Evaluation of the accuracy and intra‐ and interobserver reliability of three manual laxity tests for canine cranial cruciate ligament rupture—An ex vivo kinetic and kinematic study

Objectives: To investigate the accuracy and intra‐ and interobserver reliability of the cranial drawer test (CD), tibial compression test (TCT), and the new tibial pivot compression test (TPCT) in an experimental setting resembling acute cranial cruciate ligament rupture (CCLR) and to elucidate the ability to subjectively estimate cranial tibial translation (CTT) during testing. Study design: Experimental ex vivo study.Sample populationTen cadaveric hindlimbs of large dogs. Methods: Kinetic and 3D‐kinematic data was collected while three observers performed the tests on each specimen with intact (INTACT) and transected cranial cruciate ligament (CCLD) and compared using three‐way repeated‐measures ANOVA. Subjectively estimated CTT (SCTT), obtained during a separate round of testing, was compared to kinematic data by Pearson correlation.ResultsCTT was significantly higher for CCLD than for INTACT for all tests, resulting in 100% sensitivity and specificity. TPCT induced the highest CTT and internal rotation. Intra‐ and interobserver agreement of translation was excellent. For rotation and kinetics, agreement was more variable. SCTT strongly correlated with the objectively measured values. Conclusion: The CD, TCT and the new TPCT were all accurate and reliable. The high translations and rotations during TPCT are promising, encouraging further development of this test. SCTT was reliable in our experimental setting.Clinical significanceVeterinary manual laxity tests are accurate and reliable in acute CCLR. The TPCT might have potential for the assessment of subtle and rotational canine stifle instabilities. The high reliability of SCTT implies that grading schemes for stifle laxity, similar to human medicine, could be developed

Deep learning features encode interpretable morphologies within histological images.

Convolutional neural networks (CNNs) are revolutionizing digital pathology by enabling machine learning-based classification of a variety of phenotypes from hematoxylin and eosin (H&E) whole slide images (WSIs), but the interpretation of CNNs remains difficult. Most studies have considered interpretability in a post hoc fashion, e.g. by presenting example regions with strongly predicted class labels. However, such an approach does not explain the biological features that contribute to correct predictions. To address this problem, here we investigate the interpretability of H&E-derived CNN features (the feature weights in the final layer of a transfer-learning-based architecture). While many studies have incorporated CNN features into predictive models, there has been little empirical study of their properties. We show such features can be construed as abstract morphological genes ( mones ) with strong independent associations to biological phenotypes. Many mones are specific to individual cancer types, while others are found in multiple cancers especially from related tissue types. We also observe that mone-mone correlations are strong and robustly preserved across related cancers. Importantly, linear mone-based classifiers can very accurately separate 38 distinct classes (19 tumor types and their adjacent normals, AUC = [Formula: see text] for each class prediction), and linear classifiers are also highly effective for universal tumor detection (AUC = [Formula: see text]). This linearity provides evidence that individual mones or correlated mone clusters may be associated with interpretable histopathological features or other patient characteristics. In particular, the statistical similarity of mones to gene expression values allows integrative mone analysis via expression-based bioinformatics approaches. We observe strong correlations between individual mones and individual gene expression values, notably mones associated with collagen gene expression in ovarian cancer. Mone-expression comparisons also indicate that immunoglobulin expression can be identified using mones in colon adenocarcinoma and that immune activity can be identified across multiple cancer types, and we verify these findings by expert histopathological review. Our work demonstrates that mones provide a morphological H&E decomposition that can be effectively associated with diverse phenotypes, analogous to the interpretability of transcription via gene expression values. Our work also demonstrates mones can be interpreted without using a classifier as a proxy

Early-phase clinical trial eligibility and response evaluation criteria for refractory, relapsed, or progressive neuroblastoma: A consensus statement from the National Cancer Institute Clinical Trials Planning Meeting

Consensus criteria; Early phase; NeuroblastomaCriteris de consens; Fase inicial; NeuroblastomaCriterios de consenso; Fase inicial; NeuroblastomaBackground International standardized criteria for eligibility, evaluable disease sites, and disease response assessment in patients with refractory, progressive, or relapsed high-risk neuroblastoma enrolled in early-phase clinical trials are lacking. Methods A National Cancer Institute–sponsored Clinical Trials Planning Meeting was convened to develop an international consensus to refine the tumor site eligibility criteria and evaluation of disease response for early-phase clinical trials in children with high-risk neuroblastoma. Results Standardized data collection of patient and disease characteristics (including specified genomic data), eligibility criteria, a definition of evaluable disease, and response evaluations for primary and metastatic sites of disease were developed. Eligibility included two distinct patient groups: progressive disease and refractory disease. The refractory disease group was subdivided into responding persistent disease and stable persistent disease to better capture the clinical heterogeneity of refractory neuroblastoma. Requirements for defining disease evaluable for a response assessment were provided; they included requirements for biopsy to confirm viable neuroblastoma and/or ganglioneuroblastoma in those patients with soft tissue or bone disease not avid for iodine-123 meta-iodobenzylguanidine. Standardized evaluations for response components and time intervals for response evaluations were established. Conclusions The use of international consensus eligibility, evaluability, and response criteria for early-phase clinical studies will facilitate the collection of comparable data across international trials and promote more rapid identification of effective treatment regimens for high-risk neuroblastoma.National Cancer Institute Pediatric and Adolescent Solid Tumor Steering Committee; Alex's Lemonade Stand Foundation for Childhood Cancer; Ben Towne Foundation; EVAN Foundation; Cancer Research UK Institute of Cancer Research, Grant/Award Number C347/A15403; National Institute for Health Research Research Methods Programme/Institute of Cancer Research Biomedical Research Centre

Emergence of Superlattice Dirac Points in Graphene on Hexagonal Boron Nitride

The Schr\"odinger equation dictates that the propagation of nearly free electrons through a weak periodic potential results in the opening of band gaps near points of the reciprocal lattice known as Brillouin zone boundaries. However, in the case of massless Dirac fermions, it has been predicted that the chirality of the charge carriers prevents the opening of a band gap and instead new Dirac points appear in the electronic structure of the material. Graphene on hexagonal boron nitride (hBN) exhibits a rotation dependent Moir\'e pattern. In this letter, we show experimentally and theoretically that this Moir\'e pattern acts as a weak periodic potential and thereby leads to the emergence of a new set of Dirac points at an energy determined by its wavelength. The new massless Dirac fermions generated at these superlattice Dirac points are characterized by a significantly reduced Fermi velocity. The local density of states near these Dirac cones exhibits hexagonal modulations indicating an anisotropic Fermi velocity.Comment: 16 pages, 6 figure

The tempo of cetacean cranial evolution

The evolution of cetaceans (whales and dolphins) represents one of the most extreme adaptive transitions known, from terrestrial mammals to a highly specialized aquatic radiation that includes the largest animals alive today. Many anatomical shifts in this transition involve the feeding, respiratory, and sensory structures of the cranium, which we quantified with a high-density, three-dimensional geometric morphometric analysis of 201 living and extinct cetacean species spanning the entirety of their ∼50-million-year evolutionary history. Our analyses demonstrate that cetacean suborders occupy distinct areas of cranial morphospace, with extinct, transitional taxa bridging the gap between archaeocetes (stem whales) and modern mysticetes (baleen whales) and odontocetes (toothed whales). This diversity was obtained through three key periods of rapid evolution: first, the initial evolution of archaeocetes in the early to mid-Eocene produced the highest evolutionary rates seen in cetaceans, concentrated in the maxilla, frontal, premaxilla, and nasal; second, the late Eocene divergence of the mysticetes and odontocetes drives a second peak in rates, with high rates and disparity sustained through the Oligocene; and third, the diversification of odontocetes, particularly sperm whales, in the Miocene (∼18-10 Mya) propels a final peak in the tempo of cetacean morphological evolution. Archaeocetes show the fastest evolutionary rates but the lowest disparity. Odontocetes exhibit the highest disparity, while mysticetes evolve at the slowest pace, particularly in the Neogene. Diet and echolocation have the strongest influence on cranial morphology, with habitat, size, dentition, and feeding method also significant factors impacting shape, disparity, and the pace of cetacean cranial evolution

An infrared survey of brightest cluster galaxies: Paper I

We report on an imaging survey with the Spitzer Space Telescope of 62 brightest cluster galaxies with optical line emission. These galaxies are located in the cores of X-ray luminous clusters selected from the ROSAT All-Sky Survey. We find that about half of these sources have a sign of excess infrared emission; 22 objects out of 62 are detected at 70 microns, 18 have 8 to 5.8 micron flux ratios above 1.0 and 28 have 24 to 8 micron flux ratios above 1.0. Altogether 35 of 62 objects in our survey exhibit at least one of these signs of infrared excess. Four galaxies with infrared excesses have a 4.5/3.6 micron flux ratio indicating the presence of hot dust, and/or an unresolved nucleus at 8 microns. Three of these have high measured [OIII](5007A)/Hbeta flux ratios suggesting that these four, Abell 1068, Abell 2146, and Zwicky 2089, and R0821+07, host dusty active galactic nuclei (AGNs). 9 objects (including the four hosting dusty AGNs) have infrared luminosities greater than 10^11 L_sol and so can be classified as luminous infrared galaxies (LIRGs). Excluding the four systems hosting dusty AGNs, the excess mid-infrared emission in the remaining brightest cluster galaxies is likely related to star formation.Comment: accepted for publication in ApJ

Early (and Later) LHC Search Strategies for Broad Dimuon Resonances

Resonance searches generally focus on narrow states that would produce a sharp peak rising over background. Early LHC running will, however, be sensitive primarily to broad resonances. In this paper we demonstrate that statistical methods should suffice to find broad resonances and distinguish them from both background and contact interactions over a large range of previously unexplored parameter space. We furthermore introduce an angular measure we call ellipticity, which measures how forward (or backward) the muon is in eta, and allows for discrimination between models with different parity violation early in the LHC running. We contrast this with existing angular observables and demonstrate that ellipticity is superior for discrimination based on parity violation, while others are better at spin determination.Comment: 31 pages, 19 figures. References added, minor modifications made to section

A Defined and Flexible Pocket Explains Aryl Substrate Promiscuity of the Cahuitamycin Starter Unit–Activating Enzyme CahJ

Cahuitamycins are biofilm inhibitors assembled by a convergent nonribosomal peptide synthetase pathway. Previous genetic analysis indicated that a discrete enzyme, CahJ, serves as a gatekeeper for cahuitamycin structural diversification. Here, the CahJ protein was probed structurally and functionally to guide the formation of new analogues by mutasynthetic studies. This analysis enabled the in vivo production of a new cahuitamycin congener through targeted precursor incorporation.Breaking the barrier: Biofilm formation is employed by pathogenic microbes to defend against antibiotic action. This study probes both structurally and functionally CahJ, a key biosynthetic adenylation enzyme involved in generation of the cahuitamycin biofilm inhibitors, and lays a foundation for the development of effective new analogues.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145379/1/cbic201800233_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145379/2/cbic201800233.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145379/3/cbic201800233-sup-0001-misc_information.pd