Self-assembly of pH-responsive fluorinated dendrimer-based particulates for drug delivery and noninvasive imaging

a b s t r a c t Dendrimers are nanoscale macromolecules with well-defined branching chemical structures. Control over the architecture and function of these structures has enabled many advances in materials science and biomedical applications. Though dendrimers are directly synthesized by iteration of simple repetitive steps, generation of the larger, more complex structures required for many biomedical applications by covalent synthetic methods has been challenging. Here we demonstrate a spontaneous self-assembly of poly(amidoamine) dendrimers into complex nanoscopic and microscopic particulates following partial fluorination of the constituent dendrimer subunits. These dense particulates exhibit a stimulus-induced response to low external pH that causes their disassembly over time, enabling controlled release of encapsulated agents. In addition, we show that these assemblies offer a sufficiently high density of fluorine spins to enable detection of their site-specific accumulation in vivo b

Bacteriophage application restores ethanol fermentation characteristics disrupted by Lactobacillusfermentum

BACKGROUND: Contamination of corn mash by lactic acid bacteria (LAB) reduces the efficiency of the ethanol fermentation process. The industry relies heavily on antibiotics for contamination control and there is a need to develop alternative methods. The goals of this study were to determine the diversity and abundance of bacteria contaminating commercial ethanol fermentations, and to evaluate the potential of anti-LAB bacteriophages in controlling production losses. RESULTS: Bacterial populations in 27 corn mash samples collected from nine different commercial plants were determined by pyrosequencing of 16S rRNA amplicons. The results showed that the most abundant bacteria (>50 % of total population) in 24 of the 27 samples included LAB genera such as Lactobacillus, Streptococcus, Lactococcus, Weissella, Enterococcus, and Pediococcus. Lactobacillus was identified as the most prevalent genus at all fermentation stages in all plants, accounting for between 2.3 and 93.7 % of each population and constituting the major genus (>50 %) in nine samples from five plants and the most abundant genus in five other samples. Lactobacillus species, including L. delbrueckii, L. fermentum, L. mucosae, and L. reuteri were the most well-represented species. Two bacteriophages that target L. fermentum strains from ethanol plants, vB_LfeS_EcoSau and vB_LfeM_EcoInf (EcoSau and EcoInf), were isolated and characterized as a siphophage and a myophage, respectively. Analysis of the 31,703 bp genome of EcoSau revealed its similarity to the P335-like phage group, and the 106,701 bp genome of phage EcoInf was determined to be a novel phage type despite its distant relationship to the SPO1-like phages. Addition of phages EcoSau and EcoInf to L. fermentum-contaminated corn mash fermentation models restored the yields of ethanol and reduced levels of residual glucose, lactic acid, and acetic acid to that comparable to the infection-free control. CONCLUSIONS: This study provides detailed insight into the microbiota contaminating commercial ethanol fermentations, and highlights the abundance of LAB, especially L. delbrueckii, L. fermentum, L. mucosae, and L. reuteri, in the process. This study suggests that phages with broad coverage of major LAB species can be applied directly to corn mash for antibiotic-free control of contamination in the ethanol fermentation industry. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13068-015-0325-9) contains supplementary material, which is available to authorized users

How Well Do Rheumatology Fellows Manage Acute Infusion Reactions? A Pilot Curricular Intervention

Background Infusible DMARDs are commonly prescribed in rheumatology and other fields. There are no published formal educational curricula rheumatology fellowship programs can use to teach infusion reaction management skills to fellows. We aimed to better understand this educational gap, and implement and assess the effectiveness of an experiential curriculum on acute infusion reaction management. Methods We included current rheumatology fellows and recent graduates from five fellowship programs. Using a novel behavioral checklist we assessed fellows’ performance managing an infusion reaction in a simulation, followed by a didactic focused on infusion reactions. Pre and post-surveys assessed experiences to determine relevance, as well as attitudes and knowledge. Results Despite ubiquitous prescribing of infusible biologic DMARDs, \u3e50% of fellows were uncomfortable managing infusion reactions. Only 11% of fellows reported infusion reaction training during fellowship, but 56% reported managing actual patient infusion reactions. In the simulated infusion reaction, fellows managed grade 1 reactions appropriately, but grade 4 reactions poorly, meeting \u3c50% of objectives. All fellows discontinued the infusion in the setting of anaphylaxis, but only 56% administered epinephrine. There was no difference in performance or written knowledge by training year. All fellows felt more prepared to manage infusion reactions post-curriculum and were satisfied with the experience. Conclusion We confirmed an education gap in rheumatology fellowship training regarding infusion reactions, both in knowledge and performance. We developed and implemented a brief experiential curriculum including simulation of a high-risk patient care scenario. This curriculum was well received and is easily exportable to other programs

Incorporating Telemedicine in Rheumatology Fellowship Training Programs: Needs Assessment, Curricular Intervention, and Evaluation

OBJECTIVE: To increase rheumatology fellows\u27 in training (FITs) confidence in delivering virtual care (VC) and prepare them for independent practice, we developed educational materials addressing gaps in their skills. METHODS: We identified gaps in telemedicine skills based on FIT performance in a virtual rheumatology observed structured clinical examination (vROSCE) station on VC delivery using videoteleconference technology and survey (Survey1) responses. We created educational materials including videos of mediocre and excellent VC examples, discussion/reflection questions, and a document summarizing key practices. We measured change in FITs\u27 confidence levels for delivering VC with a post-intervention survey (Survey2). RESULTS: Thirty-seven FITs (19 first-year, 18 second + third-year fellows) from seven rheumatology fellowship training programs participated in a vROSCE and demonstrated gaps in skills mapping to several Rheumatology Telehealth Competency domains. FITs\u27 confidence levels improved significantly from Survey1 to Survey2 for 22 of 34 (65%) questions. All participating FITs found the educational materials helpful for learning and reflecting on their own VC practice; 18 FITs (64%) qualified usefulness as moderately or a lot . Through surveying, 17 FITs (61%) reported implementing skills from the instructional videos into VC visits. DISCUSSION: Continually assessing our learners\u27 needs and creating educational materials addressing gaps in training is requisite. Using a vROSCE station, needs assessments, and targeted learning with videos and discussion-guidance materials enhanced the confidence level for FITs in VC delivery. It is imperative to incorporate VC delivery into fellowship training program curricula to ensure breadth in skills, attitudes, and knowledge of new entrants into the rheumatology workforce. This article is protected by copyright. All rights reserved

Metabolic and immunomodulatory control of type 1 diabetes via orally delivered bile-acid-polymer nanocarriers of insulin or rapamycin

We describe oral nanocarriers, termed “NanoPills” (NPs), for simultaneous short-term control and long-term reversal of pancreatic inflammation. We hypothesized that since bile acids emulsify fats during digestion, regulate glucose and modulate immunity, that NPs constructed from polymeric bile acid will be effective, multifunctional, oral therapeutics. Polymerized ursodeoxycholic acid (pUDCA) NP protected encapsulated agent in the stomach, permeated intestinal epithelia, then bound macrophage bile receptors with high avidity. Strikingly, pUDCA NPs localized to the pancreas after oral ingestion through macrophage-mediated transport and particle enterohepatic circulation. In a drug-induced pancreatic inflammation model, rapamycin-loaded NPs prevented disease. In a spontaneous model of type I diabetes (T1D), NP alone restored normoglycemia for 2 weeks and reversed disease with loaded insulin. Thus, for the first time, an integrative approach is presented enabling oral delivery through a carrier that intrinsically restores endogenous pancreatic insulin secretion, and tolerogenic immunity for rapid control and long-term regulation of T1D