Autocrine Loop Involving IL-6 Family Member LIF, LIF Receptor, and STAT4 Drives Sustained Fibroblast Production of Inflammatory Mediators.

Fibroblasts are major contributors to and regulators of inflammation and dominant producers of interleukin-6 (IL-6) in inflammatory diseases like rheumatoid arthritis. Yet, compared to leukocytes, the regulation of inflammatory pathways in fibroblasts is largely unknown. Here, we report that analyses of genes coordinately upregulated with IL-6 pointed to STAT4 and leukemia inhibitory factor (LIF) as potentially linked. Gene silencing revealed that STAT4 was required for IL-6 transcription. STAT4 was recruited to the IL-6 promoter after fibroblast activation, and LIF receptor (LIFR) and STAT4 formed a molecular complex that, together with JAK1 and TYK2 kinases, controlled STAT4 activation. Importantly, a positive feedback loop involving autocrine LIF, LIFR, and STAT4 drove sustained IL-6 transcription. Besides IL-6, this autorine loop also drove the production of other key inflammatory factors including IL-8, granulocyte-colony stimulating factor (G-CSF), IL-33, IL-11, IL-1α, and IL-1ß. These findings define the transcriptional regulation of fibroblast-mediated inflammation as distinct from leukocytes.

Changing Institutional Culture Around Hospice Using LEAN Tools to Improve Hospice Utilization in a Veteran Population.

BACKGROUND: Longer hospice length of stay improves the palliation of symptoms, quality of life, and the dying process for patients and their caregivers. We used a Lean designed Rapid Improvement Event (RIE) to facilitate earlier entry into hospice. MEASURES: Our primary outcome was hospice length of stay. Secondary outcomes were avoiding unwanted inpatient utilization and hospice location. INTERVENTIONS: We conducted a five-day RIE utilizing Lean tools targeting the inpatient medicine wards. OUTCOMES: Hospice length of stay increased from a median (interquartile range [IQR]) of 11 (7,27) days prior to 37 (7,73) days following the RIE. Home hospice and outside Skilled Nursing Home (SNF) hospice use increased while use of the onsite VA hospice decreased. CONCLUSIONS/LESSONS LEARNED: LEAN tools can be used successfully to improve end of life outcomes in an inpatient VA setting. The 90-day sustainment period following the RIE uncovers barriers to implementation and allows for adjustments to implementation.

Habits Heart App for Patient Engagement in Heart Failure Management: Pilot Feasibility Randomized Trial.

BACKGROUND: Due to the complexity and chronicity of heart failure, engaging yet simple patient self-management tools are needed. OBJECTIVE: This study aimed to assess the feasibility and patient engagement with a smartphone app designed for heart failure. METHODS: Patients with heart failure were randomized to intervention (smartphone with the Habits Heart App installed and Bluetooth-linked scale) or control (paper education material) groups. All intervention group patients were interviewed and monitored closely for app feasibility while receiving standard of care heart failure management by cardiologists. The Atlanta Heart Failure Knowledge Test, a quality of life survey (Kansas City Cardiomyopathy Questionnaire), and weight were assessed at baseline and final visits. RESULTS: Patients (N=28 patients; intervention: n=15; control: n=13) with heart failure (with reduced ejection fraction: 15/28, 54%; male: 20/28, 71%, female: 8/28, 29%; median age 63 years) were enrolled, and 82% of patients (N=23; intervention: 12/15, 80%; control: 11/13, 85%) completed both baseline and final visits (median follow up 60 days). In the intervention group, 2 out of the 12 patients who completed the study did not use the app after study onboarding due to illnesses and hospitalizations. Of the remaining 10 patients who used the app, 5 patients logged ≥1 interaction with the app per day on average, and 2 patients logged an interaction with the app every other day on average. The intervention group averaged 403 screen views (per patient) in 56 distinct sessions, 5-minute session durations, and 22 weight entries per patient. There was a direct correlation between duration of app use and improvement in heart failure knowledge (Atlanta Heart Failure Knowledge Test score; ρ=0.59, P=.04) and quality of life (Kansas City Cardiomyopathy Questionnaire score; ρ=0.63, P=.03). The correlation between app use and weight change was ρ=-0.40 (P=.19). Only 1 out of 11 patients in the control group retained education material by the follow-up visit. CONCLUSIONS: The Habits Heart App with a Bluetooth-linked scale is a feasible way to engage patients in heart failure management, and barriers to app engagement were identified. A larger multicenter study may be warranted to evaluate the effectiveness of the app. TRIAL REGISTRATION: ClinicalTrials.gov NCT03238729; http://clinicaltrials.gov/ct2/show/NCT03238729.

Resuscitating the Globally Ischemic Brain: TTM and Beyond.

Cardiac arrest (CA) afflicts ~ 550,000 people each year in the USA. A small fraction of CA sufferers survive with a majority of these survivors emerging in a comatose state. Many CA survivors suffer devastating global brain injury with some remaining indefinitely in a comatose state. The pathogenesis of global brain injury secondary to CA is complex. Mechanisms of CA-induced brain injury include ischemia, hypoxia, cytotoxicity, inflammation, and ultimately, irreversible neuronal damage. Due to this complexity, it is critical for clinicians to have access as early as possible to quantitative metrics for diagnosing injury severity, accurately predicting outcome, and informing patient care. Current recommendations involve using multiple modalities including clinical exam, electrophysiology, brain imaging, and molecular biomarkers. This multi-faceted approach is designed to improve prognostication to avoid "self-fulfilling" prophecy and early withdrawal of life-sustaining treatments. Incorporation of emerging dynamic monitoring tools such as diffuse optical technologies may provide improved diagnosis and early prognostication to better inform treatment. Currently, targeted temperature management (TTM) is the leading treatment, with the number of patients needed to treat being ~ 6 in order to improve outcome for one patient. Future avenues of treatment, which may potentially be combined with TTM, include pharmacotherapy, perfusion/oxygenation targets, and pre/postconditioning. In this review, we provide a bench to bedside approach to delineate the pathophysiology, prognostication methods, current targeted therapies, and future directions of research surrounding hypoxic-ischemic brain injury (HIBI) secondary to CA.

Myocardial contrast echocardiography (MCE) with triggered ultrasound does not cause premature ventricular complexes: evidence from PB127 MCE studies.

Previous studies suggest that myocardial contrast echocardiography using high mechanical index triggered ultrasound can be associated with increased frequency of the premature ventricular complex (PVC). However, this association has not been systematically examined. PB127 (Point Biomedical Corp, San Carlos, Calif) is a novel microsphere designed for evaluation of myocardial perfusion with ultrasound. PB127 myocardial contrast echocardiography was performed with triggered harmonic power Doppler in early/mid diastole (mechanical index .999) and was lower than untriggered intervals (P =.001) in B, suggesting that triggers do not cause PVC. PB127 does not cause increase PVC frequency during or after imaging with triggered ultrasound at mechanical index of 1.

Case Report: Reversible cabergoline-associated cardiac valvulopathy post drug discontinuation.

We present a case of a 21 year old male patient diagnosed with a 2.2 cm prolactin-secreting adenoma in contact with the optic chiasm. The patient was treated with up to 6mg/week of cabergoline (total cumulative dose 814 mg) and developed mild valvulopathy. Valvulopathy was subsequently reversed after discontinuation of cabergoline therapy.

Capture and stimulated release of circulating tumor cells on polymer-grafted silicon nanostructures.

A platform for capture and release of circulating tumor cells is demonstrated by utilizing polymer grafted silicon nanowires. In this platform, integration of ligand-receptor recognition, nanostructure amplification, and thermal responsive polymers enables a highly efficient and selective capture of cancer cells. Subsequently, these captured cells are released upon a physical stimulation with outstanding cell viability.

The role of echocardiography in hemodynamic assessment of septic shock.

Echocardiography is a rapid, noninvasive, comprehensive cardiac assessment option for patients presenting with hemodynamic instability. In patients with septic shock, echocardiography can be used to guide fluid therapy by measuring collapsibility of the inferior vena cava. Sepsis-induced myocardial dysfunction can be diagnosed, and responses to therapy can be monitored with echo. Patients with persistent shock should be evaluated for right heart failure, dynamic left ventricular obstruction, or tamponade if they do not respond to resuscitation and norepinephrine. Unexpected or rare findings that affect management may be revealed using focused echocardiography. This article presents national and international competency statements regarding critical care echocardiography and training resources for intensivists.