bluuebunny/crossref_metadata_2025 huggingface dataset:
Quorum Tree Abstractions of Consensus Protocols
Authors: Cirisci Berk , Enea Constantin , Mutluergil Suha Orhun
Published: April 2023

Distributed algorithms solving agreement problems like consensus or state machine replication are essential components of modern fault-tolerant distributed services. They are also notoriously hard to understand and reason about. Their complexity stems from the different assumptions on the environment they operate with, i.e., process or network link failures, Byzantine failures etc. In this paper, we propose a novel abstract representation of the dynamics of such protocols which focuses on quorums of responses (votes) to a request (proposal) that form during a run of the protocol. We show that focusing on such quorums, a run of a protocol can be viewed as working over a tree structure where different branches represent different possible outcomes of the protocol, the goal being to stabilize on the choice of a fixed branch. This abstraction resembles the description of recent protocols used in Blockchain infrastructures, e.g., the protocol supporting Bitcoin or Hotstuff. We show that this abstraction supports reasoning about the safety of various algorithms, e.g., Paxos, PBFT, Raft, and HotStuff, in a uniform way. In general, it provides a novel induction based argument for proving that such protocols are safe.
MAG$$\pi $$: Types for Failure-Prone Communication
Authors: Le Brun Matthew Alan , Dardha Ornela
Published: April 2023

Multiparty Session Types(MPST) are a typing discipline for communication-centric systems, guaranteeing communication safety, deadlock freedom and protocol compliance. Several works have emerged which model failures and introduce fault-tolerance techniques. However, such works often make assumptions on the underlying network,e.g., assuming TCP-based communication where messages are guaranteed to be delivered; or adopting centralised reliable nodes and ad-hoc notions of reliability; or only addressing a single kind of failure, such as node crashes. In this work, we develop MAG$$\pi $$π—a Multiparty, Asynchronous and Generalised$$\pi $$π-calculus, which is thefirst language and type systemto accommodate in unison: (i) the widest range of non-Byzantine faults, includingmessage loss, delaysandreordering;crashandlink failures; andnetwork partitioning; (ii) a novel and most general notion ofreliability, taking into account the viewpoint ofeachparticipant in the protocol; (iii) a spectrum of network assumptions from the lowest UDP-based network programming to the TCP-based application level. We prove subject reduction and session fidelity; process properties (deadlock freedom, termination,etc.); failure-handling safety and reliability adherence.
System $$F^\mu _\omega $$ with Context-free Session Types
Authors: Poças Diogo , Costa Diana , Mordido Andreia , Vasconcelos Vasco T.
Published: April 2023

We study increasingly expressive type systems, from$$F^\mu $$Fμ—an extension of the polymorphic lambda calculus with equirecursive types—to$$F^{\mu ;}_\omega $$Fωμ;—the higher-order polymorphic lambda calculus with equirecursive types and context-free session types. Type equivalence is given by a standard bisimulation defined over a novel labelled transition system for types. Our system subsumes the contractive fragment of$$F^\mu _\omega $$Fωμas studied in the literature. Decidability results for type equivalence of the various type languages are obtained from the translation of types into objects of an appropriate computational model: finite-state automata, simple grammars and deterministic pushdown automata. We show that type equivalence is decidable for a significant fragment of the type language. We further propose a message-passing, concurrent functional language equipped with the expressive type language and show that it enjoys preservation and absence of runtime errors for typable processes.
Bunched Fuzz: Sensitivity for Vector Metrics
Authors: wunder june , Amorim Arthur Azevedo de , Baillot Patrick , Gaboardi Marco
Published: April 2023

Program sensitivity measures the distance between the outputs of a program when run on two related inputs. This notion, which plays a key role in areas such as data privacy and optimization, has been the focus of several program analysis techniques introduced in recent years. Among the most successful ones, we can highlight type systems inspired by linear logic, as pioneered by Reed and Pierce in the Fuzz programming language. In Fuzz, each type is equipped with its own distance, and sensitivity analysis boils down to type checking. In particular, Fuzz features two product types, corresponding to two different notions of distance: the tensor product combines the distances of each component by adding them, while the with product takes their maximum.

In this work, we show that these products can be generalized to arbitrary $$L^p$$

L
p

distances, metrics that are often used in privacy and optimization. The original Fuzz products, tensor and with, correspond to the special cases $$L^1$$

L
1

and $$L^\infty $$

L
∞

. To ease the handling of such products, we extend the Fuzz type system with bunches—as in the logic of bunched implications—where the distances of different groups of variables can be combined using different $$L^p$$

L
p

distances. We show that our extension can be used to reason about quantitative properties of probabilistic programs.
Fast and Correct Gradient-Based Optimisation for Probabilistic Programming via Smoothing
Authors: Khajwal Basim , Ong C.-H. Luke , Wagner Dominik
Published: April 2023

We study the foundations of variational inference, which frames posterior inference as an optimisation problem, for probabilistic programming. The dominant approach for optimisation in practice is stochastic gradient descent. In particular, a variant using the so-called reparameterisation gradient estimator exhibits fast convergence in a traditional statistics setting. Unfortunately, discontinuities, which are readily expressible in programming languages, can compromise the correctness of this approach. We consider a simple (higher-order, probabilistic) programming language with conditionals, and we endow our language with both a measurable and asmoothed(approximate) value semantics. We present type systems which establish technical pre-conditions. Thus we can prove stochastic gradient descent with the reparameterisation gradient estimator to be correct when applied to the smoothed problem. Besides, we can solve the original problem up to any error tolerance by choosing an accuracy coefficient suitably. Empirically we demonstrate that our approach has a similar convergence as a key competitor, but is simpler, faster, and attains orders of magnitude reduction in work-normalised variance.
Type-safe Quantum Programming in Idris
Authors: Dandy Liliane-Joy , Jeandel Emmanuel , Zamdzhiev Vladimir
Published: April 2023

Variational Quantum Algorithms are hybrid classical-quantum algorithms where classical and quantum computation work in tandem to solve computational problems. These algorithms create interesting challenges for the design of suitable programming languages. In this paper we introduce Qimaera, which is a set of libraries for the Idris 2 programming language that enable the programmer to implement hybrid classical-quantum algorithms where the full power of the elegant Idris language works in synchrony with quantum programming primitives. The two key ingredients of Idris that make this possible are (1) dependent types which allow us to implement unitary quantum operations; and (2) linearity which allows us to enforce fine-grained control over the execution of quantum operations so that we may detect and reject many physically inadmissible programs. We also show that Qimaera is suitable for variational quantum programming by providing implementations of two prominent variational quantum algorithms – QAOA and VQE.
Automatic Alignment in Higher-Order Probabilistic Programming Languages
Authors: Lundén Daniel , Çaylak Gizem , Ronquist Fredrik , Broman David
Published: April 2023

Probabilistic Programming Languages (PPLs) allow users to encode statistical inference problems and automatically apply an inference algorithm to solve them. Popular inference algorithms for PPLs, such as sequential Monte Carlo (SMC) and Markov chain Monte Carlo (MCMC), are built around checkpoints—relevant events for the inference algorithm during the execution of a probabilistic program. Deciding the location of checkpoints is, in current PPLs, not done optimally. To solve this problem, we present a static analysis technique that automatically determines checkpoints in programs, relieving PPL users of this task. The analysis identifies a set of checkpoints that execute in the same order in every program run—they are aligned. We formalize alignment, prove the correctness of the analysis, and implement the analysis as part of the higher-order functional PPL Miking CorePPL. By utilizing the alignment analysis, we design two novel inference algorithm variants: aligned SMC and aligned lightweight MCMC. We show, through real-world experiments, that they significantly improve inference execution time and accuracy compared to standard PPL versions of SMC and MCMC.
Adversarial Reachability for Program-level Security Analysis
Authors: Ducousso Soline , Bardin Sébastien , Potet Marie-Laure
Published: April 2023

Many program analysis tools and techniques have been developed to assess program vulnerability. Yet, they are based on the standard concept of reachability and represent an attacker able to craft smartlegitimateinput, while in practice attackers can be much more powerful, using for instance micro-architectural exploits or fault injection methods. We introduceadversarial reachability, a framework allowing to reason about suchadvanced attackersand check whether a system is vulnerable or immune to a particular attacker. As equipping the attacker with new capacities significantly increases the state space of the program under analysis, we present a new symbolic exploration algorithm, namelyadversarial symbolic execution, injecting faults in aforklessmanner to prevent path explosion, together with optimizations dedicated to reduce the number of injections to consider while keeping the same attacker power. Experiments on representative benchmarks from fault injection show that our method significantly reduces the number of adversarial paths to explore, allowing to scale up to 10 faults where prior work timeout for 3 faults. In addition, we analyze the well-tested WooKey bootloader, and demonstrate the ability of our analysis to find attacks and evaluate countermeasures in real-life security scenarios. We were especially able to find an attack not mentioned in a previous patch.
Automated Grading of Regular Expressions
Authors: Kim Su-Hyeon , Kim Youngwook , Han Yo-Sub , Im Hyeonseung , Ko Sang-Ki
Published: April 2023

With the rapid transition to distance learning, automatic grading software becomes more important to both teachers and students. We study the problem of automatically grading the regular expressions submitted by students in courses related to automata and formal language theory. In order to utilize the semantic information of the regular expression, we define a declarative logic that can be described by regular language and at the same time has natural language characteristics, and use it for the following tasks: 1) to assign partial grades for incorrect regular expressions and 2) to provide helpful feedback to students to make them understand the reason for the grades and a way to revise the incorrect regular expressions into correct ones. We categorize the cases when students’ incorrect submissions deserve partial grades and suggest how to assign appropriate grades for each of the cases. In order to optimize the runtime complexity of the algorithm, two heuristics based on automata theory are proposed and evaluated on the dataset collected from undergraduate students. In addition, we suggest Regex2NL which translates regular expressions to natural language descriptions to give insight to students so that they can understand how the regular expressions work.
Builtin Types Viewed as Inductive Families
Authors: Allais Guillaume
Published: April 2023

State of the art optimisation passes for dependently typed languages can help erase the redundant information typical of invariant-rich data structures and programs. These automated processes do not dramatically change the structure of the data, even though more efficient representations could be available.

Using Quantitative Type Theory as implemented in Idris 2, we demonstrate how to define an invariant-rich, typechecking-time data structure packing an efficient runtime representation together with runtime irrelevant invariants. The compiler can then aggressively erase all such invariants during compilation.

Unlike other approaches, the complexity of the resulting representation is entirely predictable, we do not require both representations to have the same structure, and yet we are able to seamlessly program as if we were using the high-level structure.
Pragmatic Gradual Polymorphism with References
Authors: Ye Wenjia , Oliveira Bruno C. d. S.
Published: April 2023

Gradualizing System F has been widely discussed. A big challenge is to preserve relational parametricity and/or the gradual guarantee. Most past work has focused on the preservation of parametricity, but often without the gradual guarantee. A few recent works satisfy both properties by giving up System F syntax, or with some restrictions and the introduction of sophisticated mechanisms in the dynamic semantics.

While parametricity is important for polymorphic languages, most mainstream languages typically do not satisfy it, for a variety of different reasons. In this paper, we explore the design space of polymorphic languages that satisfy the gradual guarantee, but do not preserve parametricity. When parametricity is not a goal, the design of polymorphic gradual languages can be considerably simplified. Moreover, it becomes easy to add features that are of practical importance, such as mutable references. We present a new gradually typed polymorphic calculus, called $$\lambda ^{G}_{gpr}$$

λ

gpr

G

, with mutable references and with an easy proof of the gradual guarantee. In addition, compared to other gradual polymorphism work, $$\lambda ^{G}_{gpr}$$

λ

gpr

G

is defined using a Type-Directed Operational Semantics (TDOS), which allows the dynamic semantics to be defined directly instead of elaborating to a target cast language. $$\lambda ^{G}_{gpr}$$

λ

gpr

G

and all the proofs in this paper are formalized in Coq.
Gradual Tensor Shape Checking
Authors: Hattori Momoko , Kobayashi Naoki , Sato Ryosuke
Published: April 2023

Tensor shape mismatch is a common source of bugs in deep learning programs. We propose a new type-based approach to detect tensor shape mismatches. One of the main features of our approach is the best-effort shape inference. As the tensor shape inference problem is undecidable in general, we allow static type/shape inference to be performed only in a best-effort manner. If the static inference cannot guarantee the absence of the shape inconsistencies, dynamic checks are inserted into the program. Another main feature is gradual typing, where users can improve the precision of the inference by adding appropriate type annotations to the program. We formalize our approach and prove that it satisfies the criteria of gradual typing proposed by Siek et al. in 2015. We have implemented a prototype shape checking tool based on our approach and evaluated its effectiveness by applying it to some deep neural network programs.
A Type System for Effect Handlers and Dynamic Labels
Authors: de Vilhena Paulo Emílio , Pottier François
Published: April 2023

We consider a simple yet expressive $$\lambda $$
λ
-calculus equipped with references, effect handlers, and dynamic allocation of effect labels, and whose operational semantics does not involve coercions or rely on type information. We equip this language with a type system that supports type and effect polymorphism, allows reordering row entries and extending a row with new entries, and supports (but is not restricted to) lexically scoped handlers. This requires addressing the issue of potential aliasing between effect names. Our original solution is to interpret a row not only as a permission to perform certain effects but also as a disjointness requirement bearing on effect names. The type system guarantees strong type soundness: a well-typed program cannot crash or perform an unhandled effect. We prove this fact by encoding the type system into a novel Separation Logic for effect handlers, which we build on top of Iris. Our results are formalized in Coq.
Coverability in 2-VASS with One Unary Counter is in NP
Authors: Mazowiecki Filip , Sinclair-Banks Henry , Węgrzycki Karol
Published: April 2023

Coverability in Petri nets finds applications in verification of safety properties of reactive systems. We study coverability in the equivalent model: Vector Addition Systems with States (VASS).

A k-VASS can be seen as k counters and a finite automaton whose transitions are labelled with k integers. Counter values are updated by adding the respective transition labels. A configuration in this system consists of a state and k counter values. Importantly, the counters are never allowed to take negative values. The coverability problem asks whether one can traverse the k-VASS from the initial configuration to a configuration with at least the counter values of the target.

In a well-established line of work on k-VASS, coverability in 2-VASS is already -hard when the integer updates are encoded in binary. This lower bound limits the practicality of applications, so it is natural to focus on restrictions. In this paper we initiate the study of 2-VASS with one unary counter. Here, one counter receives binary encoded updates and the other receives unary encoded updates. Our main result is that coverability in 2-VASS with one unary counter is in . This improves upon the inherited state-of-the-art upper bound. Our main technical contribution is that one only needs to consider runs in a certain compressed linear form.
Fixed Points and Noetherian Topologies
Authors: Lopez Aliaume
Published: April 2023

Noetherian spaces are a generalisation of well-quasi-orderings to topologies, that can be used to prove termination of programs. They find applications in the verification of transition systems, some of which are better described using topology. The goal of this paper is to allow the systematic description of computations using inductively defined datatypes via Noetherian spaces. This is achieved through a fixed point theorem based on a topological minimal bad sequence argument.
A Formal Logic for Formal Category Theory
Authors: New Max S. , Licata Daniel R.
Published: April 2023

We present a domain-specific type theory for constructions and proofs in category theory. The type theory axiomatizes notions of category, functor, profunctor and a generalized form of natural transformations. The type theory imposes an ordered linear restriction on standard predicate logic, which guarantees that all functions between categories are functorial, all relations are profunctorial, and all transformations are natural by construction, with no separate proofs necessary. Important category-theoretic proofs such as the Yoneda lemma and Co-yoneda lemma become simple type-theoretic proofs about the relationship between unit, tensor and (ordered) function types, and can be seen to be ordered refinements of theorems in predicate logic. The type theory is sound and complete for a categorical model in virtual equipments, which model both internal and enriched category theory. While the proofs in our type theory look like standard set-based arguments, the syntactic discipline ensure that all proofs and constructions carry over to enriched and internal settings as well.
Non-operative management for osteochondral lesions of the talus: a systematic review of treatment modalities, clinical- and radiological outcomes
Authors: Buck Tristan M. F. , Lauf Kenny , Dahmen Jari , Altink J. Nienke , Stufkens Sjoerd A. S. , Kerkhoffs Gino M. M. J.
Published: April 2023

Purpose

The purpose of the present study was to assess the overall clinical success rate of non-operative management for osteochondral lesions of the talus (OLT).

Methods

A literature search was conducted in the PubMed (MEDLINE), COCHRANE and EMBASE (Ovid) databases. Clinical success rates per separate study were calculated at the latest moment of follow-up and were defined as successful when a good or excellent clinical result at follow-up was reported in a qualitative manner or when a post-operative American Orthopaedic Foot and Ankle Society (AOFAS) score at or above 80 was reached. When clinical outcomes were based on other clinical scoring systems, outcomes reported as good or excellent were considered as clinical success. Studies methodologically eligible for a simplified pooling method were combined to calculate an overall pooled clinical success rate. Radiological changes over the course of conservative treatment were assessed either considering local OLT changes and/or overall ankle joint changes.

Results

Thirty articles were included, including an overall of 868 patients. The median follow-up of the included studies was 37 months (range: 3–288 months). A simplified pooling method was possible among 16 studies and yielded an overall pooled clinical success rate of 45% (95% CI 40–50%). As assessed with plain radiographs, progression of ankle joint osteoarthritis was observed in of 9% (95% CI 6–14%) of the patients. As assessed through a Computed Tomography (CT) scan, focal OLT deterioration was observed in 11% (95% CI 7–18%) of the patients. As assessed with a Magnetic Resonance Imaging (MRI) scan, focal OLT deterioration was observed in 12% (95% CI 6–24%) of the patients. An unchanged lesion was detected on plain radiographs in 53% (48/91; CI 43–63%), 76% (99/131; 95% CI 68–82%) on a CT scan and on MRI in 84% (42/50; 95% CI 71–92%) of the patients.

Conclusion

The current literature on non-operative management of OLTs is scarce and heterogeneous on indication and type of treatment. Promising clinical results are presented but need to interpreted with caution due to the heterogeneity in indication, duration and type of treatment. Further studies need to focus on specific types on conservative management, indications and its results.

Level of evidence

Systematic review, Level IV.
Switchable CAR T cell strategy against osteosarcoma
Authors: Hidalgo Laura , Somovilla-Crespo Beatriz , Garcia-Rodriguez Patricia , Morales-Molina Alvaro , Rodriguez-Milla Miguel Angel , Garcia-Castro Javier
Published: April 2023

Immunotherapy with chimeric antigen receptor T (CAR T) cells has changed the treatment of hematological malignances, but they are still a challenge for solid tumors, including pediatric sarcomas. Here, we report a switchable CAR T cell strategy based on anti-FITC CAR T cells and a switch molecule conjugated with FITC for targeting osteosarcoma (OS) tumors. As a potential target, we analyzed the expression of B7-H3, an immune checkpoint inhibitor, in OS cell lines. In addition, we evaluate the capacity of an anti-B7-H3 monoclonal antibody conjugated with FITC (anti-B7-H3-FITC mAb) to control the antitumor activity of anti-FITC CAR T cells. The effector functions of anti-FITC CAR T cells against OS, measured in vitro by tumor cell killing activity and cytokine production, are dependent on the presence of the anti-B7-H3-FITC mAb switch. Moreover, OS cells stimulate anti-FITC CAR T cells migration. In vivo, anti-B7-H3 mAb penetrates in the tumor and binds 143B OS tumor cells. Furthermore, anti-FITC CAR T cells reach tumor region and exert antitumor effect in an OS NSG mouse model only in the presence of the switch molecule. We demonstrate that anti-B7-H3-FITC mAb redirects the cytotoxic activity of anti-FITC CAR T cells against OS tumors suggesting that switchable CAR T cell platforms might be a plausible strategy against OS.
ACL reconstruction provides superior stability than ACL repair in patients with Schenck III and IV knee joint dislocations: first results of a 12 month follow-up study
Authors: Fahlbusch H. , Behrendt P. , Akoto R. , Frosch K. H. , Krause M.
Published: April 2023

Purpose

Acute knee dislocation is a rare but devastating multi-ligamentous knee injury with only limited evidence-based surgical technique recommendations. The aim of this study was a comparison of two different anterior cruciate ligament (ACL) restoration techniques as part of an early total surgical care concept: (1) repair of ACL with additional internal bracing (ACLIB) compared to; (2) ACL reconstruction with autograft (ACLR).

Methods

Retrospective, clinical-study of patients with an acute type III or IV knee dislocation (according to Schenck classification), in which the ACL was treated with ACLIB or ACLR within 12 days. The PCL was sutured and internally braced in all cases. Medial and lateral complex injuries were repaired and additionally laterally augmented by an Arciero reconstruction. After a minimum 12 months follow-up different patient-reported outcome measurements (IKDC, Lysholm, VAS, Tegner Score) and instrumental stability assessment by Rolimeter -test and stress radiographs (Telos™) were analyzed. Groups were compared by t test with p < 0.05 considered significant.

Results

In total, 20 patients (5 IIIM, 5 IIIL and 10 IV) were included in this study with an average follow-up of 13.7 ± 2.6 months. There were significant differences in instrumental stability testing (side-to-side difference (SSD) of anterior tibial translation: ACLIB 2.7 ± 1.5 mm vs. ACLR 1.3 ± 1.3; p = 0.0339) and stress radiography (SSD ACL: ACLIB 3.4 ± 2.2 mm vs. ACLR 0.4 ± 2.7; p = 0.0249) between groups. ACLIB group showed greater ROM in terms of flexion (SSD Flexion: ACLIB 7.8 ± 9.9° vs. ACLR 16 ± 7.0°; p = 0.0466; Total Flexion overall 125.5 ± 11.8°). No clinically relevant differences in patient-reported outcome scores (Lysholm Score: ACLIB 82 ± 16.4 vs. ACLR 85 ± 10.4; IKDC subjective score: ACLIB 70.4 ± 17 vs. ACLR 76.6 ± 8.3) were determined.

Conclusion

ACLR provides superior translational stability than ACLIB in terms of instrumental testing and stress radiography. Both techniques were equivalent with respect to PROMS and led to good and excellent clinical results.

Level of evidence

Retrospective cohort study, III.
Patient- and cycle-specific factors affecting the outcome of frozen–thawed embryo transfers
Authors: Holschbach Verena , Kordes Hannah , Dietrich Jens Erik , Bruckner Thomas , Strowitzki Thomas , Germeyer Ariane
Published: April 2023

Purpose

This study attempted at identifying the main parameters influencing the outcome of frozen embryo transfers.

Methods

This is a single-center retrospective cohort study of 830 frozen-embryo-transfer cycles performed at a German university hospital from January 2012 to December 2016. Main outcome parameters were the clinical pregnancy and live birth rate. Twelve patient- and cycle-dependent factors were analyzed in terms of their influence on the outcome of frozen embryo transfers. Multivariate logistic regression analysis was used for the modelling of the dependency of the different parameters on outcomes.

Results

The clinical pregnancy rate in our study was 25.5%, the live birth rate was 16.1% with an average maternal age of 34.2 years at the time of the oocyte retrieval. In the univariate analysis age, number of transferred embryos, blastocyst versus cleavage stage transfer, embryo quality and mode of endometrial preparation affected the birth rate significantly. The birth rate after artificial endometrial preparation was significantly lower than the birth rate after transfers in modified natural cycles (12.8 versus 20.6% with p = 0.031). The multivariate logistic regression analysis showed a significant independent influence of age, number of transferred embryos, culture duration and mode of endometrial preparation on the frozen embryo transfer success rates. Body mass index, nicotine abuse, a history of PCO syndrome or endometriosis and the co-transfer of a second poor-quality embryo to a good-quality embryo appeared to be irrelevant for the outcome in our collective.

Conclusion

Age, number of transferred embryos, embryo culture duration and the mode of endometrial preparation are independent predictive factors of frozen embryo transfer outcomes.
Space radiation quality factor for Galactic Cosmic Rays and typical space mission scenarios using a microdosimetric approach
Authors: Papadopoulos Alexis , Kyriakou Ioanna , Incerti Sébastien , Santin Giovanni , Nieminen Petteri , Daglis Ioannis A. , Li Weibo , Emfietzoglou Dimitris
Published: April 2023

Space radiation exposure from omnipresent Galactic Cosmic Rays (GCRs) in interplanetary space poses a serious carcinogenic risk to astronauts due to the—limited or absent—protective effect of the Earth’s magnetosphere and, in particular, the terrestrial atmosphere. The radiation risk is directly influenced by the quality of the radiation, i.e., its pattern of energy deposition at the micron/DNA scale. For stochastic biological effects, radiation quality is described by the quality factor, $$Q$$
Q
, which can be defined as a function of Linear Energy Transfer (LET) or the microdosimetric lineal energy ($$y$$
y
). In the present work, the average $$Q$$
Q
of GCR for different mission scenarios was calculated using a modified version of the microdosimetric Theory of Dual Radiation Action (TDRA). NASA’s OLTARIS platform was utilized to generate the radiation environment behind different aluminum shielding (0–30 g/cm2) for a typical mission scenario in low-earth orbit (LEO) and in deep space. The microdosimetric lineal energy spectra of ions ($$Z\ge 1$$

Z
≥
1

) in 1 μm liquid water spheres were calculated by a generalized analytical model which considers energy-loss fluctuations and δ-ray transport inside the irradiated medium. The present TDRA-based $$Q$$
Q
-values for the LEO and deep space missions were found to differ by up to 10% and 14% from the corresponding ICRP-based $$Q$$
Q
-values and up to 3% and 6% from NASA’s $$Q$$
Q
-model. In addition, they were found to be in good agreement with the $$Q$$
Q
-values measured in the International Space Station (ISS) and by the Mars Science Laboratory (MSL) Radiation Assessment Detector (RAD) which represent, respectively, a LEO and deep space orbit.
An observational cohort study on pulmonary function in adult patients with 5q-spinal muscular atrophy under nusinersen therapy
Authors: Bjelica Bogdan , Wohnrade Camilla , Osmanovic Alma , Schreiber-Katz Olivia , Petri Susanne
Published: April 2023

Background

Few studies assessed the effect of nusinersen on respiratory function in adult patients with spinal muscular atrophy (SMA). The aim of this single-center study was to analyze pulmonary function and its association with muscle function and quality of life (QoL) in adult patients with 5q-SMA under nusinersen.

Methods

We recorded forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and peak expiratory flow (PEF) during nusinersen treatment in 38 adult SMA patients. Revised Upper Limb Module (RULM), Hammersmith Functional Motor Scale Expanded (HFMSE), 36-Item Short Form Health Survey (SF-36) questionnaire and Fatigue Severity Scale (FSS) were recorded and correlations between muscle function, QoL, fatigue and respiratory parameters were analyzed.

Results

No differences were detected between mean FVC, FEV1, PEF at different timepoints versus baseline. Ambulatory patients showed significant improvement in mean PEF at month 30, compared to non-ambulatory patients (+ 0.8 ± 0.5 vs. − 0.0 ± 0.5, p < 0.05). Patients with fatigue at baseline showed significant improvement in mean PEF at month 10, compared to patients without fatigue at baseline (+ 0.6 ± 0.9 vs. − 0.4 ± 0.5, p < 0.05). Physical domains of SF-36 positively correlated with the change in FVC and FEV1. FSS negatively correlated with the change in mean PEF.

Conclusion

Mean pulmonary function remained stable during nusinersen treatment over a period of up to 30 months. Improvement in pulmonary function was associated with improvement in motor function, fatigue and QoL, early after nusinersen initiation.
Cancer of unknown primary (CUP) through the lens of precision oncology: a single institution perspective
Authors: Weiss L. , Heinrich K. , Zhang D. , Dorman K. , Rühlmann K. , Hasselmann K. , Klauschen F. , Kumbrink J. , Jung A. , Rudelius M. , Mock A. , Ormanns Steffen , Kunz W. G. , Roessler D. , Beyer G. , Corradini S. , Heinzerling L. , Haas M. , von Bergwelt-Baildon M. , Boeck S. , Heinemann V. , Westphalen C. B.
Published: April 2023

Purpose

For patients with cancer of unknown primary (CUP), treatment options are limited. Precision oncology, the interplay of comprehensive genomic profiling (CGP) and targeted therapies, aims to offer additional treatment options to patients with advanced and hard-to-treat cancers. We aimed to highlight the use of a molecular tumor board (MTB) in the therapeutic management of CUP patients.

Methods

In this single-center observational study, CUP patients, presented to the MTB of the Comprehensive Cancer Center Munich LMU, a tertiary care center, were analyzed retrospectively. Descriptive statistics were applied to describe relevant findings.

Results

Between June 2016 and February 2022, 61 patients with unfavorable CUP were presented to the MTB, detected clinically relevant variants in 74% (45/61) of patients, of which 64% (29/45) led to therapeutic recommendation. In four out of 29 patients (14%), the treatment recommendations were implemented, unfortunately without resulting in clinical benefit. Reasons for not following the therapeutic recommendation were mainly caused by the physicians’ choice of another therapy (9/25, 36%), especially in the context of worsening of general condition, lost to follow-up (7/25, 28%) and death (6/25, 24%).

Conclusion

CGP and subsequent presentation to a molecular tumor board led to a high rate of therapeutic recommendations in patients with CUP. Recommendations were only implemented at a low rate; however, late GCP diagnostic and, respectively, MTB referral were found more frequent for the patients with implemented treatment. This contrast underscores the need for early implementation of CGP into the management of CUP patients.
Clinical and genome-wide association analysis of chemoradiation-induced hearing loss in nasopharyngeal carcinoma
Authors: He Yong-Qiao , Luo Lu-Ting , Wang Tong-Min , Xue Wen-Qiong , Yang Da-Wei , Li Dan-Hua , Diao Hua , Xiao Ruo-Wen , Deng Chang-Mi , Zhang Wen-Li , Liao Ying , Wu Yan-Xia , Wang Qiao-Ling , Zhou Ting , Li Xi-Zhao , Zheng Xiao-Hui , Zhang Pei-Fen , Zhang Shao-Dan , Hu Ye-Zhu , Sun Ying , Jia Wei-Hua
Published: April 2023

Chemoradiation-induced hearing loss (CRIHL) is one of the most devasting side effects for nasopharyngeal carcinoma (NPC) patients, which seriously affects survivors’ long-term quality of life. However, few studies have comprehensively characterized the risk factors for CRIHL. In this study, we found that age at diagnosis, tumor stage, and concurrent cisplatin dose were positively associated with chemoradiation-induced hearing loss. We performed a genome-wide association study (GWAS) in 777 NPC patients and identified rs1050851 (within the exon 2 of NFKBIA), a variant with a high deleteriousness score, to be significantly associated with hearing loss risk (HR = 5.46, 95% CI 2.93–10.18, P = 9.51 × 10–08). The risk genotype of rs1050851 was associated with higher NFKBIA expression, which was correlated with lower cellular tolerance to cisplatin. According to permutation-based enrichment analysis, the variants mapping to 149 hereditary deafness genes were significantly enriched among GWAS top signals, which indicated the genetic similarity between hereditary deafness and CRIHL. Pathway analysis suggested that synaptic signaling was involved in the development of CRIHL. Additionally, the risk score integrating genetic and clinical factors can predict the risk of hearing loss with a relatively good performance in the test set. Collectively, this study shed new light on the etiology of chemoradiation-induced hearing loss, which facilitates high-risk individuals’ identification for personalized prevention and treatment.
A maintenance planning framework using online and offline deep reinforcement learning
Authors: Bukhsh Zaharah A. , Molegraaf Hajo , Jansen Nils
Published: April 2023

Cost-effective asset management is an area of interest across several industries. Specifically, this paper develops a deep reinforcement learning (DRL) solution to automatically determine an optimal rehabilitation policy for continuously deteriorating water pipes. We approach the problem of rehabilitation planning in an online and offline DRL setting. In online DRL, the agent interacts with a simulated environment of multiple pipes with distinct lengths, materials, and failure rate characteristics. We train the agent using deep Q-learning (DQN) to learn an optimal policy with minimal average costs and reduced failure probability. In offline learning, the agent uses static data, e.g., DQN replay data, to learn an optimal policy via a conservative Q-learning algorithm without further interactions with the environment. We demonstrate that DRL-based policies improve over standard preventive, corrective, and greedy planning alternatives. Additionally, learning from the fixed DQN replay dataset in an offline setting further improves the performance. The results warrant that the existing deterioration profiles of water pipes consisting of large and diverse states and action trajectories provide a valuable avenue to learn rehabilitation policies in the offline setting, which can be further fine-tuned using the simulator.
Lewy bodies, iron, inflammation and neuromelanin: pathological aspects underlying Parkinson’s disease
Authors: Riederer Peter , Nagatsu Toshiharu , Youdim Moussa B. H. , Wulf Max , Dijkstra Johannes M. , Sian-Huelsmann Jeswinder
Published: April 2023

Since the description of some peculiar symptoms by James Parkinson in 1817, attempts have been made to define its cause or at least to enlighten the pathology of “Parkinson’s disease (PD).” The vast majority of PD subtypes and most cases of sporadic PD share Lewy bodies (LBs) as a characteristic pathological hallmark. However, the processes underlying LBs generation and its causal triggers are still unknown. ɑ-Synuclein (ɑ-syn, encoded by the SNCA gene) is a major component of LBs, and SNCA missense mutations or duplications/triplications are causal for rare hereditary forms of PD. Thus, it is imperative to study ɑ-syn protein and its pathology, including oligomerization, fibril formation, aggregation, and spreading mechanisms. Furthermore, there are synergistic effects in the underlying pathogenic mechanisms of PD, and multiple factors—contributing with different ratios—appear to be causal pathological triggers and progression factors. For example, oxidative stress, reduced antioxidative capacity, mitochondrial dysfunction, and proteasomal disturbances have each been suggested to be causal for ɑ-syn fibril formation and aggregation and to contribute to neuroinflammation and neural cell death. Aging is also a major risk factor for PD. Iron, as well as neuromelanin (NM), show age-dependent increases, and iron is significantly increased in the Parkinsonian substantia nigra (SN). Iron-induced pathological mechanisms include changes of the molecular structure of ɑ-syn. However, more recent PD research demonstrates that (i) LBs are detected not only in dopaminergic neurons and glia but in various neurotransmitter systems, (ii) sympathetic nerve fibres degenerate first, and (iii) at least in “brain-first” cases dopaminergic deficiency is evident before pathology induced by iron and NM. These recent findings support that the ɑ-syn/LBs pathology as well as iron- and NM-induced pathology in “brain-first” cases are important facts of PD pathology and via their interaction potentiate the disease process in the SN. As such, multifactorial toxic processes posted on a personal genetic risk are assumed to be causal for the neurodegenerative processes underlying PD. Differences in ratios of multiple factors and their spatiotemporal development, and the fact that common triggers of PD are hard to identify, imply the existence of several phenotypical subtypes, which is supported by arguments from both the “bottom-up/dual-hit” and “brain-first” models. Therapeutic strategies are necessary to avoid single initiation triggers leading to PD.
Unique immune and inflammatory cytokine profiles may define long COVID syndrome
Authors: Allan-Blitz Lao-Tzu , Akbari Omid , Kojima Noah , Saavedra Edwyn , Chellamuthu Prithivi , Denny Nicholas , MacMullan Melanie A. , Hess Victoria , Shacreaw Maria , Brobeck Matthew , Turner Frederick , Slepnev Vladimir I. , Ibrayeva Albina , Klausner Jeffrey D.
Published: April 2023

Purpose

Long COVID is estimated to occur in 5–10% of individuals after acute SARS-CoV-2 infection. However, the pathophysiology driving the disease process is poorly understood.

Methods

We evaluated urine and plasma inflammatory and immune cytokine profiles in 33 individuals with long COVID compared to 33 who were asymptomatic and recovered, and 34 without prior infection.

Results

Mean urinary leukotriene E4 was significantly elevated among individuals with long COVID compared to asymptomatic and recovered individuals (mean difference 774.2 pg/mL; SD 335.7) and individuals without prior SARS-CoV-2 infection (mean difference 503.1 pg/ml; SD 467.7). Plasma chemokine ligand 6 levels were elevated among individuals with long COVID compared to individuals with no prior SARS-CoV-2 infection (mean difference 0.59 units; SD 0.42). We found no significant difference in angiotensin-converting enzyme 2 antibody levels. Plasma tumor necrosis factor receptor-associated factor 2 (TRAF2) levels were reduced among individuals with long COVID compared to individuals who were asymptomatic and recovered (mean difference = 0.6 units, SD 0.46). Similarly, the mean level of Sarcoma Homology 2-B adapter protein 3 was 3.3 units (SD 1.24) among individuals with long COVID, lower than 4.2 units (SD 1.1) among individuals with recovered, asymptomatic COVID.

Conclusion

Our findings suggest that further studies should be conducted to evaluate the role of leukotriene E4 as a potential biomarker for a diagnostic test. Furthermore, based on reductions in TRAF2, long COVID may be driven in part by impaired TRAF2-dependent immune-mediated inflammation and potentially immune exhaustion.
General patterns of beavers’ selective foraging: how to evaluate the effects of a re-emerging driver of vegetation change along Central European small watercourses
Authors: Juhász Erika , Molnár Zsolt , Bede-Fazekas Ákos , Biró Marianna
Published: April 2023

Along small watercourses, the growth and renewal of native willows and poplars (Salicaceae species) are hindered by the effects of past and recent man-made landscape alteration and climate change, while the selective foraging of the beaver (Castor fiber) is also becoming an increasingly important driver. Knowledge about foraging decisions can refine predictions about vegetational processes and help to develop better nature conservation and forest management strategies. We surveyed the woody plant supply (13,304 units) and its utilization by the beaver at 11 study sites along Central European small watercourses, at two fixed distances from the water. We collected information about the taxon, trunk diameter, and type of utilization (cutting, carving, debarking) of each unit. We built (generalized) linear mixed models aimed at answering questions regarding taxon and diameter preference, their interrelatedness, and their importance in foraging decisions. All of the factors examined had a significant effect on foraging decisions. Utilization was mostly explained by the taxon, with Salicaceae species being generally preferred and utilized in all diameter classes with a high ratio. Several further genera were frequently utilized (mainly Cornus and Ulmus), while others were almost completely avoided (including invasive Amorpha and Robinia). The beavers preferred units with a diameter of 5–9 cm. The type of utilization depended primarily on diameter class. Because native softwoods are the most affected by beaver impact, regardless of trunk diameter, their survival and regrowth should be consciously supported by increasing the water table and improving hydrological conditions.
Parameterizing the cost function of dynamic time warping with application to time series classification
Authors: Herrmann Matthieu , Tan Chang Wei , Webb Geoffrey I.
Published: April 2023

Dynamic time warping (DTW) is a popular time series distance measure that aligns the points in two series with one another. These alignments support warping of the time dimension to allow for processes that unfold at differing rates. The distance is the minimum sum of costs of the resulting alignments over any allowable warping of the time dimension. The cost of an alignment of two points is a function of the difference in the values of those points. The original cost function was the absolute value of this difference. Other cost functions have been proposed. A popular alternative is the square of the difference. However, to our knowledge, this is the first investigation of both the relative impacts of using different cost functions and the potential to tune cost functions to different time series classification tasks. We do so in this paper by using a tunable cost function $$\lambda _{\gamma }$$

λ
γ

with parameter $$\gamma $$
γ
. We show that higher values of $$\gamma $$
γ
place greater weight on larger pairwise differences, while lower values place greater weight on smaller pairwise differences. We demonstrate that training $$\gamma $$
γ
significantly improves the accuracy of both the $${ DTW }$$

DTW

nearest neighbor and Proximity Forest classifiers.
Design Fire Methodology for Vehicle Spaces Onboard Ships
Authors: Koromila Ioanna A. , Spyrou Kostas J.
Published: April 2023

The purpose of this paper is to contribute towards establishing procedures of assessment of the fire safety of Ro–Ro ship cargo spaces, by employing suitable design fires. Data collected from fire experiments involving vehicles are utilized in order to deduce representative heat release rates for common types of passenger cars and heavy goods vehicles (HGVs). An existing mathematical scheme for generating parametric heat release rate curves is extended for handling vehicle fire scenarios. The methodology is demonstrated through a case study. In particular, the Fire Dynamics Simulator (FDS) code is used for investigating fire propagation on the vehicle deck of a Ro–Ro ship, initiated from a single HGV. On this deck are assumed to be transported a combination of cars and HGVs. The evolution of the fire is assessed assuming different ventilation conditions. The circumstances for spreading to adjacent vehicles are examined. Human survivability and the time that the deck remains accessible are evaluated by considering the International Maritime Organization (IMO) life safety performance criteria.