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Pre-Existing Immunocompromising Conditions and Outcomes of Acute COVID-19 Patients Admitted for Pediatric Intensive Care
No full textBACKGROUND: We aimed to determine if pre-existing immunocompromising conditions (ICCs) were associated with the presentation or outcome of patients with acute coronavirus disease 2019 (COVID-19) admitted for pediatric intensive care. METHODS: Fifty-five hospitals in 30 US states reported cases through the Overcoming COVID-19 public health surveillance registry. Patients \u3c21 years admitted 12 March 2020-30 December 2021 to the pediatric intensive care unit (PICU) or high-acuity unit for acute COVID-19 were included. RESULTS: Of 1274 patients, 105 (8.2%) had an ICC, including 33 (31.4%) hematologic malignancies, 24 (22.9%) primary immunodeficiencies and disorders of hematopoietic cells, 19 (18.1%) nonmalignant organ failure with solid-organ transplantation, 16 (15.2%) solid tumors, and 13 (12.4%) autoimmune disorders. Patients with ICCs were older, had more underlying renal conditions, and had lower white blood cell and platelet counts than those without ICCs, but had similar clinical disease severity upon admission. In-hospital mortality from COVID-19 was higher (11.4% vs 4.6%, P = .005) and hospitalization was longer (P = .01) in patients with ICCs. New major morbidities upon discharge were not different between those with and without ICC (10.5% vs 13.9%, P = .40). In patients with ICCs, bacterial coinfection was more common in those with life-threatening COVID-19. CONCLUSIONS: In this national case series of patients \u3c21 years of age with acute COVID-19 admitted for intensive care, existence of a prior ICCs were associated with worse clinical outcomes. Reassuringly, most patients with ICCs hospitalized in the PICU for severe acute COVID-19 survived and were discharged home without new severe morbidities
Sex Differences in Perihematomal Edema Volume and Outcome After Intracerebral Hemorrhage
No full textBACKGROUND: Although larger hematoma volume is associated with worse outcome after intracerebral hemorrhage (ICH), the association between perihematomal edema (PHE) volume and outcome remains uncertain, as does the impact of sex on PHE and outcome. Here we aimed to determine whether larger PHE volume is associated with worse outcome and whether PHE volume trajectories differ by sex. METHODS: We conducted a post hoc analysis of the Factor VIIa for Acute Hemorrhagic Stroke Treatment (FAST) trial, which randomized patients with ICH to receive recombinant activated factor VIIa or placebo. Computerized planimetry calculated PHE and ICH volumes on serial computed tomography (CT) scans (at baseline [within 3 h of onset], at 24 h, and at 72 h). Generalized estimating equations examined interactions between sex, CT time points, and FAST treatment arm on PHE and ICH volumes. Mixed and multivariable logistic models examined associations between sex, PHE, and outcomes. RESULTS: A total of 781 patients with supratentorial ICH (mean age 65 years) were included. Compared to women (n = 296), men (n = 485) had similar median ICH (14.9 vs. 13.6 mL, p = 0.053) and PHE volumes (11.1 vs. 10.5 mL, p = 0.56) at baseline but larger ICH and PHE volumes at 24 h (19.0 vs. 14.0 mL, p \u3c 0.001; 22.2 vs. 15.7 mL, p \u3c 0.001) and 72 h (16.0 vs. 11.8 mL, p \u3c 0.001; 28.7 vs. 19.9 mL, p \u3c 0.001). Men had higher absolute early PHE expansion (p \u3c 0.001) and more hematoma expansion (growth ≥ 33% or 6 mL at 24 h, 33% vs. 22%, p \u3c 0.001). An interaction between sex and CT time points on PHE volume (p \u3c 0.001), but not on ICH volume, confirmed a steeper PHE trajectory in men. PHE expansion (per 5 mL, odds radio 1.19, 95% confidence interval 1.10-1.28), but not sex, was associated with poor outcome. CONCLUSIONS: Early PHE expansion and trajectory in men were significantly higher. PHE expansion was associated with poor outcomes independent of sex. Mechanisms leading to sex differences in PHE trajectories merit further investigation
Zelquistinel Acts at an Extracellular Binding Domain to Modulate Intracellular Calcium Inactivation of N-Methyl-D-Aspartate Receptors
No full textStinels are a novel class of N-methyl-d-aspartate glutamate receptor (NMDAR) positive allosteric modulators. We explored mechanism of action and NR2 subtype specificity of the stinel zelquistinel (ZEL) in HEK 293 cells expressing recombinant NMDARs. ZEL potently enhanced NMDAR current at NR2A (EC50 = 9.9 ± 0.5 nM) and NR2C-containing (EC50 = 9.7 ± 0.6 nM) NMDARs, with a larger ceiling enhancement at NR2B-NMDAR (EC50 = 35.0 ± 0.7 nM), while not affecting NR2D-containing NMDARs. In cells expressing NR2A and NR2C-containing NMDARs, ZEL exhibited an inverted-U dose-response relation, with a low concentration enhancement and high concentration suppression of NMDAR currents. Extracellular application of ZEL potentiated NMDAR receptor activity via prolongation of NMDAR currents. Replacing the slow Ca intracellular chelator EGTA with the fast chelator BAPTA blocked ZEL potentiation of NMDARs, suggesting an action on intracellular Ca-calmodulin-dependent inactivation (CDI). Consistent with this mechanism of action, removal of the NR1 intracellular C-terminus, or intracellular infusion of a calmodulin blocking peptide, blocked ZEL potentiation of NMDAR current. In contrast, BAPTA did not prevent high-dose suppression of current, indicating this effect has a different mechanism of action. These data indicate ZEL is a novel positive allosteric modulator that binds extracellularly and acts through a unique long-distance mechanism to reduce NMDAR CDI, eliciting enhancement of NMDAR current. The critical role that NMDARs play in long-term, activity-dependent synaptic plasticity, learning, memory and cognition, suggests dysregulation of CDI may contribute to psychiatric disorders such as depression, schizophrenia and others, and that the stinel class of drugs can restore NMDAR-dependent synaptic plasticity by reducing activity-dependent CDI
Escalation From Impella 5.5 to ECPELLA Support as a Bridge to Mitral Valve Surgery in a Patient With Degenerative Mitral Regurgitation
No full textSevere mitral regurgitation (MR) is an important cause of acute heart failure and significant contributor to morbidity and mortality. Mechanical circulatory support (MCS) devices such as Impella are readily used to hemodynamically stabilize patients with cardiogenic shock (CS) secondary to this valvular pathology. Impella can also be combined with VA-ECMO to an ECPELLA configuration if further escalation of hemodynamic support is needed. We report a case of a 57-year-old female who presented with CS secondary to a perforated anterior mitral valve leaflet and non-ischemic cardiomyopathy that did not stabilize with initial choice of Impella 5.5. She required further escalation from axillary Impella 5.5 to the combined ECPELLA configuration, which allowed hemodynamic stabilization and ultimately a successful high-risk isolated mitral valve replacement. Despite adequate Impella flow, escalation to a combined MCS configuration, such as ECPELLA, may need to be considered upfront for acute valvular insufficiency in the setting of pre-existing cardiomyopathy
Impact of Demographics and Insurance Coverage on Schizophrenia Treatment and Healthcare Resource Utilization Within an Integrated Healthcare System
No full textPURPOSE: Little is known about the impact of health disparities on antipsychotic treatment and healthcare resource utilization (HRU) among patients with schizophrenia. The objective of this analysis is to examine treatment patterns and HRU by age, race/ethnicity, and insurance coverage among patients with schizophrenia in an integrated delivery network (IDN). PATIENTS AND METHODS: This cross-sectional study used electronic health record data from MedStar Health, an IDN in the Baltimore-Washington, DC, area. Patients were aged ≥18 years and had ≥2 outpatient encounters or ≥1 hospitalization with a diagnosis of schizophrenia between January 1, 2017 and March 31, 2021. Outcomes assessed included oral antipsychotic prescriptions, long-acting injectable antipsychotic (LAI) utilization, hospitalizations, emergency department (ED) visits, and outpatient visits. Analyses compared subgroups based on age, race/ethnicity (non-Hispanic Black, non-Hispanic White, and other), and type of insurance coverage at index (Medicare, Medicaid, and other) during 12 months of follow-up. RESULTS: A total of 78.1% of patients had ≥1 prescription for an antipsychotic and 69.1% received ≥1 second-generation antipsychotic. Second-generation long-acting injectables (SGA LAI) were utilized by 9.0% of patients, with the elderly and Medicaid beneficiaries having the lowest SGA LAI utilization. Overall, 61.7% of patients had ≥1 hospitalization, 56.4% had ≥1 outpatient visit, and 50.5% had ≥1 ED visit. Hospitalizations and ED visits were most common in those 18 to 24 years of age and in Medicaid beneficiaries, whereas outpatient visits were more common for the elderly and Medicare beneficiaries. CONCLUSION: At the population level, the results indicate widespread underprescription/underutilization of antipsychotics that have been shown to improve clinical and economic outcomes in patients with schizophrenia, particularly SGA LAI. Within specific subpopulations, disparities in treatment selection and HRU were observed, suggesting the need for increased attention to at-risk groups to ensure consistent quality of care regardless of age, race/ethnicity, or insurance coverage
Comparative Analysis of Low-Dose Oral Minoxidil With Spironolactone versus Finasteride or Dutasteride in Female Androgenetic Alopecia Management
No full textLDOM has enhanced treatment options for female AGA, yet its combined efficacy with therapies such as spironolactone, finasteride, or dutasteride remains inadequately explored. This study aims to compare the efficacy and safety of LDOM in combination with spironolactone versus LDOM with finasteride or dutasteride in women with AGA. Our analysis revealed that both combination therapies produced similar improvements in hair growth and had comparable safety profiles. Although the LDOM with finasteride/dutasteride group showed a greater average increase in hair width and density, these differences were not statistically significant. These results endorse the use of LDOM in combination with either spironolactone or finasteride/dutasteride for female AGA, and underscore the necessity for further research to validate these findings and assess long-term treatment outcomes
Forecasting the Effects of Smoking Prevalence Scenarios on Years of Life Lost and Life Expectancy From 2022 to 2050: A Systematic Analysis for the Global Burden of Disease Study 2021
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Rethinking Teacher Education: The Impact of a K-12 Online Learning Curriculum on In-Service Teachers
No full textPopulation Pharmacokinetics of Single Bolus Dose Fentanyl in Obese Children
No full textBACKGROUND: Childhood obesity is a significant problem. Obesity may alter the pharmacokinetics (PKs) of medications. Fentanyl is commonly used for procedural sedation, but there is a paucity of bolus dose fentanyl PK data in obese children. Better understanding of fentanyl PK in obese children would facilitate dosing recommendations. We conducted a study involving children with and without obesity to assess the potential differences in bolus dose fentanyl PK between the 2 groups.
METHODS: We enrolled children 2 to 12 years of age with and without obesity, defined as \u3e95th percentile body mass index (BMI) for age and sex, undergoing elective tonsillectomy ± adenoidectomy. After induction, subjects had 2 intravenous (IV) lines placed in 2 different extremities: 1 for medications and IV fluids and 1 for obtaining blood aliquots for fentanyl concentration analysis. After administration of 1 mcg/kg of fentanyl based on total body weight (TBW), blood sample collections for fentanyl concentration analysis were attempted at 5, 15, 30, 60, 90, and 120 minutes. Five-minute fentanyl concentrations were compared between obese and nonobese cohorts. Population PK analysis to examine the differences between obese and nonobese children was performed and included various body size descriptors, such as TBW, BMI, and fat-free mass (FFM), to examine their influence on model parameters.
RESULTS: Half of the 30 subjects were obese. Mean fentanyl concentrations at 5 minutes were 0.53 ng/mL for the nonobese group and 0.88 ng/mL for the obese group, difference 0.35 ng/mL (95% CI, 0.08-0.61 ng/mL; P = .01). Population PK analysis showed that FFM was a significant covariate for the central volume of distribution. The potential clinical effect of an IV bolus dose of fentanyl based on TBW versus FFM in an obese child was assessed in a simulation using our model. 1 mcg/kg fentanyl dose based on TBW resulted in an approximately 60% higher peak fentanyl effect site concentration than dosing based on FFM.
CONCLUSIONS: Our data demonstrated higher peak plasma fentanyl concentrations in obese compared to nonobese subjects. Population PK analysis found that FFM was a significant covariate for the central volume of distribution. Model simulation showed dosing of fentanyl in obese children based on TBW resulted in significantly higher peak concentrations than dosing based on FFM. Based on this modeling and the known concentration-effect relationship between fentanyl and adverse effects, our results suggest that bolus dosing of fentanyl in obese children should be based on FFM rather than TBW, particularly for procedures of short duration