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In regenerative medicine, cells, tissues and organs are often replaced, engineered or regrown in order to restore their function after they have been damaged or lost. Local anesthetics, corticosteroids and contrast agents are commonly employed for both diagnostic and therapeutic objectives in interventional pain and musculoskeletal treatments for regenerative medicine. There is growing evidence that routine injectables promote catabolism and disease processes. Thus, understanding the effects of these compounds on regenerative medicine injectates and target tissues such as tenocytes, chondrocytes, nucleus pulposus and ligamentous tissue is critical. This review includes the current research on the effects of local anesthetics and contrast agents, as well as their use and recommendations in regenerative medicine operations.In regenerative medicine, various human organs are often modified to restore their function after being damaged. Various substances are commonly injected in pain and musculoskeletal treatments for regenerative medicine. A growing body of literature indicates that common injectable substances may promote cellular destruction and pathologies. Therefore, understanding their effects on various musculoskeletal tissue and cellular components is critical. This review includes the current research on the effects of local anesthetics and contrast agents, as well as their use and recommendations in regenerative medicine operations.

The interpolation of geospatial phenomena is a common problem in Earth sciences applications that can be addressed with geostatistics, where spatial correlations are used to constrain interpolations. In certain applications, it can be particularly useful to perform geostatistical simulation, which is used to generate multiple non-unique realizations that reproduce the variability of measurements and are constrained by observations. Despite the broad utility of this approach, there are few open-access geostatistical simulation software. To address this accessibility issue, we present GStatSim, a Python package for performing geostatistical interpolation and simulation. GStatSim is distinct from previous geostatistics tools in that it emphasizes accessibility for non-experts, geostatistical simulation, and applicability to remote sensing data sets. It includes tools for performing non-stationary simulations and interpolations with secondary constraints. This package is accompanied by a Jupyter Book with user tutorials and background information on different interpolation methods. These resources are intended to significantly lower the technological barrier to using geostatistics and encourage the use of geostatistics in a wider range of applications. We demonstrate the different functionalities of this tool for the interpolation of subglacial topography measurements in Greenland.

BACKGROUND Background: Documenting clinical notes in Electronic Health Record (EHR) systems is a crucial job for physicians, yet characterizing provider documentation behavior is still difficult because of the lack of applications to do so. OBJECTIVE Objective: This study aims to analyze physician documentation behavior phenotypes at a multi-specialty clinic, as well as develop open-source software to make such profiling more easily available for other clinics to replicate. METHODS Methods: For this observational retrospective study, we analyzed data on physician note-taking behavior from EPIC Signal and applied the k-means clustering algorithm to identify and analyze different phenotypes in the data set. RESULTS Results: We developed an efficient tool and easy-to-follow protocol to profile provider documentation behavior, which identified four physician phenotype clusters within our data. Of these four, two were characterized by physicians with high note-taking efficiency, with one cluster having low documentation length and above-average efficiency, and the other having average documentation length and extremely high efficiency. Of the two remaining clusters, one was characterized by physicians with low note-taking efficiency, and the last consisted of low-volume providers. CONCLUSIONS Conclusions: Cluster analysis is a useful method to characterize different physician note-taking behaviors, which can be used to efficiently identify both physician champions and physicians in need of note-taking training.

Upper gastrointestinal hemorrhage (UGIH) and lower gastrointestinal hemorrhage (LGIH) are 2 of the most common reasons for hospital admissions across the United States. The 30-day readmission after index admission poses a major burden on the health care infrastructure, and thus, it is important to assess the causes of 30-day readmission for patients with UGIH and LGIH.The study cohort was derived from the 2013 National Readmission Database. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) Volume 3 diagnosis codes were utilized to identify UGIH and LGIH patients from this data set. Patients who were readmitted to the hospital within 30 days within the same calendar year were further analyzed. Categorical variables and continuous variables were assessed by the χ test and the student t test, respectively. The independent predictors of unplanned 30-day readmissions were recognized by multivariate logistic regression, adjusting for stratified cluster design of National Readmission Database. SAS 9.4 (SAS Institute Inc., Cary, NC) was used for data analysis.The number of index admissions identified from the National Readmission Data 2013 were 82,290 for UGIH and 133,114 for LGIH. All-cause 30-day readmission rate for UGIH versus LGIH was 14.6% (readmitted N=12,046; 56.64% age 65 y and above) versus 14.4% (readmitted N=19,128; 70.21% age 65 y and above and 49.61% men). Gastrointestinal causes were most common (33.9% vs. 39.6%), followed by cardiac (13.3% vs. 15.3%), infectious (10.4% vs. 9.1%), and respiratory causes (7.8% vs. 7.1%) for 30-day readmission for UGIH and LGIH. Significant predictors of increased 30-day readmission (odds ratio, 95% confidence interval, P-value) included metastatic disease (2.15, 1.75-2.64, P0.001), discharge against medical advice (1.85, 1.55-2.22, P0.001), and length of stay3 days (1.50, 1.38-1.63, P0.001). Predictors for 30-day readmission for LGIH included metastatic disease (1.75, 1.48-2.06, P0.001), liver disease (1.59, 1.49-1.71, P0.001), and drug abuse (1.38, 1.21-1.58, P0.001).Most common reason for UGIH and LGIH readmission was related to gastrointestinal disease, followed by cardiac, infectious, and respiratory etiologies. By addressing these etiologies for readmission, it may be possible to reduce adverse outcomes.

The elbow is a common site for sports related injuries of the upper extremity. Ultrasonography (US) is a noninvasive imaging modality that offers several distinct advantages over its cross sectional counterparts. These include real time dynamic evaluation, direct patient feedback, ability to guide therapeutic interventions, and among many others. This chapter will review the normal anatomy of the elbow and its sonographic appearance, the approach to US imaging, the commonly encountered disease pathologies, and several fundamental therapeutic interventions for the elbow.

Sample-based evolutionary algorithms (EAs) are widely used for optimizing problems with multi (greater than one but less than four) or even many (greater than or equal to four) objectives of interest. In general, the difficulty of a problem exponentially increases with the number of objectives, serving as a clear example of the curse of dimensionality. The exploratory approach an EA takes in these cases has led to it being thought of as a big data generator, progressively sampling and evaluating solutions in high performing regions of a decision space to guide the search towards optimal solutions. Notably, in both multi- and many-objective EAs, the sampled data can be further utilized for building inverse generative models, mapping points in objective space back to solutions in the decision space. Such models offer immense flexibility to a decision maker in generating new target solutions on the fly, thereby facilitating real-time a posteriori preference incorporation into the search. In this paper, we show that the data distribution resulting from a many-objective formulation is in fact more conducive to building accurate inverse models than its multiobjective counterpart. Given the potential utility of these models, we in turn shed light on a rare blessing of dimensionality that is yet to be explored in the context of optimization. We first present simple theoretical arguments supporting our claim. Thereafter, experimental studies of Gaussian process-based inverse modeling for a synthetic and a real-world example are carried out to further confirm the theory.

Lately, the Vehicle Routing Problem (VRP) in the city, known as City VRP, has gained popularity with its importance in city logistics. Similar to city logistics, City VRP mainly differs from conventional VRP in terms of the stakeholders involved, namely the shipper, carrier, resident, and administrator. Accordingly, this paper surveys the City VRP literature categorized by stakeholders and summarizes the constraints, models, and solution methods for VRP in urban cities. City VRPs are also analyzed based on the problem of interest considered by the stakeholders and the corresponding models that have been proposed in response. Through this review, we identify the state of the art of City VRP, highlight the core challenging issues, and suggest some potential research area in this field that have remained underexplored.

Anti-FVIII inhibitor development is currently considered the most serious side effect in the treatment of hemophilia A patients. In this study, we sought to address this problem by determining the efficacy of a novel tolerogenic protocol utilizing nanoparticle formulations provided by Selecta Biosciences. Thus, hemophilia A mice (FVIII KO, n = 6-8) were treated weekly for five weeks through intravenous route with 1 µg recombinant human FVIII (rFVIII), plus immune modulating agent coupled nanoparticles or control nanoparticles (coded F1 or F2 or F3). An additional control group was included, in which the mice were treated on the same schedule with high dose IVIG + rFVIII. As expected, all the mice in the control group (later revealed to be F3) developed high levels anti-FVIII IgG after the five treatments, with the average levels at 21.2 ± 4.4 µg/ml. Both the F1 and F2 nanoparticle treatments effectively prevented the anti-FVIII inhibitory antibody development throughout the course of the 5-week treatment. One week after the final treatment, the majority (5/7) of both F1 and F2 groups remained undetectable for anti-FVIII IgG antibodies. Consistent with this pattern, the anti-FVIII inhibitor titers for the F1, F2, F3 and IVIG groups were 42.3 ± 9.9, 14.3 ± 7.2, 92.9 ± 2.5, and 30.3 ± 5.6 Bethesda Units (BU)/ml, respectively after another 7 days (p < 0.01 for F1 and F2 vs. F3). To determine the duration of the FVIII-tolerance, the mice were challenged twice with rFVIII (1µg) 29 and 53 days after the final nanoparticle treatment. After the first FVIII challenge, the inhibitor titers for the F1, F2, F3 and IVIG groups were 81.3 ± 10.8, 33.1 ± 13.2, 84.1 ± 2.2 (p = 0.41 for F1 vs. F3; and p < 0.01 for F2 vs. F3), and 50.6 ± 9.7 BU/ml, respectively. Remarkably, the FVIII-tolerance in F2 group was sustained even after additional FVIII challenges ∼ 2 months later, when the effect in IVIG group was completely lost. A therapeutic protocol using mice pre-immunized with FVIII also led to substantial reductions in anti-FVIII titers. In conclusion, the concomitant Selecta F2 nanoparticle treatments not only significantly prevented the anti-FVIII inhibitory antibody development during the treatments, but also resulted in long-term FVIII-tolerance, suggesting a potential clinical application. (Supported in part by a grant-in-aid from Selecta Bioscience and by HL061883) Disclosures: Griset: Selecta Biosciences: Employment, Equity Ownership. Maldonado:Selecta Biosciences: Employment, Equity Ownership. Kishimoto:Selecta Biosciences: Employment, Equity Ownership. Scott:Selecta Biosciences: Research Funding.

Abstract 3175 Poster Board III-115 Administration of human Factor VIII to hemophilia A (FVIII-/-) mice is a useful small animal model to study the immune response in patients given therapeutic FVIII. These mice manifest a robust, T-cell dependent, antibody response to exogenous FVIII treatment even when encountered through traditionally tolerogenic routes, whereas a different foreign protein like ovalbumin (OVA) is much less immunogenic by these routes. Interestingly, administration of FVIII with OVA led to an immune response to both proteins, suggesting that the function of FVIII in the clotting cascade led to additional “danger” signals to co-administered proteins. Thus, we propose that FVIII is particularly immunogenic because of its function in the coagulation cascade that leads to thrombin formation. We showed that native FVIII is poorly immunogenic when it cannot activate downstream coagulation factors. Thus, heat-inactivated FVIII is poorly immunogenic despite containing normal T-cell epitopes. Importantly, native FVIII is less immunogenic in mice treated with warfarin (which blocks vitamin K-dependent enzymes) or with the direct thrombin-inhibitor, hirudin. Based on the hypothesis that thrombin generation is necessary for the immunogenicity and formation of inhibitors to FVIII, we wished to uncouple this immune response from the disease. When hemostatically normal BALB/c mice were injected directly with thrombin and OVA, they formed increased immune responses to OVA compared to mice given OVA alone. Thus, a likely mechanism is that FVIII treatment initiates a thrombin burst, which we propose is an immunogenic “danger” signal, leading indirectly to dendritic cell activation and promotion of an immune response. (Supported by NIH RO1 HL061883, NIH T32 HL007698, and AHA Fellowship 0815219E) Disclosures No relevant conflicts of interest to declare.

Abstract 2137 Poster Board II-114 B-cell depletion using anti-human CD20 monoclonal antibodies has been reported to be effective in autoimmunity and in temporarily eliminating inhibitory antibodies in hemophilia A patients. In the current study, we examined the effect of anti-murine CD20 (αCD20) depletion on the immune response to factor VIII (FVIII) and its influence on an immune tolerance induction (ITI) protocol. Previous studies have shown that IgG subclasses of anti-murine CD20 monoclonal antibody (αCD20) have differential effects on B-cell depletion in the mouse. Thus, IgG1 αCD20 selectively depletes follicular B cells, while sparing marginal zone (MZ) B cells. Combined with evidence that MZ B cells may be tolerogenic antigen-presenting cells, we tested the hypothesis that follicular B-cell depletion using αCD20 IgG1 might favor tolerance induction to human FVIII. Hemophilic (FVIII knockout) mice were primed with physiological doses of recombinant human FVIII by weekly IV injection, followed by αCD20 IgG1 or control IgG1 treatment. Ten days after the αCD20 treatment, the mice were treated with daily high dose (2μg) FVIII IV injections to model ITI in hemophilia A patients. After 4 weekly injections, 70% of the mice developed titers of anti-FVIII IgG as high as 1:12,800. Unlike whole B-cell depletion, subsequent follicular B-cell depletion did not significantly decrease the anti-FVIII IgG titer, compared with mice receiving control IgG1. Repeated high dose FVIII injections to mimic ITI significantly increased the anti-FVIII IgG titer in both groups. However, in the mice that received αCD20 IgG1 treatment, the increase of anti-FVIII IgG levels were significantly lower than that in control IgG1 treated mice. In conclusion, we found that follicular B-cell depletion by αCD20 IgG1 antibody in hemophilia A mice did not switch the immune response to tolerance, but it diminished the immunogenicity of human FVIII in vivo in hemophilic mice. (Supported by NIH R01 HL061883) Disclosures: No relevant conflicts of interest to declare.

Antigen-specific tolerance induction can be induced in mouse models of autoimmune diseases by adoptive transfer of genetically modified spleen B cells. We hypothesized that genetically modified marginal zone (MZ) B cells are more efficient in mediating tolerance induction. B cell-depletion using an IgG1 mouse anti-mouse CD20 monoclonal antibody (aCD20), which spares MZ B cells, was used to test our hypothesis. Mice were injected i.v. with IgG1 type aCD20 or isotype control IgG1. Two weeks later, spleens from control mice contained 75% follicular B cells (FO; CD19+CD23hiCD21low) and 8% MZ B cells (CD19+CD23intCD21hi). IgG1 aCD20 treatment reduced FO B cells by 98% but MZ B cells were relatively enriched (51% of the residual B cells). To test whether MZ B cells are enriched to function as tolerogenic antigen-presenting cells (APC), we used B cells from mOVA B cell transgenic mice (mOVA mice), which express membrane-bound OVA. C57Bl/6 recipient mice were adoptively transferred with 5 ×10E6 LPS-activated MZ B cells or whole spleen B cells from mOVA or B6 mice, as control. One week after B-cell transfer, the mice were challenged with OVA323-339/CFA, and T-cell proliferation response to OVA323-339 analyzed two weeks later. Adoptive transfer of LPS activated mOVA spleen B cells, but not B6 B cells, were tolerogenic and significantly decreased the T-cell response to OVA323-339 (p