Capturing phenotypic heterogeneity in MPS I: results of an international consensus procedure

<p>Abstract</p> <p>Background</p> <p>Mucopolysaccharidosis type I (MPS I) is traditionally divided into three phenotypes: the severe Hurler (MPS I-H) phenotype, the intermediate Hurler-Scheie (MPS I-H/S) phenotype and the attenuated Scheie (MPS I-S) phenotype. However, there are no clear criteria for delineating the different phenotypes. Because decisions about optimal treatment (enzyme replacement therapy or hematopoietic stem cell transplantation) need to be made quickly and depend on the presumed phenotype, an assessment of phenotypic severity should be performed soon after diagnosis. Therefore, a numerical severity scale for classifying different MPS I phenotypes at diagnosis based on clinical signs and symptoms was developed.</p> <p>Methods</p> <p>A consensus procedure based on a combined modified Delphi method and a nominal group technique was undertaken. It consisted of two written rounds and a face-to-face meeting. Sixteen MPS I experts participated in the process. The main goal was to identify the most important indicators of phenotypic severity and include these in a numerical severity scale. The correlation between the median subjective expert MPS I rating and the scores derived from this severity scale was used as an indicator of validity.</p> <p>Results</p> <p>Full consensus was reached on six key clinical items for assessing severity: age of onset of signs and symptoms, developmental delay, joint stiffness/arthropathy/contractures, kyphosis, cardiomyopathy and large head/frontal bossing. Due to the remarkably large variability in the expert MPS I assessments, however, a reliable numerical scale could not be constructed. Because of this variability, such a scale would always result in patients whose calculated severity score differed unacceptably from the median expert severity score, which was considered to be the 'gold standard'.</p> <p>Conclusions</p> <p>Although consensus was reached on the six key items for assessing phenotypic severity in MPS I, expert opinion on phenotypic severity at diagnosis proved to be highly variable. This subjectivity emphasizes the need for validated biomarkers and improved genotype-phenotype correlations that can be incorporated into phenotypic severity assessments at diagnosis.</p

Factorizations of complete graphs into tadpoles

A tadpole (also a canoe paddle or lollipop) is a graph that arises from a cycle and a path by gluing a terminal vertex of the path to an arbitrary vertex of the cycle. In this article, we show that all tadpoles factorize the complete graph K2n+1 if n is odd. We use methods similar to those used for isomorphic factorizations of complete graphs K2n into spanning trees. In Section 4 of this article, we show that our methods do not work for isomorphic factorizations of K2n+1 into tadpoles if n is even.Web of Science17393492

PrefixRL: Optimization of Parallel Prefix Circuits using Deep Reinforcement Learning

In this work, we present a reinforcement learning (RL) based approach to designing parallel prefix circuits such as adders or priority encoders that are fundamental to high-performance digital design. Unlike prior methods, our approach designs solutions tabula rasa purely through learning with synthesis in the loop. We design a grid-based state-action representation and an RL environment for constructing legal prefix circuits. Deep Convolutional RL agents trained on this environment produce prefix adder circuits that Pareto-dominate existing baselines with up to 16.0% and 30.2% lower area for the same delay in the 32b and 64b settings respectively. We observe that agents trained with open-source synthesis tools and cell library can design adder circuits that achieve lower area and delay than commercial tool adders in an industrial cell library.Comment: Copyright 2021 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other work