The six investigators awarded AGA’s flagship research grant are working on impressive research projects that address important unmet needs for GI patients.

In partnership with generous supporters, the AGA Research Foundation provided more than $2 million in research funding to 41 investigators in 2018. The AGA Research Scholar Award was given to 6 exceptional early-career investigators who represent the future of GI research. Read about their research projects below.
 

Sarah Andres, PhD

University of Pennsylvania, Philadelphia

Project title: The mRNA binding protein IMP1 regulates intestinal epithelial exosome biology during homeostasis and metastasis

Swathi Eluri, MD, MSCR

University of North Carolina at Chapel Hill

Project title: Improving Barrett’s esophagus screening practices in primary care

Jill Hoffman, PhD

University of California, Los Angeles

AGA-Takeda Pharmaceuticals Research Scholar Award in IBD

Project title: Characterization of CRHR₂-mediated enteric glial cell function during colitis

Dr. Hoffman will use her AGA-Takeda funding to define a role for corticotropin-releasing hormone (CRH) signaling in enteric glial cell function, and determine CRHR₂-dependent crosstalk between enteric glial cells and the intestinal epithelium during inflammation. Through research aiming to understand the basic mechanisms of cell-to-cell signaling during intestinal inflammation, Dr. Hoffman hopes to determine how to harness these pathways to limit inflammation and promote repair in patients with IBD.
 

Elizabeth Jensen, MPH, PhD

Wake Forest University, Winston-Salem, NC

Project title: Early life factors, gene-environment interaction, and eosinophilic esophagitis (EoE)

With this funding, Dr. Jensen will conduct the largest study to date on early life factors and EoE, using data that have been collected prospectively through population-based registries in Denmark. Ultimately, Dr. Jensen hopes her research will lead to advancements in our understanding of etiologic factors for development of immune-mediated GI diseases, such as EoE, and will lead to the identification of modifiable factors for disease prevention.
 

Sumera Rizvi, MD

Mayo Clinic, Rochester, MN

Project title: Necrosis enhances tumor immunogenicity and augments cholangiocarcinoma tumor suppression in combination with PD-L1 blockade

Niels Vande Casteele, PhD

University of California, San Diego

Project title: Identifying optimal thresholds and personalized dosing regimens of infliximab to maximize endoscopic remission rates in patients with ulcerative colitis

[email protected]

The six investigators awarded AGA’s flagship research grant are working on impressive research projects that address important unmet needs for GI patients.

In partnership with generous supporters, the AGA Research Foundation provided more than $2 million in research funding to 41 investigators in 2018. The AGA Research Scholar Award was given to 6 exceptional early-career investigators who represent the future of GI research. Read about their research projects below.
 

Sarah Andres, PhD

University of Pennsylvania, Philadelphia

Project title: The mRNA binding protein IMP1 regulates intestinal epithelial exosome biology during homeostasis and metastasis

Swathi Eluri, MD, MSCR

University of North Carolina at Chapel Hill

Project title: Improving Barrett’s esophagus screening practices in primary care

Jill Hoffman, PhD

University of California, Los Angeles

AGA-Takeda Pharmaceuticals Research Scholar Award in IBD

Project title: Characterization of CRHR₂-mediated enteric glial cell function during colitis

Dr. Hoffman will use her AGA-Takeda funding to define a role for corticotropin-releasing hormone (CRH) signaling in enteric glial cell function, and determine CRHR₂-dependent crosstalk between enteric glial cells and the intestinal epithelium during inflammation. Through research aiming to understand the basic mechanisms of cell-to-cell signaling during intestinal inflammation, Dr. Hoffman hopes to determine how to harness these pathways to limit inflammation and promote repair in patients with IBD.
 

Elizabeth Jensen, MPH, PhD

Wake Forest University, Winston-Salem, NC

Project title: Early life factors, gene-environment interaction, and eosinophilic esophagitis (EoE)

With this funding, Dr. Jensen will conduct the largest study to date on early life factors and EoE, using data that have been collected prospectively through population-based registries in Denmark. Ultimately, Dr. Jensen hopes her research will lead to advancements in our understanding of etiologic factors for development of immune-mediated GI diseases, such as EoE, and will lead to the identification of modifiable factors for disease prevention.
 

Sumera Rizvi, MD

Mayo Clinic, Rochester, MN

Project title: Necrosis enhances tumor immunogenicity and augments cholangiocarcinoma tumor suppression in combination with PD-L1 blockade

Niels Vande Casteele, PhD

University of California, San Diego

Project title: Identifying optimal thresholds and personalized dosing regimens of infliximab to maximize endoscopic remission rates in patients with ulcerative colitis

[email protected]

The six investigators awarded AGA’s flagship research grant are working on impressive research projects that address important unmet needs for GI patients.

In partnership with generous supporters, the AGA Research Foundation provided more than $2 million in research funding to 41 investigators in 2018. The AGA Research Scholar Award was given to 6 exceptional early-career investigators who represent the future of GI research. Read about their research projects below.
 

Sarah Andres, PhD

University of Pennsylvania, Philadelphia

Project title: The mRNA binding protein IMP1 regulates intestinal epithelial exosome biology during homeostasis and metastasis

Swathi Eluri, MD, MSCR

University of North Carolina at Chapel Hill

Project title: Improving Barrett’s esophagus screening practices in primary care

Jill Hoffman, PhD

University of California, Los Angeles

AGA-Takeda Pharmaceuticals Research Scholar Award in IBD

Project title: Characterization of CRHR₂-mediated enteric glial cell function during colitis

Dr. Hoffman will use her AGA-Takeda funding to define a role for corticotropin-releasing hormone (CRH) signaling in enteric glial cell function, and determine CRHR₂-dependent crosstalk between enteric glial cells and the intestinal epithelium during inflammation. Through research aiming to understand the basic mechanisms of cell-to-cell signaling during intestinal inflammation, Dr. Hoffman hopes to determine how to harness these pathways to limit inflammation and promote repair in patients with IBD.
 

Elizabeth Jensen, MPH, PhD

Wake Forest University, Winston-Salem, NC

Project title: Early life factors, gene-environment interaction, and eosinophilic esophagitis (EoE)

With this funding, Dr. Jensen will conduct the largest study to date on early life factors and EoE, using data that have been collected prospectively through population-based registries in Denmark. Ultimately, Dr. Jensen hopes her research will lead to advancements in our understanding of etiologic factors for development of immune-mediated GI diseases, such as EoE, and will lead to the identification of modifiable factors for disease prevention.
 

Sumera Rizvi, MD

Mayo Clinic, Rochester, MN

Project title: Necrosis enhances tumor immunogenicity and augments cholangiocarcinoma tumor suppression in combination with PD-L1 blockade

Niels Vande Casteele, PhD

University of California, San Diego

Project title: Identifying optimal thresholds and personalized dosing regimens of infliximab to maximize endoscopic remission rates in patients with ulcerative colitis

[email protected]

Photo courtesy of Janssen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended broadening the existing marketing authorization for daratumumab (Darzalex).

The CHMP is recommending approval for daratumumab in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of adults with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplant.

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Daratumumab already has EC approval for the following indications:

• For use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, to treat adults with MM who have received at least 1 prior therapy
• As monotherapy for adults with relapsed and refractory MM whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on their last therapy.

The CHMP’s recommendation to expand the existing marketing authorization for daratumumab is based on results from the phase 3 ALCYONE (MMY3007) study.

Results from this study were presented at the 2017 ASH Annual Meeting and simultaneously published in NEJM.

ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant. Patients were randomized to receive VMP or daratumumab plus VMP (D-VMP).

The overall response rates were 91% in the D-VMP arm and 74% in the VMP arm (P<0.0001). Rates of complete response were 43% and 24%, respectively. Rates of minimal residual disease negativity were 22% and 6%, respectively.

The median progression-free survival (PFS) was not reached in the D-VMP arm and was 18.1 months in the VMP arm. The 12-month PFS was 87% and 76%, respectively. The 18-month PFS was 72% and 50%, respectively.

The most common treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).

Infusion-related reactions occurred in 28% of patients in the D-VMP arm and 0% of those in the VMP arm.

The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. In both arms, most infections resolved.

The most common grade 3/4 treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).

The rate of discontinuation due to adverse events was 5% in the D-VMP arm and 9% in the VMP arm.

Photo courtesy of Janssen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended broadening the existing marketing authorization for daratumumab (Darzalex).

The CHMP is recommending approval for daratumumab in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of adults with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplant.

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Daratumumab already has EC approval for the following indications:

• For use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, to treat adults with MM who have received at least 1 prior therapy
• As monotherapy for adults with relapsed and refractory MM whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on their last therapy.

The CHMP’s recommendation to expand the existing marketing authorization for daratumumab is based on results from the phase 3 ALCYONE (MMY3007) study.

Results from this study were presented at the 2017 ASH Annual Meeting and simultaneously published in NEJM.

ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant. Patients were randomized to receive VMP or daratumumab plus VMP (D-VMP).

The overall response rates were 91% in the D-VMP arm and 74% in the VMP arm (P<0.0001). Rates of complete response were 43% and 24%, respectively. Rates of minimal residual disease negativity were 22% and 6%, respectively.

The median progression-free survival (PFS) was not reached in the D-VMP arm and was 18.1 months in the VMP arm. The 12-month PFS was 87% and 76%, respectively. The 18-month PFS was 72% and 50%, respectively.

The most common treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).

Infusion-related reactions occurred in 28% of patients in the D-VMP arm and 0% of those in the VMP arm.

The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. In both arms, most infections resolved.

The most common grade 3/4 treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).

The rate of discontinuation due to adverse events was 5% in the D-VMP arm and 9% in the VMP arm.

Photo courtesy of Janssen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended broadening the existing marketing authorization for daratumumab (Darzalex).

The CHMP is recommending approval for daratumumab in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of adults with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplant.

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Daratumumab already has EC approval for the following indications:

• For use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, to treat adults with MM who have received at least 1 prior therapy
• As monotherapy for adults with relapsed and refractory MM whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on their last therapy.

The CHMP’s recommendation to expand the existing marketing authorization for daratumumab is based on results from the phase 3 ALCYONE (MMY3007) study.

Results from this study were presented at the 2017 ASH Annual Meeting and simultaneously published in NEJM.

ALCYONE enrolled 706 patients with newly diagnosed MM who were not eligible for high-dose chemotherapy with autologous stem cell transplant. Patients were randomized to receive VMP or daratumumab plus VMP (D-VMP).

The overall response rates were 91% in the D-VMP arm and 74% in the VMP arm (P<0.0001). Rates of complete response were 43% and 24%, respectively. Rates of minimal residual disease negativity were 22% and 6%, respectively.

The median progression-free survival (PFS) was not reached in the D-VMP arm and was 18.1 months in the VMP arm. The 12-month PFS was 87% and 76%, respectively. The 18-month PFS was 72% and 50%, respectively.

The most common treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (50% and 53%), thrombocytopenia (49% and 54%), anemia (28% and 38%), peripheral sensory neuropathy (28% and 34%), upper respiratory tract infection (26% and 14%), diarrhea (24% and 25%), pyrexia (23% and 21%), and nausea (21% and 22%).

Infusion-related reactions occurred in 28% of patients in the D-VMP arm and 0% of those in the VMP arm.

The rate of grade 3/4 infections was higher in the D-VMP arm than the VMP arm—23% and 15%, respectively. In both arms, most infections resolved.

The most common grade 3/4 treatment-emergent adverse events (in the D-VMP and VMP arms, respectively) were neutropenia (40% and 39%), thrombocytopenia (34% and 38%), and anemia (16% and 20%).

The rate of discontinuation due to adverse events was 5% in the D-VMP arm and 9% in the VMP arm.

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has released 2 new opinions regarding blinatumomab (Blincyto).

The CHMP recommended expanding the approved use of blinatumomab to include pediatric patients, but the committee also recommended against approving blinatumomab to treat patients with minimal residual disease (MRD).

Blinatumomab is already approved by the European Commission (EC) as monotherapy for adults with Philadelphia chromosome-negative (Ph-), CD19-positive, relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Now, the CHMP has recommended expanding this use to include blinatumomab as monotherapy for patients age 1 and older with Ph-, CD19-positive, relapsed/refractory BCP-ALL. These patients must have at least 2 prior therapies or have relapsed after allogeneic hematopoietic stem cell transplant.

This recommendation was supported by data from Study ‘205. Results from this phase 1/2 study were published in the Journal of Clinical Oncology in 2016.

The CHMP has also recommended against approving blinatumomab to treat BCP-ALL patients with MRD.

This decision was influenced by data from the BLAST study. Results from this phase 2 study were published in Blood earlier this year.

The CHMP noted that, although blinatumomab helped clear away residual cells in many patients in the BLAST trial, there is no strong evidence that this leads to improved survival.

Given the uncertainty, the CHMP was of the opinion that the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

Amgen, the company developing and marketing blinatumomab, can request a re-examination of the CHMP’s opinion within 15 days of receiving it.

The CHMP’s recommendations are reviewed by the EC, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of CHMP recommendations.

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has released 2 new opinions regarding blinatumomab (Blincyto).

The CHMP recommended expanding the approved use of blinatumomab to include pediatric patients, but the committee also recommended against approving blinatumomab to treat patients with minimal residual disease (MRD).

Blinatumomab is already approved by the European Commission (EC) as monotherapy for adults with Philadelphia chromosome-negative (Ph-), CD19-positive, relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Now, the CHMP has recommended expanding this use to include blinatumomab as monotherapy for patients age 1 and older with Ph-, CD19-positive, relapsed/refractory BCP-ALL. These patients must have at least 2 prior therapies or have relapsed after allogeneic hematopoietic stem cell transplant.

This recommendation was supported by data from Study ‘205. Results from this phase 1/2 study were published in the Journal of Clinical Oncology in 2016.

The CHMP has also recommended against approving blinatumomab to treat BCP-ALL patients with MRD.

This decision was influenced by data from the BLAST study. Results from this phase 2 study were published in Blood earlier this year.

The CHMP noted that, although blinatumomab helped clear away residual cells in many patients in the BLAST trial, there is no strong evidence that this leads to improved survival.

Given the uncertainty, the CHMP was of the opinion that the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

Amgen, the company developing and marketing blinatumomab, can request a re-examination of the CHMP’s opinion within 15 days of receiving it.

The CHMP’s recommendations are reviewed by the EC, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of CHMP recommendations.

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has released 2 new opinions regarding blinatumomab (Blincyto).

The CHMP recommended expanding the approved use of blinatumomab to include pediatric patients, but the committee also recommended against approving blinatumomab to treat patients with minimal residual disease (MRD).

Blinatumomab is already approved by the European Commission (EC) as monotherapy for adults with Philadelphia chromosome-negative (Ph-), CD19-positive, relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Now, the CHMP has recommended expanding this use to include blinatumomab as monotherapy for patients age 1 and older with Ph-, CD19-positive, relapsed/refractory BCP-ALL. These patients must have at least 2 prior therapies or have relapsed after allogeneic hematopoietic stem cell transplant.

This recommendation was supported by data from Study ‘205. Results from this phase 1/2 study were published in the Journal of Clinical Oncology in 2016.

The CHMP has also recommended against approving blinatumomab to treat BCP-ALL patients with MRD.

This decision was influenced by data from the BLAST study. Results from this phase 2 study were published in Blood earlier this year.

The CHMP noted that, although blinatumomab helped clear away residual cells in many patients in the BLAST trial, there is no strong evidence that this leads to improved survival.

Given the uncertainty, the CHMP was of the opinion that the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

Amgen, the company developing and marketing blinatumomab, can request a re-examination of the CHMP’s opinion within 15 days of receiving it.

The CHMP’s recommendations are reviewed by the EC, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of CHMP recommendations.

Red blood cells

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a change to the terms of marketing authorization for 3 versions of epoetin alfa—Abseamed, Binocrit, and Epoetin alfa Hexal.

The CHMP is recommending that all 3 products be approved to treat symptomatic anemia (hemoglobin concentration of ≤ 10 g/dL) in adults with low- or intermediate-1-risk primary myelodysplastic syndromes who have low serum erythropoietin (< 200 mU/mL).

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Abseamed, Binocrit, and Epoetin alfa Hexal are already EC-approved for the following indications:

• To treat symptomatic anemia associated with chronic renal failure in adults and children ages 1 to 18 on hemodialysis and adults on peritoneal dialysis
• To treat symptomatic anemia associated with chronic renal failure in adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anemia of renal origin accompanied by clinical symptoms in patients
• For adults receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma who are at risk of transfusion as assessed by the patient’s general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy) for the treatment of anemia and reduction of transfusion requirements
• For adults in a predonation program to increase the yield of autologous blood; treatment should only be given to patients with moderate anemia (hemoglobin concentration range between 10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency) if blood-saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units for females or 5 or more units for males)
• For non-iron-deficient adults set to undergo major elective orthopedic surgery who have a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions; use should be restricted to patients with moderate anemia (eg, hemoglobin concentration range between 10 to 13 g/dL or 6.2 to 8.1 mmol/L) who do not have an autologous predonation program available and with expected moderate blood loss (900 to 1800 mL).

The marketing authorization holders are Medice Arzneimittel Pütter GmbH & Co. KG for Abseamed, Sandoz GmbH for Binocrit, and Hexal AG for Epoetin alfa Hexal.

Red blood cells

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a change to the terms of marketing authorization for 3 versions of epoetin alfa—Abseamed, Binocrit, and Epoetin alfa Hexal.

The CHMP is recommending that all 3 products be approved to treat symptomatic anemia (hemoglobin concentration of ≤ 10 g/dL) in adults with low- or intermediate-1-risk primary myelodysplastic syndromes who have low serum erythropoietin (< 200 mU/mL).

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Abseamed, Binocrit, and Epoetin alfa Hexal are already EC-approved for the following indications:

• To treat symptomatic anemia associated with chronic renal failure in adults and children ages 1 to 18 on hemodialysis and adults on peritoneal dialysis
• To treat symptomatic anemia associated with chronic renal failure in adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anemia of renal origin accompanied by clinical symptoms in patients
• For adults receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma who are at risk of transfusion as assessed by the patient’s general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy) for the treatment of anemia and reduction of transfusion requirements
• For adults in a predonation program to increase the yield of autologous blood; treatment should only be given to patients with moderate anemia (hemoglobin concentration range between 10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency) if blood-saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units for females or 5 or more units for males)
• For non-iron-deficient adults set to undergo major elective orthopedic surgery who have a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions; use should be restricted to patients with moderate anemia (eg, hemoglobin concentration range between 10 to 13 g/dL or 6.2 to 8.1 mmol/L) who do not have an autologous predonation program available and with expected moderate blood loss (900 to 1800 mL).

The marketing authorization holders are Medice Arzneimittel Pütter GmbH & Co. KG for Abseamed, Sandoz GmbH for Binocrit, and Hexal AG for Epoetin alfa Hexal.

Red blood cells

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a change to the terms of marketing authorization for 3 versions of epoetin alfa—Abseamed, Binocrit, and Epoetin alfa Hexal.

The CHMP is recommending that all 3 products be approved to treat symptomatic anemia (hemoglobin concentration of ≤ 10 g/dL) in adults with low- or intermediate-1-risk primary myelodysplastic syndromes who have low serum erythropoietin (< 200 mU/mL).

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Abseamed, Binocrit, and Epoetin alfa Hexal are already EC-approved for the following indications:

• To treat symptomatic anemia associated with chronic renal failure in adults and children ages 1 to 18 on hemodialysis and adults on peritoneal dialysis
• To treat symptomatic anemia associated with chronic renal failure in adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anemia of renal origin accompanied by clinical symptoms in patients
• For adults receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma who are at risk of transfusion as assessed by the patient’s general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy) for the treatment of anemia and reduction of transfusion requirements
• For adults in a predonation program to increase the yield of autologous blood; treatment should only be given to patients with moderate anemia (hemoglobin concentration range between 10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency) if blood-saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units for females or 5 or more units for males)
• For non-iron-deficient adults set to undergo major elective orthopedic surgery who have a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions; use should be restricted to patients with moderate anemia (eg, hemoglobin concentration range between 10 to 13 g/dL or 6.2 to 8.1 mmol/L) who do not have an autologous predonation program available and with expected moderate blood loss (900 to 1800 mL).

The marketing authorization holders are Medice Arzneimittel Pütter GmbH & Co. KG for Abseamed, Sandoz GmbH for Binocrit, and Hexal AG for Epoetin alfa Hexal.

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for 2 pegfilgrastim biosimilar candidates—Udenyca and Pelgraz.

Both products have been deemed highly similar to the reference product, Neulasta, a growth-colony-stimulating factor intended to reduce the duration of neutropenia and the incidence of febrile neutropenia due to chemotherapy.

The CHMP’s recommendations for Pelgraz and Udenyca will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.

If approved, Udenyca and Pelgraz will be available as 6 mg solutions for injection.

The full indication for both products will be to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving cytotoxic chemotherapy for malignancies, except chronic myeloid leukemia and myelodysplastic syndromes.

The CHMP said data have shown that Pelgraz and Udenyca both have comparable quality, safety, and efficacy to Neulasta.

Pelgraz’s marketing authorization application is supported by data from a phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study in healthy volunteers and a phase 3 study of breast cancer patients receiving docetaxel, doxorubicin, and cyclophosphamide.

Results from the phase 1 study were published in Clinical Pharmacology in Drug Development in 2016.

Udenyca’s marketing authorization application is supported by data from an immunogenicity study as well as a PK/PD study comparing Udenyca (formerly CHS-1701) and Neulasta in healthy subjects.

Results from the PK/PD trial were presented at the 2017 ASCO Annual Meeting.

The applicant for Udenyca is ERA Consulting GmbH. The applicant for Pelgraz is Accord Healthcare Limited (the international arm of Intas Pharmaceuticals Ltd).

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for 2 pegfilgrastim biosimilar candidates—Udenyca and Pelgraz.

Both products have been deemed highly similar to the reference product, Neulasta, a growth-colony-stimulating factor intended to reduce the duration of neutropenia and the incidence of febrile neutropenia due to chemotherapy.

The CHMP’s recommendations for Pelgraz and Udenyca will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.

If approved, Udenyca and Pelgraz will be available as 6 mg solutions for injection.

The full indication for both products will be to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving cytotoxic chemotherapy for malignancies, except chronic myeloid leukemia and myelodysplastic syndromes.

The CHMP said data have shown that Pelgraz and Udenyca both have comparable quality, safety, and efficacy to Neulasta.

Pelgraz’s marketing authorization application is supported by data from a phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study in healthy volunteers and a phase 3 study of breast cancer patients receiving docetaxel, doxorubicin, and cyclophosphamide.

Results from the phase 1 study were published in Clinical Pharmacology in Drug Development in 2016.

Udenyca’s marketing authorization application is supported by data from an immunogenicity study as well as a PK/PD study comparing Udenyca (formerly CHS-1701) and Neulasta in healthy subjects.

Results from the PK/PD trial were presented at the 2017 ASCO Annual Meeting.

The applicant for Udenyca is ERA Consulting GmbH. The applicant for Pelgraz is Accord Healthcare Limited (the international arm of Intas Pharmaceuticals Ltd).

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for 2 pegfilgrastim biosimilar candidates—Udenyca and Pelgraz.

Both products have been deemed highly similar to the reference product, Neulasta, a growth-colony-stimulating factor intended to reduce the duration of neutropenia and the incidence of febrile neutropenia due to chemotherapy.

The CHMP’s recommendations for Pelgraz and Udenyca will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.

If approved, Udenyca and Pelgraz will be available as 6 mg solutions for injection.

The full indication for both products will be to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving cytotoxic chemotherapy for malignancies, except chronic myeloid leukemia and myelodysplastic syndromes.

The CHMP said data have shown that Pelgraz and Udenyca both have comparable quality, safety, and efficacy to Neulasta.

Pelgraz’s marketing authorization application is supported by data from a phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study in healthy volunteers and a phase 3 study of breast cancer patients receiving docetaxel, doxorubicin, and cyclophosphamide.

Results from the phase 1 study were published in Clinical Pharmacology in Drug Development in 2016.

Udenyca’s marketing authorization application is supported by data from an immunogenicity study as well as a PK/PD study comparing Udenyca (formerly CHS-1701) and Neulasta in healthy subjects.

Results from the PK/PD trial were presented at the 2017 ASCO Annual Meeting.

The applicant for Udenyca is ERA Consulting GmbH. The applicant for Pelgraz is Accord Healthcare Limited (the international arm of Intas Pharmaceuticals Ltd).

Image by Andre E.X. Brown

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has reiterated its negative opinion of betrixaban.

Once again, the CHMP has concluded that it cannot recommend approval of betrixaban for the prevention of venous thromboembolism (VTE) in adults hospitalized for an acute medical illness with risk factors for VTE, including VTE-related death.

The CHMP previously issued a negative opinion of betrixaban in March, but Portola Pharmaceuticals, Inc., requested a re-examination of that opinion.

The CHMP agreed to re-examine the opinion and confirmed the refusal of the marketing authorization on July 26.

The marketing authorization application for betrixaban was supported by data from the phase 3 APEX study. In this trial, researchers compared oral betrixaban to injectable enoxaparin for the prevention of VTE in patients with acute medical illnesses.

The CHMP said APEX did not satisfactorily show betrixaban’s effectiveness when used for preventing VTE in patients admitted to the hospital for recent medical illness.

In addition, patients treated with betrixaban had more episodes of bleeding than patients who received enoxaparin.

The CHMP said the excess bleeding was an important concern because betrixaban was expected to be used in patients with serious underlying conditions for whom any episode of bleeding could have serious consequences, and betrixaban’s long persistence in the body could complicate management of bleeding.

Overall, the CHMP said the benefits of betrixaban did not outweigh its risks.

Portola said this decision will not affect patients currently enrolled in clinical trials of betrixaban.

The company also said it will continue working with regulatory authorities in countries outside the European Union to potentially bring betrixaban to patients as quickly as possible.

“We are disappointed by the committee’s assessment given both the unmet need and the clinically meaningful outcomes of the APEX trial in reducing VTE and VTE-related deaths in a vulnerable patient population,” said John T. Curnutte, MD, PhD, interim co-president and head of research and development for Portola.

“We remain confident in the potential public health impact of betrixaban and will maintain focus on the US commercial launch as we continue to work toward our goal of expanding patient access to betrixaban around the world.”

Betrixaban was approved in the US in June 2017 under the trade name Bevyxxa.

Image by Andre E.X. Brown

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has reiterated its negative opinion of betrixaban.

Once again, the CHMP has concluded that it cannot recommend approval of betrixaban for the prevention of venous thromboembolism (VTE) in adults hospitalized for an acute medical illness with risk factors for VTE, including VTE-related death.

The CHMP previously issued a negative opinion of betrixaban in March, but Portola Pharmaceuticals, Inc., requested a re-examination of that opinion.

The CHMP agreed to re-examine the opinion and confirmed the refusal of the marketing authorization on July 26.

The marketing authorization application for betrixaban was supported by data from the phase 3 APEX study. In this trial, researchers compared oral betrixaban to injectable enoxaparin for the prevention of VTE in patients with acute medical illnesses.

The CHMP said APEX did not satisfactorily show betrixaban’s effectiveness when used for preventing VTE in patients admitted to the hospital for recent medical illness.

In addition, patients treated with betrixaban had more episodes of bleeding than patients who received enoxaparin.

The CHMP said the excess bleeding was an important concern because betrixaban was expected to be used in patients with serious underlying conditions for whom any episode of bleeding could have serious consequences, and betrixaban’s long persistence in the body could complicate management of bleeding.

Overall, the CHMP said the benefits of betrixaban did not outweigh its risks.

Portola said this decision will not affect patients currently enrolled in clinical trials of betrixaban.

The company also said it will continue working with regulatory authorities in countries outside the European Union to potentially bring betrixaban to patients as quickly as possible.

“We are disappointed by the committee’s assessment given both the unmet need and the clinically meaningful outcomes of the APEX trial in reducing VTE and VTE-related deaths in a vulnerable patient population,” said John T. Curnutte, MD, PhD, interim co-president and head of research and development for Portola.

“We remain confident in the potential public health impact of betrixaban and will maintain focus on the US commercial launch as we continue to work toward our goal of expanding patient access to betrixaban around the world.”

Betrixaban was approved in the US in June 2017 under the trade name Bevyxxa.

Image by Andre E.X. Brown

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has reiterated its negative opinion of betrixaban.

Once again, the CHMP has concluded that it cannot recommend approval of betrixaban for the prevention of venous thromboembolism (VTE) in adults hospitalized for an acute medical illness with risk factors for VTE, including VTE-related death.

The CHMP previously issued a negative opinion of betrixaban in March, but Portola Pharmaceuticals, Inc., requested a re-examination of that opinion.

The CHMP agreed to re-examine the opinion and confirmed the refusal of the marketing authorization on July 26.

The marketing authorization application for betrixaban was supported by data from the phase 3 APEX study. In this trial, researchers compared oral betrixaban to injectable enoxaparin for the prevention of VTE in patients with acute medical illnesses.

The CHMP said APEX did not satisfactorily show betrixaban’s effectiveness when used for preventing VTE in patients admitted to the hospital for recent medical illness.

In addition, patients treated with betrixaban had more episodes of bleeding than patients who received enoxaparin.

The CHMP said the excess bleeding was an important concern because betrixaban was expected to be used in patients with serious underlying conditions for whom any episode of bleeding could have serious consequences, and betrixaban’s long persistence in the body could complicate management of bleeding.

Overall, the CHMP said the benefits of betrixaban did not outweigh its risks.

Portola said this decision will not affect patients currently enrolled in clinical trials of betrixaban.

The company also said it will continue working with regulatory authorities in countries outside the European Union to potentially bring betrixaban to patients as quickly as possible.

“We are disappointed by the committee’s assessment given both the unmet need and the clinically meaningful outcomes of the APEX trial in reducing VTE and VTE-related deaths in a vulnerable patient population,” said John T. Curnutte, MD, PhD, interim co-president and head of research and development for Portola.

“We remain confident in the potential public health impact of betrixaban and will maintain focus on the US commercial launch as we continue to work toward our goal of expanding patient access to betrixaban around the world.”

Betrixaban was approved in the US in June 2017 under the trade name Bevyxxa.

Photo courtesy of the CDC

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a new indication for rivaroxaban (Xarelto) 2.5 mg tablets.

The recommendation is for rivaroxaban co-administered with acetylsalicylic acid (ASA) for the prevention of atherothrombotic events in adults with coronary artery disease or symptomatic peripheral artery disease at high risk of ischemic events.

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Rivaroxaban is already EC-approved for use in combination with ASA alone or ASA plus clopidogrel or ticlopidine for the prevention of atherothrombotic events in adults with acute coronary syndrome and elevated cardiac biomarkers.

The CHMP’s positive opinion for rivaroxaban in coronary artery disease and symptomatic peripheral artery disease is based on data from the COMPASS study. Results from this study were presented at ESC Congress 2017 and published simultaneously in NEJM.

COMPASS enrolled 27,395 patients with stable atherosclerotic vascular disease. They were randomized to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban alone (5 mg twice daily), or aspirin alone (100 mg once daily).

The study’s primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. This outcome occurred in 4.1% of patients in the rivaroxaban-aspirin arm, 4.9% of those in the rivaroxaban-alone arm, and 5.4% of those in the aspirin-alone arm.

There was a significant difference in the primary outcome between the rivaroxaban-aspirin arm and the aspirin-alone arm (P<0.001) but not between the rivaroxaban-alone arm and the aspirin-alone arm (P=0.12).

The incidence of major bleeding was 3.1% in the rivaroxaban-aspirin arm, 2.8% in the rivaroxaban-alone arm, and 1.9% in the aspirin-alone arm.

There was a significant difference in major bleeding between the rivaroxaban-aspirin arm and the aspirin-alone arm (P<0.001) as well as between the rivaroxaban-alone arm and the aspirin-alone arm (P<0.001).

Photo courtesy of the CDC

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a new indication for rivaroxaban (Xarelto) 2.5 mg tablets.

The recommendation is for rivaroxaban co-administered with acetylsalicylic acid (ASA) for the prevention of atherothrombotic events in adults with coronary artery disease or symptomatic peripheral artery disease at high risk of ischemic events.

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Rivaroxaban is already EC-approved for use in combination with ASA alone or ASA plus clopidogrel or ticlopidine for the prevention of atherothrombotic events in adults with acute coronary syndrome and elevated cardiac biomarkers.

The CHMP’s positive opinion for rivaroxaban in coronary artery disease and symptomatic peripheral artery disease is based on data from the COMPASS study. Results from this study were presented at ESC Congress 2017 and published simultaneously in NEJM.

COMPASS enrolled 27,395 patients with stable atherosclerotic vascular disease. They were randomized to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban alone (5 mg twice daily), or aspirin alone (100 mg once daily).

The study’s primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. This outcome occurred in 4.1% of patients in the rivaroxaban-aspirin arm, 4.9% of those in the rivaroxaban-alone arm, and 5.4% of those in the aspirin-alone arm.

There was a significant difference in the primary outcome between the rivaroxaban-aspirin arm and the aspirin-alone arm (P<0.001) but not between the rivaroxaban-alone arm and the aspirin-alone arm (P=0.12).

The incidence of major bleeding was 3.1% in the rivaroxaban-aspirin arm, 2.8% in the rivaroxaban-alone arm, and 1.9% in the aspirin-alone arm.

There was a significant difference in major bleeding between the rivaroxaban-aspirin arm and the aspirin-alone arm (P<0.001) as well as between the rivaroxaban-alone arm and the aspirin-alone arm (P<0.001).

Photo courtesy of the CDC

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a new indication for rivaroxaban (Xarelto) 2.5 mg tablets.

The recommendation is for rivaroxaban co-administered with acetylsalicylic acid (ASA) for the prevention of atherothrombotic events in adults with coronary artery disease or symptomatic peripheral artery disease at high risk of ischemic events.

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Rivaroxaban is already EC-approved for use in combination with ASA alone or ASA plus clopidogrel or ticlopidine for the prevention of atherothrombotic events in adults with acute coronary syndrome and elevated cardiac biomarkers.

The CHMP’s positive opinion for rivaroxaban in coronary artery disease and symptomatic peripheral artery disease is based on data from the COMPASS study. Results from this study were presented at ESC Congress 2017 and published simultaneously in NEJM.

COMPASS enrolled 27,395 patients with stable atherosclerotic vascular disease. They were randomized to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban alone (5 mg twice daily), or aspirin alone (100 mg once daily).

The study’s primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. This outcome occurred in 4.1% of patients in the rivaroxaban-aspirin arm, 4.9% of those in the rivaroxaban-alone arm, and 5.4% of those in the aspirin-alone arm.

There was a significant difference in the primary outcome between the rivaroxaban-aspirin arm and the aspirin-alone arm (P<0.001) but not between the rivaroxaban-alone arm and the aspirin-alone arm (P=0.12).

The incidence of major bleeding was 3.1% in the rivaroxaban-aspirin arm, 2.8% in the rivaroxaban-alone arm, and 1.9% in the aspirin-alone arm.

There was a significant difference in major bleeding between the rivaroxaban-aspirin arm and the aspirin-alone arm (P<0.001) as well as between the rivaroxaban-alone arm and the aspirin-alone arm (P<0.001).

Non–private clinical encounters tied to diagnostic error and delays in delivery of care.

In a cross-sectional survey of 409 emergency physicians attending the American College of Emergency Physicians Scientific Assembly conference, a majority of respondents reported deviating from their standard history-taking and physical exam practices when practicing in a hallway location or when a patient had a companion present during the clinical encounter. Of those physicians who reported changing their practices during non–private clinical encounters, a significant proportion reported that these changes had led to a delay in patient care or diagnostic error.

Citation: Stoklosa H et al. Do EPs change their clinical behaviour in the hallway or when a companion is present? A cross-sectional survey. Emerg Med J. 2018 Feb 13. doi: 10.1136/emermed-2017-207119.

Retrospective case series of fluoroquinolone-induced acute interstitial nephritis (AIN).

A 23-year retrospective review of biopsy-proven cases of acute interstitial nephritis secondary to fluoroquinolones revealed that only 17% of cases presented with the typical triad of fever, rash, and eosinophilia, but that discontinuation of the offending agent resulted in complete or partial recovery in a majority of patients, with a median time to recovery of 20.5 days.

Citation: Farid S et al. Clinical manifestations and outcomes of fluoroquinolone-related acute interstitial nephritis. Mayo Clin Proc. 2018 Jan;93(1):25-31.

Trimethoprim associated with increased risk of AKI and hyperkalemia.

In a cohort study of older patients with urinary tract infections, trimethoprim was associated with increased risk of acute kidney injury and hyperkalemia, but not increased risk of death, in comparison to other antibiotics for UTIs. These risks were amplified for patients simultaneously taking renin-angiotensin system blockers or spironolactone.

Citation: Crellin E et al. Trimethoprim use for urinary tract infection and risk of adverse outcomes in older patients: cohort study. BMJ. 2018;360:k341.

Mortality of in-hospital cardiac arrest is decreasing, but disparities between on- and off-hours persist.

An analysis of 151,071 in-hospital cardiac arrests (IHCA) during 2000-2014 found that patient survival to hospital discharge increased from 13.6% to 22.0%, but return of spontaneous circulation, post-resuscitation survival, and overall survival to hospital discharge were all significantly lower for IHCA that occurred during nights or weekends, compared with weekday IHCA. The difference in on- and off-hours post-resuscitation survival rates did not significantly change over the 14-year study period.

Citation: Ofoma UR et al. Trends in survival after in-hospital cardiac arrest during nights and weekends. J Am Coll Cardiol. 2018;71(4):402-11.

Young women with acute myocardial infarction present differently than young men.

Interviews of 2,009 young women and 976 young men hospitalized for acute MI at U.S. hospitals revealed that, while both groups of patients reported chest pain as the predominant symptom, women were more likely to report a greater number of additional, non–chest pain symptoms.

Citation: Lichtman JH et al. Sex difference in the presentation and perception of symptoms among young patients with myocardial infarction. Circulation. 2018;137(8):781-90.

Non–private clinical encounters tied to diagnostic error and delays in delivery of care.

In a cross-sectional survey of 409 emergency physicians attending the American College of Emergency Physicians Scientific Assembly conference, a majority of respondents reported deviating from their standard history-taking and physical exam practices when practicing in a hallway location or when a patient had a companion present during the clinical encounter. Of those physicians who reported changing their practices during non–private clinical encounters, a significant proportion reported that these changes had led to a delay in patient care or diagnostic error.

Citation: Stoklosa H et al. Do EPs change their clinical behaviour in the hallway or when a companion is present? A cross-sectional survey. Emerg Med J. 2018 Feb 13. doi: 10.1136/emermed-2017-207119.

Retrospective case series of fluoroquinolone-induced acute interstitial nephritis (AIN).

A 23-year retrospective review of biopsy-proven cases of acute interstitial nephritis secondary to fluoroquinolones revealed that only 17% of cases presented with the typical triad of fever, rash, and eosinophilia, but that discontinuation of the offending agent resulted in complete or partial recovery in a majority of patients, with a median time to recovery of 20.5 days.

Citation: Farid S et al. Clinical manifestations and outcomes of fluoroquinolone-related acute interstitial nephritis. Mayo Clin Proc. 2018 Jan;93(1):25-31.

Trimethoprim associated with increased risk of AKI and hyperkalemia.

In a cohort study of older patients with urinary tract infections, trimethoprim was associated with increased risk of acute kidney injury and hyperkalemia, but not increased risk of death, in comparison to other antibiotics for UTIs. These risks were amplified for patients simultaneously taking renin-angiotensin system blockers or spironolactone.

Citation: Crellin E et al. Trimethoprim use for urinary tract infection and risk of adverse outcomes in older patients: cohort study. BMJ. 2018;360:k341.

Mortality of in-hospital cardiac arrest is decreasing, but disparities between on- and off-hours persist.

An analysis of 151,071 in-hospital cardiac arrests (IHCA) during 2000-2014 found that patient survival to hospital discharge increased from 13.6% to 22.0%, but return of spontaneous circulation, post-resuscitation survival, and overall survival to hospital discharge were all significantly lower for IHCA that occurred during nights or weekends, compared with weekday IHCA. The difference in on- and off-hours post-resuscitation survival rates did not significantly change over the 14-year study period.

Citation: Ofoma UR et al. Trends in survival after in-hospital cardiac arrest during nights and weekends. J Am Coll Cardiol. 2018;71(4):402-11.

Young women with acute myocardial infarction present differently than young men.

Interviews of 2,009 young women and 976 young men hospitalized for acute MI at U.S. hospitals revealed that, while both groups of patients reported chest pain as the predominant symptom, women were more likely to report a greater number of additional, non–chest pain symptoms.

Citation: Lichtman JH et al. Sex difference in the presentation and perception of symptoms among young patients with myocardial infarction. Circulation. 2018;137(8):781-90.

Non–private clinical encounters tied to diagnostic error and delays in delivery of care.

In a cross-sectional survey of 409 emergency physicians attending the American College of Emergency Physicians Scientific Assembly conference, a majority of respondents reported deviating from their standard history-taking and physical exam practices when practicing in a hallway location or when a patient had a companion present during the clinical encounter. Of those physicians who reported changing their practices during non–private clinical encounters, a significant proportion reported that these changes had led to a delay in patient care or diagnostic error.

Citation: Stoklosa H et al. Do EPs change their clinical behaviour in the hallway or when a companion is present? A cross-sectional survey. Emerg Med J. 2018 Feb 13. doi: 10.1136/emermed-2017-207119.

Retrospective case series of fluoroquinolone-induced acute interstitial nephritis (AIN).

A 23-year retrospective review of biopsy-proven cases of acute interstitial nephritis secondary to fluoroquinolones revealed that only 17% of cases presented with the typical triad of fever, rash, and eosinophilia, but that discontinuation of the offending agent resulted in complete or partial recovery in a majority of patients, with a median time to recovery of 20.5 days.

Citation: Farid S et al. Clinical manifestations and outcomes of fluoroquinolone-related acute interstitial nephritis. Mayo Clin Proc. 2018 Jan;93(1):25-31.

Trimethoprim associated with increased risk of AKI and hyperkalemia.

In a cohort study of older patients with urinary tract infections, trimethoprim was associated with increased risk of acute kidney injury and hyperkalemia, but not increased risk of death, in comparison to other antibiotics for UTIs. These risks were amplified for patients simultaneously taking renin-angiotensin system blockers or spironolactone.

Citation: Crellin E et al. Trimethoprim use for urinary tract infection and risk of adverse outcomes in older patients: cohort study. BMJ. 2018;360:k341.

Mortality of in-hospital cardiac arrest is decreasing, but disparities between on- and off-hours persist.

An analysis of 151,071 in-hospital cardiac arrests (IHCA) during 2000-2014 found that patient survival to hospital discharge increased from 13.6% to 22.0%, but return of spontaneous circulation, post-resuscitation survival, and overall survival to hospital discharge were all significantly lower for IHCA that occurred during nights or weekends, compared with weekday IHCA. The difference in on- and off-hours post-resuscitation survival rates did not significantly change over the 14-year study period.

Citation: Ofoma UR et al. Trends in survival after in-hospital cardiac arrest during nights and weekends. J Am Coll Cardiol. 2018;71(4):402-11.

Young women with acute myocardial infarction present differently than young men.

Interviews of 2,009 young women and 976 young men hospitalized for acute MI at U.S. hospitals revealed that, while both groups of patients reported chest pain as the predominant symptom, women were more likely to report a greater number of additional, non–chest pain symptoms.

Citation: Lichtman JH et al. Sex difference in the presentation and perception of symptoms among young patients with myocardial infarction. Circulation. 2018;137(8):781-90.

For patients with pancreatic masses, infiltrated lymph nodes, or submucosal tumors, endoscopic ultrasound-guided fine-needle aspirate and fine-needle biopsy produced a comparable diagnostic yield with a similar number of needle passes, according to the results of a multicenter, randomized clinical trial.

Diagnostic yields were 91% for fine-needle aspirate versus 89% for fine-needle biopsy, with a median of one needle pass needed to obtain a diagnostic sample for each technique, reported Satish Nagula, MD, of the Icahn School of Medicine at Mount Sinai, New York, and his associates. The findings were published in the August issue of Clinical Gastroenterology and Hepatology.

Previously, two small, single-center randomized trials yielded conflicting data on whether fine-needle biopsy produces better diagnostic yield than fine-needle aspirate, the investigators noted. The results of four other studies indicated that the two techniques performed similarly. However, “many of these trials had study designs that did not allow for realistic comparisons of needle performance,” they noted. For example, the studies only analyzed the results of the first needle pass or only included specimens with visible core tissue.

The current study included six tertiary care centers that perform high volumes of endoscopic ultrasound. In all, 135 patients were randomly assigned to undergo fine-needle aspirate or fine-needle biopsy. When rapid on-site cytologic evaluation was used, the clinicians made consecutive needle passes until they considered the specimen adequate. Most lesions (77%) were masses, but 17% were lymph nodes, and 7% were submucosal tumors, the researchers said. The endoscopists used a curvilinear array echoendoscope (GF-UC140P or GF-UCT140; Olympus America, Central Valley, Penn.). They performed fine-needle aspirate or biopsy by using either a 22-gauge or 25-gauge needle at their own discretion.

The final diagnosis was malignancy for 70% of lesions, reactive lymphadenopathy for 11% of lesions, and spindle cell tumors in 9% of cases, the investigators said. Diagnostic yield was similar whether or not rapid on-site cytologic evaluation was used. Fine-needle aspiration detected cancer with a sensitivity of 90% and a specificity of 100%. Fine-needle biopsy had a sensitivity of 89% and a specificity of 100%. Adverse events were uncommon (1%), but one patient was hospitalized with pancreatitis for 2 days after undergoing fine-needle biopsy of a pancreatic body lesion.

The researchers noted several study limitations. “Ideally, each patient would undergo both fine-needle aspirate and fine-needle biopsy, allowing each as their own internal control,” they wrote. “It was considered too expensive to use two different needles in this unfunded study.” There also was no central pathology review, which they called “fiscally not feasible.”

There were no funding sources, and the investigators reported having no relevant conflicts of interest.SOURCE: Nagula S et al. Clin Gastroenterol Hepatol. 2017 Jun 14. doi: 10.1016/j.cgh.2017.06.013.

For patients with pancreatic masses, infiltrated lymph nodes, or submucosal tumors, endoscopic ultrasound-guided fine-needle aspirate and fine-needle biopsy produced a comparable diagnostic yield with a similar number of needle passes, according to the results of a multicenter, randomized clinical trial.

Diagnostic yields were 91% for fine-needle aspirate versus 89% for fine-needle biopsy, with a median of one needle pass needed to obtain a diagnostic sample for each technique, reported Satish Nagula, MD, of the Icahn School of Medicine at Mount Sinai, New York, and his associates. The findings were published in the August issue of Clinical Gastroenterology and Hepatology.

Previously, two small, single-center randomized trials yielded conflicting data on whether fine-needle biopsy produces better diagnostic yield than fine-needle aspirate, the investigators noted. The results of four other studies indicated that the two techniques performed similarly. However, “many of these trials had study designs that did not allow for realistic comparisons of needle performance,” they noted. For example, the studies only analyzed the results of the first needle pass or only included specimens with visible core tissue.

The current study included six tertiary care centers that perform high volumes of endoscopic ultrasound. In all, 135 patients were randomly assigned to undergo fine-needle aspirate or fine-needle biopsy. When rapid on-site cytologic evaluation was used, the clinicians made consecutive needle passes until they considered the specimen adequate. Most lesions (77%) were masses, but 17% were lymph nodes, and 7% were submucosal tumors, the researchers said. The endoscopists used a curvilinear array echoendoscope (GF-UC140P or GF-UCT140; Olympus America, Central Valley, Penn.). They performed fine-needle aspirate or biopsy by using either a 22-gauge or 25-gauge needle at their own discretion.

The final diagnosis was malignancy for 70% of lesions, reactive lymphadenopathy for 11% of lesions, and spindle cell tumors in 9% of cases, the investigators said. Diagnostic yield was similar whether or not rapid on-site cytologic evaluation was used. Fine-needle aspiration detected cancer with a sensitivity of 90% and a specificity of 100%. Fine-needle biopsy had a sensitivity of 89% and a specificity of 100%. Adverse events were uncommon (1%), but one patient was hospitalized with pancreatitis for 2 days after undergoing fine-needle biopsy of a pancreatic body lesion.

The researchers noted several study limitations. “Ideally, each patient would undergo both fine-needle aspirate and fine-needle biopsy, allowing each as their own internal control,” they wrote. “It was considered too expensive to use two different needles in this unfunded study.” There also was no central pathology review, which they called “fiscally not feasible.”

There were no funding sources, and the investigators reported having no relevant conflicts of interest.SOURCE: Nagula S et al. Clin Gastroenterol Hepatol. 2017 Jun 14. doi: 10.1016/j.cgh.2017.06.013.

For patients with pancreatic masses, infiltrated lymph nodes, or submucosal tumors, endoscopic ultrasound-guided fine-needle aspirate and fine-needle biopsy produced a comparable diagnostic yield with a similar number of needle passes, according to the results of a multicenter, randomized clinical trial.

Diagnostic yields were 91% for fine-needle aspirate versus 89% for fine-needle biopsy, with a median of one needle pass needed to obtain a diagnostic sample for each technique, reported Satish Nagula, MD, of the Icahn School of Medicine at Mount Sinai, New York, and his associates. The findings were published in the August issue of Clinical Gastroenterology and Hepatology.

Previously, two small, single-center randomized trials yielded conflicting data on whether fine-needle biopsy produces better diagnostic yield than fine-needle aspirate, the investigators noted. The results of four other studies indicated that the two techniques performed similarly. However, “many of these trials had study designs that did not allow for realistic comparisons of needle performance,” they noted. For example, the studies only analyzed the results of the first needle pass or only included specimens with visible core tissue.

The current study included six tertiary care centers that perform high volumes of endoscopic ultrasound. In all, 135 patients were randomly assigned to undergo fine-needle aspirate or fine-needle biopsy. When rapid on-site cytologic evaluation was used, the clinicians made consecutive needle passes until they considered the specimen adequate. Most lesions (77%) were masses, but 17% were lymph nodes, and 7% were submucosal tumors, the researchers said. The endoscopists used a curvilinear array echoendoscope (GF-UC140P or GF-UCT140; Olympus America, Central Valley, Penn.). They performed fine-needle aspirate or biopsy by using either a 22-gauge or 25-gauge needle at their own discretion.

The final diagnosis was malignancy for 70% of lesions, reactive lymphadenopathy for 11% of lesions, and spindle cell tumors in 9% of cases, the investigators said. Diagnostic yield was similar whether or not rapid on-site cytologic evaluation was used. Fine-needle aspiration detected cancer with a sensitivity of 90% and a specificity of 100%. Fine-needle biopsy had a sensitivity of 89% and a specificity of 100%. Adverse events were uncommon (1%), but one patient was hospitalized with pancreatitis for 2 days after undergoing fine-needle biopsy of a pancreatic body lesion.

The researchers noted several study limitations. “Ideally, each patient would undergo both fine-needle aspirate and fine-needle biopsy, allowing each as their own internal control,” they wrote. “It was considered too expensive to use two different needles in this unfunded study.” There also was no central pathology review, which they called “fiscally not feasible.”

There were no funding sources, and the investigators reported having no relevant conflicts of interest.SOURCE: Nagula S et al. Clin Gastroenterol Hepatol. 2017 Jun 14. doi: 10.1016/j.cgh.2017.06.013.

As an inpatient child psychiatrist, I see children with some of the most difficult emotional and behavioral issues. And among them, children with adverse childhood experiences (ACE) make up a significant portion. But early childhood adversity is common not just among children who present to the hospital. In the landmark ACE study, which was an ongoing collaboration between Kaiser Permanente and the Centers for Disease Control and Prevention to assess impact of ACEs on various health outcomes, 40% percent of the participants reported experiencing two or more ACEs.¹ Subsequent studies have shown even higher numbers. The study by Copeland et al. on traumatic events based on the Great Smokey Mountains Study showed that more than two-thirds of children reported at least one traumatic event by the age of 16 years.²

diego_cervo/Thinkstock

The significance of this finding cannot be overstated. It is clear that the cumulative incidences of ACEs are associated with poorer health outcomes in a graded dose-response relationship. Those exposed are at great risk of developing PTSD, ADHD, mood disorders, anxiety disorders, and substance use disorder.³ Furthermore, they also are at risk for developing asthma, obesity, ischemic heart disease, diabetes, chronic obstructive pulmonary disease, autoimmune disease, and sexually transmitted disease.⁴ They have lower quality of life, use more health care services, and die nearly 20 years younger.⁵

Currently, the biology of adverse childhood experiences is being elucidated. The deleterious effects of chronically elevated cortisol leading to smaller hippocampal volume through atrophy, neurotoxicity, and disruption of neurogenesis has been demonstrated in adults, but children and adolescents have been found to have reduced medial and posterior corpus callosum.^6-10 Other alterations include changes in EEG activity, and dysregulation of the sympathetic nervous system.^11-13 New systems or neuropeptides that could potentially be beneficial in the treatment of trauma include tempering down of the locus coeruleus–norepinephrine system, the anxiolytic effect of neuropeptide Y, and brain-derived neurotrophic factor.^14,15

Despite all the progress, the treatment for trauma remains imperfect. Depending on the presenting symptoms, stimulants, alpha-agonists (guanfacine or clonidine), alpha-1 blocker, and/or SSRIs all could be a good first step. Medication could reduce the burden of some of the symptoms, but its effects are limited. During the 1970s, researchers started noticing that some children were able to thrive despite substantial risk factors for mental illness. This led to research identifying individual and environmental factors that could be protective against ACEs.

So, what is resilience? It is the development of positive adaptations in the context of significant adversity.¹⁶ But this ability is not purely incumbent on the child. The individual characteristics that lead to resilience such as internal locus of control, optimism, and determination also are dependent on their environment. As such, it is a complex dynamic interplay of genetics, temperament, experience, and environmental supports. As much as the environment can affect resilience, this gives us opportunities to help the child be more resilient, perhaps before an adverse event happens.

One, emphasize the family! A strong family relationship is among the most robust predictor of resilient adaptation. Early experiences and attachments will shape the lens through which people view their subsequent relationships and place them on probabilistic trajectories of “relatively good or bad adaptation.”¹⁷ And just what constitutes “good parenting”? The authoritative parenting style that balances appropriate controls and warmth with consistency and responsiveness generally lead to better outcomes.¹⁸ Other important features include reasonable limit-setting, monitoring, and containment.^{19, 20} Clinicians with expertise in one of the parent-coaching manuals (i.e., “Helping the Noncompliant Child,” by McMahon and Forehand; and “Your Defiant Child: Eight Steps to Better Behavior,” by Barkley and Benton and others) can be helpful in answering parenting questions whether individually or in the group setting.

In addition, parental mental health issues also can adversely affect family relationships. Based on previous studies, mothers who suffer from depression have more difficulty being responsive and warm to their child.²¹ They are often times more punitive and less consistent. Children of mothers with depression are at risk for internalizing, externalizing, and general psychopathology.²² Mothers with history of ACEs are less able to modulate stress and model coping skills. As such, it can be just as important to screen the parents for mental health issues and refer to the appropriate clinician.

Two, community supports also can facilitate development of resilience. Studies have shown participants in the Big Brothers and Big Sisters programs of America exhibit more positive behavior such as better academic behaviors, better relationships with family and friends, and decreased substance use.²³ Furthermore, studies on minority students (African American and Hispanic) suggest improved relationship with teachers led to less behavioral problems and improved social competence. Religious affiliations and other social supports can serve similar purposes as well.²⁴

Three, keep in mind the malleability of the child. Many child attributes are dependent on environmental influences and resilience should focus more on what adults can do to bolster the child’s own efforts.

Dr. Chung is a child and adolescent psychiatrist at the University of Vermont Medical Center, Burlington, and practices at Champlain Valley Physician’s Hospital in Plattsburgh, N.Y. Email him at [email protected].

References

1. Am J Prev Med. 1998 May;14(4):245-58.

2. Arch Gen Psychiatry. 2007 May;64(5):577-84.

3. Eur Arch Psychiatry Clin Neurosci. 2006 Apr;256(3):174-86.

4. Am J Prev Med. 1998 May;14(4):245-58.

5. Pediatr Res. 2016 Jan;79(1-2):227-33.

6. Prog Neuropsychopharmacol Biol Psychiatry. 2010 Oct 1;34(7):1181-8.

7. Brain Res. 1992 Aug 21;588(2):341-5.

8. J Neurosci. 1985 May;5(5):1222-7.

9. J Comp Neurol. 1996 May 20;369(1):56-63.

10. Biol Psychiatry. 2002 Dec 1;52(11):1066-78.

11. J Neuropsychiatry Clin Neurosci. 1998 Summer;10(3):298-307.

12. Biol Psychiatry. 2002 Apr 1;51(7):575-82.

13. Brain Res. 2009 Oct 13;1293:13-23.

14. Neuropeptides. 2016 Apr;56:19-24.

15. Cell. 2007 Oct 19;131(2):391-404.

16. Child Dev. 2000; 71(3): 543-62.

17. Lewis’s Child and Adolescent Psychiatry: A Comprehensive Textbook, 4th ed. (Baltimore: Lippincott Williams & Wilkins, 2007)

18. Early Hum Dev. 2010 Nov;86(11):689-93.

19. Clin Child Fam Psychol Rev. 1998 Mar;1(1):61-75.

20. Dev Psychopathol. 2003 Winter;15(1):95-117.

21. Clin Psychol Rev. 2000 Aug;20(5):561-92.

22. Clin Child Fam Psychol Rev. 2011 Mar;14(1):1-27.

23. “Making a Difference: An Impact Study of Big Brothers Big Sisters,” (Philadelphia: Public/Private Ventures, 1995).

24. Child Dev. 2003 Nov-Dec;74(6):1682-96.


 

As an inpatient child psychiatrist, I see children with some of the most difficult emotional and behavioral issues. And among them, children with adverse childhood experiences (ACE) make up a significant portion. But early childhood adversity is common not just among children who present to the hospital. In the landmark ACE study, which was an ongoing collaboration between Kaiser Permanente and the Centers for Disease Control and Prevention to assess impact of ACEs on various health outcomes, 40% percent of the participants reported experiencing two or more ACEs.¹ Subsequent studies have shown even higher numbers. The study by Copeland et al. on traumatic events based on the Great Smokey Mountains Study showed that more than two-thirds of children reported at least one traumatic event by the age of 16 years.²

diego_cervo/Thinkstock

The significance of this finding cannot be overstated. It is clear that the cumulative incidences of ACEs are associated with poorer health outcomes in a graded dose-response relationship. Those exposed are at great risk of developing PTSD, ADHD, mood disorders, anxiety disorders, and substance use disorder.³ Furthermore, they also are at risk for developing asthma, obesity, ischemic heart disease, diabetes, chronic obstructive pulmonary disease, autoimmune disease, and sexually transmitted disease.⁴ They have lower quality of life, use more health care services, and die nearly 20 years younger.⁵

Currently, the biology of adverse childhood experiences is being elucidated. The deleterious effects of chronically elevated cortisol leading to smaller hippocampal volume through atrophy, neurotoxicity, and disruption of neurogenesis has been demonstrated in adults, but children and adolescents have been found to have reduced medial and posterior corpus callosum.^6-10 Other alterations include changes in EEG activity, and dysregulation of the sympathetic nervous system.^11-13 New systems or neuropeptides that could potentially be beneficial in the treatment of trauma include tempering down of the locus coeruleus–norepinephrine system, the anxiolytic effect of neuropeptide Y, and brain-derived neurotrophic factor.^14,15

Despite all the progress, the treatment for trauma remains imperfect. Depending on the presenting symptoms, stimulants, alpha-agonists (guanfacine or clonidine), alpha-1 blocker, and/or SSRIs all could be a good first step. Medication could reduce the burden of some of the symptoms, but its effects are limited. During the 1970s, researchers started noticing that some children were able to thrive despite substantial risk factors for mental illness. This led to research identifying individual and environmental factors that could be protective against ACEs.

So, what is resilience? It is the development of positive adaptations in the context of significant adversity.¹⁶ But this ability is not purely incumbent on the child. The individual characteristics that lead to resilience such as internal locus of control, optimism, and determination also are dependent on their environment. As such, it is a complex dynamic interplay of genetics, temperament, experience, and environmental supports. As much as the environment can affect resilience, this gives us opportunities to help the child be more resilient, perhaps before an adverse event happens.

One, emphasize the family! A strong family relationship is among the most robust predictor of resilient adaptation. Early experiences and attachments will shape the lens through which people view their subsequent relationships and place them on probabilistic trajectories of “relatively good or bad adaptation.”¹⁷ And just what constitutes “good parenting”? The authoritative parenting style that balances appropriate controls and warmth with consistency and responsiveness generally lead to better outcomes.¹⁸ Other important features include reasonable limit-setting, monitoring, and containment.^{19, 20} Clinicians with expertise in one of the parent-coaching manuals (i.e., “Helping the Noncompliant Child,” by McMahon and Forehand; and “Your Defiant Child: Eight Steps to Better Behavior,” by Barkley and Benton and others) can be helpful in answering parenting questions whether individually or in the group setting.

In addition, parental mental health issues also can adversely affect family relationships. Based on previous studies, mothers who suffer from depression have more difficulty being responsive and warm to their child.²¹ They are often times more punitive and less consistent. Children of mothers with depression are at risk for internalizing, externalizing, and general psychopathology.²² Mothers with history of ACEs are less able to modulate stress and model coping skills. As such, it can be just as important to screen the parents for mental health issues and refer to the appropriate clinician.

Two, community supports also can facilitate development of resilience. Studies have shown participants in the Big Brothers and Big Sisters programs of America exhibit more positive behavior such as better academic behaviors, better relationships with family and friends, and decreased substance use.²³ Furthermore, studies on minority students (African American and Hispanic) suggest improved relationship with teachers led to less behavioral problems and improved social competence. Religious affiliations and other social supports can serve similar purposes as well.²⁴

Three, keep in mind the malleability of the child. Many child attributes are dependent on environmental influences and resilience should focus more on what adults can do to bolster the child’s own efforts.

Dr. Chung is a child and adolescent psychiatrist at the University of Vermont Medical Center, Burlington, and practices at Champlain Valley Physician’s Hospital in Plattsburgh, N.Y. Email him at [email protected].

References

1. Am J Prev Med. 1998 May;14(4):245-58.

2. Arch Gen Psychiatry. 2007 May;64(5):577-84.

3. Eur Arch Psychiatry Clin Neurosci. 2006 Apr;256(3):174-86.

4. Am J Prev Med. 1998 May;14(4):245-58.

5. Pediatr Res. 2016 Jan;79(1-2):227-33.

6. Prog Neuropsychopharmacol Biol Psychiatry. 2010 Oct 1;34(7):1181-8.

7. Brain Res. 1992 Aug 21;588(2):341-5.

8. J Neurosci. 1985 May;5(5):1222-7.

9. J Comp Neurol. 1996 May 20;369(1):56-63.

10. Biol Psychiatry. 2002 Dec 1;52(11):1066-78.

11. J Neuropsychiatry Clin Neurosci. 1998 Summer;10(3):298-307.

12. Biol Psychiatry. 2002 Apr 1;51(7):575-82.

13. Brain Res. 2009 Oct 13;1293:13-23.

14. Neuropeptides. 2016 Apr;56:19-24.

15. Cell. 2007 Oct 19;131(2):391-404.

16. Child Dev. 2000; 71(3): 543-62.

17. Lewis’s Child and Adolescent Psychiatry: A Comprehensive Textbook, 4th ed. (Baltimore: Lippincott Williams & Wilkins, 2007)

18. Early Hum Dev. 2010 Nov;86(11):689-93.

19. Clin Child Fam Psychol Rev. 1998 Mar;1(1):61-75.

20. Dev Psychopathol. 2003 Winter;15(1):95-117.

21. Clin Psychol Rev. 2000 Aug;20(5):561-92.

22. Clin Child Fam Psychol Rev. 2011 Mar;14(1):1-27.

23. “Making a Difference: An Impact Study of Big Brothers Big Sisters,” (Philadelphia: Public/Private Ventures, 1995).

24. Child Dev. 2003 Nov-Dec;74(6):1682-96.


 

As an inpatient child psychiatrist, I see children with some of the most difficult emotional and behavioral issues. And among them, children with adverse childhood experiences (ACE) make up a significant portion. But early childhood adversity is common not just among children who present to the hospital. In the landmark ACE study, which was an ongoing collaboration between Kaiser Permanente and the Centers for Disease Control and Prevention to assess impact of ACEs on various health outcomes, 40% percent of the participants reported experiencing two or more ACEs.¹ Subsequent studies have shown even higher numbers. The study by Copeland et al. on traumatic events based on the Great Smokey Mountains Study showed that more than two-thirds of children reported at least one traumatic event by the age of 16 years.²

diego_cervo/Thinkstock

The significance of this finding cannot be overstated. It is clear that the cumulative incidences of ACEs are associated with poorer health outcomes in a graded dose-response relationship. Those exposed are at great risk of developing PTSD, ADHD, mood disorders, anxiety disorders, and substance use disorder.³ Furthermore, they also are at risk for developing asthma, obesity, ischemic heart disease, diabetes, chronic obstructive pulmonary disease, autoimmune disease, and sexually transmitted disease.⁴ They have lower quality of life, use more health care services, and die nearly 20 years younger.⁵

Currently, the biology of adverse childhood experiences is being elucidated. The deleterious effects of chronically elevated cortisol leading to smaller hippocampal volume through atrophy, neurotoxicity, and disruption of neurogenesis has been demonstrated in adults, but children and adolescents have been found to have reduced medial and posterior corpus callosum.^6-10 Other alterations include changes in EEG activity, and dysregulation of the sympathetic nervous system.^11-13 New systems or neuropeptides that could potentially be beneficial in the treatment of trauma include tempering down of the locus coeruleus–norepinephrine system, the anxiolytic effect of neuropeptide Y, and brain-derived neurotrophic factor.^14,15

Despite all the progress, the treatment for trauma remains imperfect. Depending on the presenting symptoms, stimulants, alpha-agonists (guanfacine or clonidine), alpha-1 blocker, and/or SSRIs all could be a good first step. Medication could reduce the burden of some of the symptoms, but its effects are limited. During the 1970s, researchers started noticing that some children were able to thrive despite substantial risk factors for mental illness. This led to research identifying individual and environmental factors that could be protective against ACEs.

So, what is resilience? It is the development of positive adaptations in the context of significant adversity.¹⁶ But this ability is not purely incumbent on the child. The individual characteristics that lead to resilience such as internal locus of control, optimism, and determination also are dependent on their environment. As such, it is a complex dynamic interplay of genetics, temperament, experience, and environmental supports. As much as the environment can affect resilience, this gives us opportunities to help the child be more resilient, perhaps before an adverse event happens.

One, emphasize the family! A strong family relationship is among the most robust predictor of resilient adaptation. Early experiences and attachments will shape the lens through which people view their subsequent relationships and place them on probabilistic trajectories of “relatively good or bad adaptation.”¹⁷ And just what constitutes “good parenting”? The authoritative parenting style that balances appropriate controls and warmth with consistency and responsiveness generally lead to better outcomes.¹⁸ Other important features include reasonable limit-setting, monitoring, and containment.^{19, 20} Clinicians with expertise in one of the parent-coaching manuals (i.e., “Helping the Noncompliant Child,” by McMahon and Forehand; and “Your Defiant Child: Eight Steps to Better Behavior,” by Barkley and Benton and others) can be helpful in answering parenting questions whether individually or in the group setting.

In addition, parental mental health issues also can adversely affect family relationships. Based on previous studies, mothers who suffer from depression have more difficulty being responsive and warm to their child.²¹ They are often times more punitive and less consistent. Children of mothers with depression are at risk for internalizing, externalizing, and general psychopathology.²² Mothers with history of ACEs are less able to modulate stress and model coping skills. As such, it can be just as important to screen the parents for mental health issues and refer to the appropriate clinician.

Two, community supports also can facilitate development of resilience. Studies have shown participants in the Big Brothers and Big Sisters programs of America exhibit more positive behavior such as better academic behaviors, better relationships with family and friends, and decreased substance use.²³ Furthermore, studies on minority students (African American and Hispanic) suggest improved relationship with teachers led to less behavioral problems and improved social competence. Religious affiliations and other social supports can serve similar purposes as well.²⁴

Three, keep in mind the malleability of the child. Many child attributes are dependent on environmental influences and resilience should focus more on what adults can do to bolster the child’s own efforts.

Dr. Chung is a child and adolescent psychiatrist at the University of Vermont Medical Center, Burlington, and practices at Champlain Valley Physician’s Hospital in Plattsburgh, N.Y. Email him at [email protected].

References

1. Am J Prev Med. 1998 May;14(4):245-58.

2. Arch Gen Psychiatry. 2007 May;64(5):577-84.

3. Eur Arch Psychiatry Clin Neurosci. 2006 Apr;256(3):174-86.

4. Am J Prev Med. 1998 May;14(4):245-58.

5. Pediatr Res. 2016 Jan;79(1-2):227-33.

6. Prog Neuropsychopharmacol Biol Psychiatry. 2010 Oct 1;34(7):1181-8.

7. Brain Res. 1992 Aug 21;588(2):341-5.

8. J Neurosci. 1985 May;5(5):1222-7.

9. J Comp Neurol. 1996 May 20;369(1):56-63.

10. Biol Psychiatry. 2002 Dec 1;52(11):1066-78.

11. J Neuropsychiatry Clin Neurosci. 1998 Summer;10(3):298-307.

12. Biol Psychiatry. 2002 Apr 1;51(7):575-82.

13. Brain Res. 2009 Oct 13;1293:13-23.

14. Neuropeptides. 2016 Apr;56:19-24.

15. Cell. 2007 Oct 19;131(2):391-404.

16. Child Dev. 2000; 71(3): 543-62.

17. Lewis’s Child and Adolescent Psychiatry: A Comprehensive Textbook, 4th ed. (Baltimore: Lippincott Williams & Wilkins, 2007)

18. Early Hum Dev. 2010 Nov;86(11):689-93.

19. Clin Child Fam Psychol Rev. 1998 Mar;1(1):61-75.

20. Dev Psychopathol. 2003 Winter;15(1):95-117.

21. Clin Psychol Rev. 2000 Aug;20(5):561-92.

22. Clin Child Fam Psychol Rev. 2011 Mar;14(1):1-27.

23. “Making a Difference: An Impact Study of Big Brothers Big Sisters,” (Philadelphia: Public/Private Ventures, 1995).

24. Child Dev. 2003 Nov-Dec;74(6):1682-96.