bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple‐echo steady‐state (MESS): Extending DESS for joint T2 mapping and chemical‐shift corrected water‐fat separation
Authors: Zijlstra Frank , Seevinck Peter R.
Published: July 2021

Purpose

To extend the double echo steady‐state (DESS) sequence to enable chemical‐shift corrected water‐fat separation.

Methods

This study proposes multiple‐echo steady‐state (MESS), a sequence that modifies the readouts of the DESS sequence to acquire two echoes each with bipolar readout gradients with higher readout bandwidth. This enables water‐fat separation and eliminates the need for water‐selective excitation that is often used in combination with DESS, without increasing scan time. An iterative fitting approach was used to perform joint chemical‐shift corrected water‐fat separation and T2 estimation on all four MESS echoes simultaneously. MESS and water‐selective DESS images were acquired for five volunteers, and were compared qualitatively as well as quantitatively on cartilage T2 and thickness measurements. Signal‐to‐noise ratio (SNR) and T2 quantification were evaluated numerically using pseudo‐replications of the acquisition.

Results

The water‐fat separation provided by MESS was robust and with quality comparable to water‐selective DESS. MESS T2 estimation was similar to DESS, albeit with slightly higher variability. Noise analysis showed that SNR in MESS was comparable to DESS on average, but did exhibit local variations caused by uncertainty in the water‐fat separation.

Conclusion

In the same acquisition time as DESS, MESS provides water‐fat separation with comparable SNR in the reconstructed water and fat images. By providing additional image contrasts in addition to the water‐selective DESS images, MESS provides a promising alternative to DESS.
Body composition in patients with type 2 intestinal failure
Authors: Kopczynska Maja , Barrett Maria P. , Cloutier Anabelle , Farrer Kirstine , Taylor Michael , Burden Sorrel , Lal Simon
Published: July 2021

Background

Measurement of body composition is a valuable clinical tool for nutrition assessments, but there are no data on the merits of assessment modalities in type 2 intestinal failure (IF). The aim of this study was to evaluate the prevalence of low muscle mass and quality in type 2 IF, comparing bioelectric impedance analysis (BIA) and computed tomography (CT) at the third lumbar vertebra level.

Methods

Patients admitted with acute severe (type 2) IF to a national UK IF center who had BIA measurement and CT scan as part of routine care within 40 days of anthropometric measurement were included in this cross‐sectional study. Data were also collected on patient demographics and clinical characteristics.

Results

Forty‐four patients meeting inclusion criteria were included. Low muscle mass was detected in 37 out of 44 (84.1%) patients by CT scan and in 30 of out 44 (68.2%) by BIA. Low muscle quality was detected in 22 out of 44 (50%) patients by CT scan and in 40 out of 44 (90.1%) by BIA. Comparison of CT and BIA measurements showed a moderate correlation of muscle, Spearman ρ 0.65 (95% CI, 0.42–0.81; P < 0.001), and a strong correlation of body fat mass measurements, Spearman ρ 0.79 (95% CI, 0.62–0.89; P < 0.001).

Conclusion

This is the first study to demonstrate that low muscle mass is common in patients with type 2 IF, regardless of body composition assessment modality. A larger cohort study is required to validate the impact of low muscle mass and quality on clinical outcomes and the role of targeted interventions to improve the care of patients with type 2 IF.
Clinical significance of prognostic nutrition index in hospitalized patients with COVID‐19: Results from single‐center experience with systematic review and meta‐analysis
Authors: Rashedi Sina , Keykhaei Mohammad , Pazoki Marzieh , Ashraf Haleh , Najafi Atabak , Kafan Samira , Peirovi Niloufar , Najmeddin Farhad , Jazayeri Seyed Aboozar , Kashani Mehdi , Moharari Reza Shariat , Montazeri Mahnaz
Published: July 2021

Background

We aimed to ascertain risk indicators of in‐hospital mortality and severity as well as to provide a comprehensive systematic review and meta‐analysis to investigate the prognostic significance of the prognostic nutrition index (PNI) as a predictor of adverse outcomes in hospitalized coronavirus disease 2019 (COVID‐19) patients.

Methods

In this cross‐sectional study, we studied patients with COVID‐19 who were referred to our hospital from February 16 to November 1, 2020. Patients with either a real‐time reverse‐transcriptase polymerase chain reaction test that was positive for COVID‐19 or high clinical suspicion based on the World Health Organization (WHO) interim guidance were enrolled. A parallel systematic review/meta‐analysis (in PubMed, Embase, and Web of Science) was performed.

Results

A total of 504 hospitalized COVID‐19 patients were included in this study, among which 101 (20.04%) patients died during hospitalization, and 372 (73.81%) patients were categorized as severe cases. At a multivariable level, lower PNI, higher lactate dehydrogenase (LDH), and higher D‐dimer levels were independent risk indicators of in‐hospital mortality. Additionally, patients with a history of diabetes, lower PNI, and higher LDH levels had a higher tendency to develop severe disease. The meta‐analysis indicated the PNI as an independent predictor of in‐hospital mortality (odds ratio [OR] = 0.80; P < .001) and disease severity (OR = 0.78; P = .009).

Conclusion

Our results emphasized the predictive value of the PNI in the prognosis of patients with COVID‐19, necessitating the implementation of a risk stratification index based on PNI values in hospitalized patients with COVID‐19.
Flow mark defects reduction of injection‐molded polypropylene by dynamically vulcanized polyolefin elastomer
Authors: Zhu Guodian , Li Zhuoxi , Shang Jingqi , Ding Jiao , Li Yuanyuan , Yin Guoqiang
Published: July 2021

Flow mark defects (FMs) worsen surface esthetics and mechanical properties of injection‐molded polypropylene (PP). In this work, experiments and dissipative particle dynamic (DPD) simulations were used to investigate the effect of dynamically vulcanized polyolefin elastomer (POE) on FMs of injection‐molded PP. Significant FMs reduction was achieved by dynamically vulcanized POE. DPD simulations indicated that POE molecules were randomly distributed in the PP, while dynamic vulcanization led to the formation of elastomeric quasi‐clusters, and these quasi‐clusters were able to reduce FMs. Both DPD simulations and scanning electron microscopy results showed that more agglomerates with longer and irregular shapes formed with longer vulcanization time and more initiators. The formation of too many agglomerates resulted in different pock surface defects. Dynamically vulcanized POE produced at optimal reaction conditions did not affect the tensile strength, tensile modulus, flexural strength, and flexural modulus, while breaking elongation and notched Izod impact strength of injection‐molded PP decreased slightly. This work suggests that the addition of dynamically vulcanized POE may be a promising way to reduce FMs of injection‐molded PP.
Magnetic Field Mapping Around Individual Magnetic Nanoparticle Agglomerates Using Nitrogen‐Vacancy Centers in Diamond
Authors: Camarneiro Filipe , Bocquel Juanita , Gallo Juan , Bañobre‐López Manuel , Berg‐Sørensen Kirstine , Andersen Ulrik Lund , Huck Alexander , Nieder Jana B.
Published: July 2021

A modified diamond–photonics based metrology is proposed to explore the magnetic fields created by agglomerates of magnetic nanoparticles (MNPs). MNPs are promising for environmental and medical applications; those proposed for cancer magnetic hyperthermia treatments are small superparamagnetic <20 nm iron oxide particles. Inside cells, they assemble in larger MNP agglomerates, reaching cross‐sections of several micrometers. Here, these conditions are reproduced and MNP agglomerates immobilized. Optically detected magnetic resonance (ODMR) signals recorded without a bias field in a confocal microscope and scanning across a homogenous shallow layer of fluorescent nitrogen‐vacancy centers in a bulk diamond sample placed in direct contact with the MNP agglomerates are used to determine magnetic fields with a spatial resolution of 500 nm in a lateral direction. This spatial resolution allows determining magnetic field maps around individual MNP agglomerates, for which magnetic fields with strengths ranging from 0.03 mT to maximal 1.2 mT in the direct vicinity of the agglomerates and with detectable fields up to 5 µm away from the agglomerates, are determined. Based on the findings, a pathway to non‐invasively study the micro/nano topology of MNP agglomerates is proposed.
What is the association between the ethnic composition of neighbourhoods, workplaces and schools and the formation of mixed‐ethnic unions?
Authors: Puur Allan , Rahnu Leen , Tammaru Tiit
Published: July 2021

Although ethnic diversity and the types of interpersonal ties that are experienced in various domains of life may vary considerably, studies regarding the local marriage market rarely focus on the relationship between the formation of mixed‐ethnic unions and the ethnic composition of more than one spatial context. In this study, by applying event history analysis methods to longitudinal register data from Finland, we address three spatial contexts: residential neighbourhoods, workplaces and schools. The main finding is that getting in contact with natives in all three spatial contexts elevates the probability of the formation of a mixed‐ethnic union between migrants and natives. Exposure to natives in residential neighbourhoods and workplaces does not lose its relevance for partnership outcomes among immigrants who have arrived in the host country as children, or among the descendants of immigrants. On the contrary, the effects that can be associated with higher concentrations of immigrants in neighbourhoods and workplaces tend to increase in strength for the second generation rather than decrease.
Towards a more “scale‐aware” orographic gravity wave drag parametrization: Description and initial testing
Authors: van Niekerk A. , Vosper S.B.
Published: July 2021

Many current orographic gravity wave drag parametrizations employed in numerical weather prediction and climate models assume idealised elliptical subgrid orography. As a result, they do not fully capture the spectrum of subgrid orographic scales and do not exhibit the desired behaviour when the model grid length is varied. This article describes the motivation, formulation, and testing of a new orographic gravity wave drag parametrization in the Met Office Unified Model that is more “scale‐aware”. The scheme circumvents the need to make assumptions about the shape and distribution of the subgrid orography, moving away from elliptical mountains, through the use of Fourier transforms. The reduction in gravity wave surface stress when orographic flow blocking is present is also accounted for. The result is a new scheme that represents subgrid mountain scales more faithfully and consistently, rather than assuming a single mountain scale for each grid box. Tests using both regional and global simulations, ranging in grid spacing from 2–130 km, demonstrate that the scale‐aware scheme provides a more constant total, resolved plus parametrized, orographic gravity wave momentum flux, when the grid length is varied over most regions of the globe. Global five‐day forecasts also show a significant reduction in the too‐strong zonal wind bias within the Northern and Southern Hemisphere upper troposphere to lower stratosphere at grid spacings of 130 and 40 km when the scale‐aware scheme is employed. Some discussion on future developments for the scheme is also presented, noting that improvements to the orographic flow‐blocking drag component are required before the scheme can be implemented operationally.
Research progress and development trend of surgical robot and surgical instrument arm
Authors: Zhang Wu , Li Haiyuan , Cui Linlin , Li Haiyang , Zhang Xiangyan , Fang Shanxiang , Zhang Qinjian
Published: July 2021

Background

In recent years, surgical robots have become an indispensable part of the medical field. Surgical robots are increasingly being used in the areas of gynaecological surgery, urological surgery, orthopaedic surgery, general surgery and so forth. In this paper, the development of surgical robots in different operations is reviewed and analysed. In the type of master–slave surgical robotic system, the robotic surgical instrument arms were located in the execution terminal of a surgical robot system, as one of the core components, and directly contact with the patient during the operation, which plays an important role in the efficiency and safety of the operation. In clinical, the arm function and design in different systems varies. Furtherly, the current research progress of robotic surgical instrument arms used in different operations is analysed and summarised. Finally, the challenge and trend are concluded.

Methods

According to the classification of surgical types, the development of surgical robots for laparoscopic surgery, neurosurgery, orthopaedics and microsurgery are analysed and summarised. Then, focusing on the research of robotic surgical instrument arms, according to structure type, the research and application of straight‐rod surgical instrument arm, joint surgical instrument arm and continuous surgical instrument arm are analysed respectively.

Results

According to the discussion and summary of the characteristics of the existing surgical robots and instrument arms, it is concluded that they still have a lot of room for development in the future. Therefore, the development trends of the surgical robot and instrument arm are discussed and analysed in the five aspects of structural materials, modularisation, telemedicine, intelligence and human–machine collaboration.

Conclusion

Surgical robots have shown the development trend of miniaturisation, intelligence, autonomy and dexterity. Thereby, in the field of science and technology, the research on the next generation of minimally invasive surgical robots will usher in a peak period of development.
Active disturbance rejection adaptive output feedback control of uncertain nonlinear systems
Authors: Mi Yize , Yao Jianyong
Published: July 2021

This article concerns the output feedback tracking control problem for a class of single‐input‐single‐output (SISO) nonlinear systems in a semistrict feedback form, which possesses both matched and mismatched uncertainties, including parametric uncertainties and unknown nonlinear disturbances. An active disturbance rejection adaptive output feedback control scheme is proposed via backstepping method, in which parametric uncertainties are handled by adaptation law and disturbances are estimated by a series of linear extended state observers (LESOs). The learning burden of LESOs is much alleviated due to active compensation of parametric uncertainties via adaptation. In addition, both matched and mismatched disturbances are estimated in the construction of LESO for each channel of the considered nonlinear plant. Hence, all various of uncertainties can be mostly compensated. Consequently, prescribed transient performance and steady‐state tracking accuracy can be guaranteed. Theoretical analysis reveals the tracking error can be made arbitrarily small. Furthermore, exponentially asymptotic output tracking can be achieved when unknown disturbances are constants. Finally, comparative simulation studies are presented to illustrate the effectiveness of the proposed scheme.
Electrospun Polymer‐Derived Carbyne Supercapacitor for Alternating Current Line Filtering
Authors: Mariappan Vimal Kumar , Krishnamoorthy Karthikeyan , Manoharan Sindhuja , Pazhamalai Parthiban , Kim Sang‐Jae
Published: July 2021

The filtering device is a vital component of electronic goods that rectifies ripples which occur upon converting alternating current (AC) to direct current (DC) and attenuates high‐frequency noise during switching or voltage declines. Classical filtering devices suffer from low performance metrics and are bulky, limiting their use in modern electronic devices. The fabrication process of electrode materials for high‐frequency symmetric supercapacitor (HFSSC) is complicated, hindering commercialization. Herein, for the first time, the design of a high‐performance stand‐alone carbyne film comprised of sp/sp2‐hybridized carbon as an electrode for AC filtering under a wide frequency range is reported. The carbyne film as HFSSC shows the ideal capacitive behavior at ultrahigh scan rate of 10 000 V s−1 with excellent linearity which is top among the reported AC line filter capacitor. The carbyne HFSSC exhibits a high energy density of 703.25 µF V2 cm−2 at 120 Hz, which is superior to that of current commercial electrolytic filters and many reported AC line supercapacitors. As a proof of concept, a carbyne device is implemented in a real time AC to DC adaptor that demonstrates excellent filtering performance at high frequencies.
Patent citation‐based knowledge inflow measures: The case of emerging economy multinational corporations
Authors: Zhang Feng
Published: July 2021

Empirical analyses of multinationals from emerging economies (EMNCs) have been a challenge because of the absence of systematic and consistent data. This study focuses on the impacts of patent examiner added citations on citation‐based measures of EMNC subsidiary knowledge inflows. The US patents of leading innovation‐oriented EMNCs from China and India between 2002 and 2014 are analyzed, with their major competitors from mature industrialized countries as a benchmark group. We find that, subsidiary knowledge inflow variables in the current study are not significantly distorted by examiner added citations. This study offers the validity evidence of employing the US patent and citation data in studying EMNCs. The results also contribute to patent economics literature in general by testing the impacts of examiner added citations on citation‐based measures of knowledge flows.
On a three step two‐grid finite element method for the Oldroyd model of order one
Authors: Bir Bikram , Goswami Deepjyoti
Published: July 2021

In this work, an optimal error analysis of a three step two‐grid method for the equations of motion arising in the 2DOldroyd model of order one is discussed. The model, which can be thought of as an integral perturbation of Navier‐Stokes equations (NSE), represents linear viscoelastic fluid flows. This non‐linear model is analyzed here using a three step numerical scheme. In the first step the problem is solved on a coarse grid, and we use this course grid solution to linearize the problem and solve it in second step, on a finer grid. Third step is a correcting step done on the finer grid. Optimal error estimates for the velocity in and ‐norms and for the pressure in ‐norm in the semidiscrete case are established. Estimates are shown to be uniform under the uniqueness assumption. Then, based on backward Euler method, a completely discrete scheme is analyzed and optimal a priori error estimates are derived. All the analysis are carried out for the non‐smooth initial data. Finally we present some numerical results to validate our theoretical results. These examples show that the three step two‐grid method is efficient than solving a nonlinear problem directly, as is expected.
Challenging “Play”
Authors: Wardle Heather
Published: July 2021

Our understanding of when gaming ends and gambling begins is unclear. This has been hotly debated among theorists and the inclusion of gambling-like practices within digital games makes this even more indistinct, arguably subverting traditional notions of what it means to play. We are hyper-attuned to changes in game play because we know the learning power and potential of games and thus worry, rightly or wrongly, about their content: debate over loot boxes is the latest example of this. Whilst young people themselves have varied perspectives on whether wagering with or for in-game currency or items is gambling or not, they do tend to see these practices as coercive and as potentially addictive. They are acutely aware that these gambling-like mechanics do precisely what they were designed to—obtain money—raising broader questions about the ethics and responsibilities of the games industry as the creators of this content.
Interpolation and Model Checking for Nonlinear Arithmetic
Authors: Jovanović Dejan , Dutertre Bruno
Published: July 2021

We present a new model-based interpolation procedure for satisfiability modulo theories (SMT). The procedure uses a new mode of interaction with the SMT solver that we call solving modulo a model. This either extends a given partial model into a full model for a set of assertions or returns an explanation (a model interpolant) when no solution exists. This mode of interaction fits well into the model-constructing satisfiability (MCSAT) framework of SMT. We use it to develop an interpolation procedure for any MCSAT-supported theory. In particular, this method leads to an effective interpolation procedure for nonlinear real arithmetic. We evaluate the new procedure by integrating it into a model checker and comparing it with state-of-art model-checking tools for nonlinear arithmetic.
Progress in Certifying Hardware Model Checking Results
Authors: Yu Emily , Biere Armin , Heljanko Keijo
Published: July 2021

We present a formal framework to certifyk-induction-based model checking results. The key idea is the notion of ak-witness circuit which simulates the given circuit and has a simple inductive invariant serving as proof certificate. Our approach allows to check proofs with an independent proof checker by reducing the certification problem to pure SAT checks and checking a simple QBF with one quantifier alternation. We also presentCertifaiger, the resulting certification toolkit, and evaluate it on instances from the hardware model checking competition. Our experiments show the practical use of our certification method.
Model-Checking Structured Context-Free Languages
Authors: Chiari Michele , Mandrioli Dino , Pradella Matteo
Published: July 2021

The problem of model checking procedural programs has fostered much research towards the definition of temporal logics for reasoning on context-free structures. The most notable of such results are temporal logics on Nested Words, such as CaRet and NWTL. Recently, the logic OPTL was introduced, based on the class of Operator Precedence Languages (OPL), more powerful than Nested Words. We define the new OPL-based logic POTL, and provide a model checking procedure for it. POTL improves on NWTL by enabling the formulation of requirements involving pre/post-conditions, stack inspection, and others in the presence of exception-like constructs. It improves on OPTL by being FO-complete, and by expressing more easily stack inspection and function-local properties. We developed a model checking tool for POTL, which we experimentally evaluate on some interesting use-cases.
Model Checking $$\omega $$-Regular Properties with Decoupled Search
Authors: Gnad Daniel , Eisenhut Jan , Lluch Lafuente Alberto , Hoffmann Jörg
Published: July 2021

Decoupled search is a state space search method originally introduced in AI Planning. Similar to partial-order reduction methods, decoupled search exploits the independence of components to tackle the state explosion problem. Similar to symbolic representations, it does not construct the explicit state space, but sets of states are represented in a compact manner, exploiting component independence. Given the success of both partial-order reduction and symbolic representations when model checking liveness properties, our goal is to add decoupled search to the toolset of liveness checking methods. Specifically, we show how decoupled search can be applied to liveness verification for composed Büchi automata by adapting, and showing correct, a standard algorithm for detecting lassos (i.e., infinite accepting runs), namely nested depth-first search. We evaluate our approach using a prototype implementation.
Ghost Signals: Verifying Termination of Busy Waiting
Authors: Reinhard Tobias , Jacobs Bart
Published: July 2021

Programs for multiprocessor machines commonly perform busy waiting for synchronization. We propose the first separation logic for modularly verifying termination of such programs under fair scheduling. Our logic requires the proof author to associate a ghost signal with each busy-waiting loop and allows such loops to iterate while their corresponding signal $$s$$
s
 is not set. The proof author further has to define a well-founded order on signals and to prove that if the looping thread holds an obligation to set a signal $$s'$$

s
′

, then $$s'$$

s
′

  is ordered above $$s$$
s
. By using conventional shared state invariants to associate the state of ghost signals with the state of data structures, programs busy-waiting for arbitrary conditions over arbitrary data structures can be verified.
AIGEN: Random Generation of Symbolic Transition Systems
Authors: Jacobs Swen , Sakr Mouhammad
Published: July 2021

AIGEN is an open source tool for the generation of transition systems in a symbolic representation. To ensure diversity, it employs a uniform random sampling over the space of all Boolean functions with a given number of variables. AIGEN relies on reduced ordered binary decision diagrams (ROBDDs) and canonical disjunctive normal form (CDNF) as canonical representations that allow us to enumerate Boolean functions, in the former case with an encoding that is inspired by data structures used to implement ROBDDs. Several parameters allow the user to restrict generation to Boolean functions or transition systems with certain properties, which are then output in AIGER format. We report on the use of AIGEN to generate random benchmark problems for the reactive synthesis competition SYNTCOMP 2019, and present a comparison of the two encodings with respect to time and memory efficiency in practice.
Reflections on Termination of Linear Loops
Authors: Zhu Shaowei , Kincaid Zachary
Published: July 2021

This paper shows how techniques for linear dynamical systems can be used to reason about the behavior of general loops. We present two main results. First, we show that every loop that can be expressed as a transition formula in linear integer arithmetic has a best model as a deterministic affine transition system. Second, we show that for any linear dynamical system f with integer eigenvalues and any integer arithmetic formula G, there is a linear integer arithmetic formula that holds exactly for the states of f for which G is eventually invariant. Combining the two, we develop a monotone conditional termination analysis for general loops.
Model-Free Reinforcement Learning for Branching Markov Decision Processes
Authors: Hahn Ernst Moritz , Perez Mateo , Schewe Sven , Somenzi Fabio , Trivedi Ashutosh , Wojtczak Dominik
Published: July 2021

We study reinforcement learning for the optimal control of Branching Markov Decision Processes (BMDPs), a natural extension of (multitype) Branching Markov Chains (BMCs). The state of a (discrete-time) BMCs is a collection of entities of various types that, while spawning other entities, generate a payoff. In comparison with BMCs, where the evolution of a each entity of the same type follows the same probabilistic pattern, BMDPs allow an external controller to pick from a range of options. This permits us to study the best/worst behaviour of the system. We generalise model-free reinforcement learning techniques to compute an optimal control strategy of an unknown BMDP in the limit. We present results of an implementation that demonstrate the practicality of the approach.
Cameleer: A Deductive Verification Tool for OCaml
Authors: Pereira Mário , Ravara António
Published: July 2021

We present , an automated deductive verification tool for OCaml. We leverage on the recently proposed GOSPEL (Generic OCaml SPEcification Language) to attach rigorous, yet readable, behavioral specification to OCaml code. The formally-specified program is fed to our toolchain, which translates it into an equivalent one in WhyML, the programming and specification language of the Why3 verification framework. We report on successful case studies conducted in .
LLMC: Verifying High-Performance Software
Authors: van der Berg Freark I.
Published: July 2021

Multi-threaded unit tests for high-performance thread-safe data structures typically do not test all behaviour, because only a single scheduling of threads is witnessed per invocation of the unit tests. Model checking such unit tests allows to verify all interleavings of threads. These tests could be written in or compiled to LLVM IR. Existing LLVM IR model checkers like divine and Nidhugg, use an LLVM IR interpreter to determine the next state. This paper introduces llmc, a multi-core explicit-state model checker of multi-threaded LLVM IR that translates LLVM IR to LLVM IR that is executed instead of interpreted. A test suite of 24 tests, stressing data structures, shows that on average llmc clearly outperforms the state-of-the-art tools divine and Nidhugg.
An SMT Encoding of LLVM’s Memory Model for Bounded Translation Validation
Authors: Lee Juneyoung , Kim Dongjoo , Hur Chung-Kil , Lopes Nuno P.
Published: July 2021

Several automatic verification tools have been recently developed to verify subsets of LLVM’s optimizations. However, none of these tools has robust support to verify memory optimizations.

In this paper, we present the first SMT encoding of LLVM’s memory model that 1) is sufficiently precise to validate all of LLVM’s intra-procedural memory optimizations, and 2) enables bounded translation validation of programs with up to hundreds of thousands of lines of code. We implemented our new encoding in Alive2, a bounded translation validation tool, and used it to uncover 21 new bugs in LLVM memory optimizations, 10 of which have been already fixed. We also found several inconsistencies in LLVM IR’s official specification document (LangRef) and fixed LLVM’s code and the document so they are in agreement.
Lower-Bound Synthesis Using Loop Specialization and Max-SMT
Authors: Albert Elvira , Genaim Samir , Martin-Martin Enrique , Merayo Alicia , Rubio Albert
Published: July 2021

This paper presents a new framework to synthesize lower-bounds on the worst-case cost for non-deterministic integer loops. As in previous approaches, the analysis searches for a metering function that under-approximates the number of loop iterations. The key novelty of our framework is the specialization of loops, which is achieved by restricting their enabled transitions to a subset of the inputs combined with the narrowing of their transition scopes. Specialization allows us to find metering functions for complex loops that could not be handled before or be more precise than previous approaches. Technically, it is performed (1) by using quasi-invariants while searching for the metering function, (2) by strengthening the loop guards, and (3) by narrowing the space of non-deterministic choices. We also propose a Max-SMT encoding that takes advantage of the use of soft constraints to force the solver look for more accurate solutions. We show our accuracy gains on benchmarks extracted from the 2020 Termination and Complexity Competition by comparing our results to those obtained by the
"Image missing"
system.
ATLAS: Automated Amortised Complexity Analysis of Self-adjusting Data Structures
Authors: Leutgeb Lorenz , Moser Georg , Zuleger Florian
Published: July 2021

Being able to argue about the performance of self-adjusting data structures such as splay trees has been a main objective, when Sleator and Tarjan introduced the notion ofamortisedcomplexity.

Analysing these data structures requires sophisticated potential functions, which typically contain logarithmic expressions. Possibly for these reasons, and despite the recent progress in automated resource analysis, they have so far eluded automation. In this paper, we report on the first fully-automated amortised complexity analysis of self-adjusting data structures. Following earlier work, our analysis is based on potential function templates with unknown coefficients.

We make the following contributions: 1) We encode the search for concrete potential function coefficients as an optimisation problem over a suitable constraint system. Our target function steers the search towards coefficients that minimise the inferred amortised complexity. 2) Automation is achieved by using a linear constraint system in conjunction with suitable lemmata schemes that encapsulate the required non-linear facts about the logarithm. We discuss our choices that achieve a scalable analysis. 3) We present our tool$$\mathsf {ATLAS}$$ATLASand report on experimental results forsplay trees,splay heapsandpairing heaps. We completely automatically infer complexity estimates that match previous results (obtained by sophisticated pen-and-paper proofs), and in some cases even infer better complexity estimates than previously published.
Improving clinical utility of GAD65 autoantibodies by electrochemiluminescence assay and clinical phenotype when identifying autoimmune adult-onset diabetes
Authors: Gu Yong , Jia Xiaofan , Vartak Tanwi , Miao Dongmei , Dong Fran , Jerram Samuel T. , Rewers Marian , Ferrara Assiamira , Lawrence Jean M. , Yu Liping , Leslie R. David ,   the Action LADA consortium and the Diabetes in Young Adults (DiYA) Study Group, Leslie Richard David , Hawa Mohammed I , Pozzilli Paolo , Beck-Nielsen Henning , Yderstraede Knud , Hunter Steven , Hadden David , Buzzetti Raffaella , Scherbaum Werner , Kolb Hubert , Schloot Nanette C. , Seissler Jochen , Schernthaner Guntram , Tuomilehto Jaakko , Sarti Cinzia , De Leiva Alberto , Brugues Eulalia , Mauricio Didac , Thivolet Charles , Lawrence Jean M , Ferrara Assiamira , Slezak Jeff M. , Quesenberry Charles , Saydah Sharon , Yu Liping , Rewers Marian
Published: July 2021

Aims/hypothesis

It is important to differentiate the two major phenotypes of adult-onset diabetes, autoimmune type 1 diabetes and non-autoimmune type 2 diabetes, especially as type 1 diabetes presents in adulthood. Serum GAD65 autoantibodies (GADA) are the most sensitive biomarker for adult-onset autoimmune type 1 diabetes, but the clinical value of GADA by current standard radiobinding assays (RBA) remains questionable. The present study focused on the clinical utility of GADA differentiated by a new electrochemiluminescence (ECL) assay in patients with adult-onset diabetes.

Methods

Two cohorts were analysed including 771 diabetic participants, 30–70 years old, from the Action LADA study (n = 6156), and 2063 diabetic participants, 20–45 years old, from the Diabetes in Young Adults (DiYA) study. Clinical characteristics of participants, including requirement of early insulin treatment, BMI and development of multiple islet autoantibodies, were analysed according to the status of RBA-GADA and ECL-GADA, respectively, and compared between these two assays.

Results

GADA was the most prevalent and predominant autoantibody, >90% in both cohorts. GADA positivity by either RBA or ECL assay significantly discriminated clinical type 1 from type 2 diabetes. However, in both cohorts, participants with ECL-GADA positivity were more likely to require early insulin treatment, have multiple islet autoantibodies, and be less overweight (for all p < 0.0001). However, clinical phenotype, age at diagnosis and BMI independently improved positive predictive value (PPV) for the requirement of insulin treatment, even augmenting ECL-GADA. Participants with GADA detectable by RBA, but not confirmed by ECL, had a phenotype more similar to type 2 diabetes. These RBA-GADA positive individuals had lower affinity GADA compared with participants in which GADA was confirmed by ECL assay.

Conclusions/interpretation

Detection of GADA by ECL assay, given technical advantages over RBA-GADA, identified adult-onset diabetes patients at higher risk of requiring early insulin treatment, as did clinical phenotype, together allowing for more accurate clinical diagnosis and management.

Graphical abstract
Experimental analysis and development of an in-house CFD condensation hood model
Authors: Tokarski Mieszko , Ryfa Arkadiusz , Bulinski Piotr , Rojczyk Marek , Ziarko Krzysztof , Ostrowski Ziemowit , Nowak Andrzej J.
Published: July 2021

An existing condensation hood has been numerically investigated using k-ε turbulence and species transport models. Due to the geometrical complexity of the appliance, two additional mathematical models were introduced with the use of User Defined Functions (UDFs). They were a model of a fan and a model of the internally finned pipes of a heat exchanger. The latter also involved a condensation model of steam implemented by mass and energy source terms. Such an approach allowed us to avoid troublesome two-phase flow simulation and thus significantly reduced the computational effort. Based on the results provided by the numerical model, potential improvements of the heat exchanger were proposed and implemented into a second, modified numerical model. Reduction of the number of the pipes by 25% is the most important change of the developed device. Its negative effect on condensation efficiency was to be compensated by improvements of steam flow in the device. Once the modifications had been evaluated, the prototype of the device was built and tested experimentally. Both the numerical and experimental results agree and show that, the modified condensation hood is comparable to the original construction in terms of condensation efficiency, despite the significant heat transfer surface area reduction.
D-Galacturonic acid reduction by S. cerevisiae for L-galactonate production from extracted sugar beet press pulp hydrolysate
Authors: Wagner J. , Schäfer D. , von den Eichen N. , Haimerl C. , Harth S. , Oreb M. , Benz J. P. , Weuster-Botz D.
Published: July 2021

Pectin-rich residues are considered as promising feedstocks for sustainable production of platform chemicals. Enzymatic hydrolysis of extracted sugar beet press pulp (SBPP) releases the main constituent of pectin, d-galacturonic acid (d-GalA). Using engineered Saccharomyces cerevisiae, d-GalA is then reduced to l-galactonate (l-GalOA) with sorbitol as co-substrate. The current work addresses the combination of enzymatic hydrolysis of pectin in SBPP with a consecutive optimized biotransformation of the released d-GalA to l-GalOA in simple batch processes in stirred-tank bioreactors. Process conditions were first identified with synthetic media, where a product concentration of 9.9 g L-1 L-GalOA was obtained with a product selectivity of 99% (L-GalOA D-GalA-1) at pH 5 with 4% (w/v) sorbitol within 48 h. A very similar batch process performance with a product selectivity of 97% was achieved with potassium citrate buffered SBPP hydrolysate, demonstrating for the first time direct production of L-GalOA from hydrolyzed biomass using engineered S. cerevisiae. Combining the hydrolysis process of extracted SBPP and the biotransformation process with engineered S. cerevisiae paves the way towards repurposing pectin-rich residues as substrates for value-added chemicals.

Key points

• Efficient bioreduction of D-GalA with S. cerevisiae in stirred-tank reactors

• Batch production of L-GalOA by engineered S. cerevisiae with high selectivity

• Direct L-GalOA production from hydrolyzed sugar beet press pulp

Graphical abstract
Age estimation comparison between whole and thin-sectioned otoliths and pelvic fin-ray sections of long-lived lake trout, Salvelinus namaycush, from Great Bear Lake, Northwest Territories, Canada
Authors: Gallagher Colin P. , Wastle Rick J. , Marentette Julie R. , Chavarie Louise , Howland Kimberly L.
Published: July 2021

Studies to determine precision and bias of both methods and age-readers are important to evaluate reliability of age data used for developing fisheries management objectives. We assessed within-reader, between-reader, and between-method precision (coefficient of variation, CV%) and bias of age estimations for long-lived lake trout, Salvelinus namaycush, from Great Bear Lake using three readers with different levels of experience. The assessment used independent age estimates (n = 3 per reader) from whole and transverse-sectioned otoliths (range = 1–67 years), and pelvic fin-ray sections (range = 3–26 years). We also examined between-method differences in assigned confidence scores. Within readers, age estimates from sectioned otoliths were more precise (2.6–3.0%) than whole (3.6–4.5%) otoliths. Between whole and sectioned otoliths, precision of age estimates was 5.4% and bias was low up to age 20. Age was typically under-estimated from whole otoliths compared to sections for fish ≥ 34 years. Increased reader confidence was correlated with greater precision and younger age estimates, particularly for whole otoliths, but less so for fin rays. Age was estimated with higher confidence from otolith sections than other methods. The least experienced reader estimated age with the lowest precision, and between-reader bias was evident among older ages. Age was consistently under-estimated and less precise from pelvic fins compared to sectioned otoliths, and are therefore an unsuitable non-lethal alternative. Sectioned otoliths revealed longevity was greater (67 years) than historically documented using whole otoliths (53 years) for these fish. Our findings contribute to those relying on otoliths or pelvic fin rays to estimate ages of long-lived lake trout populations, which are a key component of freshwater fauna in polar North America.
In vivo cardiopulmonary impact of skeletal M3Dq DREADD expression: a pilot study
Authors: Vincent Sandra G. , Fisher John T.
Published: July 2021

The muscarinic M3 receptor (M3R) is implicated in cardiopulmonary control and many other peripheral physiologic functions. Previous observations report mortality in mice expressing a Gq-linked designer G-protein coupled receptor (Dq) selectively in striated muscle, while M3Dq DREADD (Designer Receptor Exclusively Activated by Designer Drug), selectively expressed in skeletal muscle (SKM) impacts glucose metabolism. We investigated whether activation of SKM M3Dq impacts cardiopulmonary function. Heart rate (HR), body temperature (Tb) and locomotor activity (ACT) were measured in 4 conscious, chronically instrumented M3Dq DREADD mice and 4 wildtype controls. Circadian values of HR, BT and ACT were not different between genotypes (p > 0.05). Activation of the M3Dq DREADD by clozapine N-oxide (CNO; 0.1 mg/kg) resulted in: a significant drop in heart rate, 2 h after injection, compared with a time-matched baseline control period from the same animals (460 ± 28 vs. 532 ± 6, p < 0.05), significantly lower ACT compared to the baseline control (p < 0.05) and reduced pulmonary minute ventilation compared to pre-CNO control (p < 0.05). M3Dq DREADD activation did not cause bronchoconstriction (separate protocol), however, there was a concomitant reduction in HR, Tb and ventilation, accompanied by cardiac arrhythmias. We speculate that reductions in Tb, HR and ventilation reflect a mechanistic link between SKM Gq signaling and the metabolic responses associated with the initiation of torpor. Supported by the Canadian Institutes of Health Research (CIHR MOP-81211).
Sufficient Spectral Radius Conditions for Hamilton-Connectivity of k-Connected Graphs
Authors: Zhou Qiannan , Broersma Hajo , Wang Ligong , Lu Yong
Published: July 2021

We present two new sufficient conditions in terms of the spectral radius $$\rho (G)$$

ρ
(
G
)

guaranteeing that a k-connected graph G is Hamilton-connected, unless G belongs to a collection of exceptional graphs. We use the Bondy–Chvátal closure to characterize these exceptional graphs.
Failed preoperative vacuum bell therapy does not affect outcomes following minimally invasive repair of pectus excavatum
Authors: Muff J. L. , Guglielmetti L. C. , Gros S. J. , Buchmüller L. , Frongia G. , Haecker F. -M. , Holland-Cunz S. G. , de Trey T. , Vuille-dit-Bille Raphael N.
Published: July 2021

Purpose

It is unknown if failed preoperative vacuum bell (VB) treatment in patients undergoing minimally invasive repair of pectus excavatum (MIRPE), delays repair and/or affects postoperative outcomes.

Methods

A retrospective data analysis including all consecutive patients treated at one single institution undergoing MIRPE was performed between 2000 and 2016. Patients were stratified into preoperative VB therapy versus no previous VB therapy.

Results

In total, 127 patients were included. Twenty-seven (21.3%) patients had preoperative VB treatment for 17 months (median, IQR 8–34). All 27 patients stopped VB treatment due to the lack of treatment effect. Eight (47.1%) of 17 assessed VB patients showed signs of skin irritation or hematoma. VB treatment had no effect on length of hospital stay (p = 0.385), postoperative complications (p = 1.0), bar dislocations (p = 1.0), and duration of bar treatment (p = 0.174). Time spent in intensive care unit was shorter in patients with VB therapy (p = 0.007). Long-term perception of treatment including rating of primary operation (p = 0.113), pain during primary operation (p = 0.838), own perspective of look of chest (p = 0.545), satisfaction with the procedure (p = 0.409), and intention of doing surgery again (p = 1.0) were not different between groups.

Conclusions

Failed preoperative VB therapy had no or minimal effect on short-term outcomes and long-term perceptions following MIRPE.
Neuronal spreading and plaque induction of intracellular Aβ and its disruption of Aβ homeostasis
Authors: Roos Tomas T. , Garcia Megg G. , Martinsson Isak , Mabrouk Rana , Israelsson Bodil , Deierborg Tomas , Kobro-Flatmoen Asgeir , Tanila Heikki , Gouras Gunnar K.
Published: July 2021

The amyloid-beta peptide (Aβ) is thought to have prion-like properties promoting its spread throughout the brain in Alzheimer’s disease (AD). However, the cellular mechanism(s) of this spread remains unclear. Here, we show an important role of intracellular Aβ in its prion-like spread. We demonstrate that an intracellular source of Aβ can induce amyloid plaques in vivo via hippocampal injection. We show that hippocampal injection of mouse AD brain homogenate not only induces plaques, but also damages interneurons and affects intracellular Aβ levels in synaptically connected brain areas, paralleling cellular changes seen in AD. Furthermore, in a primary neuron AD model, exposure of picomolar amounts of brain-derived Aβ leads to an apparent redistribution of Aβ from soma to processes and dystrophic neurites. We also observe that such neuritic dystrophies associate with plaque formation in AD-transgenic mice. Finally, using cellular models, we propose a mechanism for how intracellular accumulation of Aβ disturbs homeostatic control of Aβ levels and can contribute to the up to 10,000-fold increase of Aβ in the AD brain. Our data indicate an essential role for intracellular prion-like Aβ and its synaptic spread in the pathogenesis of AD.