Detecting and Characterizing Inferior Vena Cava Filters on Abdominal Computed Tomography with Data-Driven Computational Frameworks.

Two data-driven algorithms were developed for detecting and characterizing Inferior Vena Cava (IVC) filters on abdominal computed tomography to assist healthcare providers with the appropriate management of these devices to decrease complications: one based on 2-dimensional data and transfer learning (2D + TL) and an augmented version of the same algorithm which accounts for the 3-dimensional information leveraging recurrent convolutional neural networks (3D + RCNN). The study contains 2048 abdominal computed tomography studies obtained from 439 patients who underwent IVC filter placement during the 10-year period from January 1st, 2009, to January 1st, 2019. Among these, 399 patients had retrievable filters, and 40 had non-retrievable filter types. The reference annotations for the filter location were obtained through a custom-developed interface. The ground truth annotations for the filter types were determined based on the electronic medical record and physician review of imaging. The initial stage of the framework returns a list of locations containing metallic objects based on the density of the structure. The second stage processes the candidate locations and determines which one contains an IVC filter. The final stage of the pipeline classifies the filter types as retrievable vs. non-retrievable. The computational models are trained using Tensorflow Keras API on an Nvidia Quadro GV100 system. We utilized a fine-tuning supervised training strategy to conduct our experiments. We find that the system achieves high sensitivity on detecting the filter locations with a high confidence value. The 2D + TL model achieved a sensitivity of 0.911 and a precision of 0.804, and the 3D + RCNN model achieved a sensitivity of 0.923 and a precision of 0.853 for filter detection. The system confidence for the IVC location predictions is high: 0.993 for 2D + TL and 0.996 for 3D + RCNN. The filter type prediction component of the system achieved 0.945 sensitivity, 0.882 specificity, and 0.97 AUC score with 2D + TL and 0. 940 sensitivity, 0.927 specificity, and 0.975 AUC score with 3D + RCNN. With the intent to create tools to improve patient outcomes, this study describes the initial phase of a computational framework to support healthcare providers in detecting patients with retained IVC filters, so an individualized decision can be made to remove these devices when appropriate, to decrease complications. To our knowledge, this is the first study that curates abdominal computed tomography (CT) scans and presents an algorithm for automated detection and characterization of IVC filters.

UBR7 acts as a histone chaperone for post-nucleosomal histone H3.

Histone chaperones modulate the stability of histones beginning from histone synthesis, through incorporation into DNA, and during recycling during transcription and replication. Following histone removal from DNA, chaperones regulate histone storage and degradation. Here, we demonstrate that UBR7 is a histone H3.1 chaperone that modulates the supply of pre-existing post-nucleosomal histone complexes. We demonstrate that UBR7 binds to post-nucleosomal H3K4me3 and H3K9me3 histones via its UBR box and PHD. UBR7 binds to the non-nucleosomal histone chaperone NASP. In the absence of UBR7, the pool of NASP-bound post-nucleosomal histones accumulate and chromatin is depleted of H3K4me3-modified histones. We propose that the interaction of UBR7 with NASP and histones opposes the histone storage functions of NASP and that UBR7 promotes reincorporation of post-nucleosomal H3 complexes.

NOTCH1-driven UBR7 stimulates nucleotide biosynthesis to promote T cell acute lymphoblastic leukemia.

Ubiquitin protein ligase E3 component N-recognin 7 (UBR7) is the most divergent member of UBR box-containing E3 ubiquitin ligases/recognins that mediate the proteasomal degradation of its substrates through the N-end rule. Here, we used a proteomic approach and found phosphoribosyl pyrophosphate synthetases (PRPSs), the essential enzymes for nucleotide biosynthesis, as strong interacting partners of UBR7. UBR7 stabilizes PRPS catalytic subunits by mediating the polyubiquitination-directed degradation of PRPS-associated protein (PRPSAP), the negative regulator of PRPS. Loss of UBR7 leads to nucleotide biosynthesis defects. We define UBR7 as a transcriptional target of NOTCH1 and show that UBR7 is overexpressed in NOTCH1-driven T cell acute lymphoblastic leukemia (T-ALL). Impaired nucleotide biosynthesis caused by UBR7 depletion was concomitant with the attenuated cell proliferation and oncogenic potential of T-ALL. Collectively, these results establish UBR7 as a critical regulator of nucleotide metabolism through the regulation of the PRPS enzyme complex and uncover a metabolic vulnerability in NOTCH1-driven T-ALL.

Postoperative Pain Management of Non-"Opioid-Naive" Patients Undergoing Hand and Upper-Extremity Surgery.

Background: Patients with prior opioid use are often difficult to manage postoperatively. We examined potential strategies for managing these patients: (1) prescribing a different opioid; and (2) encouraging the use of nonopioid analgesics over opioids. Methods: A pain control program was implemented at an outpatient hand and upper-extremity center. Patients were recruited before (n = 305) and after (n = 225) implementation. Seventy of them were taking opioids prior to surgery. Information about pain control satisfaction and opioid use was collected. The Fisher exact test was used to compare categorical variables with small expected frequencies. Wilcoxon rank sum test was used to compare nonnormally distributed continuous variables. Results: Opioid users used 28.8 ± 25.6 opioid pills; nonopioid users used 14.5 ± 21.5 pills. Furthermore, 41.4% of opioid users sought more pills after surgery compared with 14.0% among nonopioid users. The pain control program was more effective in reducing opioid consumption and waste and increasing nonopioid consumption for nonopioid users than for opioid users. Prior opioid users who were prescribed a different opioid after surgery used 24.6 ± 22.0 opioid pills. Patients prescribed the same opioid used 37.9 ± 30.8 pills. Conclusions: Patients taking opioids prior to hand and upper-extremity surgery use more opioid pills, seek more pills after surgery, and are less satisfied with their pain control than their nonopioid user counterparts. Furthermore, the comprehensive pain plan was less effective in this patient population. Prescribing a different opioid reduced medication requirements for these patients, but additional strategies are needed to address postoperative pain management.

Inheritance of CENP-A Nucleosomes during DNA Replication Requires HJURP.

Centromeric chromatin defines the site of kinetochore formation and ensures faithful chromosome segregation. Centromeric identity is epigenetically specified by the incorporation of CENP-A nucleosomes. DNA replication presents a challenge for inheritance of centromeric identity because nucleosomes are removed to allow for replication fork progression. Despite this challenge, CENP-A nucleosomes are stably retained through S phase. We used BioID to identify proteins transiently associated with CENP-A during DNA replication. We found that during S phase, HJURP transiently associates with centromeres and binds to pre-existing CENP-A, suggesting a distinct role for HJURP in CENP-A retention. We demonstrate that HJURP is required for centromeric nucleosome inheritance during S phase. HJURP co-purifies with the MCM2-7 helicase complex and, together with the MCM2 subunit, binds CENP-A simultaneously. Therefore, pre-existing CENP-A nucleosomes require an S phase function of the HJURP chaperone and interaction with MCM2 to ensure faithful inheritance of centromere identity through DNA replication.