Search

Pancreatic necroses are a major challenge in the treatment of patients with pancreatitis, causing high morbidity. When indicated, these lesions are usually drained endoscopically using plastic or metal stents. However, data on factors associated with the occurrence of failure or adverse events during stent therapy are scarce. We retrospectively analyzed all adverse events and their associated features which occurred in patients who underwent a first-time endoscopic drainage of pancreatic necrosis from 2009 to 2019. During the observation period, a total of 89 eligible cases were identified. Adverse events occurred in 58.4% of the cases, of which 76.9% were minor (e.g., stent dislocation, residual lesions, or stent obstruction). However, these events triggered repeated interventions (63.5% vs. 0%, p < 0.001) and prolonged hospital stays (21.0 [11.8−63.0] vs. 14.0 [7.0−31.0], p = 0.003) compared to controls without any adverse event. Important factors associated with the occurrence of adverse events during endoscopic drainage therapy were positive necrosis cultures (6.1 [2.3−16.1], OR [95% CI], p < 0.001) and a larger diameter of the treated lesion (1.3 [1.1−1.5], p < 0.001). Superinfection of pancreatic necrosis is the most significant factor increasing the likelihood of adverse events during endoscopic drainage. Therefore, control of infection is crucial for successful drainage therapy, and future studies need to consider superinfection of pancreatic necrosis as a possible confounding factor when comparing different therapeutic modalities.

Toxoplasmosis causes substantial morbidity and mortality in the United States (US). Clinical manifestations to toxoplasmosis vary and there is limited information on incidence or treatment patterns in the US. Treatment pathways for pyrimethamine-based regimens and trimethoprim-sulfamethoxazole (TMP-SMX) for toxoplasmosis hospitalizations were investigated using the Vizient Health Systems inpatient and outpatient data. Between January 1 st , 2011 and December 31 st , 2017, 10,273 hospital visits from 4,736 unique patients received a primary or secondary ICD-9/ICD-10 diagnosis for toxoplasmosis. The projected annual hospital visits with a diagnosis of toxoplasmosis was 68,821, corresponding to a total annual incidence of 9,832 comprising ocular toxoplasmosis of 2,169, toxoplasmic encephalitis of 1,399, unspecified toxoplasmosis of 4,368, congenital toxoplasmosis of 381, multisystemic toxoplasmosis of 69 and other toxoplasmosis of 1,446. Only 16.3% of the study population received treatment with pyrimethamine-based regimens or TMP-SMX. Pyrimethamine-based regimens were used significantly more often than TMP-SMX in toxoplasmic encephalitis (88.7% vs 79.6%, p = 0.01), other toxoplasmosis (85.0% vs 79.2%, p = 0.04), and unspecified toxoplasmosis (87.6% vs 77.9%, p = 0.03) in hospitals with 300 beds or more. A significantly higher percentage of visits with TMP-SMX as first-line treatment switched to pyrimethamine-based regimens compared to visits initiated on pyrimethamine-based treatments (26.7% vs 4.1%, p < .001). Ocular toxoplasmosis patients receiving pyrimethamine-based therapy were more likely to be discharged home compared to TMP-SMC at rates of 72.4% and 55.2%, respectively. Our analysis of commercial insurance records suggest toxoplasmosis is undertreated. Overall, pyrimethamine-based regimens are favored over TMP-SMX, have higher rates of discharge home, and have lower switch rates.

Previously we have encapsulated host-directed therapy AR-12 into acetalated dextran (Ace-DEX) microparticles (MPs) to mitigate drug toxicity and passively target phagocytic host cells. Herein, we have improved upon our initial emulsion-based formulation of Ace-DEX MPs encapsulating AR-12 (AR-12/MPs) by improving the drug encapsulation efficiency, evaluating sterilization processes for manufacturing, and understanding cellular and in vivo trafficking of the MPs. By using an alternative solvent system, ethyl acetate, we report an increased encapsulation efficiency of AR-12 while maintaining the pH-responsive degradation kinetics of Ace-DEX MPs. To better manufacture this novel antimicrobial formulation, we sterilized AR-12/MPs by gamma irradiation or ethylene oxide and evaluated their efficacy against intracellular Salmonella enterica serovar Typhi. Sterilized AR-12/MPs resulted in a significant reduction in intracellular bacterial burden compared to Blank/MPs. We also characterized intracellular trafficking of Ace-DEX MPs encapsulating fluorophores, which demonstrated internalization of MPs in endo/lysosomal compartments and time and degradation-rate dependent lysosomal escape into cytosolic compartments. Additionally, in vivo toxicity was mitigated following encapsulation of AR-12, where the maximum tolerated dose of AR-12 was increased compared to soluble treatment via intranasal, intravenous, and intraperitoneal administration routes. Following in vivo trafficking of Ace-DEX MPs via the same routes, intranasal administration demonstrated the highest accumulation in the lungs, liver, and kidneys, which persisted out to 240 h. Overall, we have advanced the formulation of this host-directed therapy and broadened the understanding of Ace-DEX MP delivery.

Protective efficacy of Bacillus Calmette-Guérin (BCG) may be affected by the methods and routes of vaccine administration. We have studied the safety and immunogenicity of oral (PO) and/or intradermal (ID) administration of BCG in healthy human subjects. No major safety concerns were detected in the 68 healthy adults vaccinated with PO and/or ID BCG. Although both PO and ID BCG could induce systemic Th1 responses capable of IFN-γ production, ID BCG more strongly induced systemic Th1 responses. In contrast, stronger mucosal responses (TB-specific secretory IgA and bronchoalveolar lavage T cells) were induced by PO BCG vaccination. To generate preliminary data comparing the early gene signatures induced by mucosal and systemic BCG vaccination, CD4 + memory T cells were isolated from subsets of BCG vaccinated subjects pre- (Day 0) and post-vaccination (Days 7 and 56), rested or stimulated with BCG infected dendritic cells, and then studied by Illumina BeadArray transcriptomal analysis. Notably, distinct gene expression profiles were identified both on Day 7 and Day 56 comparing the PO and ID BCG vaccinated groups by GSEA analysis. Future correlation analyses between specific gene expression patterns and distinct mucosal and systemic immune responses induced will be highly informative for TB vaccine development.