Defect-Driven Configurational Entropy in the High-Entropy Oxide Li1.5MO3-δ.

Layered lithiated oxides are promising materials for next generation Li-ion battery cathode materials; however, instability during cycling results in poor performance over time compared to the high capacities theoretically possible with these materials. Here we report the characterizations of a Li1.47Mn0.57Al0.13Fe0.095Co0.105Ni0.095O2.49 high-entropy layered oxide (HELO) with the Li2MO3 structure where M = Mn, Al, Fe, Co, and Ni. Using electron microscopy and X-ray spectroscopy, we identify a homogeneous Li2MO3 structure stabilized by the entropic contribution of oxygen vacancies. This defect-driven entropy would not be attainable in the LiMO2 structure sometimes observed in similar materials as a secondary phase owing to the presence of fewer O sites and a 3+ oxidation state for the metal site; instead, a Li2-γMO3-δ is produced. Beyond Li2MO3, this defect-driven entropy approach to stabilizing novel compositions and phases can be applied to a wide array of future cathode materials including spinel and rock salt structures.

High-Entropy Spinel Oxide Ferrites for Battery Applications.

Four different high-entropy spinel oxide ferrite (HESO) electrode materials containing 5-6 distinct metals were synthesized by a simple, rapid combustion synthesis process and evaluated as conversion anode materials in lithium half-cells. All showed markedly superior electrochemical performance compared to conventional spinel ferrites such as Fe3O4 and MgFe2O4, having capacities that could be maintained above 600 mAh g-1 for 150 cycles, in most cases. X-ray absorption spectroscopy (XAS) results on pristine, discharged, and charged electrodes show that Fe, Co, Ni, and Cu are reduced to the elemental state during the first discharge (lithiation), while Mn is only slightly reduced. Upon recharge (delithiation), Fe is reoxidized to an average oxidation state of about 2.6+, while Co, Ni, and Cu are not reoxidized. The ability of Fe to be oxidized past 2+ accounts for the high capacities observed in these materials, while the presence of metallic elements after the initial lithiation provides an electronically conductive network that aids in charge transfer.

A duplex droplet digital PCR assay for absolute quantification and characterization of long self-amplifying RNA.

Self-amplifying messenger ribonucleic acid (saRNA) provides extended expression of genes of interest by encoding an alphavirus-derived RNA replicase and thus is 2-3 times larger than conventional messenger RNA. However, quality assessment of long RNA transcripts is challenging using standard techniques. Here, we utilized a multiplex droplet digital polymerase chain reaction (ddPCR) assay to assess the quality of saRNA produced from an in vitro transcription reaction and the replication kinetics in human cell lines. Using the one-step reverse transcription ddPCR, we show that an in vitro transcription generates 50-60% full-length saRNA transcripts. However, we note that the two-step reverse transcription ddPCR assay results in a 20% decrease from results obtained using the one-step and confirmed using capillary gel electrophoresis. Additionally, we provided three formulas that differ in the level of stringency and assumptions made to calculate the fraction of intact saRNA. Using ddPCR, we also showed that subgenomic transcripts of saRNA were 19-to-108-fold higher than genomic transcripts at different hours post-transfection of mammalian cells in copies. Therefore, we demonstrate that multiplex ddPCR is well suited for quality assessment of long RNA and replication kinetics of saRNA based on absolute quantification.

Augmented reality glasses improve adherence to evidence-based intubation practice.

Background: The risk of failing or delaying endotracheal intubation in critically ill patients has commonly been associated with inadequate procedure preparation. Clinicians and trainees in simulation courses for tracheal intubation are encouraged to recall the steps of how to intubate in order to mitigate the risk of a failed intubation. The purpose of this study was to assess the effectiveness of using optical head mounted display augmented reality (AR) glasses as an assistance tool to perform intubation simulation procedure. Methods: A total of 32 subjects with a mean age of 30±7.8, AR (n1=15) vs non-augmented reality(non-AR) (n2=17). The majority were males (n=22, 68.7%). Subjects were randomly assigned into two groups: the AR group and the non-AR group. Both groups reviewed a video on how to intubate following the New England Journal of Medicine (NEJM) intubation guidelines. The AR group had to intubate using the AR glasses head mount display compared to the non-AR where they performed regular intubation. Results: The AR group took longer median (min, max) time (seconds) to ventilate than the non-AR group (280 (130,740) vs 205 (100,390); η 2 =1.0, p=0.005, respectively). Similarly, there was a higher percent adherence of NEJM intubation checklist (100% in the AR group vs 82.4% in the non-AR group; η2=1.8, p<0.001). Conclusion: The AR glasses showed promise in assisting different health care professionals on endotracheal intubation simulation. Participants in the AR group took a longer time to ventilate but scored 100% in the developed checklist that followed the NEJM protocol. This finding shows that the AR technology can be used in a simulation setting and requires further study before clinical use.

Life after sepsis: an international survey of survivors to understand the post-sepsis syndrome.

OBJECTIVE: In this study, we aim to describe the post-sepsis syndrome from the perspective of the sepsis survivors. DESIGN AND SETTING: The study is a prospective, observational online international survey. PARTICIPANTS: Sepsis survivors enrolled via social media from 13 September 2014 to 13 September 2016. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Physiologic, physical and psychological function post-sepsis; and patient satisfaction with sepsis-centered care. RESULTS: 1731 completed surveys from 41 countries were analyzed, with 79.9% female respondents, age 47.6 ± 14.4 years. The majority of respondents (47.8%) had sepsis within the last year. Survivors reported an increase in sensory, integumentary, digestive, breathing, chest pain, kidney and musculoskeletal problems after sepsis (all P-value <0.0001). Physical functions such as daily chores, running errands, spelling, reading and reduced libido posed increased difficulty (all P-value <0.0001). Within 7 days prior to completing the survey, the survivors reported varying degrees of anxiety, depression, fatigue and sleep disturbance. Sepsis survivors reported dissatisfaction with a number of hospital support services, with up to 29.3% of respondents stating no social services support was provided for their condition. CONCLUSIONS: Sepsis survivors suffer from a myriad of physiologic, physical and psychological challenges. Survivors overall reveal dissatisfaction with sepsis-related care, suggesting areas for improvement both in-hospital and post-discharge.

A multi-center evaluation of a disposable catheter to aid in correct positioning of the endotracheal tube after intubation in critically ill patients.

PURPOSE: To demonstrate that use of a minimally invasive catheter reduces endotracheal tube (ETT) malposition rate after intubation. MATERIALS AND METHODS: This study is a multi-center, prospective observational cohort of intubated patients in the medical intensive care unit. The catheter was inserted into the ETT immediately after intubation. The ETT was adjusted accordingly based on qualitative color markers on the catheter. A confirmatory chest radiograph was obtained to determine the ETT position. Malposition of the ETT was defined by the distal ETT not being within 2-5 cm above the carina. RESULTS: Sixty-nine patients were enrolled, age 56.2 ±â€¯19.5 years, body mass index 31.0 ±â€¯13.8 kg/m2. The catheter prompted repositioning of the ETT in 39 (56.5%) patients. Using the catheter, the rate of malposition decreased to 7.2%, with the distal ETT position at 3.7 ±â€¯1.2 cm above the carina. Without the catheter, the ETT malposition rate would have been 39.1%. The time for catheter use and chest radiograph completion at our institutions was 1.7 ±â€¯1.5 and 44.4 ±â€¯36.4 min, respectively. CONCLUSIONS: With use of an ETT positioning catheter after intubation, the ETT malposition rate was reduced by 82%. This catheter-based system was safe, and its use may perhaps decrease the need for the post-intubation chest radiograph.

The use of augmented reality glasses in central line simulation: "see one, simulate many, do one competently, and teach everyone".

OBJECTIVE: The aim of this study was to investigate the feasibility of using augmented reality (AR) glasses in central line simulation by novice operators and compare its efficacy to standard central line simulation/teaching. DESIGN: This was a prospective randomized controlled study enrolling 32 novice operators. Subjects were randomized on a 1:1 basis to either simulation using the augmented virtual reality glasses or simulation using conventional instruction. SETTING: The study was conducted in tertiary-care urban teaching hospital. SUBJECTS: A total of 32 adult novice central line operators with no visual or auditory impairments were enrolled. Medical doctors, respiratory therapists, and sleep technicians were recruited from the medical field. MEASUREMENTS AND MAIN RESULTS: The mean time for AR placement in the AR group was 71±43 s, and the time to internal jugular (IJ) cannulation was 316±112 s. There was no significant difference in median (minimum, maximum) time (seconds) to IJ cannulation for those who were in the AR group and those who were not (339 [130, 550] vs 287 [35, 475], p=0.09), respectively. There was also no significant difference between the two groups in median total procedure time (524 [329, 792] vs 469 [198, 781], p=0.29), respectively. There was a significant difference in the adherence level between the two groups favoring the AR group (p=0.003). CONCLUSION: AR simulation of central venous catheters in manikins is feasible and efficacious in novice operators as an educational tool. Future studies are recommended in this area as it is a promising area of medical education.

Reduction of pulmonary toxicity of metal oxide nanoparticles by phosphonate-based surface passivation.

BACKGROUND: The wide application of engineered nanoparticles has induced increasing exposure to humans and environment, which led to substantial concerns on their biosafety. Some metal oxides (MOx) have shown severe toxicity in cells and animals, thus safe designs of MOx with reduced hazard potential are desired. Currently, there is a lack of a simple yet effective safe design approach for the toxic MOx. In this study, we determined the key physicochemical properties of MOx that lead to cytotoxicity and explored a safe design approach for toxic MOx by modifying their hazard properties. RESULTS: THP-1 and BEAS-2B cells were exposed to 0-200 µg/mL MOx for 24 h, we found some toxic MOx including CoO, CuO, Ni2O3 and Co3O4, could induce reactive oxygen species (ROS) generation and cell death due to the toxic ion shedding and/or oxidative stress generation from the active surface of MOx internalized into lysosomes. We thus hypothesized that surface passivation could reduce or eliminate the toxicity of MOx. We experimented with a series of surface coating molecules and discovered that ethylenediamine tetra (methylene phosphonic acid) (EDTMP) could form stable hexadentate coordination with MOx. The coating layer can effectively reduce the surface activity of MOx with 85-99% decrease of oxidative potential, and 65-98% decrease of ion shedding. The EDTMP coated MOx show negligible ROS generation and cell death in THP-1 and BEAS-2B cells. The protective effect of EDTMP coating was further validated in mouse lungs exposed to 2 mg/kg MOx by oropharyngeal aspiration. After 40 h exposure, EDTMP coated MOx show significant decreases of neutrophil counts, lactate dehydrogenase (LDH) release, MCP-1, LIX and IL-6 in bronchoalveolar lavage fluid (BALF), compared to uncoated particles. The haematoxylin and eosin (H&E) staining results of lung tissue also show EDTMP coating could significantly reduce the pulmonary inflammation of MOx. CONCLUSIONS: The surface reactivity of MOx including ion shedding and oxidative potential is the dominated physicochemical property that is responsible for the cytotoxicity induced by MOx. EDTMP coating could passivate the surface of MOx, reduce their cytotoxicity and pulmonary hazard effects. This coating would be an effective safe design approach for a broad spectrum of toxic MOx, which will facilitate the safe use of MOx in commercial nanoproducts.

Enhanced osseous integration of human trabecular allografts following surface modification with bioactive lipids.

In this study, we used extracellular matrix (ECM) gels and human bone allograft as matrix vehicles to deliver the sphingolipid growth factor FTY720 to rodent models of tibial fracture and a critical-sized cranial defect. We show that FTY720 released from injectable ECM gels may accelerate callous formation and resolution and bone volume in a mouse tibial fracture model. We then show that FTY720 binds directly to human trabecular allograft bone and releases over 1 week in vitro. Rat critical-sized cranial defects treated with FTY720-coated grafts show increases in vascularization and bone deposition, with histological and micro-computed topography (microCT) evidence of enhanced bone formation within the graft and defect void. Immunohistochemical analysis suggests that osteogenesis within FTY720-coated grafts is associated with reduced CD68(+) macrophage infiltration and recruitment of CD29(+) bone progenitor cells. Matrix binding of FTY720 thus represents a promising and robust bone regeneration strategy with potential clinical translatability.

Risk factors for locoregional recurrence after mastectomy in stage T1 N0 breast cancer.

OBJECTIVES: Postmastectomy radiotherapy (PMRT) is proven to decrease locoregional recurrence (LRR) in locally advanced breast cancer. However, there is little data regarding PMRT in early stage disease. This study examines risk factors for LRR in patients who underwent mastectomy for T1 N0 breast cancer, with the aim of identifying a subgroup who may potentially benefit from PMRT. METHODS: From 1994 to 2004, there were 1259 pathologic stage T1 N0 breast cancers treated with mastectomy and no radiation within the Kaiser Permanente Southern California medical system. Kaplan-Meier survival curves for LRR were compared using the log-rank test, and multivariate analysis was done using Cox proportional hazard ratios to identify risk factors for LRR. RESULTS: Median follow-up was 8.15 years. The 10-year Kaplan-Meier LRR rate was 3.2% (95% confidence interval [CI], 2%-4.3%). The median time to LRR was 2.5 years after mastectomy, and the most common site was chest wall (68%). Grade 3 (hazard ratio 3.97; 95% CI, 1.94-8.14; P = 0.0002) and margins ≤ 3 mm (hazard ratio 2.97; 95% CI, 1.21-7.29; P = 0.02) were significantly associated with LRR on multivariate analysis. The 10-year Kaplan-Meier rate of LRR for the 1230 patients with neither or one factor was 2.7% (95% CI, 1.6%-3.8%), compared with a LRR rate of 25% (95% CI, 2.2%-42.7%) among the 29 patients with both high grade and margins ≤ 3 mm (P < 0.0001). CONCLUSIONS: After mastectomy for pT1 N0 breast cancer, there is a small subgroup of patients with grade 3 disease and a close or positive margin (≤ 3 mm) who have an increased risk of LRR. These patients may benefit from the administration of PMRT.

Neuropeptide PACAP in mouse liver ischemia and reperfusion injury: immunomodulation by the cAMP-PKA pathway.

UNLABELLED: Hepatic ischemia and reperfusion injury (IRI), an exogenous antigen-independent local inflammation response, occurs in multiple clinical settings, including liver transplantation, hepatic resection, trauma, and shock. The immune system and the nervous system maintain extensive communication and mount a variety of integrated responses to danger signals through intricate chemical messengers. This study examined the function and potential therapeutic potential of neuropeptide pituitary adenylate cyclase-activating polypeptides (PACAP) in a murine model of partial liver "warm" ischemia (90 minutes) followed by reperfusion. Liver IRI readily triggered the expression of intrinsic PACAP and its receptors, whereas the hepatocellular damage was exacerbated in PACAP-deficient mice. Conversely, PACAP27, or PACAP38 peptide monotherapy, which elevates intracellular cyclic adenosine monophosphate/protein kinase A (cAMP-PKA) signaling, protected livers from IRI, as evidenced by diminished serum alanine aminotransferase levels and well-preserved tissue architecture. The liver protection rendered by PACAP peptides was accompanied by diminished neutrophil/macrophage infiltration and activation, reduced hepatocyte necrosis/apoptosis, and selectively augmented hepatic interleukin (IL)-10 expression. Strikingly, PKA inhibition readily restored liver damage in otherwise IR-resistant, PACAP-conditioned mice. In vitro, PACAP treatment not only diminished macrophage tumor necrosis factor alpha/IL-6/IL-12 levels in a PKA-dependent manner, but also prevented necrosis and apoptosis in primary mouse hepatocyte cultures. CONCLUSION: Our novel findings document the importance of PACAP-mediated cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. Because the enhancement of neural modulation differentially regulates local inflammation and prevents hepatocyte death, these results provide the rationale for novel approaches to manage liver inflammation and IRI in transplant patients.

Regulation of osteoclast structure and function by FAK family kinases.

Osteoclasts are highly specialized cells that resorb bone and contribute to bone remodeling. Diseases such as osteoporosis and osteolytic bone metastasis occur when osteoclast-mediated bone resorption takes place in the absence of concurrent bone synthesis. Considerable effort has been placed on identifying molecules that regulate the bone resorption activity of osteoclasts. To this end, we investigated unique and overlapping functions of members of the FAK family (FAK and Pyk2) in osteoclast functions. With the use of a conditional knockout mouse model, in which FAK is selectively targeted for deletion in osteoclast precursors (FAK(Δmyeloid)), we found that loss of FAK resulted in reduced bone resorption by osteoclasts in vitro, coincident with impaired signaling through the CSF-1R. However, bone architecture appeared normal in FAK(Δmyeloid) mice, suggesting that Pyk2 might functionally compensate for reduced FAK levels in vivo. This was supported by data showing that podosome adhesion structures, which are essential for bone degradation, were significantly more impaired in osteoclasts when FAK and Pyk2 were reduced than when either molecule was depleted individually. We conclude that FAK contributes to cytokine signaling and bone resorption in osteoclasts and partially compensates for the absence of Pyk2 to maintain proper adhesion structures in these cells.

Activation of cyclic adenosine monophosphate-dependent protein kinase a signaling prevents liver ischemia/reperfusion injury in mice.

Hepatic ischemia/reperfusion injury (IRI) occurs in multiple clinical settings, including liver transplantation. The cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) pathway inhibits hepatocellular apoptosis and regulates toll-like receptor 4-triggered inflammation responses in vitro. Here we examined the function and therapeutic potential of cAMP-PKA activation in a murine (C57/BL6) model of liver warm ischemia (90 minutes) followed by reperfusion. Liver IRI triggered cAMP-PKA activation, whereas the administration of its specific inhibitor, H89, exacerbated hepatocellular damage. Conversely, forskolin therapy, which activates PKA by elevating cAMP levels, protected livers from IRI; this was evidenced by diminished serum alanine aminotransferase levels and well-preserved tissue architecture. Liver protection due to cAMP-PKA stimulation was accompanied by diminished neutrophil and macrophage infiltration/activation, reduced hepatocyte necrosis/apoptosis, and increased cAMP response element-binding protein (CREB) expression and augmented interleukin-10 (IL-10) expression. The neutralization of IL-10 restored liver damage in otherwise ischemia/reperfusion-resistant, forskolin-treated mice. In vitro, cAMP-PKA activation diminished macrophage tumor necrosis factor α, IL-6, and IL-12 in an IL-10-dependent manner and prevented necrosis/apoptosis in primary mouse hepatocyte cultures. Our novel findings in a mouse model of liver IRI document the importance of cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. The activation of cAMP-PKA signaling differentially regulates local inflammation and prevents hepatocyte death, and this provides a rationale for novel therapeutic approaches to combating liver IRI in transplant recipients.

Local delivery of FTY720 accelerates cranial allograft incorporation and bone formation.

Endogenous stem cell recruitment to the site of skeletal injury is key to enhanced osseous remodeling and neovascularization. To this end, this study utilized a novel bone allograft coating of poly(lactic-co-glycolic acid) (PLAGA) to sustain the release of FTY720, a selective agonist for sphingosine 1-phosphate (S1P) receptors, from calvarial allografts. Uncoated allografts, vehicle-coated, low dose FTY720 in PLAGA (1:200 w:w) and high dose FTY720 in PLAGA (1:40) were implanted into critical size calvarial bone defects. The ability of local FTY720 delivery to promote angiogenesis, maximize osteoinductivity and improve allograft incorporation by recruitment of bone progenitor cells from surrounding soft tissues and microcirculation was evaluated. FTY720 bioactivity after encapsulation and release was confirmed with sphingosine kinase 2 assays. HPLC-MS quantified about 50% loaded FTY720 release of the total encapsulated drug (4.5 µg) after 5 days. Following 2 weeks of defect healing, FTY720 delivery led to statistically significant increases in bone volumes compared to controls, with total bone volume increases for uncoated, coated, low FTY720 and high FTY720 of 5.98, 3.38, 7.2 and 8.9 mm(3), respectively. The rate and extent of enhanced bone growth persisted through week 4 but, by week 8, increases in bone formation in FTY720 groups were no longer statistically significant. However, micro-computed tomography (microCT) of contrast enhanced vascular ingrowth (MICROFIL®) and histological analysis showed enhanced integration as well as directed bone growth in both high and low dose FTY720 groups compared to controls.

Development of an advanced nomogram for myopic astigmatic wavefront-guided laser in situ keratomileusis (LASIK).

BACKGROUND AND OBJECTIVE: To identify the relationship between preoperative parameters and postoperative overcorrection or undercorrection in eyes with myopic astigmatism treated with wavefront-guided laser in situ keratomileusis (LASIK), and to develop an advanced surgical nomogram. PATIENTS AND METHODS: A retrospective chart review of 468 eyes that underwent wavefront-guided LASIK for myopia with astigmatism with the Alcon LADARVision 4000 (Alcon Laboratories, Fort Worth, TX), of which 235 had flaps created by microkeratome (OneUse; Moria Surgical, Doylestown, PA) and 233 by femtosecond laser (Intralase; AMO, Santa Ana, CA). Manifest sphere, cylinder, and spherical equivalent were recorded preoperatively and 3 months postoperatively. Various parameters from patient records were analyzed to identify which had greatest influence on outcomes. RESULTS: Manifest spherical equivalent was the most important predictor of surgical overcorrection, with the second being spherical aberration. In both groups, there was a statistically significant (P < .0001) correlation of spherical aberration with the amount of overcorrection. Using these two parameters, compensatory nomograms were derived. CONCLUSION: Surgical overcorrection in wavefront-guided LASIK for myopic astigmatism correlates positively with the amount of spherical equivalent treated and preoperative spherical aberration. Nomograms incorporating spherical aberration may improve accuracy of outcomes.