Publications by authors named "Jonathan Fisher"

171 Publications

Dissecting the microvascular contributions to diffuse correlation spectroscopy measurements of cerebral hemodynamics using optical coherence tomography angiography.

Neurophotonics 2021 Apr 25;8(2):025006. Epub 2021 Apr 25.

New York Medical College, Department of Physiology, Valhalla, New York, United States.

Diffuse correlation spectroscopy (DCS) is an emerging noninvasive, diffuse optical modality that purportedly enables direct measurements of microvasculature blood flow. Functional optical coherence tomography angiography (OCT-A) can resolve blood flow in vessels as fine as capillaries and thus has the capability to validate key attributes of the DCS signal. To characterize activity in cortical vasculature within the spatial volume that is probed by DCS and to identify populations of blood vessels that are most representative of the DCS signals. We performed simultaneous measurements of somatosensory-evoked cerebral blood flow in mice using both DCS and OCT-A. We resolved sensory-evoked blood flow in the somatosensory cortex with both modalities. Vessels with diameters smaller than featured higher peak flow rates during the initial poststimulus positive increase in flow, whereas larger vessels exhibited considerably larger magnitude of the subsequent undershoot. The simultaneously recorded DCS waveforms correlated most highly with flow in the smallest vessels, yet featured a more prominent undershoot. Our direct, multiscale, multimodal cross-validation measurements of functional blood flow support the assertion that the DCS signal preferentially represents flow in microvasculature. The significantly greater undershoot in DCS, however, suggests a more spatially complex relationship to flow in cortical vasculature during functional activation.
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http://dx.doi.org/10.1117/1.NPh.8.2.025006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071783PMC
April 2021

Chromosome level reference of Atlantic halibut Hippoglossus hippoglossus provides insight into the evolution of sexual determination systems.

Mol Ecol Resour 2021 Mar 2. Epub 2021 Mar 2.

Biology Department, Dalhousie University, Halifax, NS, Canada.

Changes in the genetic mechanisms that control sexual determination have occurred independently across the tree of life, and with exceptional frequency in teleost fishes. To investigate the genomic changes underlying the evolution of sexual determination, we sequenced a chromosome-level genome, multitissue transcriptomes, and reduced representation population data for the Atlantic halibut (Hippoglossus hippoglossus), which has an XY/XX sex determination mechanism and has recently diverged (0.9-3.8 Ma) from the Pacific halibut (Hippoglossus stenolepis), which has a ZZ/ZW system. We used frequency and coverage-based population approaches to identify a putative sex-determining factor, GSDF. We characterized regions with elevated heterozygosity and linkage disequilibrium indicating suppression of recombination across a nascent sex chromosome. We detected testis-specific expression of GSDF, the sequence of which is highly conserved across flatfishes. Based on evidence from genome-wide association, coverage, linkage disequilibrium, testis and brain transcriptomes, and sequence conservation with other flatfishes, we propose a mechanism for the recent evolution of an XY sex-determination mechanism in Atlantic halibut. Changes to the ancestral sex-determining gene DMRT1 in regulating the downstream gene GSDF probably coincided with GSDF, or a proximal regulatory element of it, becoming the primary sex-determining factor. Our results suggest changes to a small number of elements can have drastic repercussions for the genomic substrate available to sex-specific evolutionary forces, providing insight into how certain elements repeatedly evolve to control sex across taxa. Our chromosome-level assembly, multitissue transcriptomes, and population genomic data provide a valuable resource and understanding of the evolution of sexual systems in fishes.
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http://dx.doi.org/10.1111/1755-0998.13369DOI Listing
March 2021

Safety and Efficacy of a Steroid Avoidance Immunosuppression Regimen in Renal Transplant Patients With De Novo or Preformed Donor-Specific Antibodies: A Single-Center Study.

Transplant Proc 2021 Apr 5;53(3):950-961. Epub 2020 Dec 5.

Scripps Center for Organ & Cell Transplantation, Scripps Clinic & Green Hospital, La Jolla, California; Scripps Clinic Bio-Repository and Bio-Informatics Core, Scripps Clinic & Green Hospital, La Jolla, California. Electronic address:

Although interest in the role of donor-specific antibodies (DSAs) in kidney transplant rejection, graft survival, and histopathological outcomes is increasing, their impact on steroid avoidance or minimization in renal transplant populations is poorly understood. Primary outcomes of graft survival, rejection, and histopathological findings were assessed in 188 patients who received transplants between 2012 and 2015 at the Scripps Center for Organ Transplantation, which follows a steroid avoidance protocol. Analyses were performed using data from the United Network for Organ Sharing. Cohorts included kidney transplant recipients with de novo DSAs (dnDSAs; n = 27), preformed DSAs (pfDSAs; n = 15), and no DSAs (nDSAs; n = 146). Median time to dnDSA development (classes I and II) was shorter (102 days) than in previous studies. Rejection of any type was associated with DSAs to class I HLA (P < .05) and class II HLA (P < .01) but not with graft loss. Although mean fluorescence intensity (MFI) independently showed no association with rejection, an MFI >5000 showed a trend toward more antibody-mediated rejection (P < .06), though graft loss was not independently associated. Banff chronic allograft nephropathy scores and a modified chronic injury score were increased in the dnDSA cohort at 6 months, but not at 2 years (P < .001 and P < .08, respectively). Our data suggest that dnDSAs and pfDSAs impact short-term rejection rates but do not negatively impact graft survival or histopathological outcomes at 2 years. Periodic protocol post-transplant DSA monitoring may preemptively identify patients who develop dnDSAs who are at a higher risk for rejection.
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http://dx.doi.org/10.1016/j.transproceed.2020.10.021DOI Listing
April 2021

Asymmetric, dynamic adaptation in prefrontal cortex during dichotic listening tasks.

Neurophotonics 2020 Oct 4;7(4):045008. Epub 2020 Nov 4.

University of Texas Southwestern Medical Center, Department of Anesthesiology and Pain Management, Dallas, Texas, United States.

Speech processing tasks can be used to assess the integrity and health of many functional and structural aspects of the brain. Despite the potential merits of such behavioral tests as clinical assessment tools, however, the underlying neural substrates remain relatively unclear. We aimed to obtain a more in-depth portrait of hemispheric asymmetry during dichotic listening tasks at the level of the prefrontal cortex, where prior studies have reported inconsistent results. To avoid central confounds that limited previous studies, we used diffuse correlation spectroscopy to optically monitor cerebral blood flow (CBF) in the dorsolateral prefrontal cortex during dichotic listening tasks in human subjects. We found that dichotic listening tasks elicited hemispheric asymmetries in both amplitude as well as kinetics. When listening task blocks were repeated, there was an accommodative reduction in the response amplitude of the left, but not the right hemisphere. These heretofore unobserved trends depict a more nuanced portrait of the functional asymmetry that has been observed previously. To our knowledge, these results additionally represent the first direct measurements of CBF during a speech processing task recommended by the American Speech-Language-Hearing Association for diagnosing auditory processing disorders.
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http://dx.doi.org/10.1117/1.NPh.7.4.045008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641958PMC
October 2020

Intramyofibrillar glycogen drives endurance exercise capacity.

J Physiol 2020 10 16;598(19):4145-4146. Epub 2020 Aug 16.

Department of Biology and Center for Cardiovascular Research, Saint Louis University, 3507 Laclede Ave, St Louis, MO, 63103, USA.

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http://dx.doi.org/10.1113/JP280546DOI Listing
October 2020

Reversible Oxidative Modifications in Myoglobin and Functional Implications.

Antioxidants (Basel) 2020 Jun 24;9(6). Epub 2020 Jun 24.

Department of Biology, Saint Louis University, St. Louis, MO 63103, USA.

Myoglobin (Mb), an oxygen-binding heme protein highly expressed in heart and skeletal muscle, has been shown to undergo oxidative modifications on both an inter- and intramolecular level when exposed to hydrogen peroxide (HO) in vitro. Here, we show that exposure to HO increases the peroxidase activity of Mb. Reaction of Mb with HO causes covalent binding of heme to the Mb protein (Mb-X), corresponding to an increase in peroxidase activity when ascorbic acid is the reducing co-substrate. Treatment of HO-reacted Mb with ascorbic acid reverses the Mb-X crosslink. Reaction with HO causes Mb to form dimers, trimers, and larger molecular weight Mb aggregates, and treatment with ascorbic acid regenerates Mb monomers. Reaction of Mb with HO causes formation of dityrosine crosslinks, though the labile nature of the crosslinks broken by treatment with ascorbic acid suggests that the reversible aggregation of Mb is mediated by crosslinks other than dityrosine. Disappearance of a peptide containing a tryptophan residue when Mb is treated with HO and the peptide's reappearance after subsequent treatment with ascorbic acid suggest that tryptophan side chains might participate in the labile crosslinking. Taken together, these data suggest that while exposure to HO causes Mb-X formation, increases Mb peroxidase activity, and causes Mb aggregation, these oxidative modifications are reversible by treatment with ascorbic acid. A caveat is that future studies should demonstrate that these and other in vitro findings regarding properties of Mb have relevance in the intracellular milieu, especially in regard to actual concentrations of metMb, HO, and ascorbate that would be found in vivo.
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http://dx.doi.org/10.3390/antiox9060549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346209PMC
June 2020

Association of Hospital Discharge Against Medical Advice With Readmission and In-Hospital Mortality.

JAMA Netw Open 2020 06 1;3(6):e206009. Epub 2020 Jun 1.

Department of Internal Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

Importance: Hospital readmissions contribute to higher expenditures and may sometimes reflect suboptimal patient care. Individuals discharged against medical advice (AMA) are a vulnerable patient population and may have higher risk for readmission.

Objectives: To determine odds of readmission and mortality for patients discharged AMA vs all others, to characterize patient and hospital-level factors associated with readmissions, and to quantify their overall cost burden.

Design, Setting, And Participants: Nationally representative, all-payer cohort study using the 2014 National Readmissions Database. Eligible index admissions were nonobstetrical/newborn hospitalizations for patients 18 years and older discharged between January 2014 and November 2014. Admissions were excluded if there was a missing primary diagnosis, discharge disposition, length of stay, or if the patient died during that hospitalization. Data were analyzed between January 2018 and June 2018.

Exposures: Discharge AMA and non-AMA discharge.

Main Outcomes And Measures: Thirty-day all-cause readmission and in-hospital mortality rate.

Results: There were 19.9 million weighted index admissions, of which 1.5% resulted in an AMA discharge. Within the AMA cohort, 85% were younger than 65 years, 63% were male, 55% had Medicaid or other (including uninsured) coverage, and 39% were in the lowest income quartile. Thirty-day all-cause readmission was 21.0% vs 11.9% for AMA vs non-AMA discharge (P < .001), and 30-day in-hospital mortality was 2.5% vs 5.6% (P < .001), respectively. Individuals discharged AMA were more likely to be readmitted to a different hospital compared with non-AMA patients (43.0% vs 23.9%; P < .001). Of all 30-day readmissions, 19.0% occurred within the first day after AMA discharge vs 6.1% for non-AMA patients (P < .001). On multivariable regression, AMA discharge was associated with a 2.01 (95% CI, 1.97-2.05) increased adjusted odds of readmission and a 0.80 (95% CI, 0.74-0.87) decreased adjusted odds of in-hospital mortality compared with non-AMA discharge. Nationwide readmissions after AMA discharge accounted for more than 400 000 inpatient hospitalization days at a total cost of $822 million in 2014.

Conclusions And Relevance: Individuals discharged AMA have higher odds of 30-day readmission at significant cost to the health care system and lower in-hospital mortality rates compared with non-AMA patients. Patients discharged AMA are also more likely to be readmitted to different hospitals and to have earlier bounce-back readmissions, which may reflect dissatisfaction with their initial episode of care.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.6009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290410PMC
June 2020

A peroxidase mimetic protects skeletal muscle cells from peroxide challenge and stimulates insulin signaling.

Am J Physiol Cell Physiol 2020 06 29;318(6):C1214-C1225. Epub 2020 Apr 29.

Department of Biology, Saint Louis University, St. Louis, Missouri.

Reactive oxygen species such as hydrogen peroxide have been implicated in causing metabolic dysfunction such as insulin resistance. Heme groups, either by themselves or when incorporated into proteins, have been shown to scavenge peroxide and demonstrate protective effects in various cell types. Thus, we hypothesized that a metalloporphyrin similar in structure to heme, Fe(III)tetrakis(4-benzoic acid)porphyrin (FeTBAP), would be a peroxidase mimetic that could defend cells against oxidative stress. After demonstrating that FeTBAP has peroxidase activity with reduced nicotinamide adenine dinucleotide phosphate (NADPH) and NADH as reducing substrates, we determined that FeTBAP partially rescued C2C12 myotubes from peroxide-induced insulin resistance as measured by phosphorylation of AKT (S473) and insulin receptor substrate 1 (IRS-1, Y612). Furthermore, we found that FeTBAP stimulates insulin signaling in myotubes and mouse soleus skeletal muscle to about the same level as insulin for phosphorylation of AKT, IRS-1, and glycogen synthase kinase 3β (S9). We found that FeTBAP lowers intracellular peroxide levels and protects against carbonyl formation in myotubes exposed to peroxide. Additionally, we found that FeTBAP stimulates glucose transport in myotubes and skeletal muscle to about the same level as insulin. We conclude that a peroxidase mimetic can blunt peroxide-induced insulin resistance and also stimulate insulin signaling and glucose transport, suggesting a possible role of peroxidase activity in regulation of insulin signaling.
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http://dx.doi.org/10.1152/ajpcell.00167.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311744PMC
June 2020

A pediatric approach to management of skin growths in basal cell nevus syndrome.

Pediatr Dermatol 2020 May 17;37(3):527-530. Epub 2020 Feb 17.

Harvard Medical School, Boston, MA, USA.

Little guidance on management of basal cell nevus syndrome in children exists. We report a case series of four patients diagnosed with BCNS in early childhood, in whom several highly suspicious lesions were biopsied, but several smaller and questionably concerning lesions were treated with therapies that are more tolerable for children, including topical imiquimod, 5-fluorouracil, cryotherapy, or touch electrodessication following topical anesthetic cream. These therapies were well tolerated, and all residual or persistent lesions were subsequently biopsied and found to be benign. This approach is often preferable for pediatric BCNS patients, in whom concerning lesions can be identified clinically and managed compassionately. However, any lesion that exhibits growth, bleeding, or symptoms should be biopsied for definitive diagnosis.
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http://dx.doi.org/10.1111/pde.14122DOI Listing
May 2020

: software for simulating and fitting grazing-incidence small-angle scattering.

J Appl Crystallogr 2020 Feb 1;53(Pt 1):262-276. Epub 2020 Feb 1.

Jülich Centre for Neutron Science (JCNS) at Heinz Maier-Leibnitz Zentrum (MLZ), Forschungszentrum Jülich GmbH, Lichtenbergstrasse 1, Garching, 85748, Germany.

is a free and open-source multi-platform software framework for simulating and fitting X-ray and neutron reflectometry, off-specular scattering, and grazing-incidence small-angle scattering (GISAS). This paper concentrates on GISAS. Support for reflectometry and off-specular scattering has been added more recently, is still under intense development and will be described in a later publication. supports neutron polarization and magnetic scattering. Users can define sample and instrument models through Python scripting. A large subset of the functionality is also available through a graphical user interface. This paper describes the software in terms of the realized non-functional and functional requirements. The web site https://www.bornagainproject.org/ provides further documentation.
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http://dx.doi.org/10.1107/S1600576719016789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998781PMC
February 2020

The value of hydrologic information for watershed management programs: The case of Camboriú, Brazil.

Sci Total Environ 2020 Feb 2;705:135871. Epub 2019 Dec 2.

Institute on the Environment, University of Minnesota, St. Paul, MN 55108, United States.

Investments in watershed services programs hold the promise to protect and restore ecosystems and water resources. The design and implementation of such programs is often accompanied by hydrologic modeling and monitoring, although the role of hydrologic information in meeting the needs of program managers remains unclear. In the Camboriú watershed, Brazil, we explored the value of hydrologic modeling and monitoring with respect to two dimensions: scientific credibility and use of generated knowledge in the design, implementation, and evaluation of the watershed management program. We used a combination of semi-structured interviews, focus groups, and hydrologic modeling under various levels of data availability to examine when improved models and data availability might build credibility and provide more useful information for decision makers. We found that hydrologic information was not actually used for the detailed design, but rather contributed to broad-scale support of the program by increasing scientific credibility. Model sophistication and data availability improved the credibility of hydrologic information but did not affect actual decisions related to program design. Hydrologic monitoring data were critical for model calibration, and high-resolution land use and land cover data, obtained via remote sensing, affected some model outputs which were not used to design the program. Our study suggests that identifying how hydrologic data will inform decision making should guide the level of effort used in hydrologic modeling and monitoring.
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http://dx.doi.org/10.1016/j.scitotenv.2019.135871DOI Listing
February 2020

Longitudinal Functional Assessment of Brain Injury Induced by High-Intensity Ultrasound Pulse Sequences.

Sci Rep 2019 10 29;9(1):15518. Epub 2019 Oct 29.

Division of Biomedical Physics, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD, USA.

Exposure of the brain to high-intensity stress waves creates the potential for long-term functional deficits not related to thermal or cavitational damage. Possible sources of such exposure include overpressure from blast explosions or high-intensity focused ultrasound (HIFU). While current ultrasound clinical protocols do not normally produce long-term neurological deficits, the rapid expansion of potential therapeutic applications and ultrasound pulse-train protocols highlights the importance of establishing a safety envelope beyond which therapeutic ultrasound can cause neurological deficits not detectable by standard histological assessment for thermal and cavitational damage. In this study, we assessed the neuroinflammatory response, behavioral effects, and brain micro-electrocorticographic (µECoG) signals in mice following exposure to a train of transcranial pulses above normal clinical parameters. We found that the HIFU exposure induced a mild regional neuroinflammation not localized to the primary focal site, and impaired locomotor and exploratory behavior for up to 1 month post-exposure. In addition, low frequency (δ) and high frequency (β, γ) oscillations recorded by ECoG were altered at acute and chronic time points following HIFU application. ECoG signal changes on the hemisphere ipsilateral to HIFU exposure are of greater magnitude than the contralateral hemisphere, and persist for up to three months. These results are useful for describing the upper limit of transcranial ultrasound protocols, and the neurological sequelae of injury induced by high-intensity stress waves.
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http://dx.doi.org/10.1038/s41598-019-51876-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820547PMC
October 2019

Engineering γδT cells limits tonic signaling associated with chimeric antigen receptors.

Sci Signal 2019 09 10;12(598). Epub 2019 Sep 10.

Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Despite the benefits of chimeric antigen receptor (CAR)-T cell therapies against lymphoid malignancies, responses in solid tumors have been more limited and off-target toxicities have been more marked. Among the possible design limitations of CAR-T cells for cancer are unwanted tonic (antigen-independent) signaling and off-target activation. Efforts to overcome these hurdles have been blunted by a lack of mechanistic understanding. Here, we showed that single-cell analysis with time course mass cytometry provided a rapid means of assessing CAR-T cell activation. We compared signal transduction in expanded T cells to that in T cells transduced to express second-generation CARs and found that cell expansion enhanced the response to stimulation. However, expansion also induced tonic signaling and reduced network plasticity, which were associated with expression of the T cell exhaustion markers PD-1 and TIM-3. Because this was most evident in pathways downstream of CD3ζ, we performed similar analyses on γδT cells that expressed chimeric costimulatory receptors (CCRs) lacking CD3ζ but containing DAP10 stimulatory domains. These CCR-γδT cells did not exhibit tonic signaling but were efficiently activated and mounted cytotoxic responses in the presence of CCR-specific stimuli or cognate leukemic cells. Single-cell signaling analysis enabled detailed characterization of CAR-T and CCR-T cell activation to better understand their functional activities. Furthermore, we demonstrated that CCR-γδT cells may offer the potential to avoid on-target, off-tumor toxicity and allo-reactivity in the context of myeloid malignancies.
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http://dx.doi.org/10.1126/scisignal.aax1872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055420PMC
September 2019

Tumor infiltrating lymphocytes expanded from pediatric neuroblastoma display heterogeneity of phenotype and function.

PLoS One 2019 9;14(8):e0216373. Epub 2019 Aug 9.

Cancer Section, Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, London, England, United Kingdom.

Adoptive transfer of ex vivo expanded tumor infiltrating lymphocytes (TILs) has led to clinical benefit in some patients with melanoma but has not demonstrated convincing efficacy in other solid cancers. Whilst the presence of TILs in many types of cancer is often associated with better clinical prognosis, their function has not been systematically evaluated across cancer types. Responses to immunological checkpoint inhibitors in a wide range of cancers, including those for which adoptive transfer of expanded TILs has not shown clinical benefit, has clearly delineated a number of tumor type associated with tumor-reactive lymphocytes capable of effecting tumor remissions. Neuroblastoma is an aggressive childhood solid cancer in which immunotherapy with GD2-directed antibodies confers a proven survival advantage through incompletely understood mechanisms. We therefore evaluated the feasibility of ex vivo expansion of TILs from freshly resected neuroblastoma tumors and the potential therapeutic utility of TIL expansions. TILs were successfully expanded from both tumor biopsies or resections. Significant numbers of NKT and γδT cells were identified alongside the mixed population of cytotoxic (CD8+) and helper (CD4+) T cells of both effector and central memory phenotypes. Isolated TILs were broadly non-reactive against autologous tumor and neuroblastoma cell lines, so enhancement of neuroblastoma killing was attained by transducing TILs with a second-generation chimeric antigen receptor (CAR) targeting GD2. CAR-TILs demonstrated antigen-specific cytotoxicity against tumor cell lines. This study is the first to show reproducible expansion of TILs from pediatric neuroblastoma, the high proportion of innate-like lymphocytes, and the feasibility to use CAR-TILs therapeutically.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216373PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688820PMC
February 2020

Regulation of Myogenic Activity by Substrate and Electrical Stimulation .

Biores Open Access 2019 30;8(1):129-138. Epub 2019 Jul 30.

Department of Biomedical Engineering, Parks College of Engineering, Aviation, and Technology, Saint Louis University, St. Louis, Missouri.

Skeletal muscle has a remarkable regenerative capacity in response to mild injury. However, when muscle is severely injured, muscle regeneration is impaired due to the loss of muscle-resident stem cells, known as satellite cells. Fibrotic tissue, primarily comprising collagen I (COL), is deposited with this critical loss of muscle. In recent studies, supplementation of laminin (LM)-111 has been shown to improve skeletal muscle regeneration in several models of disease and injury. Additionally, electrical stimulation (E-stim) has been investigated as a possible rehabilitation therapy to improve muscle's functional recovery. This study investigated the role of E-stim and substrate in regulating myogenic response. C2C12 myoblasts were allowed to differentiate into myotubes on COL- and LM-coated polydimethylsiloxane molds. The myotubes were subjected to E-stim and compared with nonstimulated controls. While E-stim resulted in increased myogenic activity, irrespective of substrate, LM supported increased proliferation and uniform distribution of C2C12 myoblasts. In addition, C2C12 myoblasts cultured on LM showed higher Sirtuin 1, mammalian target of rapamycin, desmin, nitric oxide, and vascular endothelial growth factor expression. Taken together, these results suggest that an LM substrate is more conducive to myoblast growth and differentiation in response to E-stim .
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http://dx.doi.org/10.1089/biores.2019.0016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664826PMC
July 2019

Myoglobin as a versatile peroxidase: Implications for a more important role for vertebrate striated muscle in antioxidant defense.

Comp Biochem Physiol B Biochem Mol Biol 2019 Aug 30;234:9-17. Epub 2019 Apr 30.

Department of Biology, Saint Louis University, USA. Electronic address:

Myoglobins (Mb) are ubiquitous proteins found in striated muscle of nearly all vertebrate taxa. Although their function is most commonly associated with facilitating oxygen storage and diffusion, Mb has also been implicated in cellular antioxidant defense. The oxidized (Fe) form of Mb (metMB) can react with hydrogen peroxide (HO) to produce ferrylMb. FerrylMb can be reduced back to metMb for another round of reaction with HO. In the present study, we have shown that horse skeletal muscle Mb displays peroxidase activity using 2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS) and 3,3',5,5'-tetramethylbenzidine (TMB) as reducing substrates, as well as the biologically-relevant substrates NADH/NADPH, ascorbate, caffeic acid, and resveratrol. We have also shown that ferrylMb can be reduced by both ethanol and acetaldehyde, which are known to accumulate in some vertebrate tissues under anaerobic conditions, such as anoxic goldfish and crucian carp, implying a potential mechanism for ethanol detoxification in striated muscle. We found that metMb peroxidase activity is pH-dependent, increasing as pH decreases from 7.4 to 6.1, which is biologically relevant to anaerobic vertebrate muscle when incurring intracellular lactic acidosis. Finally, we found that metMb reacts with hypochlorite in a heme-dependent fashion, indicating that Mb could play a role in hypochlorite detoxification. Taken together, these data suggest that Mb peroxidase activity might be an important antioxidant mechanism in vertebrate cardiac and skeletal muscle under a variety of physiological conditions, such as those that might occur in contracting skeletal muscle or during hypoxia.
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http://dx.doi.org/10.1016/j.cbpb.2019.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594547PMC
August 2019

Spatial and ontogenetic variation in isotopic niche among recovering fish communities revealed by Bayesian modeling.

PLoS One 2019 18;14(4):e0215747. Epub 2019 Apr 18.

Centre for Fisheries Ecosystems Research, Fisheries and Marine Institute of Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada.

Exploitation and changing ocean conditions have resulted in altered species interactions and varied population dynamics within marine fish communities off northeast Newfoundland and southern Labrador, Canada. To understand contemporary species interactions, we quantified the isotopic niches, niche overlap, and ontogenetic niche change among seven dominant fish species using stable isotope analyses. Analyses used fishes from three regions differing in fish and prey diversities. Differences in fish and diet composition diversity among regions were found using Simpson's inverse diversity index. The regions of lowest diversities had higher instances of niche overlap and higher percentage of niche overlap area. The region of highest diversity had the widest spread of niches with greater distances from the community centroid. Ontogenetic shifts were observed such that larger individuals shifted towards the community centroid with the exception of Atlantic cod. Atlantic cod in particular was found to consistently be the top predator of the analyzed species. Our results reveal: (a) overlap in isotopic niches and spread within niche space was correlated with fish and diet diversity; (b) ontogenetic shifts are important when considering a species' niche and quantifying spatial variation in community niche profiles.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215747PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472828PMC
January 2020

Change in Policy Allowing Overlapping Surgery Decreases Length of Stay in an Academic, Safety-Net Hospital.

Oper Neurosurg (Hagerstown) 2019 12;17(6):543-548

Department of Neurosurgery, Louisiana State University Health Sciences Center, New Orleans, Louisiana.

Background: The practice of surgeons running overlapping operating rooms has recently come under scrutiny.

Objective: To examine the impact of hospital policy allowing overlapping rooms in the case of patients admitted to a tertiary care, safety-net hospital for urgent neurosurgical procedures.

Methods: The neurosurgery service at the hospital being studied transitioned from routinely allowing 1 room per day (period 1) to overlapping rooms (period 2), with the second room being staffed by the same attending surgeon. Patients undergoing neurosurgical intervention in each period were retrospectively compared. Demographics, indication, case type, complications, outcomes, and total charges were tracked.

Results: There were 59 urgent cases in period 1 and 63 in period 2. In the case of these patients, the length of stay was significantly decreased in period 2 (13.09 d vs 19.52; P = .006). The time from admission to surgery (wait time) was also significantly decreased in period 2 (5.12 d vs 7.00; P = .04). Total charges also trended towards less in period 2 (${\$}$150 942 vs ${\$}$200 075; P = .05). Surgical complications were no different between the groups (16.9% vs 14.3%; P = .59), but medical complications were significantly decreased in period 2 (14.3% vs 30.5%; P = .009). Significantly more patients were discharged to home in period 2 (69.8% vs 42.4%; P = .003).

Conclusion: As a matter of policy, allowing overlapping rooms significantly reduces the length of stay in the case of a vulnerable population in need of urgent surgery at a single safety-net academic institution. This may be due to a reduction in medical complications in these patients.
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http://dx.doi.org/10.1093/ons/opz009DOI Listing
December 2019

Analysis of Readmissions Following Hospitalization for Cellulitis in the United States.

JAMA Dermatol 2019 06;155(6):720-723

Harvard Medical School, Boston, Massachusetts.

Importance: Cellulitis commonly results in hospitalization. Limited data on the proportion of cellulitis admissions associated with readmission are available.

Objective: To characterize the US national readmission rate associated with hospitalization for treatment of cellulitis.

Design, Setting, And Participants: This retrospective cohort analysis of cellulitis admissions from the nationally representative 2014 Nationwide Readmissions Database calculated readmission rates for all cellulitis admissions and subsets of admissions. The multicenter population-based cohort included adult patients admitted for conditions other than obstetrical or newborn care. Data were collected from January 1 through November 30, 2014, and analyzed from February 1 through September 18, 2018. Bivariate logistic regression models were used to assess differences in readmission rates by patient characteristics. Costs were calculated for all readmissions after discharge from hospitalization for cellulitis (hereinafter referred to as cellulitis discharge) and by readmission diagnosis.

Exposures: Admission with a primary diagnosis of cellulitis.

Main Outcomes And Measures: Proportion of cellulitis admissions associated with nonelective readmission within 30 days, characteristics of patients readmitted after cellulitis discharge, and costs associated with cellulitis readmission.

Results: A total of 447 080 (95% CI, 429 927-464 233) index admissions with a primary diagnosis of cellulitis (53.8% male [95% CI, 53.5%-54.2%]; mean [SD] age, 56.1 [18.9] years) were included. Overall 30-day all-cause nonelective readmission rate after cellulitis discharge was 9.8% (95% CI, 9.6%-10.0%). Among patients with cellulitis, age (odds ratio for 45-64 years, 0.78; 95% CI, 0.75-0.81; P = .001) and insurance status (odds ratio for Medicare, 2.45; 95% CI, 2.33-2.58; P < .001) were associated with increased readmission rates. The most common diagnosis of readmissions included skin and subcutaneous tissue infections. The total cost associated with nonelective readmissions attributed to skin and subcutaneous infections within 30 days of a cellulitis discharge during the study period was $114.4 million (95% CI, $106.8-$122.0 million).

Conclusions And Relevance: Readmission after hospitalization for cellulitis is common and costly and may be preventable with improved diagnostics, therapeutics, and discharge care coordination.
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http://dx.doi.org/10.1001/jamadermatol.2018.4650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563554PMC
June 2019

Dehydration: A Multidisciplinary Case-Based Discussion for First-Year Medical Students.

MedEdPORTAL 2018 06 26;14:10725. Epub 2018 Jun 26.

Assistant Professor, Pediatrics and Cancer Biology and Pharmacology Department, University of Illinois College of Medicine.

Introduction: As many medical school curricula shift to integrated learning of multiple basic science topics as well as clinical concepts, there is an increasing need for instructional materials that incorporate multiple topics yet are targeted to the knowledge basis of first-year medical students. This interactive case-based session for first-year medical students centers on the clinical presentation and initial evaluation of a patient experiencing dehydration after running a marathon in a high-altitude city.

Methods: After completion of assigned out-of-class preparation, students followed the patient from a healthy state to moderate dehydration over the course of two 2-hour class sessions. Throughout discussion of the case, students answered questions requiring them to integrate elements of cell biology, biochemistry, physiology, and clinical reasoning with minimal faculty involvement. The learning activity was administered at University of Illinois College of Medicine campuses in both a small-group setting (10 students, one faculty facilitator) and a large-group format (55-90 students, multiple faculty facilitators). Following the activity, we assessed student perceptions of the design and implementation of the materials as well as effectiveness at meeting the learning goals.

Results: Of 198 students who participated in the case discussions on dehydration, the majority rated the case positively, indicated by a rating of good or excellent.

Discussion: This multidisciplinary case on dehydration can be used early in medical education to introduce students to clinical scenarios while learning fundamental science content. An integrated approach to medical content and versatility with regard to class size make this case a valuable teaching tool.
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http://dx.doi.org/10.15766/mep_2374-8265.10725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342389PMC
June 2018

Critical Appraisal of Emergency Medicine Educational Research: The Best Publications of 2016.

AEM Educ Train 2019 Jan 14;3(1):58-73. Epub 2018 Dec 14.

University of Arizona College of Medicine Phoenix Maricopa Medical Center Phoenix AZ.

Objectives: The objectives were to critically appraise the emergency medicine (EM) medical education literature published in 2016 and review the highest-quality quantitative and qualitative studies.

Methods: A search of the English language literature in 2016 querying MEDLINE, Scopus, Education Resources Information Center (ERIC), and PsychInfo identified 510 papers related to medical education in EM. Two reviewers independently screened all of the publications using previously established exclusion criteria. The 25 top-scoring quantitative studies based on methodology and all six qualitative studies were scored by all reviewers using selected scoring criteria that have been adapted from previous installments. The top-scoring articles were highlighted and trends in medical education research were described.

Results: Seventy-five manuscripts met inclusion criteria and were scored. Eleven quantitative and one qualitative papers were the highest scoring and are summarized in this article.

Conclusion: This annual critical appraisal series highlights the best EM education research articles published in 2016.
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http://dx.doi.org/10.1002/aet2.10203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339548PMC
January 2019

Returns on investment in watershed conservation: Application of a best practices analytical framework to the Rio Camboriú Water Producer program, Santa Catarina, Brazil.

Sci Total Environ 2019 Mar 11;657:1368-1381. Epub 2018 Dec 11.

Empresa Municipal de Água e Saneamento, 4a Avenida n250 Centro, CEP 88330-104 Balneário Camboriú, Santa Catarina, Brazil.

Watershed management may have widespread potential to cost-effectively deliver hydrologic services. Mobilizing the needed investments requires credible assessments of how watershed conservation compares to conventional solutions on cost and effectiveness, utilizing an integrated analytical framework that links the bio-, litho-, hydro- and economic spheres and uses counterfactuals. We apply such a framework to a payment for watershed services (PWS) program in Camboriú, Santa Catarina State, Brazil. Using 1 m resolution satellite imagery, we assess recent land use and land cover (LULC) change and apply the Land Change Modeler tool to predict future LULC without the PWS program. We use current and predicted counterfactual LULC, site costs and a Soil and Water Assessment Tool model calibrated to the watershed to both target watershed interventions for sediment reduction and predict program impact on total suspended solids (TSS) concentrations at the municipal water intake-the principal program objective. Using local water treatment and PWS program costs, we estimate the return on investment (ROI; benefit/costs) of the program. Program ROI exceeds 1 for the municipal water utility in year 44, well within common drinking water infrastructure planning horizons. Because some program costs are borne by third parties, over that same period, for overall (social) program ROI to exceed 1 requires delivery of very modest flood and supply risk reduction and biodiversity co-benefits, making co-benefits crucial for social program justification. Transaction costs account for half of total program costs, a result of large investments in efficient targeting and program sustainability. Co-benefits justify increased cost sharing with other beneficiaries, which would increase ROI for the utility, demonstrating the sensitivity of the business case for watershed conservation to its broader social-economic case and the ability to forge institutional arrangements to internalize third-party benefits.
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http://dx.doi.org/10.1016/j.scitotenv.2018.12.116DOI Listing
March 2019

Glucose-dependent trans-plasma membrane electron transport and p70 phosphorylation in skeletal muscle cells.

Redox Biol 2019 10 12;27:101075. Epub 2018 Dec 12.

Department of Biology, Saint Louis University, St. Louis, MO, United States. Electronic address:

The reduction of extracellular oxidants by intracellular electrons is known as trans-plasma membrane electron transport (tPMET). The goal of this study was to characterize a role of tPMET in the sensing of glucose as a physiological signal. tPMET from C2C12 myotubes was monitored using a cell-impermeable extracellular electron acceptor, water-soluble tetrazolium salt-1 (WST-1). Superoxide dismutase in the incubation medium or exposure to an NADPH oxidase (NOX) isoform 1/4 inhibitor suppressed WST-1 reduction by 70%, suggesting a role of NOXs in tPMET. There was a positive correlation between medium glucose concentration and WST-1 reduction, suggesting that tPMET is a glucose-sensing process. WST-1 reduction was also decreased by an inhibitor of the pentose phosphate pathway, dehydroepiandrosterone. In contrast, glycolytic inhibitors, 3PO and sodium fluoride, did not affect WST-1 reduction. Thus, it appears that glucose uptake and processing in the pentose phosphate pathway drives NOX-dependent tPMET. Western blot analysis demonstrated that p70 phosphorylation is glucose-dependent, while the phosphorylation of AKT and MAPK did not differ in the presence or absence of glucose. Further, phosphorylation of p70 was dependent upon NOX enzymes. Finally, glucose was required for full stimulation of p70 by insulin, again in a fashion prevented by NOX inhibition. Taken together, the data suggest that muscle cells have a novel glucose-sensing mechanism dependent on NADPH production and NOX activity, culminating in increased p70 phosphorylation.
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http://dx.doi.org/10.1016/j.redox.2018.101075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859557PMC
October 2019

Clinical Cybersecurity Training Through Novel High-Fidelity Simulations.

J Emerg Med 2019 02 12;56(2):233-238. Epub 2018 Dec 12.

Department of Anesthesia and Pain Medicine, University of California Davis, Davis, California.

Background: Cybersecurity risks in health care systems have traditionally been measured in data breaches of protected health information, but compromised medical devices and critical medical infrastructure present risks of disruptions to patient care. The ubiquitous prevalence of connected medical devices and systems may be associated with an increase in these risks.

Objective: This article details the development and execution of three novel high-fidelity clinical simulations designed to teach clinicians to recognize, treat, and prevent patient harm from vulnerable medical devices.

Methods: Clinical simulations were developed that incorporated patient-care scenarios featuring hacked medical devices based on previously researched security vulnerabilities.

Results: Clinicians did not recognize the etiology of simulated patient pathology as being the result of a compromised device.

Conclusions: Simulation can be a useful tool in educating clinicians in this new, critically important patient-safety space.
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http://dx.doi.org/10.1016/j.jemermed.2018.10.029DOI Listing
February 2019

C-peptide levels do not correlate with pancreas allograft failure: Multicenter retrospective analysis and discussion of the new OPT definition of pancreas allograft failure.

Am J Transplant 2019 04 22;19(4):1178-1186. Epub 2018 Oct 22.

Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.

The OPTN Pancreas Transplantation Committee performed a multicenter retrospective study to determine if undetectable serum C-peptide levels correspond to center-reported pancreas graft failures. C-peptide data from seven participating centers (n = 415 graft failures for transplants performed from 2002 to 2012) were analyzed pretransplant, at graft failure, and at return to insulin. One hundred forty-nine C-peptide values were submitted at pretransplant, 94 at return to insulin, and 233 at graft failure. There were 77 transplants with two available values (at pretransplant and at graft failure). For recipients in the study with pretransplant C-peptide <0.75 ng/mL who had a posttransplant C-peptide value available (n = 61), graft failure was declared at varying levels of C-peptide. High C-peptide values at graft failure were not explained by nonfasting testing or by individual center bias. Transplant centers declare pancreas graft failure at varying levels of C-peptide and do not consistently report C-peptide data. Until February 28, 2018, OPTN did not require reporting of posttransplant C-peptide levels and it appears that C-peptide levels are not consistently used for evaluating graft function. C-peptide levels should not be used as the sole criterion for the definition of pancreas graft failure.
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http://dx.doi.org/10.1111/ajt.15118DOI Listing
April 2019

Fourth-year medical students do not perform a focused physical examination during a case-based simulation scenario.

Adv Med Educ Pract 2018 17;9:583-588. Epub 2018 Aug 17.

Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA,

Background: The art of physical examination is one of the most valuable diagnostic tools bestowed upon new generations of medical students. Despite traditional educational techniques and significant attention on a national level, both trainees and educators have noticed a decrease in physical examination proficiency. Simulation has been identified as a potential way to improve physical examination techniques within undergraduate medical education. We sought to determine the utility of a cardiac case-based simulation scenario to assess physical examination performance of fourth-year medical students during an emergency medicine (EM) clerkship.

Materials And Methods: Fourth-year medical students enrolled in a 4-week EM clerkship were prospectively evaluated during a case-based scenario using a simulation mannequin (Laerdal SimMan). The case involved a patient presenting with chest pain that evolved into cardiac arrest. All simulations were video recorded and two emergency physicians reviewed each video. The reviewers recorded whether or not each student completed the essential components of a focused physical examination.

Results: Twenty-seven students participated in the simulation. The percentage of students completing each of the four components of the physical examination was as follows: cardiac auscultation 33.3% (95% CI 18.5-52.3), lung auscultation 29.6% (95% CI 15.7-48.7), pulse and extremity examination 55.6% (95% CI 37.3-72.4), and abdominal examination 3.70% (95% CI 0-19.8). None of the students completed all four of these components.

Conclusion: Our study showed that fourth-year medical students did not uniformly perform components of a focused physical examination during a high-acuity chest pain simulation scenario. Although our study showed limited physical examination performance, simulation allows evaluators to observe and provide constructive feedback and may lead to an improvement in these skills. These findings call for improved technology to increase authenticity of simulators and continued faculty development for more creative, meaningful integration of physical examination skills into high-acuity simulation cases.
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http://dx.doi.org/10.2147/AMEP.S160701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103551PMC
August 2018

The Council of Emergency Medicine Residency Directors Speaker Evaluation Form for Medical Conference Planners.

AEM Educ Train 2017 Oct 21;1(4):340-345. Epub 2017 Sep 21.

Department of Emergency Medicine Lewis Katz School of Medicine of Temple University Philadelphia PA.

Objectives: No summative speaker evaluation form with validity and reliability evidence currently exists in the English medical education literature specifically to help conference planners make future decisions on speakers. We seek to perform a proof-of-concept evaluation of a concise, effective evaluation form to be filled out by audience members to aid conference planners.

Methods: We created the Council of Emergency Medicine Residency Directors (CORD-EM) form, a novel, three-question speaker evaluation form for the CORD-EM national conference and evaluated it for proof of concept. The CORD-EM form was analyzed with three evaluators and randomized to select only two evaluators' ratings to make results more generalizable to a generic audience evaluating the speaker.

Results: Forty-six total evaluations ranged from 6 to 9 (mean ± standard deviation = 8.1 ± 1.2). The form demonstrated excellent internal consistency (Cronbach's alpha = 0.923) with good inter-rater reliability (intraclass correlation = 0.617) in the conference context.

Conclusions: The CORD-EM speaker evaluation form is, to our knowledge, the first evaluation form with early reliability and validity evidence specifically designed to help conference planners. Our results suggest that a short speaker evaluation form can be an effective instrument in the toolbox for conference planners.
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http://dx.doi.org/10.1002/aet2.10051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001733PMC
October 2017

Critical Appraisal of Emergency Medicine Educational Research: The Best Publications of 2015.

AEM Educ Train 2017 Oct 17;1(4):255-268. Epub 2017 Oct 17.

Oregon Health & Science University Portland OR.

Objective: The objectives were to critically appraise the medical education research literature of 2015 and review the highest-quality quantitative and qualitative examples.

Methods: A total of 434 emergency medicine (EM)-related articles were discovered upon a search of ERIC, PsychINFO, PubMED, and SCOPUS. These were both quantitative and qualitative in nature. All were screened by two of the authors using previously published exclusion criteria, and the remaining were appraised by all authors using a previously published scoring system. The highest scoring articles were then reviewed.

Results: Sixty-one manuscripts were scored, and 10 quantitative and two qualitative papers were the highest scoring and are reviewed and summarized in this article.

Conclusions: This installment in this critical appraisal series reviews 12 of the highest-quality EM-related medical education research manuscripts published in 2015.
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http://dx.doi.org/10.1002/aet2.10063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001510PMC
October 2017

Engineering Approaches in Human Gamma Delta T Cells for Cancer Immunotherapy.

Front Immunol 2018 26;9:1409. Epub 2018 Jun 26.

University College London, London, United Kingdom.

Sharing both innate and adaptive immune properties, γδT cells are attractive candidates for cellular engineering. As the cancer immunotherapy field becomes increasingly busy, orthogonal approaches are required to drive advancement. Engineering of alternative effector cell types such as γδT cells represents one such approach. γδT cells can be modified using many of the techniques used in αβT cell engineering, with the added advantage of innate-like tumor recognition and killing. Progress has been made in T-cell receptor transfer to and from γδT cells as well as in a number of chimeric antigen receptor-based strategies. As the cancer immunotherapy field moves beyond repetitive iteration of established constructs to more creative solutions, γδT cells may offer an attractive chassis to drive anti-tumor responses that are not only broader, but also possess a more favorable safety profile.
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http://dx.doi.org/10.3389/fimmu.2018.01409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028554PMC
June 2018

The Effect of Signed-Out Emergency Department Patients on Resident Productivity.

J Emerg Med 2018 08 25;55(2):244-251. Epub 2018 Jun 25.

Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.

Background: Transitions of care and patient hand-offs between physicians have important implications for patient care. However, what effect caring for signed-out patients has on providing care to new patients and education is unclear.

Objective: We sought to determine whether the number of patients a physician receives in sign-out affects productivity.

Methods: This was a retrospective cohort study, conducted at an emergency medicine residency program. A general estimation equation was constructed to model productivity, defined as new patients evaluated and relative value units (RVUs) generated per shift, relative to the number of sign-outs received, and training year. A secondary analysis evaluated the effect of signed-out patients in observation.

Results: We evaluated 19,389 shifts from July 1, 2010 to July 1, 2017. Postgraduate year (PGY)-1 residents without sign-out evaluated 10.3 patients (95% confidence interval [CI] 9.83 to 10.7), generating 31.6 RVUs (95% CI 30.5 to 32.7). Each signed-out patient was associated with -0.07 new patients (95% CI -0.12 to -0.01), but no statistically significant decrease in RVUs (95% CI -0.07 to 0.28). PGY-2 residents without sign-out evaluated 13.6 patients (95% CI 12.6 to 14.6), generating 47.7 RVUs (95% CI 45.1 to 50.3). Each signed-out patient was associated with -0.25 (95% CI -0.40 to -0.10) new patients, and -0.89 (95% CI -1.22 to -0.55) RVUs. For all residents, observation patients were associated with more substantial decreases in new patients (-0.40; 95% CI -0.47 to -0.33) and RVUs (-1.11; 95% CI -1.40 to -0.82).

Conclusions: Overall, sign-out burden is associated with a small decrease in resident productivity, except for observation patients. Program faculty should critically examine how signed-out patients are distributed to address residents' educational needs, throughput, and patient safety.
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http://dx.doi.org/10.1016/j.jemermed.2018.05.020DOI Listing
August 2018