Publications by authors named "Joshua Olson"

63 Publications

Dexmedetomidine does not directly inhibit neutrophil extracellular trap production.

Br J Anaesth 2022 02 19;128(2):e51-e54. Epub 2021 Nov 19.

Department of Anesthesiology, Division of Critical Care Medicine, University of California San Diego, La Jolla, CA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.bja.2021.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603039PMC
February 2022

Heat shock protein 27 activity is linked to endothelial barrier recovery after proinflammatory GPCR-induced disruption.

Sci Signal 2021 Aug 31;14(698):eabc1044. Epub 2021 Aug 31.

Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.

Vascular inflammation causes endothelial barrier disruption and tissue edema. Several inflammatory mediators act through G protein–coupled receptors (GPCRs), including protease-activated receptor-1 (PAR1), to elicit inflammatory responses. The activation of PAR1 by its ligand thrombin stimulates proinflammatory, p38 mitogen-activated protein kinase (MAPK) signaling that promotes endothelial barrier disruption. Through mass spectrometry phosphoproteomics, we identified heat shock protein 27 (HSP27), which exists as a large oligomer that binds to actin, as a promising candidate for the p38-mediated regulation of barrier integrity. Depletion of HSP27 by siRNA enhanced endothelial cell barrier permeability and slowed recovery after thrombin stimulation. We further showed that two effector kinases of p38 MAPK, MAPKAPK2 (MK2) and MAPKAPK3 (MK3), differentially phosphorylated HSP27 at Ser, Ser, and Ser. Whereas inhibition of thrombin-stimulated p38 activation blocked HSP27 phosphorylation at all three sites, inhibition of MK2 reduced the phosphorylation of only Ser and Ser. Inhibition of both MK2 and MK3 was necessary to attenuate Ser phosphorylation. Thrombin-stimulated p38-MK2-MK3 signaling induced HSP27 oligomer disassembly. However, a phosphorylation-deficient mutant of HSP27 exhibited defective oligomer disassembly and altered the dynamics of barrier recovery after thrombin stimulation. Moreover, blocking HSP27 oligomer reassembly with the small-molecule inhibitor J2 enhanced endothelial barrier permeability in vitro and vascular leakage in vivo in response to PAR1 activation. These studies reveal the distinct regulation of HSP27 phosphorylation and function induced by the GPCR-stimulated p38-MK2-MK3 signaling axis that controls the dynamics of endothelial barrier recovery in vitro and vascular leakage in vivo.
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http://dx.doi.org/10.1126/scisignal.abc1044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8538426PMC
August 2021

Yoga-induced uveitis glaucoma hyphema syndrome.

Digit J Ophthalmol 2021 Feb 20;26(4):46-48. Epub 2020 Dec 20.

Department of Ophthalmology & Visual Neurosciences, University of Minnesota, Minneapolis.

A 74-year-old pseudophakic white woman with pseudoexfoliation syndrome presented with right eye pain and photophobia and was found to have pseudophacodenesis with recurrent episodes of anterior uveitis, microhyphema, and elevated intraocular pressure (IOP). All episodes occurred after yoga sessions with intensive facedown postures. Ultrasound biomicroscopy (UBM) performed in supine and prone positions demonstrated significant change in the lens-bag complex position, with lens-iris touch. The patient underwent intraocular lens (IOL) explantation, anterior vitrectomy, and flanged intrascleral haptic-fixated IOL placement via double-needle technique, with resolution of all symptoms.
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http://dx.doi.org/10.5693/djo.02.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031953PMC
February 2021

Repurposed drugs block toxin-driven platelet clearance by the hepatic Ashwell-Morell receptor to clear bacteremia.

Sci Transl Med 2021 03;13(586)

Biomedical Sciences Graduate Program, UC San Diego, La Jolla, CA 92093, USA.

(SA) bloodstream infections cause high morbidity and mortality (20 to 30%) despite modern supportive care. In a human bacteremia cohort, we found that development of thrombocytopenia was correlated to increased mortality and increased α-toxin expression by the pathogen. Platelet-derived antibacterial peptides are important in bloodstream defense against SA, but α-toxin decreased platelet viability, induced platelet sialidase to cause desialylation of platelet glycoproteins, and accelerated platelet clearance by the hepatic Ashwell-Morell receptor (AMR). Ticagrelor (Brilinta), a commonly prescribed P2Y12 receptor inhibitor used after myocardial infarction, blocked α-toxin-mediated platelet injury and resulting thrombocytopenia, thereby providing protection from lethal SA infection in a murine intravenous challenge model. Genetic deletion or pharmacological inhibition of AMR stabilized platelet counts and enhanced resistance to SA infection, and the anti-influenza sialidase inhibitor oseltamivir (Tamiflu) provided similar therapeutic benefit. Thus, a "toxin-platelet-AMR" regulatory pathway plays a critical role in the pathogenesis of SA bloodstream infection, and its elucidation provides proof of concept for repurposing two commonly prescribed drugs as adjunctive therapies to improve patient outcomes.
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http://dx.doi.org/10.1126/scitranslmed.abd6737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9121309PMC
March 2021

Chordoma: F-FDG PET/CT and MRI imaging features.

Skeletal Radiol 2021 Aug 1;50(8):1657-1666. Epub 2021 Feb 1.

Department of Radiology, Mayo Clinic, Charlton Building North, 1st Floor, 200 First Street SW, Rochester, MN, 55905, USA.

Objective: Examine the F-FDG PET/CT and MRI imaging characteristics of chordoma.

Materials And Methods: Biopsy-proven chordoma with a pre-therapy F-FDG PET/CT from 2001 through 2019 in patients > 18 years old were retrospectively reviewed. Multiple PET/CT and MRI imaging parameters were assessed.

Results: A total of 23 chordoma patients were included (16 M, 7 F; average age of 60.1 ± 13.0 years) with comparative MRI available in 22 cases. This included 13 sacrococcygeal, 9 mobile spine, and one clival lesions. On F-FDG PET/CT, chordomas demonstrated an average SUVmax of 5.8 ± 3.7, average metabolic tumor volume (MTV) of 160.2 ± 263.8 cm, and average total lesion glycolysis (TLG) of 542.6 ± 1210 g. All demonstrated heterogeneous FDG activity. On MRI, chordomas were predominantly T2 hyperintense (22/22) and T1 isointense (18/22), contained small foci of T1 hyperintensity (17/22), and demonstrated heterogeneous enhancement (14/20). There were no statistically significant associations found between F-FDG PET/CT and MRI imaging features. There was no relationship of SUVmax (p = 0.53), MTV (p = 0.47), TLG (p = 0.48), maximal dimension (p = 0.92), or volume (p = 0.45) to the development of recurrent or metastatic disease which occurred in 6/22 patients over a mean follow-up duration of 4.1 ± 2.0 years.

Conclusion: On F-FDG PET/CT imaging, chordomas demonstrate moderate, heterogeneous FDG uptake. Predominant T2 hyperintensity and small foci of internal increased T1 signal are common on MRI. The inherent FDG avidity of chordomas suggests that F-FDG PET/CT may be a useful modality for staging, evaluating treatment response, and assessing for recurrent or metastatic disease.
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http://dx.doi.org/10.1007/s00256-021-03723-wDOI Listing
August 2021

Novel Models of Colonization and Disease Reveal Modest Contributions of M-Like (SCM) Protein.

Microorganisms 2021 Jan 16;9(1). Epub 2021 Jan 16.

Department of Molecular Virology and Microbiology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.

is a common colonizing bacterium of the urogenital tract of cats and dogs that can also cause invasive disease in these animal populations and in humans. Although the virulence mechanisms of are not well-characterized, an M-like protein, SCM, has recently identified been as a potential virulence factor. SCM is a surface-associated protein that binds to host plasminogen and IgGs suggesting its possible importance in host-pathogen interactions. In this study, we developed in vitro and ex vivo blood component models and murine models of vaginal colonization, systemic infection, and dermal infection to compare the virulence potential of the zoonotic vaginal isolate G361 and its isogenic SCM-deficient mutant (G361∆). We found that while establishes vaginal colonization and causes invasive disease in vivo, the contribution of the SCM protein to virulence phenotypes in these models is modest. We conclude that SCM is dispensable for invasive disease in murine models and for resistance to human blood components ex vivo, but may contribute to mucosal persistence, highlighting a potential contribution to the recently appreciated genetic diversity of SCM across strains and hosts.
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http://dx.doi.org/10.3390/microorganisms9010183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829700PMC
January 2021

Hepatic Mucinous Cystic Neoplasm Versus Simple Biliary Cyst: Assessment of Distinguishing Imaging Features Using CT and MRI.

AJR Am J Roentgenol 2021 02 23;216(2):403-411. Epub 2020 Dec 23.

Department of Radiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.

The purpose of our study was to identify the imaging features that differentiate a hepatic mucinous cystic neoplasm (MCN) from a simple biliary cyst. Surgically resected hepatic MCNs and simple biliary cysts over a 20-year period (October 29, 1997-January 23, 2018) with preoperative CT, MRI, or both were retrospectively identified. Included cases underwent histopathologic confirmation of diagnosis based on the 2010 World Health Organization criteria and blinded imaging review. Various imaging features, including cyst shape and septal enhancement, were assessed for performance. For septate cysts, the relationship of the septation to the cyst wall-that is, arising from the wall without an indentation versus arising from an external macrolobulation-was recorded. Statistical analysis was performed for the imaging features with the chi-square test. The study group comprised 22 hepatic MCNs and 56 simple biliary cysts. A unilocular hepatic cystic lesion was highly predictive of a simple biliary cyst (positive predictive value = 95.2%). The imaging feature of septations arising only from macro-lobulations was 100% specific for a simple biliary cyst on CT ( = 0.001). The presence of septations arising from the cyst wall without indentation was 100% sensitive for hepatic MCN but was only 56.3% specific on CT. Septal enhancement reached 100% sensitivity for hepatic MCN on MRI ( = 0.018). The presence of septations, relationship of the septations to the cyst wall, and septal enhancement were sensitive imaging features in the detection of hepatic MCN. The imaging feature of septations arising only from macrolobulations in the cyst wall was specific for simple biliary cysts on CT and helped differentiate simple biliary cysts from hepatic MCNs.
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http://dx.doi.org/10.2214/AJR.20.22768DOI Listing
February 2021

TLR4 signaling and macrophage inflammatory responses are dampened by GIV/Girdin.

Proc Natl Acad Sci U S A 2020 10 14;117(43):26895-26906. Epub 2020 Oct 14.

Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093;

Sensing of pathogens by Toll-like receptor 4 (TLR4) induces an inflammatory response; controlled responses confer immunity but uncontrolled responses cause harm. Here we define how a multimodular scaffold, GIV (a.k.a. Girdin), titrates such inflammatory response in macrophages. Upon challenge with either live microbes or microbe-derived lipopolysaccharides (a ligand for TLR4), macrophages with GIV mount a more tolerant (hypo-reactive) transcriptional response and suppress proinflammatory cytokines and signaling pathways (i.e., NFkB and CREB) downstream of TLR4 compared to their GIV-depleted counterparts. Myeloid-specific gene-depletion studies confirmed that the presence of GIV ameliorates dextran sodium sulfate-induced colitis and sepsis-induced death. The antiinflammatory actions of GIV are mediated via its C-terminally located TIR-like BB-loop (TILL) motif which binds the cytoplasmic TIR modules of TLR4 in a manner that precludes receptor dimerization; such dimerization is a prerequisite for proinflammatory signaling. Binding of GIV's TILL motif to TIR modules inhibits proinflammatory signaling via other TLRs, suggesting a convergent paradigm for fine-tuning macrophage inflammatory responses.
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http://dx.doi.org/10.1073/pnas.2011667117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604444PMC
October 2020

The Pseudomonas aeruginosa protease LasB directly activates IL-1β.

EBioMedicine 2020 Oct 23;60:102984. Epub 2020 Sep 23.

Department of Microbiology and Immunology, Emory School of Medicine, Atlanta GA, United States; Division of Infectious Diseases, Emory School of Medicine, Atlanta GA, United States; Antimicrobial Resistance Center, Emory University, Atlanta GA, United States. Electronic address:

Background: Pulmonary damage by Pseudomonas aeruginosa during cystic fibrosis lung infection and ventilator-associated pneumonia is mediated both by pathogen virulence factors and host inflammation. Impaired immune function due to tissue damage and inflammation, coupled with pathogen multidrug resistance, complicates the management of these deep-seated infections. Pathological inflammation during infection is driven by interleukin-1β (IL-1β), but the molecular processes involved are not fully understood.

Methods: We examined IL-1β activation in a pulmonary model infection of Pseudomonas aeruginosa and in vitro using genetics, specific inhibitors, recombinant proteins, and targeted reporters of protease activity and IL-1β bioactivity.

Findings: Caspase-family inflammasome proteases canonically regulate maturation of this proinflammatory cytokine, but we report that plasticity in IL-1β proteolytic activation allows for its direct maturation by the pseudomonal protease LasB. LasB promotes IL-1β activation, neutrophilic inflammation, and destruction of lung architecture characteristic of severe P. aeruginosa pulmonary infection.

Interpretation: Preservation of lung function and effective immune clearance may be enhanced by selectively controlling inflammation. Discovery of this IL-1β regulatory mechanism provides a distinct target for anti-inflammatory therapeutics, such as matrix metalloprotease inhibitors that inhibit LasB and limit inflammation and pathology during P. aeruginosa pulmonary infections.

Funding: Full details are provided in the Acknowledgements section.
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http://dx.doi.org/10.1016/j.ebiom.2020.102984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511813PMC
October 2020

Real-time jitter correction in a photonic analog-to-digital converter.

Opt Lett 2020 Sep;45(18):5089-5092

A real-time jitter meter is used to measure and digitally sample the pulse-to-pulse timing error in a laser pulse train. The jitter meter is self-referenced using a single-pulse delay line interferometer and measures timing jitter using optical heterodyne detection between two frequency channels of the pulse train. Jitter sensitivity down to 3×10/ at 500 MHz has been demonstrated with a pulse-to-pulse noise floor of 1.6 fs. As a proof of principle, the digital correction of the output of a high-frequency photonic analog-to-digital converter (PADC) is demonstrated with an emulated jitter signal. Up to 23 dB of jitter correction, down to the noise floor of the PADC, is accomplished with radio-frequency modulation up to 40 GHz.
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http://dx.doi.org/10.1364/OL.397249DOI Listing
September 2020

Mortality Risk Profiling of Staphylococcus aureus Bacteremia by Multi-omic Serum Analysis Reveals Early Predictive and Pathogenic Signatures.

Cell 2020 09;182(5):1311-1327.e14

Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Collaborative to Halt Antibiotic-Resistant Microbes, University of California, San Diego, La Jolla, CA 92093, USA; Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

Staphylococcus aureus bacteremia (SaB) causes significant disease in humans, carrying mortality rates of ∼25%. The ability to rapidly predict SaB patient responses and guide personalized treatment regimens could reduce mortality. Here, we present a resource of SaB prognostic biomarkers. Integrating proteomic and metabolomic techniques enabled the identification of >10,000 features from >200 serum samples collected upon clinical presentation. We interrogated the complexity of serum using multiple computational strategies, which provided a comprehensive view of the early host response to infection. Our biomarkers exceed the predictive capabilities of those previously reported, particularly when used in combination. Last, we validated the biological contribution of mortality-associated pathways using a murine model of SaB. Our findings represent a starting point for the development of a prognostic test for identifying high-risk patients at a time early enough to trigger intensive monitoring and interventions.
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http://dx.doi.org/10.1016/j.cell.2020.07.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494005PMC
September 2020

Multidimensional Proteome Profiling of Blood-Brain Barrier Perturbation by Group B .

mSystems 2020 Aug 25;5(4). Epub 2020 Aug 25.

Department of Pharmacology, University of California, San Diego, La Jolla, California, USA

Group B (GBS) remains the leading cause of neonatal meningitis, a disease associated with high rates of adverse neurological sequelae. The relationship between GBS and brain tissues remains poorly characterized, partly because past studies had focused on microbial rather than host processes. Additionally, the field has not capitalized on systems-level technologies to probe the host-pathogen relationship. Here, we use multiplexed quantitative proteomics to investigate the effect of GBS infection in the murine brain at various levels of tissue complexity, beginning with the whole organ and moving to brain vascular substructures. Infected whole brains showed classical signatures associated with the acute-phase response. In isolated brain microvessels, classical blood-brain barrier proteins were unaltered, but interferon signaling and leukocyte recruitment proteins were upregulated. The choroid plexus showed increases in peripheral immune cell proteins. Proteins that increased in abundance in the vasculature during GBS invasion were associated with major histocompatibility complex (MHC) class I antigen processing and endoplasmic reticulum dysfunction, a finding which correlated with altered host protein glycosylation profiles. Globally, there was low concordance between the infection proteome of whole brains and isolated vascular tissues. This report underscores the utility of unbiased, systems-scale analyses of functional tissue substructures for understanding disease. Group B (GBS) meningitis remains a major cause of poor health outcomes very early in life. Both the host-pathogen relationship leading to disease and the massive host response to infection contributing to these poor outcomes are orchestrated at the tissue and cell type levels. GBS meningitis is thought to result when bacteria present in the blood circumvent the selectively permeable vascular barriers that feed the brain. Additionally, tissue damage subsequent to bacterial invasion is mediated by inflammation and by immune cells from the periphery crossing the blood-brain barrier. Indeed, the vasculature plays a central role in disease processes occurring during GBS infection of the brain. Here, we employed quantitative proteomic analysis of brain vascular substructures during invasive GBS disease. We used the generated data to map molecular alterations associated with tissue perturbation, finding widespread intracellular dysfunction and punctuating the importance of investigations relegated to tissue type over the whole organ.
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http://dx.doi.org/10.1128/mSystems.00368-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449606PMC
August 2020

Functional and Proteomic Analysis of Virulence Upon Loss of Its Native Cas9 Nuclease.

Front Microbiol 2019 22;10:1967. Epub 2019 Aug 22.

Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, United States.

The public health impact of (group A , GAS) as a top 10 cause of infection-related mortality in humans contrasts with its benefit to biotechnology as the main natural source of Cas9 nuclease, the key component of the revolutionary CRISPR-Cas9 gene editing platform. Despite widespread knowledge acquired in the last decade on the molecular mechanisms by which GAS Cas9 achieves precise DNA targeting, the functions of Cas9 in the biology and pathogenesis of its native organism remain unknown. In this study, we generated an isogenic serotype M1 GAS mutant deficient in Cas9 protein and compared its behavior and phenotypes to the wild-type parent strain. Absence of Cas9 was linked to reduced GAS epithelial cell adherence, reduced growth in human whole blood , and attenuation of virulence in a murine necrotizing skin infection model. Virulence defects of the GAS Δ strain were explored through quantitative proteomic analysis, revealing a significant reduction in the abundance of key GAS virulence determinants. Similarly, deletion of affected the expression of several known virulence regulatory proteins, indicating that Cas9 impacts the global architecture of GAS gene regulation.
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http://dx.doi.org/10.3389/fmicb.2019.01967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714885PMC
August 2019

Postoperative Cataract Endophthalmitis Masquerading as Hemorrhagic Occlusive Retinal Vasculitis (HORV): A Case Report.

Ocul Immunol Inflamm 2021 May 15;29(4):758-761. Epub 2019 Aug 15.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, USA.

: To report a case of postoperative cataract bacterial endophthalmitis masquerading as hemorrhagic occlusive retinal vasculitis (HORV).: A 69-year-old female presents following uncomplicated cataract surgery of her right eye with new onset floaters, aching pain, decreased visual acuity, increased intraocular pressure, deep anterior chamber reaction, vitritis, and retinal vascular sheathing with diffuse blot hemorrhages. The majority of these clinical symptoms are commonly seen in bacterial endophthalmitis with exception to the retinal findings, which point to possible diagnosis of HORV, a recently described, largely untreatable phenomena associated with intracameral vancomycin use during surgery. After careful investigation and examination, our patient was successfully treated with pars plana vitrectomy and intravitreal antibiotics.: This case report describes the unusual case of a postoperative bacterial endophthalmitis presenting with characteristic signs of HORV, a largely untreatable, exceedingly rare phenomena that commonly results in poor visual acuity.
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http://dx.doi.org/10.1080/09273948.2019.1634216DOI Listing
May 2021

Gender Differences in Case Volume Among Ophthalmology Residents.

JAMA Ophthalmol 2019 Sep;137(9):1015-1020

Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University Medical Center, New York, New York.

Importance: Although almost equal numbers of male and female medical students enter into ophthalmology residency programs, whether they have similar surgical experiences during training is unclear.

Objective: To determine differences for cataract surgery and total procedural volume between male and female residents during ophthalmology residency.

Design, Setting, Participants: This retrospective, longitudinal analysis of resident case logs from 24 US ophthalmology residency programs spanned July 2005 to June 2017. A total of 1271 residents were included. Data were analyzed from August 12, 2017, through April 4, 2018.

Main Outcomes And Measures: Variables analyzed included mean volumes of cataract surgery and total procedures, resident gender, and maternity or paternity leave status.

Results: Among the 1271 residents included in the analysis (815 men [64.1%]), being female was associated with performing fewer cataract operations and total procedures. Male residents performed a mean (SD) of 176.7 (66.2) cataract operations, and female residents performed a mean (SD) of 161.7 (56.2) (mean difference, -15.0 [95% CI, -22.2 to -7.8]; P < .001); men performed a mean (SD) of 509.4 (208.6) total procedures and women performed a mean (SD) of 451.3 (158.8) (mean difference, -58.1 [95% CI, -80.2 to -36.0]; P < .001). Eighty-five of 815 male residents (10.4%) and 71 of 456 female residents (15.6%) took parental leave. Male residents who took paternity leave performed a mean of 27.5 (95% CI, 13.3 to 41.6; P < .001) more cataract operations compared with men who did not take leave, but female residents who took maternity leave performed similar numbers of operations as women who did not take leave (mean difference, -2.0 [95% CI, -18.0 to 14.0]; P = .81). From 2005 to 2017, each additional year was associated with a 5.5 (95% CI, 4.4 to 6.7; P < .001) increase in cataract volume and 24.4 (95% CI, 20.9 to 27.8; P < .001) increase in total procedural volume. This increase was not different between genders for cataract procedure volume (β = -1.6 [95% CI, -3.7 to 0.4]; P = .11) but was different for total procedural volume such that the increase in total procedural volume over time for men was greater than that for women (β = -8.0 [95% CI, -14.0 to -2.1]; P = .008).

Conclusions And Relevance: Female residents performed 7.8 to 22.2 fewer cataract operations and 36.0 to 80.2 fewer total procedures compared with their male counterparts from 2005 to 2017, a finding that warrants further exploration to ensure that residents have equivalent surgical training experiences during residency regardless of gender. However, this study included a limited number of programs (24 of 119 [20.2%]). Future research including all ophthalmology residency programs may minimize the selection bias issues present in this study.
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http://dx.doi.org/10.1001/jamaophthalmol.2019.2427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646997PMC
September 2019

IOL-Induced Extreme Blur to Alleviate Intractable Diplopia Secondary to Dragged-Fovea Diplopia Syndrome.

J Binocul Vis Ocul Motil 2019 Apr-Jun;69(2):69-72. Epub 2019 May 22.

a Department of Ophthalmology and Visual Neurosciences , University of Minnesota , Minneapolis , Minnesota.

A 73-year-old male presented with one year of intractable binocular diplopia and metamorphopsia in the right eye. He was unable to maintain fusion with prismatic correction, refused cosmetically noticeable forms of occlusion, and was not an occlusive contact lens candidate due to chronic neuropathy affecting his hands. The patient underwent cataract surgery with placement of a high plus intraocular lens to induce extreme blur. The uncomplicated procedure was successful in eliminating his diplopia. Cataract extraction with a high minus refractive target is an option for treating intractable diplopia associated with dragged-fovea diplopia syndrome.
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http://dx.doi.org/10.1080/2576117X.2019.1607426DOI Listing
December 2019

Augmentation of Urinary Lactoferrin Enhances Host Innate Immune Clearance of Uropathogenic Escherichia coli.

J Innate Immun 2019 3;11(6):481-495. Epub 2019 May 3.

Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, UC San Diego, La Jolla, California, USA,

Urinary tract infection (UTI) is a prominent global health care burden. Although UTI is readily treated with antibiotics in healthy adults, complicated cases in immune-compromised individuals and the emerging antibiotic resistance of several uropathogens have accelerated the need for new treatment strategies. Here, we surveyed the composition of urinary exosomes in a mouse model of uropathgenic Escherichia coli (UPEC) UTI to identify specific urinary tract defense constituents for therapeutic development. We found an enrichment of the iron-binding glycoprotein lactoferrin in the urinary exosomes of infected mice. In subsequent in vitro studies, we identified human bladder epithelial cells as a source of lactoferrin during UPEC infection. We further established that exogenous treatment with human lactoferrin (hLf) reduces UPEC epithelial adherence and enhances neutrophil antimicrobial functions including bacterial killing and extracellular trap production. Notably, a single intravesicular dose of hLf drastically reduced bladder bacterial burden and neutrophil infiltration in our murine UTI model. We propose that lactoferrin is an important modulator of innate immune responses in the urinary tract and has potential application in novel therapeutic design for UTI.
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http://dx.doi.org/10.1159/000499342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6758950PMC
July 2020

Tamm-Horsfall Protein Protects the Urinary Tract against .

Infect Immun 2018 12 20;86(12). Epub 2018 Nov 20.

Department of Pediatrics, University of California, San Diego, La Jolla, California, USA

Urinary tract infections (UTIs) caused by the human fungal pathogen and related species are prevalent in hospitalized patients, especially those on antibiotic therapy, with indwelling catheters, or with predisposing conditions such as diabetes or immunodeficiency. Understanding of key host defenses against UTI is critical for developing effective treatment strategies. Tamm-Horsfall glycoprotein (THP) is the most abundant urine protein, with multiple roles in renal physiology and bladder protection. THP protects against bacterial UTI by blocking bacterial adherence to the bladder epithelium, but its role in defense against fungal pathogens is not yet described. Here we demonstrate that THP restricts colonization of the urinary tract by THP binds to hyphae, but not the yeast form, in a manner dependent on fungal expression of the Als3 adhesion glycoprotein. THP directly blocks adherence to bladder epithelial cells , and THP-deficient mice display increased fungal burden in a UTI model. This work outlines a previously unknown role for THP as an essential component for host immune defense against fungal urinary tract infection.
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http://dx.doi.org/10.1128/IAI.00451-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246913PMC
December 2018

Synergy between Ursolic and Oleanolic Acids from Vitellaria paradoxa Leaf Extract and β-Lactams against Methicillin-Resistant Staphylococcus aureus: In Vitro and In Vivo Activity and Underlying Mechanisms.

Molecules 2017 Dec 16;22(12). Epub 2017 Dec 16.

Pharmacognosy Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Brussels, Belgium.

Combining antibiotics with resistance reversing agents is a key strategy to overcome bacterial resistance. Upon screening antimicrobial activities of plants used in traditional medicine, we found that a leaf dichloromethane extract from the shea butter tree () had antimicrobial activity against methicillin-resistant (MRSA) with further evidence of synergy when combined with β-lactams. Using HPLC-MS, we identified ursolic (UA) and oleanolic acids (OA) in leaves and twigs of this species, and quantified them by HPLC-UV as the major constituents in leaf extracts (21% and 6% respectively). Both pure triterpenic acids showed antimicrobial activity against reference and clinical strains of MRSA, with MICs ranging from 8-16 mg/L for UA to 32-128 mg/L for OA. They were highly synergistic with β-lactams (ampicillin and oxacillin) at subMIC concentrations. Reversion of MRSA phenotype was attributed to their capacity to delocalize PBP2 from the septal division site, as observed by fluorescence microscopy, and to disturb thereby peptidoglycan synthesis. Moreover, both compounds also inhibited β-lactamases activity of living bacteria (as assessed by inhibition of nitrocefin hydrolysis), but not in bacterial lysates, suggesting an indirect mechanism for this inhibition. In a murine model of subcutaneous MRSA infection, local administration of UA was synergistic with nafcillin to reduce lesion size and inflammatory cytokine (IL-1β) production. Thus, these data highlight the potential interest of triterpenic acids as resistance reversing agents in combination with β-lactams against MRSA.
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http://dx.doi.org/10.3390/molecules22122245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149719PMC
December 2017

Marine Natural Product Honaucin A Attenuates Inflammation by Activating the Nrf2-ARE Pathway.

J Nat Prod 2018 03 7;81(3):506-514. Epub 2017 Dec 7.

College of Pharmacy , Yeungnam University , Gyeongsan 38541 , Republic of Korea.

The cyanobacterial marine natural product honaucin A inhibits mammalian innate inflammation in vitro and in vivo. To decipher its mechanism of action, RNA sequencing was used to evaluate differences in gene expression of cultured macrophages following honaucin A treatment. This analysis led to the hypothesis that honaucin A exerts its anti-inflammatory activity through activation of the cytoprotective nuclear erythroid 2-related factor 2 (Nrf2)-antioxidant response element/electrophile response element (ARE/EpRE) signaling pathway. Activation of this pathway by honaucin A in cultured human MCF7 cells was confirmed using an Nrf2 luciferase reporter assay. In vitro alkylation experiments with the natural product and N-acetyl-l-cysteine suggest that honaucin A activates this pathway through covalent interaction with the sulfhydryl residues of the cytosolic repressor protein Keap1. Honaucin A presents a potential therapeutic lead for diseases with an inflammatory component modulated by Nrf2-ARE.
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http://dx.doi.org/10.1021/acs.jnatprod.7b00734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553616PMC
March 2018

Macrophage-like nanoparticles concurrently absorbing endotoxins and proinflammatory cytokines for sepsis management.

Proc Natl Acad Sci U S A 2017 10 9;114(43):11488-11493. Epub 2017 Oct 9.

Department of Nanoengineering, University of California, San Diego, La Jolla, CA 92093;

Sepsis, resulting from uncontrolled inflammatory responses to bacterial infections, continues to cause high morbidity and mortality worldwide. Currently, effective sepsis treatments are lacking in the clinic, and care remains primarily supportive. Here we report the development of macrophage biomimetic nanoparticles for the management of sepsis. The nanoparticles, made by wrapping polymeric cores with cell membrane derived from macrophages, possess an antigenic exterior the same as the source cells. By acting as macrophage decoys, these nanoparticles bind and neutralize endotoxins that would otherwise trigger immune activation. In addition, these macrophage-like nanoparticles sequester proinflammatory cytokines and inhibit their ability to potentiate the sepsis cascade. In a mouse bacteremia model, treatment with macrophage mimicking nanoparticles, termed MΦ-NPs, reduced proinflammatory cytokine levels, inhibited bacterial dissemination, and ultimately conferred a significant survival advantage to infected mice. Employing MΦ-NPs as a biomimetic detoxification strategy shows promise for improving patient outcomes, potentially shifting the current paradigm of sepsis management.
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http://dx.doi.org/10.1073/pnas.1714267114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664555PMC
October 2017

The Mla pathway is critical for Pseudomonas aeruginosa resistance to outer membrane permeabilization and host innate immune clearance.

J Mol Med (Berl) 2017 10 26;95(10):1127-1136. Epub 2017 Aug 26.

Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.

Pseudomonas aeruginosa is an important opportunistic pathogen that has become a serious problem due to increased rates of antibiotic resistance. Due to this along with a dearth in novel antibiotic development, especially against Gram-negative pathogens, new therapeutic strategies are needed to prevent a post-antibiotic era. Here, we describe the importance of the vacJ/Mla pathway in resisting bactericidal actions of the host innate immune response. P. aeruginosa tn5 transposon mutants in genes from the VacJ/Mla pathway showed increased susceptibility to killing by the host cathelicidin antimicrobial peptide, LL-37, when compared to the wild-type parent strain. The P. aeruginosa vacJ mutant demonstrated increased membrane permeability upon damage as well as sensitivity to killing in the presence of the detergent sodium dodecyl sulfate and the divalent cation chelator EDTA. When exposed to human whole blood and serum complement, the vacJ mutant was killed more rapidly when compared to the wild-type parent strain and complemented mutant. Finally, in an in vivo mouse lung infection model, infection with the vacJ mutant resulted in reduced mortality, lower bacterial burden, and reduced lung damage when compared to the wild-type strain. This study highlights the potential in therapeutically targeting the VacJ/Mla pathway in sensitizing P. aeruginosa to killing by the host innate immune response.

Key Messages: • The Mla pathway regulates outer membrane dynamics in human pathogen Pseudomonas aeruginosa (PA). • Disruption of Mla pathway gene vacJ sensitizes PA to host cathelicidin antimicrobial peptide LL-37. • Loss of vacJ expression renders PA more sensitive to human whole blood and serum killing. • Loss of vacJ expression reduces PA survival and virulence in a murine lung infection model. • The Mla pathway merits exploration as a pharmacologic target to sensitize PA to host innate immunity.
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http://dx.doi.org/10.1007/s00109-017-1579-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5671890PMC
October 2017

Tamm-Horsfall glycoprotein engages human Siglec-9 to modulate neutrophil activation in the urinary tract.

Immunol Cell Biol 2017 11 22;95(10):960-965. Epub 2017 Aug 22.

Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics, UC San Diego, La Jolla, CA, USA.

Urinary tract infections are a major problem in human medicine for which better understanding of native immune defenses may reveal new pathways for therapeutic intervention. Tamm-Horsfall glycoprotein (THP), the most abundant urinary protein, interacts with bacteria including uropathogenic Escherichia coli (UPEC) as well host immune cells. In addition to its well-studied functions to antagonize bacterial colonization, we hypothesize that THP serves a critical host defense function through innate immune modulation. Using isolated human neutrophils, we found that THP binds neutrophils and that this interaction reduces reactive oxygen species generation, chemotaxis and killing of UPEC. We discovered that THP engages the inhibitory neutrophil receptor sialic acid-binding Ig-like lectin-9 (Siglec-9), and mouse functional ortholog Siglec-E, in a manner dependent on sialic acid on its N-glycan moieties. THP-null mice have significantly more neutrophils present in the urine compared with wild-type mice, both with and without the presence of inflammatory stimuli. These data support THP as an important negative regulator of neutrophil activation in the urinary tract, with dual functions to counteract bacterial colonization and suppress excessive inflammation within the urinary tract.
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http://dx.doi.org/10.1038/icb.2017.63DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698129PMC
November 2017

A Red Blood Cell Membrane-Camouflaged Nanoparticle Counteracts Streptolysin -Mediated Virulence Phenotypes of Invasive Group A .

Front Pharmacol 2017 18;8:477. Epub 2017 Jul 18.

Biomedical Sciences Graduate Program, University of California, San Diego, La JollaCA, United States.

Group A (GAS), an important human-specific Gram-positive bacterial pathogen, is associated with a broad spectrum of disease, ranging from mild superficial infections such as pharyngitis and impetigo, to serious invasive infections including necrotizing fasciitis and streptococcal toxic shock syndrome. The GAS pore-forming streptolysin O (SLO) is a well characterized virulence factor produced by nearly all GAS clinical isolates. High level expression of SLO is epidemiologically linked to intercontinental dissemination of hypervirulent clonotypes and poor clinical outcomes. SLO can trigger macrophage and neutrophil cell death and/or the inactivation of immune cell functions, and promotes tissue injury and bacterial survival in animal models of infection. In the present work, we describe how the pharmacological presentation of red blood cell (RBC) derived biomimetic nanoparticles ("nanosponges") can sequester SLO and block the ability of GAS to damage host cells, thereby preserving innate immune function and increasing bacterial clearance and . Nanosponge administration protected human neutrophils, macrophages, and keratinocytes against SLO-mediated cytotoxicity. This therapeutic intervention prevented SLO-induced macrophage apoptosis and increased neutrophil extracellular trap formation, allowing increased GAS killing by the respective phagocytic cell types. In a murine model of GAS necrotizing skin infection, local administration of the biomimetic nanosponges was associated with decreased lesion size and reduced bacterial colony-forming unit recovery. Utilization of a toxin decoy and capture platform that inactivates the secreted SLO before it contacts the host cell membrane, presents a novel virulence factor targeted strategy that could be a powerful adjunctive therapy in severe GAS infections where morbidity and mortality are high despite antibiotic treatment.
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http://dx.doi.org/10.3389/fphar.2017.00477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513932PMC
July 2017

Paired Siglec receptors generate opposite inflammatory responses to a human-specific pathogen.

EMBO J 2017 03 18;36(6):751-760. Epub 2017 Jan 18.

Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA

Paired immune receptors display near-identical extracellular ligand-binding regions but have intracellular sequences with opposing signaling functions. While inhibitory receptors dampen cellular activation by recognizing self-associated molecules, the functions of activating counterparts are less clear. Here, we studied the inhibitory receptor Siglec-11 that shows uniquely human expression in brain microglia and engages endogenous polysialic acid to suppress inflammation. We demonstrated that the human-specific pathogen K1 uses its polysialic acid capsule as a molecular mimic to engage Siglec-11 and escape killing. In contrast, engagement of the activating counterpart Siglec-16 increases elimination of bacteria. Since mice do not have paired Siglec receptors, we generated a model by replacing the inhibitory domain of mouse Siglec-E with the activating module of Siglec-16. Siglec-E16 enhanced proinflammatory cytokine expression and bacterial killing in macrophages and boosted protection against intravenous bacterial challenge. These data elucidate uniquely human interactions of a pathogen with Siglecs and support the long-standing hypothesis that activating counterparts of paired immune receptors evolved as a response to pathogen molecular mimicry of host ligands for inhibitory receptors.
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http://dx.doi.org/10.15252/embj.201695581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350563PMC
March 2017

Collective Resistance in Microbial Communities by Intracellular Antibiotic Deactivation.

PLoS Biol 2016 Dec 27;14(12):e2000631. Epub 2016 Dec 27.

Molecular Genetics Group, Groningen Biomolecular Sciences and Biotechnology Institute, Centre for Synthetic Biology, University of Groningen, Groningen, The Netherlands.

The structure and composition of bacterial communities can compromise antibiotic efficacy. For example, the secretion of β-lactamase by individual bacteria provides passive resistance for all residents within a polymicrobial environment. Here, we uncover that collective resistance can also develop via intracellular antibiotic deactivation. Real-time luminescence measurements and single-cell analysis demonstrate that the opportunistic human pathogen Streptococcus pneumoniae grows in medium supplemented with chloramphenicol (Cm) when resistant bacteria expressing Cm acetyltransferase (CAT) are present. We show that CAT processes Cm intracellularly but not extracellularly. In a mouse pneumonia model, more susceptible pneumococci survive Cm treatment when coinfected with a CAT-expressing strain. Mathematical modeling predicts that stable coexistence is only possible when antibiotic resistance comes at a fitness cost. Strikingly, CAT-expressing pneumococci in mouse lungs were outcompeted by susceptible cells even during Cm treatment. Our results highlight the importance of the microbial context during infectious disease as a potential complicating factor to antibiotic therapy.
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http://dx.doi.org/10.1371/journal.pbio.2000631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5189934PMC
December 2016

Classical β-Lactamase Inhibitors Potentiate the Activity of Daptomycin against Methicillin-Resistant Staphylococcus aureus and Colistin against Acinetobacter baumannii.

Antimicrob Agents Chemother 2017 02 24;61(2). Epub 2017 Jan 24.

University of California-San Diego School of Medicine, La Jolla, California, USA.

We asked whether beta-lactamase inhibitors (BLIs) increased the activity of daptomycin (DAP) against methicillin-resistant Staphylococcus aureus (MRSA), the peptide antibiotic colistin (COL) against the emerging Gram-negative nosocomial pathogen Acinetobacter baumannii, and the human host defense peptide cathelicidin LL37 against either pathogen. DAP and LL37 kill curves were performed with or without BLIs against MRSA, vancomycin-intermediate S. aureus (VISA), and heterogeneous VISA (hVISA). COL and LL37 kill curves were performed against A. baumannii Boron-dipyrromethene (BODIPY)-labeled DAP binding to MRSA grown with the BLI tazobactam (TAZ) was assessed microscopically. The combination of COL plus TAZ was studied in a murine model of A. baumannii pneumonia. TAZ alone lacked in vitro activity against MRSA or A. baumannii The addition of TAZ to DAP resulted in a 2- to 5-log reduction in recoverable MRSA CFU at 24 h compared to the recoverable CFU with DAP alone. TAZ plus COL showed synergy by kill curves for 4 of 5 strains of A. baumannii tested. Growth with 20 mg/liter TAZ resulted in 2- to 2.5-fold increases in the intensity of BODIPY-DAP binding to MRSA and hVISA strains. TAZ significantly increased the killing of MRSA and A. baumannii by LL37 in vitro TAZ increased the activity of COL in a murine model of A. baumannii pneumonia. Classical BLIs demonstrate synergy with peptide antibiotics. Since BLIs have scant antimicrobial activity on their own and are thus not expected to increase selective pressure toward antibiotic resistance, their use in combination with peptide antibiotics warrants further study.
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http://dx.doi.org/10.1128/AAC.01745-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278754PMC
February 2017

When the grass isn't greener: a case series of young children with accidental marijuana ingestion.

CJEM 2016 Nov;18(6):480-483

‡Department of Pediatrics,BC Children's Hospital,Vancouver,BC.

Marijuana is the most commonly used illicit drug in Canada, with 10% of the general population admitting to its use in the past year. This high prevalence increases risk of accidental ingestion in young children. We report four pediatric cases of accidental marijuana ingestion who presented to our local emergency department with altered mental status. Three patients had extensive testing, including one patient who underwent lumbar puncture and empirical treatment for meningitis. To our knowledge, this is the first Canadian case series since McNabb et al., published over 2 decades ago. The case series aims to highlight the importance of considering acute marijuana intoxication in the differential diagnosis when assessing young children with altered level of consciousness.
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http://dx.doi.org/10.1017/cem.2015.44DOI Listing
November 2016

Cefazolin and Ertapenem, a Synergistic Combination Used To Clear Persistent Staphylococcus aureus Bacteremia.

Antimicrob Agents Chemother 2016 11 21;60(11):6609-6618. Epub 2016 Oct 21.

University of California San Diego School of Medicine, La Jolla, California, USA.

Ertapenem and cefazolin were used in combination to successfully clear refractory methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. In addition, recent work has demonstrated activity of combination therapy with beta-lactams from different classes against methicillin-resistant S. aureus (MRSA). The ertapenem-plus-cefazolin combination was evaluated for synergy in vitro and in vivo in a murine skin infection model using an index MSSA bloodstream isolate from a patient in whom persistent bacteremia was cleared with this combination and against a cadre of well-described research strains and clinical strains of MSSA and MRSA. Against the index MSSA bloodstream isolate, ertapenem and cefazolin showed synergy using both checkerboard (fractional inhibitory concentration [FIC] index = 0.375) and time-kill assays. Using a disk diffusion ertapenem potentiation assay, the MSSA isolate showed a cefazolin disk zone increased from 34 to 40 mm. In vitro pharmacokinetic/pharmacodynamic modeling at clinically relevant drug concentrations demonstrated bactericidal activity (>3 log-CFU/ml reduction) of the combination but bacteriostatic activity of ether drug alone at 48 h. A disk diffusion potentiation assay showed that ertapenem increased the cefazolin zone of inhibition by >3 mm for 34/35 (97%) MSSA and 10/15 (67%) MRSA strains. A murine skin infection model of MSSA showed enhanced activity of cefazolin plus ertapenem compared to monotherapy with these agents. After successful use in clearance of MSSA bacteremia, the combination of ertapenem and cefazolin showed synergy against MSSA in vitro and in vivo This combination may warrant consideration for future clinical study in MSSA bacteremia.
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http://dx.doi.org/10.1128/AAC.01192-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075066PMC
November 2016
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