Emergency Department Trauma Activation Fees by Payer Type.

This cross-sectional study examines the wide variations in prices of emergency medical services at US hospitals.

Risk of ocular adverse events with aromatase inhibitors.

OBJECTIVE: Aromatase inhibitors (AIs) are a class of medications used for adjuvant treatment of breast cancer. Recent case reports suggest that AIs may be associated with various ocular adverse events (AEs). This study evaluates the risk of ocular AEs in patients who take AIs. METHOD: Disproportionality analysis was performed using data from the U.S. Food and Drug Administration's Adverse Events Reporting System database from 2004 to 2022. All cases of vitreomacular traction, macular edema, retinal deposits, retinal artery occlusion, macular hole, retinal hemorrhage, uveitis, retinal tear, retinal detachment, dry eye disease, blepharitis, and optic neuropathy were searched for the 3 AIs anastrozole, letrozole, and exemestane. A search also was performed on trastuzumab as a control. Reported odds ratios (RORs) and corresponding 95% CIs were computed. RESULTS: We identified 322 ocular AEs of interest for the 3 AIs and 55 for trastuzumab. Anastrozole had the most AEs (n = 163) and was found to have strong associations with vitreomacular traction (ROR = 665; 95% CI, 352-1255), macular edema (ROR = 37; 95% CI, 25-54), retinal deposits (ROR = 11; 95% CI, 2-77), and uveitis (ROR = 6; 95% CI, 4-9). Letrozole had strong associations with retinal deposits (ROR = 8, 95% CI, 1-57) and retinal artery occlusion (ROR = 6; 95% CI, 3-11). Exemestane had a strong association with macular holes (ROR = 10; 95% CI, 3-30). CONCLUSION: Disproportionality analysis revealed an increased risk of ocular AEs with each of the AIs. This study calls for clinicians, especially oncologists and ophthalmologists, to be vigilant in patients who are on AI therapy, allowing them to provide prompt interventions to mitigate further ocular morbidities.

TREM1 activation of myeloid cells promotes antitumor immunity.

Myeloid cells in the tumor microenvironment (TME) can exist in immunosuppressive and immunostimulatory states that impede or promote antitumor immunity, respectively. Blocking suppressive myeloid cells or increasing stimulatory cells to enhance antitumor immune responses is an area of interest for therapeutic intervention. Triggering receptor expressed on myeloid cells-1 (TREM1) is a proinflammatory receptor that amplifies immune responses. TREM1 is expressed on neutrophils, subsets of monocytes and tissue macrophages, and suppressive myeloid populations in the TME, including tumor-associated neutrophils, monocytes, and tumor-associated macrophages. Depletion or inhibition of immunosuppressive myeloid cells, or stimulation by TREM1-mediated inflammatory signaling, could be used to promote an immunostimulatory TME. We developed PY159, an afucosylated humanized anti-TREM1 monoclonal antibody with enhanced FcγR binding. PY159 is a TREM1 agonist that induces signaling, leading to up-regulation of costimulatory molecules on monocytes and macrophages, production of proinflammatory cytokines and chemokines, and enhancement of T cell activation in vitro. An antibody against mouse TREM1, PY159m, promoted antitumor efficacy in syngeneic mouse tumor models. These results suggest that PY159-mediated agonism of TREM1 on tumoral myeloid cells can promote a proinflammatory TME and offer a promising strategy for immunotherapy.

Conceptual Models and Mechanisms of Action that Underpin End-of-Life Care Interventions to Improve Spiritual Well-Being.

Background: Understanding the conceptual models that underpin interventions, and the linkage between mechanisms of action and their intended outcomes, makes replication possible. Aim: To identify and appraise conceptual models and mechanisms of action underpinning end-of-life care interventions to improve spiritual well-being. Design: A systematic review following the Preferred Reporting Items for Systematic Review and Meta-Analysis was conducted. Data sources: A comprehensive search was performed in eight databases from inception to January 12, 2021. Results: A logic model was developed and potential mechanisms of action were identified from the seven included studies. Conclusion: First, conceptual models that have relevance and appropriateness to cultural setting are required to underpin future intervention development and implementation. Second, careful intervention development should articulate the link between concept, mechanisms, and outcomes. Third, selection of valid outcome measured must have a strong justification of how the construct being measured relates to the intervention goals.

Association of p155/140 Autoantibody With Loss of Nailfold Capillaries but not Generalized Lipodystrophy: A Study of Ninety-Six Children With Juvenile Dermatomyositis.

OBJECTIVE: Myositis-specific antibodies (MSAs) facilitate grouping children with juvenile dermatomyositis (DM) into distinct phenotypes. The first aim of this study was to investigate the link between anti-p155/140 and lipodystrophy as determined by dual x-ray absorptiometry (DXA) assessment of fat distribution. The second aim was to examine the relationship between anti-p155/140 and damage to the nailfold capillary system. METHODS: Children with juvenile DM followed for a minimum of 5 years were included. The study population was divided into 3 groups (anti-p155/140, other MSA, and MSA negative). Lipodystrophy was assessed by physician assessment and DXA fat distribution (trunk-to-leg fat ratio). Documentation of nailfold capillary end row loops (ERLs) was obtained at diagnosis. RESULTS: A total of 96 subjects (44% anti-p155/140, 23% other MSA, 33% MSA negative) were included. There was no significant difference in age, disease activity scores, or lipodystrophy between the 3 groups. The trunk-to-leg fat ratios were similar among the 3 groups at different time points. However, the anti-p155/140 group had significantly decreased ERL counts (P = 0.006) at baseline as well as a prolonged duration of untreated disease at diagnosis (P = 0.027). Also, the anti-p155/140 group had fewer patients with a monophasic disease course than the other 2 groups (P = 0.008). CONCLUSION: Generalized lipodystrophy frequency was equivalent in all 3 groups based on physician assessments and trunk-to-leg fat ratios. The anti-p155/140 group had a greater loss of ERLs, suggesting that this MSA may impact the vascular component of juvenile DM.

Targeting TREM2 on tumor-associated macrophages enhances immunotherapy.

Converting checkpoint inhibitor (CPI)-resistant individuals to being responsive requires identifying suppressive mechanisms. We identify TREM2+ tumor-associated macrophages (TAMs) as being correlated with exhausted CD8+ tumor-infiltrating lymphocytes (TILs) in mouse syngeneic tumor models and human solid tumors of multiple histological types. Fc domain-enhanced anti-TREM2 monoclonal antibody (mAb) therapy promotes anti-tumor immunity by elimination and modulation of TAM populations, which leads to enhanced CD8+ TIL infiltration and effector function. TREM2+ TAMs are most enriched in individuals with ovarian cancer, where TREM2 expression corresponds to disease grade accompanied by worse recurrence-free survival. In an aggressive orthotopic ovarian cancer model, anti-TREM2 mAb therapy drives potent anti-tumor immunity. These results highlight TREM2 as a highly attractive target for immunotherapy modulation in individuals who are refractory to CPI therapy and likely have a TAM-rich tumor microenvironment.

Changes in total body fat and body mass index among children with juvenile dermatomyositis treated with high-dose glucocorticoids.

OBJECTIVE: High-dose glucocorticoids (GC) remain the primary therapy to induce remission in Juvenile Dermatomyositis (JDM). Studies of the natural history of GC associated weight gain in children are very limited, especially in the JDM population. This study aims to measure BMI changes in a cohort of JDM subjects over 60 months and to examine the changes in body composition by DXA. METHODS: We included all subjects with JDM who had 5 years of follow-up data and multiple DXA studies. BMI and total body fat (TBF) percentiles were calculated based on the CDC published percentile charts. To study the natural history of weight gain and TBF, we assessed the data at four-time points (T0 = baseline, T1 > 1.5 years, T2 = 1.51-3.49 years, T3 = 3.5-5 years). RESULTS: 68 subjects (78% female, 70% white) were included in this retrospective study. Paired T-test showed a significant increase in the mean BMI percentile by 17.5 points (P = 0.004) after the initiation of medical treatment, followed by a gradual decrease over the study period. However, the TBF percentile did not change over the study period. TBF in the last visit (T3) had a strong correlation with the T1 BMI, and T1 TBF percentile (correlation coefficients 0.63, 0.56 P < 0.001, 0.002 respectively). Also, there was a positive correlation (correlation coefficients 0.39, P = 0.002) between the TBF percentile and muscle DAS but not the skin DAS. CONCLUSIONS: Although the BMI percentile decreased throughout the study, the TBF percentile remained high until the end of the study (60 months). This finding raises the concern that some of the reduction in the BMI percentile could reflect a drop in the lean body mass from muscle wasting rather than actual fat loss.

Interleukin-22 signaling attenuates necrotizing enterocolitis by promoting epithelial cell regeneration.

Necrotizing enterocolitis (NEC) is a deadly intestinal inflammatory disorder that primarily affects premature infants and lacks adequate therapeutics. Interleukin (IL)-22 plays a critical role in gut barrier maintenance, promoting epithelial regeneration, and controlling intestinal inflammation in adult animal models. However, the importance of IL-22 signaling in neonates during NEC remains unknown. We investigated the role of IL-22 in the neonatal intestine under homeostatic and inflammatory conditions by using a mouse model of NEC. Our data reveal that Il22 expression in neonatal murine intestine is negligible until weaning, and both human and murine neonates lack IL-22 production during NEC. Mice deficient in IL-22 or lacking the IL-22 receptor in the intestine display a similar susceptibility to NEC, consistent with the lack of endogenous IL-22 during development. Strikingly, treatment with recombinant IL-22 during NEC substantially reduces inflammation and enhances epithelial regeneration. These findings may provide a new therapeutic strategy to attenuate NEC.

Endogenous Streptococcus mitis panophthalmitis in a patient visiting the Dominican Republic.

A 67-year-old woman presented with painful, acute vision loss after 5 days of fever and muscle aches while visiting the Dominican Republic. She had no recent history of ocular surgery, dental work or recent trauma. Anterior chamber aspiration confirmed an initial diagnosis of endogenous endophthalmitis, positive for Streptococcus mitis that progressed to panophthalmitis on return to Canada. Treatment included systemic antibiotics, intravitreal antibiotics and intravitreal dexamethasone. Despite the best medical treatment, the left eye progressed to corneal perforation 5 weeks after presentation. An evisceration with fitted orbital implant was successful in alleviating pain following the surgery. S. mitis is a rare, but possible cause of endogenous endophthalmitis and panophthalmitis. It was important to work with a multidisciplinary and global team to coordinate and offer appropriate treatment measures. Although vision was lost, evisceration of the left eye provided ocular comfort and good cosmetic outcomes for the patient.

Leadership development facilitated by the "sandwich" and related glaucoma fellowship programs.

PURPOSE: The purpose of this paper is to evaluate leadership training in the Sandwich Glaucoma Fellowship (SGF), a program in which fellows learn skills in a developed world institution and their home country to become leaders in glaucoma care. DESIGN/METHODOLOGY/APPROACH: This paper is a retrospective, qualitative and quantitative evaluation. Participants of the SGF between 2007 and 2019 were provided a survey eliciting demographic information, leadership training exposure, development of leadership competencies and feedback for the fellowship program. FINDINGS: Seven of nine alumni responded. The fellowship strongly impacted leadership competencies including integrity (8.8, 95% CI 7.8-9.8), work ethic (8.64, 95% CI 7.7-9.6) and empathy (8.6, 95% CI 7.7-9.5). A total of 85% of alumni indicated positive changes in their professional status and described an increasing role in mentorship of colleagues or residents as a result of new skills. Lack of formal leadership training was noted by three respondents. Informal mentorship equipped fellows practicing in regions of Sub Saharan Africa with competencies to rise in their own leadership and mentoring roles related to enhancing glaucoma management. Suggested higher-order learning objectives and a formal curriculum can be included to optimize leadership training catered to the individual fellow experience. ORIGINALITY/VALUE: Leadership is necessary in health care and specifically in the context of low- and middle-income countries to bring about sustainable developments. The SGF contains a unique "Sandwich" design, focusing on the acquisition of medical and leadership skills. This evaluation outlines successes and challenges of this, and similar fellowship programs. Other programs can use a similar model to promote the development of skills in partnership with the fellows' home country to strengthen health-care leaders.

Indole-3-Carbinol-Dependent Aryl Hydrocarbon Receptor Signaling Attenuates the Inflammatory Response in Experimental Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) causes significant morbidity and mortality in premature infants; therefore, the identification of therapeutic and preventative strategies against NEC remains a high priority. The ligand-dependent transcription factor aryl hydrocarbon receptor (AhR) is well known to contribute to the regulation of intestinal microbial communities and amelioration of intestinal inflammation. However, the role of AhR signaling in NEC is unclear. Experimental NEC was induced in 4-d-old wild-type mice or mice lacking AhR expression in the intestinal epithelial cells or AhR expression in CD11c+ cells (AhRΔCD11c) by subjecting animals to twice daily hypoxic stress and gavage feeding with formula supplemented with LPS and enteric bacteria. During NEC, compared with wild-type mice treated with vehicle, littermates treated with an AhR proligand, indole-3-carbinol, had reduced expression of Il1b and Marco, a scavenger receptor that mediates dendritic cell activation and the recognition and clearance of bacterial pathogens by macrophages. Furthermore, indole-3-carbinol treatment led to the downregulation of genes involved in cytokine and chemokine, as revealed by pathway enrichment analysis. AhR expression in the intestinal epithelial cells and their cre-negative mouse littermates were similarly susceptible to experimental NEC, whereas AhRΔCD11c mice with NEC exhibited heightened inflammatory responses compared with their cre-negative mouse littermates. In seeking to determine the mechanisms involved in this increased inflammatory response, we identified the Tim-4- monocyte-dependent subset of macrophages as increased in AhRΔCD11c mice compared with their cre-negative littermates. Taken together, these findings demonstrate the potential for AhR ligands as a novel immunotherapeutic approach to the management of this devastating disease.

Evaluating the Dietary Intakes of Energy, Macronutrients, Sugar, Fiber, and Micronutrients in Children With Celiac Disease.

OBJECTIVES: Children with celiac disease (CD) follow a lifelong gluten-free diet. This restrictive diet may be associated with nutritional compromise. Our objectives were, therefore, to evaluate the dietary composition (energy, macronutrients and micronutrients, and fiber) in children with CD compared with healthy controls (HC) and relationship between dietary composition and socioeconomic status. METHODS: This cross-sectional, case-control study recruited children with CD ages 2 to 18 years and HC matched for age, sex, and socioeconomic status. Clinical, sociodemographic, and dietary information were collected. A false discovery rate correction was applied to the P-value for multiple comparisons (q-value). RESULTS: Sixty-five CD children were matched with 65 HC (mean [SD] age: 10.2 [3.6] vs 10.1 [3.7] years, P = 0.96). Compared with HC, CD children had higher intakes of energy (2413.2 [489.9] vs 2190.8 (593.5) kcal/day, P = 0.02), total fat (818.1 ±â€Š180.9 vs 714.3 ±â€Š212.2 kcal/day, q = 0.018), and subtypes of fat (saturated, polyunsaturated, and monounsaturated). There were no differences in other macronutrients, sugar, micronutrients, or fiber between CD and HC, and no difference in dietary intake among CD between socioeconomic disadvantage versus advantage. Children with CD had lower weight z-scores (-0.06 [1.05] vs 0.47 [0.96], P = 0.003) and body mass index (BMI) z-scores (-0.02 [0.88] vs 0.41 [1.09], P = 0.02) than HC. CONCLUSIONS: Children with CD had higher calorie and fat intake compared with HC. Despite this, CD children had lower weight and BMI z-scores compared with HC.

Micronutrient intake in children with cystic fibrosis in Sydney, Australia.

BACKGROUND: Children with CF have been reported to consume significantly more energy-dense, nutrient-poor foods than controls where there are now concerns of inadequate micronutrient intake. There are no current or comprehensive dietary studies assessing micronutrient intake in CF children. OBJECTIVES: To evaluate micronutrient intake in children with CF compared to recommended dietary intakes (RDIs). METHODS: Dietary intake of 13 micronutrients was measured in CF children aged 2-18 years and age- and sex-matched controls using a validated food frequency questionnaire (The Australian Child and Adolescent Eating Survey). RESULTS: CF children (n = 82) consumed significantly more energy than controls (n = 82) [3142(2531-3822) kcal vs 2216(1660-2941) kcal; p < .001]. Absolute intake in CF children was significantly higher in all micronutrients except vitamin C and folate, however energy-adjusted intake was significantly lower for all micronutrients except vitamin A, sodium, calcium and phosphorous. Energy-adjusted intake in primary school CF children was significantly less than controls in 8/13 micronutrients. Overall, median intakes exceeded the RDIs for all micronutrients however CF children fell short of the RDIs for folate (26.8%), iron (15.9%) and calcium (9.8%). In pre-school, 50% of CF children and 91.7% of controls did not meet the iron RDI. High school CF and control children failed to meet RDIs for 7/13 and 9/13 micronutrients respectively. CONCLUSION: Increased intake of most micronutrients in CF children was largely attributed to higher energy consumption. However, micronutrient density of the diet declined with increasing age, where high school children failed to meet RDIs for most key micronutrients.

Phenotypic heterogeneity and evolution of melanoma cells associated with targeted therapy resistance.

Phenotypic plasticity is associated with non-genetic drug tolerance in several cancers. Such plasticity can arise from chromatin remodeling, transcriptomic reprogramming, and/or protein signaling rewiring, and is characterized as a cell state transition in response to molecular or physical perturbations. This, in turn, can confound interpretations of drug responses and resistance development. Using BRAF-mutant melanoma cell lines as the prototype, we report on a joint theoretical and experimental investigation of the cell-state transition dynamics associated with BRAF inhibitor drug tolerance. Thermodynamically motivated surprisal analysis of transcriptome data was used to treat the cell population as an entropy maximizing system under the influence of time-dependent constraints. This permits the extraction of an epigenetic potential landscape for drug-induced phenotypic evolution. Single-cell flow cytometry data of the same system were modeled with a modified Fokker-Planck-type kinetic model. The two approaches yield a consistent picture that accounts for the phenotypic heterogeneity observed over the course of drug tolerance development. The results reveal that, in certain plastic cancers, the population heterogeneity and evolution of cell phenotypes may be understood by accounting for the competing interactions of the epigenetic potential landscape and state-dependent cell proliferation. Accounting for such competition permits accurate, experimentally verifiable predictions that can potentially guide the design of effective treatment strategies.

Post-discharge Medication Reconciliation: Reduction in Readmissions in a Geriatric Primary Care Clinic.

Objectives: This study aimed to evaluate hospital utilization and characterize interventions of pharmacist-led telephonic post-discharge medication reconciliation. Method: A retrospective analysis was conducted, including 833 index events in 586 geriatric patients receiving the intervention. Medicare claims were used to capture 30-day hospital utilization (admission to the emergency department, observation unit, or inpatient hospitalization) following discharge from any of these locations. Medication-related interventions were described. Results: Hospital utilization within 30 days after discharge from any location was greater for patients receiving usual care compared with the intervention (32.5% vs. 22.2%; odds ratio [OR] = 1.69, 95% confidence interval [CI] = [1.06, 2.68]). Inpatient admission within 30 days after discharge from any location was greater for those receiving usual care (14.7% vs. 6.4%; OR = 2.54, 95% CI = [1.18, 5.44]). At least one medication-related problem was identified and addressed in 89.8% of patients receiving the intervention. Discussion: A telephonic post-discharge medication reconciliation program can lead to reduction in hospital utilization in a geriatric population.

Dietary intake of energy-dense, nutrient-poor and nutrient-dense food sources in children with cystic fibrosis.

BACKGROUND: Prescription of a high-energy, high-fat diet is a mainstay of nutrition management in cystic fibrosis (CF). However, families may be relying on energy-dense, nutrient-poor (EDNP) foods rather than nutrient-dense (ND) foods to meet dietary targets. We aimed to evaluate the relative contribution of EDNP and ND foods to the usual diets of children with CF and identify sociodemographic factors associated with higher EDNP intakes. METHODS: This is a cross-sectional comparison of children with CF aged 2-18 years and age- and gender-matched controls. Dietary intake was assessed using the Australian Child and Adolescent Eating Survey (ACAES) food frequency questionnaire. RESULTS: Children with CF (n = 80: 37 males; mean age 9.3 years) consumed significantly more EDNP foods than controls (mean age 9.8 years) in terms of both total energy (median [IQR]: 1301 kcal/day (843-1860) vs. 686 kcal/day (480-1032); p < 0.0001), and as a proportion of energy intake (median [IQR]: 44% (34-51) vs. 31% (24-43); p < 0.0001). Although children with CF met their estimated energy requirements (median [IQR]: 158% (124-187) vs. 112% (90-137); p < 0.0001) and their diets were high in fat (median [IQR]: 38% (35-41) vs. 34% (32-36); p < 0.0001), this was largely attributable to EDNP foods. High EDNP intakes (≥10 serves/day) were associated with socioeconomic disadvantage (p = 0.01) and rural residential location (p = 0.03). DISCUSSION: The energy- and fat-dense CF diet is primarily achieved by overconsumption of EDNP foods, rather than ND sources. This dietary pattern may not be optimal for the future health of children with CF, who are now expected to survive well into adulthood.

Breast Milk Enhances Growth of Enteroids: An Ex Vivo Model of Cell Proliferation.

Human small intestinal enteroids are derived from the crypts and when grown in a stem cell niche contain all of the epithelial cell types. The ability to establish human enteroid ex vivo culture systems are important to model intestinal pathophysiology and to study the particular cellular responses involved. In recent years, enteroids from mice and humans are being cultured, passaged, and banked away for future use in several laboratories across the world. This enteroid platform can be used to test the effects of various treatments and drugs and what effects are exerted on different cell types in the intestine. Here, a protocol for establishing primary stem cell-derived small intestinal enteroids derived from neonatal mice and premature human intestine is provided. Moreover, this enteroid culture system was utilized to test the effects of species-specific breast milk. Mouse breast milk can be obtained efficiently using a modified human breast pump and expressed mouse milk can then be used for further research experiments. We now demonstrate the effects of expressed mouse, human, and donor breast milk on the growth and proliferation of enteroids derived from neonatal mice or premature human small intestine.

Impaired resting vagal tone in patients with functional movement disorders.

INTRODUCTION: The autonomic nervous system plays an integral role in the maintenance of homeostasis during times of stress. The functioning of the autonomic nervous system in patients with functional movement disorders (FMD) is of particular interest given the hypothesis that converted psychological stress plays a critical role in FMD disease pathogenesis. We sought to investigate autonomic nervous system activity in FMD patients by examining heart rate variability (HRV), a quantitative marker of autonomic function. METHODS: 35 clinically definite FMD patients and 38 age- and sex-matched healthy controls were hospitalized overnight for continuous electrocardiogram recording. Standard time and frequency domain measures of HRV were calculated in the awake and asleep stages. All participants underwent a thorough neuropsychological battery, including the Hamilton Anxiety and Depression scales and the Beck Depression Inventory. RESULTS: Compared to controls, patients with FMD exhibited decreased root mean square of successive differences between adjacent NN intervals (RMSSD) (p = 0.02), a marker of parasympathetic activity, as well as increased mean heart rate (p = 0.03). These measures did not correlate with the depression and anxiety scores included in our assessment as potential covariates. CONCLUSION: In this exploratory study, patients with FMD showed evidence of impaired resting state vagal tone, as demonstrated by reduced RMSSD. This decreased vagal tone may reflect increased stress vulnerability in patients with FMD.