A high-throughput cigarette smoke-treated bronchosphere model for disease-relevant phenotypic compound screening.

Cigarette smoking (CS) is the leading cause of COPD, and identifying the pathways that are driving pathogenesis in the airway due to CS exposure can aid in the discovery of novel therapies for COPD. An additional barrier to the identification of key pathways that are involved in the CS-induced pathogenesis is the difficulty in building relevant and high throughput models that can recapitulate the phenotypic and transcriptomic changes associated with CS exposure. To identify these drivers, we have developed a cigarette smoke extract (CSE)-treated bronchosphere assay in 384-well plate format that exhibits CSE-induced decreases in size and increase in luminal secretion of MUC5AC. Transcriptomic changes in CSE-treated bronchospheres resemble changes that occur in human smokers both with and without COPD compared to healthy groups, indicating that this model can capture human smoking signature. To identify new targets, we ran a small molecule compound deck screening with diversity in target mechanisms of action and identified hit compounds that attenuated CSE induced changes, either decreasing spheroid size or increasing secreted mucus. This work provides insight into the utility of this bronchopshere model to examine human respiratory disease impacted by CSE exposure and the ability to screen for therapeutics to reverse the pathogenic changes caused by CSE.

A high-throughput 3D cantilever array to model airway smooth muscle hypercontractility in asthma.

Asthma is often characterized by tissue-level mechanical phenotypes that include remodeling of the airway and an increase in airway tightening, driven by the underlying smooth muscle. Existing therapies only provide symptom relief and do not improve the baseline narrowing of the airway or halt progression of the disease. To investigate such targeted therapeutics, there is a need for models that can recapitulate the 3D environment present in this tissue, provide phenotypic readouts of contractility, and be easily integrated into existing assay plate designs and laboratory automation used in drug discovery campaigns. To address this, we have developed DEFLCT, a high-throughput plate insert that can be paired with standard labware to easily generate high quantities of microscale tissues in vitro for screening applications. Using this platform, we exposed primary human airway smooth muscle cell-derived microtissues to a panel of six inflammatory cytokines present in the asthmatic niche, identifying TGF-ß1 and IL-13 as inducers of a hypercontractile phenotype. RNAseq analysis further demonstrated enrichment of contractile and remodeling-relevant pathways in TGF-ß1 and IL-13 treated tissues as well as pathways generally associated with asthma. Screening of 78 kinase inhibitors on TGF-ß1 treated tissues suggests that inhibition of protein kinase C and mTOR/Akt signaling can prevent this hypercontractile phenotype from emerging, while direct inhibition of myosin light chain kinase does not. Taken together, these data establish a disease-relevant 3D tissue model for the asthmatic airway, which combines niche specific inflammatory cues and complex mechanical readouts that can be utilized in drug discovery efforts.

Implementation of a Knowledge Management System in Mental Health and Addictions: Mixed Methods Case Study.

BACKGROUND: Mental health and addictions (MHA) care is complex and individualized and requires coordination across providers and areas of care. Knowledge management is an essential facilitator and common challenge in MHA services. OBJECTIVE: This paper aimed to describe the development of a knowledge management system (KMS) and the associated processes in 1 MHA program. We also aimed to examine the uptake and use, satisfaction, and feedback on implementation among a group of pilot testers. METHODS: This project was conducted as a continuous quality-improvement initiative. Integrated stakeholder engagement was used to scope the content and design the information architecture to be implemented using a commercially available knowledge management platform. A group of 30 clinical and administrative staff were trained and tested with the KMS over a period of 10 weeks. Feedback was collected via surveys and focus groups. System analytics were used to characterize engagement. The content, design, and full-scale implementation planning of the KMS were refined based on the results. RESULTS: Satisfaction with accessing the content increased from baseline to after the pilot. Most testers indicated that they would recommend the KMS to a colleague, and satisfaction with KMS functionalities was high. A median of 7 testers was active each week, and testers were active for a median of 4 days over the course of the pilot. Focus group themes included the following: the KMS was a solution to problems for staff members, functionality of the KMS was important, quality content matters, training was helpful and could be improved, and KMS access was required to be easy and barrier free. CONCLUSIONS: Knowledge management is an ongoing need in MHA services, and KMSs hold promise in addressing this need. Testers in 1 MHA program found a KMS that is easy to use and would recommend it to colleagues. Opportunities to improve implementation and increase uptake were identified. Future research is needed to understand the impact of KMSs on quality of care and organizational efficiency.

Episode-Based Payment and Direct Employer Purchasing of Healthcare Services: Recent Bundled Payment Innovations and the Geisinger Health System Experience.

One significant driver of the disjointed healthcare often observed in the United States is the traditional fee-for-service payment model which financially incentivizes the volume of care delivered over the quality and coordination of care. This problem is compounded by the wide, often unwarranted variation in healthcare charges that purchasers of health services encounter for substantially similar episodes of care. The last 10 years have seen many stakeholder organizations begin to experiment with novel financial payment models that strive to obviate many of the challenges inherent in customary quantity-based cost paradigms. The Patient Protection and Affordable Care Act has allowed many care delivery systems to partner with Medicare in episode-based payment programs such as the Bundled Payments for Care Improvement (BPCI) initiative, and in patient-based models such as the Medicare Shared Savings Program. Several employer purchasers of healthcare services are experimenting with innovative payment models to include episode-based bundled rate destination centers of excellence programs and the direct purchasing of accountable care organization services. The Geisinger Health System has over 10 years of experience with episode-based payment bundling coupled with the care delivery reengineering which is integral to its ProvenCare® program. Recent experiences at Geisinger have included participation in BPCI and also partnership with employer-purchasers of healthcare through the Pacific Business Group on Health (representing Walmart, Lowe's, and JetBlue Airways). As the shift towards value-focused care delivery and patient experience progresses forward, bundled payment arrangements and direct purchasing of healthcare will be critical financial drivers in effecting change.

ω-3 Supplementation increases amyloid-ß phagocytosis and resolvin D1 in patients with minor cognitive impairment.

We investigated the effects of 4-17 month supplementation with ω-3 fatty acids and antioxidants (Smartfish drink; Smartfish AS, Oslo, Norway) in 12 patients with minor cognitive impairment (MCI) [minimental state examination (MMSE) ≥19], 2 patients with pre-MCI (normal MMSE), and 7 patients with Alzheimer disease (AD) (MMSE <19). We measured the phagocytosis of amyloid-ß 1-42 (Aß) by flow cytometry and microscopy, the transcription of inflammatory genes by RT-PCR, the production of resolvin D1 (RvD1) by enzyme immunoassay, and the cognitive status by MMSE. In patients with MCI and pre-MCI, phagocytosis of Aß by monocytes increased from 530 to 1306 mean fluorescence intensity units (P = 0.016). The increase in patients with AD was not significant (N.S.). The lipidic mediator RvD1, which stimulates Aß phagocytosis in vitro, increased in macrophages in 80% of patients with MCI and pre-MCI (mean increase 9.95 pg/ml) (N.S.). Transcription of inflammatory genes' mRNAs was increased in a subgroup of patients with low transcription at baseline, whereas it was not significantly changed in patients with high transcription at baseline. The mean MMSE score of patients with MCI and pre-MCI was 25.9 at baseline and 25.7 after 4-17 months (N.S.). Our study is the first to show significant immune and biochemical effects of ω-3 fatty acids with antioxidants in patients with MCI. Cognitive benefits of ω-3 supplementation in patients with MCI should be tested in a clinical trial.

Detection of medical errors in kidney transplantation: a pilot study comparing proactive clinician debriefings to a hospital-wide incident reporting system.

BACKGROUND: Rates of medical errors and adverse events remain high for patients who undergo kidney transplantation; they are particularly vulnerable because of the complexity of their disease and the kidney transplantation procedure. Although institutional incident-reporting systems are used in hospitals around the country, they often fail to capture a substantial proportion of medical errors. The goal of this study was to assess the ability of a proactive, web-based clinician safety debriefing to augment the information about medical errors and adverse events obtained via traditional incident reporting systems. METHODS: Debriefings were sent to all individuals listed on operating room personnel reports for kidney transplantation surgeries between April 2010 and April 2011, and incident reports were collected for the same time period. The World Health Organization International Classification for Patient Safety was used to classify all issues reported. RESULTS: A total of 270 debriefings reported 334 patient safety issues (179 safety incidents, 155 contributing factors), and 57 incident reports reported 92 patient safety issues (56 safety incidents, 36 contributing factors). Compared with incident reports, more attending physicians completed the debriefings (32.0 vs 3.5%). DISCUSSION: The use of a proactive, web-based debriefing to augment an incident reporting system in assessing safety risks in kidney transplantation demonstrated increased information, more perspectives of a single safety issue, and increased breadth of participants.

NUTORC-a transdisciplinary health services and outcomes research team in transplantation.

The field of solid organ transplantation has historically concentrated research efforts on basic science and translational studies. However, there has been increasing interest in health services and outcomes research. The aim was to build an effective and sustainable, inter- and transdisciplinary health services and outcomes research team (NUTORC), that leveraged institutional strengths in social science, engineering, and management disciplines, coupled with an international recognized transplant program. In 2008, leading methodological experts across the university were identified and intramural funding was obtained for the NUTORC initiative. Inter- and transdisciplinary collaborative teams were created across departments and schools within the university. Within 3 years, NUTORC became fiscally sustainable, yielding more than tenfold return of the initial investment. Academic productivity included funding for 39 grants, publication of 60 manuscripts, and 166 national presentations. Sustainable educational opportunities for students were created. Inter- and transdisciplinary health services and outcomes research in transplant can be innovative and sustainable.

A bovine whole-genome radiation hybrid panel and outline map.

A 3000-rad radiation hybrid panel was constructed for cattle and used to build outline RH maps for all 29 autosomes and the X and Y chromosomes. These outline maps contain about 1200 markers, most of which are anonymous microsatellite loci. Comparisons between the RH chromosome maps, other published RH maps, and linkage maps allow regions of chromosomes that are poorly mapped or that have sparse marker coverage to be identified. In some cases, mapping ambiguities can be resolved. The RH maps presented here are the starting point for mapping additional loci, in particular genes and ESTs that will allow detailed comparative maps between cattle and other species to be constructed. Radiation hybrid cell panels allow high-density genetic maps to be constructed, with the advantage over linkage mapping that markers do not need to be polymorphic. A large quantity of DNA has been prepared from the cells forming the RH panel reported here and is publicly available for mapping large numbers of loci.