Transcript Profiles of Microglia/Macrophage Cells at the Borders of Chronic Active and Subpial Gray Matter Lesions in Multiple Sclerosis.

OBJECTIVE: Microglia/macrophages line the border of demyelinated lesions in both cerebral white matter and the cortex in the brains of multiple sclerosis patients. Microglia/macrophages associated with chronic white matter lesions are thought to be responsible for slow lesion expansion and disability progression in progressive multiple sclerosis, whereas those lining gray matter lesions are less studied. Profiling these microglia/macrophages could help to focus therapies on genes or pathways specific to lesion expansion and disease progression. METHODS: We compared the morphology and transcript profiles of microglia/macrophages associated with borders of white matter (WM line) and subpial gray matter lesions (GM line) using laser capture microscopy. We performed RNA sequencing on isolated cells followed by immunocytochemistry to determine the distribution of translational products of transcripts increased in WM line microglia. RESULTS: Cells in the WM line appear activated, with shorter processes and larger cell bodies, whereas those in the GM line appear more homeostatic, with smaller cell bodies and multiple thin processes. Transcript profiling revealed 176 genes in WM lines and 111 genes in GM lines as differentially expressed. Transcripts associated with immune activation and iron homeostasis were increased in WM line microglia, whereas genes belonging to the canonical Wnt signaling pathway were increased in GM line microglia. INTERPRETATION: We propose that the mechanisms of demyelination and dynamics of lesion expansion are responsible for differential transcript expression in WM lines and GM lines, and posit that increased expression of the Fc epsilon receptor, spleen tyrosine kinase, and Bruton's tyrosine kinase, play a key role in regulating microglia/macrophage function at the border of chronic active white matter lesions. ANN NEUROL 2024;95:907-916.

EMS Administration of Systemic Corticosteroids to Pediatric Asthma Patients: An Analysis by Severity and Transport Interval.

INTRODUCTION: Pediatric asthma exacerbations are a common cause of emergency medical services (EMS) encounters. Bronchodilators and systemic corticosteroids are mainstays of asthma exacerbation therapy, yet data on the efficacy of EMS administration of systemic corticosteroids are mixed. This study's objective was to assess the association between EMS administration of systemic corticosteroids to pediatric asthma patients on hospital admission rates based on asthma exacerbation severity and EMS transport intervals. METHODS: This is a sub-analysis of the Early Administration of Steroids in the Ambulance Setting: An Observational Design Trial (EASI AS ODT). EASI AS ODT is a non-randomized, stepped wedge, observational study examining outcomes one year before and one year after seven EMS agencies incorporated an oral systemic corticosteroid option into their protocols for the treatment of pediatric asthma exacerbations. We included EMS encounters for patients ages 2-18 years confirmed by manual chart review to have asthma exacerbations. We compared hospital admission rates across asthma exacerbation severities and EMS transport intervals using univariate analyses. We geocoded patients and created maps to visualize the general trends of patient characteristics. RESULTS: A total of 841 pediatric asthma patients met inclusion criteria. While most patients were administered inhaled bronchodilators by EMS (82.3%), only 21% received systemic corticosteroids, and only 19% received both inhaled bronchodilators and systemic corticosteroids. Overall, there was no significant difference in hospitalization rates between patients who did and did not receive systemic corticosteroids from EMS (33% vs. 32%, p = 0.78). However, although not statistically significant, for patients who received systemic corticosteroids from EMS, there was an 11% decrease in hospitalizations for mild exacerbation patients and a 16% decrease in hospitalizations for patients with EMS transport intervals greater than 40 min. CONCLUSION: In this study, systemic corticosteroids were not associated with a decrease in hospitalizations of pediatric patients with asthma overall. However, while limited by small sample size and lack of statistical significance, our results suggest there may be a benefit in certain subgroups, particularly patients with mild exacerbations and those with transport intervals longer than 40 min. Given the heterogeneity of EMS agencies, EMS agencies should consider local operational and pediatric patient characteristics when developing standard operating protocols for pediatric asthma.

Early Administration of Steroids in the Ambulance Setting: An Observational Design Trial (EASI-AS-ODT).

BACKGROUND: In the emergency department (ED), prompt administration of systemic corticosteroids for pediatric asthma exacerbations decreases hospital admission rates. However, there is sparse evidence for whether earlier administration of systemic corticosteroids by emergency medical services (EMS) clinicians, prior to ED arrival, further improves pediatric asthma outcomes. METHODS: Early Administration of Steroids in the Ambulance Setting: An Observational Design Trial is a multicenter, observational, nonrandomized stepped-wedge design study with seven participating EMS agencies who adopted an oral systemic corticosteroid (OCS) into their protocols for pediatric asthma treatment. Using univariate analyses and multivariable mixed-effects models, we compared hospital admission rates for pediatric asthma patients ages 2-18 years before and after the introduction of a prehospital OCS and for those who did and did not receive a systemic corticosteroid from EMS. RESULTS: A total of 834 patients were included, 21% of whom received a systemic corticosteroid from EMS. EMS administration of systemic corticosteroids increased after the introduction of an OCS from 14.7% to 28.1% (p < 0.001). However, there was no significant difference between hospital admission rates and ED length of stay before and after the introduction of OCS or between patients who did and did not receive a systemic corticosteroid from EMS. Mixed-effects models revealed that age 14-18 years (coefficient -0.83, p = 0.002), EMS administration of magnesium (coefficient 1.22, p = 0.04), and initial EMS respiratory severity score (coefficient 0.40, p < 0.001) were significantly associated with hospital admission. CONCLUSIONS: In this multicenter study, the addition of an OCS into EMS agency protocols for pediatric asthma exacerbations significantly increased systemic corticosteroid administration but did not significantly decrease hospital admission rates. As overall EMS systemic corticosteroid administration rates were low, further work is required to understand optimal implementation of EMS protocol changes to better assess potential benefits to patients.

Absorption, Metabolism, and Excretion of [14C]-Tolebrutinib After Oral Administration in Humans, Contribution of the Metabolites to Pharmacological Activity.

BACKGROUND AND OBJECTIVE: Tolebrutinib is a covalent inhibitor of Bruton's tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are thought to be major drivers of inflammation in multiple sclerosis. This excretion balance and metabolism study evaluated the metabolite profile of tolebrutinib in healthy male volunteers. METHODS: Six healthy volunteers received a 60-mg oral dose of [14C]-tolebrutinib, and metabolite profiling of 14C-labeled metabolites was performed using a combination of liquid chromatography, mass spectrometry, and radioactivity assay methods. RESULTS: Tolebrutinib was rapidly and completely absorbed from the gastrointestinal tract, followed by rapid and extensive metabolism. Excretion via feces was the major elimination pathway of the administered radioactivity (78%). Tolebrutinib was highly metabolized, with 19 metabolites identified in human plasma. Phase 1 biotransformations were primarily responsible for the circulating metabolites in plasma. Seven metabolites that achieved exposure in plasma similar to or higher than the parent compound were characterized biochemically for inhibition of Bruton's tyrosine kinase activity. Metabolite M8 exceeded the exposure threshold of 10% (18%) of the total radioactivity but had little if any pharmacological activity. Metabolite M2 (4% of circulating radioactivity) retained the ability to irreversibly and potently inhibit Bruton's tyrosine kinase in vitro, similar to the parent compound. Tolebrutinib and metabolite M2 had short (3.5-h) half-lives but durable pharmacodynamic effects as expected for an irreversible antagonist. CONCLUSIONS: Tolebrutinib was extensively metabolized to multiple metabolites. The hydroxylated metabolite M2 demonstrated similar inhibitory potency toward Bruton's tyrosine kinase as the parent compound. Both tolebrutinib and metabolite M2 likely contributed to pharmacological activity in vivo.

Examination of disparities in prehospital encounters for pediatric asthma exacerbations.

Introduction: There are disparities in multiple aspects of pediatric asthma care; however, prehospital care disparities are largely undescribed. This study's objective was to examine racial and geographic disparities in emergency medical services (EMS) medication administration to pediatric patients with asthma. Methods: This is a substudy of the Early Administration of Steroids in the Ambulance Setting: An Observational Design Trial, which includes data from pediatric asthma patients ages 2-18 years. We examined rates of EMS administration of systemic corticosteroids and inhaled bronchodilators by patient race. We geocoded EMS scene addresses, characterized the locations' neighborhood-based conditions and resources relevant to children using the Child Opportunity Index (COI) 2.0, and analyzed associations between EMS scene address COI with medications administered by EMS. Results: A total of 765 patients had available racial data and 825 had scene addresses that were geocoded to a COI. EMS administered at least 1 bronchodilator to 84.7% (n = 492) of non-White patients and 83.2% of White patients (n = 153), P = 0.6. EMS administered a systemic corticosteroid to 19.4% (n = 113) of non-White patients and 20.1% (n = 37) of White patients, P = 0.8. There was a significant difference in bronchodilator administration between COI categories of low/very low versus moderate/high/very high (85.0%, n = 485 vs. 75.9%, n = 192, respectively, P = 0.003). Conclusions: There were no racial differences in EMS administration of medications to pediatric asthma patients. However, there were significantly higher rates of EMS bronchodilator administration for encounters in low/very low COIs. That latter finding may reflect inequities in asthma exacerbation severity for patients living in disadvantaged areas.

Disneyization: A framework for understanding illicit drug use in bounded play spaces.

BACKGROUND: This paper combines evidence from an ethnographic study of illicit drug use amongst tourists in Ibiza with Bryman's (2004) theoretical model of Disneyization. The principal aim was to construct a new conceptual framework that may help scholars, practitioners and policy makers make sense of dynamic patterns of illegal drug use across bounded play spaces such as tourist resorts, music festivals and nightclubs. METHODS: Ethnographic fieldwork employing a grounded theory design was undertaken over three summers in tourist locations on the Balearic island of Ibiza, including nightclubs, bars, cafes, beaches, airports and hotels. Field notes from participant observation were supplemented with data from semi-structured interviews (n = 56) and secondary sources gathered from tourist marketing. RESULTS: The framework of Disneyization has been discussed in terms of 5 constructs: theming, hybrid consumption, branding, performative labour and atmospheres; each having a specific role in relation to understanding illicit drug use in bounded play spaces. Thus: Theming sets the stage, by physically and symbolically demarcating space with indelible themes of hedonism that open up the possibility of illicit drug use. Hybrid-consumption blurs the distinction between legal and illegal forms of intoxication, making the trading and consumption of illegal drugs appear like a natural feature of the consumer space. Branding demonstrates how participants construct intricate hierarchies of taste and credibility related to drug of choice. Performative labour re-enforces hybrid consumption, with participants working in the bounded play spaces of Ibiza immersed within the illicit drug market. Atmospheres represents the alchemic synergy of bounded play space and is important to understanding illicit drug use as a sensorial, deeply immersive but transitory experience. CONCLUSION: This research offers Disneyization as a new conceptual framework for making sense of deeply complex spatial, socio-cultural, psychological and economic processes that underpin dynamic patterns of drug use in bounded play spaces.

Accuracy and predictability of the compensatory function of Orbscan II in intraocular pressure measurements after laser in situ keratomileusis.

PURPOSE: To evaluate the usefulness of the compensatory function of Orbscan II (Orbtek, Bausch & Lomb) for measuring postoperative intraoperative pressure (IOP) in laser in situ keratomileusis (LASIK) patients. SETTING: Department of Ophthalmology, Ilsan Paik Hospital, Inje University, Ilsan, Korea. METHODS: Two hundred ten patients had LASIK using the Hansatome microkeratome (Bausch & Lomb) and the MEL 70 G-scan laser (Aesclepion-Meditec) and were examined retrospectively. The patients included in the study were divided into 2 groups: Group 1, 123 eyes with less than -6.0 diopters (D) of myopia; Group 2, 60 eyes with more than -6.0 D of myopia. The IOP was measured preoperatively and 2 and 4 weeks after LASIK using a noncontact tonometer (NCT CT-60, Topcon). The results were corrected with the Orbscan II program. RESULTS: The mean IOPs in Group 1 were 16.35 mm Hg +/- 2.90 (SD) preoperatively, 10.80 +/- 2.21 mm Hg at 2 weeks, and 10.63 +/- 2.28 mm Hg at 4 weeks. After compensation with Orbscan II, the 2-week and 4-week values were 16.81 +/- 3.14 mm Hg and 16.68 +/- 3.22 mm Hg, respectively. The mean IOPs in Group 2 were 17.63 +/- 2.93 mm Hg, 10.07 +/-1.55 mm Hg, and 10.43 +/- 1.84 mm Hg, respectively; after compensation, they were 18.40 +/- 4.09 mm Hg and 18.05 +/- 4.09 mm Hg, respectively. After compensation with Orbscan II, there were no statistically significant differences between the preoperative and postoperative IOPs. CONCLUSIONS: Orbscan II may help predict actual IOP values after LASIK and avoid the misinterpretation of high IOPs as normal IOPs.

The practical synthesis of a novel and highly potent analogue of bryostatin.

Macrocycle 1 is a new highly potent analogue of bryostatin 1, a promising anti-cancer agent currently in human clinical trials. In vitro, 1 displays picomolar affinity for PKC and exhibits over 100-fold greater potency than bryostatin 1 when tested against various human cancer cell lines. Macrocycle 1 can be generated in clinically required amounts by chemical synthesis in only 19 steps (LLS) and represents a new clinical lead for the treatment of cancer.