GM-CSF provides autocrine protection for murine alveolar epithelial cells from oxidant-induced mitochondrial injury.

Exposure of mice to hyperoxia induces alveolar epithelial cell (AEC) injury, acute lung injury and death. Overexpression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the lung protects against these effects, although the mechanisms are not yet clear. Hyperoxia induces cellular injury via effects on mitochondrial integrity, associated with induction of proapoptotic members of the Bcl-2 family. We hypothesized that GM-CSF protects AEC through effects on mitochondrial integrity. MLE-12 cells (a murine type II cell line) and primary murine type II AEC were subjected to oxidative stress by exposure to 80% oxygen and by exposure to H(2)O(2). Exposure to H(2)O(2) induced cytochrome c release and decreased mitochondrial reductase activity in MLE-12 cells. Incubation with GM-CSF significantly attenuated these effects. Protection induced by GM-CSF was associated with Akt activation. GM-CSF treatment also resulted in increased expression of the antiapoptotic Bcl-2 family member, Mcl-1. Primary murine AEC were significantly more tolerant of oxidative stress than MLE-12 cells. In contrast to MLE-12 cells, primary AEC expressed significant GM-CSF at baseline and demonstrated constitutive activation of Akt and increased baseline expression of Mcl-1. Treatment with exogenous GM-CSF further increased Akt activation and Mcl-1 expression in primary AEC. Conversely, suppression of AEC GM-CSF expression by use of GM-CSF-specific small interfering RNA resulted in decreased tolerance of oxidative stress, Furthermore, silencing of Mcl-1 prevented GM-CSF-induced protection. We conclude that GM-CSF protects alveolar epithelial cells against oxidative stress-induced mitochondrial injury via the Akt pathway and its downstream components, including Mcl-1. Epithelial cell-derived GM-CSF may contribute to intrinsic defense mechanisms limiting lung injury.

Establishing a multidisciplinary initiative for interoperable electronic health record innovations at an academic medical center.

OBJECTIVE: To establish an enterprise initiative for improving health and health care through interoperable electronic health record (EHR) innovations. MATERIALS AND METHODS: We developed a unifying mission and vision, established multidisciplinary governance, and formulated a strategic plan. Key elements of our strategy include establishing a world-class team; creating shared infrastructure to support individual innovations; developing and implementing innovations with high anticipated impact and a clear path to adoption; incorporating best practices such as the use of Fast Healthcare Interoperability Resources (FHIR) and related interoperability standards; and maximizing synergies across research and operations and with partner organizations. RESULTS: University of Utah Health launched the ReImagine EHR initiative in 2016. Supportive infrastructure developed by the initiative include various FHIR-related tooling and a systematic evaluation framework. More than 10 EHR-integrated digital innovations have been implemented to support preventive care, shared decision-making, chronic disease management, and acute clinical care. Initial evaluations of these innovations have demonstrated positive impact on user satisfaction, provider efficiency, and compliance with evidence-based guidelines. Return on investment has included improvements in care; over $35 million in external grant funding; commercial opportunities; and increased ability to adapt to a changing healthcare landscape. DISCUSSION: Key lessons learned include the value of investing in digital innovation initiatives leveraging FHIR; the importance of supportive infrastructure for accelerating innovation; and the critical role of user-centered design, implementation science, and evaluation. CONCLUSION: EHR-integrated digital innovation initiatives can be key assets for enhancing the EHR user experience, improving patient care, and reducing provider burnout.

Integrated displays to improve chronic disease management in ambulatory care: A SMART on FHIR application informed by mixed-methods user testing.

OBJECTIVE: The study sought to evaluate a novel electronic health record (EHR) add-on application for chronic disease management that uses an integrated display to decrease user cognitive load, improve efficiency, and support clinical decision making. MATERIALS AND METHODS: We designed a chronic disease management application using the technology framework known as SMART on FHIR (Substitutable Medical Applications and Reusable Technologies on Fast Healthcare Interoperability Resources). We used mixed methods to obtain user feedback on a prototype to support ambulatory providers managing chronic obstructive pulmonary disease. Each participant managed 2 patient scenarios using the regular EHR with and without access to our prototype in block-randomized order. The primary outcome was the percentage of expert-recommended ideal care tasks completed. Timing, keyboard and mouse use, and participant surveys were also collected. User experiences were captured using a retrospective think-aloud interview analyzed by concept coding. RESULTS: With our prototype, the 13 participants completed more recommended care (81% vs 48%; P < .001) and recommended tasks per minute (0.8 vs 0.6; P = .03) over longer sessions (7.0 minutes vs 5.4 minutes; P = .006). Keystrokes per task were lower with the prototype (6 vs 18; P < .001). Qualitative themes elicited included the desire for reliable presentation of information which matches participants' mental models of disease and for intuitive navigation in order to decrease cognitive load. DISCUSSION: Participants completed more recommended care by taking more time when using our prototype. Interviews identified a tension between using the inefficient but familiar EHR vs learning to use our novel prototype. Concept coding of user feedback generated actionable insights. CONCLUSIONS: Mixed methods can support the design and evaluation of SMART on FHIR EHR add-on applications by enhancing understanding of the user experience.

Primary Pulmonary Carcinoid Tumor: A Long-term Single Institution Experience.

OBJECTIVES: Primary carcinoid tumors of the lung are rare tumors which comprise approximately 0.5% to 5% of all lung malignancies in adults and roughly 20% to 30% of all carcinoid tumors. The purpose of this retrospective, descriptive study was to describe the incidence, characteristics, and outcomes of patients treated for primary pulmonary carcinoid tumor at a single institution. MATERIALS AND METHODS: All patients with a diagnosis of primary pulmonary carcinoid tumor treated from 1989 to 2009 were reviewed. Data collected included demographics, pathology, tobacco use, clinical presentation, tumor location, tumor spread, treatment, and survival. RESULTS: There were 59 cases of pulmonary carcinoid tumors: 47 typical (80%) and 12 atypical (20%). All but 4 patients underwent surgery, including 54 (92%) lung-sparing resections and 1 pneumonectomy. Five of 55 patients received concurrent adjuvant chemoradiation therapy; 4 patients with atypical and 1 with typical histology. Three additional patients with atypical carcinoid were treated only with adjuvant radiotherapy, palliative radiotherapy, or palliative chemotherapy, respectively. The Kaplan-Meier 5- and 10-year overall survivals were both 80% within the entire population. In the 88% of patients who achieved complete remission, disease-free survival was 98%. A review of a large series from the literature is also presented. CONCLUSIONS: Surgical resection was primary and adequate therapy for most typical carcinoid tumors with high overall survival and disease-free survival. Adjuvant chemotherapy or radiotherapy might be considered for patients with atypical carcinoid tumors who present with adverse pathologic findings.

Publisher Correction: Combating subclonal evolution of resistant cancer phenotypes.

The originally published version of this Article contained an error in Figure 4. In panel a, grey boxes surrounding the subclones associated with patients #2 and #4 obscured adjacent portions of the heatmap. This error has now been corrected in both the PDF and HTML versions of the Article.

Pleural Effusion Caused by Bacillus Calmette-Guérin Immunotherapy for Bladder Cancer.

Intravesical bacillus Calmette Guérin (BCG) instillation has been used as immunotherapy for early stage bladder cancer for >40 years. Complications from this therapy are rare but may result in a spectrum of infectious sequelae. Here we describe the case of an elderly man who presented with a pleural effusion and subcutaneous nodule several years after treatment with BCG.

Combating subclonal evolution of resistant cancer phenotypes.

Metastatic breast cancer remains challenging to treat, and most patients ultimately progress on therapy. This acquired drug resistance is largely due to drug-refractory sub-populations (subclones) within heterogeneous tumors. Here, we track the genetic and phenotypic subclonal evolution of four breast cancers through years of treatment to better understand how breast cancers become drug-resistant. Recurrently appearing post-chemotherapy mutations are rare. However, bulk and single-cell RNA sequencing reveal acquisition of malignant phenotypes after treatment, including enhanced mesenchymal and growth factor signaling, which may promote drug resistance, and decreased antigen presentation and TNF-α signaling, which may enable immune system avoidance. Some of these phenotypes pre-exist in pre-treatment subclones that become dominant after chemotherapy, indicating selection for resistance phenotypes. Post-chemotherapy cancer cells are effectively treated with drugs targeting acquired phenotypes. These findings highlight cancer's ability to evolve phenotypically and suggest a phenotype-targeted treatment strategy that adapts to cancer as it evolves.

Cesarean delivery for life-threatening status asthmaticus.

BACKGROUND: Asthma remains a common chronic illness in pregnancy with the potential for catastrophic complications. Most women with asthma exacerbation can be treated with medical management and continuation of pregnancy. However, refractory cases may necessitate delivery for fetal or maternal indications. CASE: We report a case of status asthmaticus at 33 weeks of gestation with significant maternal respiratory acidosis and difficulty with ventilation necessitating delivery by cesarean delivery in the medical intensive care unit. The patient was unresponsive to standard medical therapies. Delivery resulted in immediate improvement in maternal ventilation parameters. CONCLUSION: In cases of life-threatening status asthmaticus refractory to standard medical and ventilatory therapies in the third trimester, cesarean delivery should be considered as a final effort to increase tidal volumes and improve maternal gas exchange.

Lung cancer screening: a review of available data and current guidelines.

Lung cancer is the leading cause of cancer mortality worldwide. A lack of clinical symptoms in early-stage disease frequently leads to diagnosis at a late stage, and a 15% 5-year survival rate in all patients so diagnosed. This has led to significant interest in effective screening methods to detect early-stage cancers, particularly for high-risk groups, such as current or former smokers. Early clinical trials focused on chest radiograph with or without sputum cytology and failed to show an improvement in mortality with screening. A meta-analysis also failed to show a difference in all-cause mortality. Subsequent protocols compared low-dose computed tomography (LDCT) scan with chest radiograph and documented increased detection of early-stage disease; however, they were not designed to prove a reduction in mortality. The most recent trials have focused on LDCT scans, including the National Lung Screening Trial. Data released from the National Lung Screening Trial demonstrated a statistically significant reduction in lung cancer deaths in patients screened with LDCT scans. When data from the study, including cost-effectiveness, are completely analyzed, they may lead to revision of current lung cancer screening recommendations to include LDCT scans in specific populations at high risk of developing lung cancer.

A modified sequential organ failure assessment score for critical care triage.

OBJECTIVE: The Sequential Organ Failure Assessment (SOFA) score has been recommended for triage during a mass influx of critically ill patients, but it requires laboratory measurement of 4 parameters, which may be impractical with constrained resources. We hypothesized that a modified SOFA (MSOFA) score that requires only 1 laboratory measurement would predict patient outcome as effectively as the SOFA score. METHODS: After a retrospective derivation in a prospective observational study in a 24-bed medical, surgical, and trauma intensive care unit, we determined serial SOFA and MSOFA scores on all patients admitted during the 2008 calendar year and compared the ability to predict mortality and the need for mechanical ventilation. RESULTS: A total of 1770 patients (56% male patients) with a 30-day mortality of 10.5% were included in the study. Day 1 SOFA and MSOFA scores performed equally well at predicting mortality with an area under the receiver operating curve (AUC) of 0.83 (95% confidence interval 0.81-.85) and 0.84 (95% confidence interval 0.82-.85), respectively (P = .33 for comparison). Day 3 SOFA and MSOFA predicted mortality for the 828 patients remaining in the intensive care unit with an AUC of 0.78 and 0.79, respectively. Day 5 scores performed less well at predicting mortality. Day 1 SOFA and MSOFA predicted the need for mechanical ventilation on day 3, with an AUC of 0.83 and 0.82, respectively. Mortality for the highest category of SOFA and MSOFA score (>11 points) was 53% and 58%, respectively. CONCLUSIONS: The MSOFA predicts mortality as well as the SOFA and is easier to implement in resource-constrained settings, but using either score as a triage tool would exclude many patients who would otherwise survive.