between patients of European and African descent.

And a variant in one of these miRNAs is associated with a significantly increased risk of non-Hodgkin lymphoma (NHL).

These findings appear in BMC Medical Genomics.

To better understand miRNA diversity across the world, the researchers searched for miRNA variants in the genome sequences of 69 individuals from 14 populations in Europe, Asia, the Americas, and Africa. The samples included genetic material from diverse African populations, including 3 hunter-gatherer populations.

“We wanted to try to see if there was variability in miRNA that hadn’t been identified before,” said study author Renata A. Rawlings-Goss, PhD, of the University of Pennsylvania’s Perelman School of Medicine in Philadelphia.

Overall, the researchers found that miRNA sequences were similar across the populations they sampled. But they did identify 33 novel variants and found that variants in 31 miRNAs were population-differentiated.

The team searched available databases to see which genes these miRNAs were known to inhibit. Their query turned up a large proportion of genes involved in glucose and insulin metabolism, indicating a possible connection between diabetes risk and possessing one of these variants. The search also pointed to effects on genes implicated in cancers.

Specifically, 7 of the population-differentiated miRNAs are currently implicated as cancer biomarkers: hsa-mir-202, hsa-mir-423, hsa-mir-196a-2, hsa-mir-520h, hsa-mir-647, hsa-mir-943, and hsa-mir-1908.

Of particular interest was hsa-mir-202, which contained one of the most highly population-differentiated variants in the dataset and is under investigation as a marker for NHL and early stage breast cancer.

Recent research suggested that a T allele at SNP rs12355840 in hsa-mir-202 helps protect against death from breast cancer by increasing mature hsa-mir-202 expression levels, which leads to downregulation of its gene targets.

On the other hand, diminished expression of mature hsa-mir-202 in subjects harboring at least 1 non-T allele resulted in a significantly elevated risk of NHL (odds ratio=1.83, P=0.008).

Dr Rawlings-Goss and her colleagues found that African/African-American populations had a lower frequency of the T allele compared to European/Asian populations—26% vs 65%, on average. And this suggests decreased baseline expression levels of mature hsa-mir-202 in African populations.

“It’s becoming more and more apparent that miRNAs can have a broad-reaching and global effect on our health and adaptation to disease,” Dr Rawlings-Goss said. “Learning more about differences across populations could be helpful to doing early diagnostics and treating disease across diverse populations.”

Genome testing

Credit: NIGMS

Researchers have identified mutations in microRNAs (miRNAs) that are closely associated with certain global populations and have been implicated in cancers.

The group discovered 31 miRNAs containing variants that occur with different frequencies in African and non-African populations.

Seven of these miRNAs have been linked to the onset, progression, and spread of cancers with known health disparities between patients of European and African descent.

And a variant in one of these miRNAs is associated with a significantly increased risk of non-Hodgkin lymphoma (NHL).

These findings appear in BMC Medical Genomics.

To better understand miRNA diversity across the world, the researchers searched for miRNA variants in the genome sequences of 69 individuals from 14 populations in Europe, Asia, the Americas, and Africa. The samples included genetic material from diverse African populations, including 3 hunter-gatherer populations.

“We wanted to try to see if there was variability in miRNA that hadn’t been identified before,” said study author Renata A. Rawlings-Goss, PhD, of the University of Pennsylvania’s Perelman School of Medicine in Philadelphia.

Overall, the researchers found that miRNA sequences were similar across the populations they sampled. But they did identify 33 novel variants and found that variants in 31 miRNAs were population-differentiated.

The team searched available databases to see which genes these miRNAs were known to inhibit. Their query turned up a large proportion of genes involved in glucose and insulin metabolism, indicating a possible connection between diabetes risk and possessing one of these variants. The search also pointed to effects on genes implicated in cancers.

Specifically, 7 of the population-differentiated miRNAs are currently implicated as cancer biomarkers: hsa-mir-202, hsa-mir-423, hsa-mir-196a-2, hsa-mir-520h, hsa-mir-647, hsa-mir-943, and hsa-mir-1908.

Of particular interest was hsa-mir-202, which contained one of the most highly population-differentiated variants in the dataset and is under investigation as a marker for NHL and early stage breast cancer.

Recent research suggested that a T allele at SNP rs12355840 in hsa-mir-202 helps protect against death from breast cancer by increasing mature hsa-mir-202 expression levels, which leads to downregulation of its gene targets.

On the other hand, diminished expression of mature hsa-mir-202 in subjects harboring at least 1 non-T allele resulted in a significantly elevated risk of NHL (odds ratio=1.83, P=0.008).

Dr Rawlings-Goss and her colleagues found that African/African-American populations had a lower frequency of the T allele compared to European/Asian populations—26% vs 65%, on average. And this suggests decreased baseline expression levels of mature hsa-mir-202 in African populations.

“It’s becoming more and more apparent that miRNAs can have a broad-reaching and global effect on our health and adaptation to disease,” Dr Rawlings-Goss said. “Learning more about differences across populations could be helpful to doing early diagnostics and treating disease across diverse populations.”

The National Institutes of Health has launched an online public database called ClinRegs, which includes country-specific information on

clinical research regulations.

ClinRegs currently provides information for 12 countries, but additional countries will likely be added in the future.

The goal of ClinRegs is to make it easier for investigators to find and understand country-specific requirements on topics such as clinical trial application submission and ethics committee approvals.

The database allows users to review regulatory requirements in 7 topic areas, including informed consent practices and trial sponsorship.

The site was created—and will be updated—by the National Institute of Allergy and Infectious Diseases.

The National Institutes of Health has launched an online public database called ClinRegs, which includes country-specific information on

clinical research regulations.

ClinRegs currently provides information for 12 countries, but additional countries will likely be added in the future.

The goal of ClinRegs is to make it easier for investigators to find and understand country-specific requirements on topics such as clinical trial application submission and ethics committee approvals.

The database allows users to review regulatory requirements in 7 topic areas, including informed consent practices and trial sponsorship.

The site was created—and will be updated—by the National Institute of Allergy and Infectious Diseases.

The National Institutes of Health has launched an online public database called ClinRegs, which includes country-specific information on

clinical research regulations.

ClinRegs currently provides information for 12 countries, but additional countries will likely be added in the future.

The goal of ClinRegs is to make it easier for investigators to find and understand country-specific requirements on topics such as clinical trial application submission and ethics committee approvals.

The database allows users to review regulatory requirements in 7 topic areas, including informed consent practices and trial sponsorship.

The site was created—and will be updated—by the National Institute of Allergy and Infectious Diseases.

Bone marrow aspirate

showing multiple myeloma

A newly discovered mechanism has paved the way for the next generation of proteasome inhibitors, according to a paper published in Chemistry & Biology.

Investigators developed a series of molecules that employ this mechanism, inhibiting the proteasome in 2 ways.

They are now planning to synthesize related compounds that may offer improved proteasome inhibition, target cancer cells more selectivity, and eliminate the resistance problems that occur with current drugs.

The group’s research began with epoxyketone, a molecule isolated from a cyanobacterium called carmaphycin, whose reactive group is the same as that of the proteasome inhibitor carfilzomib.

“Epoxyketones are very potent, selective inhibitors of the proteasome because they interact with this enzyme in 2 stages—the first reversible, and the second irreversible,” noted study author Daniela Trivella, PhD, of the Brazilian Biosciences National Laboratory at the Brazilian Center for Research in Energy and Materials in Campinas.

To optimize epoxyketone’s effects and find new reactive groups, the investigators developed and tested a series of synthetic analogs with slight structural modifications.

One of the molecules had an enone as a reactive group and had characteristics of carmaphycin and another natural molecule called syringolin, which was isolated from plant pathogens.

By investigating the reaction mechanisms of the new molecule, called carmaphycin-syringolin enone, the team verified that the enone interacts with the proteasome in 2 stages, with the second stage being irreversible.

The investigators also observed that, in the case of the enone, the second reaction occurs more slowly, increasing the duration of the reversible phase of carmaphycin-syringolin enone inhibition.

“Because the irreversible inactivation of the proteasome has toxic effects, the best window of reversibility observed for the carmaphycin-syringolin enone will potentially reduce the toxicity of this new class of proteasome inhibitors,” Dr Trivella said. “The compound would therefore present a balance between selectivity and potency.”

Toxicity tests are still underway. But the investigators have already conducted studies to determine exactly how the interaction between the enzyme target and the carmaphycin-syringolin enone target occurs.

“We discovered that a chemical reaction called hydroamination occurs, which had never before [been] seen under physiological conditions,” Dr Trivella said.

“This type of reaction is frequently used by synthetic chemists in preparing substances, but, normally, it requires very specific temperature and pH conditions and the use of catalysts to occur. It has never been reported as a mechanism of enzyme inhibition.”

Inspired by this new mechanism for proteasome inhibition, the investigators plan to synthesize and test a new series of carmaphycin-syringolin enone analogs to determine their effects on the therapeutic window and assess whether they are also capable of reacting with proteasomes that are resistant to traditional inhibitors.

Bone marrow aspirate

showing multiple myeloma

A newly discovered mechanism has paved the way for the next generation of proteasome inhibitors, according to a paper published in Chemistry & Biology.

Investigators developed a series of molecules that employ this mechanism, inhibiting the proteasome in 2 ways.

They are now planning to synthesize related compounds that may offer improved proteasome inhibition, target cancer cells more selectivity, and eliminate the resistance problems that occur with current drugs.

The group’s research began with epoxyketone, a molecule isolated from a cyanobacterium called carmaphycin, whose reactive group is the same as that of the proteasome inhibitor carfilzomib.

“Epoxyketones are very potent, selective inhibitors of the proteasome because they interact with this enzyme in 2 stages—the first reversible, and the second irreversible,” noted study author Daniela Trivella, PhD, of the Brazilian Biosciences National Laboratory at the Brazilian Center for Research in Energy and Materials in Campinas.

To optimize epoxyketone’s effects and find new reactive groups, the investigators developed and tested a series of synthetic analogs with slight structural modifications.

One of the molecules had an enone as a reactive group and had characteristics of carmaphycin and another natural molecule called syringolin, which was isolated from plant pathogens.

By investigating the reaction mechanisms of the new molecule, called carmaphycin-syringolin enone, the team verified that the enone interacts with the proteasome in 2 stages, with the second stage being irreversible.

The investigators also observed that, in the case of the enone, the second reaction occurs more slowly, increasing the duration of the reversible phase of carmaphycin-syringolin enone inhibition.

“Because the irreversible inactivation of the proteasome has toxic effects, the best window of reversibility observed for the carmaphycin-syringolin enone will potentially reduce the toxicity of this new class of proteasome inhibitors,” Dr Trivella said. “The compound would therefore present a balance between selectivity and potency.”

Toxicity tests are still underway. But the investigators have already conducted studies to determine exactly how the interaction between the enzyme target and the carmaphycin-syringolin enone target occurs.

“We discovered that a chemical reaction called hydroamination occurs, which had never before [been] seen under physiological conditions,” Dr Trivella said.

“This type of reaction is frequently used by synthetic chemists in preparing substances, but, normally, it requires very specific temperature and pH conditions and the use of catalysts to occur. It has never been reported as a mechanism of enzyme inhibition.”

Inspired by this new mechanism for proteasome inhibition, the investigators plan to synthesize and test a new series of carmaphycin-syringolin enone analogs to determine their effects on the therapeutic window and assess whether they are also capable of reacting with proteasomes that are resistant to traditional inhibitors.

Bone marrow aspirate

showing multiple myeloma

A newly discovered mechanism has paved the way for the next generation of proteasome inhibitors, according to a paper published in Chemistry & Biology.

Investigators developed a series of molecules that employ this mechanism, inhibiting the proteasome in 2 ways.

They are now planning to synthesize related compounds that may offer improved proteasome inhibition, target cancer cells more selectivity, and eliminate the resistance problems that occur with current drugs.

The group’s research began with epoxyketone, a molecule isolated from a cyanobacterium called carmaphycin, whose reactive group is the same as that of the proteasome inhibitor carfilzomib.

“Epoxyketones are very potent, selective inhibitors of the proteasome because they interact with this enzyme in 2 stages—the first reversible, and the second irreversible,” noted study author Daniela Trivella, PhD, of the Brazilian Biosciences National Laboratory at the Brazilian Center for Research in Energy and Materials in Campinas.

To optimize epoxyketone’s effects and find new reactive groups, the investigators developed and tested a series of synthetic analogs with slight structural modifications.

One of the molecules had an enone as a reactive group and had characteristics of carmaphycin and another natural molecule called syringolin, which was isolated from plant pathogens.

By investigating the reaction mechanisms of the new molecule, called carmaphycin-syringolin enone, the team verified that the enone interacts with the proteasome in 2 stages, with the second stage being irreversible.

The investigators also observed that, in the case of the enone, the second reaction occurs more slowly, increasing the duration of the reversible phase of carmaphycin-syringolin enone inhibition.

“Because the irreversible inactivation of the proteasome has toxic effects, the best window of reversibility observed for the carmaphycin-syringolin enone will potentially reduce the toxicity of this new class of proteasome inhibitors,” Dr Trivella said. “The compound would therefore present a balance between selectivity and potency.”

Toxicity tests are still underway. But the investigators have already conducted studies to determine exactly how the interaction between the enzyme target and the carmaphycin-syringolin enone target occurs.

“We discovered that a chemical reaction called hydroamination occurs, which had never before [been] seen under physiological conditions,” Dr Trivella said.

“This type of reaction is frequently used by synthetic chemists in preparing substances, but, normally, it requires very specific temperature and pH conditions and the use of catalysts to occur. It has never been reported as a mechanism of enzyme inhibition.”

Inspired by this new mechanism for proteasome inhibition, the investigators plan to synthesize and test a new series of carmaphycin-syringolin enone analogs to determine their effects on the therapeutic window and assess whether they are also capable of reacting with proteasomes that are resistant to traditional inhibitors.

Doctor examines patient while

attending physician looks on

Credit: NCI

Research has shown that many patients with sickle cell disease (SCD) do not consistently follow their doctor’s orders, and a new study suggests discrimination may be partly to blame.

Patients who felt they experienced discrimination because of their race or health status were 53% more likely than their peers to disregard physician recommendations.

However, reports of discrimination were also common among patients who said they followed doctors’ orders to the letter.

Carlton Haywood Jr, PhD, of the Johns Hopkins School of Medicine in Baltimore, Maryland, and his colleagues conducted this research and detailed the results in the Journal of General Internal Medicine.

Dr Haywood’s team monitored the experiences of 291 SCD patients (aged 15 and older) who were participating in the Improving Patient Outcomes with Respect and Trust (IMPORT) study.

Patients completed surveys to report perceived discrimination from healthcare providers and their adherence to physician recommendations.

More than a third of patients (36%) reported non-adherence to a doctor’s recommendations in the 2 years prior to completing the survey.

Fifty-eight percent of the non-adherent patients and 43% of the adherent group reported at least 1 incident of discrimination due to their race or health status.

Patients who had experienced discrimination were 53% more likely than their peers to follow physicians’ recommendations inconsistently.

Trust in medical professionals appeared to mediate the discrimination/non-adherence relationship. It accounted for 50% of the excess prevalence of non-adherence among patients who reported incidents of discrimination.

The researchers said these findings are consistent with previous studies among other chronically ill patient groups. They also show how discrimination affects a patient’s trust in the healthcare system, as well as the person’s subsequent willingness to follow prescribed treatment regimens.

Dr Haywood believes the perceptions and experiences of discrimination may increase the chances that SCD patients will not fully benefit from the care available to them.

“A good relationship between the patient and provider can facilitate adherence, while a problematic relationship can negatively impact patient adherence,” he said.

“Improving relationships between healthcare providers and such patients may improve their trust in medical professionals, which, in turn, may improve other outcomes among this underserved patient population.”

Doctor examines patient while

attending physician looks on

Credit: NCI

Research has shown that many patients with sickle cell disease (SCD) do not consistently follow their doctor’s orders, and a new study suggests discrimination may be partly to blame.

Patients who felt they experienced discrimination because of their race or health status were 53% more likely than their peers to disregard physician recommendations.

However, reports of discrimination were also common among patients who said they followed doctors’ orders to the letter.

Carlton Haywood Jr, PhD, of the Johns Hopkins School of Medicine in Baltimore, Maryland, and his colleagues conducted this research and detailed the results in the Journal of General Internal Medicine.

Dr Haywood’s team monitored the experiences of 291 SCD patients (aged 15 and older) who were participating in the Improving Patient Outcomes with Respect and Trust (IMPORT) study.

Patients completed surveys to report perceived discrimination from healthcare providers and their adherence to physician recommendations.

More than a third of patients (36%) reported non-adherence to a doctor’s recommendations in the 2 years prior to completing the survey.

Fifty-eight percent of the non-adherent patients and 43% of the adherent group reported at least 1 incident of discrimination due to their race or health status.

Patients who had experienced discrimination were 53% more likely than their peers to follow physicians’ recommendations inconsistently.

Trust in medical professionals appeared to mediate the discrimination/non-adherence relationship. It accounted for 50% of the excess prevalence of non-adherence among patients who reported incidents of discrimination.

The researchers said these findings are consistent with previous studies among other chronically ill patient groups. They also show how discrimination affects a patient’s trust in the healthcare system, as well as the person’s subsequent willingness to follow prescribed treatment regimens.

Dr Haywood believes the perceptions and experiences of discrimination may increase the chances that SCD patients will not fully benefit from the care available to them.

“A good relationship between the patient and provider can facilitate adherence, while a problematic relationship can negatively impact patient adherence,” he said.

“Improving relationships between healthcare providers and such patients may improve their trust in medical professionals, which, in turn, may improve other outcomes among this underserved patient population.”

Doctor examines patient while

attending physician looks on

Credit: NCI

Research has shown that many patients with sickle cell disease (SCD) do not consistently follow their doctor’s orders, and a new study suggests discrimination may be partly to blame.

Patients who felt they experienced discrimination because of their race or health status were 53% more likely than their peers to disregard physician recommendations.

However, reports of discrimination were also common among patients who said they followed doctors’ orders to the letter.

Carlton Haywood Jr, PhD, of the Johns Hopkins School of Medicine in Baltimore, Maryland, and his colleagues conducted this research and detailed the results in the Journal of General Internal Medicine.

Dr Haywood’s team monitored the experiences of 291 SCD patients (aged 15 and older) who were participating in the Improving Patient Outcomes with Respect and Trust (IMPORT) study.

Patients completed surveys to report perceived discrimination from healthcare providers and their adherence to physician recommendations.

More than a third of patients (36%) reported non-adherence to a doctor’s recommendations in the 2 years prior to completing the survey.

Fifty-eight percent of the non-adherent patients and 43% of the adherent group reported at least 1 incident of discrimination due to their race or health status.

Patients who had experienced discrimination were 53% more likely than their peers to follow physicians’ recommendations inconsistently.

Trust in medical professionals appeared to mediate the discrimination/non-adherence relationship. It accounted for 50% of the excess prevalence of non-adherence among patients who reported incidents of discrimination.

The researchers said these findings are consistent with previous studies among other chronically ill patient groups. They also show how discrimination affects a patient’s trust in the healthcare system, as well as the person’s subsequent willingness to follow prescribed treatment regimens.

Dr Haywood believes the perceptions and experiences of discrimination may increase the chances that SCD patients will not fully benefit from the care available to them.

“A good relationship between the patient and provider can facilitate adherence, while a problematic relationship can negatively impact patient adherence,” he said.

“Improving relationships between healthcare providers and such patients may improve their trust in medical professionals, which, in turn, may improve other outcomes among this underserved patient population.”