Is it worth it? Greater risk aversion with lower life satisfaction among depressed individuals.

Decisions of individuals with depression are often risk-averse. Risk-aversion may also extend to decisions regarding treatment, which may cause individuals to forgo or delay treatment. It is also well established that depression is associated with lower satisfaction with life. However, whether life satisfaction is associated with risk aversion for individuals with depression is not yet known. Three groups of participants (Depressed: n = 61; Chronic pain: n = 61; Comorbid depression and pain: n = 58) completed a clinical interview and several self-report questionnaires, including the Satisfaction with Life Scale (SWLS). Participants also completed two utility elicitation tasks: time trade-off (TTO), which measures utilities of health states without implied risks, and standard gamble (SG), which measures utilities of health states in the presence of risk (presented in this study as a hypothetical clinical trial described as having both potential harms and benefits). Risk aversion is defined as the difference in the utility ratings generated via SG and via TTO. For both TTO and SG, individuals evaluated their own depression or pain. When perfect health was used as a hypothetical benefit in TTO and SG tasks, satisfaction with life was not associated with risk preferences, for either depressed participants or participants with chronic pain (all ps ns). However, for participants with depression, when the hypothetical benefit was a more ecologically valid 'mild' depression in TTO and SG tasks, lower satisfaction with life was associated with greater risk aversion (p < .005; p < .03). For depressed individuals, therefore, lower satisfaction with life may be associated with risk aversion regarding treatments when benefits are seen as minor, which may result in treatment avoidance and, consequently, further worsening of both symptoms and life satisfaction.

Standardized Transfer Process for a Neurointensive Care Unit and Assessment of Patient Bounceback.

BACKGROUND: Patients who require readmission to an intensive care unit (ICU) after transfer to a lower level of care ("bounceback") suffer from increased mortality and longer hospital stays. We aimed to create a multifaceted standardized transfer process for patients moving from the neurointensive care unit (neuro-ICU) to a lower level of care. We hypothesized that this process would lead to improvement in provider-rated safety and a decreased rate of bouncebacks to the neuro-ICU after transfer. METHODS: The study took place at the Hospital of the University of Pennsylvania from October 2018 to October 2020. A standardized five-step transfer process was created and implemented for transferring patients from the neuro-ICU to a lower level of care. Patient care providers completed a survey before and after implementation of the protocol to assess a variety of components related to safety concerns when transferring patients. The rate of bouncebacks pre and post intervention was calculated by using a two-sample Wilcoxon rank-sum test, and disposition at discharge was calculated by using Fisher's exact test. RESULTS: Of the 1176 total patient transfers out of the neuro-ICU, 29 patients bounced back within 48 h. The average age of patients who bounced back was 63.3 years old, with a similar distribution among men and women. The most common reason for bounceback was respiratory distress, followed by cardiac arrhythmia, stroke, and sepsis. Implementation of the standardized process led to a decrease in provider-rated concern of overall safety (5 to 3, p = 0.008). There was improvement in transfer delays due to bed availability (3 to 4.5, p = 0.020), identification of high-risk patients (5 to 6, p = 0.021), patient assignment to the appropriate level of care (5 to 6, p = 0.019), and use of the electronic medical record handoff indicator (5 to 6, p = 0.003). There was no statistically significant difference in terms of patient bounceback rate after implementation of the process (2.4% vs. 2.5%, p = 1.00) or patient disposition at discharge (p = 0.553). CONCLUSIONS: Patients who bounceback to the neuro-ICU within 48 h had an increased length of hospital stay, had an increased length of ICU stay, and were more likely to be intubated for more than 96 h. Implementation of a standardized five-step transfer process from the neuro-ICU to a lower level of care resulted in improvement in multiple provider-rated safety outcomes and identification of high-risk patients but led to no difference in the patient bounceback rate or patient disposition at discharge.

A Two-Step Bioreactor for Decellularized Lung Epithelialization.

Bioreactors for the reseeding of decellularized lung scaffolds have evolved with various advancements, including biomimetic mechanical stimulation, constant nutrient flow, multi-output monitoring, and large mammal scaling. Although dynamic bioreactors are not new to the field of lung bioengineering, ideal conditions during cell seeding have not been extensively studied or controlled. To address the lack of cell dispersal in traditional seeding methods, we have designed a two-step bioreactor. The first step is a novel system that rotates a seeded lung every 20 min at different angles in a sequence designed to anchor 20% of cells to a particular location based on the known rate of attachment. The second step involves perfusion-ventilation culture to ensure nutrient dispersion and cellular growth. Compared to statically seeded lungs, rotationally seeded lungs had significantly increased dsDNA content and more uniform cellular distribution after perfusion and ventilation had been administered. The addition of this novel seeding system before traditional culture methods will aid in recellularizing the lung and other geometrically complex organs for tissue engineering.

Safety and Feasibility of Early Mobilization in Patients with Subarachnoid Hemorrhage and External Ventricular Drain.

BACKGROUND/OBJECTIVE: In November 2014, our Neurointensive Care Unit began a multi-phased progressive early mobilization initiative for patients with subarachnoid hemorrhage and an external ventricular drain (EVD). Our goal was to transition from a culture of complete bed rest (Phase 0) to a physical and occupational therapy (PT/OT)-guided mobilization protocol (Phase I), and ultimately to a nurse-driven mobilization protocol (Phase II). We hypothesized that nurses could mobilize patients as safely as an exclusively PT/OT-guided approach. METHODS: In Phase I, patients were mobilized only with PT/OT at bedside; no independent time out of bed occurred. In Phase II, nurses independently mobilized patients with EVDs, and patients could remain out of bed for up to 3 h at a time. Physical and occupational therapists continued routine consultation during Phase II. RESULTS: Phase II patients were mobilized more frequently than Phase I patients [7.1 times per ICU stay (± 4.37) versus 3.0 times (± 1.33); p = 0.02], although not earlier [day 4.9 (± 3.46) versus day 6.0 (± 3.16); p = 0.32]. All Phase II patients were discharged to home PT services or acute rehabilitation centers. No patients were discharged to skilled nursing or long-term acute care hospitals, versus 12.5% in Phase I. In a multivariate analysis, odds of discharge to home/rehab were 3.83 for mobilized patients, independent of age and severity of illness. Other quality outcomes (length of stay, ventilator days, tracheostomy placement) between Phase I and Phase II patients were similar. No adverse events were attributable to early mobilization. CONCLUSIONS: Nurse-driven mobilization for patients with EVDs is safe, feasible, and leads to more frequent ambulation compared to a therapy-driven protocol. Nurse-driven mobilization may be associated with improved discharge disposition, although exact causation cannot be determined by these data.

A novel role for primary cilia in airway remodeling.

Primary cilia (PC) are solitary cellular organelles that play critical roles in development, homeostasis, and disease pathogenesis by modulating key signaling pathways such as Sonic Hedgehog and calcium flux. The antenna-like shape of PC enables them also to facilitate sensing of extracellular and mechanical stimuli into the cell, and a critical role for PC has been described for mesenchymal cells such as chondrocytes. However, nothing is known about the role of PC in airway smooth muscle cells (ASMCs) in the context of airway remodeling. We hypothesized that PC on ASMCs mediate cell contraction and are thus integral in the remodeling process. We found that PC are expressed on ASMCs in asthmatic lungs. Using pharmacological and genetic methods, we demonstrated that PC are necessary for ASMC contraction in a collagen gel three-dimensional model both in the absence of external stimulus and in response to the extracellular component hyaluronan. Mechanistically, we demonstrate that the effect of PC on ASMC contraction is, to a small extent, due to their effect on Sonic Hedgehog signaling and, to a larger extent, due to their effect on calcium influx and membrane depolarization. In conclusion, PC are necessary for the development of airway remodeling by mediating calcium flux and Sonic Hedgehog signaling.

Associations of Delirium to Posthospital Outcomes After Acute Stroke: A Scoping Review.

ABSTRACT: Background: Delirium is a common and distressing manifestation of acute brain dysfunction that is associated with poor outcomes in various critically ill patient populations. Although patients with acute stroke experience delirium, understanding of delirium in this population is limited. The purpose of this scoping review is to describe existing evidence about delirium and associations with posthospital outcomes after acute stroke. Methods: Arksey and O'Malley's 5-stage framework was used to perform a scoping review. PubMed, CINAHL, and EMBASE electronic databases were searched. Outcome domains of interest included mortality, cognitive function, physical function, mental health, and quality of life. Full-text, peer-reviewed articles with adult stroke sample populations (acute ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage) were included. Results: Nineteen articles, involving 5611 unique patients, were included. Most sample populations included patients with either acute ischemic stroke or intracerebral hemorrhage. Heterogeneous research aims, methods, and outcome measures limit the ability to compare specific findings across studies. However, included studies suggest higher mortality at 12 months, worse cognition, and greater functional impairment in patients who have experienced acute stroke and delirium. Limited information regarding associations of delirium with posthospital mental health outcomes and quality of life precluded the ability to analyze these relationships and warrants further investigation. Conclusion: This review suggests concerning findings about associations of delirium to posthospital outcomes after acute stroke. Better characterization of delirium after acute stroke and analysis of its impact on long-term outcomes are needed.

Porcine Lung-Derived Extracellular Matrix Hydrogel Properties Are Dependent on Pepsin Digestion Time.

Hydrogels derived from decellularized lungs are promising materials for tissue engineering in the development of clinical therapies and for modeling the lung extracellular matrix (ECM) in vitro. Characterizing and controlling the resulting physical, biochemical, mechanical, and biologic properties of decellularized ECM (dECM) after enzymatic solubilization and gelation are thus of key interest. As the role of enzymatic pepsin digestion in effecting these properties has been understudied, we investigated the digestion time-dependency on key parameters of the resulting ECM hydrogel. Using resolubilized, homogenized decellularized pig lung dECM as a model system, significant time-dependent changes in protein concentration, turbidity, and gelation potential were found to occur between the 4 and 24 h digestion time points, and plateauing with longer digestion times. These results correlated with qualitative scanning electron microscopy images and quantitative analysis of hydrogel interconnectivity and average fiber diameter. Interestingly, the time-dependent changes in the storage modulus tracked with the hydrogel interconnectivity results, while the Young's modulus values were more closely related to average fiber size at each time point. The structural and biochemical alterations correlated with significant changes in metabolic activity of several representative lung cells seeded onto the hydrogels with progressive decreases in cell viability and alterations in morphology observed in cells cultured on hydrogels produced with dECM digested for >12 and up to 72 h of digestion. These studies demonstrate that 12 h pepsin digest of pig lung dECM provides an optimal balance between desirable physical ECM hydrogel properties and effects on lung cell behaviors.

Implementation of a Data Acquisition and Integration Device in the Neurologic Intensive Care Unit.

The neurologic intensive care unit has evolved into a data-rich, complex arena. Various neurologic monitors, collectively referred to as multimodality monitoring, provide clinicians with a plethora of real-time information about a comatose patient's condition. The time and cognitive burden required to synthesize the available data and reach meaningful clinical conclusions can be overwhelming. The Moberg Component Neuromonitoring System (Moberg Research, Inc) is a data acquisition and integration device that collects data from multiple monitors, displaying them on a single screen in a way that highlights physiological trends throughout a patient's clinical course. Implementation of the Moberg Component Neuromonitoring System in the neurologic intensive care unit can improve understanding of a patient's neurophysiology, enhance clinical decision-making, and improve quality of care. Use of a staged process of implementation including exploration, installation, initial implementation, and full implementation can bring technology to the bedside in a sustainable fashion.

Laminin-driven Epac/Rap1 regulation of epithelial barriers on decellularized matrix.

Decellularized tissues offer a unique tool for developing regenerative biomaterials or in vitro platforms for the study of cell-extracellular matrix (ECM) interactions. One main challenge associated with decellularized lung tissue is that ECM components can be stripped away or altered by the detergents used to remove cellular debris. Without characterizing the composition of lung decellularized ECM (dECM) and the cellular response caused by the altered composition, it is difficult to utilize dECM for regeneration and specifically, engineering the complexities of the alveolar-capillary barrier. This study takes steps towards uncovering if dECM must be enhanced with lost ECM proteins to achieve proper epithelial barrier formation. To achieve this, the epithelial barrier function was assessed on dECM coatings with and without the systematic addition of several key basement membrane proteins. After comparing barrier function on collagen I, fibronectin, laminin, and dECM in varying combinations as an in vitro coating, the alveolar epithelium exhibited superior barrier function when dECM was supplemented with laminin as evidenced by trans-epithelial electrical resistance (TEER) and permeability assays. Increased barrier resistance with laminin addition was associated with upregulation of Claudin-18, E-cadherin, and junction adhesion molecule (JAM)-A, and stabilization of zonula occludens (ZO)-1 at junction complexes. The Epac/Rap1 pathway was observed to play a role in the ECM-mediated barrier function determined by protein expression and Epac inhibition. These findings revealed potential ECM coatings and molecular therapeutic targets for improved regeneration with decellularized scaffolds. STATEMENT OF SIGNIFICANCE: Efforts to produce a transplantable organ-scale biomaterial for lung regeneration has not been entirely successful to date, due to incomplete cell-cell junction formation, ultimately leading to severe edema in vivo. To fully understand the process of alveolar junction formation on ECM-derived biomaterials, this research has characterized and tailored decellularized ECM (dECM) to mitigate reductions in barrier strength or cell attachment caused by abnormal ECM compositions or detergent damage to dECM. These results indicate that laminin-driven Epac signaling plays a vital role in the stabilization of the alveolar barrier. Addition of laminin or Epac agonists during alveolar regeneration can reduce epithelial permeability within bioengineered lungs.

Tunable Hydrogels from Pulmonary Extracellular Matrix for 3D Cell Culture.

Here we present a method for establishing multiple component cell culture hydrogels for in vitro lung cell culture. Beginning with healthy en bloc lung tissue from porcine, rat, or mouse, the tissue is perfused and submerged in subsequent chemical detergents to remove the cellular debris. Histological comparison of the tissue before and after processing confirms removal of over 95% of double stranded DNA and alpha galactosidase staining suggests the majority of cellular debris is removed. After decellularization, the tissue is lyophilized and then cryomilled into a powder. The matrix powder is digested for 48 hr in an acidic pepsin digestion solution and then neutralized to form the pregel solution. Gelation of the pregel solution can be induced by incubation at 37 °C and can be used immediately following neutralization or stored at 4 °C for up to two weeks. Coatings can be formed using the pregel solution on a non-treated plate for cell attachment. Cells can be suspended in the pregel prior to self-assembly to achieve a 3D culture, plated on the surface of a formed gel from which the cells can migrate through the scaffold, or plated on the coatings. Alterations to the strategy presented can impact gelation temperature, strength, or protein fragment sizes. Beyond hydrogel formation, the hydrogel stiffness may be increased using genipin.

Electrospun Decellularized Lung Matrix Scaffold for Airway Smooth Muscle Culture.

Chronic respiratory disease affects many people worldwide with little known about the intricate mechanisms driving the pathology, making it difficult to develop novel therapies. Improving the understanding of airway smooth muscle and extracellular matrix (ECM) interactions is key to developing treatments for this leading cause of death. With currently no relevant or controllable in vivo or in vitro models to investigate cell-ECM interactions in the small airways, the development of a biomimetic in vitro model with cell attachment, signaling, and organization is needed. The goal of this study was to create a biologically and structurally relevant in vitro model of small airway smooth muscle. In order to achieve this goal, a scaffold was engineered from synthetic poly-l-lactic acid (PLLA) and decellularized pig lung ECM (PLECM). PLECM scaffolds have improved physical characteristics over synthetic scaffolds, by exhibiting a significant decrease in the elastic modulus and an increase in hydrophilicity. Histological staining and SDS-PAGE showed that essential proteins or protein fragments found in natural ECM were present after processing. Human bronchial smooth muscle cells (HBSMCs) seeded onto PLECM 3D scaffolds formed confluent layers and maintained a contractile phenotype, as demonstrated by the organized arrangement of actin filaments within the cell and expected contractile protein expression of calponin 1. HBSMCs cultured on electrospun PLECM scaffold also increased alpha-1 type 1 collagen compared to those cultured on PLLA scaffolds. In summary, this research demonstrates that a PLLA/PLECM composite electrospun mat is a promising tool to produce an in vitro model of the airway with the potential for a better understanding of bronchiole smooth muscle behavior in diseased or normal states.

Implementation of an Early Mobility Pathway in Neurointensive Care Unit Patients With External Ventricular Devices.

BACKGROUND: Patients with an external ventricular drain (EVD) may not be readily mobilized because of concerns of catheter dislodgment and/or inappropriate cerebrospinal fluid drainage. Delayed mobilization may result in longer hospital stays and an increased risk for complications related to immobility. We aimed to determine the safety, feasibility, and outcome of an EVD mobilization protocol in patients with subarachnoid hemorrhage (SAH). METHODS: A multidisciplinary group developed a formal algorithm for the mobilization of patients with SAH with EVDs. Outcome measures included intensive care unit (ICU) length of stay (LOS), day to first mobilization, and discharge disposition. Patients were prospectively enrolled during a 12-month period and compared with a historical control group of patients with SAH for the preceding 12-month period. RESULTS: Thirty-nine of 45 (86.7%) patients were women. Mean age did not differ significantly between the preintervention (n = 19) and postintervention (n = 26) groups (59.6 vs 55.7). Number of EVD device days did not differ significantly between groups (16.3 vs 15, P = .422]. Of 101 attempted postintervention mobilization sessions, six were aborted for increased lethargy (1), pain (1), elevated intracranial pressure (1), drain malfunction (1), and hypotension (2). Twenty-four sessions were attempted but never initiated because of worsening neurologic examination (10), pulmonary instability (2), hemodynamic instability (2), medical instability (3), and provider request (1). No patient experienced catheter dislodgment. Mean ICU LOS was not different between groups (20.7 vs 18.2, P = .262). The day of first mobilization was significantly earlier in the postintervention group (18.7 vs 6.5, P < .0001). The percentage of patients discharged home or to acute rehabilitation was higher in the postintervention group (63.2% vs 88.5%, P = .018], when accounting for Hunt and Hess grade. CONCLUSIONS: The mobilization of patients with EVDs is safe and feasible; it may be associated with earlier mobilization, reduced ICU LOS, and better discharge disposition. No major complications were attributable to early mobilization.

Cerebral Microdialysis.

A variety of neuromonitoring techniques are available to aid in the care of neurocritically ill patients. However, traditional monitors lack the ability to measure brain biochemistry and may provide inadequate warning of potentially reversible deleterious conditions. Cerebral microdialysis (CMD) is a safe, novel method of monitoring regional brain biochemistry. Analysis of CMD analytes as part of a multimodal approach may help inform clinical decision making, guide medical treatments, and aid in prognostication of patient outcome. Its use is most frequently documented in traumatic brain injury and subarachnoid hemorrhage. Incorporating CMD into clinical practice is a multidisciplinary effort.