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Recent data indicate that overuse of short-acting beta2-agonists (SABAs) results in an increased risk of asthma exacerbations and mortality. The use of inhaled corticosteroid-formoterol as both maintenance and reliever therapy has become a preferred regimen for asthma management. Clinicians should be aware of the pharmacology, dosing, and prescribing considerations regarding the use of budesonide-formoterol as the available combination in the United States. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to determine the incidence of significant delays in administration of the second antibiotic dose in patients treated for severe sepsis and septic shock at a single community teaching hospital as well as to assess patient outcomes associated with second dose delays. Methods: This single-center, retrospective chart review evaluated patients who received at least 2 antibiotic doses for severe sepsis or septic shock. Patients were classified as having experienced a significant second dose delay if the actual interval between the first and the second antibiotic doses was greater than or equal to 125% of the recommended dosing interval. Results: Of 197 patients, 38 (19.3%) experienced a significant second antibiotic dose delay. The rate of significant delays was 17.1% in patients treated initially in the emergency department and 30.3% in patients treated initially in another inpatient location. Conclusions: This single-center study found a 19.3% rate of significant delays in antibiotic second dose administration in patients with severe sepsis and septic shock. This study was not powered to identify differences in outcomes in patients with and without significant second dose delays. Additional large-scale studies are needed to investigate the impact of antibiotic second dose delays on outcomes in patients with sepsis. [ABSTRACT FROM AUTHOR]

Preventing inside attacks: Graft-versus-host disease, where transplanted immune cells attack the recipient, is a major complication of hematopoietic cell transplantation and remains difficult to treat. By examining immune cells involved in graft-versus-host disease, Adom et al. identified specific subsets of T cells and dendritic cells that play a role in the development of this disorder. The authors identified these cells in human patients with different forms of graft-versus-host disease and examined their activity in mouse models. Last, they developed a dual targeting molecule that prevented the development of graft-versus-host disease in humanized mice by targeting two costimulation pathways in the pathogenic immune cells, suggesting a potential intervention for transplant recipients. Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic hematopoietic cell transplantation (HCT). CD146 and CCR5 are proteins that mark activated T helper 17 (Th17) cells. The Th17 cell phenotype is promoted by the interaction of the receptor ICOS on T cells with ICOS ligand (ICOSL) on dendritic cells (DCs). We performed multiparametric flow cytometry in a cohort of 156 HCT recipients and conducted experiments with aGVHD murine models to understand the role of ICOSL+ DCs. We observed an increased frequency of ICOSL+ plasmacytoid DCs, correlating with CD146+CCR5+ T cell frequencies, in the 64 HCT recipients with gastrointestinal aGVHD. In murine models, donor bone marrow cells from ICOSL-deficient mice compared to those from wild-type mice reduced aGVHD-related mortality. Reduced aGVHD resulted from lower intestinal infiltration of pDCs and pathogenic Th17 cells. We transplanted activated human ICOSL+ pDCs along with human peripheral blood mononuclear cells into immunocompromised mice and observed infiltration of intestinal CD146+CCR5+ T cells. We found that prophylactic administration of a dual human ICOS/CD28 antagonist (ALPN-101) prevented aGVHD in this model better than did the clinically approved belatacept (CTLA-4-Fc), which binds CD80 (B7-1) and CD86 (B7-2) and interferes with the CD28 T cell costimulatory pathway. When started at onset of aGVHD signs, ALPN-101 treatment alleviated symptoms of ongoing aGVHD and improved survival while preserving antitumoral cytotoxicity. Our data identified ICOSL+-pDCs as an aGVHD biomarker and suggest that coinhibition of the ICOSL/ICOS and B7/CD28 axes with one biologic drug may represent a therapeutic opportunity to prevent or treat aGVHD. [ABSTRACT FROM AUTHOR]

Impaired blood flow and oxygenation contribute to many ocular pathologies, including glaucoma. Here, a mathematical model is presented that combines an image-based heterogeneous representation of retinal arterioles with a compartmental description of capillaries and venules. The arteriolar model of the human retina is extrapolated from a previous mouse model based on confocal microscopy images. Every terminal arteriole is connected in series to compartments for capillaries and venules, yielding a hybrid model for predicting blood flow and oxygenation throughout the retinal microcirculation. A metabolic wall signal is calculated in each vessel according to blood and tissue oxygen levels. As expected, a higher average metabolic signal is generated in pathways with a lower average oxygen level. The model also predicts a wide range of metabolic signals dependent on oxygen levels and specific network location. For example, for high oxygen demand, a threefold range in metabolic signal is predicted despite nearly identical PO2 levels. This whole-network approach, including a spatially nonuniform structure, is needed to describe the metabolic status of the retina. This model provides the geometric and hemodynamic framework necessary to predict ocular blood flow regulation and will ultimately facilitate early detection and treatment of ischemic and metabolic disorders of the eye. [ABSTRACT FROM AUTHOR]

Background: Despite growing recognition of health disparities faced by the Lesbian, Gay, Bisexual, Transgender, Queer (or Questioning) (LGBTQ+) population, significant gaps remain for inclusion of LGBTQ+ content in health professions education, particularly dental curricula. This study aims to address these gaps by investigating the integration of LGBTQ+ content in a midwestern dental school curriculum., Methods: Curriculum mapping and focus group discussions were utilized to identify gaps and recommend integrating LGBTQ+ content into a predoctoral dental curriculum. The Doctor of Dental Surgery program was mapped to identify LGBTQ+ specific content relevant to cultural competency. A focus group of nine faculty members provided insights and recommendations, with data transcribed and analyzed for themes., Results: Out of 121 courses, 28 included or had potential for LGBTQ+ content, with 16 already inclusive and 12 involving direct patient interaction. Integration varied, highest in the first year (28.6%) and lowest in the fourth year (5%). Focus group themes included the need for broader awareness and education about LGBTQ+ health, integrating topics into basic and behavioral science courses, and addressing practical clinical skills (e.g., using pronouns). Barriers included personal discomfort, lack of formal training, and potential conflicts with personal or religious beliefs., Conclusions: This study highlighted the need for increased faculty awareness and enhanced inclusion of LGBTQ+ content throughout the predoctoral dental curriculum to prepare future practitioners for culturally competent care., (© 2024 The Author(s). Journal of Dental Education published by Wiley Periodicals LLC on behalf of American Dental Education Association.)

Abstract: Recent data indicate that overuse of short-acting beta2-agonists (SABAs) results in an increased risk of asthma exacerbations and mortality. The use of inhaled corticosteroid-formoterol as both maintenance and reliever therapy has become a preferred regimen for asthma management. Clinicians should be aware of the pharmacology, dosing, and prescribing considerations regarding the use of budesonide-formoterol as the available combination in the United States., (Copyright © 2023 American Academy of Physician Associates.)

The retinal vascular network supplies perfusion to vital visual structures, including retinal ganglion cells responsible for vision. Impairments in retinal blood flow and oxygenation are involved in the progression of many ocular diseases, including glaucoma. In this study, an established theoretical hybrid model of a retinal microvascular network is extended to include the effects of local blood flow regulation on oxygenation. A heterogeneous representation of the arterioles based on confocal microscopy images is combined with a compartmental description of the downstream capillaries and venules. A Green's function method is used to simulate oxygen transport in the arterioles, and a Krogh cylinder model is applied to the capillary and venular compartments. Acute blood flow regulation is simulated in response to changes in pressure, shear stress, and metabolism. Model results predict that both increased intraocular pressure and impairment of blood flow regulation can cause decreased tissue oxygenation, indicating that both mechanisms represent factors that could lead to impaired oxygenation characteristic of ocular disease. Results also indicate that the metabolic response mechanism reduces the fraction of poorly oxygenated tissue but that the pressure- and shear stress-dependent response mechanisms may hinder the vascular response to changes in oxygenation. Importantly, the heterogeneity of the vascular network demonstrates that traditionally reported average values of tissue oxygen levels hide significant localized defects in tissue oxygenation that may be involved in disease processes, including glaucoma. Ultimately, the model framework presented in this study will facilitate future comparisons to sectorial-specific clinical data to better assess the role of impaired blood flow regulation in ocular disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic hematopoietic cell transplantation (HCT). CD146 and CCR5 are proteins that mark activated T helper 17 (Th17) cells. The Th17 cell phenotype is promoted by the interaction of the receptor ICOS on T cells with ICOS ligand (ICOSL) on dendritic cells (DCs). We performed multiparametric flow cytometry in a cohort of 156 HCT recipients and conducted experiments with aGVHD murine models to understand the role of ICOSL + DCs. We observed an increased frequency of ICOSL + plasmacytoid DCs, correlating with CD146 + CCR5 + T cell frequencies, in the 64 HCT recipients with gastrointestinal aGVHD. In murine models, donor bone marrow cells from ICOSL-deficient mice compared to those from wild-type mice reduced aGVHD-related mortality. Reduced aGVHD resulted from lower intestinal infiltration of pDCs and pathogenic Th17 cells. We transplanted activated human ICOSL + pDCs along with human peripheral blood mononuclear cells into immunocompromised mice and observed infiltration of intestinal CD146 + CCR5 + T cells. We found that prophylactic administration of a dual human ICOS/CD28 antagonist (ALPN-101) prevented aGVHD in this model better than did the clinically approved belatacept (CTLA-4-Fc), which binds CD80 (B7-1) and CD86 (B7-2) and interferes with the CD28 T cell costimulatory pathway. When started at onset of aGVHD signs, ALPN-101 treatment alleviated symptoms of ongoing aGVHD and improved survival while preserving antitumoral cytotoxicity. Our data identified ICOSL + -pDCs as an aGVHD biomarker and suggest that coinhibition of the ICOSL/ICOS and B7/CD28 axes with one biologic drug may represent a therapeutic opportunity to prevent or treat aGVHD., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)