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Controlled Release of Vancomycin and Tigecycline from an Orthopaedic Implant Coating Prevents Staphylococcus aureus Infection in an Open Fracture Animal Model.
Introduction:Treatment of open fractures routinely involves multiple surgeries and delayed definitive fracture fixation because of concern for infection. If implants were made less susceptible to infection, a one-stage procedure with intramedullary nailing would be more feasible, which would reduce morbidity and improve outcomes. Methods:In this study, a novel open fracture mouse model was developed using Staphylococcus aureus (S. aureus) and single-stage intramedullary fixation. The model was used to evaluate whether implants coated with a novel "smart" polymer coating containing vancomycin or tigecycline would be colonized by bacteria in an open fracture model infected with S. aureus. In vivo bioluminescence, ex vivo CFUs, and X-ray images were evaluated over a 42-day postoperative period. Results:We found evidence of a markedly decreased bacterial burden with the local release of vancomycin and tigecycline from the PEG-PPS polymer compared to polymer alone. Vancomycin was released in a controlled fashion and maintained local drug concentrations above the minimum inhibition concentration for S. aureus for greater than 7 days postoperatively. Bacteria were reduced 139-fold from implants containing vancomycin and undetected from the bone and soft tissue. Tigecycline coatings led to a 5991-fold reduction in bacteria isolated from bone and soft tissue and 15-fold reduction on the implants compared to polymer alone. Antibiotic coatings also prevented osteomyelitis and implant loosening as observed on X-ray. Conclusion:Vancomycin and tigecycline can be encapsulated in a polymer coating and released over time to maintain therapeutic levels during the perioperative period. Our results suggest that antibiotic coatings can be used to prevent implant infection and osteomyelitis in the setting of open fracture. This novel open fracture mouse model can be used as a powerful in vivo preclinical tool to evaluate and optimize the treatment of open fractures before further studies in humans
Scanner Invariant Representations for Diffusion MRI Harmonization
Purpose: In the present work we describe the correction of diffusion-weighted
MRI for site and scanner biases using a novel method based on invariant
representation.
Theory and Methods: Pooled imaging data from multiple sources are subject to
variation between the sources. Correcting for these biases has become very
important as imaging studies increase in size and multi-site cases become more
common. We propose learning an intermediate representation invariant to
site/protocol variables, a technique adapted from information theory-based
algorithmic fairness; by leveraging the data processing inequality, such a
representation can then be used to create an image reconstruction that is
uninformative of its original source, yet still faithful to underlying
structures. To implement this, we use a deep learning method based on
variational auto-encoders (VAE) to construct scanner invariant encodings of the
imaging data.
Results: To evaluate our method, we use training data from the 2018 MICCAI
Computational Diffusion MRI (CDMRI) Challenge Harmonization dataset. Our
proposed method shows improvements on independent test data relative to a
recently published baseline method on each subtask, mapping data from three
different scanning contexts to and from one separate target scanning context.
Conclusion: As imaging studies continue to grow, the use of pooled multi-site
imaging will similarly increase. Invariant representation presents a strong
candidate for the harmonization of these data
A fast prunedâextreme learning machine for classification problem
Agency for Science, Technology and Research (A*STAR) Science and Engineering Research Counci
Cost-aware Generalized -investing for Multiple Hypothesis Testing
We consider the problem of sequential multiple hypothesis testing with
nontrivial data collection costs. This problem appears, for example, when
conducting biological experiments to identify differentially expressed genes of
a disease process. This work builds on the generalized -investing
framework which enables control of the false discovery rate in a sequential
testing setting. We make a theoretical analysis of the long term asymptotic
behavior of -wealth which motivates a consideration of sample size in
the -investing decision rule. Posing the testing process as a game with
nature, we construct a decision rule that optimizes the expected
-wealth reward (ERO) and provides an optimal sample size for each test.
Empirical results show that a cost-aware ERO decision rule correctly rejects
more false null hypotheses than other methods for where is the sample
size. When the sample size is not fixed cost-aware ERO uses a prior on the null
hypothesis to adaptively allocate of the sample budget to each test. We extend
cost-aware ERO investing to finite-horizon testing which enables the decision
rule to allocate samples in a non-myopic manner. Finally, empirical tests on
real data sets from biological experiments show that cost-aware ERO balances
the allocation of samples to an individual test against the allocation of
samples across multiple tests.Comment: 26 pages, 5 figures, 8 table
Histamine increases neuronal excitability and sensitivity of the lateral vestibular nucleus and promotes motor behaviors via HCN channel coupled to H2 receptor
published_or_final_versio
Neurite Orientation Dispersion and Density Imaging Color Maps to Characterize Brain Diffusion in Neurologic Disorders
Purpose: Neurite orientation dispersion and density imaging (NODDI) has recently been developed to overcome diffusion technique limitations in modeling biological systems. This manuscript reports a preliminary investigation into the use of a single color-coded map to represent NODDI-derived information.
Materials and methods: An optimized diffusion-weighted imaging protocol was acquired in several clinical neurological contexts including demyelinating disease, neoplastic process, stroke, and toxic/metabolic disease. The NODDI model was fitted to the diffusion datasets. NODDI is based on a three-compartment diffusion model and provides maps that quantify the contributions to the total diffusion signal in each voxel. The NODDI compartment maps were combined into a single 4-dimensional volume visualized as RGB image (red for anisotropic Gaussian diffusion, green for non-Gaussian anisotropic diffusion, and blue for isotropic Gaussian diffusion), in which the relative contributions of the different microstructural compartments can be easily appreciated.
Results: The NODDI color maps better describe the heterogeneity of neoplastic as well inflammatory lesions by identifying different tissue components within areas apparently homogeneous on conventional imaging. Moreover, NODDI color maps seem to be useful for identifying vasogenic edema differently from tumor-infiltrated edema. In multiple sclerosis, the NODDI color maps enable a visual assessment of the underlying microstructural changes, possibly highlighting an increased inflammatory component, within lesions and potentially in normal-appearing white matter.
Conclusion: The NODDI color maps could make this technique valuable in a clinical setting, providing comprehensive and accessible information in normal and pathological brain tissues in different neurological pathologies
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Transcriptionally active HERV-H retrotransposons demarcate topologically associating domains in human pluripotent stem cells.
Chromatin architecture has been implicated in cell type-specific gene regulatory programs, yet how chromatin remodels during development remains to be fully elucidated. Here, by interrogating chromatin reorganization during human pluripotent stem cell (hPSC) differentiation, we discover a role for the primate-specific endogenous retrotransposon human endogenous retrovirus subfamily H (HERV-H) in creating topologically associating domains (TADs) in hPSCs. Deleting these HERV-H elements eliminates their corresponding TAD boundaries and reduces the transcription of upstream genes, while de novo insertion of HERV-H elements can introduce new TAD boundaries. The ability of HERV-H to create TAD boundaries depends on high transcription, as transcriptional repression of HERV-H elements prevents the formation of boundaries. This ability is not limited to hPSCs, as these actively transcribed HERV-H elements and their corresponding TAD boundaries also appear in pluripotent stem cells from other hominids but not in more distantly related species lacking HERV-H elements. Overall, our results provide direct evidence for retrotransposons in actively shaping cell type- and species-specific chromatin architecture
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