Citations

Abstract1q21 gain is a common cytogenetic abnormality featuring high‐risk multiple myeloma (HRMM). However, the molecular mechanism underlying the adverse prognostic effect of 1q21 gain remains largely unclear. Here, we report that ARNT/HIF‐1β, a 1q21 gene, is highly expressed in HRMM and induced by microenvironmental hypoxia, which confers drug resistance and correlates with inferior outcome. Analysis of the gene expression profile database revealed that ARNT expression was upregulated in MM and increased with disease progression or in HRMM subtypes (particularly 1q21 gain), while correlated to shorter overall survival. In a cohort of 40 MM patients, qPCR further validated that ARNT expression was higher in MM patients than normal donors. MM cells carrying 1q21 gain or acquired drug resistance displayed a robust increase in HIF‐1β protein level. Hypoxia induced HIF‐1β expression via a NF‐κB‐dependent process. Notably, HIF‐1β overexpression impaired bortezomib sensitivity, whereas shRNA knockdown of ARNT reversed hypoxia‐mediated drug resistance. Together, these findings suggest that ARNT/HIF‐1β might represent a novel biomarker for risk stratification and prognosis of HRMM patients, as well as a potential therapeutic target for overcoming 1q21 gain‐ or microenvironment‐mediated and acquired drug resistance in MM.

Introduction: In response to reported difficulties in selecting a Medicare Part D prescription drug plan, we designed a patient-centered online Part D plan selection tool (CHOICE1.0) to simplify the selection process and to provide personalized, expert recommendations. Methods: This ethnographic comparative usability study observed 44 patients using the first version of the tool during Medicare 2016 Open Enrollment. Participants were observed as they chose their drug plan using Medicare.gov and 1 of 3 versions of CHOICE1.0 that varied in amount of expert guidance. Descriptive statistics were used to analyze exit survey data. The observations were video-recorded, and field notes were analyzed thematically. Results: Participants were significantly more satisfied with CHOICE1.0 for choosing a plan, understanding information, and ease of use compared to Medicare.gov . Those using expert versions of CHOICE1.0 were more likely to indicate their intention to switch plans than those using Medicare.gov , though they wanted to know the source and content. Conclusion: The more patient-centered prescription drug choice tool improved user experience and enabled users to choose plans more consistent with expert recommendations.

Background Lower extremity salvage following significant soft tissue loss can be complicated by lack of recipient vessel for free tissue transfer. We describe our experience in lower limb salvage for patients with no recipient vessels with the use of pedicle, free and cable bridge flaps. Methods A retrospective review from 1985 to 2017 of patients undergoing lower limb salvage using a contralateral pedicle cross leg (PCL) flaps, free cross leg (FCL) flaps, or free cable bridge (FCB) flaps was conducted. Demographics, etiology of the reconstruction, type of flap used, donor-site vessels, defect size, operating time, time of pedicle division, length of hospital stay, time to ambulation, and complications were analyzed. Results A total of 53 patients (48 males and 5 females) with an average age of 35 years (range, 29–38 years) were identified. The etiology for the reconstruction was trauma in 52 patients and oncological resection in 1 patient. There were 18 PCL, 25 FCL, and 10 FCB completed. The recipient vessels for all flaps were the posterior tibial artery and vein. The average operating room times for PCL, FCL, and FCB flaps were 4, 9, and 10 hours, respectively. The average length of hospital stay was 5 weeks and average time to ambulation was 4 weeks. The average follow-up time was 7.5 years (range, 3–12 years). Complications encountered were hematoma (six), prolonged pain (six), total flap loss (two), reoperation (five), and infection (four). Limb salvage rates were 96.2%. Conclusion When ipsilateral limb vessels are not available, and other reconstructive options have been exhausted, cross leg flaps can be a viable option for limb salvage in the setting of extensive defects.

Abstract Lung cancer remains the leading cause of cancer-related death, partly due to the fact that most patients are diagnosed with metastatic disease, which is the main cause of death, yet effective therapeutics are lacking. Utilizing mouse models of metastatic lung adenocarcinomas, we report that the transcription factor GATA3 and its cofactor FOG2 play critical roles in lung adenocarcinoma metastasis by promoting the expression of the lysyl hydroxylase (LH) family members, which in turn regulate the tumorigenicity and motility of lung tumor cells through both EMT and EMT-independent mechanisms. In vivo, LHs are elevated in human lung adenocarcinomas and are associated with worse patient survival. Collectively, our data suggest that targeting LHs may be useful for treating metastatic lung cancer. Citation Format: Wei Liu, Ting Zhang, Lixia Guo, Yuanyuan Wang, Yanan Yang. Role of lysyl hydroxylases in metastatic lung cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B07.

Abstract Background The American Board of Anesthesiology recently introduced the BASIC Examination, a component of its new staged examinations for primary certification, typically offered to residents at the end of their first year of clinical anesthesiology training. This analysis tested the hypothesis that the introduction of the BASIC Examination was associated with an acceleration of knowledge acquisition during the residency training period, as measured by increments in annual In-Training Examination scores. Methods In-Training Examination performance was compared longitudinally among four resident cohorts (n = 6,488) before and after the introduction of the staged system using mixed-effects models that accounted for possible covariates. Results Compared with previous cohorts in the traditional examination system, the first resident cohort in the staged system had a greater improvement in In-Training Examination scores between the first and second years of clinical anesthesiology training (by an estimated 2.0 points in scaled score on a scale of 1 to 50 [95% CI, 1.7 to 2.3]). By their second year, they had achieved a score similar to that of third-year clinical anesthesiology residents in previous cohorts. The second cohort to enter the staged system had a greater improvement of the scores between the clinical base year and the first clinical anesthesiology year, compared with the previous cohorts. Conclusions These results support the hypothesis that the introduction of the BASIC Examination is associated with accelerated knowledge acquisition in residency training and provides evidence for the value of the new staged system in promoting desired educational outcomes of anesthesiology training.

Background Quality collaboratives are widely endorsed as a potentially effective method for translating and spreading best practices for acute myocardial infarction (AMI) care. Nevertheless, hospital success in improving performance through participation in collaboratives varies markedly. We sought to understand what distinguished hospitals that succeeded in shifting culture and reducing 30-day risk-standardised mortality rate (RSMR) after AMI through their participation in the Leadership Saves Lives (LSL) collaborative. Procedures We conducted a longitudinal, mixed methods intervention study of 10 hospitals over a 2-year period; data included surveys of 223 individuals (response rates 83%–94% depending on wave) and 393 in-depth interviews with clinical and management staff most engaged with the LSL intervention in the 10 hospitals. We measured change in culture and RSMR, and key aspects of working related to team membership, turnover, level of participation and approaches to conflict management. Main findings The six hospitals that experienced substantial culture change and greater reductions in RSMR demonstrated distinctions in: (1) effective inclusion of staff from different disciplines and levels in the organisational hierarchy in the team guiding improvement efforts (referred to as the ‘guiding coalition’ in each hospital); (2) authentic participation in the work of the guiding coalition; and (3) distinct patterns of managing conflict. Guiding coalition size and turnover were not associated with success (p values>0.05). In the six hospitals that experienced substantial positive culture change, staff indicated that the LSL learnings were already being applied to other improvement efforts. Principal conclusions Hospitals that were most successful in a national quality collaborative to shift hospital culture and reduce RSMR showed distinct patterns in membership diversity, authentic participation and capacity for conflict management.

Background Hospital organisational culture affects patient outcomes including mortality rates for patients with acute myocardial infarction; however, little is known about whether and how culture can be positively influenced. Methods This is a 2-year, mixed-methods interventional study in 10 US hospitals to foster improvements in five domains of organisational culture: (1) learning environment, (2) senior management support, (3) psychological safety, (4) commitment to the organisation and (5) time for improvement. Outcomes were change in culture, uptake of five strategies associated with lower risk-standardised mortality rates (RSMR) and RSMR. Measures included a validated survey at baseline and at 12 and 24 months (n=223; average response rate 88%); in-depth interviews (n=393 interviews with 197 staff); and RSMR data from the Centers for Medicare and Medicaid Services. Results We observed significant changes (p<0.05) in culture between baseline and 24 months in the full sample, particularly in learning environment (p<0.001) and senior management support (p<0.001). Qualitative data indicated substantial shifts in these domains as well as psychological safety. Six of the 10 hospitals achieved substantial improvements in culture, and four made less progress. The use of evidence-based strategies also increased significantly (per hospital average of 2.4 strategies at baseline to 3.9 strategies at 24 months; p<0.05). The six hospitals that demonstrated substantial shifts in culture also experienced significantly greater reductions in RSMR than the four hospitals that did not shift culture (reduced RSMR by 1.07 percentage points vs 0.23 percentage points; p=0.03) between 2011–2014 and 2012–2015. Conclusions Investing in strategies to foster an organisational culture that supports high performance may help hospitals in their efforts to improve clinical outcomes.

Background: Following anterior cruciate ligament (ACL) reconstruction, the mechanical loading of the tissues has a significant impact on tendon-to-bone healing. The purpose of this study was to determine the effect of the timing of the initiation of mechanical loading on healing of a tendon graft in a bone tunnel. Methods: ACL reconstruction using a flexor tendon autograft was performed in 56 mice randomized to 4 groups with differing times to initiation of postoperative mechanical loading: (1) immediate, (2) 5 days, (3) 10 days, or (4) 21 days following surgery. An external fixator was placed across the knee at the time of surgery and removed when mechanical loading was scheduled to commence. Following removal of the external fixator, animals were permitted free, unrestricted cage activity. All mice were killed on postoperative day 28, and tendon-to-bone healing was assessed by biomechanical testing, microcomputed tomography (micro-CT), and histological analysis. Results: The mean failure force (and standard deviation) of the reconstructed ACL at the time of sacrifice was highest for Group 2 (3.29 ± 0.68 N) compared with Groups 1, 3, and 4 (p = 0.008). Micro-CT bone volume fraction was greatest for Group 2 in the femoral tunnel (p = 0.001), tibial tunnel (p = 0.063), and both bones (p < 0.001). Similarly, histological analysis demonstrated a narrower scar tissue interface and increased direct contact at the tendon-bone interface (p = 0.012) for Group 2. Conclusions: Following ACL reconstruction, a defined period of immobilization without weight-bearing appears to improve biomechanical strength of the healing tendon-bone interface, while prolonged periods without mechanical load and motion decrease the ultimate load to failure in this murine model. Clinical Relevance: The ideal period of restricted weight-bearing and motion following ACL reconstruction remains undefined. In a murine model, improved healing was noted for animals immobilized for a brief period of 5 days. This work may serve as an initial step in determining the ideal time period in a clinical population.