Evaluating the implementation of a chronic obstructive pulmonary disease management program using the Consolidated Framework for Implementation Research: a case study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a prevalent chronic disease that requires comprehensive approaches to manage; it accounts for a significant portion of Canada\u27s annual healthcare spending. Interprofessional teams are effective at providing chronic disease management that meets the needs of patients. As part of an ongoing initiative, a COPD management program, the Best Care COPD program was implemented in a primary care setting. The objectives of this research were to determine site-specific factors facilitating or impeding the implementation of a COPD program in a new setting, while evaluating the implementation strategy used. METHODS: A qualitative case study was conducted using interviews, focus groups, document analysis, and site visits. Data were deductively analyzed using the Consolidated Framework for Implementation Research (CFIR) to assess the impact of each of its constructs on Best Care COPD program implementation at this site. RESULTS: Eleven CFIR constructs were determined to meaningfully affect implementation. Five were identified as the most influential in the implementation process. Cosmopolitanism (partnerships with other organizations), networks and communication (amongst program providers), engaging (key individuals to participate in program implementation), design quality and packaging (of the program), and reflecting and evaluating (throughout the implementation process). A peer-to-peer implementation strategy included training of registered respiratory therapists (RRT) as certified respiratory educators and the establishment of a communication network among RRTs to discuss experiences, collectively solve problems, and connect with the program lead. CONCLUSIONS: This study provides a practical example of the various factors that facilitated the implementation of the Best Care COPD program. It also demonstrates the potential of using a peer-to-peer implementation strategy. Focusing on these factors will be useful for informing the continued spread and success of the Best Care COPD program and future implementation of other chronic care programs

Nucleated polymerisation in the presence of pre-formed seed filaments

We revisit the classical problem of nucleated polymerisation and derive a range of exact results describing polymerisation in systems intermediate between the well-known limiting cases of a reaction starting from purely soluble material and for a reaction where no new growth nuclei are formed

Unraveling UBC 274: a morphological, kinematical and chemical analysis of a disrupting open cluster

We do a morphological, kinematic and chemical analysis of the disrupting cluster UBC 274 (2.5 Gyr, $d=1778$ pc) to study its global properties. We use HDBSCAN to obtain a new membership list up to 50 pc from its centre and up to magnitude $G=19$ using Gaia EDR3 data. We use high resolution and high signal-to-noise spectra to obtain atmospheric parameters of 6 giants and subgiants, and individual abundances of 18 chemical species. The cluster has a highly eccentric (0.93) component, tilted $\sim$10 deg with respect to the plane of the Galaxy, which is morphologically compatible with the result of a test-particle simulation of a disrupting cluster. Our abundance analysis shows that the cluster has a subsolar metallicity of [Fe/H]$=-0.08\pm0.02$. Its chemical pattern is compatible with that of Ruprecht 147, of similar age but located closer to the Sun, with the remarkable exception of neutron-capture elements, which present an overabundance of $[n\mathrm{/Fe]}\sim0.1$. The cluster's elongated morphology is associated with the internal part of its tidal tail, following the expected dynamical process of disruption. We find a significant sign of mass segregation where the most massive stars appear 1.5 times more concentrated than other stars. The cluster's overabundance of neutron-capture elements can be related to the metallicity dependence of the neutron-capture yields due to the secondary nature of these elements, predicted by some models. UBC 274 presents a high chemical homogeneity at the level of $0.03$ dex in the sampled region of its tidal tails.Comment: Accepted by A&

IRX-2, a Novel Immunotherapeutic, Enhances Functions of Human Dendritic Cells

Background: In a recent phase II clinical trial for HNSCC patients, IRX-2, a cell-derived biologic, promoted T-cell infiltration into the tumor and prolonged overall survival. Mechanisms responsible for these IRX-2-mediated effects are unknown. We hypothesized that IRX-2 enhanced tumor antigen-(TA)-specific immunity by up-regulating functions of dendritic cells (DC). Methodology/Principal Findings: Monocyte-derived DC obtained from 18 HNSCC patients and 12 healthy donors were matured using IRX-2 or a mix of TNF-α, IL-1β and IL-6 ("conv. mix"). Multicolor flow cytometry was used to study the DC phenotype and antigen processing machinery (APM) component expression. ELISPOT and cytotoxicity assays were used to evaluate tumor-reactive cytotoxic T lymphocytes (CTL). IL-12p70 and IL-10 production by DC was measured by Luminex® and DC migration toward CCL21 was tested in transwell migration assays. IRX-2-matured DC functions were compared with those of conv. mix-matured DC. IRX-2-matured DC expressed higher levels (p<0.05) of CD11c, CD40, CCR7 as well as LMP2, TAP1, TAP2 and tapasin than conv. mix-matured DC. IRX-2-matured DC migrated significantly better towards CCL21, produced more IL-12p70 and had a higher IL12p70/IL-10 ratio than conv. mix-matured DC (p<0.05 for all). IRX-2-matured DC carried a higher density of tumor antigen-derived peptides, and CTL primed with these DC mediated higher cytotoxicity against tumor targets (p<0.05) compared to the conv. mix-matured DC. Conclusion: Excellent ability of IRX-2 to induce ex vivo DC maturation in HNSCC patients explains, in part, its clinical benefits and emphasizes its utility in ex vivo maturation of DC generated for therapy. © 2013 Schilling et al

Stem cells and cancer immunotherapy: Arrowhead’s 2nd annual cancer immunotherapy conference

Investigators from academia and industry gathered on April 4 and 5, 2013, in Washington DC at the Arrowhead’s 2nd Annual Cancer Immunotherapy Conference. Two complementary concepts were discussed: cancer “stem cells” as targets and therapeutic platforms based on stem cells

?2-Microglobulin Amyloid Fibril-Induced Membrane Disruption Is Enhanced by Endosomal Lipids and Acidic pH

Although the molecular mechanisms underlying the pathology of amyloidoses are not well understood, the interaction between amyloid proteins and cell membranes is thought to play a role in several amyloid diseases. Amyloid fibrils of ?2-microglobulin (?2m), associated with dialysis-related amyloidosis (DRA), have been shown to cause disruption of anionic lipid bilayers in vitro. However, the effect of lipid composition and the chemical environment in which ?2m-lipid interactions occur have not been investigated previously. Here we examine membrane damage resulting from the interaction of ?2m monomers and fibrils with lipid bilayers. Using dye release, tryptophan fluorescence quenching and fluorescence confocal microscopy assays we investigate the effect of anionic lipid composition and pH on the susceptibility of liposomes to fibril-induced membrane damage. We show that ?2m fibril-induced membrane disruption is modulated by anionic lipid composition and is enhanced by acidic pH. Most strikingly, the greatest degree of membrane disruption is observed for liposomes containing bis(monoacylglycero)phosphate (BMP) at acidic pH, conditions likely to reflect those encountered in the endocytic pathway. The results suggest that the interaction between ?2m fibrils and membranes of endosomal origin may play a role in the molecular mechanism of ?2m amyloid-associated osteoarticular tissue destruction in DRA

A tunable delivery platform to provide local chemotherapy for pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating and painful cancers. Pancreatic cancer is often highly resistant to therapy owing to inherent chemoresistance and the desmoplastic response that creates a barrier of fibrous tissue preventing transport of chemotherapeutics into the tumor. The growth of the tumor in pancreatic cancer often leads to invasion of other organs and partial or complete biliary obstruction, inducing intense pain for patients and necessitating tumor resection or repeated stenting. Here, we have developed a delivery device to provide enhanced palliative therapy for pancreatic cancer patients by providing high concentrations of chemotherapeutic compounds locally at the tumor site. This treatment could reduce the need for repeated procedures in advanced PDAC patients to debulk the tumor mass or stent the obstructed bile duct. To facilitate clinical translation, we created the device out of currently approved materials and drugs. We engineered an implantable poly(lactic-co-glycolic)-based biodegradable device that is able to linearly release high doses of chemotherapeutic drugs for up to 60 days. We created five patient-derived PDAC cell lines and tested their sensitivity to approved chemotherapeutic compounds. These in vitro experiments showed that paclitaxel was the most effective single agent across all cell lines. We compared the efficacy of systemic and local paclitaxel therapy on the patient-derived cell lines in an orthotopic xenograft model in mice (PDX). In this model, we found up to a 12-fold increase in suppression of tumor growth by local therapy in comparison to systemic administration and reduce retention into off-target organs. Herein, we highlight the efficacy of a local therapeutic approach to overcome PDAC chemoresistance and reduce the need for repeated interventions and biliary obstruction by preventing local tumor growth. Our results underscore the urgent need for an implantable drug-eluting platform to deliver cytotoxic agents directly within the tumor mass as a novel therapeutic strategy for patients with pancreatic cancer