Distinct Airway Inflammatory Pathways Associated with Asthma Exacerbations are Modulated by Mepolizumab Therapy in Children

Rationale: Identification of specific airway inflammatory pathways can lead to effective personalized treatment with biologics in asthma and insights to mechanisms of action. Methods: 290 urban children with exacerbation-prone asthma and ≥150/mm3 blood eosinophils were randomized (1:1) to placebo or mepolizumab added to guideline-based care. Nasal lavage samples were collected at randomization and during treatment for RNA-sequencing, and analyzed by cell-deconvolution modular analysis to assess genome-wide expression patterns associated with exacerbation number and effect of treatment. Results: Mepolizumab significantly reduced the frequency of exacerbations compared to placebo. At randomization, there were no differences in expression between treatment groups; multiple modules were subsequently differentially expressed during mepolizumab but not placebo treatment. Furthermore, expression levels of multiple modules were associated with the exacerbation number during the study, with distinct relationships observed in the placebo and/or mepolizumab groups. Notably, higher expression at randomization of an eosinophil-associated module enriched for Type-2 genes including IL4, IL5, and IL13, was associated with increased exacerbations in placebo (β=0.19, p\u3c0.001), but not mepolizumab-treated children (interaction p\u3c0.01). Furthermore, mepolizumab treatment reduced expression of this module (Fold-change=0.62, p\u3c0.001). In contrast, higher expression at randomization of an eosinophil-associated module enriched for eosinophil activation (e.g. CD9) and mucus hypersecretion (e.g. MUC5AC) genes was associated with exacerbation number in both groups throughout the study (β=0.18, p\u3c0.01) and was unaltered by mepolizumab therapy. Conclusions: Multiple distinct airway inflammation patterns were identified associated with exacerbation frequency. These findings identify inflammatory endotypes and indicate likelihood and potential mechanisms of a beneficial clinical response to mepolizumab therapy to prevent exacerbations

Binary systems and their nuclear explosions

Peer ReviewedPreprin

Cutaneous Mucormycosis in Solid Organ Transplant Recipients after Hurricane Harvey: Short- and Long-term Management

Summary:. In the fall of 2017, Hurricane Harvey, one of the most costly hurricanes in American history, ravaged the Texas Gulf Coast, interrupting basic sanitation systems to hundreds of thousands of Texas residents. In the aftermath of Hurricane Harvey, our Houston hospitals noted an uptick in the incidence of cases of mucormycosis. Among the most vulnerable and affected have been immunocompromised transplant recipients. Here, we describe the successful management of 2 patients with atypical presentations of mucormycosis, 2 cutaneous infections after liver transplantation. Our comprehensive treatment strategy based upon guidelines and experience included coordinating aggressive surgical and medical therapies. We discuss our approach to surgical management including the extent and frequency of debridement, the methods of assessing disease-free margins, and minimizing the morbidity of radical debridement with temporary coverage and forethought to long-term reconstruction. Additionally, we describe the concurrent medical management, including type, route, and duration of antifungal therapy, minimizing suppression of the innate immune system, and optimizing the wound healing environment through maintaining nutritional status

Sentinel node in oral cancer: the nuclear medicine aspects: a survey from the sentinel european node trial

PURPOSE: Nuclear imaging plays a crucial role in lymphatic mapping of oral cancer. This evaluation represents a subanalysis of the original multicenter SENT trial data set, involving 434 patients with T1-T2, N0, and M0 oral squamous cell carcinoma. The impact of acquisition techniques, tracer injection timing relative to surgery, and causes of false-negative rate were assessed. METHODS: Three to 24 hours before surgery, all patients received a dose of Tc-nanocolloid (10-175 MBq), followed by lymphoscintigraphy. According to institutional protocols, all patients underwent preoperative dynamic/static scan and/or SPECT/CT. RESULTS: Lymphoscintigraphy identified 723 lymphatic basins. 1398 sentinel lymph nodes (SNs) were biopsied (3.2 SN per patient; range, 1-10). Dynamic scan allowed the differentiation of sentinel nodes from second tier lymph nodes. SPECT/CT allowed more accurate anatomical localization and estimated SN depth more efficiently. After pathological examination, 9.9% of the SN excised (138 of 1398 SNs) showed metastases. The first neck level (NL) containing SN+ was NL I in 28.6%, NL IIa in 44.8%, NL IIb in 2.8%, NL III in 17.1%, and NL IV in 6.7% of positive patients. Approximately 96% of positive SNs were localized in the first and second lymphatic basin visualized using lymphoscintigraphy. After neck dissection, the SN+ was the only lymph node containing metastasis in approximately 80% of patients. CONCLUSIONS: Best results were observed using a dynamic scan in combination with SPECT/CT. A shorter interval between tracer injection, imaging, and surgery resulted in a lower false-negative rate. At least 2 NLs have to be harvested, as this may increase the detection of lymphatic metastases

Phenotype-directed Therapy with Mepolizumab for Urban Children with Exacerbation-Prone Asthma

Rationale: Asthma exacerbations are common in urban children and have significant short- and long-term consequences. Elevated peripheral blood and airway eosinophils have been identified as risk factors for exacerbations, and therapies targeting these biomarkers reduce exacerbations in adults; however, data on anti-eosinophil treatment in children and adolescents are limited. The primary objective of this study is to determine if phenotype-directed use of mepolizumab reduces the rate of asthma exacerbations in urban children. Methods: Urban children 6-17 years of age (n=290) with exacerbation-prone asthma (2+ exacerbations in previous year) and blood eosinophils ≥150/mm3 were randomized 1:1 to mepolizumab (6-11 years: 40 mg; 12-17 years: 100 mg) or placebo every 4 weeks added to guideline-based care for 1 year. The primary outcome was the number of asthma exacerbations treated with systemic corticosteroids; a comparison of the two treatment groups was evaluated using a negative-binomial model. Results: Mepolizumab significantly reduced peripheral blood eosinophils (p\u3c0.01) and nasal eosinophils (p\u3c0.01). The rate of asthma exacerbations was significantly lower in mepolizumab (0.96 exacerbations/year) vs. placebo (1.30 exacerbations/year) treated participants [relative risk 0.73 (95% confidence interval 0.56-0.96), p=0.027]. There were no significant differences in secondary outcomes, including time to first exacerbation, lung function, quality of life, or composite asthma severity index (CASI). Post hoc, the time to second asthma exacerbation increased significantly with mepolizumab (p=0.02). Adverse events were similar between groups. Conclusions: Phenotype-directed therapy with mepolizumab in urban children and adolescents with exacerbation-prone eosinophilic asthma significantly reduced recurrent exacerbations and was well tolerated, but did not impact other asthma outcomes