Extracellular Vesicles in Serum and Central Nervous System Tissues Contain microRNA Signatures in Sporadic Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a terminalneurodegenerative disease. Clinical and molecular observations suggest that ALS pathology originates at a single site and spreads in an organized and prion-like manner, possibly driven by extracellular vesicles. Extracellular vesicles (EVs) transfer cargo molecules associated with ALS pathogenesis, such as misfolded and aggregated proteins and dysregulated microRNAs (miRNAs). However, it is poorly understood whether altered levels of circulating extracellular vesicles or their cargo components reflect pathological signatures of the disease. In this study, we used immuno-affinity-based microfluidic technology, electron microscopy, and NanoString miRNA profiling to isolate and characterize extracellular vesicles and their miRNA cargo from frontal cortex, spinal cord, and serum of sporadic ALS (n = 15) and healthy control (n = 16) participants. We found larger extracellular vesicles in ALS spinal cord versus controls and smaller sized vesicles in ALS serum. However, there were no changes in the number of extracellular vesicles between cases and controls across any tissues. Characterization of extracellular vesicle-derived miRNA cargo in ALS compared to controls identified significantly altered miRNA levels in all tissues; miRNAs were reduced in ALS frontal cortex and spinal cord and increased in serum. Two miRNAs were dysregulated in all three tissues: miR-342-3p was increased in ALS, and miR-1254 was reduced in ALS. Additional miRNAs overlapping across two tissues included miR-587, miR-298, miR-4443, and miR-450a-2-3p. Predicted targets and pathways associated with the dysregulated miRNAs across the ALS tissues were associated with common biological pathways altered in neurodegeneration, including axon guidance and long-term potentiation. A predicted target of one identified miRNA (N-deacetylase and N-sulfotransferase 4; NDST4) was likewise dysregulated in an in vitro model of ALS, verifying potential biological relevance. Together, these findings demonstrate that circulating extracellular vesicle miRNA cargo mirror those of the central nervous system disease state in ALS, and thereby offer insight into possible pathogenic factors and diagnostic opportunities.

The relationship of 26 clinical factors to weaning outcome.

BACKGROUND: The Burns Wean Assessment Program (BWAP) assessment checklist is designed to assist clinicians in the systematic evaluation of 26 clinical factors important to weaning. The authors recently described the relationship of the BWAP score (derived from the checklist) to weaning trial outcomes (weaning success or failure) in patients receiving mechanical ventilation for 3 days or longer in 5 adult critical care units. A BWAP score of 50 or higher was significantly associated with weaning success regardless of the specific category of patient (surgical, medical, cardiovascular, etc). This secondary analysis extends the evaluation of the BWAP checklist as it focuses on the importance of each individual BWAP factor to weaning outcomes in 5 different populations of patients. OBJECTIVES: To identify the relative importance of the 26 BWAP factors to weaning success in patients undergoing mechanical ventilation for 3 days or longer in 5 adult critical care units. METHODS: BWAP checklists were completed within 24 hours of a weaning attempt in surgical-trauma, medical, neurological, thoracic-cardiovascular, and coronary care units in a 5-year period. Advanced practice nurses using a multidisciplinary pathway, the BWAP checklist, protocols for weaning trials, and sedation guidelines managed the patients similarly. RESULTS: A total of 20 BWAP factors were significantly associated with successful weaning in all units combined (P ≤ .02). However, some differences in the importance of the BWAP factors to weaning outcome exist between units, with the neuroscience intensive care unit deviating the most from the other units. CONCLUSIONS: Although not all BWAP factors are significantly associated with weaning success, most are predictive. Restructuring the BWAP as a unit-specific weaning checklist and potential predictor may assist clinicians to address factors that may impede weaning more efficiently and effectively.

Multifactor clinical score and outcome of mechanical ventilation weaning trials: Burns Wean Assessment Program.

BACKGROUND: The Burns Wean Assessment Program is a 26-factor weaning assessment worksheet and scoring instrument used to reduce practice variability in the clinical management of patients receiving mechanical ventilation. The instrument has been tested in patients in a medical-surgical intensive care unit, but further testing in different populations of adult patients is needed. OBJECTIVES: To determine the relationship between Burns Wean Assessment Program scores and outcomes of weaning trials in patients treated with mechanical ventilation for 3 or more days. METHODS: For 5 years in 5 adult critical care units (surgical, medical, neurological, thoracic-cardiovascular, and coronary care), advanced practice nurses collected scores within 24 hours of a weaning attempt. All patients were managed similarly by using a multidisciplinary pathway, the Burns Wean Assessment Program checklist, protocols for weaning trials, and sedation guidelines. RESULTS: Of 1889 weaning attempts, 1669 (88%) were successful, and 220 (12%) were unsuccessful. Weaning outcomes did not differ according to sex, but significantly more trials were successful in younger patients than in older patients (P = .002) and in patients in different units (P = .01). Regardless of unit, patients with Burns Wean Assessment Program scores greater than 50 were significantly more likely to be weaned successfully (P = .001) than were patients with lower scores. CONCLUSIONS: Systematic tracking of the factors and scores on the Burns Wean Assessment Program may be helpful in care planning and management and in determining weaning potential.

Weaning of the neurologically impaired patient.

Many studies have been published on weaning patients from mechanical ventilation, but few have addressed the unique needs of patients with neurologic impairment. Typically, neuroscience patients remain intubated because of concerns over airway protection or neuromuscular weakness. This article discusses special weaning considerations for this patient population. Neurologic-specific weaning trends from a comprehensive ventilator weaning program are also presented.

The experience of four outcomes managers: an institutional approach to weaning patients from long-term mechanical ventilation.

Care of patients requiring long-term mechanical ventilation (LTMV) is the focus of many hospitals nationwide. Because the care of patients who require LTMV is complex and morbidity and mortality are high, associated costs often exceed reimbursement. This article describes a successful institutional program for the care of the patient population requiring LTMV using advanced practice nurses (APNs) in the role of outcomes managers (OMs). So that others may benefit from the experiences of the clinicians, this article describes the historical background, the selection and qualifications of APNs, the process APNs use to manage and monitor the patients, role challenges, and associated outcomes.

Implementation of an institutional program to improve clinical and financial outcomes of mechanically ventilated patients: one-year outcomes and lessons learned.

OBJECTIVE: To determine the effect of an institutional approach to the care of patients requiring mechanical ventilation for longer than three consecutive days in five adult intensive care units (ICU) on clinical and financial outcomes. DESIGN: A multidisciplinary team was selected from five adult ICUs to design the approach. Planning occurred from August 1999 to September 2000. The process was called outcomes management (OM) and included an evidence-based clinical pathway, protocols for weaning and sedation use, and the selection of four advanced practice nurses (called outcomes managers) to manage and monitor the program. SETTING: The project was completed in a 550-bed mid-Atlantic academic medical center. The ICUs included the following: coronary care, medical ICU, neuroscience ICU, surgical trauma ICU, and thoracic cardiovascular ICU. PATIENTS: The sample included 595 pre-OM patients and 510 post-OM patients mechanically ventilated for greater than three consecutive days. INTERVENTIONS: Full implementation of the OM approach occurred in March 2001. Retrospective baseline (18 months pre-OM) and prospective (12 months OM) clinical and financial data were compared. MEASUREMENTS AND MAIN RESULTS: Statistically significant differences in clinical outcomes were demonstrated in the managed patients compared with those managed before the institutional approach. Outcomes include ventilator duration (median days declined from ten to nine; p =.0001), ICU length of stay (median days declined from 15 to 12; p =.0008), hospital length of stay (median days declined from 22 to 20; p =.0001), and mortality rate (declined from 38% to 31%, p =.02). More than 3,000,000 US dollars cost savings were realized in the OM group. CONCLUSIONS: This institutional approach to the care of patients ventilated >3 days improved all clinical and financial outcomes of interest. To date, few similar initiatives have demonstrated similar results. The approach and lessons learned in this process improvement project may be helpful to other institutions attempting to improve outcomes in this vulnerable population.