Publications by authors named "Michael Joyce"

121 Publications

Efficacy of a Broadly Neutralizing SARS-CoV-2 Ferritin Nanoparticle Vaccine in Nonhuman Primates.

bioRxiv 2021 Mar 25. Epub 2021 Mar 25.

The emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants stresses the continued need for next-generation vaccines that confer broad protection against coronavirus disease 2019 (COVID-19). We developed and evaluated an adjuvanted SARS-CoV-2 Spike Ferritin Nanoparticle (SpFN) vaccine in nonhuman primates (NHPs). High-dose (50 g) SpFN vaccine, given twice within a 28 day interval, induced a Th1-biased CD4 T cell helper response and a peak neutralizing antibody geometric mean titer of 52,773 against wild-type virus, with activity against SARS-CoV-1 and minimal decrement against variants of concern. Vaccinated animals mounted an anamnestic response upon high-dose SARS-CoV-2 respiratory challenge that translated into rapid elimination of replicating virus in their upper and lower airways and lung parenchyma. SpFN's potent and broad immunogenicity profile and resulting efficacy in NHPs supports its utility as a candidate platform for SARS-like betacoronaviruses.

One-sentence Summary: A SARS-CoV-2 Spike protein ferritin nanoparticle vaccine, co-formulated with a liposomal adjuvant, elicits broad neutralizing antibody responses that exceed those observed for other major vaccines and rapidly protects against respiratory infection and disease in the upper and lower airways and lung tissue of nonhuman primates.
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http://dx.doi.org/10.1101/2021.03.24.436523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010721PMC
March 2021

Antibodies to neutralising epitopes synergistically block the interaction of the receptor-binding domain of SARS-CoV-2 to ACE 2.

Clin Transl Immunology 2021 7;10(3):e1260. Epub 2021 Mar 7.

Institute for Glycomics Griffith University Gold Coast QLD Australia.

Objectives: A major COVID-19 vaccine strategy is to induce antibodies that prevent interaction between the Spike protein's receptor-binding domain (RBD) and angiotensin-converting enzyme 2 (ACE2). These vaccines will also induce T-cell responses. However, concerns were raised that aberrant vaccine-induced immune responses may exacerbate disease. We aimed to identify minimal epitopes on the RBD that would induce antibody responses that block the interaction of the RBD and ACE2 as a strategy leading to an effective vaccine with reduced risk of inducing immunopathology.

Methods: We procured a series of overlapping 20-amino acid peptides spanning the RBD and asked which were recognised by plasma from COVID-19 convalescent patients. Identified epitopes were conjugated to diphtheria-toxoid and used to vaccinate mice. Immune sera were tested for binding to the RBD and for their ability to block the interaction of the RBD and ACE2.

Results: Seven putative vaccine epitopes were identified. Memory B-cells (MBCs) specific for one of the epitopes were identified in the blood of convalescent patients. When used to vaccinate mice, six induced antibodies that bound recRBD and three induced antibodies that could partially block the interaction of the RBD and ACE2. However, when the sera were combined in pairs, we observed significantly enhanced inhibition of binding of RBD to ACE2. Two of the peptides were located in the main regions of the RBD known to contact ACE2. Of significant importance to vaccine development, two of the peptides were in regions that are invariant in the UK and South African strains.

Conclusion: COVID-19 convalescent patients have SARS-CoV-2-specific antibodies and MBCs, the specificities of which can be defined with short peptides. Epitope-specific antibodies synergistically block RBD-ACE2 interaction.
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http://dx.doi.org/10.1002/cti2.1260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937407PMC
March 2021

Expansion of Patient Education Programming Regarding Live Donor Liver Transplantation via Virtual Group Encounters During the COVID-19 Pandemic.

Transplant Proc 2021 Jan 31. Epub 2021 Jan 31.

Yale New Haven Transplantation Center, New Haven, Connecticut. Electronic address:

During the coronavirus 2019 pandemic we converted our liver transplant waitlist candidate education and support program to a virtual format and expanded it to include ongoing engagement sessions aimed to educate and empower patients to maximize opportunity for live donor liver transplantation. Over a period of 6 months from April 2020 to Sept 2020 we included 21 patients in this pilot quality improvement program. We collected data regarding patient response and potential donor referral activity. Overall, patient response was positive, and some patients saw progress toward live donor liver transplantation by fostering inquiry of potential live liver donors. Optimization of logistical aspects of the program including program flow, technology access, and utilization is required to enhance patient experience. Long-term follow-up is needed to assess impact on the outcome of transplantation rates. Future data collection and analysis should focus on assessment of any potential disparity that may result from utilization of virtual programming. Herein we provide a framework for this type of virtual program and describe our experience.
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http://dx.doi.org/10.1016/j.transproceed.2021.01.038DOI Listing
January 2021

Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain-of-function.

Blood 2020 Dec 23. Epub 2020 Dec 23.

Washington University, St. Louis, Missouri, United States.

Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment and an understanding of the human immune response. We identified six unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with three different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, five patients had somatic variants in TLR8 with less than 30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype. Mosaicism was also detected in skin-derived fibroblasts in three patients, demonstrating that mutations were not limited to the hematopoietic compartment. All patients had refractory chronic neutropenia, and three patients underwent allogeneic hematopoietic cell transplantation. All variants conferred gain-of-function to TLR8 protein, and immune phenotyping demonstrated a pro-inflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B cell maturation. Differentiation of myeloid cells from patient-derived induce pluripotent stem cells demonstrated increased responsiveness to TLR8. Together these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B and T cell defects, and in some cases bone marrow failure. Somatic mosaicism is a prominent molecular mechanism of this new disease.
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http://dx.doi.org/10.1182/blood.2020009620DOI Listing
December 2020

In Vitro Infection with Hepatitis B Virus Using Differentiated Human Serum Culture of Huh7.5-NTCP Cells without Requiring Dimethyl Sulfoxide.

Viruses 2021 Jan 12;13(1). Epub 2021 Jan 12.

Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, 6010 Katz Centre for Health Research, University of Alberta, Edmonton, AB T6G 2E1, Canada.

An estimated two billion people worldwide have been infected with hepatitis B virus (HBV). Despite the high infectivity of HBV in vivo, a lack of easily infectable in vitro culture systems hinders studies of HBV. Overexpression of the sodium taurocholate co-transporting polypeptide (NTCP) bile acid transporter in hepatoma cells improved infection efficiency. We report here a hepatoma cell culture system that does not require dimethyl sulfoxide (DMSO) for HBV infection. We overexpressed NTCP in Huh7.5 cells and allowed these cells to differentiate in a medium supplemented with human serum (HS) instead of fetal bovine serum (FBS). We show that human serum culture enhanced HBV infection in Huh7.5-NTCP cells, e.g., in HS cultures, HBV pgRNA levels were increased by as much as 200-fold in comparison with FBS cultures and 19-fold in comparison with FBS+DMSO cultures. Human serum culture increased levels of hepatocyte differentiation markers, such as albumin secretion, in Huh7.5-NTCP cells to similar levels found in primary human hepatocytes. N-glycosylation of NTCP induced by culture in human serum may contribute to viral entry. Our study demonstrates an in vitro HBV infection of Huh7.5-NTCP cells without the use of potentially toxic DMSO.
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http://dx.doi.org/10.3390/v13010097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828204PMC
January 2021

Central Venous Catheter Confirmation by Ultrasonography: A Novel Instructional Protocol.

South Med J 2020 Dec;113(12):614-617

From the Division of Ultrasound, Department of Emergency Medicine, Virginia Commonwealth University, Richmond.

Objectives: Ultrasound (US)-only confirmation of central venous catheter (CVC) placement has proven to be accurate and fast when compared with the current standard chest radiograph. This procedure depends on the detection of appropriately timed atrial bubbles during central line flushing, called the rapid atrial swirl sign (RASS). The most obvious barrier to increasing the use of this technique is appropriate education and training; therefore, we proposed a novel educational approach to training emergency department (ED) physicians in the confirmation of CVC location using US and then tested its effectiveness.

Methods: Using an online educational model, participants were taught the background and procedural steps to confirm CVC placement using US. Subsequently, they were asked to use this knowledge to place central lines in simulation and confirm them using US. They were tested with various scenarios, including correctly and incorrectly placed lines. Their accuracy was measured, and a survey was used to assess their satisfaction with the training and applicability to practice.

Results: A total of 47 ED physicians completed the online training module and 24 completed the simulation testing that followed. Results showed 100% accuracy in detecting appropriately timed RASS (<2 seconds), delayed RASS (>2 seconds), and no RASS in simulation. All of the participants "agreed" or "strongly agreed" that the didactic and simulation sessions improved their understanding of US confirmation of central line placement.

Conclusions: The use of US to confirm central line placement can be effectively taught to ED physicians using short didactic and simulation-based training. This is a reasonable approach to integrate this protocol into practice, and allow for more widespread use of this emerging technique.
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http://dx.doi.org/10.14423/SMJ.0000000000001187DOI Listing
December 2020

Pediatric HCT in Florida (2014 -2016): A report from the FPBCC.

Pediatr Transplant 2020 Nov 27:e13931. Epub 2020 Nov 27.

University of Florida, Gainesville, FL, USA.

FPBCC was formed in 2018 by five pediatric transplant programs in Florida. One of the key objectives of the consortium is to provide outcome analyses by combining HCT data from all the participating centers in order to identify areas for improvement. In this first FPBCC landscape report we describe the patient and transplant characteristics of pediatric patients undergoing first allo and auto HCT between 2014 and 2016 in Florida. The source of data was eDBtC of the CIBMTR. Over the span of 3 years, a total of 230 pediatric patients underwent allo-HCT and 104 underwent auto-HCT at the participating centers. The most significant predictor of survival in allo-HCT recipients with malignant disorders was the degree of HLA- match, while in the recipients of allo-HCT with non-malignant disorders the predictors of survival included age, donor relationship and degree of HLA match. Our analyses identified the need to improve reporting of primary cause of death and improve on donor selection process given that the degree of HLA match remains the most important predictor of survival. This first FPBCC-wide review describes the trends in pediatric HCT activity between 2014 and 2016 among the participating centers in Florida and confirms feasibility of using eDBtC data platform and collaborative approach in order to identify areas for improvement in outcomes.
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http://dx.doi.org/10.1111/petr.13931DOI Listing
November 2020

Isothermal Amplification and Ambient Visualization in a Single Tube for the Detection of SARS-CoV-2 Using Loop-Mediated Amplification and CRISPR Technology.

Anal Chem 2020 12 26;92(24):16204-16212. Epub 2020 Nov 26.

Division of Analytical and Environmental Toxicology, Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G3.

We have developed a single-tube assay for SARS-CoV-2 in patient samples. This assay combined advantages of reverse transcription (RT) loop-mediated isothermal amplification (LAMP) with clustered regularly interspaced short palindromic repeats (CRISPRs) and the CRISPR-associated (Cas) enzyme Cas12a. Our assay is able to detect SARS-CoV-2 in a single tube within 40 min, requiring only a single temperature control (62 °C). The RT-LAMP reagents were added to the sample vial, while CRISPR Cas12a reagents were deposited onto the lid of the vial. After a half-hour RT-LAMP amplification, the tube was inverted and flicked to mix the detection reagents with the amplicon. The sequence-specific recognition of the amplicon by the CRISPR guide RNA and Cas12a enzyme improved specificity. Visible green fluorescence generated by the CRISPR Cas12a system was recorded using a smartphone camera. Analysis of 100 human respiratory swab samples for the N and/or E gene of SARS-CoV-2 produced 100% clinical specificity and no false positive. Analysis of 50 samples that were detected positive using reverse transcription quantitative polymerase chain reaction (RT-qPCR) resulted in an overall clinical sensitivity of 94%. Importantly, this included 20 samples that required 30-39 threshold cycles of RT-qPCR to achieve a positive detection. Integration of the exponential amplification ability of RT-LAMP and the sequence-specific processing by the CRISPR-Cas system into a molecular assay resulted in improvements in both analytical sensitivity and specificity. The single-tube assay is beneficial for future point-of-care applications.
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http://dx.doi.org/10.1021/acs.analchem.0c04047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724759PMC
December 2020

Comparison of synthetic mesh erosion and chronic pain rates after surgery for pelvic organ prolapse and stress urinary incontinence: a systematic review.

Int Urogynecol J 2021 Mar 25;32(3):573-580. Epub 2020 Nov 25.

Royal College of Surgeons in Ireland, Tissue Engineering Research Group, Dublin, Ireland.

Background: The aim of this study is to systematically compare rates of erosion and chronic pain after mesh insertion for pelvic organ prolapse (POP) and stress urinary incontinence (SUI) surgery.

Methods: A systematic electronic search was performed on studies that evaluated the incidence of erosion and chronic pain after mesh insertion for POP or SUI. The primary outcome measurement was to compare mesh erosion rates for POP and SUI surgery. Secondary outcome measurements were incidence of de novo pain and a comparison of patient demographics for both surgeries.

Results: Twenty-six studies on 292,606 patients (n = 9077 for POP surgery and n = 283,529 for SUI surgery) met the inclusion criteria. Median follow-up was 26.38 ± 22.17 months for POP surgery and 39.33 ± 27.68 months for SUI surgery. Overall, the POP group were older (p < 0.0001) and had a lower BMI (p < 0.0001). Mesh erosion rates were significantly greater in the POP group compared to the SUI group (4% versus 1.9%) (OR 2.13; 95% CI 1.91-2.37; p < 0.0001). The duration from surgery to onset of mesh erosion was 306.84 ± 183.98 days. There was no difference in erosion rates between abdominal and transvaginal mesh for POP. There was no difference in erosion rates between the transobturator and retropubic approach for SUI. The incidence of chronic pain was significantly greater in the POP group compared to the SUI group (6.7% versus 0.6%) (OR 11.02; 95% CI 8.15-14.9; p < 0.0001). The duration from surgery to onset of chronic pain was 325.88 ± 226.31 days.

Conclusions: The risk of mesh erosion and chronic pain is significantly higher after surgery for POP compared to SUI. These significant complications occur within the first year after surgery.
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http://dx.doi.org/10.1007/s00192-020-04612-xDOI Listing
March 2021

What Opinions Do Tumor Reconstructive Surgeons Have about Sports Activity after Megaprosthetic Replacement in Hip and Knee? Results of the MoReSports Expert Opinion Online Survey.

J Clin Med 2020 Nov 12;9(11). Epub 2020 Nov 12.

Department of Orthopaedic and Trauma Surgery, Medical University of Vienna, 1090 Vienna, Austria.

Sports activity has many benefits in cancer survivors. A key one is having sport activity contribute to the well-being of the individual. However, there are no guidelines about the intensity and kind of postoperative mobility workouts after hip or knee megaprosthetic treatment. Opinion research about sports after modular bone and joint replacement may provide an understanding of surgeons' attitudes on sports activity after megaprostheses of the hip and knee joint. A web survey with members of three international professional organizations of orthopedic tumor reconstructive surgeons was conducted between September 2016 and January 2018. Members were invited via personalized emails by the European Musculoskeletal Oncology Society (EMSOS), the International Society of Limb Salvage (ISOLS), and the Musculoskeletal Tumor Society (MSTS). The questionnaire included 26 questions. A total of 149 surgeons started the survey, and 76 finished the entire survey (American Association for Public Opinion Research (AAPOR) second response rate (RR2) EMSOS: 12.3%; ISOLS: 21.9%; MSTS: n/a). More than half of the respondents encourage sarcoma survivors after megaprosthetic treatment to reach an activity level that would allow them to regularly participate in active sporting events of University of California, Los Angeles (UCLA) activity level 7 and higher. Orthopedic tumor reconstructive surgeons do fear a number of complications (periprosthetic fracture, allograft failure/fracture, loosening, prosthetic or bearing failure, and early polyethylene wear) due to sports activity after modular bone-joint replacement, but they actually witness fewer complications than they conceptually anticipated. According to the surgeons' opinions, between four to seven types of sports after surgery could reasonably be recommended depending on the type of hip or knee procedures. This survey provides insights into opinions on what could be recommended, what could be allowed if surgeons and their patients agree on the potential negative outcome, and which sports should definitely not be allowed after hip and knee megaprostheses.
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http://dx.doi.org/10.3390/jcm9113638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698049PMC
November 2020

Mechanical characterization of a biodegradable mesh for the treatment of stress urinary incontinence.

Int J Urol 2021 Feb 11;28(2):243-245. Epub 2020 Nov 11.

Tissue Engineering Research Group, Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.

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http://dx.doi.org/10.1111/iju.14430DOI Listing
February 2021

Author Correction: Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication.

Nat Commun 2020 Oct 20;11(1):5409. Epub 2020 Oct 20.

Department of Biochemistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton, T6G 2R3, AB, Canada.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-19339-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574666PMC
October 2020

Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication.

Nat Commun 2020 08 27;11(1):4282. Epub 2020 Aug 27.

Department of Biochemistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton, T6G 2R3, AB, Canada.

The main protease, M (or 3CL) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide. Feline infectious peritonitis, a fatal coronavirus infection in cats, was successfully treated previously with a prodrug GC376, a dipeptide-based protease inhibitor. Here, we show the prodrug and its parent GC373, are effective inhibitors of the M from both SARS-CoV and SARS-CoV-2 with IC values in the nanomolar range. Crystal structures of SARS-CoV-2 M with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 replication in cell culture. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals. The work here lays the framework for their use in human trials for the treatment of COVID-19.
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http://dx.doi.org/10.1038/s41467-020-18096-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453019PMC
August 2020

Ability of Critical Care Medics to Confirm Endotracheal Tube Placement by Ultrasound.

Prehosp Disaster Med 2020 Dec 25;35(6):629-631. Epub 2020 Aug 25.

Virginia Commonwealth University School of Medicine, Department of Emergency Medicine, Richmond, VirginiaUSA.

Introduction: The Advanced Cardiac Life Support (ACLS) guidelines were recently updated to include ultrasound confirmation of endotracheal tube (ETT) location as an adjunctive tool to verify placement. While this method is employed in the emergency department under the guidance of the most recent American College of Emergency Physicians (ACEP; Irving, Texas USA) guidelines, it has yet to gain wide acceptance in the prehospital setting where it has the potential for greater impact. The objective of this study to is determine if training critical care medics using simulation was a feasible and reliable method to learn this skill.

Methods: Twenty critical care paramedics with no previous experience with point-of-care ultrasound volunteered for advanced training in prehospital ultrasound. Four ultrasound fellowship trained emergency physicians proctored two three-hour training sessions. Each session included a brief introduction to ultrasound "knobology," normal sonographic neck and lung anatomy, and how to identify ETT placement within the trachea or esophagus. Immediately following this, the paramedics were tested with five simulated case scenarios using pre-obtained images that demonstrated a correctly placed ETT, an esophageal intubation, a bronchial intubation, and an improperly functioning ETT. Their accuracy, length of time to respond, and comfort with using ultrasound were all assessed.

Results: All 20 critical care medics completed the training and testing session. During the five scenarios, 37/40 (92.5%) identified the correct endotracheal placements, 18/20 (90.0%) identified the esophageal intubations, 18/20 (90.0%) identified the bronchial intubation, and 20/20 (100.0%) identified the ETT malfunctions correctly. The average time to diagnosis was 10.6 seconds for proper placement, 15.5 seconds for esophageal, 15.6 seconds for bronchial intubation, and 11.8 seconds for ETT malfunction.

Conclusions: The use of ultrasound to confirm ETT placement can be effectively taught to critical care medics using a short, simulation-based training session. Further studies on implementation into patient care scenarios are needed.
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http://dx.doi.org/10.1017/S1049023X20001004DOI Listing
December 2020

Irradiating Residual Disease to 30 Gy with Proton Therapy in Pediatric Mediastinal Hodgkin Lymphoma.

Int J Part Ther 2020 27;6(4):11-16. Epub 2020 Apr 27.

Department of Radiation Oncology, Emory University, Atlanta, GA, USA.

Background: Local relapse is a predominant form of recurrence among pediatric patients with Hodgkin lymphoma (PHL). Although PHL radiotherapy doses have been approximately 20 Gy, adults with Hodgkin lymphoma receiving 30 to 36 Gy experience fewer in-field relapses. We investigated the dosimetric effect of such a dose escalation to the organs at risk (OARs).

Materials And Methods: Ten patients with PHL treated with proton therapy to 21 Gy involved-site radiation therapy (ISRT) were replanned to deliver 30 Gy by treating the ISRT to 30 Gy (ISRT), delivering 21 Gy to the ISRT plus a 9-Gy boost to postchemotherapy residual volume (rISRT), and delivering 30 Gy to the residual ISRT target only (rISRT). Radiation doses to the OARs were compared.

Results: The ISRT escalated the dose to the target by 42% but also to the OARs. The rISRT escalated the residual target dose by 42%, and the OAR dose by only 17% to 26%. The rISRT escalated the residual target dose by 42% but reduced the OAR dose by 25% to 46%.

Conclusion: Boosting the postchemotherapy residual target dose to 30Gy can allow for dose escalation with a slight OAR dose increase. Treating the residual disease for the full 30Gy, however, would reduce the OAR dose significantly compared with ISRT. Studies should evaluate these strategies to improve outcomes and minimize the late effects.
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http://dx.doi.org/10.14338/IJPT-19-00077.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302731PMC
April 2020

Focused Cardiac Ultrasound in Dyspnea of Unclear Etiology in the Emergency Department: Utility of the FLUID Score.

J Ultrasound Med 2020 Nov 12;39(11):2211-2217. Epub 2020 May 12.

Division of Cardiology, Virginia Commonwealth University, Richmond, Virginia, USA.

Objectives: We evaluated the utility of focused cardiac ultrasound to predict the length of stay in patients presenting to the emergency department with dyspnea of unclear etiology.

Methods: Patients with focused cardiac ultrasound examinations performed in the emergency department for dyspnea over a 34-month period were retrospectively identified. Patients were excluded if they had a prior diagnosis of heart failure, dialysis requirement, or an etiology of dyspnea unrelated to the volume status. Left ventricular function was categorized as normal or reduced, and the inferior vena cava was categorized as normal or increased volume. A fast limited ultrasound to investigate dyspnea (FLUID) score was calculated by adding 1 point for reduced left ventricular function and 1 point for increased volume, producing a score of 0, 1, or 2.

Results: There were 123 patients included. There was a significant correlation between the FLUID score and length of stay, with longer stays for higher scores (FLUID score 0, 7.4 hours median; FLUID score 1, 2.34 days; FLUID score 2, 5.56 days; analysis of variance P < .001). Of the other variables collected, only age, hypertension, diabetes, heart rate, and brain natriuretic peptide were significantly correlated with the length of stay. A multivariate analysis including those variables and the FLUID score showed that the FLUID score was the strongest independent predictor of the length of stay.

Conclusions: Focused cardiac ultrasound and calculation of a FLUID score for patients with undifferentiated dyspnea can be a powerful tool to predict the hospital length of stay.
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http://dx.doi.org/10.1002/jum.15332DOI Listing
November 2020

Differential expression of interferon-lambda receptor 1 splice variants determines the magnitude of the antiviral response induced by interferon-lambda 3 in human immune cells.

PLoS Pathog 2020 04 30;16(4):e1008515. Epub 2020 Apr 30.

Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.

Type III interferons (IFN-lambdas(λ)) are important cytokines that inhibit viruses and modulate immune responses by acting through a unique IFN-λR1/IL-10RB heterodimeric receptor. Until now, the primary antiviral function of IFN-λs has been proposed to be at anatomical barrier sites. Here, we examine the regulation of IFN-λR1 expression and measure the downstream effects of IFN-λ3 stimulation in primary human blood immune cells, compared with lung or liver epithelial cells. IFN-λ3 directly bound and upregulated IFN-stimulated gene (ISG) expression in freshly purified human B cells and CD8+ T cells, but not monocytes, neutrophils, natural killer cells, and CD4+ T cells. Despite similar IFNLR1 transcript levels in B cells and lung epithelial cells, lung epithelial cells bound more IFN-λ3, which resulted in a 50-fold greater ISG induction when compared to B cells. The reduced response of B cells could be explained by higher expression of the soluble variant of IFN-λR1 (sIFN-λR1), which significantly reduced ISG induction when added with IFN-λ3 to peripheral blood mononuclear cells or liver epithelial cells. T-cell receptor stimulation potently, and specifically, upregulated membrane-bound IFNLR1 expression in CD4+ T cells, leading to greater antiviral gene induction, and inhibition of human immunodeficiency virus type 1 infection. Collectively, our data demonstrate IFN-λ3 directly interacts with the human adaptive immune system, unlike what has been previously shown in published mouse models, and that type III IFNs could be potentially utilized to suppress both mucosal and blood-borne viral infections.
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http://dx.doi.org/10.1371/journal.ppat.1008515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217487PMC
April 2020

Stress Urinary Incontinence and Pelvic Organ Prolapse: Biologic Graft Materials Revisited.

Tissue Eng Part B Rev 2020 10 21;26(5):475-483. Epub 2020 Apr 21.

Department of Urology and Transplant Surgery, Beaumont Hospital, Co Dublin, Ireland.

Symptomatic stress urinary incontinence (SUI) and pelvic organ prolapse (POP) refractory to conservative management with pelvic floor muscle training or vaginal pessaries may warrant surgical intervention with different forms of biologic or synthetic material. However, in recent years, several global regulatory agencies have issued health warnings and recalled several mesh products due to an increase in complications such as mesh erosion, infection, chronic pain, and perioperative bleeding. At present, current surgical treatment strategies for SUI and POP are aimed at developing biological graft materials with similar mechanical properties to established synthetic meshes, but with improved tissue integration and minimal host response. This narrative review aims to highlight recent studies related to the development of biomimetic and biologic graft materials as alternatives to traditional synthetic materials for SUI/POP repair in female patients. We also investigate complications and technical limitations associated with synthetic mesh and biological biomaterials in conventional SUI and POP surgery. Our findings demonstrate that newly developed biologic grafts have a lower incidence of adverse events compared to synthetic biomaterials. However there remains a significant disparity between success in preclinical trials and long-term clinical translation. Further characterization on the optimal structural, integrative, and mechanical properties of biological grafts is required before they can be reliably introduced into clinical practice for SUI and POP surgery. Impact statement Our review article aims to outline the clinical history of developments and controversies associated with the use of synthetic mesh materials in the surgical treatment of stress urinary incontinence and pelvic organ prolapse, as well as highlighting recent advancements in the area of biological graft materials and their potential importance in an area that remains an enduring issue for patients and clinicians alike. This article aims to provide a concise summary of previous controversies in the field of urinary incontinence, while evaluating the future of potential biomaterials in this field.
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http://dx.doi.org/10.1089/ten.TEB.2020.0024DOI Listing
October 2020

Immune profile differences between chronic GVHD and late acute GVHD: results of the ABLE/PBMTC 1202 studies.

Blood 2020 04;135(15):1287-1298

CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada.

Human graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study (ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1- and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.
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http://dx.doi.org/10.1182/blood.2019003186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146024PMC
April 2020

Exploring Action Items to Address Resident Mistreatment through an Educational Workshop.

West J Emerg Med 2019 Dec 9;21(1):42-46. Epub 2019 Dec 9.

Virginia Commonwealth University School of Medicine, Department of Emergency Medicine, Richmond, Virginia.

Mistreatment of trainees is common in the clinical learning environment. Resident mistreatment is less frequently tracked than medical student mistreatment, but data suggest mistreatment remains prevalent at the resident level. To address resident mistreatment, the authors developed an Educational Advance to engage emergency medicine residents and faculty in understanding and improving their learning environment. The authors designed a small-group session with the following goals: 1) Develop a shared understanding of mistreatment and its magnitude; 2) Recognize the prevalence of resident mistreatment data and identify the most common types of mistreatment; 3) Relate study findings to personal or institutional experiences; and 4) Generate strategies for combating mistreatment and strengthening the clinical learning environment at their home institutions. Design was a combination of presentation, small group discussion, and facilitated discussion. Results were presented to participants from a previously administered survey of resident mistreatment. Public humiliation and sexist remarks were the most commonly reported forms. Faculty were the most frequent perpetrators, followed by residents and nurses. A majority of respondents who experienced mistreatment did not report the incident. Session participants were then asked to brainstorm strategies to combat mistreatment. Participants rated the session as effective in raising awareness about resident mistreatment and helping departments develop methods to improve the learning environment. Action items proposed by the group included coaching residents about how to respond to mistreatment, displaying signage in support of a positive learning environment, zero tolerance for mistreatment, clear instructions for reporting, and intentionality training to improve behavior.
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http://dx.doi.org/10.5811/westjem.2019.9.44253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948710PMC
December 2019

HCV and flaviviruses hijack cellular mechanisms for nuclear STAT2 degradation: Up-regulation of PDLIM2 suppresses the innate immune response.

PLoS Pathog 2019 08 2;15(8):e1007949. Epub 2019 Aug 2.

Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.

Host encounters with viruses lead to an innate immune response that must be rapid and broadly targeted but also tightly regulated to avoid the detrimental effects of unregulated interferon expression. Viral stimulation of host negative regulatory mechanisms is an alternate method of suppressing the host innate immune response. We examined three key mediators of the innate immune response: NF-KB, STAT1 and STAT2 during HCV infection in order to investigate the paradoxical induction of an innate immune response by HCV despite a multitude of mechanisms combating the host response. During infection, we find that all three are repressed only in HCV infected cells but not in uninfected bystander cells, both in vivo in chimeric mouse livers and in cultured Huh7.5 cells after IFNα treatment. We show here that HCV and Flaviviruses suppress the innate immune response by upregulation of PDLIM2, independent of the host interferon response. We show PDLIM2 is an E3 ubiquitin ligase that also acts to stimulate nuclear degradation of STAT2. Interferon dependent relocalization of STAT1/2 to the nucleus leads to PDLIM2 ubiquitination of STAT2 but not STAT1 and the proteasome-dependent degradation of STAT2, predominantly within the nucleus. CRISPR/Cas9 knockout of PDLIM2 results in increased levels of STAT2 following IFNα treatment, retention of STAT2 within the nucleus of HCV infected cells after IFNα stimulation, increased interferon response, and increased resistance to infection by several flaviviruses, indicating that PDLIM2 is a global regulator of the interferon response.
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http://dx.doi.org/10.1371/journal.ppat.1007949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677295PMC
August 2019

The Main Predictors of Length of Stay After Total Knee Arthroplasty: Patient-Related or Procedure-Related Risk Factors.

J Bone Joint Surg Am 2019 Jun;101(12):1093-1101

1Orthopaedics Department, Cleveland Clinic Foundation, Cleveland, Ohio.

Background: Often, differences in length of stay after total knee arthroplasty are solely attributed to patient factors. Therefore, our aim was to determine the influence of patient-related and procedure or structural-related risk factors as predictors of length of stay after total knee arthroplasty.

Methods: A prospective cohort of 4,509 patients (54.6% of whom had Medicare for insurance) underwent primary total knee arthroplasty across 4 facilities in a single health-care system (from January 1, 2016, to September 30, 2017). Risk factors were categorized as patient-related risk factors (demographic characteristics, smoking status, Veterans RAND 12 Item Health Survey Mental Component Summary score [VR-12 MCS], Charlson Comorbidity Index, surgical indication, Knee injury and Osteoarthritis Outcome Score [KOOS], deformity, range of motion, and discharge location probability assessed by a nomogram predicting location after arthroplasty) or as procedure or structural-related risk factors (hospital site, surgeon, day of the week when the surgical procedure was performed, implant type, and surgical procedure start time). Multivariable cumulative link (proportional odds logistic regression) models were built to identify significant predictors from candidate risk factors for 1-day, 2-day, and ≥3-day length of stay. Performance was compared between a model containing patient-related risk factors only and a model with both patient-related and procedure or structural-related risk factors, utilizing the Akaike information criterion (AIC) and internally validated concordance probabilities (C-index) for discriminating a 1-day length of stay compared with >1-day length of stay.

Results: Patient-related risk factors were significant predictors of length of stay (p < 0.05). A longer length of stay was predicted by older age, higher body mass index (BMI), higher Charlson Comorbidity Index, lower VR-12 MCS, and female sex. However, when the procedure or structural factors were added to the patients' risk factors, the AIC decreased by approximately 1,670 units. This indicates that procedure or structural-related risk factors provide clinically relevant improvement in explaining length of stay in addition to patient-related risk factors.

Conclusions: Despite patient-related factors such as age, sex, and comorbidities providing substantial predictive value for length of stay after total knee arthroplasty, the main driving predictors of single-day length of stay after total knee arthroplasty were procedure or structural-related factors, including hospital site and surgeon. Understanding the risk factors that affect outcomes after total knee arthroplasty provides the opportunity to influence and potentially modify them favorably to optimize care.
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http://dx.doi.org/10.2106/JBJS.18.00758DOI Listing
June 2019

Benefits and challenges with diagnosing chronic and late acute GVHD in children using the NIH consensus criteria.

Blood 2019 07 1;134(3):304-316. Epub 2019 May 1.

British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.

Chronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients <18 years of age. The objectives of this prospective multi-institution study were to determine: (1) whether the NIH-CC could be used to diagnose pediatric cGVHD and whether the criteria operationalize well in a multi-institution study; (2) the frequency of cGVHD and L-aGVHD in children using the NIH-CC; and (3) the clinical features and risk factors for cGVHD and L-aGVHD using the NIH-CC. Twenty-seven transplant centers enrolled 302 patients <18 years of age before conditioning and prospectively followed them for 1 year posttransplant for development of cGVHD. Centers justified their cGVHD diagnosis according to the NIH-CC using central review and a study adjudication committee. A total of 28.2% of reported cGVHD cases was reclassified, usually as L-aGVHD, following study committee review. Similar incidence of cGVHD and L-aGVHD was found (21% and 24.7%, respectively). The most common organs involved with diagnostic or distinctive manifestations of cGVHD in children include the mouth, skin, eyes, and lungs. Importantly, the 2014 NIH-CC for bronchiolitis obliterans syndrome perform poorly in children. Past acute GVHD and peripheral blood grafts are major risk factors for cGVHD and L-aGVHD, with recipients ≥12 years of age being at risk for cGVHD. Applying the NIH-CC in pediatrics is feasible and reliable; however, further refinement of the criteria specifically for children is needed.
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http://dx.doi.org/10.1182/blood.2019000216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911839PMC
July 2019

Long-lived transient structure in collisionless self-gravitating systems.

Phys Rev E 2019 Feb;99(2-1):022125

Laboratoire de Physique Nucléaire et de Hautes Énergies, UPMC, IN2P3, CNRS, UMR No. 7585, Sorbonne Université, 4 Place Jussieu, 75252 Paris Cedex 05, France.

The evolution of self-gravitating systems, and long-range interacting systems more generally, from initial configurations far from dynamical equilibrium is often described as a simple two-phase process: a first phase of violent relaxation bringing it to a quasistationary state in a few dynamical times, followed by a slow adiabatic evolution driven by collisional processes. In this context the complex spatial structure evident, for example, in spiral galaxies is understood either in terms of instabilities of quasistationary states or as a result of dissipative nongravitational interactions. We illustrate here, using numerical simulations, that purely self-gravitating systems evolving from quite simple initial configurations can in fact give rise easily to structures of this kind, of which the lifetime can be large compared to the dynamical characteristic time but short compared to the collisional relaxation timescale. More specifically, for a broad range of nonspherical and nonuniform rotating initial conditions, gravitational relaxation gives rise quite generically to long-lived nonstationary structures of a rich variety, characterized by spiral-like arms, bars, and even ringlike structures in special cases. These structures are a feature of the intrinsically out-of-equilibrium nature of the system's collapse, associated with a part of the system's mass while the bulk is well virialized. They are characterized by predominantly radial motions in their outermost parts, but also incorporate an extended flattened region which rotates coherently about a well-virialized core of triaxial shape with an approximately isotropic velocity dispersion. We characterize the kinematical and dynamical properties of these complex velocity fields and we briefly discuss the possible relevance of these simple toy models to the observed structure of real galaxies, emphasizing the difference between dissipative and dissipationless disk formation.
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http://dx.doi.org/10.1103/PhysRevE.99.022125DOI Listing
February 2019

Diagnostic Yield and Accuracy of Bedside Echocardiography in the Emergency Department in Hemodynamically Stable Patients.

J Ultrasound Med 2019 Nov 18;38(11):2845-2851. Epub 2019 Mar 18.

Department of Emergency Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.

Objectives: The goal of this study was to determine the diagnostic yield of focused cardiac ultrasound (FOCUS) in hemodynamically stable patients in the emergency department and secondarily to confirm the accuracy of these studies when compared to formal echocardiography.

Methods: All hemodynamically stable adult patients who had an emergency physician-performed FOCUS examination completed over a 1-year period were identified using our electronic ultrasound database. Hemodynamic stability was defined as presenting systolic blood pressure higher than 90 mm Hg and not requiring any form of positive pressure ventilation.

Results: There were 1198 FOCUS examinations performed: 976 in hemodynamically stable patients who were included in our analysis. Twenty-seven percent of patients had new findings, including 154 (16%) new diagnoses of reduced left ventricular function, 105 (11%) new pericardial effusions, and 44 (5%) new diagnoses of RV dilatation. Dyspnea as an indication for the FOCUS examination was the strongest predictor of a positive study. Of patients included, 28% underwent formal echocardiography within 2 days and were analyzed for concordance with regard to left ventricular function and the presence of pericardial effusion. Of 270 studies, 208 were accurate, and 62 were inaccurate, for raw agreement of 77% (κ = 0.53). When stratified by sonographer experience, there was no impact on accuracy.

Conclusions: Focused cardiac ultrasound in the emergency department for hemodynamically stable patients revealed new findings in 27% of studies, with a modest correlation with formal echocardiography. In stable patients, FOCUS has the potential for rapid diagnosis of cardiac disease, particularly in patients with dyspnea.
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http://dx.doi.org/10.1002/jum.14985DOI Listing
November 2019

Global Outbreaks and Origins of a Chikungunya Virus Variant Carrying Mutations Which May Increase Fitness for : Revelations from the 2016 Mandera, Kenya Outbreak.

Am J Trop Med Hyg 2019 05;100(5):1249-1257

United States Army Medical Research Directorate - Kenya, Nairobi, Kenya.

In 2016, a chikungunya virus (CHIKV) outbreak was reported in Mandera, Kenya. This was the first major CHIKV outbreak in the country since the global reemergence of this virus in Kenya in 2004. We collected samples and sequenced viral genomes from this outbreak. All Kenyan genomes contained two mutations, E1:K211E and E2:V264A, recently reported to have an association with increased infectivity, dissemination, and transmission in the vector. Phylogeographic inference of temporal and spatial virus relationships showed that this variant emerged within the East, Central, and South African lineage between 2005 and 2008, most probably in India. It was also in India where the first large outbreak caused by this virus appeared, in New Delhi, 2010. More importantly, our results also showed that this variant is no longer contained to India. We found it present in several major outbreaks, including the 2016 outbreaks in Pakistan and Kenya, and the 2017 outbreak in Bangladesh. Thus, this variant may have a capability of driving large CHIKV outbreaks in different regions of the world. Our results point to the importance of continued genomic-based surveillance and prompt urgent vector competence studies to assess the level of vector susceptibility and virus transmission, and the impact this might have on this variant's epidemic potential and global spread.
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http://dx.doi.org/10.4269/ajtmh.18-0980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493958PMC
May 2019

Ultrasound-guided thoracostomy site identification in healthy volunteers.

Crit Ultrasound J 2018 Oct 15;10(1):28. Epub 2018 Oct 15.

Virginia Commonwealth University Emergency Medicine, 1250 E Marshall Street, 2nd Floor, Suite 500, P.O. Box 980401, Richmond, VA, 23298, USA.

Background: Traditional landmark thoracostomy technique has a known complication rate up to 30%. The goal of this study is to determine whether novice providers could more accurately identify the appropriate intercostal site for thoracostomy by ultrasound guidance.

Methods: 33 emergency medicine residents and medical students volunteered to participate in this study during routine thoracostomy tube education. A healthy volunteer was used as the standardized patient for this study. An experienced physician sonographer used ultrasound to locate a site at mid-axillary line between ribs 4 and 5 and marked the site with invisible ink that can only be revealed with a commercially available UV LED light. Participants were asked to identify the thoracostomy site by placing an opaque marker where they would make their incision. The distance from the correct insertion site was measured in rib spaces. The participants were then given a brief hands-on training session using ultrasound to identify the diaphragm and count rib spaces. The participants were then asked to use ultrasound to identify the proper thoracostomy site and mark it with an opaque marker. The distance from the proper insertion site was measured and recorded in rib spaces.

Results: The participants correctly identified the pre-determined intercostal space using palpation 48% (16/33) of the time, versus the ultrasound group who identified the proper intercostal space 91% (30/33) of the time. On average, the traditional technique was placed 0.88 rib spaces away (95 CI 0.43-1.03), while the ultrasound-guided technique was placed 0.09 rib spaces away (95 CI 0.0-0.19) [P = 0.003].

Conclusions: The ability to accurately locate the correct intercostal space for thoracostomy incision was improved under ultrasound guidance. Further studies are warranted to determine if this ultrasound-guided technique will decrease complications with chest tube insertion and improve patient outcomes.
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http://dx.doi.org/10.1186/s13089-018-0108-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186530PMC
October 2018

Comparison of Ultrasound-Guided and Landmark-Based Lumbar Punctures in Inexperienced Resident Physicians.

J Ultrasound Med 2019 Mar 12;38(3):613-620. Epub 2018 Aug 12.

Department of Emergency Medicine, Virginia Commonwealth University Health System, Richmond, Virginia, USA.

Objectives: We sought to determine whether US-guided lumbar puncture reduced the rate of lumbar puncture failures for providers at an academic teaching hospital with variable lumbar puncture and US experience compared to the traditional landmark-based technique.

Methods: We conducted a prospective randomized controlled trial to compare US-guided lumbar puncture to the traditional landmark technique in an academic emergency department. Thirty-five patients were randomized to either have their lumbar puncture performed either via the landmark or US-guided technique. All procedures were completed by an emergency medicine resident with variable lumbar puncture and US experience. Procedural failures, the number of attempts, the time to completion, and patient pain scores were all recorded.

Results: The adjusted odds ratio of successfully obtaining cerebrospinal fluid (CSF) in the US-guided lumbar puncture group was 2.31 compared to the landmark-based lumbar puncture group (P = .377). It took 1.54 times more attempts to obtain CSF in the landmark group as it did in the US group (P = .046). It seemed to have no effect on postprocedural pain or the time to obtain CSF.

Conclusions: The use of US guidance to assist in lumbar punctures did not improve the procedural success rate over traditional landmark techniques in an academic setting with novice providers. Although using US for procedural guidance significantly decreased the number of attempts, it seemed to have no effect on postprocedural pain or the time to obtain CSF.
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http://dx.doi.org/10.1002/jum.14728DOI Listing
March 2019

Cellulose and nanocellulose-based flexible-hybrid printed electronics and conductive composites - A review.

Carbohydr Polym 2018 Oct 12;198:249-260. Epub 2018 Jun 12.

Department of Forest Biomaterials, NC State University, Raleigh, NC 27695, USA. Electronic address:

Flexible-hybrid printed electronics (FHPE) is a rapidly growing discipline that may be described as the precise imprinting of electrically functional traces and components onto a substrate such as paper to create functional electronic devices. The mass production of low-cost devices and components such as environmental sensors, bio-sensors, actuators, lab on chip (LOCs), radio frequency identification (RFID) smart tags, light emitting diodes (LEDs), smart fabrics and labels, wallpaper, solar cells, fuel cells, and batteries are major driving factors for the industry. Using renewable and bio-friendly materials would be advantageous for both manufacturers and consumers with the increased use of (FHPE) electronics in our daily lives. This review article describes recent developments in cellulose and nanocellulose-based materials for FHPE, and the necessary developments required to propagate their use in commercial applications. The aim of these developments is to enable the creation of FHPE devices and components made almost entirely of cellulose materials.
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http://dx.doi.org/10.1016/j.carbpol.2018.06.045DOI Listing
October 2018

Establishing normal metabolism and differentiation in hepatocellular carcinoma cells by culturing in adult human serum.

Sci Rep 2018 08 3;8(1):11685. Epub 2018 Aug 3.

Li Ka Shing Institute of Virology, Dept. of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada.

Tissue culture medium routinely contains fetal bovine serum (FBS). Here we show that culturing human hepatoma cells in their native, adult serum (human serum, HS) results in the restoration of key morphological and metabolic features of normal liver cells. When moved to HS, these cells show differential transcription of 22-32% of the genes, stop proliferating, and assume a hepatocyte-like morphology. Metabolic analysis shows that the Warburg-like metabolic profile, typical for FBS-cultured cells, is replaced by a diverse metabolic profile consistent with in vivo hepatocytes, including the formation of large lipid and glycogen stores, increased glycogenesis, increased beta-oxidation and ketogenesis, and decreased glycolysis. Finally, organ-specific functions are restored, including xenobiotics degradation and secretion of bile, VLDL and albumin. Thus, organ-specific functions are not necessarily lost in cell cultures, but might be merely suppressed in FBS. The effect of serum is often overseen in cell culture and we provide a detailed study in the changes that occur and provide insight in some of the serum components that may play a role in the establishment of the differentiated phenotype.
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http://dx.doi.org/10.1038/s41598-018-29763-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076254PMC
August 2018