Elevated depressive symptoms were associated with an additional brain age of nearly 3 years, based on data from more than 600 individuals.

Previous research suggests a possible link between depression and increased risk of dementia in older adults, but the association between depression and brain health in early adulthood and midlife has not been well studied, wrote Christina S. Dintica, PhD, of the University of California, San Francisco, and colleagues.

In a study published in the Journal of Affective Disorders, the researchers identified 649 individuals aged 23-36 at baseline who were part of the Coronary Artery Risk Development in Young Adults (CARDIA) study. All participants underwent brain MRI and cognitive testing. Depressive symptoms were assessed six times over a 25-year period using the Center for Epidemiological Studies Depression scale (CES–D), and the scores were analyzed as time-weighted averages (TWA). Elevated depressive symptoms were defined as CES-D scores of 16 or higher. Brain age was assessed via high-dimensional neuroimaging. Approximately half of the participants were female, and half were Black.

Overall, each 5-point increment in TWA depression symptoms over 25 years was associated with a 1-year increase in brain age, and individuals with elevated TWA depression averaged a 3-year increase in brain age compared with those with lower levels of depression after controlling for factors including chronological age, sex, education, race, MRI scanning site, and intracranial volume, they said. The association was attenuated in a model controlling for antidepressant use, and further attenuated after adjusting for smoking, alcohol consumption, income, body mass index, diabetes, and physical exercise.

The researchers also investigated the impact of the age period of elevated depressive symptoms on brain age. Compared with low depressive symptoms, elevated TWA CES-D at ages 30-39 years, 40-49 years, and 50-59 years was associated with increased brain ages of 2.43, 3.19, and 1.82.

In addition, elevated depressive symptoms were associated with a threefold increase in the odds of poor cognitive function at midlife (odds ratio, 3.30), although these odds were reduced after adjusting for use of antidepressants (OR, 1.47).

The mechanisms of action for the link between depression and accelerated brain aging remains uncertain, the researchers wrote in their discussion. “Studies over the last 20 years have demonstrated that increased inflammation and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis are two of the most consistent biological findings in major depression, which have been linked to premature aging,” they noted. “Alternative explanations for the link between depression and adverse brain health could be underlying factors that explain both outcomes rather independently, such as low socioeconomic status, childhood maltreatment, or shared genetic effects,” they added.

Adjustment for antidepressant use had little effect overall on the association between depressive symptom severity and brain age, they said.

The current study findings were limited by the single assessment of brain age, which prevented evaluation of the temporality of the association between brain aging and depression, the researchers noted.

However, the results were strengthened by the large and diverse cohort, long-term follow-up, and use of high-dimensional neuroimaging, they said. Longitudinal studies are needed to explore mechanisms of action and the potential benefits of antidepressants, they added.

In the meantime, monitoring and treating depressive symptoms in young adults may help promote brain health in midlife and older age, they concluded.

The CARDIA study was supported by the National Heart, Lung, and Blood Institute, the National Institute on Aging, and the Alzheimer’s Association. The researchers had no financial conflicts to disclose.

Elevated depressive symptoms were associated with an additional brain age of nearly 3 years, based on data from more than 600 individuals.

Previous research suggests a possible link between depression and increased risk of dementia in older adults, but the association between depression and brain health in early adulthood and midlife has not been well studied, wrote Christina S. Dintica, PhD, of the University of California, San Francisco, and colleagues.

In a study published in the Journal of Affective Disorders, the researchers identified 649 individuals aged 23-36 at baseline who were part of the Coronary Artery Risk Development in Young Adults (CARDIA) study. All participants underwent brain MRI and cognitive testing. Depressive symptoms were assessed six times over a 25-year period using the Center for Epidemiological Studies Depression scale (CES–D), and the scores were analyzed as time-weighted averages (TWA). Elevated depressive symptoms were defined as CES-D scores of 16 or higher. Brain age was assessed via high-dimensional neuroimaging. Approximately half of the participants were female, and half were Black.

Overall, each 5-point increment in TWA depression symptoms over 25 years was associated with a 1-year increase in brain age, and individuals with elevated TWA depression averaged a 3-year increase in brain age compared with those with lower levels of depression after controlling for factors including chronological age, sex, education, race, MRI scanning site, and intracranial volume, they said. The association was attenuated in a model controlling for antidepressant use, and further attenuated after adjusting for smoking, alcohol consumption, income, body mass index, diabetes, and physical exercise.

The researchers also investigated the impact of the age period of elevated depressive symptoms on brain age. Compared with low depressive symptoms, elevated TWA CES-D at ages 30-39 years, 40-49 years, and 50-59 years was associated with increased brain ages of 2.43, 3.19, and 1.82.

In addition, elevated depressive symptoms were associated with a threefold increase in the odds of poor cognitive function at midlife (odds ratio, 3.30), although these odds were reduced after adjusting for use of antidepressants (OR, 1.47).

The mechanisms of action for the link between depression and accelerated brain aging remains uncertain, the researchers wrote in their discussion. “Studies over the last 20 years have demonstrated that increased inflammation and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis are two of the most consistent biological findings in major depression, which have been linked to premature aging,” they noted. “Alternative explanations for the link between depression and adverse brain health could be underlying factors that explain both outcomes rather independently, such as low socioeconomic status, childhood maltreatment, or shared genetic effects,” they added.

Adjustment for antidepressant use had little effect overall on the association between depressive symptom severity and brain age, they said.

The current study findings were limited by the single assessment of brain age, which prevented evaluation of the temporality of the association between brain aging and depression, the researchers noted.

However, the results were strengthened by the large and diverse cohort, long-term follow-up, and use of high-dimensional neuroimaging, they said. Longitudinal studies are needed to explore mechanisms of action and the potential benefits of antidepressants, they added.

In the meantime, monitoring and treating depressive symptoms in young adults may help promote brain health in midlife and older age, they concluded.

The CARDIA study was supported by the National Heart, Lung, and Blood Institute, the National Institute on Aging, and the Alzheimer’s Association. The researchers had no financial conflicts to disclose.

Elevated depressive symptoms were associated with an additional brain age of nearly 3 years, based on data from more than 600 individuals.

Previous research suggests a possible link between depression and increased risk of dementia in older adults, but the association between depression and brain health in early adulthood and midlife has not been well studied, wrote Christina S. Dintica, PhD, of the University of California, San Francisco, and colleagues.

In a study published in the Journal of Affective Disorders, the researchers identified 649 individuals aged 23-36 at baseline who were part of the Coronary Artery Risk Development in Young Adults (CARDIA) study. All participants underwent brain MRI and cognitive testing. Depressive symptoms were assessed six times over a 25-year period using the Center for Epidemiological Studies Depression scale (CES–D), and the scores were analyzed as time-weighted averages (TWA). Elevated depressive symptoms were defined as CES-D scores of 16 or higher. Brain age was assessed via high-dimensional neuroimaging. Approximately half of the participants were female, and half were Black.

Overall, each 5-point increment in TWA depression symptoms over 25 years was associated with a 1-year increase in brain age, and individuals with elevated TWA depression averaged a 3-year increase in brain age compared with those with lower levels of depression after controlling for factors including chronological age, sex, education, race, MRI scanning site, and intracranial volume, they said. The association was attenuated in a model controlling for antidepressant use, and further attenuated after adjusting for smoking, alcohol consumption, income, body mass index, diabetes, and physical exercise.

The researchers also investigated the impact of the age period of elevated depressive symptoms on brain age. Compared with low depressive symptoms, elevated TWA CES-D at ages 30-39 years, 40-49 years, and 50-59 years was associated with increased brain ages of 2.43, 3.19, and 1.82.

In addition, elevated depressive symptoms were associated with a threefold increase in the odds of poor cognitive function at midlife (odds ratio, 3.30), although these odds were reduced after adjusting for use of antidepressants (OR, 1.47).

The mechanisms of action for the link between depression and accelerated brain aging remains uncertain, the researchers wrote in their discussion. “Studies over the last 20 years have demonstrated that increased inflammation and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis are two of the most consistent biological findings in major depression, which have been linked to premature aging,” they noted. “Alternative explanations for the link between depression and adverse brain health could be underlying factors that explain both outcomes rather independently, such as low socioeconomic status, childhood maltreatment, or shared genetic effects,” they added.

Adjustment for antidepressant use had little effect overall on the association between depressive symptom severity and brain age, they said.

The current study findings were limited by the single assessment of brain age, which prevented evaluation of the temporality of the association between brain aging and depression, the researchers noted.

However, the results were strengthened by the large and diverse cohort, long-term follow-up, and use of high-dimensional neuroimaging, they said. Longitudinal studies are needed to explore mechanisms of action and the potential benefits of antidepressants, they added.

In the meantime, monitoring and treating depressive symptoms in young adults may help promote brain health in midlife and older age, they concluded.

The CARDIA study was supported by the National Heart, Lung, and Blood Institute, the National Institute on Aging, and the Alzheimer’s Association. The researchers had no financial conflicts to disclose.

The Diagnosis: Endocrine Mucin-Producing Sweat Gland Carcinoma

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare cutaneous adnexal tumor that characteristically presents as slowgrowing, flesh-colored papules, nodules, or cystic lesions around the periorbital skin in elderly female patients.¹ Histopathology of EMPSGCs reveals well-circumscribed multinodular dermal lesions that can be either cystic or solid and often are arranged in papillary and cribriform patterns (quiz image). Nests of uniform tumor cells are composed of small- to medium-sized epithelial cells with monomorphic nuclei showing fine to stippled chromatin.² Histologically, EMPSGC resembles a solid papillary carcinoma of the breast, which is attributed to their common embryologic origin.³ Intracytoplasmic and extracellular mucin often are seen on hematoxylin and eosin staining.² Variable immunohistochemical stain expression has been reported, including positive staining with synaptophysin and chromogranin. Other markers include cytokeratin CAM 5.2, epithelial membrane antigen, estrogen or progesterone receptors, and cytokeratin 7.⁴ Endocrine mucin-producing sweat gland carcinoma is thought to be a precursor to invasive neuroendocrine-type primary cutaneous mucinous carcinoma. Primary cutaneous mucinous carcinoma has been associated with EMPSGC in approximately 35.7% of cases. Histologically, primary cutaneous mucinous carcinoma that has transformed from EMPSGC would show an infiltration of tumor nests with desmoplastic stroma or mucin pools with clusters of tumor cells.²

Primary cutaneous adenoid cystic carcinoma is a rare malignant tumor that often presents on the head and neck. It usually appears as a single, slowly growing subcutaneous nodule or multinodular plaque.^5,6 Histologic features include basaloid cells in alternating tubular and cribriform patterns. The cribriform areas are composed of pseudoglandular adenoid spaces that contain mucin, basement membrane zone material, and cellular debris from necrotic neoplastic cells (Figure 1).⁷ Primary cutaneous adenoid cystic carcinoma predominantly is dermal with extension to the subcutaneous tissue. True ductal structures that demonstrate decapitation secretion also may be present.⁷

Basal cell carcinoma (adenoid type) presents as a pigmented or nonpigmented nodule or ulcer on sunexposed areas of the head and neck. Histopathology reveals basaloid cells surrounding islands of connective tissue resulting in a lacelike pattern (Figure 2). The lumina may contain a colloidal substance or amorphous granular material.⁸ The characteristic features of basal cell carcinomas, such as nests of basaloid cells with peripheral palisading cells, retraction of adjacent stroma, increased apoptosis and mitotic figures, and connection to the epidermis, can be helpful to distinguish basal cell carcinoma histologically from EMPSGC.²

Apocrine hidrocystomas clinically present as round, flesh-colored, shiny or translucent, dome-shaped papules or nodules near the eyelid margin or lateral canthus.⁹ Histologically, they are composed of proliferating apocrine secretory coils with an epithelial side of cuboidal or columnar cells and a luminal side exhibiting decapitation secretion (Figure 3).² An epidermal connection is absent.⁹ Apocrine hidrocystomas may exhibit complex architecture and papillary ductal hyperplasia that are difficult to distinguish from EMPSGC, especially if EMPSGC presents with cystic morphology. Apocrine cytomorphology and the lack of neuroendocrine marker expression and mucin production distinguish apocrine hidrocystomas. Furthermore, hidrocystomas infrequently demonstrate the nodular, solid, cribriform areas appreciated in EMPSGC.²

Microcystic adnexal carcinoma is a rare, slowly growing, locally aggressive sweat gland tumor that commonly presents as a flesh-colored to yellow papule, nodule, or plaque on the central face.¹⁰ Histopathologic examination reveals both eccrine and follicular differentiation. Keratin cysts, bland keratinocyte cords, and epithelium with ductal differentiation is observed in the superficial layers (Figure 4). Deep invasion into the subcutis and perineural invasion frequently is observed.

The Diagnosis: Endocrine Mucin-Producing Sweat Gland Carcinoma

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare cutaneous adnexal tumor that characteristically presents as slowgrowing, flesh-colored papules, nodules, or cystic lesions around the periorbital skin in elderly female patients.¹ Histopathology of EMPSGCs reveals well-circumscribed multinodular dermal lesions that can be either cystic or solid and often are arranged in papillary and cribriform patterns (quiz image). Nests of uniform tumor cells are composed of small- to medium-sized epithelial cells with monomorphic nuclei showing fine to stippled chromatin.² Histologically, EMPSGC resembles a solid papillary carcinoma of the breast, which is attributed to their common embryologic origin.³ Intracytoplasmic and extracellular mucin often are seen on hematoxylin and eosin staining.² Variable immunohistochemical stain expression has been reported, including positive staining with synaptophysin and chromogranin. Other markers include cytokeratin CAM 5.2, epithelial membrane antigen, estrogen or progesterone receptors, and cytokeratin 7.⁴ Endocrine mucin-producing sweat gland carcinoma is thought to be a precursor to invasive neuroendocrine-type primary cutaneous mucinous carcinoma. Primary cutaneous mucinous carcinoma has been associated with EMPSGC in approximately 35.7% of cases. Histologically, primary cutaneous mucinous carcinoma that has transformed from EMPSGC would show an infiltration of tumor nests with desmoplastic stroma or mucin pools with clusters of tumor cells.²

Primary cutaneous adenoid cystic carcinoma is a rare malignant tumor that often presents on the head and neck. It usually appears as a single, slowly growing subcutaneous nodule or multinodular plaque.^5,6 Histologic features include basaloid cells in alternating tubular and cribriform patterns. The cribriform areas are composed of pseudoglandular adenoid spaces that contain mucin, basement membrane zone material, and cellular debris from necrotic neoplastic cells (Figure 1).⁷ Primary cutaneous adenoid cystic carcinoma predominantly is dermal with extension to the subcutaneous tissue. True ductal structures that demonstrate decapitation secretion also may be present.⁷

Basal cell carcinoma (adenoid type) presents as a pigmented or nonpigmented nodule or ulcer on sunexposed areas of the head and neck. Histopathology reveals basaloid cells surrounding islands of connective tissue resulting in a lacelike pattern (Figure 2). The lumina may contain a colloidal substance or amorphous granular material.⁸ The characteristic features of basal cell carcinomas, such as nests of basaloid cells with peripheral palisading cells, retraction of adjacent stroma, increased apoptosis and mitotic figures, and connection to the epidermis, can be helpful to distinguish basal cell carcinoma histologically from EMPSGC.²

Apocrine hidrocystomas clinically present as round, flesh-colored, shiny or translucent, dome-shaped papules or nodules near the eyelid margin or lateral canthus.⁹ Histologically, they are composed of proliferating apocrine secretory coils with an epithelial side of cuboidal or columnar cells and a luminal side exhibiting decapitation secretion (Figure 3).² An epidermal connection is absent.⁹ Apocrine hidrocystomas may exhibit complex architecture and papillary ductal hyperplasia that are difficult to distinguish from EMPSGC, especially if EMPSGC presents with cystic morphology. Apocrine cytomorphology and the lack of neuroendocrine marker expression and mucin production distinguish apocrine hidrocystomas. Furthermore, hidrocystomas infrequently demonstrate the nodular, solid, cribriform areas appreciated in EMPSGC.²

Microcystic adnexal carcinoma is a rare, slowly growing, locally aggressive sweat gland tumor that commonly presents as a flesh-colored to yellow papule, nodule, or plaque on the central face.¹⁰ Histopathologic examination reveals both eccrine and follicular differentiation. Keratin cysts, bland keratinocyte cords, and epithelium with ductal differentiation is observed in the superficial layers (Figure 4). Deep invasion into the subcutis and perineural invasion frequently is observed.

The Diagnosis: Endocrine Mucin-Producing Sweat Gland Carcinoma

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare cutaneous adnexal tumor that characteristically presents as slowgrowing, flesh-colored papules, nodules, or cystic lesions around the periorbital skin in elderly female patients.¹ Histopathology of EMPSGCs reveals well-circumscribed multinodular dermal lesions that can be either cystic or solid and often are arranged in papillary and cribriform patterns (quiz image). Nests of uniform tumor cells are composed of small- to medium-sized epithelial cells with monomorphic nuclei showing fine to stippled chromatin.² Histologically, EMPSGC resembles a solid papillary carcinoma of the breast, which is attributed to their common embryologic origin.³ Intracytoplasmic and extracellular mucin often are seen on hematoxylin and eosin staining.² Variable immunohistochemical stain expression has been reported, including positive staining with synaptophysin and chromogranin. Other markers include cytokeratin CAM 5.2, epithelial membrane antigen, estrogen or progesterone receptors, and cytokeratin 7.⁴ Endocrine mucin-producing sweat gland carcinoma is thought to be a precursor to invasive neuroendocrine-type primary cutaneous mucinous carcinoma. Primary cutaneous mucinous carcinoma has been associated with EMPSGC in approximately 35.7% of cases. Histologically, primary cutaneous mucinous carcinoma that has transformed from EMPSGC would show an infiltration of tumor nests with desmoplastic stroma or mucin pools with clusters of tumor cells.²

Primary cutaneous adenoid cystic carcinoma is a rare malignant tumor that often presents on the head and neck. It usually appears as a single, slowly growing subcutaneous nodule or multinodular plaque.^5,6 Histologic features include basaloid cells in alternating tubular and cribriform patterns. The cribriform areas are composed of pseudoglandular adenoid spaces that contain mucin, basement membrane zone material, and cellular debris from necrotic neoplastic cells (Figure 1).⁷ Primary cutaneous adenoid cystic carcinoma predominantly is dermal with extension to the subcutaneous tissue. True ductal structures that demonstrate decapitation secretion also may be present.⁷

Basal cell carcinoma (adenoid type) presents as a pigmented or nonpigmented nodule or ulcer on sunexposed areas of the head and neck. Histopathology reveals basaloid cells surrounding islands of connective tissue resulting in a lacelike pattern (Figure 2). The lumina may contain a colloidal substance or amorphous granular material.⁸ The characteristic features of basal cell carcinomas, such as nests of basaloid cells with peripheral palisading cells, retraction of adjacent stroma, increased apoptosis and mitotic figures, and connection to the epidermis, can be helpful to distinguish basal cell carcinoma histologically from EMPSGC.²

Apocrine hidrocystomas clinically present as round, flesh-colored, shiny or translucent, dome-shaped papules or nodules near the eyelid margin or lateral canthus.⁹ Histologically, they are composed of proliferating apocrine secretory coils with an epithelial side of cuboidal or columnar cells and a luminal side exhibiting decapitation secretion (Figure 3).² An epidermal connection is absent.⁹ Apocrine hidrocystomas may exhibit complex architecture and papillary ductal hyperplasia that are difficult to distinguish from EMPSGC, especially if EMPSGC presents with cystic morphology. Apocrine cytomorphology and the lack of neuroendocrine marker expression and mucin production distinguish apocrine hidrocystomas. Furthermore, hidrocystomas infrequently demonstrate the nodular, solid, cribriform areas appreciated in EMPSGC.²

Microcystic adnexal carcinoma is a rare, slowly growing, locally aggressive sweat gland tumor that commonly presents as a flesh-colored to yellow papule, nodule, or plaque on the central face.¹⁰ Histopathologic examination reveals both eccrine and follicular differentiation. Keratin cysts, bland keratinocyte cords, and epithelium with ductal differentiation is observed in the superficial layers (Figure 4). Deep invasion into the subcutis and perineural invasion frequently is observed.

The various Camellia species originated in Eastern Asia and are believed to have been introduced in northwestern Spain in the 18th century. Camellia japonica, a flowering evergreen tree with various medical and cosmetic applications, is found throughout Galicia, Spain, where it is cultivated as an ornamental plant, and is native to Japan, South Korea, and China.^1-4 The flowers and seeds of C. japonica have been used in traditional medicine and cosmetics in East Asia, with the oil of C. japonica used there to restore skin elasticity and to enhance skin health.^4-6The identification of bioactive constituents in C. japonica is a relatively recent phenomenon and accounts for the emerging interest in its potential medical applications.^1,7

manuel m. v./flickr/Attribution CC BY 2.0

While the use of C. sinensis in traditional and modern medicine is much better researched, understood, and characterized, C. japonica is now being considered for various health benefits. This column will focus on the bioactivity and scientific support for dermatologic applications of C. japonica. It is worth noting that a dry oil known as tsubaki oil, derived from C. japonica and rich in oleic acid, polyphenols, as well as vitamins A, C, D, and E, is used for skin and hair care in moisturizers produced primarily in Japan.
 

Antioxidant activity

In 2005, Lee and colleagues determined that C. japonica leaf and flower extracts display antioxidant, antifungal, and antibacterial activities (with the latter showing greater gram-positive than gram-negative activity).⁸ Investigating the antioxidant characteristics of the ethanol extract of the C. japonica flower in 2011, Piao and colleagues reported that the botanical exerted scavenging activity against reactive oxygen species in human HaCaT keratinocytes and enhanced protein expression and function of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase.⁹

Less than a decade later, Yoon and colleagues determined that C. japonica leaf extract contains high concentrations of vitamin E and rutin as well as other active constituents and that it exhibits antioxidant and antihyperuricemic activity in vitro and in vivo.⁴

Since then, Kim and colleagues have demonstrated, using cultured normal human dermal fibroblasts, that C. japonica flower extract effectively hindered urban air pollutants–induced reactive oxygen species synthesis. In ex vivo results, the investigators showed that the botanical agent suppressed matrix metalloproteinase (MMP)-1 expression, fostered collagen production, and decreased levels of pollutants-induced malondialdehyde. The authors concluded that C. japonica flower extract shows promise as a protective agent against pollutant-induced cutaneous damage.¹⁰

Anti-inflammatory and wound-healing activity

In 2012, Kim and colleagues found that C. japonica oil imparts anti-inflammatory activity via down-regulation of iNOS and COX-2 gene expression by suppressing of NF-KB and AP-1 signaling.⁶

Jeon and colleagues determined, in a 2018 investigation of 3,695 native plant extracts, that extracts from C. japonica fruit and stems improved induced pluripotent stem cell (iPSC) generation in mouse and human skin and enhanced wound healing in an in vivo mouse wound model. They suggested that their findings may point toward more effective approaches to developing clinical-grade iPSCs and wound-healing therapies.¹¹

Cosmeceutical potential

Among the important bioactive ingredients present in C. japonica are phenolic compounds, terpenoids, and fatty acids, which are thought to account for the anti-inflammatory, antioxidant, antimicrobial, and anticancer activity associated with the plant.¹ The high concentration of polyphenolic substances, in particular, is thought to at least partly account for the inclusion of C. japonica leaf extracts in antiaging cosmetics and cosmeceuticals.¹² Specifically, some of the antioxidant substances found in C. japonica extracts include quercetin, quercetin-3-O-glucoside, quercitrin, and kaempferol.⁹

Wrinkle reduction and moisturization

In 2007, Jung and colleagues found that C. japonica oil activated collagen 1A2 promotion in human dermal fibroblast cells in a concentration-dependent fashion. The oil also suppressed MMP-1 functions and spurred the production of human type I procollagen. On human skin, C. japonica oil was tested on the upper back of 30 volunteers and failed to provoke any adverse reactions. The oil also diminished transepidermal water loss on the forearm. The researchers concluded that C. japonica oil merits consideration as an antiwrinkle ingredient in topical formulations.¹³

More recently, Choi and colleagues showed that ceramide nanoparticles developed through the use of natural oils derived from Korean traditional plants (including C. japonica, along with Panax ginseng, C. sinensis, Glycine max napjakong, and Glycine max seoritae) improve skin carrier functions and promote gene expressions needed for epidermal homeostasis. The expressions of the FLG, CASP14, and INV genes were notably enhanced by the tested formulation. The researchers observed from in vivo human studies that the application of the ceramide nanoparticles yielded more rapid recovery in impaired skin barriers than the control formulation. Amelioration of stratum corneum cohesion was also noted. The investigators concluded that this and other natural oil–derived ceramide nanoparticle formulations may represent the potential for developing better moisturizers for enhancing skin barrier function.¹⁴

Hair-growth promotion and skin-whitening activity

Early in 2021, Cho and colleagues demonstrated that C. japonica phytoplacenta extract spurred the up-regulation of the expression of hair growth–marker genes in human follicle dermal papilla cells in vitro. In clinical tests with 42 adult female volunteers, a solution with 0.5% C. japonica placenta extract raised moisture content of the scalp and reduced sebum levels, dead scalp keratin, and redness. The researchers concluded that C. japonica phytoplacenta extract displays promise as a scalp treatment and hair growth–promoting agent.²

Later that year, Ha and colleagues reported on their findings regarding the tyrosinase inhibitory activity of the essential oil of C. japonica seeds. They identified hexamethylcyclotrisiloxane (42.36%) and octamethylcyclotetrasiloxane (23.28%) as the main constituents of the oil, which demonstrated comparable inhibitory activity to arbutin (positive control) against mushroom tyrosinase. Melanogenesis was also significantly suppressed by C. japonica seed essential oil in B16F10 melanoma cells. The investigators concluded that the essential oil of C. japonica seeds exhibits robust antityrosinase activity and, therefore, warrants consideration as a skin-whitening agent.¹⁵
 

Conclusion

C. japonica is not as popular or well researched as another Camellia species, C. sinensis (the primary tea plant consumed globally and highly touted and appreciated for its multitude of health benefits), but it has its own history of traditional uses for medical and cosmetic purposes and is a subject of increasing research interest along with popular applications. Its antioxidant and anti-inflammatory properties are thought to be central in conferring the ability to protect the skin from aging. Its effects on the skin barrier help skin hydration. More research is necessary to elucidate the apparently widespread potential of this botanical agent that is already found in some over-the-counter products.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions, a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at [email protected].

References

1. Pereira AG et al. Food Chem X. 2022 Feb 17;13:100258.

2. Cho WK et al. FEBS Open Bio. 2021 Mar;11(3):633-51.

3. Chung MY et al. Evolution. 2003 Jan;57(1):62-73.

4. Yoon IS et al. Int J Mol Med. 2017 Jun;39(6):1613-20.

5. Lee HH et al. Evid Based Complement Alternat Med. 2016;2016:9679867.

6. Kim S et al. BMB Rep. 2012 Mar;45(3):177-82.

7. Majumder S et al. Bull Nat Res Cen. 2020 Dec;44(1):1-4.

8. Lee SY et al. Korean Journal of Medicinal Crop Science. 2005;13(3):93-100.

9. Piao MJ et al. Int J Mol Sci. 2011;12(4):2618-30.

10. Kim M et al. BMC Complement Altern Med. 2019 Jan 28;19(1):30.

11. Jeon H et al. J Clin Med. 2018 Nov 20;7(11):449.

12. Mizutani T, Masaki H. Exp Dermatol. 2014 Oct;23 Suppl 1:23-6.

13. Jung E et al. J Ethnopharmacol. 2007 May 30;112(1):127-31.

14. Choi HK et al. J Cosmet Dermatol. 2022 Oct;21(10):4931-41.

15. Ha SY et al. Evid Based Complement Alternat Med. 2021 Nov 16;2021:6328767.

The various Camellia species originated in Eastern Asia and are believed to have been introduced in northwestern Spain in the 18th century. Camellia japonica, a flowering evergreen tree with various medical and cosmetic applications, is found throughout Galicia, Spain, where it is cultivated as an ornamental plant, and is native to Japan, South Korea, and China.^1-4 The flowers and seeds of C. japonica have been used in traditional medicine and cosmetics in East Asia, with the oil of C. japonica used there to restore skin elasticity and to enhance skin health.^4-6The identification of bioactive constituents in C. japonica is a relatively recent phenomenon and accounts for the emerging interest in its potential medical applications.^1,7

manuel m. v./flickr/Attribution CC BY 2.0

While the use of C. sinensis in traditional and modern medicine is much better researched, understood, and characterized, C. japonica is now being considered for various health benefits. This column will focus on the bioactivity and scientific support for dermatologic applications of C. japonica. It is worth noting that a dry oil known as tsubaki oil, derived from C. japonica and rich in oleic acid, polyphenols, as well as vitamins A, C, D, and E, is used for skin and hair care in moisturizers produced primarily in Japan.
 

Antioxidant activity

In 2005, Lee and colleagues determined that C. japonica leaf and flower extracts display antioxidant, antifungal, and antibacterial activities (with the latter showing greater gram-positive than gram-negative activity).⁸ Investigating the antioxidant characteristics of the ethanol extract of the C. japonica flower in 2011, Piao and colleagues reported that the botanical exerted scavenging activity against reactive oxygen species in human HaCaT keratinocytes and enhanced protein expression and function of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase.⁹

Less than a decade later, Yoon and colleagues determined that C. japonica leaf extract contains high concentrations of vitamin E and rutin as well as other active constituents and that it exhibits antioxidant and antihyperuricemic activity in vitro and in vivo.⁴

Since then, Kim and colleagues have demonstrated, using cultured normal human dermal fibroblasts, that C. japonica flower extract effectively hindered urban air pollutants–induced reactive oxygen species synthesis. In ex vivo results, the investigators showed that the botanical agent suppressed matrix metalloproteinase (MMP)-1 expression, fostered collagen production, and decreased levels of pollutants-induced malondialdehyde. The authors concluded that C. japonica flower extract shows promise as a protective agent against pollutant-induced cutaneous damage.¹⁰

Anti-inflammatory and wound-healing activity

In 2012, Kim and colleagues found that C. japonica oil imparts anti-inflammatory activity via down-regulation of iNOS and COX-2 gene expression by suppressing of NF-KB and AP-1 signaling.⁶

Jeon and colleagues determined, in a 2018 investigation of 3,695 native plant extracts, that extracts from C. japonica fruit and stems improved induced pluripotent stem cell (iPSC) generation in mouse and human skin and enhanced wound healing in an in vivo mouse wound model. They suggested that their findings may point toward more effective approaches to developing clinical-grade iPSCs and wound-healing therapies.¹¹

Cosmeceutical potential

Among the important bioactive ingredients present in C. japonica are phenolic compounds, terpenoids, and fatty acids, which are thought to account for the anti-inflammatory, antioxidant, antimicrobial, and anticancer activity associated with the plant.¹ The high concentration of polyphenolic substances, in particular, is thought to at least partly account for the inclusion of C. japonica leaf extracts in antiaging cosmetics and cosmeceuticals.¹² Specifically, some of the antioxidant substances found in C. japonica extracts include quercetin, quercetin-3-O-glucoside, quercitrin, and kaempferol.⁹

Wrinkle reduction and moisturization

In 2007, Jung and colleagues found that C. japonica oil activated collagen 1A2 promotion in human dermal fibroblast cells in a concentration-dependent fashion. The oil also suppressed MMP-1 functions and spurred the production of human type I procollagen. On human skin, C. japonica oil was tested on the upper back of 30 volunteers and failed to provoke any adverse reactions. The oil also diminished transepidermal water loss on the forearm. The researchers concluded that C. japonica oil merits consideration as an antiwrinkle ingredient in topical formulations.¹³

More recently, Choi and colleagues showed that ceramide nanoparticles developed through the use of natural oils derived from Korean traditional plants (including C. japonica, along with Panax ginseng, C. sinensis, Glycine max napjakong, and Glycine max seoritae) improve skin carrier functions and promote gene expressions needed for epidermal homeostasis. The expressions of the FLG, CASP14, and INV genes were notably enhanced by the tested formulation. The researchers observed from in vivo human studies that the application of the ceramide nanoparticles yielded more rapid recovery in impaired skin barriers than the control formulation. Amelioration of stratum corneum cohesion was also noted. The investigators concluded that this and other natural oil–derived ceramide nanoparticle formulations may represent the potential for developing better moisturizers for enhancing skin barrier function.¹⁴

Hair-growth promotion and skin-whitening activity

Early in 2021, Cho and colleagues demonstrated that C. japonica phytoplacenta extract spurred the up-regulation of the expression of hair growth–marker genes in human follicle dermal papilla cells in vitro. In clinical tests with 42 adult female volunteers, a solution with 0.5% C. japonica placenta extract raised moisture content of the scalp and reduced sebum levels, dead scalp keratin, and redness. The researchers concluded that C. japonica phytoplacenta extract displays promise as a scalp treatment and hair growth–promoting agent.²

Later that year, Ha and colleagues reported on their findings regarding the tyrosinase inhibitory activity of the essential oil of C. japonica seeds. They identified hexamethylcyclotrisiloxane (42.36%) and octamethylcyclotetrasiloxane (23.28%) as the main constituents of the oil, which demonstrated comparable inhibitory activity to arbutin (positive control) against mushroom tyrosinase. Melanogenesis was also significantly suppressed by C. japonica seed essential oil in B16F10 melanoma cells. The investigators concluded that the essential oil of C. japonica seeds exhibits robust antityrosinase activity and, therefore, warrants consideration as a skin-whitening agent.¹⁵
 

Conclusion

C. japonica is not as popular or well researched as another Camellia species, C. sinensis (the primary tea plant consumed globally and highly touted and appreciated for its multitude of health benefits), but it has its own history of traditional uses for medical and cosmetic purposes and is a subject of increasing research interest along with popular applications. Its antioxidant and anti-inflammatory properties are thought to be central in conferring the ability to protect the skin from aging. Its effects on the skin barrier help skin hydration. More research is necessary to elucidate the apparently widespread potential of this botanical agent that is already found in some over-the-counter products.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions, a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at [email protected].

References

1. Pereira AG et al. Food Chem X. 2022 Feb 17;13:100258.

2. Cho WK et al. FEBS Open Bio. 2021 Mar;11(3):633-51.

3. Chung MY et al. Evolution. 2003 Jan;57(1):62-73.

4. Yoon IS et al. Int J Mol Med. 2017 Jun;39(6):1613-20.

5. Lee HH et al. Evid Based Complement Alternat Med. 2016;2016:9679867.

6. Kim S et al. BMB Rep. 2012 Mar;45(3):177-82.

7. Majumder S et al. Bull Nat Res Cen. 2020 Dec;44(1):1-4.

8. Lee SY et al. Korean Journal of Medicinal Crop Science. 2005;13(3):93-100.

9. Piao MJ et al. Int J Mol Sci. 2011;12(4):2618-30.

10. Kim M et al. BMC Complement Altern Med. 2019 Jan 28;19(1):30.

11. Jeon H et al. J Clin Med. 2018 Nov 20;7(11):449.

12. Mizutani T, Masaki H. Exp Dermatol. 2014 Oct;23 Suppl 1:23-6.

13. Jung E et al. J Ethnopharmacol. 2007 May 30;112(1):127-31.

14. Choi HK et al. J Cosmet Dermatol. 2022 Oct;21(10):4931-41.

15. Ha SY et al. Evid Based Complement Alternat Med. 2021 Nov 16;2021:6328767.

The various Camellia species originated in Eastern Asia and are believed to have been introduced in northwestern Spain in the 18th century. Camellia japonica, a flowering evergreen tree with various medical and cosmetic applications, is found throughout Galicia, Spain, where it is cultivated as an ornamental plant, and is native to Japan, South Korea, and China.^1-4 The flowers and seeds of C. japonica have been used in traditional medicine and cosmetics in East Asia, with the oil of C. japonica used there to restore skin elasticity and to enhance skin health.^4-6The identification of bioactive constituents in C. japonica is a relatively recent phenomenon and accounts for the emerging interest in its potential medical applications.^1,7

manuel m. v./flickr/Attribution CC BY 2.0

While the use of C. sinensis in traditional and modern medicine is much better researched, understood, and characterized, C. japonica is now being considered for various health benefits. This column will focus on the bioactivity and scientific support for dermatologic applications of C. japonica. It is worth noting that a dry oil known as tsubaki oil, derived from C. japonica and rich in oleic acid, polyphenols, as well as vitamins A, C, D, and E, is used for skin and hair care in moisturizers produced primarily in Japan.
 

Antioxidant activity

In 2005, Lee and colleagues determined that C. japonica leaf and flower extracts display antioxidant, antifungal, and antibacterial activities (with the latter showing greater gram-positive than gram-negative activity).⁸ Investigating the antioxidant characteristics of the ethanol extract of the C. japonica flower in 2011, Piao and colleagues reported that the botanical exerted scavenging activity against reactive oxygen species in human HaCaT keratinocytes and enhanced protein expression and function of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase.⁹

Less than a decade later, Yoon and colleagues determined that C. japonica leaf extract contains high concentrations of vitamin E and rutin as well as other active constituents and that it exhibits antioxidant and antihyperuricemic activity in vitro and in vivo.⁴

Since then, Kim and colleagues have demonstrated, using cultured normal human dermal fibroblasts, that C. japonica flower extract effectively hindered urban air pollutants–induced reactive oxygen species synthesis. In ex vivo results, the investigators showed that the botanical agent suppressed matrix metalloproteinase (MMP)-1 expression, fostered collagen production, and decreased levels of pollutants-induced malondialdehyde. The authors concluded that C. japonica flower extract shows promise as a protective agent against pollutant-induced cutaneous damage.¹⁰

Anti-inflammatory and wound-healing activity

In 2012, Kim and colleagues found that C. japonica oil imparts anti-inflammatory activity via down-regulation of iNOS and COX-2 gene expression by suppressing of NF-KB and AP-1 signaling.⁶

Jeon and colleagues determined, in a 2018 investigation of 3,695 native plant extracts, that extracts from C. japonica fruit and stems improved induced pluripotent stem cell (iPSC) generation in mouse and human skin and enhanced wound healing in an in vivo mouse wound model. They suggested that their findings may point toward more effective approaches to developing clinical-grade iPSCs and wound-healing therapies.¹¹

Cosmeceutical potential

Among the important bioactive ingredients present in C. japonica are phenolic compounds, terpenoids, and fatty acids, which are thought to account for the anti-inflammatory, antioxidant, antimicrobial, and anticancer activity associated with the plant.¹ The high concentration of polyphenolic substances, in particular, is thought to at least partly account for the inclusion of C. japonica leaf extracts in antiaging cosmetics and cosmeceuticals.¹² Specifically, some of the antioxidant substances found in C. japonica extracts include quercetin, quercetin-3-O-glucoside, quercitrin, and kaempferol.⁹

Wrinkle reduction and moisturization

In 2007, Jung and colleagues found that C. japonica oil activated collagen 1A2 promotion in human dermal fibroblast cells in a concentration-dependent fashion. The oil also suppressed MMP-1 functions and spurred the production of human type I procollagen. On human skin, C. japonica oil was tested on the upper back of 30 volunteers and failed to provoke any adverse reactions. The oil also diminished transepidermal water loss on the forearm. The researchers concluded that C. japonica oil merits consideration as an antiwrinkle ingredient in topical formulations.¹³

More recently, Choi and colleagues showed that ceramide nanoparticles developed through the use of natural oils derived from Korean traditional plants (including C. japonica, along with Panax ginseng, C. sinensis, Glycine max napjakong, and Glycine max seoritae) improve skin carrier functions and promote gene expressions needed for epidermal homeostasis. The expressions of the FLG, CASP14, and INV genes were notably enhanced by the tested formulation. The researchers observed from in vivo human studies that the application of the ceramide nanoparticles yielded more rapid recovery in impaired skin barriers than the control formulation. Amelioration of stratum corneum cohesion was also noted. The investigators concluded that this and other natural oil–derived ceramide nanoparticle formulations may represent the potential for developing better moisturizers for enhancing skin barrier function.¹⁴

Hair-growth promotion and skin-whitening activity

Early in 2021, Cho and colleagues demonstrated that C. japonica phytoplacenta extract spurred the up-regulation of the expression of hair growth–marker genes in human follicle dermal papilla cells in vitro. In clinical tests with 42 adult female volunteers, a solution with 0.5% C. japonica placenta extract raised moisture content of the scalp and reduced sebum levels, dead scalp keratin, and redness. The researchers concluded that C. japonica phytoplacenta extract displays promise as a scalp treatment and hair growth–promoting agent.²

Later that year, Ha and colleagues reported on their findings regarding the tyrosinase inhibitory activity of the essential oil of C. japonica seeds. They identified hexamethylcyclotrisiloxane (42.36%) and octamethylcyclotetrasiloxane (23.28%) as the main constituents of the oil, which demonstrated comparable inhibitory activity to arbutin (positive control) against mushroom tyrosinase. Melanogenesis was also significantly suppressed by C. japonica seed essential oil in B16F10 melanoma cells. The investigators concluded that the essential oil of C. japonica seeds exhibits robust antityrosinase activity and, therefore, warrants consideration as a skin-whitening agent.¹⁵
 

Conclusion

C. japonica is not as popular or well researched as another Camellia species, C. sinensis (the primary tea plant consumed globally and highly touted and appreciated for its multitude of health benefits), but it has its own history of traditional uses for medical and cosmetic purposes and is a subject of increasing research interest along with popular applications. Its antioxidant and anti-inflammatory properties are thought to be central in conferring the ability to protect the skin from aging. Its effects on the skin barrier help skin hydration. More research is necessary to elucidate the apparently widespread potential of this botanical agent that is already found in some over-the-counter products.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions, a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at [email protected].

References

1. Pereira AG et al. Food Chem X. 2022 Feb 17;13:100258.

2. Cho WK et al. FEBS Open Bio. 2021 Mar;11(3):633-51.

3. Chung MY et al. Evolution. 2003 Jan;57(1):62-73.

4. Yoon IS et al. Int J Mol Med. 2017 Jun;39(6):1613-20.

5. Lee HH et al. Evid Based Complement Alternat Med. 2016;2016:9679867.

6. Kim S et al. BMB Rep. 2012 Mar;45(3):177-82.

7. Majumder S et al. Bull Nat Res Cen. 2020 Dec;44(1):1-4.

8. Lee SY et al. Korean Journal of Medicinal Crop Science. 2005;13(3):93-100.

9. Piao MJ et al. Int J Mol Sci. 2011;12(4):2618-30.

10. Kim M et al. BMC Complement Altern Med. 2019 Jan 28;19(1):30.

11. Jeon H et al. J Clin Med. 2018 Nov 20;7(11):449.

12. Mizutani T, Masaki H. Exp Dermatol. 2014 Oct;23 Suppl 1:23-6.

13. Jung E et al. J Ethnopharmacol. 2007 May 30;112(1):127-31.

14. Choi HK et al. J Cosmet Dermatol. 2022 Oct;21(10):4931-41.

15. Ha SY et al. Evid Based Complement Alternat Med. 2021 Nov 16;2021:6328767.

Childhood stress can change the brain negatively, according to a new study that says Black children are affected more because they experience more poverty and adversity.

“The researchers analyzed MRI scans to identify small differences in the volume of certain brain structures, and said these could accumulate as children age and play a role in the later development of mental health problems,” STAT News reported. “The finding, part of an emerging research field looking at how racism and other social factors may affect the physical architecture of the brain, may help explain longstanding racial disparities in the prevalence of psychiatric disorders such as PTSD.”

The study was published in The American Journal of Psychiatry.

Brain development is affected by “disparities faced by certain groups of people,” even among children as young as 9 years old, said Nathaniel Harnett, an assistant professor of psychiatry at Harvard Medical School, Boston, and the study’s senior author. “If we’re going to treat the world as colorblind, we’re not going to create mental health solutions that are effective for all people.”

The study used evidence from the Adolescent Brain Cognitive Development Study, which the National Institutes of Health established in 2015 to study the brains and experiences of thousands of American children through early adulthood.

Brain scans revealed that Black children had less gray matter in 11 of 14 brain areas that were examined. Disparities in 8 of the 14 brain areas were affected by childhood adversity, particularly poverty.

A version of this article first appeared on WebMD.com.

Childhood stress can change the brain negatively, according to a new study that says Black children are affected more because they experience more poverty and adversity.

“The researchers analyzed MRI scans to identify small differences in the volume of certain brain structures, and said these could accumulate as children age and play a role in the later development of mental health problems,” STAT News reported. “The finding, part of an emerging research field looking at how racism and other social factors may affect the physical architecture of the brain, may help explain longstanding racial disparities in the prevalence of psychiatric disorders such as PTSD.”

The study was published in The American Journal of Psychiatry.

Brain development is affected by “disparities faced by certain groups of people,” even among children as young as 9 years old, said Nathaniel Harnett, an assistant professor of psychiatry at Harvard Medical School, Boston, and the study’s senior author. “If we’re going to treat the world as colorblind, we’re not going to create mental health solutions that are effective for all people.”

The study used evidence from the Adolescent Brain Cognitive Development Study, which the National Institutes of Health established in 2015 to study the brains and experiences of thousands of American children through early adulthood.

Brain scans revealed that Black children had less gray matter in 11 of 14 brain areas that were examined. Disparities in 8 of the 14 brain areas were affected by childhood adversity, particularly poverty.

A version of this article first appeared on WebMD.com.

Childhood stress can change the brain negatively, according to a new study that says Black children are affected more because they experience more poverty and adversity.

“The researchers analyzed MRI scans to identify small differences in the volume of certain brain structures, and said these could accumulate as children age and play a role in the later development of mental health problems,” STAT News reported. “The finding, part of an emerging research field looking at how racism and other social factors may affect the physical architecture of the brain, may help explain longstanding racial disparities in the prevalence of psychiatric disorders such as PTSD.”

The study was published in The American Journal of Psychiatry.

Brain development is affected by “disparities faced by certain groups of people,” even among children as young as 9 years old, said Nathaniel Harnett, an assistant professor of psychiatry at Harvard Medical School, Boston, and the study’s senior author. “If we’re going to treat the world as colorblind, we’re not going to create mental health solutions that are effective for all people.”

The study used evidence from the Adolescent Brain Cognitive Development Study, which the National Institutes of Health established in 2015 to study the brains and experiences of thousands of American children through early adulthood.

Brain scans revealed that Black children had less gray matter in 11 of 14 brain areas that were examined. Disparities in 8 of the 14 brain areas were affected by childhood adversity, particularly poverty.

A version of this article first appeared on WebMD.com.

People with untreatable dystrophic epidermolysis bullosa (DEB) may soon have access to an investigational gene therapy delivered in a topical gel that is currently under review by the Food and Drug Administration.

In a phase 3 study of patients with DEB, “we found that repeated topical application of B-VEC [beremagene geperpavec], an HSV-1–based gene therapy, resulted in a greater likelihood of complete wound healing than the topical application of placebo at up to 6 months,” the authors wrote. The study was published in The New England Journal of Medicine. “Longer and larger trials are warranted to determine the durability of effect and risks of this approach,” the authors noted.

“The results prove that B-VEC, the first topical in vivo gene therapy to reach late-stage development, can heal DEB,” senior author M. Peter Marinkovich, MD, associate professor of dermatology at Stanford University, Redwood City, Calif., said in an interview.

“In the past, DEB was a very specialized disease that only a handful of dermatologists would see but could not do much to treat,” he said. “With gene therapy, many more dermatologists who may not be familiar with DEB will be able to treat these patients in their offices.” It is expected that nurses will be able to administer the treatment to patients at home, he added.
 

Rare, life-threatening, genetic blistering disease

DEB, a rare disease that affects one to three persons per million in the United States, is caused by mutations in the COL7A1 gene that encodes the alpha-1 chain of collagen type VII (C7) protein. C7 forms the anchoring fibrils that attach the epidermis to the underlying dermal connective tissue.

COL71A mutations that lead to defective, decreased, or absent C7 can make the skin so fragile it tears with the slightest touch. This has led to patients being called “butterfly children.” Epithelial tissues blister and scar, causing esophageal and genitourinary strictures, adhesion of digits, malnutrition, anemia, infection, and bothersome itch and pain. Morbidity and mortality are high. The leading cause of death in adults is chronic wounds leading to aggressive squamous cell cancers.
 

The first therapy for DEB, under FDA review

B-VEC restores C7 protein by using an engineered replication-defective herpes simplex virus type 1 (HSV-1) vector to deliver the COL7A1 gene directly to skin cells to restore functional C7 protein fibrils that stabilize the skin structure.

On the basis of manufacturing information submitted to the FDA in December 2022, the agency extended the date for a decision on approval by 3 months, to May 19, 2023, according to a statement from Krystal Biotech, the developer of B-VEC and the sponsor of the NEJM study.

Dr. Marinkovich and his colleagues conducted the double-blind, randomized, controlled GEM-3 trial of B-VEC at three sites in the United States. The 31 study participants ranged in age from 1 to 44 years (median age, 16 years) and had genetically confirmed DEB (30 with the recessive form and 1 with the dominant form).

For each participant, a pair of wounds was chosen that were matched in size, region, and appearance. The wounds within each pair were randomly allocated to receive weekly applications of either B-VEC or placebo gel for 26 weeks.

The results of the study included the following:

• Complete healing at 6 months occurred in 67% of the wounds treated with B-VEC (including a wound in the patient with dominant DEB), vs. 22% of those who received placebo (95% confidence interval [CI], 24-68; P = .002).
• Complete healing at 3 months occurred in 71% of the wounds treated with B-VEC, vs. 20% of those who received placebo (95% CI, 29-73; P < .001).
• The mean change from baseline to week 22 in pain severity during wound-dressing changes for patients aged 6 years and older, as determined on the basis of a visual analogue scale, was –0.88 with B-VEC, vs. –0.71 with placebo (adjusted least-squares mean difference, –0.61; 95% CI, –1.10 to –0.13); similar mean changes were seen at weeks 24 and 26.
• Among all patients, 58% had at least one adverse event. Most adverse events were mild or moderate. The most common were pruritus, chills, and squamous cell carcinoma (SCC), which were reported in three patients each (SCC cases occurred at wound sites that had not been exposed to B-VEC or placebo). Serious adverse events, which were unrelated to the treatment, occurred in three patients: diarrhea, anemia, cellulitis, and a positive blood culture related to a hemodialysis catheter.

“With the ability to treat patients with topical gene therapy, dermatology is entering a new age of treatment possibilities,” Dr. Marinkovich said in the interview.

The researchers were surprised that the redosable in vivo gene therapy worked so well, he added. In vivo gene therapy has been plagued by the occurrence of immune reactions against the viral vectors used, Dr. Marinkovich explained. But because the herpes simplex virus has evolved to evade the immune system, his team could use the viral vector every week for 6 months without inflammatory reactions.

“The immune system’s inability to fight off or get rid of the herpes simplex vector makes it bad as a disease, but as a gene therapy vector, it provides a huge advantage,” he added.

Asked to comment on the results, Christen Ebens, MD, MPH, assistant professor in the department of pediatrics at the University of Minnesota, Minneapolis, whose clinical and research interests include EB, called the results exciting for patients, families, and doctors.

“Side effects were minimal, and importantly, use of the replication-incompetent HSV vector means that the payload gene does not integrate into the patient’s DNA,” Dr. Ebens, who was not involved in the study, said in an interview. “B-VEC is not a lifelong cure but potentially an effective maintenance therapy requiring repeated doses,” she added.

Although the researchers found no clinically important immune reactions to B-VEC, Dr. Ebens said she would like to see results from longer studies of the treatment. “We will want to see that patients do not produce neutralizing antibodies against B-VEC or its components, as such antibodies may yield the treatment ineffective or cause significant side effects.”

In an interview, Vanessa R. Holland, MD, associate clinical professor in the division of dermatology at UCLA Health, Burbank, Calif., who was not involved in the study, said that “topical replication-defective HSV-1 is a brilliant vector to deliver the depleted collagen.” She added that “such a vehicle may significantly alter management of these disorders and improve or extend lives by minimizing potentially fatal complications.”

Paras P. Vakharia, MD, PharmD, assistant professor of dermatology at Northwestern University, Chicago, who was not involved in the study, was surprised by the high percentage of healed wounds and wounds that remained healed over time.

B-VEC for treating other conditions

Dr. Marinkovich noted that an ongoing phase 1 clinical trial, also sponsored by Krystal Biotech, is using the HSV-1 vector to deliver a different biologic (KB105) to establish dose and safety in the treatment of ichthyosis. He added that he would like to explore the use of B-VEC to treat DEB at mucosal surfaces, including inside the mouth, the eye, and the esophagus.

Authors of two editorials that accompanied the study also referred to other conditions B-VEC might treat.

This study “highlights potential future investigations,” David V. Schaffer, PhD, professor of chemical and biomolecular engineering, bioengineering, and molecular and cell biology at the University of California, Berkeley, wrotes in one of the editorials.

Important considerations he mentioned include the likelihood of the treatment becoming lifelong; the inability of HSV to penetrate intact skin, making B-VEC unsuitable for preventing the development of new wounds; and the inability of this treatment to treat EB lesions along the digestive tract. “This important trial builds on and extends gene-therapy successes to new targets and vectors, an advance for patients,” he added.

In the second editorial, Aimee S. Payne, MD, PhD, professor of dermatology at the University of Pennsylvania, Philadelphia, raised the question of whether B-VEC’s clinical success for treating DEB can translate to other genetic diseases.

“Formulations for ophthalmic, oral-gastrointestinal, or respiratory delivery would be of great value to address the extracutaneous manifestations of epidermolysis bullosa and other genetic diseases,” she wrote.

Referring to an ongoing trial of a topical gene therapy for cystic fibrosis that is delivered by a nebulizer, Dr. Payne noted, “Ultimately, the completion of clinical trials such as this one will be required to determine whether HSV-1–mediated gene delivery can go more than skin deep.”

Earlier data and more details of the study were presented in a poster at the annual meeting of the Society for Pediatric Dermatology in July 2022.

Dr. Marinkovich has disclosed no relevant financial relationships. Several coauthors are employees of or have other financial relationships with Krystal Biotech, the study’s sponsor and the developer of beremagene geperpavec. Dr. Schaffer and Dr. Payne have financial relationships with the pharmaceutical industry. Dr. Ebens, Dr. Holland, and Dr. Vakharia have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

People with untreatable dystrophic epidermolysis bullosa (DEB) may soon have access to an investigational gene therapy delivered in a topical gel that is currently under review by the Food and Drug Administration.

In a phase 3 study of patients with DEB, “we found that repeated topical application of B-VEC [beremagene geperpavec], an HSV-1–based gene therapy, resulted in a greater likelihood of complete wound healing than the topical application of placebo at up to 6 months,” the authors wrote. The study was published in The New England Journal of Medicine. “Longer and larger trials are warranted to determine the durability of effect and risks of this approach,” the authors noted.

“The results prove that B-VEC, the first topical in vivo gene therapy to reach late-stage development, can heal DEB,” senior author M. Peter Marinkovich, MD, associate professor of dermatology at Stanford University, Redwood City, Calif., said in an interview.

“In the past, DEB was a very specialized disease that only a handful of dermatologists would see but could not do much to treat,” he said. “With gene therapy, many more dermatologists who may not be familiar with DEB will be able to treat these patients in their offices.” It is expected that nurses will be able to administer the treatment to patients at home, he added.
 

Rare, life-threatening, genetic blistering disease

DEB, a rare disease that affects one to three persons per million in the United States, is caused by mutations in the COL7A1 gene that encodes the alpha-1 chain of collagen type VII (C7) protein. C7 forms the anchoring fibrils that attach the epidermis to the underlying dermal connective tissue.

COL71A mutations that lead to defective, decreased, or absent C7 can make the skin so fragile it tears with the slightest touch. This has led to patients being called “butterfly children.” Epithelial tissues blister and scar, causing esophageal and genitourinary strictures, adhesion of digits, malnutrition, anemia, infection, and bothersome itch and pain. Morbidity and mortality are high. The leading cause of death in adults is chronic wounds leading to aggressive squamous cell cancers.
 

The first therapy for DEB, under FDA review

B-VEC restores C7 protein by using an engineered replication-defective herpes simplex virus type 1 (HSV-1) vector to deliver the COL7A1 gene directly to skin cells to restore functional C7 protein fibrils that stabilize the skin structure.

On the basis of manufacturing information submitted to the FDA in December 2022, the agency extended the date for a decision on approval by 3 months, to May 19, 2023, according to a statement from Krystal Biotech, the developer of B-VEC and the sponsor of the NEJM study.

Dr. Marinkovich and his colleagues conducted the double-blind, randomized, controlled GEM-3 trial of B-VEC at three sites in the United States. The 31 study participants ranged in age from 1 to 44 years (median age, 16 years) and had genetically confirmed DEB (30 with the recessive form and 1 with the dominant form).

For each participant, a pair of wounds was chosen that were matched in size, region, and appearance. The wounds within each pair were randomly allocated to receive weekly applications of either B-VEC or placebo gel for 26 weeks.

The results of the study included the following:

• Complete healing at 6 months occurred in 67% of the wounds treated with B-VEC (including a wound in the patient with dominant DEB), vs. 22% of those who received placebo (95% confidence interval [CI], 24-68; P = .002).
• Complete healing at 3 months occurred in 71% of the wounds treated with B-VEC, vs. 20% of those who received placebo (95% CI, 29-73; P < .001).
• The mean change from baseline to week 22 in pain severity during wound-dressing changes for patients aged 6 years and older, as determined on the basis of a visual analogue scale, was –0.88 with B-VEC, vs. –0.71 with placebo (adjusted least-squares mean difference, –0.61; 95% CI, –1.10 to –0.13); similar mean changes were seen at weeks 24 and 26.
• Among all patients, 58% had at least one adverse event. Most adverse events were mild or moderate. The most common were pruritus, chills, and squamous cell carcinoma (SCC), which were reported in three patients each (SCC cases occurred at wound sites that had not been exposed to B-VEC or placebo). Serious adverse events, which were unrelated to the treatment, occurred in three patients: diarrhea, anemia, cellulitis, and a positive blood culture related to a hemodialysis catheter.

“With the ability to treat patients with topical gene therapy, dermatology is entering a new age of treatment possibilities,” Dr. Marinkovich said in the interview.

The researchers were surprised that the redosable in vivo gene therapy worked so well, he added. In vivo gene therapy has been plagued by the occurrence of immune reactions against the viral vectors used, Dr. Marinkovich explained. But because the herpes simplex virus has evolved to evade the immune system, his team could use the viral vector every week for 6 months without inflammatory reactions.

“The immune system’s inability to fight off or get rid of the herpes simplex vector makes it bad as a disease, but as a gene therapy vector, it provides a huge advantage,” he added.

Asked to comment on the results, Christen Ebens, MD, MPH, assistant professor in the department of pediatrics at the University of Minnesota, Minneapolis, whose clinical and research interests include EB, called the results exciting for patients, families, and doctors.

“Side effects were minimal, and importantly, use of the replication-incompetent HSV vector means that the payload gene does not integrate into the patient’s DNA,” Dr. Ebens, who was not involved in the study, said in an interview. “B-VEC is not a lifelong cure but potentially an effective maintenance therapy requiring repeated doses,” she added.

Although the researchers found no clinically important immune reactions to B-VEC, Dr. Ebens said she would like to see results from longer studies of the treatment. “We will want to see that patients do not produce neutralizing antibodies against B-VEC or its components, as such antibodies may yield the treatment ineffective or cause significant side effects.”

In an interview, Vanessa R. Holland, MD, associate clinical professor in the division of dermatology at UCLA Health, Burbank, Calif., who was not involved in the study, said that “topical replication-defective HSV-1 is a brilliant vector to deliver the depleted collagen.” She added that “such a vehicle may significantly alter management of these disorders and improve or extend lives by minimizing potentially fatal complications.”

Paras P. Vakharia, MD, PharmD, assistant professor of dermatology at Northwestern University, Chicago, who was not involved in the study, was surprised by the high percentage of healed wounds and wounds that remained healed over time.

B-VEC for treating other conditions

Dr. Marinkovich noted that an ongoing phase 1 clinical trial, also sponsored by Krystal Biotech, is using the HSV-1 vector to deliver a different biologic (KB105) to establish dose and safety in the treatment of ichthyosis. He added that he would like to explore the use of B-VEC to treat DEB at mucosal surfaces, including inside the mouth, the eye, and the esophagus.

Authors of two editorials that accompanied the study also referred to other conditions B-VEC might treat.

This study “highlights potential future investigations,” David V. Schaffer, PhD, professor of chemical and biomolecular engineering, bioengineering, and molecular and cell biology at the University of California, Berkeley, wrotes in one of the editorials.

Important considerations he mentioned include the likelihood of the treatment becoming lifelong; the inability of HSV to penetrate intact skin, making B-VEC unsuitable for preventing the development of new wounds; and the inability of this treatment to treat EB lesions along the digestive tract. “This important trial builds on and extends gene-therapy successes to new targets and vectors, an advance for patients,” he added.

In the second editorial, Aimee S. Payne, MD, PhD, professor of dermatology at the University of Pennsylvania, Philadelphia, raised the question of whether B-VEC’s clinical success for treating DEB can translate to other genetic diseases.

“Formulations for ophthalmic, oral-gastrointestinal, or respiratory delivery would be of great value to address the extracutaneous manifestations of epidermolysis bullosa and other genetic diseases,” she wrote.

Referring to an ongoing trial of a topical gene therapy for cystic fibrosis that is delivered by a nebulizer, Dr. Payne noted, “Ultimately, the completion of clinical trials such as this one will be required to determine whether HSV-1–mediated gene delivery can go more than skin deep.”

Earlier data and more details of the study were presented in a poster at the annual meeting of the Society for Pediatric Dermatology in July 2022.

Dr. Marinkovich has disclosed no relevant financial relationships. Several coauthors are employees of or have other financial relationships with Krystal Biotech, the study’s sponsor and the developer of beremagene geperpavec. Dr. Schaffer and Dr. Payne have financial relationships with the pharmaceutical industry. Dr. Ebens, Dr. Holland, and Dr. Vakharia have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

People with untreatable dystrophic epidermolysis bullosa (DEB) may soon have access to an investigational gene therapy delivered in a topical gel that is currently under review by the Food and Drug Administration.

In a phase 3 study of patients with DEB, “we found that repeated topical application of B-VEC [beremagene geperpavec], an HSV-1–based gene therapy, resulted in a greater likelihood of complete wound healing than the topical application of placebo at up to 6 months,” the authors wrote. The study was published in The New England Journal of Medicine. “Longer and larger trials are warranted to determine the durability of effect and risks of this approach,” the authors noted.

“The results prove that B-VEC, the first topical in vivo gene therapy to reach late-stage development, can heal DEB,” senior author M. Peter Marinkovich, MD, associate professor of dermatology at Stanford University, Redwood City, Calif., said in an interview.

“In the past, DEB was a very specialized disease that only a handful of dermatologists would see but could not do much to treat,” he said. “With gene therapy, many more dermatologists who may not be familiar with DEB will be able to treat these patients in their offices.” It is expected that nurses will be able to administer the treatment to patients at home, he added.
 

Rare, life-threatening, genetic blistering disease

DEB, a rare disease that affects one to three persons per million in the United States, is caused by mutations in the COL7A1 gene that encodes the alpha-1 chain of collagen type VII (C7) protein. C7 forms the anchoring fibrils that attach the epidermis to the underlying dermal connective tissue.

COL71A mutations that lead to defective, decreased, or absent C7 can make the skin so fragile it tears with the slightest touch. This has led to patients being called “butterfly children.” Epithelial tissues blister and scar, causing esophageal and genitourinary strictures, adhesion of digits, malnutrition, anemia, infection, and bothersome itch and pain. Morbidity and mortality are high. The leading cause of death in adults is chronic wounds leading to aggressive squamous cell cancers.
 

The first therapy for DEB, under FDA review

B-VEC restores C7 protein by using an engineered replication-defective herpes simplex virus type 1 (HSV-1) vector to deliver the COL7A1 gene directly to skin cells to restore functional C7 protein fibrils that stabilize the skin structure.

On the basis of manufacturing information submitted to the FDA in December 2022, the agency extended the date for a decision on approval by 3 months, to May 19, 2023, according to a statement from Krystal Biotech, the developer of B-VEC and the sponsor of the NEJM study.

Dr. Marinkovich and his colleagues conducted the double-blind, randomized, controlled GEM-3 trial of B-VEC at three sites in the United States. The 31 study participants ranged in age from 1 to 44 years (median age, 16 years) and had genetically confirmed DEB (30 with the recessive form and 1 with the dominant form).

For each participant, a pair of wounds was chosen that were matched in size, region, and appearance. The wounds within each pair were randomly allocated to receive weekly applications of either B-VEC or placebo gel for 26 weeks.

The results of the study included the following:

• Complete healing at 6 months occurred in 67% of the wounds treated with B-VEC (including a wound in the patient with dominant DEB), vs. 22% of those who received placebo (95% confidence interval [CI], 24-68; P = .002).
• Complete healing at 3 months occurred in 71% of the wounds treated with B-VEC, vs. 20% of those who received placebo (95% CI, 29-73; P < .001).
• The mean change from baseline to week 22 in pain severity during wound-dressing changes for patients aged 6 years and older, as determined on the basis of a visual analogue scale, was –0.88 with B-VEC, vs. –0.71 with placebo (adjusted least-squares mean difference, –0.61; 95% CI, –1.10 to –0.13); similar mean changes were seen at weeks 24 and 26.
• Among all patients, 58% had at least one adverse event. Most adverse events were mild or moderate. The most common were pruritus, chills, and squamous cell carcinoma (SCC), which were reported in three patients each (SCC cases occurred at wound sites that had not been exposed to B-VEC or placebo). Serious adverse events, which were unrelated to the treatment, occurred in three patients: diarrhea, anemia, cellulitis, and a positive blood culture related to a hemodialysis catheter.

“With the ability to treat patients with topical gene therapy, dermatology is entering a new age of treatment possibilities,” Dr. Marinkovich said in the interview.

The researchers were surprised that the redosable in vivo gene therapy worked so well, he added. In vivo gene therapy has been plagued by the occurrence of immune reactions against the viral vectors used, Dr. Marinkovich explained. But because the herpes simplex virus has evolved to evade the immune system, his team could use the viral vector every week for 6 months without inflammatory reactions.

“The immune system’s inability to fight off or get rid of the herpes simplex vector makes it bad as a disease, but as a gene therapy vector, it provides a huge advantage,” he added.

Asked to comment on the results, Christen Ebens, MD, MPH, assistant professor in the department of pediatrics at the University of Minnesota, Minneapolis, whose clinical and research interests include EB, called the results exciting for patients, families, and doctors.

“Side effects were minimal, and importantly, use of the replication-incompetent HSV vector means that the payload gene does not integrate into the patient’s DNA,” Dr. Ebens, who was not involved in the study, said in an interview. “B-VEC is not a lifelong cure but potentially an effective maintenance therapy requiring repeated doses,” she added.

Although the researchers found no clinically important immune reactions to B-VEC, Dr. Ebens said she would like to see results from longer studies of the treatment. “We will want to see that patients do not produce neutralizing antibodies against B-VEC or its components, as such antibodies may yield the treatment ineffective or cause significant side effects.”

In an interview, Vanessa R. Holland, MD, associate clinical professor in the division of dermatology at UCLA Health, Burbank, Calif., who was not involved in the study, said that “topical replication-defective HSV-1 is a brilliant vector to deliver the depleted collagen.” She added that “such a vehicle may significantly alter management of these disorders and improve or extend lives by minimizing potentially fatal complications.”

Paras P. Vakharia, MD, PharmD, assistant professor of dermatology at Northwestern University, Chicago, who was not involved in the study, was surprised by the high percentage of healed wounds and wounds that remained healed over time.

B-VEC for treating other conditions

Dr. Marinkovich noted that an ongoing phase 1 clinical trial, also sponsored by Krystal Biotech, is using the HSV-1 vector to deliver a different biologic (KB105) to establish dose and safety in the treatment of ichthyosis. He added that he would like to explore the use of B-VEC to treat DEB at mucosal surfaces, including inside the mouth, the eye, and the esophagus.

Authors of two editorials that accompanied the study also referred to other conditions B-VEC might treat.

This study “highlights potential future investigations,” David V. Schaffer, PhD, professor of chemical and biomolecular engineering, bioengineering, and molecular and cell biology at the University of California, Berkeley, wrotes in one of the editorials.

Important considerations he mentioned include the likelihood of the treatment becoming lifelong; the inability of HSV to penetrate intact skin, making B-VEC unsuitable for preventing the development of new wounds; and the inability of this treatment to treat EB lesions along the digestive tract. “This important trial builds on and extends gene-therapy successes to new targets and vectors, an advance for patients,” he added.

In the second editorial, Aimee S. Payne, MD, PhD, professor of dermatology at the University of Pennsylvania, Philadelphia, raised the question of whether B-VEC’s clinical success for treating DEB can translate to other genetic diseases.

“Formulations for ophthalmic, oral-gastrointestinal, or respiratory delivery would be of great value to address the extracutaneous manifestations of epidermolysis bullosa and other genetic diseases,” she wrote.

Referring to an ongoing trial of a topical gene therapy for cystic fibrosis that is delivered by a nebulizer, Dr. Payne noted, “Ultimately, the completion of clinical trials such as this one will be required to determine whether HSV-1–mediated gene delivery can go more than skin deep.”

Earlier data and more details of the study were presented in a poster at the annual meeting of the Society for Pediatric Dermatology in July 2022.

Dr. Marinkovich has disclosed no relevant financial relationships. Several coauthors are employees of or have other financial relationships with Krystal Biotech, the study’s sponsor and the developer of beremagene geperpavec. Dr. Schaffer and Dr. Payne have financial relationships with the pharmaceutical industry. Dr. Ebens, Dr. Holland, and Dr. Vakharia have disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

A restrictive fluid strategy had no significant impact on mortality in patients with sepsis-induced hypotension compared to the typical liberal fluid strategy, based on data from 1,563 individuals.

Intravenous fluids are standard in the early resuscitation of sepsis patients, as are vasopressor agents, but data comparing restrictive or liberal use in these patients are limited, wrote Nathan I. Shapiro, MD, of Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, and colleagues.

In a study published in the New England Journal of Medicine the researchers randomized 782 patients to the restrictive fluid group and 781 to the liberal fluid group. Patients aged 18 years and older were enrolled between March 7, 2018, and Jan. 31, 2022, at 60 centers in the United States. Participants were randomized within 4 hours of meeting the criteria for sepsis-induced hypotension that was refractory to initial treatment with 1-3 L of intravenous fluid. Baseline characteristics were similar between the groups. At randomization, 21% of patients in the restrictive fluid group and 18% in the liberal fluid group received vasopressors.

The primary outcome was 90-day all-cause mortality, which occurred in 109 and 116 patients in the liberal and restricted groups, respectively (approximately 14% of each group). No significant differences were noted among subgroups based on factors including systolic blood pressure and the use of vasopressors at randomization, chronic heart failure, end-stage renal disease, and pneumonia.

The restrictive fluid protocol called for vasopressors as the primary treatment for sepsis-induced hypotension, with “rescue fluids” to be used for prespecified situations of severe intravascular volume depletion. The liberal fluid protocol was a recommended initial intravenous infusion of 2,000 mL of isotonic crystalloid, followed by fluid boluses given based on clinical triggers such as tachycardia, along with “rescue vasopressors,” the researchers wrote.

The median volume of fluid administered in the first 24-hour period after randomization was 1,267 mL in the restrictive group and 3,400 mL in the liberal group. Adherence to the treatment protocols was greater than 90% for both groups.

The current study is distinct in its enrollment of patients with primary presentations of sepsis to a hospital emergency department, the researchers wrote in their discussion. “The patients who were enrolled in this trial were representative of the types of patients who present to the hospital with sepsis-induced hypotension; we expect our findings to be generalizable to these types of patients,” they said.

Reported serious adverse events were similar between the groups, though fewer episodes of fluid overload and pulmonary edema occurred in the restricted group.

The findings were limited by several factors including some cases in which patients in the restrictive group received more fluid than called for by the protocol, the researchers noted. Other limitations included the lack of subgroups with different coexisting conditions, the lack of blinding, and the lack of a control with no instructions for treatment protocol, they said. However, the results suggest that a restrictive fluid strategy had no significant advantage over a liberal strategy in terms of mortality for patients with sepsis-induced hypotension, they concluded.

The study was supported by the National Heart, Lung, and Blood Institute. Dr. Shapiro disclosed serving as a consultant for and having stock options in Diagnostic Robotics, as well as grant support from Inflammatrix and Rapid Pathogen Screening, and serving as a consultant for Prenosis.

A restrictive fluid strategy had no significant impact on mortality in patients with sepsis-induced hypotension compared to the typical liberal fluid strategy, based on data from 1,563 individuals.

Intravenous fluids are standard in the early resuscitation of sepsis patients, as are vasopressor agents, but data comparing restrictive or liberal use in these patients are limited, wrote Nathan I. Shapiro, MD, of Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, and colleagues.

In a study published in the New England Journal of Medicine the researchers randomized 782 patients to the restrictive fluid group and 781 to the liberal fluid group. Patients aged 18 years and older were enrolled between March 7, 2018, and Jan. 31, 2022, at 60 centers in the United States. Participants were randomized within 4 hours of meeting the criteria for sepsis-induced hypotension that was refractory to initial treatment with 1-3 L of intravenous fluid. Baseline characteristics were similar between the groups. At randomization, 21% of patients in the restrictive fluid group and 18% in the liberal fluid group received vasopressors.

The primary outcome was 90-day all-cause mortality, which occurred in 109 and 116 patients in the liberal and restricted groups, respectively (approximately 14% of each group). No significant differences were noted among subgroups based on factors including systolic blood pressure and the use of vasopressors at randomization, chronic heart failure, end-stage renal disease, and pneumonia.

The restrictive fluid protocol called for vasopressors as the primary treatment for sepsis-induced hypotension, with “rescue fluids” to be used for prespecified situations of severe intravascular volume depletion. The liberal fluid protocol was a recommended initial intravenous infusion of 2,000 mL of isotonic crystalloid, followed by fluid boluses given based on clinical triggers such as tachycardia, along with “rescue vasopressors,” the researchers wrote.

The median volume of fluid administered in the first 24-hour period after randomization was 1,267 mL in the restrictive group and 3,400 mL in the liberal group. Adherence to the treatment protocols was greater than 90% for both groups.

The current study is distinct in its enrollment of patients with primary presentations of sepsis to a hospital emergency department, the researchers wrote in their discussion. “The patients who were enrolled in this trial were representative of the types of patients who present to the hospital with sepsis-induced hypotension; we expect our findings to be generalizable to these types of patients,” they said.

Reported serious adverse events were similar between the groups, though fewer episodes of fluid overload and pulmonary edema occurred in the restricted group.

The findings were limited by several factors including some cases in which patients in the restrictive group received more fluid than called for by the protocol, the researchers noted. Other limitations included the lack of subgroups with different coexisting conditions, the lack of blinding, and the lack of a control with no instructions for treatment protocol, they said. However, the results suggest that a restrictive fluid strategy had no significant advantage over a liberal strategy in terms of mortality for patients with sepsis-induced hypotension, they concluded.

The study was supported by the National Heart, Lung, and Blood Institute. Dr. Shapiro disclosed serving as a consultant for and having stock options in Diagnostic Robotics, as well as grant support from Inflammatrix and Rapid Pathogen Screening, and serving as a consultant for Prenosis.

A restrictive fluid strategy had no significant impact on mortality in patients with sepsis-induced hypotension compared to the typical liberal fluid strategy, based on data from 1,563 individuals.

Intravenous fluids are standard in the early resuscitation of sepsis patients, as are vasopressor agents, but data comparing restrictive or liberal use in these patients are limited, wrote Nathan I. Shapiro, MD, of Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, and colleagues.

In a study published in the New England Journal of Medicine the researchers randomized 782 patients to the restrictive fluid group and 781 to the liberal fluid group. Patients aged 18 years and older were enrolled between March 7, 2018, and Jan. 31, 2022, at 60 centers in the United States. Participants were randomized within 4 hours of meeting the criteria for sepsis-induced hypotension that was refractory to initial treatment with 1-3 L of intravenous fluid. Baseline characteristics were similar between the groups. At randomization, 21% of patients in the restrictive fluid group and 18% in the liberal fluid group received vasopressors.

The primary outcome was 90-day all-cause mortality, which occurred in 109 and 116 patients in the liberal and restricted groups, respectively (approximately 14% of each group). No significant differences were noted among subgroups based on factors including systolic blood pressure and the use of vasopressors at randomization, chronic heart failure, end-stage renal disease, and pneumonia.

The restrictive fluid protocol called for vasopressors as the primary treatment for sepsis-induced hypotension, with “rescue fluids” to be used for prespecified situations of severe intravascular volume depletion. The liberal fluid protocol was a recommended initial intravenous infusion of 2,000 mL of isotonic crystalloid, followed by fluid boluses given based on clinical triggers such as tachycardia, along with “rescue vasopressors,” the researchers wrote.

The median volume of fluid administered in the first 24-hour period after randomization was 1,267 mL in the restrictive group and 3,400 mL in the liberal group. Adherence to the treatment protocols was greater than 90% for both groups.

The current study is distinct in its enrollment of patients with primary presentations of sepsis to a hospital emergency department, the researchers wrote in their discussion. “The patients who were enrolled in this trial were representative of the types of patients who present to the hospital with sepsis-induced hypotension; we expect our findings to be generalizable to these types of patients,” they said.

Reported serious adverse events were similar between the groups, though fewer episodes of fluid overload and pulmonary edema occurred in the restricted group.

The findings were limited by several factors including some cases in which patients in the restrictive group received more fluid than called for by the protocol, the researchers noted. Other limitations included the lack of subgroups with different coexisting conditions, the lack of blinding, and the lack of a control with no instructions for treatment protocol, they said. However, the results suggest that a restrictive fluid strategy had no significant advantage over a liberal strategy in terms of mortality for patients with sepsis-induced hypotension, they concluded.

The study was supported by the National Heart, Lung, and Blood Institute. Dr. Shapiro disclosed serving as a consultant for and having stock options in Diagnostic Robotics, as well as grant support from Inflammatrix and Rapid Pathogen Screening, and serving as a consultant for Prenosis.

Sleep disturbances are consistently high throughout the course of psychosis, with later stages associated with distinctive brain wave activity during sleep, a new review and meta-analysis shows.

For example, compared with their healthy peers, participants in a chronic psychosis stage had reduced density, amplitude, and duration of spindles – or bursts of brainwave activity during sleep identified by electroencephalography.

“The results suggest sleep could be an important target [and] an area of research and clinical intervention that could make a difference” in the lives of patients at risk for psychosis, study investigator Fabio Ferrarelli, MD, PhD, associate professor of psychiatry and director of the Sleep and Schizophrenia Program, University of Pittsburgh School of Medicine, told this news organization.

University of Pittsburgh

‘Window of opportunity’

Researchers separate psychosis into stages. During the “clinically high-risk for psychosis” (CHR-P) stage, patients have milder symptoms but do not have a diagnosable psychotic disorder. Those in the early psychosis (EP) stage have had a first episode of psychosis. When they reach a cut-off, often at 5 years, they are considered to have chronic psychosis (CP).

Previous studies have shown that altered sleep often precedes a psychotic episode in early psychosis, and disrupted sleep contributes to predicting transition to psychosis in youth at risk for the condition. Individuals with CP commonly report sleep disturbances, such as insomnia.

Following a literature search, the investigators for this current meta-analysis selected 21 studies assessing sleep disturbance prevalence in 5,135 patients. They also selected 39 studies measuring sleep alterations subjectively (for example, sleep quality) and/or objectively (for example, sleep architecture and sleep oscillation) in 1,575 patients and 977 healthy controls.

The included studies measured the prevalence of sleep disturbances and/or sleep characteristics at different psychosis stages using polysomnography, EEG, actigraphy, or self-reports.

The pooled prevalence of sleep disturbances was 50% across clinical stages (95% confidence interval, 40%-61%). The prevalence was 54% in CHR-P, 68% in EP, and 44% in CP.

The prevalence of insomnia as the primary sleep disturbance was 34% of pooled cases, 48% of the EP group, and 27% of the CP group.

“What’s interesting is the rate of sleep disturbances is relatively stable across stages,” said Dr. Ferrarelli. “This is important because you have a window of opportunity to do some early intervention in people who are at risk that can prevent things from getting worse.”

He suggests clinicians screen for insomnia in early-course patients and perhaps recommend cognitive behavioral therapy (CBT) for insomnia. As well, they should promote sleep hygiene measures for at-risk patients, including such things as avoiding caffeine, alcohol, and screen time before bedtime and adopting a regular sleep pattern.

“These are people at risk, which means they have a 20%-30% chance of eventually developing a psychotic disorder,” said Dr. Ferrarelli. “Maybe disrupted sleep is one of the factors that can make a difference.”
 

Altered sleep architecture

To compare sleep quality between clinical and control groups, studies used total scores on the Pittsburgh Sleep Quality Index (PSQI), where a score over 5 indicates a sleep problem.

There was a significant standardized mean difference in pooled cases versus controls (SMD, 1.0; 95% CI, 0.7-1.3; P < .001). Each clinical group showed poorer sleep quality, compared with controls.

When assessing sleep architecture abnormalities, stage-specific case-control comparisons showed these were driven by EP and CP stages.

Altered sleep characteristics in both these stages included increased sleep onset latency, increased wake after sleep onset, and reduced sleep efficiency.

Compared with controls, CP was the only clinical group with more arousals. Patients with CP also had more arousals than the CHR-P group, and the number of arousals was significantly affected by medication.

The findings indicate the effects of antipsychotic medications on sleep should be closely monitored, especially in CP, the investigators write.

They add that clinicians should consider medication adjustments, such as decreased doses or switches to another compound.
 

‘Robust’ spindle results

As for spindle parameters, pooled cases showed significantly decreased spindle density (SMD, –1.06), spindle amplitude (SMD, –1.08), and spindle duration (SMD, −1.21), compared with controls. Stage-specific comparisons revealed these deficits were present in both EP and CP relative to controls.

Dr. Ferrarelli noted the results for spindle abnormalities were among “the most robust” and show that these abnormalities “tend to get worse over the course of the illness.”

The spindle data are “a lot more informative” than that provided by other sleep parameters “in the sense they can yield what could be wrong, where it could be, and potentially what you can do about it,” said Dr. Ferrarelli.

“This might be an objective measure that could be used to identify individuals who have a psychosis disorder, monitor progression of illness, and for prognostic reasons,” he added.

He noted that spindles may also represent a promising target for treatment interventions and added that non-invasive transcranial magnetic stimulation has shown promise in restoring sleep oscillations, including spindles.

Another way to evoke target-brain activity may be through auditory tones – with a patient listening to a particular sound through headphones while asleep, Dr. Ferrarelli said.
 

Reaffirms previous data

Commenting on the study, Jeffrey A. Lieberman, MD, professor and chair in psychiatry at Columbia University, New York, and a past president of the American Psychiatric Association, noted that the review “just reaffirms what has been reported by individual studies for decades.”

That so many at-risk study subjects had a sleep abnormality is not surprising, said Dr. Lieberman, who was not involved with the current research.

“How many individuals in late adolescence or early adulthood have sleep problems?” he asked. “I would venture to say it’s probably a lot. So the question is: How distinctive is this from what occurs in people who don’t develop the illness?”

The aim of sleep research in the area of schizophrenia has long been to disentangle the effects of medication and environmental factors from the disease and to be able to treat patients to normalize their sleep, said Dr. Lieberman.

“But it’s not clear from these results how one would do that,” he added.

The authors “don’t fundamentally tell us anything about the underlying cause of the illness or the pathophysiology, and they don’t really offer any kind of clear direction for clinical intervention,” he said.

The study was supported by the National Institute of Mental Health. Dr. Ferrarelli reported grants from the National Institute of Mental Health during the conduct of the study. Dr. Lieberman has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Sleep disturbances are consistently high throughout the course of psychosis, with later stages associated with distinctive brain wave activity during sleep, a new review and meta-analysis shows.

For example, compared with their healthy peers, participants in a chronic psychosis stage had reduced density, amplitude, and duration of spindles – or bursts of brainwave activity during sleep identified by electroencephalography.

“The results suggest sleep could be an important target [and] an area of research and clinical intervention that could make a difference” in the lives of patients at risk for psychosis, study investigator Fabio Ferrarelli, MD, PhD, associate professor of psychiatry and director of the Sleep and Schizophrenia Program, University of Pittsburgh School of Medicine, told this news organization.

University of Pittsburgh

‘Window of opportunity’

Researchers separate psychosis into stages. During the “clinically high-risk for psychosis” (CHR-P) stage, patients have milder symptoms but do not have a diagnosable psychotic disorder. Those in the early psychosis (EP) stage have had a first episode of psychosis. When they reach a cut-off, often at 5 years, they are considered to have chronic psychosis (CP).

Previous studies have shown that altered sleep often precedes a psychotic episode in early psychosis, and disrupted sleep contributes to predicting transition to psychosis in youth at risk for the condition. Individuals with CP commonly report sleep disturbances, such as insomnia.

Following a literature search, the investigators for this current meta-analysis selected 21 studies assessing sleep disturbance prevalence in 5,135 patients. They also selected 39 studies measuring sleep alterations subjectively (for example, sleep quality) and/or objectively (for example, sleep architecture and sleep oscillation) in 1,575 patients and 977 healthy controls.

The included studies measured the prevalence of sleep disturbances and/or sleep characteristics at different psychosis stages using polysomnography, EEG, actigraphy, or self-reports.

The pooled prevalence of sleep disturbances was 50% across clinical stages (95% confidence interval, 40%-61%). The prevalence was 54% in CHR-P, 68% in EP, and 44% in CP.

The prevalence of insomnia as the primary sleep disturbance was 34% of pooled cases, 48% of the EP group, and 27% of the CP group.

“What’s interesting is the rate of sleep disturbances is relatively stable across stages,” said Dr. Ferrarelli. “This is important because you have a window of opportunity to do some early intervention in people who are at risk that can prevent things from getting worse.”

He suggests clinicians screen for insomnia in early-course patients and perhaps recommend cognitive behavioral therapy (CBT) for insomnia. As well, they should promote sleep hygiene measures for at-risk patients, including such things as avoiding caffeine, alcohol, and screen time before bedtime and adopting a regular sleep pattern.

“These are people at risk, which means they have a 20%-30% chance of eventually developing a psychotic disorder,” said Dr. Ferrarelli. “Maybe disrupted sleep is one of the factors that can make a difference.”
 

Altered sleep architecture

To compare sleep quality between clinical and control groups, studies used total scores on the Pittsburgh Sleep Quality Index (PSQI), where a score over 5 indicates a sleep problem.

There was a significant standardized mean difference in pooled cases versus controls (SMD, 1.0; 95% CI, 0.7-1.3; P < .001). Each clinical group showed poorer sleep quality, compared with controls.

When assessing sleep architecture abnormalities, stage-specific case-control comparisons showed these were driven by EP and CP stages.

Altered sleep characteristics in both these stages included increased sleep onset latency, increased wake after sleep onset, and reduced sleep efficiency.

Compared with controls, CP was the only clinical group with more arousals. Patients with CP also had more arousals than the CHR-P group, and the number of arousals was significantly affected by medication.

The findings indicate the effects of antipsychotic medications on sleep should be closely monitored, especially in CP, the investigators write.

They add that clinicians should consider medication adjustments, such as decreased doses or switches to another compound.
 

‘Robust’ spindle results

As for spindle parameters, pooled cases showed significantly decreased spindle density (SMD, –1.06), spindle amplitude (SMD, –1.08), and spindle duration (SMD, −1.21), compared with controls. Stage-specific comparisons revealed these deficits were present in both EP and CP relative to controls.

Dr. Ferrarelli noted the results for spindle abnormalities were among “the most robust” and show that these abnormalities “tend to get worse over the course of the illness.”

The spindle data are “a lot more informative” than that provided by other sleep parameters “in the sense they can yield what could be wrong, where it could be, and potentially what you can do about it,” said Dr. Ferrarelli.

“This might be an objective measure that could be used to identify individuals who have a psychosis disorder, monitor progression of illness, and for prognostic reasons,” he added.

He noted that spindles may also represent a promising target for treatment interventions and added that non-invasive transcranial magnetic stimulation has shown promise in restoring sleep oscillations, including spindles.

Another way to evoke target-brain activity may be through auditory tones – with a patient listening to a particular sound through headphones while asleep, Dr. Ferrarelli said.
 

Reaffirms previous data

Commenting on the study, Jeffrey A. Lieberman, MD, professor and chair in psychiatry at Columbia University, New York, and a past president of the American Psychiatric Association, noted that the review “just reaffirms what has been reported by individual studies for decades.”

That so many at-risk study subjects had a sleep abnormality is not surprising, said Dr. Lieberman, who was not involved with the current research.

“How many individuals in late adolescence or early adulthood have sleep problems?” he asked. “I would venture to say it’s probably a lot. So the question is: How distinctive is this from what occurs in people who don’t develop the illness?”

The aim of sleep research in the area of schizophrenia has long been to disentangle the effects of medication and environmental factors from the disease and to be able to treat patients to normalize their sleep, said Dr. Lieberman.

“But it’s not clear from these results how one would do that,” he added.

The authors “don’t fundamentally tell us anything about the underlying cause of the illness or the pathophysiology, and they don’t really offer any kind of clear direction for clinical intervention,” he said.

The study was supported by the National Institute of Mental Health. Dr. Ferrarelli reported grants from the National Institute of Mental Health during the conduct of the study. Dr. Lieberman has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Sleep disturbances are consistently high throughout the course of psychosis, with later stages associated with distinctive brain wave activity during sleep, a new review and meta-analysis shows.

For example, compared with their healthy peers, participants in a chronic psychosis stage had reduced density, amplitude, and duration of spindles – or bursts of brainwave activity during sleep identified by electroencephalography.

“The results suggest sleep could be an important target [and] an area of research and clinical intervention that could make a difference” in the lives of patients at risk for psychosis, study investigator Fabio Ferrarelli, MD, PhD, associate professor of psychiatry and director of the Sleep and Schizophrenia Program, University of Pittsburgh School of Medicine, told this news organization.

University of Pittsburgh

‘Window of opportunity’

Researchers separate psychosis into stages. During the “clinically high-risk for psychosis” (CHR-P) stage, patients have milder symptoms but do not have a diagnosable psychotic disorder. Those in the early psychosis (EP) stage have had a first episode of psychosis. When they reach a cut-off, often at 5 years, they are considered to have chronic psychosis (CP).

Previous studies have shown that altered sleep often precedes a psychotic episode in early psychosis, and disrupted sleep contributes to predicting transition to psychosis in youth at risk for the condition. Individuals with CP commonly report sleep disturbances, such as insomnia.

Following a literature search, the investigators for this current meta-analysis selected 21 studies assessing sleep disturbance prevalence in 5,135 patients. They also selected 39 studies measuring sleep alterations subjectively (for example, sleep quality) and/or objectively (for example, sleep architecture and sleep oscillation) in 1,575 patients and 977 healthy controls.

The included studies measured the prevalence of sleep disturbances and/or sleep characteristics at different psychosis stages using polysomnography, EEG, actigraphy, or self-reports.

The pooled prevalence of sleep disturbances was 50% across clinical stages (95% confidence interval, 40%-61%). The prevalence was 54% in CHR-P, 68% in EP, and 44% in CP.

The prevalence of insomnia as the primary sleep disturbance was 34% of pooled cases, 48% of the EP group, and 27% of the CP group.

“What’s interesting is the rate of sleep disturbances is relatively stable across stages,” said Dr. Ferrarelli. “This is important because you have a window of opportunity to do some early intervention in people who are at risk that can prevent things from getting worse.”

He suggests clinicians screen for insomnia in early-course patients and perhaps recommend cognitive behavioral therapy (CBT) for insomnia. As well, they should promote sleep hygiene measures for at-risk patients, including such things as avoiding caffeine, alcohol, and screen time before bedtime and adopting a regular sleep pattern.

“These are people at risk, which means they have a 20%-30% chance of eventually developing a psychotic disorder,” said Dr. Ferrarelli. “Maybe disrupted sleep is one of the factors that can make a difference.”
 

Altered sleep architecture

To compare sleep quality between clinical and control groups, studies used total scores on the Pittsburgh Sleep Quality Index (PSQI), where a score over 5 indicates a sleep problem.

There was a significant standardized mean difference in pooled cases versus controls (SMD, 1.0; 95% CI, 0.7-1.3; P < .001). Each clinical group showed poorer sleep quality, compared with controls.

When assessing sleep architecture abnormalities, stage-specific case-control comparisons showed these were driven by EP and CP stages.

Altered sleep characteristics in both these stages included increased sleep onset latency, increased wake after sleep onset, and reduced sleep efficiency.

Compared with controls, CP was the only clinical group with more arousals. Patients with CP also had more arousals than the CHR-P group, and the number of arousals was significantly affected by medication.

The findings indicate the effects of antipsychotic medications on sleep should be closely monitored, especially in CP, the investigators write.

They add that clinicians should consider medication adjustments, such as decreased doses or switches to another compound.
 

‘Robust’ spindle results

As for spindle parameters, pooled cases showed significantly decreased spindle density (SMD, –1.06), spindle amplitude (SMD, –1.08), and spindle duration (SMD, −1.21), compared with controls. Stage-specific comparisons revealed these deficits were present in both EP and CP relative to controls.

Dr. Ferrarelli noted the results for spindle abnormalities were among “the most robust” and show that these abnormalities “tend to get worse over the course of the illness.”

The spindle data are “a lot more informative” than that provided by other sleep parameters “in the sense they can yield what could be wrong, where it could be, and potentially what you can do about it,” said Dr. Ferrarelli.

“This might be an objective measure that could be used to identify individuals who have a psychosis disorder, monitor progression of illness, and for prognostic reasons,” he added.

He noted that spindles may also represent a promising target for treatment interventions and added that non-invasive transcranial magnetic stimulation has shown promise in restoring sleep oscillations, including spindles.

Another way to evoke target-brain activity may be through auditory tones – with a patient listening to a particular sound through headphones while asleep, Dr. Ferrarelli said.
 

Reaffirms previous data

Commenting on the study, Jeffrey A. Lieberman, MD, professor and chair in psychiatry at Columbia University, New York, and a past president of the American Psychiatric Association, noted that the review “just reaffirms what has been reported by individual studies for decades.”

That so many at-risk study subjects had a sleep abnormality is not surprising, said Dr. Lieberman, who was not involved with the current research.

“How many individuals in late adolescence or early adulthood have sleep problems?” he asked. “I would venture to say it’s probably a lot. So the question is: How distinctive is this from what occurs in people who don’t develop the illness?”

The aim of sleep research in the area of schizophrenia has long been to disentangle the effects of medication and environmental factors from the disease and to be able to treat patients to normalize their sleep, said Dr. Lieberman.

“But it’s not clear from these results how one would do that,” he added.

The authors “don’t fundamentally tell us anything about the underlying cause of the illness or the pathophysiology, and they don’t really offer any kind of clear direction for clinical intervention,” he said.

The study was supported by the National Institute of Mental Health. Dr. Ferrarelli reported grants from the National Institute of Mental Health during the conduct of the study. Dr. Lieberman has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration approved elacestrant (Orserdu, Stemline Therapeutics) for postmenopausal women or men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer that progressed on at least one line of endocrine therapy.

The agency also approved the Guardant360 CDx assay as a companion diagnostic to identify breast cancer patients who meet the treatment requirements, according to the agency’s press release announcing the approval.

The novel oral selective estrogen receptor degrader was approved based on the phase 3 EMERALD trial, which included 478 postmenopausal women and men with ER-positive, HER2-negative advanced or metastatic breast cancer, about half of whom had ESR1 mutations. Patients had progressed on one or two prior lines of endocrine therapy, including one containing a CDK4/6 inhibitor. Participants could also have had one prior line of chemotherapy in the advanced or metastatic setting.

Participants were randomized 1:1 to either elacestrant 345 mg orally once daily or investigator’s choice of endocrine therapy, which included fulvestrant or an aromatase inhibitor.

In the 228 patients (48%) with ESR1 mutations, median progression-free survival (PFS) was 3.8 months with elacestrant versus 1.9 months in the fulvestrant or aromatase inhibitor arm (hazard ratio, 0.55; P = .0005). Investigators observed no statistically significant PFS difference between the treatment arms in patients who didn’t have the mutation.
 

Fair comparison?

In June, experts raised concerns about the adequacy of the “standard of care” control arm in EMERALD, particularly that single agents were used at a time when combination therapy is becoming more common.

“The expression ‘standard of care’ is applied generously, as the control arm is restricted” to single agents and no combinations, which “may have led to a substandard” comparison group, Timothée Olivier, MD, Geneva University Hospital, and Vinay Prasad, MD, MPH, University of California, San Francisco, said in an editorial quoted in the piece.

EMERALD investigators acknowledged that there were issues with the control group, noting that in the “United States and Europe, combination therapy with fulvestrant” – instead of single agents – “is increasingly being used as the second-line [standard of care] treatment.”

However, the goal of the study “was to compare a novel endocrine therapy vs. currently available endocrine therapies,” not combination regimens, the investigators said.

Also, “the benefit of elacestrant over fulvestrant and AIs [aromatase inhibitors] in our monotherapy trial ... suggests that incorporating elacestrant as the preferred endocrine therapy backbone in future earlier-line combination studies is a promising strategy.”
 

Lipid monitoring necessary

The most common adverse events with elacestrant, occurring in 10% or more of patients, are musculoskeletal pain, nausea, increased cholesterol, increased AST, increased triglycerides, fatigue, decreased hemoglobin, vomiting, increased ALT, decreased sodium, increased creatinine, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flush, and dyspepsia, according to labeling.

Labeling warns that elacestrant “may cause hypercholesterolemia and hypertriglyceridemia. Monitor lipid profile prior to starting treatment and periodically thereafter.”

The recommended elacestrant dose is the trial dose, 345 mg orally with food once daily until disease progression or unacceptable toxicity.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration approved elacestrant (Orserdu, Stemline Therapeutics) for postmenopausal women or men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer that progressed on at least one line of endocrine therapy.

The agency also approved the Guardant360 CDx assay as a companion diagnostic to identify breast cancer patients who meet the treatment requirements, according to the agency’s press release announcing the approval.

The novel oral selective estrogen receptor degrader was approved based on the phase 3 EMERALD trial, which included 478 postmenopausal women and men with ER-positive, HER2-negative advanced or metastatic breast cancer, about half of whom had ESR1 mutations. Patients had progressed on one or two prior lines of endocrine therapy, including one containing a CDK4/6 inhibitor. Participants could also have had one prior line of chemotherapy in the advanced or metastatic setting.

Participants were randomized 1:1 to either elacestrant 345 mg orally once daily or investigator’s choice of endocrine therapy, which included fulvestrant or an aromatase inhibitor.

In the 228 patients (48%) with ESR1 mutations, median progression-free survival (PFS) was 3.8 months with elacestrant versus 1.9 months in the fulvestrant or aromatase inhibitor arm (hazard ratio, 0.55; P = .0005). Investigators observed no statistically significant PFS difference between the treatment arms in patients who didn’t have the mutation.
 

Fair comparison?

In June, experts raised concerns about the adequacy of the “standard of care” control arm in EMERALD, particularly that single agents were used at a time when combination therapy is becoming more common.

“The expression ‘standard of care’ is applied generously, as the control arm is restricted” to single agents and no combinations, which “may have led to a substandard” comparison group, Timothée Olivier, MD, Geneva University Hospital, and Vinay Prasad, MD, MPH, University of California, San Francisco, said in an editorial quoted in the piece.

EMERALD investigators acknowledged that there were issues with the control group, noting that in the “United States and Europe, combination therapy with fulvestrant” – instead of single agents – “is increasingly being used as the second-line [standard of care] treatment.”

However, the goal of the study “was to compare a novel endocrine therapy vs. currently available endocrine therapies,” not combination regimens, the investigators said.

Also, “the benefit of elacestrant over fulvestrant and AIs [aromatase inhibitors] in our monotherapy trial ... suggests that incorporating elacestrant as the preferred endocrine therapy backbone in future earlier-line combination studies is a promising strategy.”
 

Lipid monitoring necessary

The most common adverse events with elacestrant, occurring in 10% or more of patients, are musculoskeletal pain, nausea, increased cholesterol, increased AST, increased triglycerides, fatigue, decreased hemoglobin, vomiting, increased ALT, decreased sodium, increased creatinine, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flush, and dyspepsia, according to labeling.

Labeling warns that elacestrant “may cause hypercholesterolemia and hypertriglyceridemia. Monitor lipid profile prior to starting treatment and periodically thereafter.”

The recommended elacestrant dose is the trial dose, 345 mg orally with food once daily until disease progression or unacceptable toxicity.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration approved elacestrant (Orserdu, Stemline Therapeutics) for postmenopausal women or men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer that progressed on at least one line of endocrine therapy.

The agency also approved the Guardant360 CDx assay as a companion diagnostic to identify breast cancer patients who meet the treatment requirements, according to the agency’s press release announcing the approval.

The novel oral selective estrogen receptor degrader was approved based on the phase 3 EMERALD trial, which included 478 postmenopausal women and men with ER-positive, HER2-negative advanced or metastatic breast cancer, about half of whom had ESR1 mutations. Patients had progressed on one or two prior lines of endocrine therapy, including one containing a CDK4/6 inhibitor. Participants could also have had one prior line of chemotherapy in the advanced or metastatic setting.

Participants were randomized 1:1 to either elacestrant 345 mg orally once daily or investigator’s choice of endocrine therapy, which included fulvestrant or an aromatase inhibitor.

In the 228 patients (48%) with ESR1 mutations, median progression-free survival (PFS) was 3.8 months with elacestrant versus 1.9 months in the fulvestrant or aromatase inhibitor arm (hazard ratio, 0.55; P = .0005). Investigators observed no statistically significant PFS difference between the treatment arms in patients who didn’t have the mutation.
 

Fair comparison?

In June, experts raised concerns about the adequacy of the “standard of care” control arm in EMERALD, particularly that single agents were used at a time when combination therapy is becoming more common.

“The expression ‘standard of care’ is applied generously, as the control arm is restricted” to single agents and no combinations, which “may have led to a substandard” comparison group, Timothée Olivier, MD, Geneva University Hospital, and Vinay Prasad, MD, MPH, University of California, San Francisco, said in an editorial quoted in the piece.

EMERALD investigators acknowledged that there were issues with the control group, noting that in the “United States and Europe, combination therapy with fulvestrant” – instead of single agents – “is increasingly being used as the second-line [standard of care] treatment.”

However, the goal of the study “was to compare a novel endocrine therapy vs. currently available endocrine therapies,” not combination regimens, the investigators said.

Also, “the benefit of elacestrant over fulvestrant and AIs [aromatase inhibitors] in our monotherapy trial ... suggests that incorporating elacestrant as the preferred endocrine therapy backbone in future earlier-line combination studies is a promising strategy.”
 

Lipid monitoring necessary

The most common adverse events with elacestrant, occurring in 10% or more of patients, are musculoskeletal pain, nausea, increased cholesterol, increased AST, increased triglycerides, fatigue, decreased hemoglobin, vomiting, increased ALT, decreased sodium, increased creatinine, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flush, and dyspepsia, according to labeling.

Labeling warns that elacestrant “may cause hypercholesterolemia and hypertriglyceridemia. Monitor lipid profile prior to starting treatment and periodically thereafter.”

The recommended elacestrant dose is the trial dose, 345 mg orally with food once daily until disease progression or unacceptable toxicity.

A version of this article first appeared on Medscape.com.

As physicians well know, magic wands don’t exist. If they did, every patient would recover in the exam room, prior authorization wouldn’t exist, and continuing medical education credits would be printed on bearer bonds.

But in the spirit of suspended disbelief, we asked physicians and other contributors what their three wishes would be for their patients, practice/hospital, and health systems. Because, hey – we all need to dream.
 

Suzanne C. Boulter, MD, adjunct professor of pediatrics and community and family medicine, Geisel School of Medicine at Dartmouth, Hanover, N.H.
Patients: An end to gun violence.
Practice/hospital: Adequate staffing and pediatric bed availability.
Health system: Universal access to health insurance.

Sarah G. Candler, MD, MPH, care team medical director and director of academic relations, Iora Primary Care, Northside Clinic, Houston
Patients: Systems of health that start with communities of safety, including access to affordable housing, food, transportation, and health care.
Practice/hospital: I.N.T.E.R.O.P.E.R.A.B.I.L.I.T.Y.
Health system: Clinician leadership that has the power (often aka funding) to do what’s right, not just what’s right in front of us.

Arthur L. Caplan, PhD, bioethicist, New York University Langone Health
Patients: I wish for patients in the United States greater access to affordable primary care. There are still too many people without insurance or a reasonably accessible quality provider. And I especially wish for the rapid expansion of affordable training programs to meet staffing needs, including more scholarships, 3-year programs, and more new primary care–oriented schools.
Hospital: Increased staffing, especially nursing. There are too many retirements, too much burnout, and too much privatization into boutique practices to ensure the ability to provide high-quality, safe, patient-oriented care.
Health system: I wish for health systems to seriously move into electronic medicine. While billing has become electronic, there is still much to be done to supplement diagnosis, training, and standardized data collection on key metrics. Systems are not yet behaving in a manner consistent with the hype in this regard.

Stephen Devries, MD, executive director, Gaples Institute (nonprofit) and adjunct associate professor of nutrition, Harvard School of Public Health, Boston
Patients: Patients continue to demand more from their health care professionals and insist that they are offered evidence-based counseling on nutrition and lifestyle strategies.
Practice: Quality-based reimbursement for medical services will take hold that will incentivize much-needed preventive care.
Hospital: Hospitals will more fully embrace the role of serving as true centers of health and focus as much on preventive medicine as on the more lucrative areas of high-tech treatment.

Peter D. Friedmann, MD, MPH, chief research officer, Baystate Health, Springfield, Mass.
Seconded by: Elisabeth Poorman, MD, general internist, University of Washington Clinic, Kent
Patients: Don’t forget the ongoing epidemic of substance use disorder, a major cause of premature mortality. Descheduling of cannabis and expungement of cannabis-related convictions.
Practice/hospital: Commitment of hospitals and practices to address stigma and ensure delivery of medications for opioid use disorder in primary care, the emergency department, and inpatient settings.
Health system: Reform of antiquated methadone regulations to permit office-based prescription and pharmacy dispensing to treat opioid use disorder, as is the case in most of the world.

Robert Glatter, MD, emergency physician, New York
Patients: I want all patients to understand the enormous strain the health care system has been under – not just with the pandemic, the tripledemic, and mpox [previously called monkeypox], but well before the onset of these public health crises.
Hospital: The medical profession has endured not only burnout but a growing mental health crisis, staffing shortages, a physician addiction crisis, and increased attrition in the decade leading up to the pandemic. The pandemic was like a punch in the gut, occurring at the most inopportune time one could imagine.
Health system: The intersection of health and the state of our public health deserves important mention. Unless we take action to bolster our public health infrastructure, our health care system will be in jeopardy, unable to handle the next pandemic, which could be just around the corner.

William E. Golden, MD, medical director of Arkansas Medicaid, professor of medicine and public health, University of Arkansas for Medical Sciences, Little Rock
Patients: Affordable options for diabetes and obesity management.
Health system: Greater investment by health systems and third-party payers in primary care infrastructure.

Gregory A. Hood, MD, Baptist Health, Lexington, Ky.
Patients: To embrace the gift of getting out in the world, being active, and connecting with others – having put down the screens.
Health system: To be freed from the financial gamesmanship of the insurers as they continue to serve their goals of promoting their hedge fund investing over meaningful and productive partnering with primary care physicians, and that they gain insight that they are one of the main reasons they can’t find PCPs to connect with to render care in disadvantaged environments – because they made it economically impossible to do so.

Robert H. Hopkins Jr., MD, associate professor of internal medicine and pediatrics and director of the division of general internal medicine, University of Arkansas for Medical Sciences, Little Rock
Patients/Health system: I would wish for staged implementation of universal basic health coverage for all, perhaps closest to the French or Canadian model. This would need to be coupled with expanded funding for nursing education, graduate medical education, and tracing of other health-related professionals.

Harvey Hsu, MD, Banner Health, Phoenix
Patients: More clear guidelines that are simple to understand. This can apply to colonoscopy (now age 45), immunizations, blood pressure goals. I wish medications were not as expensive so patients can take the best medicine for them and not stop taking them when they hit their donut hole in coverage.
Practice: We have been functioning on a leaner basis to cut down costs. When the pandemic hit, turnover was high and we lost PAs, nurses, front-office staff, and physicians. Having adequate staffing is probably number one on many lists. One way we dealt with lack of staffing was converting in-person visits to telehealth. Video visits are paid the same as in-person visits, but if the patient could not get their video to work, then it would be a telephone visit. Now many insurances do not even pay for telephone visits. So I would wish that we could still be reimbursed for telehealth visits.
Health system: I would wish for our health system to recognize the extra work required to take care of patients while improving quality and meeting quality measures. Allowing more time for patient visits could be one way to meet those goals or having more support staff to make sure patients get their colonoscopy/mammograms done, improve their sugars, and take their medications.

Jan L. Shifren, MD, Vincent Trustees Professor, obstetrics, gynecology, and reproductive biology, Harvard Medical School, and director of the Midlife Women’s Health Center at Massachusetts General Hospital, Boston
Patients: I wish for patients to be actively involved in all aspects of their care, well informed with shared decision-making.
Practice: I wish for the enormous time demands of electronic medical records and documentation to not distract from the pleasure of caring for patients.
Health system: Patient care remains at the center of decisions and programs.

Timothy J. Joos, MD, MPH, internal medicine/pediatrics, Seattle
Health system: I wish someone could figure out how we could be reimbursed for the quality of care we provide instead of the volume of patients we see. I wish EMRs could become less complicated and more user-friendly rather than needing advanced training to use.

Peter Kovacs, MD, medical director, Kaali Institute IVF Center, Budapest
Patients: I work as an infertility specialist, so when we talk about infectious diseases and associated risks, we talk about a minimum of two (female and male partner) and ideally three (plus the pregnancy) individuals. We have learned that SARS-CoV-2 affects reproductive health. It may compromise sperm production, could delay fertility treatment, could be associated with lower success rates; and if the treatment is successful, it may harm the pregnant woman/fetus/newborn. The best preventive measure that we can offer is vaccination. One cannot overemphasize the importance of preventive measures, paying attention to personal hygiene and social distancing. Therefore, I wish those planning to become pregnant to listen to their health care provider and accept the recommended vaccines to minimize the risk of getting infected and to minimize the risk for severe disease, especially if one undergoes successful fertility treatment and achieves a long-desired pregnancy.
Practice: During the 2022 calendar year we had many days when one or more employees were out of work on sick leave. This puts extra stress on the others to allow uncompromised work in the clinic. In addition, we all have to work in a less-comfortable environment if we consider mask use every day, all day. For health care workers, vaccination is mandated but many still are affected by milder forms of coronavirus infection and other respiratory diseases. Therefore, I wish my colleagues patience toward the preventive measures to lower the individual risk for infections. As a result, hopefully we will have a less stressful 2023.
Health system: Many resources had to be delegated to dealing with acute and chronic COVID, and this was at the expense of routine daily elective and preventive medical services. I wish the health care system to return to normal daily operations, to have the personnel and financial resources to carry on with the required preventive and elective medical services to avoid long-term consequences of not being able to provide such services. It would be sad if we had to treat otherwise preventable illnesses in the upcoming years that went undiagnosed and/or were not properly managed due to limited resources as the result of the pandemic.

Alan R. Nelson, MD, internist-endocrinologist, retired
Patients: Expansion of the FDA’s authority into over-the-counter drugs, including the veracity of their advertising claims.
Practice: Make diabetes drugs available at a reasonable cost.
Health system: With the expansion of Medicaid eligibility during COVID-19 coming to a close, federal government actions are necessary for those who once again have been dropped from coverage to have their legitimate needs met.

Kevin Powell, MD, PhD, St. Louis
Patients: To be cared for and about, and not just medically, even when illness strikes and health fails.
Hospitals: To hear the thankfulness of a grateful public for the care you provide, and to hear that above the angry noise of outraged individuals who spout vitriol and focus on how they believe others have harmed them.
Health system: A truer understanding of mercy and justice.

Margaret Thew, DNP, FNP-BC, director, department of adolescent medicine, Children’s Hospital of Wisconsin, Milwaukee
Seconded by: M. Susan Jay, MD, professor of pediatrics, chief of adolescent medicine, Medical College of Wisconsin and Children’s Hospital of Wisconsin, Milwaukee
My wish for patients, hospital, and system: health, calm, and grace.

Mark P. Trolice, MD, director of Fertility CARE, the IVF Center, Winter Park, Fla.
Patients: To be proactive in their health care and be their own advocates. Question when unclear and only consult credible resources.
Practice/hospital: Improve support of physicians and all health care providers to allow more input in their practice operations and growth.
Health system: Reduce interference of the “business of medicine” and ensure that the patient experience is the priority.

Charles P. Vega, MD, University of California, Irvine
Three minutes on a routine basis for everyone in health care to reflect on our blessings and the honor and gravity – as well as joy – that are integral to health care. Three minutes that will also help us to recognize our challenges and put them in the proper context. I know 3 minutes is not meeting any standard for reflective practice. But it’s 3 minutes more than I have right now.

Karen Breach Washington, MD, medical director of WellCare of North Carolina/Centene, Charlotte
Seconded by: Lillian M. Beard, MD, physician director, Children’s Pediatricians and Associates, Silver Spring, Md.
Patients: Access to affordable health care.
Hospital: Resources to care for patients (sufficient number of beds and a healthy staff).
Health system: Equity for all.

Andrew Wilner, MD, host of the podcast “The Art of Medicine with Dr. Andrew Wilner,” www.andrewwilner.com
Let’s put patients first! Too many extraneous considerations other than the patient’s best interest obstruct optimal patient care.

Here are just a few examples of patients coming last instead of first.

• If a patient needs to start a new medication in hospital, we shouldn’t have to wait until the patient is an outpatient because “that’s when insurance will pay.”
• If there’s a new medication that’s better than the old medication, we shouldn’t be forced to choose the old medication and provide inferior care because “that’s when insurance will pay.”
• If patients need to stay in hospital, we shouldn’t be pressured to discharge them because the hospital has decided that decreasing “length of stay” is its highest priority.

Dr. Francis Peabody said it best in 1927: “The secret of the care of the patient is in caring for the patient.” How hard is that?

In 2023, why don’t we follow Dr. Peabody’s sage advice from nearly 100 years ago and see what happens?
 

James M. Wooten, PharmD, University of Missouri–Kansas City, University Health, Kansas City, Mo.
Patients: I want patients to understand and properly realize the advantage of vaccinations – not only for COVID-19 but also for influenza. There is so much misinformation that I spend a lot of time trying to convince patients to get vaccinated. Most patients don’t realize that through their lives, most of them have already been vaccinated for something just to be able to attend school. How the COVID-19 vaccine created so much stigma makes little sense to me. I also want patients to understand that COVID-19 vaccination and boosters do not always prevent infection but will many times prevent severe infection. I believe that better patient communication and education is the key and will always be the key to improving vaccination numbers. Not only communicating and educating patients on vaccination itself but also making patients realize that personal vaccination decisions may affect what happens to your neighbor. Allowing infection means that you may be more likely to infect someone else. As a society, we must take care of each other.
Health system: It will be interesting to see what happens when vaccines are no longer reimbursed by the federal government. Understanding which vaccines work best and are better tolerated will be key to choosing appropriate vaccine brands. Health care providers will need to be very selective regarding which vaccines are selected for formulary inclusion. Thorough meta-analysis studies must be done to provide more evaluable information to allow for appropriate selection. “Knowledge is power!” Appropriate knowledge will help distinguish which vaccines work best for various patient populations.

A version of this article first appeared on Medscape.com.

As physicians well know, magic wands don’t exist. If they did, every patient would recover in the exam room, prior authorization wouldn’t exist, and continuing medical education credits would be printed on bearer bonds.

But in the spirit of suspended disbelief, we asked physicians and other contributors what their three wishes would be for their patients, practice/hospital, and health systems. Because, hey – we all need to dream.
 

Suzanne C. Boulter, MD, adjunct professor of pediatrics and community and family medicine, Geisel School of Medicine at Dartmouth, Hanover, N.H.
Patients: An end to gun violence.
Practice/hospital: Adequate staffing and pediatric bed availability.
Health system: Universal access to health insurance.

Sarah G. Candler, MD, MPH, care team medical director and director of academic relations, Iora Primary Care, Northside Clinic, Houston
Patients: Systems of health that start with communities of safety, including access to affordable housing, food, transportation, and health care.
Practice/hospital: I.N.T.E.R.O.P.E.R.A.B.I.L.I.T.Y.
Health system: Clinician leadership that has the power (often aka funding) to do what’s right, not just what’s right in front of us.

Arthur L. Caplan, PhD, bioethicist, New York University Langone Health
Patients: I wish for patients in the United States greater access to affordable primary care. There are still too many people without insurance or a reasonably accessible quality provider. And I especially wish for the rapid expansion of affordable training programs to meet staffing needs, including more scholarships, 3-year programs, and more new primary care–oriented schools.
Hospital: Increased staffing, especially nursing. There are too many retirements, too much burnout, and too much privatization into boutique practices to ensure the ability to provide high-quality, safe, patient-oriented care.
Health system: I wish for health systems to seriously move into electronic medicine. While billing has become electronic, there is still much to be done to supplement diagnosis, training, and standardized data collection on key metrics. Systems are not yet behaving in a manner consistent with the hype in this regard.

Stephen Devries, MD, executive director, Gaples Institute (nonprofit) and adjunct associate professor of nutrition, Harvard School of Public Health, Boston
Patients: Patients continue to demand more from their health care professionals and insist that they are offered evidence-based counseling on nutrition and lifestyle strategies.
Practice: Quality-based reimbursement for medical services will take hold that will incentivize much-needed preventive care.
Hospital: Hospitals will more fully embrace the role of serving as true centers of health and focus as much on preventive medicine as on the more lucrative areas of high-tech treatment.

Peter D. Friedmann, MD, MPH, chief research officer, Baystate Health, Springfield, Mass.
Seconded by: Elisabeth Poorman, MD, general internist, University of Washington Clinic, Kent
Patients: Don’t forget the ongoing epidemic of substance use disorder, a major cause of premature mortality. Descheduling of cannabis and expungement of cannabis-related convictions.
Practice/hospital: Commitment of hospitals and practices to address stigma and ensure delivery of medications for opioid use disorder in primary care, the emergency department, and inpatient settings.
Health system: Reform of antiquated methadone regulations to permit office-based prescription and pharmacy dispensing to treat opioid use disorder, as is the case in most of the world.

Robert Glatter, MD, emergency physician, New York
Patients: I want all patients to understand the enormous strain the health care system has been under – not just with the pandemic, the tripledemic, and mpox [previously called monkeypox], but well before the onset of these public health crises.
Hospital: The medical profession has endured not only burnout but a growing mental health crisis, staffing shortages, a physician addiction crisis, and increased attrition in the decade leading up to the pandemic. The pandemic was like a punch in the gut, occurring at the most inopportune time one could imagine.
Health system: The intersection of health and the state of our public health deserves important mention. Unless we take action to bolster our public health infrastructure, our health care system will be in jeopardy, unable to handle the next pandemic, which could be just around the corner.

William E. Golden, MD, medical director of Arkansas Medicaid, professor of medicine and public health, University of Arkansas for Medical Sciences, Little Rock
Patients: Affordable options for diabetes and obesity management.
Health system: Greater investment by health systems and third-party payers in primary care infrastructure.

Gregory A. Hood, MD, Baptist Health, Lexington, Ky.
Patients: To embrace the gift of getting out in the world, being active, and connecting with others – having put down the screens.
Health system: To be freed from the financial gamesmanship of the insurers as they continue to serve their goals of promoting their hedge fund investing over meaningful and productive partnering with primary care physicians, and that they gain insight that they are one of the main reasons they can’t find PCPs to connect with to render care in disadvantaged environments – because they made it economically impossible to do so.

Robert H. Hopkins Jr., MD, associate professor of internal medicine and pediatrics and director of the division of general internal medicine, University of Arkansas for Medical Sciences, Little Rock
Patients/Health system: I would wish for staged implementation of universal basic health coverage for all, perhaps closest to the French or Canadian model. This would need to be coupled with expanded funding for nursing education, graduate medical education, and tracing of other health-related professionals.

Harvey Hsu, MD, Banner Health, Phoenix
Patients: More clear guidelines that are simple to understand. This can apply to colonoscopy (now age 45), immunizations, blood pressure goals. I wish medications were not as expensive so patients can take the best medicine for them and not stop taking them when they hit their donut hole in coverage.
Practice: We have been functioning on a leaner basis to cut down costs. When the pandemic hit, turnover was high and we lost PAs, nurses, front-office staff, and physicians. Having adequate staffing is probably number one on many lists. One way we dealt with lack of staffing was converting in-person visits to telehealth. Video visits are paid the same as in-person visits, but if the patient could not get their video to work, then it would be a telephone visit. Now many insurances do not even pay for telephone visits. So I would wish that we could still be reimbursed for telehealth visits.
Health system: I would wish for our health system to recognize the extra work required to take care of patients while improving quality and meeting quality measures. Allowing more time for patient visits could be one way to meet those goals or having more support staff to make sure patients get their colonoscopy/mammograms done, improve their sugars, and take their medications.

Jan L. Shifren, MD, Vincent Trustees Professor, obstetrics, gynecology, and reproductive biology, Harvard Medical School, and director of the Midlife Women’s Health Center at Massachusetts General Hospital, Boston
Patients: I wish for patients to be actively involved in all aspects of their care, well informed with shared decision-making.
Practice: I wish for the enormous time demands of electronic medical records and documentation to not distract from the pleasure of caring for patients.
Health system: Patient care remains at the center of decisions and programs.

Timothy J. Joos, MD, MPH, internal medicine/pediatrics, Seattle
Health system: I wish someone could figure out how we could be reimbursed for the quality of care we provide instead of the volume of patients we see. I wish EMRs could become less complicated and more user-friendly rather than needing advanced training to use.

Peter Kovacs, MD, medical director, Kaali Institute IVF Center, Budapest
Patients: I work as an infertility specialist, so when we talk about infectious diseases and associated risks, we talk about a minimum of two (female and male partner) and ideally three (plus the pregnancy) individuals. We have learned that SARS-CoV-2 affects reproductive health. It may compromise sperm production, could delay fertility treatment, could be associated with lower success rates; and if the treatment is successful, it may harm the pregnant woman/fetus/newborn. The best preventive measure that we can offer is vaccination. One cannot overemphasize the importance of preventive measures, paying attention to personal hygiene and social distancing. Therefore, I wish those planning to become pregnant to listen to their health care provider and accept the recommended vaccines to minimize the risk of getting infected and to minimize the risk for severe disease, especially if one undergoes successful fertility treatment and achieves a long-desired pregnancy.
Practice: During the 2022 calendar year we had many days when one or more employees were out of work on sick leave. This puts extra stress on the others to allow uncompromised work in the clinic. In addition, we all have to work in a less-comfortable environment if we consider mask use every day, all day. For health care workers, vaccination is mandated but many still are affected by milder forms of coronavirus infection and other respiratory diseases. Therefore, I wish my colleagues patience toward the preventive measures to lower the individual risk for infections. As a result, hopefully we will have a less stressful 2023.
Health system: Many resources had to be delegated to dealing with acute and chronic COVID, and this was at the expense of routine daily elective and preventive medical services. I wish the health care system to return to normal daily operations, to have the personnel and financial resources to carry on with the required preventive and elective medical services to avoid long-term consequences of not being able to provide such services. It would be sad if we had to treat otherwise preventable illnesses in the upcoming years that went undiagnosed and/or were not properly managed due to limited resources as the result of the pandemic.

Alan R. Nelson, MD, internist-endocrinologist, retired
Patients: Expansion of the FDA’s authority into over-the-counter drugs, including the veracity of their advertising claims.
Practice: Make diabetes drugs available at a reasonable cost.
Health system: With the expansion of Medicaid eligibility during COVID-19 coming to a close, federal government actions are necessary for those who once again have been dropped from coverage to have their legitimate needs met.

Kevin Powell, MD, PhD, St. Louis
Patients: To be cared for and about, and not just medically, even when illness strikes and health fails.
Hospitals: To hear the thankfulness of a grateful public for the care you provide, and to hear that above the angry noise of outraged individuals who spout vitriol and focus on how they believe others have harmed them.
Health system: A truer understanding of mercy and justice.

Margaret Thew, DNP, FNP-BC, director, department of adolescent medicine, Children’s Hospital of Wisconsin, Milwaukee
Seconded by: M. Susan Jay, MD, professor of pediatrics, chief of adolescent medicine, Medical College of Wisconsin and Children’s Hospital of Wisconsin, Milwaukee
My wish for patients, hospital, and system: health, calm, and grace.

Mark P. Trolice, MD, director of Fertility CARE, the IVF Center, Winter Park, Fla.
Patients: To be proactive in their health care and be their own advocates. Question when unclear and only consult credible resources.
Practice/hospital: Improve support of physicians and all health care providers to allow more input in their practice operations and growth.
Health system: Reduce interference of the “business of medicine” and ensure that the patient experience is the priority.

Charles P. Vega, MD, University of California, Irvine
Three minutes on a routine basis for everyone in health care to reflect on our blessings and the honor and gravity – as well as joy – that are integral to health care. Three minutes that will also help us to recognize our challenges and put them in the proper context. I know 3 minutes is not meeting any standard for reflective practice. But it’s 3 minutes more than I have right now.

Karen Breach Washington, MD, medical director of WellCare of North Carolina/Centene, Charlotte
Seconded by: Lillian M. Beard, MD, physician director, Children’s Pediatricians and Associates, Silver Spring, Md.
Patients: Access to affordable health care.
Hospital: Resources to care for patients (sufficient number of beds and a healthy staff).
Health system: Equity for all.

Andrew Wilner, MD, host of the podcast “The Art of Medicine with Dr. Andrew Wilner,” www.andrewwilner.com
Let’s put patients first! Too many extraneous considerations other than the patient’s best interest obstruct optimal patient care.

Here are just a few examples of patients coming last instead of first.

• If a patient needs to start a new medication in hospital, we shouldn’t have to wait until the patient is an outpatient because “that’s when insurance will pay.”
• If there’s a new medication that’s better than the old medication, we shouldn’t be forced to choose the old medication and provide inferior care because “that’s when insurance will pay.”
• If patients need to stay in hospital, we shouldn’t be pressured to discharge them because the hospital has decided that decreasing “length of stay” is its highest priority.

Dr. Francis Peabody said it best in 1927: “The secret of the care of the patient is in caring for the patient.” How hard is that?

In 2023, why don’t we follow Dr. Peabody’s sage advice from nearly 100 years ago and see what happens?
 

James M. Wooten, PharmD, University of Missouri–Kansas City, University Health, Kansas City, Mo.
Patients: I want patients to understand and properly realize the advantage of vaccinations – not only for COVID-19 but also for influenza. There is so much misinformation that I spend a lot of time trying to convince patients to get vaccinated. Most patients don’t realize that through their lives, most of them have already been vaccinated for something just to be able to attend school. How the COVID-19 vaccine created so much stigma makes little sense to me. I also want patients to understand that COVID-19 vaccination and boosters do not always prevent infection but will many times prevent severe infection. I believe that better patient communication and education is the key and will always be the key to improving vaccination numbers. Not only communicating and educating patients on vaccination itself but also making patients realize that personal vaccination decisions may affect what happens to your neighbor. Allowing infection means that you may be more likely to infect someone else. As a society, we must take care of each other.
Health system: It will be interesting to see what happens when vaccines are no longer reimbursed by the federal government. Understanding which vaccines work best and are better tolerated will be key to choosing appropriate vaccine brands. Health care providers will need to be very selective regarding which vaccines are selected for formulary inclusion. Thorough meta-analysis studies must be done to provide more evaluable information to allow for appropriate selection. “Knowledge is power!” Appropriate knowledge will help distinguish which vaccines work best for various patient populations.

A version of this article first appeared on Medscape.com.

As physicians well know, magic wands don’t exist. If they did, every patient would recover in the exam room, prior authorization wouldn’t exist, and continuing medical education credits would be printed on bearer bonds.

But in the spirit of suspended disbelief, we asked physicians and other contributors what their three wishes would be for their patients, practice/hospital, and health systems. Because, hey – we all need to dream.
 

Suzanne C. Boulter, MD, adjunct professor of pediatrics and community and family medicine, Geisel School of Medicine at Dartmouth, Hanover, N.H.
Patients: An end to gun violence.
Practice/hospital: Adequate staffing and pediatric bed availability.
Health system: Universal access to health insurance.

Sarah G. Candler, MD, MPH, care team medical director and director of academic relations, Iora Primary Care, Northside Clinic, Houston
Patients: Systems of health that start with communities of safety, including access to affordable housing, food, transportation, and health care.
Practice/hospital: I.N.T.E.R.O.P.E.R.A.B.I.L.I.T.Y.
Health system: Clinician leadership that has the power (often aka funding) to do what’s right, not just what’s right in front of us.

Arthur L. Caplan, PhD, bioethicist, New York University Langone Health
Patients: I wish for patients in the United States greater access to affordable primary care. There are still too many people without insurance or a reasonably accessible quality provider. And I especially wish for the rapid expansion of affordable training programs to meet staffing needs, including more scholarships, 3-year programs, and more new primary care–oriented schools.
Hospital: Increased staffing, especially nursing. There are too many retirements, too much burnout, and too much privatization into boutique practices to ensure the ability to provide high-quality, safe, patient-oriented care.
Health system: I wish for health systems to seriously move into electronic medicine. While billing has become electronic, there is still much to be done to supplement diagnosis, training, and standardized data collection on key metrics. Systems are not yet behaving in a manner consistent with the hype in this regard.

Stephen Devries, MD, executive director, Gaples Institute (nonprofit) and adjunct associate professor of nutrition, Harvard School of Public Health, Boston
Patients: Patients continue to demand more from their health care professionals and insist that they are offered evidence-based counseling on nutrition and lifestyle strategies.
Practice: Quality-based reimbursement for medical services will take hold that will incentivize much-needed preventive care.
Hospital: Hospitals will more fully embrace the role of serving as true centers of health and focus as much on preventive medicine as on the more lucrative areas of high-tech treatment.

Peter D. Friedmann, MD, MPH, chief research officer, Baystate Health, Springfield, Mass.
Seconded by: Elisabeth Poorman, MD, general internist, University of Washington Clinic, Kent
Patients: Don’t forget the ongoing epidemic of substance use disorder, a major cause of premature mortality. Descheduling of cannabis and expungement of cannabis-related convictions.
Practice/hospital: Commitment of hospitals and practices to address stigma and ensure delivery of medications for opioid use disorder in primary care, the emergency department, and inpatient settings.
Health system: Reform of antiquated methadone regulations to permit office-based prescription and pharmacy dispensing to treat opioid use disorder, as is the case in most of the world.

Robert Glatter, MD, emergency physician, New York
Patients: I want all patients to understand the enormous strain the health care system has been under – not just with the pandemic, the tripledemic, and mpox [previously called monkeypox], but well before the onset of these public health crises.
Hospital: The medical profession has endured not only burnout but a growing mental health crisis, staffing shortages, a physician addiction crisis, and increased attrition in the decade leading up to the pandemic. The pandemic was like a punch in the gut, occurring at the most inopportune time one could imagine.
Health system: The intersection of health and the state of our public health deserves important mention. Unless we take action to bolster our public health infrastructure, our health care system will be in jeopardy, unable to handle the next pandemic, which could be just around the corner.

William E. Golden, MD, medical director of Arkansas Medicaid, professor of medicine and public health, University of Arkansas for Medical Sciences, Little Rock
Patients: Affordable options for diabetes and obesity management.
Health system: Greater investment by health systems and third-party payers in primary care infrastructure.

Gregory A. Hood, MD, Baptist Health, Lexington, Ky.
Patients: To embrace the gift of getting out in the world, being active, and connecting with others – having put down the screens.
Health system: To be freed from the financial gamesmanship of the insurers as they continue to serve their goals of promoting their hedge fund investing over meaningful and productive partnering with primary care physicians, and that they gain insight that they are one of the main reasons they can’t find PCPs to connect with to render care in disadvantaged environments – because they made it economically impossible to do so.

Robert H. Hopkins Jr., MD, associate professor of internal medicine and pediatrics and director of the division of general internal medicine, University of Arkansas for Medical Sciences, Little Rock
Patients/Health system: I would wish for staged implementation of universal basic health coverage for all, perhaps closest to the French or Canadian model. This would need to be coupled with expanded funding for nursing education, graduate medical education, and tracing of other health-related professionals.

Harvey Hsu, MD, Banner Health, Phoenix
Patients: More clear guidelines that are simple to understand. This can apply to colonoscopy (now age 45), immunizations, blood pressure goals. I wish medications were not as expensive so patients can take the best medicine for them and not stop taking them when they hit their donut hole in coverage.
Practice: We have been functioning on a leaner basis to cut down costs. When the pandemic hit, turnover was high and we lost PAs, nurses, front-office staff, and physicians. Having adequate staffing is probably number one on many lists. One way we dealt with lack of staffing was converting in-person visits to telehealth. Video visits are paid the same as in-person visits, but if the patient could not get their video to work, then it would be a telephone visit. Now many insurances do not even pay for telephone visits. So I would wish that we could still be reimbursed for telehealth visits.
Health system: I would wish for our health system to recognize the extra work required to take care of patients while improving quality and meeting quality measures. Allowing more time for patient visits could be one way to meet those goals or having more support staff to make sure patients get their colonoscopy/mammograms done, improve their sugars, and take their medications.

Jan L. Shifren, MD, Vincent Trustees Professor, obstetrics, gynecology, and reproductive biology, Harvard Medical School, and director of the Midlife Women’s Health Center at Massachusetts General Hospital, Boston
Patients: I wish for patients to be actively involved in all aspects of their care, well informed with shared decision-making.
Practice: I wish for the enormous time demands of electronic medical records and documentation to not distract from the pleasure of caring for patients.
Health system: Patient care remains at the center of decisions and programs.

Timothy J. Joos, MD, MPH, internal medicine/pediatrics, Seattle
Health system: I wish someone could figure out how we could be reimbursed for the quality of care we provide instead of the volume of patients we see. I wish EMRs could become less complicated and more user-friendly rather than needing advanced training to use.

Peter Kovacs, MD, medical director, Kaali Institute IVF Center, Budapest
Patients: I work as an infertility specialist, so when we talk about infectious diseases and associated risks, we talk about a minimum of two (female and male partner) and ideally three (plus the pregnancy) individuals. We have learned that SARS-CoV-2 affects reproductive health. It may compromise sperm production, could delay fertility treatment, could be associated with lower success rates; and if the treatment is successful, it may harm the pregnant woman/fetus/newborn. The best preventive measure that we can offer is vaccination. One cannot overemphasize the importance of preventive measures, paying attention to personal hygiene and social distancing. Therefore, I wish those planning to become pregnant to listen to their health care provider and accept the recommended vaccines to minimize the risk of getting infected and to minimize the risk for severe disease, especially if one undergoes successful fertility treatment and achieves a long-desired pregnancy.
Practice: During the 2022 calendar year we had many days when one or more employees were out of work on sick leave. This puts extra stress on the others to allow uncompromised work in the clinic. In addition, we all have to work in a less-comfortable environment if we consider mask use every day, all day. For health care workers, vaccination is mandated but many still are affected by milder forms of coronavirus infection and other respiratory diseases. Therefore, I wish my colleagues patience toward the preventive measures to lower the individual risk for infections. As a result, hopefully we will have a less stressful 2023.
Health system: Many resources had to be delegated to dealing with acute and chronic COVID, and this was at the expense of routine daily elective and preventive medical services. I wish the health care system to return to normal daily operations, to have the personnel and financial resources to carry on with the required preventive and elective medical services to avoid long-term consequences of not being able to provide such services. It would be sad if we had to treat otherwise preventable illnesses in the upcoming years that went undiagnosed and/or were not properly managed due to limited resources as the result of the pandemic.

Alan R. Nelson, MD, internist-endocrinologist, retired
Patients: Expansion of the FDA’s authority into over-the-counter drugs, including the veracity of their advertising claims.
Practice: Make diabetes drugs available at a reasonable cost.
Health system: With the expansion of Medicaid eligibility during COVID-19 coming to a close, federal government actions are necessary for those who once again have been dropped from coverage to have their legitimate needs met.

Kevin Powell, MD, PhD, St. Louis
Patients: To be cared for and about, and not just medically, even when illness strikes and health fails.
Hospitals: To hear the thankfulness of a grateful public for the care you provide, and to hear that above the angry noise of outraged individuals who spout vitriol and focus on how they believe others have harmed them.
Health system: A truer understanding of mercy and justice.

Margaret Thew, DNP, FNP-BC, director, department of adolescent medicine, Children’s Hospital of Wisconsin, Milwaukee
Seconded by: M. Susan Jay, MD, professor of pediatrics, chief of adolescent medicine, Medical College of Wisconsin and Children’s Hospital of Wisconsin, Milwaukee
My wish for patients, hospital, and system: health, calm, and grace.

Mark P. Trolice, MD, director of Fertility CARE, the IVF Center, Winter Park, Fla.
Patients: To be proactive in their health care and be their own advocates. Question when unclear and only consult credible resources.
Practice/hospital: Improve support of physicians and all health care providers to allow more input in their practice operations and growth.
Health system: Reduce interference of the “business of medicine” and ensure that the patient experience is the priority.

Charles P. Vega, MD, University of California, Irvine
Three minutes on a routine basis for everyone in health care to reflect on our blessings and the honor and gravity – as well as joy – that are integral to health care. Three minutes that will also help us to recognize our challenges and put them in the proper context. I know 3 minutes is not meeting any standard for reflective practice. But it’s 3 minutes more than I have right now.

Karen Breach Washington, MD, medical director of WellCare of North Carolina/Centene, Charlotte
Seconded by: Lillian M. Beard, MD, physician director, Children’s Pediatricians and Associates, Silver Spring, Md.
Patients: Access to affordable health care.
Hospital: Resources to care for patients (sufficient number of beds and a healthy staff).
Health system: Equity for all.

Andrew Wilner, MD, host of the podcast “The Art of Medicine with Dr. Andrew Wilner,” www.andrewwilner.com
Let’s put patients first! Too many extraneous considerations other than the patient’s best interest obstruct optimal patient care.

Here are just a few examples of patients coming last instead of first.

• If a patient needs to start a new medication in hospital, we shouldn’t have to wait until the patient is an outpatient because “that’s when insurance will pay.”
• If there’s a new medication that’s better than the old medication, we shouldn’t be forced to choose the old medication and provide inferior care because “that’s when insurance will pay.”
• If patients need to stay in hospital, we shouldn’t be pressured to discharge them because the hospital has decided that decreasing “length of stay” is its highest priority.

Dr. Francis Peabody said it best in 1927: “The secret of the care of the patient is in caring for the patient.” How hard is that?

In 2023, why don’t we follow Dr. Peabody’s sage advice from nearly 100 years ago and see what happens?
 

James M. Wooten, PharmD, University of Missouri–Kansas City, University Health, Kansas City, Mo.
Patients: I want patients to understand and properly realize the advantage of vaccinations – not only for COVID-19 but also for influenza. There is so much misinformation that I spend a lot of time trying to convince patients to get vaccinated. Most patients don’t realize that through their lives, most of them have already been vaccinated for something just to be able to attend school. How the COVID-19 vaccine created so much stigma makes little sense to me. I also want patients to understand that COVID-19 vaccination and boosters do not always prevent infection but will many times prevent severe infection. I believe that better patient communication and education is the key and will always be the key to improving vaccination numbers. Not only communicating and educating patients on vaccination itself but also making patients realize that personal vaccination decisions may affect what happens to your neighbor. Allowing infection means that you may be more likely to infect someone else. As a society, we must take care of each other.
Health system: It will be interesting to see what happens when vaccines are no longer reimbursed by the federal government. Understanding which vaccines work best and are better tolerated will be key to choosing appropriate vaccine brands. Health care providers will need to be very selective regarding which vaccines are selected for formulary inclusion. Thorough meta-analysis studies must be done to provide more evaluable information to allow for appropriate selection. “Knowledge is power!” Appropriate knowledge will help distinguish which vaccines work best for various patient populations.

A version of this article first appeared on Medscape.com.

Lipoprotein(a) [Lp(a)] was first identified in 1963, just about the time that my 16-year-old arteries were probably developing fatty streaks. It soon became clear that Lp(a) was associated with atherosclerotic cardiovascular disease (ASCVD), but whether an elevated blood level was a biomarker or a causal factor proved difficult to determine. Studies of inheritance patterns confirmed that blood levels were primarily genetically determined and largely resistant to lifestyle and pharmacologic intervention. It seemed senseless to test for something that was deemed “unmodifiable,” so untreatable. That label stuck for decades.

Fortunately, a resurgent interest in molecular pathophysiology this past decade has clarified Lp(a)’s unique contribution to atherothrombotic disease and calcific aortic stenosis. While there remains much to be learned about this complex, highly atherogenic molecule and its role in cardiac disease, it seems shortsighted not to take the simple step of identifying who carries this risk. Why are we not testing everyone for an extremely common and potent risk factor for the most lethal disease on the planet?

Epidemiologic studies project a stunning number of people in the United States to be at increased risk for Lp(a)-mediated coronary and cerebrovascular events. Because the LPA gene which codes for the apo(a) component of the Lp(a) molecule is fully expressed at age 2, this is a truly lifelong risk factor for a projected 64 million individuals with blood levels (> 60 mg/dL) high enough to double their risk for ASCVD. Because risk increases linearly, this includes 16 million, like me, with levels > 116 mg/dL, who are at four times the risk for ASCVD as those with normal levels (< 30 mg/dL).

Because Lp(a) level remains relatively constant throughout life, a single blood test would help stratify the risk it confers on millions of people who, under current U.S. guidelines, would never be tested. Until Lp(a) is integrated into its algorithms, the commonly used ASCVD Risk Calculator will substantially underestimate risk in 20% of the population.

A potential barrier to universal testing is that the ideal method to measure Lp(a) has yet to be determined. Lp(a) comprises an apoB particle bonded to an apo(a) particle. Apo(a) is complex and has a number of isoforms that can result in large heterogeneity in apo(a) size between, as well as within, individuals. This contributes to controversy about the ideal assay and whether Lp(a) levels should be expressed as mass (mg/dL) or number of particles (nmols/L). This should not, however, deter universal testing.
 

One-time cost, lifetime benefit?

Absent universal testing, it’s impossible to estimate the economic toll that Lp(a) exacts, but it’s surely an extraordinary number, particularly because the highest-risk individuals are prone to recurrent, nonfatal vascular events. The substantial price tag for my personal decade of Lp(a)-induced vascular havoc included four percutaneous coronary interventions with rapid stent restenosis, an eventual bypass surgery, and an aborted left hemispheric stroke, requiring an urgent carotid endarterectomy.

As a frame of reference, U.S. expenditures related to ASCVD are estimated to be $351 billion annually. If everyone in the United States over the age of 18 were tested for Lp(a) at a cost of $100 per person, this would be a $21 billion expenditure. This nonrecurring expense would identify the 20% – or almost 42 million individuals – at high risk for ASCVD, a number of whom would have already had vascular events. This one-time cost would be a foundational step in securing year-after-year savings from enhanced ASCVD prevention and reduction in recurrent vascular events.

Such savings would be significantly enhanced if and when targeted, effective Lp(a) treatments become available, but it seems shortsighted to make this the linchpin for universal testing. It’s noteworthy that Canadian and European guidelines already endorse one-time testing for all.

The confirmation of Lp(a)’s causal role in ASCVD remains underappreciated by medical providers across all specialties. Much of the elegant Lp(a)-related science of the past decade has yet to translate to the clinical world. What better way to rectify this than by identifying those with high Lp(a)? Since the advent of the statin era, “good” and “bad” cholesterol values are common conversational fare, in part because virtually every adult has had not one, but many lipid panels. Universal Lp(a) testing would spotlight this pervasive and important risk factor that was referred to as the “horrible” cholesterol in a recent review.
 

U.S. guidelines need updating

To foster this, U.S. guidelines, which influence every aspect of care, including testing, prevention, treatment, reimbursement, and medical legal issues, need to be simplified. The discussion of Lp(a) testing in the 2018 U.S. guidelines on cholesterol management is already obsolete. The contingencies on when testing is “reasonable” or “may be reasonable” are dated and cumbersome. In contrast, a recommendation to test everyone once, perhaps in adolescence, would be a useful, forward-looking strategy.

To date, trials of an antisense oligonucleotide and a small interfering RNA molecule targeting hepatic LPA messenger RNA have confirmed that plasma Lp(a) levels can be significantly and safely lowered. If the ongoing Lp(a) HORIZON and OCEAN(a) phase 3 trials have positive outcomes in patients with known ASCVD, this would spawn a host of clinical trials to explore the possibilities of these therapies in primary prevention as well. These will require tens of thousands of enrollees, and universal testing would expand the pool of potential participants.

The majority of at-risk individuals identified through universal testing would be candidates for primary prevention. This large, currently unidentified cohort should have all coexisting risk factors assessed and managed; lowering elevated LDL cholesterol early and aggressively is paramount. Recent data from the United Kingdom suggest that attainment of specific LDL cholesterol levels may offset the risk for vascular events in those with high Lp(a) levels.

Of note, this was the advice given to the small fraction of high-risk individuals like me, who had their Lp(a) level tested long before its ominous implications were understood. This recommendation was informed mostly by common sense. For any number of reasons, the same might be said for universal testing.

Dr. Leahy, a retired cardiologist in San Diego, has an abiding professional and personal interest in Lp(a), which has been responsible for a number of cardiovascular events in his own life over the past 2 decades. He was a participant in the phase 2 clinical trial of the Lp(a)-lowering antisense oligonucleotide being studied in the Lp(a) HORIZON trial, funded by Novartis, and is currently undergoing apheresis treatment. A version of this article originally appeared on Medscape.com.

Lipoprotein(a) [Lp(a)] was first identified in 1963, just about the time that my 16-year-old arteries were probably developing fatty streaks. It soon became clear that Lp(a) was associated with atherosclerotic cardiovascular disease (ASCVD), but whether an elevated blood level was a biomarker or a causal factor proved difficult to determine. Studies of inheritance patterns confirmed that blood levels were primarily genetically determined and largely resistant to lifestyle and pharmacologic intervention. It seemed senseless to test for something that was deemed “unmodifiable,” so untreatable. That label stuck for decades.

Fortunately, a resurgent interest in molecular pathophysiology this past decade has clarified Lp(a)’s unique contribution to atherothrombotic disease and calcific aortic stenosis. While there remains much to be learned about this complex, highly atherogenic molecule and its role in cardiac disease, it seems shortsighted not to take the simple step of identifying who carries this risk. Why are we not testing everyone for an extremely common and potent risk factor for the most lethal disease on the planet?

Epidemiologic studies project a stunning number of people in the United States to be at increased risk for Lp(a)-mediated coronary and cerebrovascular events. Because the LPA gene which codes for the apo(a) component of the Lp(a) molecule is fully expressed at age 2, this is a truly lifelong risk factor for a projected 64 million individuals with blood levels (> 60 mg/dL) high enough to double their risk for ASCVD. Because risk increases linearly, this includes 16 million, like me, with levels > 116 mg/dL, who are at four times the risk for ASCVD as those with normal levels (< 30 mg/dL).

Because Lp(a) level remains relatively constant throughout life, a single blood test would help stratify the risk it confers on millions of people who, under current U.S. guidelines, would never be tested. Until Lp(a) is integrated into its algorithms, the commonly used ASCVD Risk Calculator will substantially underestimate risk in 20% of the population.

A potential barrier to universal testing is that the ideal method to measure Lp(a) has yet to be determined. Lp(a) comprises an apoB particle bonded to an apo(a) particle. Apo(a) is complex and has a number of isoforms that can result in large heterogeneity in apo(a) size between, as well as within, individuals. This contributes to controversy about the ideal assay and whether Lp(a) levels should be expressed as mass (mg/dL) or number of particles (nmols/L). This should not, however, deter universal testing.
 

One-time cost, lifetime benefit?

Absent universal testing, it’s impossible to estimate the economic toll that Lp(a) exacts, but it’s surely an extraordinary number, particularly because the highest-risk individuals are prone to recurrent, nonfatal vascular events. The substantial price tag for my personal decade of Lp(a)-induced vascular havoc included four percutaneous coronary interventions with rapid stent restenosis, an eventual bypass surgery, and an aborted left hemispheric stroke, requiring an urgent carotid endarterectomy.

As a frame of reference, U.S. expenditures related to ASCVD are estimated to be $351 billion annually. If everyone in the United States over the age of 18 were tested for Lp(a) at a cost of $100 per person, this would be a $21 billion expenditure. This nonrecurring expense would identify the 20% – or almost 42 million individuals – at high risk for ASCVD, a number of whom would have already had vascular events. This one-time cost would be a foundational step in securing year-after-year savings from enhanced ASCVD prevention and reduction in recurrent vascular events.

Such savings would be significantly enhanced if and when targeted, effective Lp(a) treatments become available, but it seems shortsighted to make this the linchpin for universal testing. It’s noteworthy that Canadian and European guidelines already endorse one-time testing for all.

The confirmation of Lp(a)’s causal role in ASCVD remains underappreciated by medical providers across all specialties. Much of the elegant Lp(a)-related science of the past decade has yet to translate to the clinical world. What better way to rectify this than by identifying those with high Lp(a)? Since the advent of the statin era, “good” and “bad” cholesterol values are common conversational fare, in part because virtually every adult has had not one, but many lipid panels. Universal Lp(a) testing would spotlight this pervasive and important risk factor that was referred to as the “horrible” cholesterol in a recent review.
 

U.S. guidelines need updating

To foster this, U.S. guidelines, which influence every aspect of care, including testing, prevention, treatment, reimbursement, and medical legal issues, need to be simplified. The discussion of Lp(a) testing in the 2018 U.S. guidelines on cholesterol management is already obsolete. The contingencies on when testing is “reasonable” or “may be reasonable” are dated and cumbersome. In contrast, a recommendation to test everyone once, perhaps in adolescence, would be a useful, forward-looking strategy.

To date, trials of an antisense oligonucleotide and a small interfering RNA molecule targeting hepatic LPA messenger RNA have confirmed that plasma Lp(a) levels can be significantly and safely lowered. If the ongoing Lp(a) HORIZON and OCEAN(a) phase 3 trials have positive outcomes in patients with known ASCVD, this would spawn a host of clinical trials to explore the possibilities of these therapies in primary prevention as well. These will require tens of thousands of enrollees, and universal testing would expand the pool of potential participants.

The majority of at-risk individuals identified through universal testing would be candidates for primary prevention. This large, currently unidentified cohort should have all coexisting risk factors assessed and managed; lowering elevated LDL cholesterol early and aggressively is paramount. Recent data from the United Kingdom suggest that attainment of specific LDL cholesterol levels may offset the risk for vascular events in those with high Lp(a) levels.

Of note, this was the advice given to the small fraction of high-risk individuals like me, who had their Lp(a) level tested long before its ominous implications were understood. This recommendation was informed mostly by common sense. For any number of reasons, the same might be said for universal testing.

Dr. Leahy, a retired cardiologist in San Diego, has an abiding professional and personal interest in Lp(a), which has been responsible for a number of cardiovascular events in his own life over the past 2 decades. He was a participant in the phase 2 clinical trial of the Lp(a)-lowering antisense oligonucleotide being studied in the Lp(a) HORIZON trial, funded by Novartis, and is currently undergoing apheresis treatment. A version of this article originally appeared on Medscape.com.

Lipoprotein(a) [Lp(a)] was first identified in 1963, just about the time that my 16-year-old arteries were probably developing fatty streaks. It soon became clear that Lp(a) was associated with atherosclerotic cardiovascular disease (ASCVD), but whether an elevated blood level was a biomarker or a causal factor proved difficult to determine. Studies of inheritance patterns confirmed that blood levels were primarily genetically determined and largely resistant to lifestyle and pharmacologic intervention. It seemed senseless to test for something that was deemed “unmodifiable,” so untreatable. That label stuck for decades.

Fortunately, a resurgent interest in molecular pathophysiology this past decade has clarified Lp(a)’s unique contribution to atherothrombotic disease and calcific aortic stenosis. While there remains much to be learned about this complex, highly atherogenic molecule and its role in cardiac disease, it seems shortsighted not to take the simple step of identifying who carries this risk. Why are we not testing everyone for an extremely common and potent risk factor for the most lethal disease on the planet?

Epidemiologic studies project a stunning number of people in the United States to be at increased risk for Lp(a)-mediated coronary and cerebrovascular events. Because the LPA gene which codes for the apo(a) component of the Lp(a) molecule is fully expressed at age 2, this is a truly lifelong risk factor for a projected 64 million individuals with blood levels (> 60 mg/dL) high enough to double their risk for ASCVD. Because risk increases linearly, this includes 16 million, like me, with levels > 116 mg/dL, who are at four times the risk for ASCVD as those with normal levels (< 30 mg/dL).

Because Lp(a) level remains relatively constant throughout life, a single blood test would help stratify the risk it confers on millions of people who, under current U.S. guidelines, would never be tested. Until Lp(a) is integrated into its algorithms, the commonly used ASCVD Risk Calculator will substantially underestimate risk in 20% of the population.

A potential barrier to universal testing is that the ideal method to measure Lp(a) has yet to be determined. Lp(a) comprises an apoB particle bonded to an apo(a) particle. Apo(a) is complex and has a number of isoforms that can result in large heterogeneity in apo(a) size between, as well as within, individuals. This contributes to controversy about the ideal assay and whether Lp(a) levels should be expressed as mass (mg/dL) or number of particles (nmols/L). This should not, however, deter universal testing.
 

One-time cost, lifetime benefit?

Absent universal testing, it’s impossible to estimate the economic toll that Lp(a) exacts, but it’s surely an extraordinary number, particularly because the highest-risk individuals are prone to recurrent, nonfatal vascular events. The substantial price tag for my personal decade of Lp(a)-induced vascular havoc included four percutaneous coronary interventions with rapid stent restenosis, an eventual bypass surgery, and an aborted left hemispheric stroke, requiring an urgent carotid endarterectomy.

As a frame of reference, U.S. expenditures related to ASCVD are estimated to be $351 billion annually. If everyone in the United States over the age of 18 were tested for Lp(a) at a cost of $100 per person, this would be a $21 billion expenditure. This nonrecurring expense would identify the 20% – or almost 42 million individuals – at high risk for ASCVD, a number of whom would have already had vascular events. This one-time cost would be a foundational step in securing year-after-year savings from enhanced ASCVD prevention and reduction in recurrent vascular events.

Such savings would be significantly enhanced if and when targeted, effective Lp(a) treatments become available, but it seems shortsighted to make this the linchpin for universal testing. It’s noteworthy that Canadian and European guidelines already endorse one-time testing for all.

The confirmation of Lp(a)’s causal role in ASCVD remains underappreciated by medical providers across all specialties. Much of the elegant Lp(a)-related science of the past decade has yet to translate to the clinical world. What better way to rectify this than by identifying those with high Lp(a)? Since the advent of the statin era, “good” and “bad” cholesterol values are common conversational fare, in part because virtually every adult has had not one, but many lipid panels. Universal Lp(a) testing would spotlight this pervasive and important risk factor that was referred to as the “horrible” cholesterol in a recent review.
 

U.S. guidelines need updating

To foster this, U.S. guidelines, which influence every aspect of care, including testing, prevention, treatment, reimbursement, and medical legal issues, need to be simplified. The discussion of Lp(a) testing in the 2018 U.S. guidelines on cholesterol management is already obsolete. The contingencies on when testing is “reasonable” or “may be reasonable” are dated and cumbersome. In contrast, a recommendation to test everyone once, perhaps in adolescence, would be a useful, forward-looking strategy.

To date, trials of an antisense oligonucleotide and a small interfering RNA molecule targeting hepatic LPA messenger RNA have confirmed that plasma Lp(a) levels can be significantly and safely lowered. If the ongoing Lp(a) HORIZON and OCEAN(a) phase 3 trials have positive outcomes in patients with known ASCVD, this would spawn a host of clinical trials to explore the possibilities of these therapies in primary prevention as well. These will require tens of thousands of enrollees, and universal testing would expand the pool of potential participants.

The majority of at-risk individuals identified through universal testing would be candidates for primary prevention. This large, currently unidentified cohort should have all coexisting risk factors assessed and managed; lowering elevated LDL cholesterol early and aggressively is paramount. Recent data from the United Kingdom suggest that attainment of specific LDL cholesterol levels may offset the risk for vascular events in those with high Lp(a) levels.

Of note, this was the advice given to the small fraction of high-risk individuals like me, who had their Lp(a) level tested long before its ominous implications were understood. This recommendation was informed mostly by common sense. For any number of reasons, the same might be said for universal testing.

Dr. Leahy, a retired cardiologist in San Diego, has an abiding professional and personal interest in Lp(a), which has been responsible for a number of cardiovascular events in his own life over the past 2 decades. He was a participant in the phase 2 clinical trial of the Lp(a)-lowering antisense oligonucleotide being studied in the Lp(a) HORIZON trial, funded by Novartis, and is currently undergoing apheresis treatment. A version of this article originally appeared on Medscape.com.