IĸB Protein BCL3 as a Controller of Osteogenesis and Bone Health.

OBJECTIVE: IĸB protein B cell lymphoma 3-encoded protein (BCL3) is a regulator of the NF-κB family of transcription factors. NF-κB signaling fundamentally influences the fate of bone-forming osteoblasts and bone-resorbing osteoclasts, but the role of BCL3 in bone biology has not been investigated. The objective of this study was to evaluate BCL3 in skeletal development, maintenance, and osteoarthritic pathology. METHODS: To assess the contribution of BCL3 to skeletal homeostasis, neonatal mice (n = 6-14) lacking BCL3 (Bcl3-/- ) and wild-type (WT) controls were characterized for bone phenotype and density. To reveal the contribution to bone phenotype by the osteoblast compartment in Bcl3-/- mice, transcriptomic analysis of early osteogenic differentiation and cellular function (n = 3-7) were assessed. Osteoclast differentiation and function in Bcl3-/- mice (n = 3-5) was assessed. Adult 20-week Bcl3-/- and WT mice bone phenotype, strength, and turnover were assessed. A destabilization of the medial meniscus model of osteoarthritic osteophytogenesis was used to understand adult bone formation in Bcl3-/- mice (n = 11-13). RESULTS: Evaluation of Bcl3-/- mice revealed congenitally increased bone density, long bone dwarfism, increased bone biomechanical strength, and altered bone turnover. Molecular and cellular characterization of mesenchymal precursors showed that Bcl3-/- cells displayed an accelerated osteogenic transcriptional profile that led to enhanced differentiation into osteoblasts with increased functional activity, which could be reversed with a mimetic peptide. In a model of osteoarthritis-induced osteophytogenesis, Bcl3-/- mice exhibited decreased pathological osteophyte formation (P < 0.05). CONCLUSION: Cumulatively, these findings demonstrate that BCL3 controls developmental mineralization to enable appropriate bone formation, whereas in a pathological setting, it contributes to skeletal pathology.

Long-Term Response to a Bioactive Biphasic Biomaterial in the Femoral Neck of Osteoporotic Rats.

Osteoporosis often leads to fragility fractures of the hip, resulting in impaired quality of life and increased mortality. Augmenting the proximal femur could be an attractive option for prevention of fracture or fixation device failure. We describe a tissue engineering based strategy to enhance long-term bone formation in the femoral neck of osteoporotic rats by locally delivering bioactive molecules; recombinant human bone morphogenic protein-2 (rhBMP-2), and zoledronic acid (ZA) by using a calcium sulfate/hydroxyapatite (CaS/HA) biomaterial. A defect was created by reaming the femoral neck canal of osteoporotic (OVX) rats and they were treated as follows: G1. Empty, G2. CaS/HA, G3. CaS/HA+Systemic ZA, G4. CaS/HA+Local ZA, and G5. CaS/HA+Local ZA+rhBMP-2. Bone formation was evaluated 6 months after treatment. Further, radioactively labeled 14C-ZA was used to study the bioavailability of ZA at the defect location, which was determined by using scintillation counting. Micro-CT indicated significantly higher bone volume in groups G4 and G5 compared with the other treatment groups. This was confirmed qualitatively by histological assessment. Addition of rhBMP-2 gave no additional benefit in this model. Local delivery of ZA performed better than systemic administration of ZA. Mechanical testing showed no differences between the groups, likely reflecting that the addition of bioactive molecules had limited effect on cortical bone or the choice of mechanical testing setup was not optimal. Scintillation counting revealed higher amounts of 14C-ZA present in the treated leg of G4 compared with its contralateral control and compared with G3, indicating that local ZA delivery can be used to achieve high local concentrations without causing a systemic effect. This long-term study shows that local delivery of ZA using a CaS/HA carrier can regenerate cancellous bone in the femoral neck canal and has clear implications for enhancing implant integration and fixation in fragile bone.

Using Lean to Rapidly and Sustainably Transform a Behavioral Health Crisis Program: Impact on Throughput and Safety.

BACKGROUND: Lean has been increasingly applied in health care to reduce waste and improve quality, particularly in fast-paced and high-acuity clinical settings such as emergency departments. In addition, Lean's focus on engagement of frontline staff in problem solving can be a catalyst for organizational change. In this study, ConnectionsAZ demonstrates how they applied Lean principles to rapidly and sustainably transform clinical operations in a behavioral health crisis facility. METHODS: A multidisciplinary team of management and frontline staff defined values-based outcome measures, mapped the current and ideal processes, and developed new processes to achieve the ideal. Phase I was implemented within three months of assuming management of the facility and involved a redesign of flow, space utilization, and clinical protocols. Phase II was implemented three months later and improved the provider staffing model. Organizational changes such as the development of shift leads and daily huddles were implemented to sustain change and create an environment supportive of future improvements. RESULTS: Post-Phase I, there were significant decreases (pre vs. post and one-year post) in median door-to-door dwell time (343 min vs. 118 and 99), calls to security for behavioral emergencies (13.5 per month vs. 4.3 and 4.8), and staff injuries (3.3 per month vs. 1.2 and 1.2). Post-Phase II, there were decreases in median door-to-doctor time (8.2 hours vs. 1.6 and 1.4) and hours on diversion (90% vs. 17% and 34%). CONCLUSIONS: Lean methods can positively affect safety and throughput and are complementary to patient-centered clinical goals in a behavioral health setting.

Crisis Reliability Indicators Supporting Emergency Services (CRISES): A Framework for Developing Performance Measures for Behavioral Health Crisis and Psychiatric Emergency Programs.

Crisis and emergency psychiatric services are an integral part of the healthcare system, yet there are no standardized measures for programs providing these services. We developed the Crisis Reliability Indicators Supporting Emergency Services (CRISES) framework to create measures that inform internal performance improvement initiatives and allow comparison across programs. The framework consists of two components-the CRISES domains (timely, safe, accessible, least-restrictive, effective, consumer/family centered, and partnership) and the measures supporting each domain. The CRISES framework provides a foundation for development of standardized measures for the crisis field. This will become increasingly important as pay-for-performance initiatives expand with healthcare reform.