Publications by authors named "Thomas Moran"

121 Publications

Percutaneous Medial Collateral Ligament Release Improves Medial Compartment Access During Knee Arthroscopy.

Arthrosc Sports Med Rehabil 2021 Feb 27;3(1):e105-e114. Epub 2020 Dec 27.

Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia, U.S.A.

Purpose: To quantify intraoperative joint space widening afforded by the outside-in, percutaneous release of the medial collateral ligament (MCL) and to evaluate its impact on medial compartment width and functional outcomes at 6-week follow-up for patients undergoing a partial medial meniscectomy without postoperative bracing.

Methods: Patients with posteromedial meniscus tears and no evidence of ipsilateral knee pathology, undergoing partial medial meniscectomy, were enrolled. Intraoperatively, medial compartment width was quantified with fluoroscopy before and after the percutaneous MCL release with an 18-gauge spinal needle proximal to the joint line. At 6-week follow-up, valgus stress radiographs re-evaluated medial compartment width. International Knee Documentation Committee (IKDC) and Patient-Reported Outcomes Measurement Information System (PROMIS) scores were completed preoperatively and at 6-week follow-up to evaluate functional outcomes. A paired sample test performed at a 95% confidence interval (CI) was used to compare these variables.

Results: Forty-two patients, mean (± standard deviation) age 55.3 ± 10.7 years, were available for analysis of intraoperative medial compartment widening. Medial compartment width increased from 5.95 ± 1.32 to 11.09 ± 1.74 mm intraoperatively after MCL release. At 6-week follow-up, radiographic assessment demonstrated a mean medial compartment width of 5.85 ± .99 mm, which represented an insignificant change compared with the preoperative value (CI -0.68 to .33,  = .474). PROMIS and IKDC scores significantly improved from baseline, with increases of 6.9 ± 12.4 (CI 2.0 to 11.8,  = .008) and 11.7 ± 17.8 (CI 4.7 to 18.8,  = .002), respectively.

Conclusions: Percutaneous MCL release during knee arthroscopy improves visualization and facilitates instrumentation by providing an almost 2× wider working space within the medial tibiofemoral joint. In this study, the performance of percutaneous MCL release did not result in any complications. Radiographic and clinical resolution of iatrogenic laxity was demonstrated by 6-weeks postoperatively, without the use of postoperative bracing.

Level Of Evidence: IV, therapeutic case series.
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http://dx.doi.org/10.1016/j.asmr.2020.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879174PMC
February 2021

Quantifying Absolute Neutralization Titers against SARS-CoV-2 by a Standardized Virus Neutralization Assay Allows for Cross-Cohort Comparisons of COVID-19 Sera.

mBio 2021 02 16;12(1). Epub 2021 Feb 16.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA

The global coronavirus disease 2019 (COVID-19) pandemic has mobilized efforts to develop vaccines and antibody-based therapeutics, including convalescent-phase plasma therapy, that inhibit viral entry by inducing or transferring neutralizing antibodies (nAbs) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (CoV2-S). However, rigorous efficacy testing requires extensive screening with live virus under onerous biosafety level 3 (BSL3) conditions, which limits high-throughput screening of patient and vaccine sera. Myriad BSL2-compatible surrogate virus neutralization assays (VNAs) have been developed to overcome this barrier. Yet, there is marked variability between VNAs and how their results are presented, making intergroup comparisons difficult. To address these limitations, we developed a standardized VNA using CoV2-S pseudotyped particles (CoV2pp) based on vesicular stomatitis virus bearing the luciferase gene in place of its G glycoprotein (VSVΔG); this assay can be robustly produced at scale and generate accurate neutralizing titers within 18 h postinfection. Our standardized CoV2pp VNA showed a strong positive correlation with CoV2-S enzyme-linked immunosorbent assay (ELISA) results and live-virus neutralizations in confirmed convalescent-patient sera. Three independent groups subsequently validated our standardized CoV2pp VNA ( > 120). Our data (i) show that absolute 50% inhibitory concentration (absIC), absIC, and absIC values can be legitimately compared across diverse cohorts, (ii) highlight the substantial but consistent variability in neutralization potency across these cohorts, and (iii) support the use of the absIC as a more meaningful metric for assessing the neutralization potency of a vaccine or convalescent-phase sera. Lastly, we used our CoV2pp in a screen to identify ultrapermissive 293T clones that stably express ACE2 or ACE2 plus TMPRSS2. When these are used in combination with our CoV2pp, we can produce CoV2pp sufficient for 150,000 standardized VNAs/week. Vaccines and antibody-based therapeutics like convalescent-phase plasma therapy are premised upon inducing or transferring neutralizing antibodies that inhibit SARS-CoV-2 entry into cells. Virus neutralization assays (VNAs) for measuring neutralizing antibody titers (NATs) are an essential part of determining vaccine or therapeutic efficacy. However, such efficacy testing is limited by the inherent dangers of working with the live virus, which requires specialized high-level biocontainment facilities. We therefore developed a standardized replication-defective pseudotyped particle system that mimics the entry of live SARS-CoV-2. This tool allows for the safe and efficient measurement of NATs, determination of other forms of entry inhibition, and thorough investigation of virus entry mechanisms. Four independent labs across the globe validated our standardized VNA using diverse cohorts. We argue that a standardized and scalable assay is necessary for meaningful comparisons of the myriad of vaccines and antibody-based therapeutics becoming available. Our data provide generalizable metrics for assessing their efficacy.
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http://dx.doi.org/10.1128/mBio.02492-20DOI Listing
February 2021

At-home exercises for 4 common musculoskeletal complaints.

J Fam Pract 2020 12;69(10):484-492

ATC National Athletic Trainers' Association.

This pictorial review can help you advise patients on how to reduce pain and increase ROM, strength, and balance following acute injury or in chronic impairment.
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December 2020

Development of a High-Throughput Homogeneous AlphaLISA Drug Screening Assay for the Detection of SARS-CoV-2 Nucleocapsid.

ACS Pharmacol Transl Sci 2020 Dec 9;3(6):1233-1241. Epub 2020 Oct 9.

National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is in urgent need of therapeutic options. High-throughput screening (HTS) offers an opportunity to rapidly identify such compounds. In this work, we have developed a homogeneous cell-based HTS system using AlphaLISA detection technology for the SARS-CoV-2 nucleocapsid protein (NP). Our assay measures both recombinant and endogenous NP from viral lysates and tissue culture supernatants (TCS) in a sandwich-based format using two monoclonal antibodies against the NP analyte. Viral NP was detected and quantified in both tissue culture supernatants and cell lysates, with large differences observed between 24 and 48 h of infection. We simulated viral infection by spiking recombinant NP into 384-well plates with live Vero-E6 cells and were able to detect the NP with high sensitivity and a large dynamic range. Antiviral agents that inhibit either viral cell entry or replication decrease the AlphaLISA NP signal. Thus, this assay can be used for high-throughput screening of small molecules and biologics in the fight against the COVID-19 pandemic.
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http://dx.doi.org/10.1021/acsptsci.0c00122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553038PMC
December 2020

Synthetic Peptide Libraries Designed From a Minimal Alpha-Helical Domain of AS-48-Bacteriocin Homologs Exhibit Potent Antibacterial Activity.

Front Microbiol 2020 12;11:589666. Epub 2020 Nov 12.

Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, United States.

The circularized bacteriocin enterocin AS-48 produced by sp. exhibits antibacterial activity through membrane disruption. The membrane-penetrating activity of enterocin AS-48 has been attributed to a specific alpha-helical region on the circular peptide. Truncated, linearized forms containing these domains have been shown to preserve limited bactericidal activity. We utilized the amino acid sequence of the active helical domain of enterocin AS-48 to perform a homology-based search of similar sequences in other bacterial genomes. We identified similar domains in three previously uncharacterized AS-48-like bacteriocin genes in , , and . Enterocin AS-48 and homologs from these bacterial species were used as scaffolds for the design of a minimal peptide library based on the active helical domain of each bacteriocin sequence. 95 synthetic peptide variants of each scaffold peptide, designated , , , and , were designed and synthesized from each scaffold sequence based on defined biophysical parameters. A total of 384 total peptides were assessed for antibacterial activity against Gram-negative and Gram-positive bacteria. Minimal Inhibitory Concentrations (MICs) as low as 15.6 nM could be observed for the most potent peptide candidate tested, with no significant cytotoxicity to eukaryotic cells. Our work demonstrates for the first time a general workflow of using minimal domains of natural bacteriocin sequences as scaffolds to design and rapidly synthesize a library of bacteriocin-based antimicrobial peptide variants for evaluation.
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http://dx.doi.org/10.3389/fmicb.2020.589666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689250PMC
November 2020

Predicting Treatment Success with Facet Syndrome: An Algorithm to Predict Lumbar Radiofrequency Ablation Responders in a Military Population.

Pain Med 2021 Feb;22(2):266-272

Department of Anesthesiology and Pain Medicine, Naval Medical Center Portsmouth, Portsmouth, Virginia, USA.

Objective: Radiofrequency ablation (RFA) of the medial branch nerve is a commonly performed procedure for patients with facet syndrome. RFA has previously been demonstrated to provide long-term functional improvement in approximately 50% of patients, including those who had significant pain relief after diagnostic medial branch block. We sought to identify factors associated with success of RFA for facet pain.

Design: Active-duty military patients who underwent lumbar RFA (L3, L4, and L5 levels) over a 3-year period were analyzed. Defense and Veterans Pain Rating Scale (DVPRS) and Oswestry Disability Index (ODI) scores were assessed the day of procedure and at the 2-month and 6-month follow-up. These data were analyzed to identify associations between patient demographics, pain, and functional status and patients' improvement after RFA, with a primary outcome of ODI improvement and a secondary outcome of pain reduction.

Results: Higher levels of starting functional impairment (starting ODI scores of 42.9 vs. 37.5; P = 0.0304) were associated with a greater likelihood of improvement in functional status 6 months after RFA, and higher starting pain scores (DVPRS pain scores of 6.1 vs. 5.1; P < 0.0001) were associated with a higher likelihood that pain scores would improve 6 months after RFA. A multivariate logistic regression was then used to develop a scoring system to predict improvement after RFA. The scoring system generated a C-statistic of 0.764, with starting ODI, pain scores, and both gender and smoking history as independent variables.

Conclusions: This algorithm compares favorably to that of diagnostic medial branch block in terms of prediction accuracy (C-statistic of 0.764 vs. 0.57), suggesting that its use may improve patient selection in patients who undergo RFA for facet syndrome.
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http://dx.doi.org/10.1093/pm/pnaa381DOI Listing
February 2021

Effective interventions to improve the quality of critically high point-of-care glucose meter results.

Pract Lab Med 2020 Nov 19;22:e00184. Epub 2020 Oct 19.

Eastern Ontario Regional Laboratories Association, Canada.

Objectives: Point-of-care testing (POCT) is testing performed outside the traditional laboratory, often at the patient bedside. In hospital settings, blood glucose is the most common POCT. Staff performing POCT are not usually laboratory trained; they are clinical staff with a primary focus on treating patients. Clinical staff find POCT quality assurance (QA) practices burdensome and are often non-compliant. In hospitals within EORLA (Eastern Ontario Regional Laboratories Association), all critically high POCT glucose results must be repeated prior to acting, according to policy. Compliance with this policy is audited regularly.

Design: and methods: All POCT glucose tests performed in participating sites between January and June 2018 and June and December 2019 were audited for compliance with the critical repeat policy. The discordant repeat rate was also determined for each audit period. Between January and May 2019, there were interventions aimed at improving compliance with the repeat policy.

Results: Compliance with the critical repeat policy increased from 30 to 57% in 2019 compared to 2018, following nursing education and implementation of notifications on the glucose meters themselves. The rate of discordant repeat results (>20% different from initial) also improved at most sites in 2019 compared to 2018. Nurses cited insufficient cleaning of patient hands prior to initial testing as the primary reason for discordant repeats.

Conclusions: Operator compliance with POCT QA policies is an ongoing challenge requiring continual audit, feedback and education. A strong POCT multi-disciplinary committee with supports from senior and clinical leadership in an organization are key to improving compliance.
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http://dx.doi.org/10.1016/j.plabm.2020.e00184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596339PMC
November 2020

Small (3.2-mm), Short, Oblique Patellar Tunnels for Patellar Fixation in MPFL Reconstruction.

Arthrosc Tech 2020 Oct 2;9(10):e1613-e1617. Epub 2020 Oct 2.

Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia, U.S.A.

Multiple techniques exist for patellar graft fixation during medial patellofemoral ligament (MPFL) reconstruction, each with their respective advantages and disadvantages. In recent studies, the use of 2 small (3.2-mm), short, oblique patellar tunnels with looped graft has been shown to be effective for patellar fixation during MPFL reconstruction. This technique does not appear to be associated with the same risk of patellar fracture as the use of larger (4.5-mm) transpatellar tunnels. A recent retrospective study also reported decreased risk of recurrent patellar instability and decreased cost compared with the use of suture anchors for patellar fixation, which is currently the most common modality. Given these promising findings relative to existing techniques for patellar fixation, further description of the senior author's technique for using these small (3.2-mm), short, oblique patellar tunnels is provided. This technique is safe, efficacious, and cost-conscious and should be considered a viable option for patellar fixation during MPFL reconstruction.
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http://dx.doi.org/10.1016/j.eats.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587330PMC
October 2020

Rapid in vitro assays for screening neutralizing antibodies and antivirals against SARS-CoV-2.

J Virol Methods 2021 01 14;287:113995. Epub 2020 Oct 14.

Texas Biomedical Research Institute, San Antonio, TX, USA. Electronic address:

Towards the end of 2019, a novel coronavirus (CoV) named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), genetically similar to severe acute respiratory syndrome coronavirus (SARS-CoV), emerged in Wuhan, Hubei province of China, and has been responsible for coronavirus disease 2019 (COVID-19) in humans. Since its first report, SARS-CoV-2 has resulted in a global pandemic, with over 10 million human infections and over 560,000 deaths reported worldwide at the end of June 2020. Currently, there are no United States (US) Food and Drug Administration (FDA)-approved vaccines and/or antivirals licensed against SARS-CoV-2. The high economical and health impacts of SARS-CoV-2 has placed global pressure on the scientific community to identify effective prophylactic and therapeutic treatments for SARS-CoV-2 infection and associated COVID-19 disease. While some compounds have been already reported to reduce SARS-CoV-2 infection and a handful of monoclonal antibodies (mAbs) have been described that neutralize SARS-CoV-2, there is an urgent need for the development and standardization of assays which can be used in high through-put screening (HTS) settings to identify new antivirals and/or neutralizing mAbs against SARS-CoV-2. Here, we described a rapid, accurate, and highly reproducible plaque reduction microneutralization (PRMNT) assay that can be quickly adapted for the identification and characterization of both neutralizing mAbs and antivirals against SARS-CoV-2. Importantly, our MNA is compatible with HTS settings to interrogate large and/or complex libraries of mAbs and/or antivirals to identify those with neutralizing and/or antiviral activity, respectively, against SARS-CoV-2.
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http://dx.doi.org/10.1016/j.jviromet.2020.113995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554492PMC
January 2021

Small, Short, Oblique Patellar Tunnels for Patellar Fixation Do Not Increase Fracture Risk or Complications in MPFL Reconstruction: A Retrospective Cohort Study.

Orthop J Sports Med 2020 Oct 1;8(10):2325967120954430. Epub 2020 Oct 1.

Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia, USA.

Background: Large (4.5 mm) and/or transpatellar bone tunnels have been associated with patellar fracture after medial patellofemoral ligament (MPFL) reconstruction. To avoid this outcome, many surgeons now employ suture anchors to affix the MPFL graft to the patella.

Purpose: To evaluate the risk of patellar fracture and other outcomes associated with smaller (3.2-mm), short, oblique patellar tunnels as compared with suture anchor fixation in MPFL reconstruction.

Study Design: Cohort study; Level of evidence, 3.

Methods: A single institution's electronic medical record was queried for all patients undergoing MPFL reconstruction between March 2010 and December 2018. A chart review of operative reports was utilized to identify those who had undergone MPFL reconstruction. Patients undergoing revision MPFL reconstruction or reconstruction with fully transpatellar bone tunnels were excluded. The incidence of patellar fracture and outcomes were evaluated from chart review. The mean duration of follow-up was >2 years.

Results: A total of 384 knees in 352 patients undergoing primary MPFL reconstruction were identified. Small (3.2-mm), short, oblique tunnels were used for patellar fixation in 215 cases, and suture anchors were utilized in 169 cases. The small, oblique tunnels and suture anchor techniques both resulted in a low incidence of patellar fracture, with rates of 0.47% and 0%, respectively. The use of suture anchors was associated with an increased risk of subluxation or dislocation compared with small, oblique tunnels (odds ratio, 3.98; = .028). No significant difference was found in the need for revision MPFL reconstruction surgery with suture anchors (odds ratio, 1.925; = .66).

Conclusion: The use of small, oblique tunnels with hamstring autograft is a safe means of patellar fixation in MPFL reconstruction. The use of small, oblique tunnels for patellar fixation versus 2 suture anchors can result in material cost savings with no significantly increased risk for fracture as well as an overall reduction in complication rates.
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http://dx.doi.org/10.1177/2325967120954430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536490PMC
October 2020

A Retrospective Analysis of Outcomes From Foot and Ankle Arthrodesis and Open Reduction and Internal Fixation Using Cellular Bone Allograft Augmentation.

Foot Ankle Spec 2020 Aug 31:1938640020952301. Epub 2020 Aug 31.

Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia (TEM, MTC, JP).

Background: ViviGen is an allogeneic cellular bone matrix product containing lineage-committed bone cells, and can be used as an alternative to autograft bone or other augments to aid in arthrodesis or to enhance bony healing in open reduction and internal fixation (ORIF) procedures.

Methods: This study included 153 consecutive patients undergoing ankle, midfoot, or hindfoot arthrodesis or ORIF procedures from January 2017 to October 2018, in which an allogeneic cellular bone matrix product was used to aid in bony healing. Retrospective chart review identified patient demographic factors and medical comorbidities and evaluated clinical and radiographic data to determine fusion/union rate and complications.

Results: The overall fusion rate for the arthrodesis cohort was 97/113 (85.8%). The overall complication rate in this cohort was 22/113 (19.5%). Smokers had significantly lower rates of fusion compared with nonsmokers ( = .01). The observed bony healing rate for the ORIF cohort was 19/22 (86.4%), with a complication rate of 3/22 (13.6%).

Conclusion: With satisfactory fusion rates and relatively few complications, our findings suggest that ViviGen is a safe and efficacious alternative to other forms of bone graft augmentation for fusion and ORIF procedures about the foot and ankle. Further study is needed to compare the efficacy of ViviGen with autograft bone and other augments.

Levels Of Evidence: Level IV: Case series.
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http://dx.doi.org/10.1177/1938640020952301DOI Listing
August 2020

Development of a high-throughput homogeneous AlphaLISA drug screening assay for the detection of SARS-CoV-2 Nucleocapsid.

bioRxiv 2020 Aug 20. Epub 2020 Aug 20.

National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850.

The coronavirus disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is in urgent need of therapeutic options. High-throughput screening (HTS) offers the research field an opportunity to rapidly identify such compounds. In this work, we have developed a homogeneous cell-based HTS system using AlphaLISA detection technology for the SARS-CoV-2 nucleocapsid protein (NP). Our assay measures both recombinant NP and endogenous NP from viral lysates and tissue culture supernatants (TCS) in a sandwich-based format using two monoclonal antibodies against the NP analyte. Viral NP was detected and quantified in both tissue culture supernatants and cell lysates, with large differences observed between 24 hours and 48 hours of infection. We simulated the viral infection by spiking in recombinant NP into 384-well plates with live Vero-E6 cells and were able to detect the NP with high sensitivity and a large dynamic range. Anti-viral agents that inhibit either viral cell entry or replication will decrease the AlphaLISA NP signal. Thus, this assay can be used for high-throughput screening of small molecules and biologics in the fight against the COVID-19 pandemic.
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http://dx.doi.org/10.1101/2020.08.20.258129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444285PMC
August 2020

Quantifying absolute neutralization titers against SARS-CoV-2 by a standardized virus neutralization assay allows for cross-cohort comparisons of COVID-19 sera.

medRxiv 2020 Aug 15. Epub 2020 Aug 15.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.

The on-going coronavirus disease 2019 (COVID-19) pandemic has mobilized a global effort to develop vaccines and therapeutics that inhibit viral entry by inducing or transferring antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (CoV2-S). Phase I/II vaccine clinical trials, monoclonal antibodies, and convalescent sera have all shown promise. However, these efforts often require extensive screening with the live virus under onerous high biocontainment conditions (BSL-3). Virus neutralization assays (VNAs) remain the gold standard for evaluating the anti-viral potency of antibodies and entry inhibitors. The proliferation of pseudotyped virus systems that can be used in BSL-2 compatible VNAs is a positive development. Yet, there is marked variability between VNAs and how the findings are presented, making inter-group comparisons difficult. To address these limitations, we developed a standardized VNA using VSVdeltaG based CoV-2-S pseudotyped particles (CoV2pp) that can be robustly produced at scale. We used our CoV2pp to interrogate the role of exogenous and endogenous proteases in CoV-2-S mediated entry and standardized our VNA based on that understanding. Our CoV2pp VNA showed a strong positive correlation with CoV2-S ELISA and live virus neutralizations in a validated set of patient sera. Our system was subsequently validated by three independent groups as an out-of-the-box VNA. More than 120 patient sera were screened, and we report descriptive statistics for absolute (abs) IC50, IC80, and IC90 values from all positive patient sera. Lastly, we used our CoV2pp in a screen to identify ultrapermissive 293T clones that stably express ACE2 or ACE2+TMPRSS2. When used in combination with our CoV2pp, we can now produce CoV2pp sufficient for 150,000 standardized VNA/week.
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http://dx.doi.org/10.1101/2020.08.13.20157222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430605PMC
August 2020

An In Vitro Microneutralization Assay for SARS-CoV-2 Serology and Drug Screening.

Curr Protoc Microbiol 2020 09;58(1):e108

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in the city of Wuhan, Hubei Province, China, in late 2019. Since then, the virus has spread globally and caused a pandemic. Assays that can measure the antiviral activity of antibodies or antiviral compounds are needed for SARS-CoV-2 vaccine and drug development. Here, we describe in detail a microneutralization assay, which can be used to assess in a quantitative manner if antibodies or drugs can block entry and/or replication of SARS-CoV-2 in vitro. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Microneutralization assay to test inhibition of virus by antibodies (purified antibodies or serum/plasma) Basic Protocol 2: Screening of anti-SARS-CoV-2 compounds in vitro Support Protocol: SARS-CoV-2 propagation.
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http://dx.doi.org/10.1002/cpmc.108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361222PMC
September 2020

A serological assay to detect SARS-CoV-2 seroconversion in humans.

medRxiv 2020 Apr 16. Epub 2020 Apr 16.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

SARS-Cov-2 (severe acute respiratory disease coronavirus 2), which causes Coronavirus Disease 2019 (COVID19) was first detected in China in late 2019 and has since then caused a global pandemic. While molecular assays to directly detect the viral genetic material are available for the diagnosis of acute infection, we currently lack serological assays suitable to specifically detect SARS-CoV-2 antibodies. Here we describe serological enzyme-linked immunosorbent assays (ELISA) that we developed using recombinant antigens derived from the spike protein of SARS-CoV-2. Using negative control samples representing pre-COVID 19 background immunity in the general adult population as well as samples from COVID19 patients, we demonstrate that these assays are sensitive and specific, allowing for screening and identification of COVID19 seroconverters using human plasma/serum as early as two days post COVID19 symptoms onset. Importantly, these assays do not require handling of infectious virus, can be adjusted to detect different antibody types and are amendable to scaling. Such serological assays are of critical importance to determine seroprevalence in a given population, define previous exposure and identify highly reactive human donors for the generation of convalescent serum as therapeutic. Sensitive and specific identification of coronavirus SARS-Cov-2 antibody titers may, in the future, also support screening of health care workers to identify those who are already immune and can be deployed to care for infected patients minimizing the risk of viral spread to colleagues and other patients.
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http://dx.doi.org/10.1101/2020.03.17.20037713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239062PMC
April 2020

Author Reply to "Regarding 'Associated Morbidity After the Percutaneous Release of the Medial Collateral Ligament for Knee Arthroscopy'".

Arthroscopy 2020 07 20;36(7):1798-1799. Epub 2020 May 20.

Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia, U.S.A.

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http://dx.doi.org/10.1016/j.arthro.2020.05.017DOI Listing
July 2020

A serological assay to detect SARS-CoV-2 seroconversion in humans.

Nat Med 2020 07 12;26(7):1033-1036. Epub 2020 May 12.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Here, we describe a serological enzyme-linked immunosorbent assay for the screening and identification of human SARS-CoV-2 seroconverters. This assay does not require the handling of infectious virus, can be adjusted to detect different antibody types in serum and plasma and is amenable to scaling. Serological assays are of critical importance to help define previous exposure to SARS-CoV-2 in populations, identify highly reactive human donors for convalescent plasma therapy and investigate correlates of protection.
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http://dx.doi.org/10.1038/s41591-020-0913-5DOI Listing
July 2020

The Outside-In, Percutaneous Release of the Medial Collateral Ligament for Knee Arthroscopy.

Arthrosc Tech 2020 Mar 25;9(3):e393-e397. Epub 2020 Feb 25.

University of Virginia Department of Orthopaedic Surgery, Charlottesville, Virginia, U.S.A.

The outside-in, percutaneous release of the medial collateral ligament (MCL) is a technique used to increase the medial tibiofemoral joint space during arthroscopy to facilitate the use of instrumentation and improve visualization without causing iatrogenic cartilage damage. A recent systematic review of the literature has shown this technique to be efficacious and safe, with no evidence of associated short- or long-term complications. This technique has been used for this indication by the senior author without requiring any deviation from our institution's standard protocol for knee arthroscopy. In an attempt to standardize this technique's utilization and allow for further evaluation in the literature, the senior author's method for this percutaneous, outside-in approach of "pie crusting" the MCL is described.
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http://dx.doi.org/10.1016/j.eats.2019.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093731PMC
March 2020

Granulocytic Sarcoma: A Rare Cause of Wrist Pain.

Ann Plast Surg 2020 07;85(1):29-32

Department of Pathology, The University of Virginia, Charlottesville, VA.

Septic, inflammatory, or crystal-induced arthritis are common etiologies of wrist pain without antecedent trauma associated with pain, loss of motion, swelling, redness, and warmth. In this report, we detail the case of granulocytic sarcoma of the wrist that presented as acute wrist pain, swelling, and limitation in motion. Granulocytic sarcoma is an exceedingly rare extramedullary tumor associated with acute myeloblastic leukemia. It may be found in any part of the body; however, upper extremity involvement is uncommon. To our knowledge, this is the first description of granulocytic sarcoma occurring in the wrist joint.
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http://dx.doi.org/10.1097/SAP.0000000000002315DOI Listing
July 2020

Measurement of bioactive osteocalcin in humans using a novel immunoassay reveals association with glucose metabolism and β-cell function.

Am J Physiol Endocrinol Metab 2020 03 14;318(3):E381-E391. Epub 2020 Jan 14.

Unité de Recherche en Physiologie Moléculaire, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada.

Osteocalcin (OCN) is a bone-derived hormone involved in the regulation of glucose metabolism. In serum, OCN exists in carboxylated and uncarboxylated forms (ucOCN), and studies in rodents suggest that ucOCN is the bioactive form of this hormone. Whether this is also the case in humans is unclear, because a reliable assay to measure ucOCN is not available. Here, we established and validated a new immunoassay (ELISA) measuring human ucOCN and used it to determine the level of bioactive OCN in two cohorts of overweight or obese subjects, with or without type 2 diabetes (T2D). The ELISA could specifically detect ucOCN concentrations ranging from 0.037 to 1.8 ng/mL. In a first cohort of overweight or obese postmenopausal women without diabetes ( = 132), ucOCN correlated negatively with fasting glucose (r = -0.18, = 0.042) and insulin resistance assessed by the homeostatic model assessment of insulin resistance (r = -0.18, = 0.038) and positively with insulin sensitivity assessed by a hyperinsulinemic-euglycemic clamp (r = 0.18, = 0.043) or insulin sensitivity index derived from an oral glucose tolerance test (r = 0.26, = 0.003). In a second cohort of subjects with severe obesity ( = 16), ucOCN was found to be lower in subjects with T2D compared with those without T2D (2.76 ± 0.38 versus 4.52 ± 0.06 ng/mL, = 0.009) and to negatively correlate with fasting glucose (r = -0.50, = 0.046) and glycated hemoglobin (r = -0.57, = 0.021). Moreover, the subjects with ucOCN levels below 3 ng/mL had a reduced insulin secretion rate during a hyperglycemic clamp ( = 0.03). In conclusion, ucOCN measured with this novel and specific assay is inversely associated with insulin resistance and β-cell dysfunction in humans.
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http://dx.doi.org/10.1152/ajpendo.00321.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395472PMC
March 2020

Associated Morbidity After the Percutaneous Release of the Medial Collateral Ligament for Knee Arthroscopy.

Arthroscopy 2020 03 29;36(3):891-900. Epub 2019 Nov 29.

Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia, U.S.A. Electronic address:

Purpose: To summarize available data on the morbidity associated with percutaneous release of the medial collateral ligament (MCL) of the knee during arthroscopy via a "pie-crusting" technique.

Methods: A search of the literature was performed using the MEDLINE and Web of Science databases to identify studies examining the morbidity of percutaneous MCL release during arthroscopy. Only English-language articles were included; technical articles and studies not focused on the use of this technique were omitted. Two independent reviewers performed the literature search, data extraction, and quality assessment. The outcomes analyzed included resultant knee instability, functional outcome scores, visual analog scale pain scores, and saphenous nerve or greater saphenous vein injury.

Results: Six studies met the eligibility criteria. The studies included a total of 234 knees undergoing MCL release, with a mean patient age of 41.1 years. This MCL release typically generated grade I MCL laxity, which usually diminished or resolved over time and did not require brace application. The functional outcome scores of patients undergoing MCL release did not differ from those of patients undergoing the same procedure without MCL release. Postoperative pain was not significantly different between patients who underwent MCL release and those who did not. There was a 0% incidence of injury to the saphenous nerve or greater saphenous vein with MCL release in the included studies.

Conclusions: Percutaneous MCL release during knee arthroscopy is a method of increasing the medial tibiofemoral joint space without causing any significant short- or long-term complications including residual valgus instability, pain, loss of function, or damage to surrounding structures.

Level Of Evidence: Level IV, systematic review of Level IV studies.
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http://dx.doi.org/10.1016/j.arthro.2019.08.051DOI Listing
March 2020

Simultaneous Use of Kocher-Langenbeck and Lateral Window Approaches for Transverse Acetabular Fracture Open Reduction and Internal Fixation: A Case Report.

JBJS Case Connect 2019 Dec;9(4):e0370

Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia.

Case: An otherwise healthy 39-year-old man presented after a fall from 30 feet with a right transverse, transtectal acetabular fracture. The fracture was not reducible with an isolated anterior or posterior approach. A simultaneous combined approach was used in the lateral decubitus position. The fracture was appropriately reduced and stabilized.

Conclusions: This combined approach with the patient in the lateral decubitus position was effective without requiring repositioning of the patient during surgery. This technique may be helpful for reduction of challenging transverse acetabular fractures.
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http://dx.doi.org/10.2106/JBJS.CC.18.00370DOI Listing
December 2019

Interleukin 22 disrupts pancreatic function in newborn mice expressing IL-23.

Nat Commun 2019 10 4;10(1):4517. Epub 2019 Oct 4.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Neonatal inflammatory diseases are associated with severe morbidity, but the inflammatory factors underlying them and their potential effector mechanisms are poorly defined. Here we show that necrotizing enterocolitis in neonate mice is accompanied by elevation of IL-23 and IL-22 and decreased production of pancreatic enzymes. These phenotypes are mirrored in neonate mice overexpressing IL-23 in CX3CR1 myeloid cells or in keratinocytes. The mice fail to grow and die prematurely, displaying systemic inflammation, nutrient malabsorption and decreased expression of intestinal and pancreatic genes mediating digestion and absorption of carbohydrates, proteins, and lipids. Germ-free environment improves, and genetic ablation of IL-22 restores normal growth in mice overexpressing IL-23. Mechanistically, IL-22 acts directly at the level of pancreatic acinar cells to decrease expression of the pancreas associated transcription factor 1a (PTF1a). These results show that augmented production of IL-23 and IL-22 in early life has a negative impact on pancreatic enzyme secretion and food absorption.
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http://dx.doi.org/10.1038/s41467-019-12540-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778080PMC
October 2019

CD46 facilitates entry and dissemination of human cytomegalovirus.

Nat Commun 2019 06 20;10(1):2699. Epub 2019 Jun 20.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Human cytomegalovirus (CMV) causes a wide array of disease to diverse populations of immune-compromised individuals. Thus, a more comprehensive understanding of how CMV enters numerous host cell types is necessary to further delineate the complex nature of CMV pathogenesis and to develop targeted therapeutics. To that end, we establish a vaccination strategy utilizing membrane vesicles derived from epithelial cells to generate a library of monoclonal antibodies (mAbs) targeting cell surface proteins in their native conformation. A high-throughput inhibition assay is employed to screen these antibodies for their ability to limit infection, and mAbs targeting CD46 are identified. In addition, a significant reduction of viral proliferation in CD46-KO epithelial cells confirms a role for CD46 function in viral dissemination. Further, we demonstrate a CD46-dependent entry pathway of virus infection in trophoblasts, but not in fibroblasts, highlighting the complexity of CMV entry and identifying CD46 as an entry factor in congenital infection.
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http://dx.doi.org/10.1038/s41467-019-10587-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586906PMC
June 2019

Local Investment in Training Drives Electronic Health Record User Satisfaction.

Appl Clin Inform 2019 03 15;10(2):331-335. Epub 2019 May 15.

University of California San Francisco Center for Clinical Informatics and Improvement Research, San Francisco, California, United States.

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http://dx.doi.org/10.1055/s-0039-1688753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520075PMC
March 2019

Vaccine hesitancy in Indonesia.

Lancet Planet Health 2019 03;3(3):e114-e115

UNICEF Headquarters, New York, NY, USA.

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http://dx.doi.org/10.1016/S2542-5196(18)30287-0DOI Listing
March 2019

Integrated respiratory and palliative care leads to high levels of satisfaction: a survey of patients and carers.

BMC Palliat Care 2019 Jan 19;18(1). Epub 2019 Jan 19.

Chair of Palliative Medicine, University of Melbourne, St Vincent's Hospital and Victorian Comprehensive Cancer Centre, Melbourne, Australia.

Background: The Advanced Lung Disease Service is a unique, new model of integrated respiratory and palliative care, which aims to address the unmet needs of patients with advanced, non-malignant, respiratory diseases. This study aimed to explore patients' and carers' experiences of integrated palliative care and identify valued aspects of care.

Methods: All current patients of the integrated service and their carers were invited to complete a confidential questionnaire by post or with an independent researcher.

Results: Eighty-eight responses were received from 64 (80.0%) eligible patients and from 24 (60%) eligible carers. Most participants (84, 95.5%) believed the integrated service helped them to manage breathlessness and nearly all participants (87, 98.9%) reported increased confidence managing symptoms. One third of patients (34.4%) had received a nurse-led domiciliary visit, with nearly all regarding this as helpful. Most participants believed the integrated respiratory and palliative care team listened to them carefully (87, 98.9%) with opportunities to express their views (88, 100%). Highly valued aspects of the service were continuity of care (82, 93.2%) and long-term care (77, 87.5%). Three quarters of participants (66, 75.0%) rated their care as excellent, with 20.5% rating it as very good. Nearly all (87, 98.9%) participants reported that they would recommend the service to others.

Conclusions: Patients and carers expressed high levels of satisfaction with this model of integrated respiratory and palliative care. Continuity of care, high quality communication and feeling cared for were greatly valued and highlight simple but important aspects of care for all patients.
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http://dx.doi.org/10.1186/s12904-019-0390-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339689PMC
January 2019

Open-label, add-on trial of cetirizine for neuromyelitis optica.

Neurol Neuroimmunol Neuroinflamm 2018 Mar 2;5(2):e441. Epub 2018 Feb 2.

Corinne Goldsmith Dickinson Center for Multiple Sclerosis (I.K.S., M.F., C.F., S.E., F.L.), Department of Neurology, Icahn School of Medicine at Mount Sinai, NY; Department of Pediatrics (R.T., L.C.), University of Utah, Salt Lake City; Drug Discovery Institute (T.A.K.), Mount Sinai Center for Eosinophilic Disorders (M.C.), Jaffe Food Allergy Institute (M.M.), Department of Pediatrics, and Department of Microbiology (T.M.), Icahn School of Medicine at Mount Sinai, NY; Department of Neurology (J.R.), University of Utah, Salt Lake City.

Objective: This pilot study preliminarily examined the efficacy and tolerability of cetirizine as an add-on to standard therapy for neuromyelitis optica (NMO).

Methods: Eligible participants met the Wingerchuk 2006 diagnostic criteria or had a single typical episode along with positive NMO immunoglobulin G. After baseline clinical and laboratory assessments, participants began treatment with cetirizine 10 mg orally daily, in addition to their usual disease-modifying therapy for NMO, and continued for 1 year. The primary end point was the annualized relapse rate (ARR) while on the same disease-modifying therapy before starting cetirizine compared with after taking cetirizine. Additional end points included disability (Expanded Disability Status Scale [EDSS]), relapse severity, tolerability, especially with respect to drowsiness measured by the Epworth Sleepiness Scale (ESS), and laboratory parameters.

Results: The ARR before cetirizine was 0.4 ± 0.80 and after cetirizine was 0.1 ± 0.24 ( = 0.047). There was no statistically significant difference in the EDSS (mean 3.9 ± 2.18 before the start of the study and 3.2 ± 2.31 at the conclusion of the study, = 0.500). The ESS remained fairly consistent throughout the study (mean 6.5 ± 5.33 at baseline and 6.9 ± 4.50 at month 12, = 0.740). Laboratory studies were unrevealing.

Conclusions: In this pilot study, cetirizine was well tolerated, and the prespecified primary efficacy end point was satisfied. However, the open-label design and the small sample size of this pilot study preclude definitive conclusions. Further research is needed.

Classification Of Evidence: This study provides Class IV evidence that in patients with NMO, the addition of cetirizine to standard therapy is safe, well tolerated, and reduces relapses.
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http://dx.doi.org/10.1212/NXI.0000000000000441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201737PMC
March 2018