Atopic dermatitis (AD) may be triggered by viral infections, food allergens, weather, and other causes, and it may trigger an inflammatory progression known as the atopic march. This article reviews research on triggers of pediatric AD so that dermatologists may discuss trigger avoidance with patients and guardians. Other factors affecting AD development include genetics and hygiene. Grading of AD also is discussed.

The Atopic March

The persistence of AD in untreated skin can trigger an inflammatory progression called the atopic march in which food and environmental allergies as well as asthma may occur progressively due to ongoing inflammatory triggering.¹ In a study of asthma and food allergy reporting and management in public schools in Chicago, Illinois, food allergies were seen in 9.3% of asthmatic students (n=18,000), and 40.1% of food allergic students (n=4000) had asthma.² An observational study by Flohr et al³ in London, England, included 619 exclusively breastfed infants who were recruited at 3 months of age. The investigators determined that food sensitization was unrelated to the presence of filaggrin mutations, type of eczema (flexural vs nonflexural), and transepidermal water loss but was associated with AD severity as determined by SCORAD (SCORing Atopic Dermatitis), a composite score of AD that includes pruritus as a factor in severity. Other AD associations included 3 leading food allergens: eggs, milk, and peanuts. No association with cod, wheat, or sesame allergy was noted. The investigators concluded that AD and AD severity were the leading skin-related risk factors for food allergies and therefore food allergy development in breastfed infants was probably mediated by cutaneous antigen-presenting cells.³

The skin has been documented to react to contact with known food allergens⁴ and is known to be a route of allergic sensitization to allergens such as fragrance in patients with AD.^5,6 Two phenotypes of eczema that have been associated with asthma development are severe AD disease and multiple environmental allergies, supporting the theory of the atopic march.⁷ There also is evidence that release of danger-associated proteins from an impaired barrier also may trigger asthma.⁸ An analysis of the 2007 National Survey of Children’s Health, a population-based study of91,642 children aged 0 to 17 years, showed that children with AD had a higher prevalence of comorbid asthma (25.1% vs 12.3%), hay fever (34.4% vs 14.3%), and food allergies (15.1% vs 3.6%) compared to children without AD.⁹ A recent article provided detailed information on how food and diet interplay with AD.¹⁰

Triggers of Disease Flares

Triggers are the leading source of AD flare initiation, and avoidance of triggers is an important mechanism by which patients can control disease activity. Despite the best skin care and trigger avoidance, disease flares occur, sometimes due to ongoing inflammation and other times due to inability to prevent flares such as heat and humidity. A survey of patients with AD in Spain identified the following triggers: cosmetic products, clothing, mites, detergents/soaps, and temperature changes.¹¹ In childhood, wool also is a known trigger of AD.¹² Viral infections including respiratory syncytial virus may trigger the first onset of AD.¹³ Patients with AD may become allergic to fragrance and metals causing disease exacerbation on exposure.^14,15 Food allergens contribute to approximately 40% of cases of AD in infancy but are not the cause of AD. The best evidence for improvement of AD with food allergen avoidance exists for egg white allergy.¹⁶ Food avoidance programs should be developed in conjunction with an allergist, as it is no longer advised in many cases to completely withdraw foods; therefore, an allergist has to assess the level of allergic severity and the risk-benefit ratio of food avoidance or introduction.¹⁷ Emotional stressors, heat, and humidity, as well as indoor heating in the winter months, can cause AD flares.¹⁸

A study by Silverberg et al¹⁹ provided evidence of climate influences on the US prevalence of childhood eczema using a merged analysis of the 2007 National Survey of Children’s Health and the 2006-2007 National Climate Data Center and Weather Service. Results showed that eczema prevalence was significantly lower when associated with higher annual relative humidity (P=.01), UV index (P<.0001), and highest-quartile air temperature (P=.002).¹⁹ The Pediatric Eczema Elective Registry also showed that warm, humid, and high-sun-exposure climates are associated with poorly controlled eczema in affected patients.²⁰ The association of eczema with latitude as well as its negative association with mean annual outdoor temperature has been described by Weiland et al²¹ in the ISAAC (International Study of Asthma and Allergies in Childhood) study. Long airplane flights in low humidity can trigger eczema in adults. Climate has been postulated to affect eczema through alterations in filaggrin and skin barrier function.²² Indoor temperature and humidity regulation may be used adjunctively for daily flare prevention.

Genetics and AD

Of 762 infants in a birth cohort with a parent with atopy in Cincinnati, Ohio, 39% developed eczema by the age of 3 years. Single nucleotide polymorphisms of IL-4Rα 175 V and CD14-159 C/T were linked to greater eczema risk at 2 to 3 years of age.²³ Monozygotic twins have a concordance rate of 0.72 to 0.86 versus 0.21 to 0.23 in dizygotic twins, demonstrating a strong genetic component in the development of AD.²⁴ Linkage to AD has been positively made to the epidermal differentiation complex on human chromosome 1q21, which contains the genes for filaggrin and other proteins such as loricrin. Other genes linked to AD include the serine protease inhibitor SPINK5 (serine peptidase inhibitor, Kazal type 5) implicated in Netherton syndrome (triad of ichthyosis linearis circumflexa, bamboo hair, and atopic disorders); RANTES (regulated on activation, normal T-expressed, and secreted), which has been associated with severity of AD; IL-4; and IL-13.^5,25,26

The Hygiene Hypothesis

Atopic dermatitis is more common in wealthy developed countries, leading some to believe that hygiene and relative reduction in illness via vaccination have contributed to the rise of AD prevalence in developed nations.^13,27 There currently is evidence demonstrating that wild-type varicella infection confers long-standing protection against AD and mediates reduced total IgE and peripheral blood lymphocytes.²⁷

Grading of AD

Grading of AD is a subject of controversy, as there currently are no uniform grading scales.²⁸ A recent outcomes group attempted to determine the best scale for disease monitoring. Schmitt et al²⁹ presented the Harmonizing Outcome Measures for Eczema (HOME) roadmap, which was intended to determine a core outcome set for eczema; however, because these outcome measurements have not yet been standardized, only the eczema assessment and severity index (EASI) scoring system meets criteria for standardization. In clinical practice, physicians often assign mild, moderate, or severe labeling based on their general sense of the disease extent using an investigator global assessment score.²⁸

The EASI score is a well-validated composite score of AD severity based on 4 body regions: (1) head and neck, (2) trunk (including genital area), (3) upper limbs, and (4) lower limbs (including buttocks). The total area of involvement in each region is graded on a scale of 0 to 6, and AD severity is graded as a composite of 4 parameters (ranked on a scale of 0–3), including redness (erythema, inflammation), thickness (induration, papulation, swelling [acute eczema]), scratching (excoriation), and lichenification (prurigo nodules [chronic eczema]). The surface area of each region relative to body size is used as a multiplying factor, resulting in the following severity strata: 0=clear; 0.1–1.0=almost clear; 1.1–7.0=mild; 7.1–21.0=moderate; 21.1–50.0=severe; 50.1–72.0=very severe (κ=0.75).^30-32 The six area, six sign AD (SASSAD) score^32,33 is a similar score without adjustment for body surface area by region.³⁴

An older, now less frequently used eczema score is the SCORAD, which addressed surface area by rule of nines and severity of 6 features—redness, swelling, oozing/crusting, scratch marks, skin thickening (lichenification), dryness (assessed in an area with no inflammation)—by region on a scale of 0 to 3. A subjective symptom parameter for itching and sleeplessness helped highlight that these comorbidities are important in gauging disease activity and impact on a child’s life.³⁵

Natural History of AD

The clinical dogma has been that AD would improve with age, with reduction at grade school entry and perhaps full disappearance in adulthood; however, 3 recent surveys have suggested otherwise. The ISAAC group has found prevalence of AD in wealthy developed countries among children aged 6 to 7 years to be at a consistent increase.³⁶ A US-based survey from the National Health Interview Survey showed a 1-year prevalence of 10.2% of active AD in adults and 9.8% when occupational dermatitis was excluded.³⁷ Halvorsen et al³⁸ demonstrated that eczema prevalence is 9.7% in individuals aged 18 to 19 years.

A prospective trial of eighth graders followed from 1995 to 2010 demonstrated that AD persisted in 50% at school age. Persistent eczema into adulthood was associated with early-onset childhood allergic rhinitis and hand eczema.³⁹ In a cohort of hand eczema patients (N=368), 28% had AD and 39% had an atopic illness.⁴⁰ An association with allergic contact dermatitis and increased IgE to Malassezia furfur was further associated.⁴¹

Conclusion

The role of triggers and allergens in disease activity in AD is an important consideration in children with AD and requires ongoing consideration with age and varied exposures. Understanding the grading of AD is important in evaluating clinical trial data. The natural history of AD has changed, which is important for the practitioner to note when counseling patients and guardians.

Atopic dermatitis (AD) may be triggered by viral infections, food allergens, weather, and other causes, and it may trigger an inflammatory progression known as the atopic march. This article reviews research on triggers of pediatric AD so that dermatologists may discuss trigger avoidance with patients and guardians. Other factors affecting AD development include genetics and hygiene. Grading of AD also is discussed.

The Atopic March

The persistence of AD in untreated skin can trigger an inflammatory progression called the atopic march in which food and environmental allergies as well as asthma may occur progressively due to ongoing inflammatory triggering.¹ In a study of asthma and food allergy reporting and management in public schools in Chicago, Illinois, food allergies were seen in 9.3% of asthmatic students (n=18,000), and 40.1% of food allergic students (n=4000) had asthma.² An observational study by Flohr et al³ in London, England, included 619 exclusively breastfed infants who were recruited at 3 months of age. The investigators determined that food sensitization was unrelated to the presence of filaggrin mutations, type of eczema (flexural vs nonflexural), and transepidermal water loss but was associated with AD severity as determined by SCORAD (SCORing Atopic Dermatitis), a composite score of AD that includes pruritus as a factor in severity. Other AD associations included 3 leading food allergens: eggs, milk, and peanuts. No association with cod, wheat, or sesame allergy was noted. The investigators concluded that AD and AD severity were the leading skin-related risk factors for food allergies and therefore food allergy development in breastfed infants was probably mediated by cutaneous antigen-presenting cells.³

The skin has been documented to react to contact with known food allergens⁴ and is known to be a route of allergic sensitization to allergens such as fragrance in patients with AD.^5,6 Two phenotypes of eczema that have been associated with asthma development are severe AD disease and multiple environmental allergies, supporting the theory of the atopic march.⁷ There also is evidence that release of danger-associated proteins from an impaired barrier also may trigger asthma.⁸ An analysis of the 2007 National Survey of Children’s Health, a population-based study of91,642 children aged 0 to 17 years, showed that children with AD had a higher prevalence of comorbid asthma (25.1% vs 12.3%), hay fever (34.4% vs 14.3%), and food allergies (15.1% vs 3.6%) compared to children without AD.⁹ A recent article provided detailed information on how food and diet interplay with AD.¹⁰

Triggers of Disease Flares

Triggers are the leading source of AD flare initiation, and avoidance of triggers is an important mechanism by which patients can control disease activity. Despite the best skin care and trigger avoidance, disease flares occur, sometimes due to ongoing inflammation and other times due to inability to prevent flares such as heat and humidity. A survey of patients with AD in Spain identified the following triggers: cosmetic products, clothing, mites, detergents/soaps, and temperature changes.¹¹ In childhood, wool also is a known trigger of AD.¹² Viral infections including respiratory syncytial virus may trigger the first onset of AD.¹³ Patients with AD may become allergic to fragrance and metals causing disease exacerbation on exposure.^14,15 Food allergens contribute to approximately 40% of cases of AD in infancy but are not the cause of AD. The best evidence for improvement of AD with food allergen avoidance exists for egg white allergy.¹⁶ Food avoidance programs should be developed in conjunction with an allergist, as it is no longer advised in many cases to completely withdraw foods; therefore, an allergist has to assess the level of allergic severity and the risk-benefit ratio of food avoidance or introduction.¹⁷ Emotional stressors, heat, and humidity, as well as indoor heating in the winter months, can cause AD flares.¹⁸

A study by Silverberg et al¹⁹ provided evidence of climate influences on the US prevalence of childhood eczema using a merged analysis of the 2007 National Survey of Children’s Health and the 2006-2007 National Climate Data Center and Weather Service. Results showed that eczema prevalence was significantly lower when associated with higher annual relative humidity (P=.01), UV index (P<.0001), and highest-quartile air temperature (P=.002).¹⁹ The Pediatric Eczema Elective Registry also showed that warm, humid, and high-sun-exposure climates are associated with poorly controlled eczema in affected patients.²⁰ The association of eczema with latitude as well as its negative association with mean annual outdoor temperature has been described by Weiland et al²¹ in the ISAAC (International Study of Asthma and Allergies in Childhood) study. Long airplane flights in low humidity can trigger eczema in adults. Climate has been postulated to affect eczema through alterations in filaggrin and skin barrier function.²² Indoor temperature and humidity regulation may be used adjunctively for daily flare prevention.

Genetics and AD

Of 762 infants in a birth cohort with a parent with atopy in Cincinnati, Ohio, 39% developed eczema by the age of 3 years. Single nucleotide polymorphisms of IL-4Rα 175 V and CD14-159 C/T were linked to greater eczema risk at 2 to 3 years of age.²³ Monozygotic twins have a concordance rate of 0.72 to 0.86 versus 0.21 to 0.23 in dizygotic twins, demonstrating a strong genetic component in the development of AD.²⁴ Linkage to AD has been positively made to the epidermal differentiation complex on human chromosome 1q21, which contains the genes for filaggrin and other proteins such as loricrin. Other genes linked to AD include the serine protease inhibitor SPINK5 (serine peptidase inhibitor, Kazal type 5) implicated in Netherton syndrome (triad of ichthyosis linearis circumflexa, bamboo hair, and atopic disorders); RANTES (regulated on activation, normal T-expressed, and secreted), which has been associated with severity of AD; IL-4; and IL-13.^5,25,26

The Hygiene Hypothesis

Atopic dermatitis is more common in wealthy developed countries, leading some to believe that hygiene and relative reduction in illness via vaccination have contributed to the rise of AD prevalence in developed nations.^13,27 There currently is evidence demonstrating that wild-type varicella infection confers long-standing protection against AD and mediates reduced total IgE and peripheral blood lymphocytes.²⁷

Grading of AD

Grading of AD is a subject of controversy, as there currently are no uniform grading scales.²⁸ A recent outcomes group attempted to determine the best scale for disease monitoring. Schmitt et al²⁹ presented the Harmonizing Outcome Measures for Eczema (HOME) roadmap, which was intended to determine a core outcome set for eczema; however, because these outcome measurements have not yet been standardized, only the eczema assessment and severity index (EASI) scoring system meets criteria for standardization. In clinical practice, physicians often assign mild, moderate, or severe labeling based on their general sense of the disease extent using an investigator global assessment score.²⁸

The EASI score is a well-validated composite score of AD severity based on 4 body regions: (1) head and neck, (2) trunk (including genital area), (3) upper limbs, and (4) lower limbs (including buttocks). The total area of involvement in each region is graded on a scale of 0 to 6, and AD severity is graded as a composite of 4 parameters (ranked on a scale of 0–3), including redness (erythema, inflammation), thickness (induration, papulation, swelling [acute eczema]), scratching (excoriation), and lichenification (prurigo nodules [chronic eczema]). The surface area of each region relative to body size is used as a multiplying factor, resulting in the following severity strata: 0=clear; 0.1–1.0=almost clear; 1.1–7.0=mild; 7.1–21.0=moderate; 21.1–50.0=severe; 50.1–72.0=very severe (κ=0.75).^30-32 The six area, six sign AD (SASSAD) score^32,33 is a similar score without adjustment for body surface area by region.³⁴

An older, now less frequently used eczema score is the SCORAD, which addressed surface area by rule of nines and severity of 6 features—redness, swelling, oozing/crusting, scratch marks, skin thickening (lichenification), dryness (assessed in an area with no inflammation)—by region on a scale of 0 to 3. A subjective symptom parameter for itching and sleeplessness helped highlight that these comorbidities are important in gauging disease activity and impact on a child’s life.³⁵

Natural History of AD

The clinical dogma has been that AD would improve with age, with reduction at grade school entry and perhaps full disappearance in adulthood; however, 3 recent surveys have suggested otherwise. The ISAAC group has found prevalence of AD in wealthy developed countries among children aged 6 to 7 years to be at a consistent increase.³⁶ A US-based survey from the National Health Interview Survey showed a 1-year prevalence of 10.2% of active AD in adults and 9.8% when occupational dermatitis was excluded.³⁷ Halvorsen et al³⁸ demonstrated that eczema prevalence is 9.7% in individuals aged 18 to 19 years.

A prospective trial of eighth graders followed from 1995 to 2010 demonstrated that AD persisted in 50% at school age. Persistent eczema into adulthood was associated with early-onset childhood allergic rhinitis and hand eczema.³⁹ In a cohort of hand eczema patients (N=368), 28% had AD and 39% had an atopic illness.⁴⁰ An association with allergic contact dermatitis and increased IgE to Malassezia furfur was further associated.⁴¹

Conclusion

The role of triggers and allergens in disease activity in AD is an important consideration in children with AD and requires ongoing consideration with age and varied exposures. Understanding the grading of AD is important in evaluating clinical trial data. The natural history of AD has changed, which is important for the practitioner to note when counseling patients and guardians.

Atopic dermatitis (AD) may be triggered by viral infections, food allergens, weather, and other causes, and it may trigger an inflammatory progression known as the atopic march. This article reviews research on triggers of pediatric AD so that dermatologists may discuss trigger avoidance with patients and guardians. Other factors affecting AD development include genetics and hygiene. Grading of AD also is discussed.

The Atopic March

The persistence of AD in untreated skin can trigger an inflammatory progression called the atopic march in which food and environmental allergies as well as asthma may occur progressively due to ongoing inflammatory triggering.¹ In a study of asthma and food allergy reporting and management in public schools in Chicago, Illinois, food allergies were seen in 9.3% of asthmatic students (n=18,000), and 40.1% of food allergic students (n=4000) had asthma.² An observational study by Flohr et al³ in London, England, included 619 exclusively breastfed infants who were recruited at 3 months of age. The investigators determined that food sensitization was unrelated to the presence of filaggrin mutations, type of eczema (flexural vs nonflexural), and transepidermal water loss but was associated with AD severity as determined by SCORAD (SCORing Atopic Dermatitis), a composite score of AD that includes pruritus as a factor in severity. Other AD associations included 3 leading food allergens: eggs, milk, and peanuts. No association with cod, wheat, or sesame allergy was noted. The investigators concluded that AD and AD severity were the leading skin-related risk factors for food allergies and therefore food allergy development in breastfed infants was probably mediated by cutaneous antigen-presenting cells.³

The skin has been documented to react to contact with known food allergens⁴ and is known to be a route of allergic sensitization to allergens such as fragrance in patients with AD.^5,6 Two phenotypes of eczema that have been associated with asthma development are severe AD disease and multiple environmental allergies, supporting the theory of the atopic march.⁷ There also is evidence that release of danger-associated proteins from an impaired barrier also may trigger asthma.⁸ An analysis of the 2007 National Survey of Children’s Health, a population-based study of91,642 children aged 0 to 17 years, showed that children with AD had a higher prevalence of comorbid asthma (25.1% vs 12.3%), hay fever (34.4% vs 14.3%), and food allergies (15.1% vs 3.6%) compared to children without AD.⁹ A recent article provided detailed information on how food and diet interplay with AD.¹⁰

Triggers of Disease Flares

Triggers are the leading source of AD flare initiation, and avoidance of triggers is an important mechanism by which patients can control disease activity. Despite the best skin care and trigger avoidance, disease flares occur, sometimes due to ongoing inflammation and other times due to inability to prevent flares such as heat and humidity. A survey of patients with AD in Spain identified the following triggers: cosmetic products, clothing, mites, detergents/soaps, and temperature changes.¹¹ In childhood, wool also is a known trigger of AD.¹² Viral infections including respiratory syncytial virus may trigger the first onset of AD.¹³ Patients with AD may become allergic to fragrance and metals causing disease exacerbation on exposure.^14,15 Food allergens contribute to approximately 40% of cases of AD in infancy but are not the cause of AD. The best evidence for improvement of AD with food allergen avoidance exists for egg white allergy.¹⁶ Food avoidance programs should be developed in conjunction with an allergist, as it is no longer advised in many cases to completely withdraw foods; therefore, an allergist has to assess the level of allergic severity and the risk-benefit ratio of food avoidance or introduction.¹⁷ Emotional stressors, heat, and humidity, as well as indoor heating in the winter months, can cause AD flares.¹⁸

A study by Silverberg et al¹⁹ provided evidence of climate influences on the US prevalence of childhood eczema using a merged analysis of the 2007 National Survey of Children’s Health and the 2006-2007 National Climate Data Center and Weather Service. Results showed that eczema prevalence was significantly lower when associated with higher annual relative humidity (P=.01), UV index (P<.0001), and highest-quartile air temperature (P=.002).¹⁹ The Pediatric Eczema Elective Registry also showed that warm, humid, and high-sun-exposure climates are associated with poorly controlled eczema in affected patients.²⁰ The association of eczema with latitude as well as its negative association with mean annual outdoor temperature has been described by Weiland et al²¹ in the ISAAC (International Study of Asthma and Allergies in Childhood) study. Long airplane flights in low humidity can trigger eczema in adults. Climate has been postulated to affect eczema through alterations in filaggrin and skin barrier function.²² Indoor temperature and humidity regulation may be used adjunctively for daily flare prevention.

Genetics and AD

Of 762 infants in a birth cohort with a parent with atopy in Cincinnati, Ohio, 39% developed eczema by the age of 3 years. Single nucleotide polymorphisms of IL-4Rα 175 V and CD14-159 C/T were linked to greater eczema risk at 2 to 3 years of age.²³ Monozygotic twins have a concordance rate of 0.72 to 0.86 versus 0.21 to 0.23 in dizygotic twins, demonstrating a strong genetic component in the development of AD.²⁴ Linkage to AD has been positively made to the epidermal differentiation complex on human chromosome 1q21, which contains the genes for filaggrin and other proteins such as loricrin. Other genes linked to AD include the serine protease inhibitor SPINK5 (serine peptidase inhibitor, Kazal type 5) implicated in Netherton syndrome (triad of ichthyosis linearis circumflexa, bamboo hair, and atopic disorders); RANTES (regulated on activation, normal T-expressed, and secreted), which has been associated with severity of AD; IL-4; and IL-13.^5,25,26

The Hygiene Hypothesis

Atopic dermatitis is more common in wealthy developed countries, leading some to believe that hygiene and relative reduction in illness via vaccination have contributed to the rise of AD prevalence in developed nations.^13,27 There currently is evidence demonstrating that wild-type varicella infection confers long-standing protection against AD and mediates reduced total IgE and peripheral blood lymphocytes.²⁷

Grading of AD

Grading of AD is a subject of controversy, as there currently are no uniform grading scales.²⁸ A recent outcomes group attempted to determine the best scale for disease monitoring. Schmitt et al²⁹ presented the Harmonizing Outcome Measures for Eczema (HOME) roadmap, which was intended to determine a core outcome set for eczema; however, because these outcome measurements have not yet been standardized, only the eczema assessment and severity index (EASI) scoring system meets criteria for standardization. In clinical practice, physicians often assign mild, moderate, or severe labeling based on their general sense of the disease extent using an investigator global assessment score.²⁸

The EASI score is a well-validated composite score of AD severity based on 4 body regions: (1) head and neck, (2) trunk (including genital area), (3) upper limbs, and (4) lower limbs (including buttocks). The total area of involvement in each region is graded on a scale of 0 to 6, and AD severity is graded as a composite of 4 parameters (ranked on a scale of 0–3), including redness (erythema, inflammation), thickness (induration, papulation, swelling [acute eczema]), scratching (excoriation), and lichenification (prurigo nodules [chronic eczema]). The surface area of each region relative to body size is used as a multiplying factor, resulting in the following severity strata: 0=clear; 0.1–1.0=almost clear; 1.1–7.0=mild; 7.1–21.0=moderate; 21.1–50.0=severe; 50.1–72.0=very severe (κ=0.75).^30-32 The six area, six sign AD (SASSAD) score^32,33 is a similar score without adjustment for body surface area by region.³⁴

An older, now less frequently used eczema score is the SCORAD, which addressed surface area by rule of nines and severity of 6 features—redness, swelling, oozing/crusting, scratch marks, skin thickening (lichenification), dryness (assessed in an area with no inflammation)—by region on a scale of 0 to 3. A subjective symptom parameter for itching and sleeplessness helped highlight that these comorbidities are important in gauging disease activity and impact on a child’s life.³⁵

Natural History of AD

The clinical dogma has been that AD would improve with age, with reduction at grade school entry and perhaps full disappearance in adulthood; however, 3 recent surveys have suggested otherwise. The ISAAC group has found prevalence of AD in wealthy developed countries among children aged 6 to 7 years to be at a consistent increase.³⁶ A US-based survey from the National Health Interview Survey showed a 1-year prevalence of 10.2% of active AD in adults and 9.8% when occupational dermatitis was excluded.³⁷ Halvorsen et al³⁸ demonstrated that eczema prevalence is 9.7% in individuals aged 18 to 19 years.

A prospective trial of eighth graders followed from 1995 to 2010 demonstrated that AD persisted in 50% at school age. Persistent eczema into adulthood was associated with early-onset childhood allergic rhinitis and hand eczema.³⁹ In a cohort of hand eczema patients (N=368), 28% had AD and 39% had an atopic illness.⁴⁰ An association with allergic contact dermatitis and increased IgE to Malassezia furfur was further associated.⁴¹

Conclusion

The role of triggers and allergens in disease activity in AD is an important consideration in children with AD and requires ongoing consideration with age and varied exposures. Understanding the grading of AD is important in evaluating clinical trial data. The natural history of AD has changed, which is important for the practitioner to note when counseling patients and guardians.

INDIAN WELLS, CALIF. – Both surgery and pessary are effective at helping women with pelvic organ prolapse attain pre-treatment goals, improvements in quality of life, and improvements in patient-reported outcome scores, results from a prospective cohort study demonstrated.

“Women seeking care for pelvic organ prolapse have a wide range of severity in symptoms and they often have highly individual goals for treatment,” Dr. Kyle J. Wohlrab said at the annual scientific meeting of the Society of Gynecologic Surgeons. “We know that when we attain those goals, we help their quality of life.”

Dr. Wohlrab, of the Division of Female Pelvic Medicine and Reconstructive Surgery at Women and Infants Hospital, Providence, R.I., and his associates set out to compare goal attainment between women who chose surgery versus pessary for treatment of their pelvic organ prolapse. Their secondary aim was to evaluate the association between improvements in symptoms and quality of life scores with goal attainment.

Women were eligible if they had symptomatic bulge symptoms and stage 2 or greater pelvic organ prolapse. They were enrolled when they chose either surgery or pessary for treatment and had a successful pessary fitting. The study participants were asked what their 10 most important goals for treatment were, and the researchers categorized them as functional goals (physical, social, emotional, and sexual) or symptom goals (prolapse, urinary, bowel, and pain/discomfort).

The secondary study outcomes were patient-reported outcomes based on the Pelvic Floor Distress Inventory-20 (PFDI-20), the Pelvic Floor Impact Questionnaire-short form 7 (PFIQ-7), the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12), and the Body Image Scale (BIS), which were administered at baseline, 6 months, and 12 months.

A total of 160 women were studied, 80 in each treatment group. Compared with those in the pessary group, women in the surgical group were younger at baseline (a mean of 59 years vs. 64 years), and had less severe prolapse (Pelvic Organ Prolapse Quantification System stage 2 vs. 3), but they had worse PFDI-20 scores (a mean of 126 vs. 104) and BIS scores (a mean of 32 vs. 22).

Dr. Wohlrab and his associates found that 75% of patients in the surgery group achieved all of their functional goals, compared with 58% of those in the pessary group, a difference that did not reach statistical significance except in the category of physical function, which favored patients in the surgery group (87% of goals attained, vs. 62% of those in the pessary group; P = .03).

At the same time, 74% of patients in the surgery group achieved all of their symptom goals, compared with 70% of those in the pessary group, a difference that did not reach statistical significance (P = .7).

Both surgery and pessary groups had significant improvements in the PFDI-20, PFIQ-7, and the BIS scores from baseline (P less than .05 for all). Mean scores on the PISQ-12 also improved from baseline in the surgery group (P less than .05), but not in the pessary group.

Dr. Wohlrab reported having no financial disclosures. The meeting was jointly sponsored by the American College of Surgeons.

[email protected]

INDIAN WELLS, CALIF. – Both surgery and pessary are effective at helping women with pelvic organ prolapse attain pre-treatment goals, improvements in quality of life, and improvements in patient-reported outcome scores, results from a prospective cohort study demonstrated.

“Women seeking care for pelvic organ prolapse have a wide range of severity in symptoms and they often have highly individual goals for treatment,” Dr. Kyle J. Wohlrab said at the annual scientific meeting of the Society of Gynecologic Surgeons. “We know that when we attain those goals, we help their quality of life.”

Dr. Wohlrab, of the Division of Female Pelvic Medicine and Reconstructive Surgery at Women and Infants Hospital, Providence, R.I., and his associates set out to compare goal attainment between women who chose surgery versus pessary for treatment of their pelvic organ prolapse. Their secondary aim was to evaluate the association between improvements in symptoms and quality of life scores with goal attainment.

Women were eligible if they had symptomatic bulge symptoms and stage 2 or greater pelvic organ prolapse. They were enrolled when they chose either surgery or pessary for treatment and had a successful pessary fitting. The study participants were asked what their 10 most important goals for treatment were, and the researchers categorized them as functional goals (physical, social, emotional, and sexual) or symptom goals (prolapse, urinary, bowel, and pain/discomfort).

The secondary study outcomes were patient-reported outcomes based on the Pelvic Floor Distress Inventory-20 (PFDI-20), the Pelvic Floor Impact Questionnaire-short form 7 (PFIQ-7), the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12), and the Body Image Scale (BIS), which were administered at baseline, 6 months, and 12 months.

A total of 160 women were studied, 80 in each treatment group. Compared with those in the pessary group, women in the surgical group were younger at baseline (a mean of 59 years vs. 64 years), and had less severe prolapse (Pelvic Organ Prolapse Quantification System stage 2 vs. 3), but they had worse PFDI-20 scores (a mean of 126 vs. 104) and BIS scores (a mean of 32 vs. 22).

Dr. Wohlrab and his associates found that 75% of patients in the surgery group achieved all of their functional goals, compared with 58% of those in the pessary group, a difference that did not reach statistical significance except in the category of physical function, which favored patients in the surgery group (87% of goals attained, vs. 62% of those in the pessary group; P = .03).

At the same time, 74% of patients in the surgery group achieved all of their symptom goals, compared with 70% of those in the pessary group, a difference that did not reach statistical significance (P = .7).

Both surgery and pessary groups had significant improvements in the PFDI-20, PFIQ-7, and the BIS scores from baseline (P less than .05 for all). Mean scores on the PISQ-12 also improved from baseline in the surgery group (P less than .05), but not in the pessary group.

Dr. Wohlrab reported having no financial disclosures. The meeting was jointly sponsored by the American College of Surgeons.

[email protected]

INDIAN WELLS, CALIF. – Both surgery and pessary are effective at helping women with pelvic organ prolapse attain pre-treatment goals, improvements in quality of life, and improvements in patient-reported outcome scores, results from a prospective cohort study demonstrated.

“Women seeking care for pelvic organ prolapse have a wide range of severity in symptoms and they often have highly individual goals for treatment,” Dr. Kyle J. Wohlrab said at the annual scientific meeting of the Society of Gynecologic Surgeons. “We know that when we attain those goals, we help their quality of life.”

Dr. Wohlrab, of the Division of Female Pelvic Medicine and Reconstructive Surgery at Women and Infants Hospital, Providence, R.I., and his associates set out to compare goal attainment between women who chose surgery versus pessary for treatment of their pelvic organ prolapse. Their secondary aim was to evaluate the association between improvements in symptoms and quality of life scores with goal attainment.

Women were eligible if they had symptomatic bulge symptoms and stage 2 or greater pelvic organ prolapse. They were enrolled when they chose either surgery or pessary for treatment and had a successful pessary fitting. The study participants were asked what their 10 most important goals for treatment were, and the researchers categorized them as functional goals (physical, social, emotional, and sexual) or symptom goals (prolapse, urinary, bowel, and pain/discomfort).

The secondary study outcomes were patient-reported outcomes based on the Pelvic Floor Distress Inventory-20 (PFDI-20), the Pelvic Floor Impact Questionnaire-short form 7 (PFIQ-7), the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12), and the Body Image Scale (BIS), which were administered at baseline, 6 months, and 12 months.

A total of 160 women were studied, 80 in each treatment group. Compared with those in the pessary group, women in the surgical group were younger at baseline (a mean of 59 years vs. 64 years), and had less severe prolapse (Pelvic Organ Prolapse Quantification System stage 2 vs. 3), but they had worse PFDI-20 scores (a mean of 126 vs. 104) and BIS scores (a mean of 32 vs. 22).

Dr. Wohlrab and his associates found that 75% of patients in the surgery group achieved all of their functional goals, compared with 58% of those in the pessary group, a difference that did not reach statistical significance except in the category of physical function, which favored patients in the surgery group (87% of goals attained, vs. 62% of those in the pessary group; P = .03).

At the same time, 74% of patients in the surgery group achieved all of their symptom goals, compared with 70% of those in the pessary group, a difference that did not reach statistical significance (P = .7).

Both surgery and pessary groups had significant improvements in the PFDI-20, PFIQ-7, and the BIS scores from baseline (P less than .05 for all). Mean scores on the PISQ-12 also improved from baseline in the surgery group (P less than .05), but not in the pessary group.

Dr. Wohlrab reported having no financial disclosures. The meeting was jointly sponsored by the American College of Surgeons.

[email protected]

FROM THE AACR ANNUAL MEETING

A differently engineered chimeric antigen receptor (CAR) T cell promises to overcome major limitations of current CAR T cell therapies. Rather than engineer the CAR T cells to have a receptor that recognizes specific tumor antigens one at a time and requiring different CAR T cells for every antigen, this technique engineers a T cell receptor that can bind one invariant end of a bifunctional molecule. The molecule is constructed such that the other end can bind to whatever tumor cell surface marker is of interest. In this way, the CAR T cells can be constructed once and be directed to various tumor markers.

Standard CAR T cells are engineered to express on their surfaces receptors that recognize a specific antigen. These cells have been used up to now to recognize and kill tumor cells – for example, B cell leukemias carrying the pan-B cell marker CD19. The CAR T cells and their progeny, including memory T cells, remain in the body and continue to carry out their functions, potentially providing immune surveillance in case cancer cells arise again. But they uniquely recognize just CD19 – a problem, in that they kill even normal B cells, so-called off-target toxicity.

Beyond the unique specificity of standard CAR T cells, Philip Low, Ph.D., director of the Center for Drug Discovery at Purdue University in West Lafayette, Indiana, said these cells have three major limitations. First, they may lyse tumor cells so rapidly that a systemic tumor lysis syndrome or “cytokine storm” occurs. Second, the persisting CAR T cells can kill normal cells – for example, ones directed against CD19 killing normal B cells. Third, tumor cells have unstable genomes, leading to tumor heterogeneity, with some cells potentially losing the targeted antigens and therefore becoming “invisible” to the CAR T cells.

“So what we have done is basically designed a solution to all three, and we call it a universal CAR T cell because of its ability, with the help of an adapter molecule, to recognize all of these mutated tumor cells within a heterogeneous tumor,” he said at the annual meeting of the American Association for Cancer Research. The key was to make a CAR T cell with a surface receptor that binds to the dye fluorescein. Then fluorescein is coupled through a short linker to a molecule that binds specifically to a molecule expressed on tumor cells. In this way the CAR T cell can be made to interact with any tumor cell, depending on what is coupled to the fluorescein. The technique is analogous to a socket wrench. Every socket has the same size hole that the ratchet handle fits into regardless of the size of the “business end” of the sockets, which recognize different size nuts.

Dr. Low gave an example of folic acid, for which he says a receptor is overexpressed on about 40% of human tumors but almost never on normal cells. “We link fluorescein to the vitamin folic acid,” he said. CAR T cells are injected into an animal, and nothing happens unless a folate-fluorescein conjugate is also injected. “As soon as we inject folate-fluorescein, the folate binds to the tumor cell surface, the fluorescein part of the folate-fluorescein binds to the CAR T cell, this forces a very tight interaction between the engineered T cell and the cancer cell, and we found it leads to melting away of the tumor,” he said.

This technique addresses the three major problems with standard CAR T cell therapy. By titrating the binding affinity, concentration, and rate of administration of the fluorescein conjugate, the rate of tumor killing can be controlled, mitigating tumor lysis syndrome. Plus, normal cells may be spared if the parameters are adjusted so that the conjugate binds only to cells with high levels of the target molecule, such as tumor cells.

Because its low molecular weight, the bi-specific conjugate rapidly disappears from the circulation, and the cell killing can be terminated, allowing normal cells to regenerate – for example, in the case of normal B cells that carry CD19. Since CAR T cells generate progeny that stay in the body, the progeny remain “dormant” but are ready to be activated again by addition of the conjugate to attack tumor cells if they arise.

A major issue is dealing with tumor heterogeneity; Dr. Low’s method seems to address that, as well. “We have tumor-specific ligands for over 90% of all human cancers,” he said. “Within another couple of months we’ll have them for 100%.”

Tumors typically contain lots of hypoxic cells, and hypoxic cells overexpress carbonic anhydrase-9. “Virtually every tumor has large fractions of the tumor mass that overexpress carbonic anhydrase-9, and we have a ligand that binds very specifically to that,” Dr. Low said.

To address the problem of tumor heterogeneity, with different mutations within different areas of the tumor or over time because of genetic instability in the cells, Dr. Low said, “We have a cocktail of about five of these small molecules… they are inexpensive to produce… and they clear very rapidly… and with the cocktail we can hit nearly all cancer cells, even in heterogeneous cancers.”

One limitation, as with standard CAR T cell therapy, is that the technique will still depend on using an individual patient’s T cells to modify through use of a lentiviral vector, so there would not be a universal, off-the-shelf T cell to use for everyone.

The technique and materials have been tested only in animals so far, using tumor-specific ligands for the folate receptor, a prostate-specific membrane antigen, and an antigen overexpressed on neuroendocrine tumors. Dr. Low has intentions to move the technology into human trials. He said the bridging molecules exist in highly purified form, and CAR T cell technology has already been developed by others. “Today we see great success in animal models and have no reason to believe that it won’t translate at least to a good extent to the clinic,” he said. Still, he expects some obstacles along the way and is willing to partner with others working on similar problems as well as large pharmaceutical companies.

The research has been supported by Endocyte, a company that Dr. Low founded and for which he is Chief Scientific Officer and a member of the board of directors. He has filed two patents on the technology, which are held by Purdue University and licensed to Endocyte.

FROM THE AACR ANNUAL MEETING

A differently engineered chimeric antigen receptor (CAR) T cell promises to overcome major limitations of current CAR T cell therapies. Rather than engineer the CAR T cells to have a receptor that recognizes specific tumor antigens one at a time and requiring different CAR T cells for every antigen, this technique engineers a T cell receptor that can bind one invariant end of a bifunctional molecule. The molecule is constructed such that the other end can bind to whatever tumor cell surface marker is of interest. In this way, the CAR T cells can be constructed once and be directed to various tumor markers.

Standard CAR T cells are engineered to express on their surfaces receptors that recognize a specific antigen. These cells have been used up to now to recognize and kill tumor cells – for example, B cell leukemias carrying the pan-B cell marker CD19. The CAR T cells and their progeny, including memory T cells, remain in the body and continue to carry out their functions, potentially providing immune surveillance in case cancer cells arise again. But they uniquely recognize just CD19 – a problem, in that they kill even normal B cells, so-called off-target toxicity.

Beyond the unique specificity of standard CAR T cells, Philip Low, Ph.D., director of the Center for Drug Discovery at Purdue University in West Lafayette, Indiana, said these cells have three major limitations. First, they may lyse tumor cells so rapidly that a systemic tumor lysis syndrome or “cytokine storm” occurs. Second, the persisting CAR T cells can kill normal cells – for example, ones directed against CD19 killing normal B cells. Third, tumor cells have unstable genomes, leading to tumor heterogeneity, with some cells potentially losing the targeted antigens and therefore becoming “invisible” to the CAR T cells.

“So what we have done is basically designed a solution to all three, and we call it a universal CAR T cell because of its ability, with the help of an adapter molecule, to recognize all of these mutated tumor cells within a heterogeneous tumor,” he said at the annual meeting of the American Association for Cancer Research. The key was to make a CAR T cell with a surface receptor that binds to the dye fluorescein. Then fluorescein is coupled through a short linker to a molecule that binds specifically to a molecule expressed on tumor cells. In this way the CAR T cell can be made to interact with any tumor cell, depending on what is coupled to the fluorescein. The technique is analogous to a socket wrench. Every socket has the same size hole that the ratchet handle fits into regardless of the size of the “business end” of the sockets, which recognize different size nuts.

Dr. Low gave an example of folic acid, for which he says a receptor is overexpressed on about 40% of human tumors but almost never on normal cells. “We link fluorescein to the vitamin folic acid,” he said. CAR T cells are injected into an animal, and nothing happens unless a folate-fluorescein conjugate is also injected. “As soon as we inject folate-fluorescein, the folate binds to the tumor cell surface, the fluorescein part of the folate-fluorescein binds to the CAR T cell, this forces a very tight interaction between the engineered T cell and the cancer cell, and we found it leads to melting away of the tumor,” he said.

This technique addresses the three major problems with standard CAR T cell therapy. By titrating the binding affinity, concentration, and rate of administration of the fluorescein conjugate, the rate of tumor killing can be controlled, mitigating tumor lysis syndrome. Plus, normal cells may be spared if the parameters are adjusted so that the conjugate binds only to cells with high levels of the target molecule, such as tumor cells.

Because its low molecular weight, the bi-specific conjugate rapidly disappears from the circulation, and the cell killing can be terminated, allowing normal cells to regenerate – for example, in the case of normal B cells that carry CD19. Since CAR T cells generate progeny that stay in the body, the progeny remain “dormant” but are ready to be activated again by addition of the conjugate to attack tumor cells if they arise.

A major issue is dealing with tumor heterogeneity; Dr. Low’s method seems to address that, as well. “We have tumor-specific ligands for over 90% of all human cancers,” he said. “Within another couple of months we’ll have them for 100%.”

Tumors typically contain lots of hypoxic cells, and hypoxic cells overexpress carbonic anhydrase-9. “Virtually every tumor has large fractions of the tumor mass that overexpress carbonic anhydrase-9, and we have a ligand that binds very specifically to that,” Dr. Low said.

To address the problem of tumor heterogeneity, with different mutations within different areas of the tumor or over time because of genetic instability in the cells, Dr. Low said, “We have a cocktail of about five of these small molecules… they are inexpensive to produce… and they clear very rapidly… and with the cocktail we can hit nearly all cancer cells, even in heterogeneous cancers.”

One limitation, as with standard CAR T cell therapy, is that the technique will still depend on using an individual patient’s T cells to modify through use of a lentiviral vector, so there would not be a universal, off-the-shelf T cell to use for everyone.

The technique and materials have been tested only in animals so far, using tumor-specific ligands for the folate receptor, a prostate-specific membrane antigen, and an antigen overexpressed on neuroendocrine tumors. Dr. Low has intentions to move the technology into human trials. He said the bridging molecules exist in highly purified form, and CAR T cell technology has already been developed by others. “Today we see great success in animal models and have no reason to believe that it won’t translate at least to a good extent to the clinic,” he said. Still, he expects some obstacles along the way and is willing to partner with others working on similar problems as well as large pharmaceutical companies.

The research has been supported by Endocyte, a company that Dr. Low founded and for which he is Chief Scientific Officer and a member of the board of directors. He has filed two patents on the technology, which are held by Purdue University and licensed to Endocyte.

FROM THE AACR ANNUAL MEETING

A differently engineered chimeric antigen receptor (CAR) T cell promises to overcome major limitations of current CAR T cell therapies. Rather than engineer the CAR T cells to have a receptor that recognizes specific tumor antigens one at a time and requiring different CAR T cells for every antigen, this technique engineers a T cell receptor that can bind one invariant end of a bifunctional molecule. The molecule is constructed such that the other end can bind to whatever tumor cell surface marker is of interest. In this way, the CAR T cells can be constructed once and be directed to various tumor markers.

Standard CAR T cells are engineered to express on their surfaces receptors that recognize a specific antigen. These cells have been used up to now to recognize and kill tumor cells – for example, B cell leukemias carrying the pan-B cell marker CD19. The CAR T cells and their progeny, including memory T cells, remain in the body and continue to carry out their functions, potentially providing immune surveillance in case cancer cells arise again. But they uniquely recognize just CD19 – a problem, in that they kill even normal B cells, so-called off-target toxicity.

Beyond the unique specificity of standard CAR T cells, Philip Low, Ph.D., director of the Center for Drug Discovery at Purdue University in West Lafayette, Indiana, said these cells have three major limitations. First, they may lyse tumor cells so rapidly that a systemic tumor lysis syndrome or “cytokine storm” occurs. Second, the persisting CAR T cells can kill normal cells – for example, ones directed against CD19 killing normal B cells. Third, tumor cells have unstable genomes, leading to tumor heterogeneity, with some cells potentially losing the targeted antigens and therefore becoming “invisible” to the CAR T cells.

“So what we have done is basically designed a solution to all three, and we call it a universal CAR T cell because of its ability, with the help of an adapter molecule, to recognize all of these mutated tumor cells within a heterogeneous tumor,” he said at the annual meeting of the American Association for Cancer Research. The key was to make a CAR T cell with a surface receptor that binds to the dye fluorescein. Then fluorescein is coupled through a short linker to a molecule that binds specifically to a molecule expressed on tumor cells. In this way the CAR T cell can be made to interact with any tumor cell, depending on what is coupled to the fluorescein. The technique is analogous to a socket wrench. Every socket has the same size hole that the ratchet handle fits into regardless of the size of the “business end” of the sockets, which recognize different size nuts.

Dr. Low gave an example of folic acid, for which he says a receptor is overexpressed on about 40% of human tumors but almost never on normal cells. “We link fluorescein to the vitamin folic acid,” he said. CAR T cells are injected into an animal, and nothing happens unless a folate-fluorescein conjugate is also injected. “As soon as we inject folate-fluorescein, the folate binds to the tumor cell surface, the fluorescein part of the folate-fluorescein binds to the CAR T cell, this forces a very tight interaction between the engineered T cell and the cancer cell, and we found it leads to melting away of the tumor,” he said.

This technique addresses the three major problems with standard CAR T cell therapy. By titrating the binding affinity, concentration, and rate of administration of the fluorescein conjugate, the rate of tumor killing can be controlled, mitigating tumor lysis syndrome. Plus, normal cells may be spared if the parameters are adjusted so that the conjugate binds only to cells with high levels of the target molecule, such as tumor cells.

Because its low molecular weight, the bi-specific conjugate rapidly disappears from the circulation, and the cell killing can be terminated, allowing normal cells to regenerate – for example, in the case of normal B cells that carry CD19. Since CAR T cells generate progeny that stay in the body, the progeny remain “dormant” but are ready to be activated again by addition of the conjugate to attack tumor cells if they arise.

A major issue is dealing with tumor heterogeneity; Dr. Low’s method seems to address that, as well. “We have tumor-specific ligands for over 90% of all human cancers,” he said. “Within another couple of months we’ll have them for 100%.”

Tumors typically contain lots of hypoxic cells, and hypoxic cells overexpress carbonic anhydrase-9. “Virtually every tumor has large fractions of the tumor mass that overexpress carbonic anhydrase-9, and we have a ligand that binds very specifically to that,” Dr. Low said.

To address the problem of tumor heterogeneity, with different mutations within different areas of the tumor or over time because of genetic instability in the cells, Dr. Low said, “We have a cocktail of about five of these small molecules… they are inexpensive to produce… and they clear very rapidly… and with the cocktail we can hit nearly all cancer cells, even in heterogeneous cancers.”

One limitation, as with standard CAR T cell therapy, is that the technique will still depend on using an individual patient’s T cells to modify through use of a lentiviral vector, so there would not be a universal, off-the-shelf T cell to use for everyone.

The technique and materials have been tested only in animals so far, using tumor-specific ligands for the folate receptor, a prostate-specific membrane antigen, and an antigen overexpressed on neuroendocrine tumors. Dr. Low has intentions to move the technology into human trials. He said the bridging molecules exist in highly purified form, and CAR T cell technology has already been developed by others. “Today we see great success in animal models and have no reason to believe that it won’t translate at least to a good extent to the clinic,” he said. Still, he expects some obstacles along the way and is willing to partner with others working on similar problems as well as large pharmaceutical companies.

The research has been supported by Endocyte, a company that Dr. Low founded and for which he is Chief Scientific Officer and a member of the board of directors. He has filed two patents on the technology, which are held by Purdue University and licensed to Endocyte.

Meaningful use would get a new name and an emphasis on flexibility under a proposal from the Centers for Medicare & Medicaid Services.

“We’re proposing today to replace meaningful use in the physician office with a new effort that moves the emphasis away from the use of information technology to one that supports patient care, supported by better and more connected technology,” CMS Acting Administrator Andy Slavitt said during an April 27 press teleconference to introduce the changes.

“The program, Advancing Care Information, is designed to be far simpler, less burdensome, and more flexible,” Mr. Slavitt said. “If this proposal is finalized, it will replace the current meaningful use program for physician offices and will be effective January 1, 2017, along with the other components of the MACRA implementations.”

Mr. Slavitt and Dr. Karen DeSalvo, National Coordinator for Health Information Technology, noted in a blog postthat the improvements “should increase providers’ ability to use technology in ways that are more relevant to their needs and the needs of their patients.”

The changes come as part of a larger proposed regulation to implement the Medicare Access and CHIP Reauthorization Act, released online April 27 and scheduled for publication in the Federal Register on May 9.

MACRA will create two systems under which doctors will be paid for the quality of care they provide. The changes to the meaningful use program will affect physicians who choose to participate in the Merit-based Incentive Payment System (MIPS). Under the proposed rule, efforts under the new Advancing Care Information program would account for 25% of the score used to determine pay for office-based physicians under Medicare.

The key difference between the proposed program and meaningful use is that physicians will no longer be faced with an all-or-nothing requirement for meeting criteria to qualify for extra payments under the MIPS program.

Advancing Care Information has been divided into two parts. The first is reporting measures and has been streamlined to 11 measures, down from 18. Reporting on computerized physician order entry and clinical decision support measures have been eliminated.

The second part is based on performance measures, with multiple pathways to achieve those targets, which allow physicians to select the measures that best align with their needs.

There also is an opportunity to earn an extra point if a physician is reporting to more than one public health registry.

“We’ve also taken this opportunity to really focus more on aligning quality, on seeing that we are streamlining workflow and creating opportunities for electronic health record and health IT developers to create products that really meet the needs and expectations of clinicians and providers on the front lines,” Dr. DeSalvo said during the April 27 call.

The proposal also emphasizes interoperability, information exchange, and security measures and requires that patients be able to access their health care information easily through the use of apps and other consumer-friendly technology, according to the blog post.

The proposed rule also emphasizes open data sharing and interoperability, something that has been a continual drag on the current meaningful use program.

Comments on the proposed rule can be made at www.regulations.gov and are due June 26.

[email protected]

Meaningful use would get a new name and an emphasis on flexibility under a proposal from the Centers for Medicare & Medicaid Services.

“We’re proposing today to replace meaningful use in the physician office with a new effort that moves the emphasis away from the use of information technology to one that supports patient care, supported by better and more connected technology,” CMS Acting Administrator Andy Slavitt said during an April 27 press teleconference to introduce the changes.

“The program, Advancing Care Information, is designed to be far simpler, less burdensome, and more flexible,” Mr. Slavitt said. “If this proposal is finalized, it will replace the current meaningful use program for physician offices and will be effective January 1, 2017, along with the other components of the MACRA implementations.”

Mr. Slavitt and Dr. Karen DeSalvo, National Coordinator for Health Information Technology, noted in a blog postthat the improvements “should increase providers’ ability to use technology in ways that are more relevant to their needs and the needs of their patients.”

The changes come as part of a larger proposed regulation to implement the Medicare Access and CHIP Reauthorization Act, released online April 27 and scheduled for publication in the Federal Register on May 9.

MACRA will create two systems under which doctors will be paid for the quality of care they provide. The changes to the meaningful use program will affect physicians who choose to participate in the Merit-based Incentive Payment System (MIPS). Under the proposed rule, efforts under the new Advancing Care Information program would account for 25% of the score used to determine pay for office-based physicians under Medicare.

The key difference between the proposed program and meaningful use is that physicians will no longer be faced with an all-or-nothing requirement for meeting criteria to qualify for extra payments under the MIPS program.

Advancing Care Information has been divided into two parts. The first is reporting measures and has been streamlined to 11 measures, down from 18. Reporting on computerized physician order entry and clinical decision support measures have been eliminated.

The second part is based on performance measures, with multiple pathways to achieve those targets, which allow physicians to select the measures that best align with their needs.

There also is an opportunity to earn an extra point if a physician is reporting to more than one public health registry.

“We’ve also taken this opportunity to really focus more on aligning quality, on seeing that we are streamlining workflow and creating opportunities for electronic health record and health IT developers to create products that really meet the needs and expectations of clinicians and providers on the front lines,” Dr. DeSalvo said during the April 27 call.

The proposal also emphasizes interoperability, information exchange, and security measures and requires that patients be able to access their health care information easily through the use of apps and other consumer-friendly technology, according to the blog post.

The proposed rule also emphasizes open data sharing and interoperability, something that has been a continual drag on the current meaningful use program.

Comments on the proposed rule can be made at www.regulations.gov and are due June 26.

[email protected]

Meaningful use would get a new name and an emphasis on flexibility under a proposal from the Centers for Medicare & Medicaid Services.

“We’re proposing today to replace meaningful use in the physician office with a new effort that moves the emphasis away from the use of information technology to one that supports patient care, supported by better and more connected technology,” CMS Acting Administrator Andy Slavitt said during an April 27 press teleconference to introduce the changes.

“The program, Advancing Care Information, is designed to be far simpler, less burdensome, and more flexible,” Mr. Slavitt said. “If this proposal is finalized, it will replace the current meaningful use program for physician offices and will be effective January 1, 2017, along with the other components of the MACRA implementations.”

Mr. Slavitt and Dr. Karen DeSalvo, National Coordinator for Health Information Technology, noted in a blog postthat the improvements “should increase providers’ ability to use technology in ways that are more relevant to their needs and the needs of their patients.”

The changes come as part of a larger proposed regulation to implement the Medicare Access and CHIP Reauthorization Act, released online April 27 and scheduled for publication in the Federal Register on May 9.

MACRA will create two systems under which doctors will be paid for the quality of care they provide. The changes to the meaningful use program will affect physicians who choose to participate in the Merit-based Incentive Payment System (MIPS). Under the proposed rule, efforts under the new Advancing Care Information program would account for 25% of the score used to determine pay for office-based physicians under Medicare.

The key difference between the proposed program and meaningful use is that physicians will no longer be faced with an all-or-nothing requirement for meeting criteria to qualify for extra payments under the MIPS program.

Advancing Care Information has been divided into two parts. The first is reporting measures and has been streamlined to 11 measures, down from 18. Reporting on computerized physician order entry and clinical decision support measures have been eliminated.

The second part is based on performance measures, with multiple pathways to achieve those targets, which allow physicians to select the measures that best align with their needs.

There also is an opportunity to earn an extra point if a physician is reporting to more than one public health registry.

“We’ve also taken this opportunity to really focus more on aligning quality, on seeing that we are streamlining workflow and creating opportunities for electronic health record and health IT developers to create products that really meet the needs and expectations of clinicians and providers on the front lines,” Dr. DeSalvo said during the April 27 call.

The proposal also emphasizes interoperability, information exchange, and security measures and requires that patients be able to access their health care information easily through the use of apps and other consumer-friendly technology, according to the blog post.

The proposed rule also emphasizes open data sharing and interoperability, something that has been a continual drag on the current meaningful use program.

Comments on the proposed rule can be made at www.regulations.gov and are due June 26.

[email protected]

Cameron Turtle, MBBS, PhD

Photo courtesy of

Fred Hutch News Service

Researchers say they have conducted the first trial of CD19-directed chimeric antigen receptor (CAR) T-cell therapy in which CD4+ and CD8+ cells were administered in equal proportions.

And the assurance that each patient received the same mixture of cells allowed the team to draw clear conclusions about the effects of administering CAR T-cell therapy at different doses.

The researchers detailed these conclusions in The Journal of Clinical Investigation.

This phase 1/2 trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing the CAR T-cell therapy as JCAR014.

The work was also funded by the National Cancer Institute, private philanthropists, and the Life Sciences Discovery Fund.

Patients and treatment

The researchers reported data on 32 patients who had relapsed or refractory, CD19+ B-cell acute lymphoblastic leukemia and a median age of 40 (range, 20–73). Two of these patients were excluded due to complications prior to receiving treatment.

The 30 patients who were treated in this study had received a median of 3 prior intensive chemotherapy regimens (range, 1–11). Eleven patients had failed a hematopoietic stem cell transplant (HSCT). And all patients had detectable disease in the bone marrow, extramedullary sites, or cerebrospinal fluid at baseline.

To create the CAR T-cell therapy, the researchers modified CD8+ and CD4+ T-cell subsets separately to express a CD19-targeted CAR incorporating 4-1BB and CD3ζ signaling domains. The cells were then formulated in a defined ratio of CD4+:CD8+ CAR T cells.

Patients underwent lymphodepletion with a cyclophosphamide-based regimen (alone or with fludarabine or etoposide) and then received CAR T cells 48 to 96 hours later. The CAR T cells were given at 3 dose levels—2 × 10⁵/kg (DL1), 2 × 10⁶/kg (DL2), and 2 × 10⁷/kg (DL3).

Toxicity

The first 2 patients who received CAR T-cell therapy at DL3 developed severe toxicities, including 1 patient who died. So DL3 was not given to any subsequent patients.

Two patients died after CAR T-cell infusion. One patient had severe cytokine release syndrome (CRS) and multiorgan failure and died on day 3. The other patient had transient severe CRS with irreversible neurologic toxicity and died on day 122.

The most common adverse event observed in the first 14 days after CAR T-cell infusion was CRS, which occurred in 25 patients. Seven patients had severe CRS that put them in the intensive care unit.

However, for the patients treated at DL1 and DL2, dexamethasone alone or with tocilizumab resolved CRS.

Fifteen patients developed severe neurotoxicity (grade 3 or higher), either with CRS or after it resolved. For all but 1 patient (the aforementioned patient who died), neurologic symptoms and signs resolved.

Response

One patient died before response assessment, so 29 patients were evaluable. Twenty-seven of these patients (93%) achieved bone marrow remission by flow cytometry.

Of the 2 patients who did not achieve a complete response (CR), 1 underwent an allogeneic HSCT after receiving CAR T cells. After HSCT, she relapsed, was re-enrolled on the trial, and achieved a CR after receiving a higher dose of CAR T cells (DL2).

Twenty-five patients (86%) achieved a CR without evidence of minimal residual disease by flow cytometry and conventional karyotyping, FISH, or QPCR.

“Patients who come onto the trial have really limited options for treatment,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“They have refractory acute leukemia. So the fact that we’re getting so many into remission is giving these people a way forward.”

Unfortunately, not all patients stayed in CR. Some relapsed and were treated again with CAR T cells, and 2 patients relapsed with leukemias that were immune to the CAR T cells. The researchers said it is still too early to know the long-term outcomes of the therapy.

“This is just the beginning,” Dr Turtle said. “It sounds fantastic to say that we get over 90% remissions, but there’s so much more work to do make sure they’re durable remissions, to work out who’s going to benefit the most, and extend this work to other diseases.”

Lessons learned

The researchers said that, because these CAR T cells had a defined CD4+:CD8+ composition, this study provides the first clear evidence of the relationships between the CAR T-cell dose patients receive and their outcomes after infusion.

The team found that high doses of CAR T cells and high tumor burden increase the risks of severe CRS and neurotoxicity. However, certain biomarkers can identify patients at the highest risk of toxicity.

Levels of IL-6, IFN-γ, and TNF-α on the first day after CAR T-cell infusion were significantly higher in patients who later developed severe neurotoxicity. Levels of these biomarkers were also higher in patients who were later sent to the intensive care unit.

Furthermore, risk-stratified CAR T-cell dosing based on bone marrow disease burden decreased toxicity.

The researchers also said they observed CD8+ T-cell-mediated anti-CAR transgene product immune responses in some patients, which limited CAR T-cell persistence and increased the risk of relapse.

And including fludarabine in the lymphodepletion regimen resulted in better CAR T-cell persistence and disease-free survival than when cyclophosphamide was given alone or with etoposide.

Cameron Turtle, MBBS, PhD

Photo courtesy of

Fred Hutch News Service

Researchers say they have conducted the first trial of CD19-directed chimeric antigen receptor (CAR) T-cell therapy in which CD4+ and CD8+ cells were administered in equal proportions.

And the assurance that each patient received the same mixture of cells allowed the team to draw clear conclusions about the effects of administering CAR T-cell therapy at different doses.

The researchers detailed these conclusions in The Journal of Clinical Investigation.

This phase 1/2 trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing the CAR T-cell therapy as JCAR014.

The work was also funded by the National Cancer Institute, private philanthropists, and the Life Sciences Discovery Fund.

Patients and treatment

The researchers reported data on 32 patients who had relapsed or refractory, CD19+ B-cell acute lymphoblastic leukemia and a median age of 40 (range, 20–73). Two of these patients were excluded due to complications prior to receiving treatment.

The 30 patients who were treated in this study had received a median of 3 prior intensive chemotherapy regimens (range, 1–11). Eleven patients had failed a hematopoietic stem cell transplant (HSCT). And all patients had detectable disease in the bone marrow, extramedullary sites, or cerebrospinal fluid at baseline.

To create the CAR T-cell therapy, the researchers modified CD8+ and CD4+ T-cell subsets separately to express a CD19-targeted CAR incorporating 4-1BB and CD3ζ signaling domains. The cells were then formulated in a defined ratio of CD4+:CD8+ CAR T cells.

Patients underwent lymphodepletion with a cyclophosphamide-based regimen (alone or with fludarabine or etoposide) and then received CAR T cells 48 to 96 hours later. The CAR T cells were given at 3 dose levels—2 × 10⁵/kg (DL1), 2 × 10⁶/kg (DL2), and 2 × 10⁷/kg (DL3).

Toxicity

The first 2 patients who received CAR T-cell therapy at DL3 developed severe toxicities, including 1 patient who died. So DL3 was not given to any subsequent patients.

Two patients died after CAR T-cell infusion. One patient had severe cytokine release syndrome (CRS) and multiorgan failure and died on day 3. The other patient had transient severe CRS with irreversible neurologic toxicity and died on day 122.

The most common adverse event observed in the first 14 days after CAR T-cell infusion was CRS, which occurred in 25 patients. Seven patients had severe CRS that put them in the intensive care unit.

However, for the patients treated at DL1 and DL2, dexamethasone alone or with tocilizumab resolved CRS.

Fifteen patients developed severe neurotoxicity (grade 3 or higher), either with CRS or after it resolved. For all but 1 patient (the aforementioned patient who died), neurologic symptoms and signs resolved.

Response

One patient died before response assessment, so 29 patients were evaluable. Twenty-seven of these patients (93%) achieved bone marrow remission by flow cytometry.

Of the 2 patients who did not achieve a complete response (CR), 1 underwent an allogeneic HSCT after receiving CAR T cells. After HSCT, she relapsed, was re-enrolled on the trial, and achieved a CR after receiving a higher dose of CAR T cells (DL2).

Twenty-five patients (86%) achieved a CR without evidence of minimal residual disease by flow cytometry and conventional karyotyping, FISH, or QPCR.

“Patients who come onto the trial have really limited options for treatment,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“They have refractory acute leukemia. So the fact that we’re getting so many into remission is giving these people a way forward.”

Unfortunately, not all patients stayed in CR. Some relapsed and were treated again with CAR T cells, and 2 patients relapsed with leukemias that were immune to the CAR T cells. The researchers said it is still too early to know the long-term outcomes of the therapy.

“This is just the beginning,” Dr Turtle said. “It sounds fantastic to say that we get over 90% remissions, but there’s so much more work to do make sure they’re durable remissions, to work out who’s going to benefit the most, and extend this work to other diseases.”

Lessons learned

The researchers said that, because these CAR T cells had a defined CD4+:CD8+ composition, this study provides the first clear evidence of the relationships between the CAR T-cell dose patients receive and their outcomes after infusion.

The team found that high doses of CAR T cells and high tumor burden increase the risks of severe CRS and neurotoxicity. However, certain biomarkers can identify patients at the highest risk of toxicity.

Levels of IL-6, IFN-γ, and TNF-α on the first day after CAR T-cell infusion were significantly higher in patients who later developed severe neurotoxicity. Levels of these biomarkers were also higher in patients who were later sent to the intensive care unit.

Furthermore, risk-stratified CAR T-cell dosing based on bone marrow disease burden decreased toxicity.

The researchers also said they observed CD8+ T-cell-mediated anti-CAR transgene product immune responses in some patients, which limited CAR T-cell persistence and increased the risk of relapse.

And including fludarabine in the lymphodepletion regimen resulted in better CAR T-cell persistence and disease-free survival than when cyclophosphamide was given alone or with etoposide.

Cameron Turtle, MBBS, PhD

Photo courtesy of

Fred Hutch News Service

Researchers say they have conducted the first trial of CD19-directed chimeric antigen receptor (CAR) T-cell therapy in which CD4+ and CD8+ cells were administered in equal proportions.

And the assurance that each patient received the same mixture of cells allowed the team to draw clear conclusions about the effects of administering CAR T-cell therapy at different doses.

The researchers detailed these conclusions in The Journal of Clinical Investigation.

This phase 1/2 trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing the CAR T-cell therapy as JCAR014.

The work was also funded by the National Cancer Institute, private philanthropists, and the Life Sciences Discovery Fund.

Patients and treatment

The researchers reported data on 32 patients who had relapsed or refractory, CD19+ B-cell acute lymphoblastic leukemia and a median age of 40 (range, 20–73). Two of these patients were excluded due to complications prior to receiving treatment.

The 30 patients who were treated in this study had received a median of 3 prior intensive chemotherapy regimens (range, 1–11). Eleven patients had failed a hematopoietic stem cell transplant (HSCT). And all patients had detectable disease in the bone marrow, extramedullary sites, or cerebrospinal fluid at baseline.

To create the CAR T-cell therapy, the researchers modified CD8+ and CD4+ T-cell subsets separately to express a CD19-targeted CAR incorporating 4-1BB and CD3ζ signaling domains. The cells were then formulated in a defined ratio of CD4+:CD8+ CAR T cells.

Patients underwent lymphodepletion with a cyclophosphamide-based regimen (alone or with fludarabine or etoposide) and then received CAR T cells 48 to 96 hours later. The CAR T cells were given at 3 dose levels—2 × 10⁵/kg (DL1), 2 × 10⁶/kg (DL2), and 2 × 10⁷/kg (DL3).

Toxicity

The first 2 patients who received CAR T-cell therapy at DL3 developed severe toxicities, including 1 patient who died. So DL3 was not given to any subsequent patients.

Two patients died after CAR T-cell infusion. One patient had severe cytokine release syndrome (CRS) and multiorgan failure and died on day 3. The other patient had transient severe CRS with irreversible neurologic toxicity and died on day 122.

The most common adverse event observed in the first 14 days after CAR T-cell infusion was CRS, which occurred in 25 patients. Seven patients had severe CRS that put them in the intensive care unit.

However, for the patients treated at DL1 and DL2, dexamethasone alone or with tocilizumab resolved CRS.

Fifteen patients developed severe neurotoxicity (grade 3 or higher), either with CRS or after it resolved. For all but 1 patient (the aforementioned patient who died), neurologic symptoms and signs resolved.

Response

One patient died before response assessment, so 29 patients were evaluable. Twenty-seven of these patients (93%) achieved bone marrow remission by flow cytometry.

Of the 2 patients who did not achieve a complete response (CR), 1 underwent an allogeneic HSCT after receiving CAR T cells. After HSCT, she relapsed, was re-enrolled on the trial, and achieved a CR after receiving a higher dose of CAR T cells (DL2).

Twenty-five patients (86%) achieved a CR without evidence of minimal residual disease by flow cytometry and conventional karyotyping, FISH, or QPCR.

“Patients who come onto the trial have really limited options for treatment,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

“They have refractory acute leukemia. So the fact that we’re getting so many into remission is giving these people a way forward.”

Unfortunately, not all patients stayed in CR. Some relapsed and were treated again with CAR T cells, and 2 patients relapsed with leukemias that were immune to the CAR T cells. The researchers said it is still too early to know the long-term outcomes of the therapy.

“This is just the beginning,” Dr Turtle said. “It sounds fantastic to say that we get over 90% remissions, but there’s so much more work to do make sure they’re durable remissions, to work out who’s going to benefit the most, and extend this work to other diseases.”

Lessons learned

The researchers said that, because these CAR T cells had a defined CD4+:CD8+ composition, this study provides the first clear evidence of the relationships between the CAR T-cell dose patients receive and their outcomes after infusion.

The team found that high doses of CAR T cells and high tumor burden increase the risks of severe CRS and neurotoxicity. However, certain biomarkers can identify patients at the highest risk of toxicity.

Levels of IL-6, IFN-γ, and TNF-α on the first day after CAR T-cell infusion were significantly higher in patients who later developed severe neurotoxicity. Levels of these biomarkers were also higher in patients who were later sent to the intensive care unit.

Furthermore, risk-stratified CAR T-cell dosing based on bone marrow disease burden decreased toxicity.

The researchers also said they observed CD8+ T-cell-mediated anti-CAR transgene product immune responses in some patients, which limited CAR T-cell persistence and increased the risk of relapse.

And including fludarabine in the lymphodepletion regimen resulted in better CAR T-cell persistence and disease-free survival than when cyclophosphamide was given alone or with etoposide.

Hospitalists’ struggles with the promise and pitfalls of the electronic health record (EHR) can also impinge on their personal satisfaction with their jobs.

The EHR has been identified as a major contributor to physician burnout. Research conducted in 2013 by the RAND Corporation and the American Medical Association (AMA) identified EHRs as the leading cause of physician dissatisfaction, emotional fatigue, depersonalization, and lost enthusiasm for the job.1 The MEMO study found that increased numbers of EHR functions in primary-care settings were associated with physician-reported stress, burnout, and desire to leave the practice.2 Daniel Roberts, MD, FHM, and colleagues found that more than half of hospitalists (52.3%) were affected by burnout, although rates were not higher than in outpatient settings.3

“It’s not fair to blame all physician burnout on the EHR, but the EHR has enabled others to place new demands on physicians and their practices,” says Christine Sinsky, MD, a former hospitalist and current vice president of professional satisfaction for AMA. “The current state of EHR technology appears to worsen professional satisfaction in multiple ways, resulting in reduced face time with patients and more time spent on data-entry functions.”

Dr. Sinsky says her association is trying to address the problem, both with advocacy to delay or revise government requirements for EHR adoption and through its STEPS Forward initiative to help physicians and their staffs redesign medical practices to minimize stress in a changing healthcare environment.

The AMA/RAND research did not break out hospital medicine specifically, although it identified high rates of job dissatisfaction for internists.

Jonathan Pell, MD, hospitalist and assistant professor of medicine at the University of Colorado in Denver, says more research is needed to connect the dots between the EHR and hospitalists’ job satisfaction.

“It makes me wonder, does the EHR affect hospitalists differently than it does outpatient doctors?” he says. “More hospitals and health systems are starting to survey physicians regarding their job satisfaction.”

Dr. Pell also points to computerized physician order entry as a related contributor to job stress.

What Can the Hospitalist Do?

“I’m a believer in the EHR,” says R.J. Bunnell, MD, hospitalist at the 321-bed McKay-Dee Hospital in Ogden, Utah, and physician champion for EHR implementation at Salt Lake City–based Intermountain Healthcare. “We have the potential to reduce medical errors and decrease the burden on physicians, eventually providing unique decision support tools.”

Dr. Bunnell says many of the issues with EHR stem from the complex designs of the systems and cumbersome data collection.

“The practice of medicine is getting more complex year by year, with more regulatory oversight and well-intentioned—but poorly designed—mandates,” he says. “Physicians spend less one-on-one time with their patients and feel they no longer have power over their jobs.”

Dr. Bunnell helped plan implementation of the Intermountain EHR, including its rollout at McKay-Dee last fall.

“We had a positive response to going electronic here,” he says. “Part of it was just the inefficiency of how we did things before, where physicians were already spending 60% of their day on documenting. We started working with our vendor in 2013 to set things up. The team was very proactive, and we spent more than a year on staff training. There’s always a steep learning curve, but it has gone better here than other places.”

Poor rollout and lack of physician involvement in system design can be major contributors to EHR burnout, he adds.

“But for hospitalists, going forward, this is the kind of thing where our specialty could really shine—creating specialized roles for ourselves as agents of change,” Dr. Bunnell says. “If we as physicians don’t recognize the drivers behind these mandates, we’ll just continue to react to them. My hope is that … we will embrace the change, get involved, and find ways to use these tools to fulfill their promise.” TH

Larry Beresford is a freelance writer in California.

References

1. Friedberg MW, Chen PG, Van Busum KR, et al. Research report: factors affecting physician professional satisfaction and their implications for patient care, health systems, and health policy. Santa Monica, CA: Rand Corporation, 2013.
2. Babbott S, Manwell LB, Brown R, et al. Electronic medical records and physician stress in primary care: results from the MEMO Study. J Am Med Inform Assoc. 2014;21(e1): e100-106.
3. Roberts DL, Shanafelt TD, Dyrbye LN, West CP. A national comparison of burnout and work-life balance among internal medicine hospitalists and outpatient general internists. J Hosp Med. 2014;9(3):176-181.

Hospitalists’ struggles with the promise and pitfalls of the electronic health record (EHR) can also impinge on their personal satisfaction with their jobs.

The EHR has been identified as a major contributor to physician burnout. Research conducted in 2013 by the RAND Corporation and the American Medical Association (AMA) identified EHRs as the leading cause of physician dissatisfaction, emotional fatigue, depersonalization, and lost enthusiasm for the job.1 The MEMO study found that increased numbers of EHR functions in primary-care settings were associated with physician-reported stress, burnout, and desire to leave the practice.2 Daniel Roberts, MD, FHM, and colleagues found that more than half of hospitalists (52.3%) were affected by burnout, although rates were not higher than in outpatient settings.3

“It’s not fair to blame all physician burnout on the EHR, but the EHR has enabled others to place new demands on physicians and their practices,” says Christine Sinsky, MD, a former hospitalist and current vice president of professional satisfaction for AMA. “The current state of EHR technology appears to worsen professional satisfaction in multiple ways, resulting in reduced face time with patients and more time spent on data-entry functions.”

Dr. Sinsky says her association is trying to address the problem, both with advocacy to delay or revise government requirements for EHR adoption and through its STEPS Forward initiative to help physicians and their staffs redesign medical practices to minimize stress in a changing healthcare environment.

The AMA/RAND research did not break out hospital medicine specifically, although it identified high rates of job dissatisfaction for internists.

Jonathan Pell, MD, hospitalist and assistant professor of medicine at the University of Colorado in Denver, says more research is needed to connect the dots between the EHR and hospitalists’ job satisfaction.

“It makes me wonder, does the EHR affect hospitalists differently than it does outpatient doctors?” he says. “More hospitals and health systems are starting to survey physicians regarding their job satisfaction.”

Dr. Pell also points to computerized physician order entry as a related contributor to job stress.

What Can the Hospitalist Do?

“I’m a believer in the EHR,” says R.J. Bunnell, MD, hospitalist at the 321-bed McKay-Dee Hospital in Ogden, Utah, and physician champion for EHR implementation at Salt Lake City–based Intermountain Healthcare. “We have the potential to reduce medical errors and decrease the burden on physicians, eventually providing unique decision support tools.”

Dr. Bunnell says many of the issues with EHR stem from the complex designs of the systems and cumbersome data collection.

“The practice of medicine is getting more complex year by year, with more regulatory oversight and well-intentioned—but poorly designed—mandates,” he says. “Physicians spend less one-on-one time with their patients and feel they no longer have power over their jobs.”

Dr. Bunnell helped plan implementation of the Intermountain EHR, including its rollout at McKay-Dee last fall.

“We had a positive response to going electronic here,” he says. “Part of it was just the inefficiency of how we did things before, where physicians were already spending 60% of their day on documenting. We started working with our vendor in 2013 to set things up. The team was very proactive, and we spent more than a year on staff training. There’s always a steep learning curve, but it has gone better here than other places.”

Poor rollout and lack of physician involvement in system design can be major contributors to EHR burnout, he adds.

“But for hospitalists, going forward, this is the kind of thing where our specialty could really shine—creating specialized roles for ourselves as agents of change,” Dr. Bunnell says. “If we as physicians don’t recognize the drivers behind these mandates, we’ll just continue to react to them. My hope is that … we will embrace the change, get involved, and find ways to use these tools to fulfill their promise.” TH

Larry Beresford is a freelance writer in California.

References

1. Friedberg MW, Chen PG, Van Busum KR, et al. Research report: factors affecting physician professional satisfaction and their implications for patient care, health systems, and health policy. Santa Monica, CA: Rand Corporation, 2013.
2. Babbott S, Manwell LB, Brown R, et al. Electronic medical records and physician stress in primary care: results from the MEMO Study. J Am Med Inform Assoc. 2014;21(e1): e100-106.
3. Roberts DL, Shanafelt TD, Dyrbye LN, West CP. A national comparison of burnout and work-life balance among internal medicine hospitalists and outpatient general internists. J Hosp Med. 2014;9(3):176-181.

Hospitalists’ struggles with the promise and pitfalls of the electronic health record (EHR) can also impinge on their personal satisfaction with their jobs.

The EHR has been identified as a major contributor to physician burnout. Research conducted in 2013 by the RAND Corporation and the American Medical Association (AMA) identified EHRs as the leading cause of physician dissatisfaction, emotional fatigue, depersonalization, and lost enthusiasm for the job.1 The MEMO study found that increased numbers of EHR functions in primary-care settings were associated with physician-reported stress, burnout, and desire to leave the practice.2 Daniel Roberts, MD, FHM, and colleagues found that more than half of hospitalists (52.3%) were affected by burnout, although rates were not higher than in outpatient settings.3

“It’s not fair to blame all physician burnout on the EHR, but the EHR has enabled others to place new demands on physicians and their practices,” says Christine Sinsky, MD, a former hospitalist and current vice president of professional satisfaction for AMA. “The current state of EHR technology appears to worsen professional satisfaction in multiple ways, resulting in reduced face time with patients and more time spent on data-entry functions.”

Dr. Sinsky says her association is trying to address the problem, both with advocacy to delay or revise government requirements for EHR adoption and through its STEPS Forward initiative to help physicians and their staffs redesign medical practices to minimize stress in a changing healthcare environment.

The AMA/RAND research did not break out hospital medicine specifically, although it identified high rates of job dissatisfaction for internists.

Jonathan Pell, MD, hospitalist and assistant professor of medicine at the University of Colorado in Denver, says more research is needed to connect the dots between the EHR and hospitalists’ job satisfaction.

“It makes me wonder, does the EHR affect hospitalists differently than it does outpatient doctors?” he says. “More hospitals and health systems are starting to survey physicians regarding their job satisfaction.”

Dr. Pell also points to computerized physician order entry as a related contributor to job stress.

What Can the Hospitalist Do?

“I’m a believer in the EHR,” says R.J. Bunnell, MD, hospitalist at the 321-bed McKay-Dee Hospital in Ogden, Utah, and physician champion for EHR implementation at Salt Lake City–based Intermountain Healthcare. “We have the potential to reduce medical errors and decrease the burden on physicians, eventually providing unique decision support tools.”

Dr. Bunnell says many of the issues with EHR stem from the complex designs of the systems and cumbersome data collection.

“The practice of medicine is getting more complex year by year, with more regulatory oversight and well-intentioned—but poorly designed—mandates,” he says. “Physicians spend less one-on-one time with their patients and feel they no longer have power over their jobs.”

Dr. Bunnell helped plan implementation of the Intermountain EHR, including its rollout at McKay-Dee last fall.

“We had a positive response to going electronic here,” he says. “Part of it was just the inefficiency of how we did things before, where physicians were already spending 60% of their day on documenting. We started working with our vendor in 2013 to set things up. The team was very proactive, and we spent more than a year on staff training. There’s always a steep learning curve, but it has gone better here than other places.”

Poor rollout and lack of physician involvement in system design can be major contributors to EHR burnout, he adds.

“But for hospitalists, going forward, this is the kind of thing where our specialty could really shine—creating specialized roles for ourselves as agents of change,” Dr. Bunnell says. “If we as physicians don’t recognize the drivers behind these mandates, we’ll just continue to react to them. My hope is that … we will embrace the change, get involved, and find ways to use these tools to fulfill their promise.” TH

Larry Beresford is a freelance writer in California.

References

1. Friedberg MW, Chen PG, Van Busum KR, et al. Research report: factors affecting physician professional satisfaction and their implications for patient care, health systems, and health policy. Santa Monica, CA: Rand Corporation, 2013.
2. Babbott S, Manwell LB, Brown R, et al. Electronic medical records and physician stress in primary care: results from the MEMO Study. J Am Med Inform Assoc. 2014;21(e1): e100-106.
3. Roberts DL, Shanafelt TD, Dyrbye LN, West CP. A national comparison of burnout and work-life balance among internal medicine hospitalists and outpatient general internists. J Hosp Med. 2014;9(3):176-181.

Have you been a practicing hospitalist for five years, a member of SHM for three years, and an attendee at an SHM annual meeting? If so, you may be eligible to set yourself apart as a leader in the hospital medicine movement who is committed to quality, improved outcomes, and exceptional patient care.

Physicians, nurse practitioners, physician assistants, and practice administrators are invited to apply to the Fellow (FHM) or Senior Fellow (SFHM) in Hospital Medicine designation from SHM.

Learn more at www.hospitalmedicine.org/fellow. Applications will be open for the SHM Fellows Class of 2017 from May 23, 2016, to November 18, 2016.

Have you been a practicing hospitalist for five years, a member of SHM for three years, and an attendee at an SHM annual meeting? If so, you may be eligible to set yourself apart as a leader in the hospital medicine movement who is committed to quality, improved outcomes, and exceptional patient care.

Physicians, nurse practitioners, physician assistants, and practice administrators are invited to apply to the Fellow (FHM) or Senior Fellow (SFHM) in Hospital Medicine designation from SHM.

Learn more at www.hospitalmedicine.org/fellow. Applications will be open for the SHM Fellows Class of 2017 from May 23, 2016, to November 18, 2016.

Have you been a practicing hospitalist for five years, a member of SHM for three years, and an attendee at an SHM annual meeting? If so, you may be eligible to set yourself apart as a leader in the hospital medicine movement who is committed to quality, improved outcomes, and exceptional patient care.

Physicians, nurse practitioners, physician assistants, and practice administrators are invited to apply to the Fellow (FHM) or Senior Fellow (SFHM) in Hospital Medicine designation from SHM.

Learn more at www.hospitalmedicine.org/fellow. Applications will be open for the SHM Fellows Class of 2017 from May 23, 2016, to November 18, 2016.

To ensure hospitalists have the latest information about diagnosis, treatment, and transition of hospitalized patients with venous thromboembolism (VTE), SHM has developed:

• An online tool kit, including a literature review; implementation guide; and other references, materials, and tools such as discharge instructions and checklists
• A webinar series with free CME

These resources are now available. Get the scoop at www.hospitalmedicine.org/VTEtreatment.

To ensure hospitalists have the latest information about diagnosis, treatment, and transition of hospitalized patients with venous thromboembolism (VTE), SHM has developed:

• An online tool kit, including a literature review; implementation guide; and other references, materials, and tools such as discharge instructions and checklists
• A webinar series with free CME

These resources are now available. Get the scoop at www.hospitalmedicine.org/VTEtreatment.

To ensure hospitalists have the latest information about diagnosis, treatment, and transition of hospitalized patients with venous thromboembolism (VTE), SHM has developed:

• An online tool kit, including a literature review; implementation guide; and other references, materials, and tools such as discharge instructions and checklists
• A webinar series with free CME

These resources are now available. Get the scoop at www.hospitalmedicine.org/VTEtreatment.

(Reuters Health) - Patients assigned a "nonurgent" status on arrival in the emergency room might still be sick enough to be hospitalized, a new study shows.

Patients deemed by triage nurses to be "nonurgent" often receive diagnostic services and procedures, and some are even admitted to critical care units, researchers found.

Triage was never intended to completely rule out severe illness, only to give patients an estimate of how long they may have to wait to see a doctor, the researchers note.

Dr. Renee Y. Hsia of the University of California, San Francisco and colleagues used a national survey of patient visits to the emergency department (E.D.) between 2009 and 2011, with triage scores assigned by a nurse when the patient arrived. The scores range from one to five, with one through three including immediate, emergency and urgent patients, and four and five being semi-urgent and nonurgent.

They used data on almost 60,000 observations of patients age 18 to 64 collected between 2009 and 2011, which represented 240 million E.D. visits. More than 90 percent had a score of one to

four and were deemed "urgent" visits, while about eight percent had a score of five and were "nonurgent."

Almost half of nonurgent visits involved diagnostic scans, imaging or blood tests, and a third involved procedures like splinting or giving intravenous fluids. For urgent visits, about three-quarters involved diagnostics and half involved procedures.

About four of every 100 non-urgent visits resulted in hospital admission, as reported in JAMA Internal Medicine.

Backache, acute upper respiratory infections, soft-tissue inflammation, and acute sore throat were among the 10 most common diagnoses for both urgent and non-urgent patients.

"Triage is normally done at the very beginning of the visit, usually by a triage nurse," Hsia told Reuters Health by email. "Triaging patients is an extremely difficult task, since patients are what we (as providers) call 'undifferentiated,' since there has not been time to do a full history and physical, and nurses have limited information upon which to base their determination."

"We should not expect triage categorization to be perfect, and one of the goals of this paper is to show that, indeed, triage is not," Hsia said.

Many states have policies that patients with Medicaid insurance who present to the E.D. for "non-urgent" visits will be charged a co-payment, which may keep people from seeking

needed care, even though the triage system is not perfect, she said.

"It is important that we do not blame the patient for going to the E.D. if there were no alternatives that were available in a timely manner," Hsia said.

"Our study cannot distinguish the reasons behind why we found such a high proportion of visits that received diagnostic services or procedures," she said.

Some of the procedures may not have needed to happen in an E.D. setting, but since the patients presented there, they were treated, Hsia added.

(Reuters Health) - Patients assigned a "nonurgent" status on arrival in the emergency room might still be sick enough to be hospitalized, a new study shows.

Patients deemed by triage nurses to be "nonurgent" often receive diagnostic services and procedures, and some are even admitted to critical care units, researchers found.

Triage was never intended to completely rule out severe illness, only to give patients an estimate of how long they may have to wait to see a doctor, the researchers note.

Dr. Renee Y. Hsia of the University of California, San Francisco and colleagues used a national survey of patient visits to the emergency department (E.D.) between 2009 and 2011, with triage scores assigned by a nurse when the patient arrived. The scores range from one to five, with one through three including immediate, emergency and urgent patients, and four and five being semi-urgent and nonurgent.

They used data on almost 60,000 observations of patients age 18 to 64 collected between 2009 and 2011, which represented 240 million E.D. visits. More than 90 percent had a score of one to

four and were deemed "urgent" visits, while about eight percent had a score of five and were "nonurgent."

Almost half of nonurgent visits involved diagnostic scans, imaging or blood tests, and a third involved procedures like splinting or giving intravenous fluids. For urgent visits, about three-quarters involved diagnostics and half involved procedures.

About four of every 100 non-urgent visits resulted in hospital admission, as reported in JAMA Internal Medicine.

Backache, acute upper respiratory infections, soft-tissue inflammation, and acute sore throat were among the 10 most common diagnoses for both urgent and non-urgent patients.

"Triage is normally done at the very beginning of the visit, usually by a triage nurse," Hsia told Reuters Health by email. "Triaging patients is an extremely difficult task, since patients are what we (as providers) call 'undifferentiated,' since there has not been time to do a full history and physical, and nurses have limited information upon which to base their determination."

"We should not expect triage categorization to be perfect, and one of the goals of this paper is to show that, indeed, triage is not," Hsia said.

Many states have policies that patients with Medicaid insurance who present to the E.D. for "non-urgent" visits will be charged a co-payment, which may keep people from seeking

needed care, even though the triage system is not perfect, she said.

"It is important that we do not blame the patient for going to the E.D. if there were no alternatives that were available in a timely manner," Hsia said.

"Our study cannot distinguish the reasons behind why we found such a high proportion of visits that received diagnostic services or procedures," she said.

Some of the procedures may not have needed to happen in an E.D. setting, but since the patients presented there, they were treated, Hsia added.

(Reuters Health) - Patients assigned a "nonurgent" status on arrival in the emergency room might still be sick enough to be hospitalized, a new study shows.

Patients deemed by triage nurses to be "nonurgent" often receive diagnostic services and procedures, and some are even admitted to critical care units, researchers found.

Triage was never intended to completely rule out severe illness, only to give patients an estimate of how long they may have to wait to see a doctor, the researchers note.

Dr. Renee Y. Hsia of the University of California, San Francisco and colleagues used a national survey of patient visits to the emergency department (E.D.) between 2009 and 2011, with triage scores assigned by a nurse when the patient arrived. The scores range from one to five, with one through three including immediate, emergency and urgent patients, and four and five being semi-urgent and nonurgent.

They used data on almost 60,000 observations of patients age 18 to 64 collected between 2009 and 2011, which represented 240 million E.D. visits. More than 90 percent had a score of one to

four and were deemed "urgent" visits, while about eight percent had a score of five and were "nonurgent."

Almost half of nonurgent visits involved diagnostic scans, imaging or blood tests, and a third involved procedures like splinting or giving intravenous fluids. For urgent visits, about three-quarters involved diagnostics and half involved procedures.

About four of every 100 non-urgent visits resulted in hospital admission, as reported in JAMA Internal Medicine.

Backache, acute upper respiratory infections, soft-tissue inflammation, and acute sore throat were among the 10 most common diagnoses for both urgent and non-urgent patients.

"Triage is normally done at the very beginning of the visit, usually by a triage nurse," Hsia told Reuters Health by email. "Triaging patients is an extremely difficult task, since patients are what we (as providers) call 'undifferentiated,' since there has not been time to do a full history and physical, and nurses have limited information upon which to base their determination."

"We should not expect triage categorization to be perfect, and one of the goals of this paper is to show that, indeed, triage is not," Hsia said.

Many states have policies that patients with Medicaid insurance who present to the E.D. for "non-urgent" visits will be charged a co-payment, which may keep people from seeking

needed care, even though the triage system is not perfect, she said.

"It is important that we do not blame the patient for going to the E.D. if there were no alternatives that were available in a timely manner," Hsia said.

"Our study cannot distinguish the reasons behind why we found such a high proportion of visits that received diagnostic services or procedures," she said.

Some of the procedures may not have needed to happen in an E.D. setting, but since the patients presented there, they were treated, Hsia added.

Cord blood donation

Photo courtesy of NHS

New research suggests an RNA-binding protein can be used to expand hematopoietic stem cells (HSCs) derived from umbilical cord blood.

Investigators found the protein, Musashi-2 (MSI2), regulates the function and development of cord-blood derived HSCs, and overexpressing MSI2 can significantly expand both short-term and long-term repopulating HSCs.

“By expanding the stem cells as we have done, many more donated [cord blood] samples could now be used for transplants,” said Kristin Hope, PhD, of McMaster University in Hamilton, Ontario, Canada.

“Providing enhanced numbers of stem cells for transplantation could alleviate some of the current post-transplantation complications and allow for faster recoveries, in turn, reducing overall healthcare costs and wait times for newly diagnosed patients seeking treatment.”

Dr Hope and her colleagues described this exploration of HSC expansion in Nature.

The team first found that expression of MSI2 messenger RNA was elevated in primitive cord blood hematopoietic stem and progenitor cells (HSPCs), but it decreased during differentiation.

They then found that overexpressing MSI2 enhances the activity of cord blood progenitors in vitro and increases the number of short-term repopulating HSCs in vitro and in vivo.

During in vitro culture, MSI2-overexpressing cells were 2.3-fold more abundant than control cells at 7 days and 6-fold more abundant at 21 days. After 7 days, MSI2-overexpressing cells showed a cumulative 9.3-fold increase in colony-forming cells but no changes in cell cycling or death.

MSI2-overexpressing short-term repopulating cells (STRCs) yielded 1.8-fold more primitive CD34+ cells than control STRCs. And the MSI2-overexpressing STRCs prompted a 17-fold increase in functional STRCs.

Furthermore, 100% of mice transplanted with MSI2-overexpressing STRCs were engrafted at 6.5 weeks, compared to 50% of mice transplanted with control STRCs.

Additional transplant experiments showed that MSI2 overexpression also impacted long-term HSCs (LT-HSCs). Compared to control cells, MSI2-overexpressing cells increased the percentage of GFP+ HSCs in the bone marrow 4.6-fold and the frequency of LT-HSCs 3.5-fold.

The researchers said the increase in LT-HSC frequency corresponded to MSI2-overexpressing GFP+ HSCs having expanded in mice 2.4-fold over input. With control HSCs, on the other hand, there was a 1.5-fold decrease.

In ex vivo culture, MSI2 overexpression induced a cumulative 23-fold expansion of secondary LT-HSCs when compared to control LT-HSCs.

Finally, the researchers performed a global analysis of MSI2–RNA interactions and found that MSI2 mediates HSPC self-renewal and ex vivo expansion by coordinating the post-transcriptional regulation of proteins belonging to a shared self-renewal regulatory pathway.

“We’ve really shone a light on the way these stem cells work,” Dr Hope said. “We now understand how they operate at a completely new level, and that provides us with a serious advantage in determining how to maximize these stem cells in therapeutics. With this newfound ability to control the regeneration of these cells, more people will be able to get the treatment they need.”

Cord blood donation

Photo courtesy of NHS

New research suggests an RNA-binding protein can be used to expand hematopoietic stem cells (HSCs) derived from umbilical cord blood.

Investigators found the protein, Musashi-2 (MSI2), regulates the function and development of cord-blood derived HSCs, and overexpressing MSI2 can significantly expand both short-term and long-term repopulating HSCs.

“By expanding the stem cells as we have done, many more donated [cord blood] samples could now be used for transplants,” said Kristin Hope, PhD, of McMaster University in Hamilton, Ontario, Canada.

“Providing enhanced numbers of stem cells for transplantation could alleviate some of the current post-transplantation complications and allow for faster recoveries, in turn, reducing overall healthcare costs and wait times for newly diagnosed patients seeking treatment.”

Dr Hope and her colleagues described this exploration of HSC expansion in Nature.

The team first found that expression of MSI2 messenger RNA was elevated in primitive cord blood hematopoietic stem and progenitor cells (HSPCs), but it decreased during differentiation.

They then found that overexpressing MSI2 enhances the activity of cord blood progenitors in vitro and increases the number of short-term repopulating HSCs in vitro and in vivo.

During in vitro culture, MSI2-overexpressing cells were 2.3-fold more abundant than control cells at 7 days and 6-fold more abundant at 21 days. After 7 days, MSI2-overexpressing cells showed a cumulative 9.3-fold increase in colony-forming cells but no changes in cell cycling or death.

MSI2-overexpressing short-term repopulating cells (STRCs) yielded 1.8-fold more primitive CD34+ cells than control STRCs. And the MSI2-overexpressing STRCs prompted a 17-fold increase in functional STRCs.

Furthermore, 100% of mice transplanted with MSI2-overexpressing STRCs were engrafted at 6.5 weeks, compared to 50% of mice transplanted with control STRCs.

Additional transplant experiments showed that MSI2 overexpression also impacted long-term HSCs (LT-HSCs). Compared to control cells, MSI2-overexpressing cells increased the percentage of GFP+ HSCs in the bone marrow 4.6-fold and the frequency of LT-HSCs 3.5-fold.

The researchers said the increase in LT-HSC frequency corresponded to MSI2-overexpressing GFP+ HSCs having expanded in mice 2.4-fold over input. With control HSCs, on the other hand, there was a 1.5-fold decrease.

In ex vivo culture, MSI2 overexpression induced a cumulative 23-fold expansion of secondary LT-HSCs when compared to control LT-HSCs.

Finally, the researchers performed a global analysis of MSI2–RNA interactions and found that MSI2 mediates HSPC self-renewal and ex vivo expansion by coordinating the post-transcriptional regulation of proteins belonging to a shared self-renewal regulatory pathway.

“We’ve really shone a light on the way these stem cells work,” Dr Hope said. “We now understand how they operate at a completely new level, and that provides us with a serious advantage in determining how to maximize these stem cells in therapeutics. With this newfound ability to control the regeneration of these cells, more people will be able to get the treatment they need.”

Cord blood donation

Photo courtesy of NHS

New research suggests an RNA-binding protein can be used to expand hematopoietic stem cells (HSCs) derived from umbilical cord blood.

Investigators found the protein, Musashi-2 (MSI2), regulates the function and development of cord-blood derived HSCs, and overexpressing MSI2 can significantly expand both short-term and long-term repopulating HSCs.

“By expanding the stem cells as we have done, many more donated [cord blood] samples could now be used for transplants,” said Kristin Hope, PhD, of McMaster University in Hamilton, Ontario, Canada.

“Providing enhanced numbers of stem cells for transplantation could alleviate some of the current post-transplantation complications and allow for faster recoveries, in turn, reducing overall healthcare costs and wait times for newly diagnosed patients seeking treatment.”

Dr Hope and her colleagues described this exploration of HSC expansion in Nature.

The team first found that expression of MSI2 messenger RNA was elevated in primitive cord blood hematopoietic stem and progenitor cells (HSPCs), but it decreased during differentiation.

They then found that overexpressing MSI2 enhances the activity of cord blood progenitors in vitro and increases the number of short-term repopulating HSCs in vitro and in vivo.

During in vitro culture, MSI2-overexpressing cells were 2.3-fold more abundant than control cells at 7 days and 6-fold more abundant at 21 days. After 7 days, MSI2-overexpressing cells showed a cumulative 9.3-fold increase in colony-forming cells but no changes in cell cycling or death.

MSI2-overexpressing short-term repopulating cells (STRCs) yielded 1.8-fold more primitive CD34+ cells than control STRCs. And the MSI2-overexpressing STRCs prompted a 17-fold increase in functional STRCs.

Furthermore, 100% of mice transplanted with MSI2-overexpressing STRCs were engrafted at 6.5 weeks, compared to 50% of mice transplanted with control STRCs.

Additional transplant experiments showed that MSI2 overexpression also impacted long-term HSCs (LT-HSCs). Compared to control cells, MSI2-overexpressing cells increased the percentage of GFP+ HSCs in the bone marrow 4.6-fold and the frequency of LT-HSCs 3.5-fold.

The researchers said the increase in LT-HSC frequency corresponded to MSI2-overexpressing GFP+ HSCs having expanded in mice 2.4-fold over input. With control HSCs, on the other hand, there was a 1.5-fold decrease.

In ex vivo culture, MSI2 overexpression induced a cumulative 23-fold expansion of secondary LT-HSCs when compared to control LT-HSCs.

Finally, the researchers performed a global analysis of MSI2–RNA interactions and found that MSI2 mediates HSPC self-renewal and ex vivo expansion by coordinating the post-transcriptional regulation of proteins belonging to a shared self-renewal regulatory pathway.

“We’ve really shone a light on the way these stem cells work,” Dr Hope said. “We now understand how they operate at a completely new level, and that provides us with a serious advantage in determining how to maximize these stem cells in therapeutics. With this newfound ability to control the regeneration of these cells, more people will be able to get the treatment they need.”