bluuebunny/crossref_metadata_2025_split huggingface dataset:
WICID framework version 1.0: criteria and considerations to guide evidence-informed decision-making on non-pharmacological interventions targeting COVID-19
Authors: Stratil Jan M , Voss Maike , Arnold Laura 
Published: November 2020

IntroductionPublic health decision-making requires the balancing of numerous, often conflicting factors. However, participatory, evidence-informed decision-making processes to identify and weigh these factors are often not possible- especially, in the context of the SARS-CoV-2 pandemic. While evidence-to-decision frameworks are not able or intended to replace stakeholder participation, they can serve as a tool to approach relevancy and comprehensiveness of the criteria considered.ObjectiveTo develop a decision-making framework adapted to the challenges of decision-making on non-pharmacological interventions to contain the global SARS-CoV-2 pandemic.MethodsWe employed the ‘best fit’ framework synthesis technique and used the WHO-INTEGRATE framework as a starting point. First, we adapted the framework through brainstorming exercises and application to case studies. Next, we conducted a content analysis of comprehensive strategy documents intended to guide policymakers on the phasing out of applied lockdown measures in Germany. Based on factors and criteria identified in this process, we developed the WICID (WHO-INTEGRATECOVID-19) framework version 1.0.ResultsTwelve comprehensive strategy documents were analysed. The revised framework consists of 11+1 criteria, supported by 48 aspects, and embraces a complex systems perspective. The criteria cover implications for the health of individuals and populations due to and beyond COVID-19, infringement on liberties and fundamental human rights, acceptability and equity considerations, societal, environmental and economic implications, as well as implementation, resource and feasibility considerations.DiscussionThe proposed framework will be expanded through a comprehensive document analysis focusing on key stakeholder groups across the society. The WICID framework can be a tool to support comprehensive evidence-informed decision-making processes.
Ran GTPase is an independent prognostic marker in malignant melanoma which promotes tumour cell migration and invasion
Authors: Elsheikh Somaia , Kouzoukakis Ilias , Fielden Catherine , Li Wei , Lashin Shaimaa Elsaid , Khair Nadia , Raposo Teresa Pereira , Fadhil Wakkas , Rudland Philip , Aleskandarany Mohammed , Patel Poulam , El-Tanani Mohamed , Ilyas Mohammad 
Published: November 2020

AimsRan GTPase is involved in nucleocytoplasmic shuttling of proteins and is overexpressed in several cancers. The expression of Ran in malignant melanoma (MM) and its functional activity have not been described and were investigated in this study.MethodsThe prognostic value of Ran expression was tested in a series of 185 primary cutaneous MM cases using immunohistochemistry. The functional activity of Ran was investigated in the two melanoma cell lines. Ran expression was knocked down using two siRNAs and the effect on the expression of the c-Met oncogene, a potential downstream target of Ran, was tested. Functional effects of Ran knockdown on cell motility and cell proliferation were also assessed.ResultsPositive Ran expression was seen in 12.4% of MM and was associated with advanced clinical stage and greater Breslow thickness. Positive expression was an independent marker of shorter overall survival (p=0.023). Knockdown of Ran results in decreased expression of c-Met and the downstream c-met signalling targets ERK1/2. There was a significant reduction in cell migration (p<0.001) and cell invasion (p<0.001). c-Met knockdown decreased the expression of Ran through MAPK and PI3K-AKT in A375 cell line, inhibited the cell viability and migration of both A375 and G361 melanoma cell lines while invasion was enhanced.ConclusionRan is a poor prognostic marker in cutaneous MM. It upregulates expression of the oncogene c-Met and, possibly through this, it promotes cell motility which may in turn promote metastasis.
Automated digital enumeration of plasma cells in bone marrow trephine biopsies of multiple myeloma
Authors: Malherbe Jacques A J , Fuller Kathryn A , Mirzai Bob , Augustson Bradley M , Erber Wendy N 
Published: November 2020

AimsDetermination of the number of plasma cells in bone marrow biopsies is required for the diagnosis and ongoing evaluation of plasma cell neoplasms. We developed an automated digital enumeration platform to assess plasma cells identified by antigen expression in whole bone marrow sections in multiple myeloma, and compared it with manual assessments.MethodsBone marrow trephine biopsy specimens from 91 patients with multiple myeloma at diagnosis, remission and relapse were stained for CD138 and multiple myeloma oncogene 1 (MUM1). Manual assessment and digital quantification were performed for plasma cells in the entire trephine section. Concordance rates between manual and digital methods were evaluated for each antigen by intraclass correlation analyses (ICC) with associated Spearman’s correlations.ResultsThe digital platform counted 16 484–1 118 868 cells and the per cent CD138 and MUM1-positive plasma cells ranged from 0.05% to 93.5%. Overall concordance between digital and manual methods was 0.63 for CD138 and 0.89 for MUM1. Concordance was highest with diffuse plasma cell infiltrates (MUM1: ICC=0.90) and lowest when in microaggregates (CD138: ICC=0.13). Manual counts exceeded digital quantifications for both antigens (CD138: mean=26.4%; MUM1: mean=9.7%). Diagnostic or relapse threshold counts, as determined by CD138 manual assessments, were not reached with digital counting for 16 cases (18%).ConclusionsAutomated digital enumeration of the entire, immunohistochemically stained bone marrow biopsy section can accurately determine plasma cell burden, irrespective of pattern and extent of disease (as low as 0.05%). This increases precision over manual visual assessments which tend to overestimate plasma burden, especially for CD138, and when plasma cells are in clusters.
Tissue methylation and demethylation influence translesion synthesis DNA polymerases (TLS) contributing to the genesis of chromosomal abnormalities in myelodysplastic syndrome
Authors: Cavalcante Gabrielle Melo , Borges Daniela Paula , de Oliveira Roberta Taiane Germano , Furtado Cristiana Libardi Miranda , Alves Ana Paula Negreiros Nunes , Sousa Alceu Machado , de Paula Dayrine Silveira , Filho Francisco Dário Rocha , Magalhães Silvia Maria Meira , Ribeiro-Jr Howard Lopes , Pinheiro Ronald Feitosa 
Published: November 2020

AimsDNA methylation has its distribution influenced by DNA demethylation processes with the catalytic conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). Myelodysplastic syndrome (MDS) has been associated with epigenetic dysregulation of genes related to DNA repair system, chronic immune response and cell cycle.MethodsWe evaluated the tissue DNA methylation/hydroxymethylation in bone marrow trephine biopsies of 73 patients with MDS, trying to correlate with the mRNA expression of 21 genes (POLH, POLL, REV3L, POLN, POLQ, POLI, POLK, IRF-1, IRF-2, IRF-3, IRF-4, IRF-5, IRF6, IRF-7, IRF-8,IRF-9, MAD2,CDC20,AURKA,AURKBandTPX2).ResultsTheM-score (5mC) was significantly higher in patients with chromosomal abnormalities than patients with normal karyotype (95% CI –27.127779 to –2.368020; p=0.022). We observed a higher 5mC/5hmC ratio in patients classified as high-risk subtypes compared with low-risk subtypes (95% CI –72.922115 to –1.855662; p=0.040) as well as patients with hypercellular bone marrow compared with patients with normocellular/hypocellular bone marrow (95% CI –69.189259 to –0.511828; p=0.047) and with the presence of dyserythropoiesis (95% CI 17.077703 to 51.331388; p=0.001). DNA pols with translesion activity are significantly influenced by methylation.As5mC immunoexpression increases, the expressions ofPOLH(r=−0.816; r2=0.665; p=0.000), POLQ(r=−0.790; r2=0.624; p=0.001), PCNA(r=−0.635; r2=0.403; p=0.020), POLK(r=−0.633; r2=0.400; p=0.036 andREV1(r=−0.578; r2=0.334; p=0.049) decrease.ConclusionsOur results confirm that there is an imbalance in the DNA methylation in MDS, influencing the development of chromosomal abnormalities which may be associated with the low expression of DNA polymerases with translesion synthesis polymerases activity.
Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma
Authors: Shigeta Kohei , Matsui Aya , Kikuchi Hiroto , Klein Sebastian , Mamessier Emilie , Chen Ivy X , Aoki Shuichi , Kitahara Shuji , Inoue Koetsu , Shigeta Ayako , Hato Tai , Ramjiawan Rakesh R , Staiculescu Daniel , Zopf Dieter , Fiebig Lukas , Hobbs Gabriela S , Quaas Alexander , Dima Simona , Popescu Irinel , Huang Peigen , Munn Lance L , Cobbold Mark , Goyal Lipika , Zhu Andrew X , Jain Rakesh K , Duda Dan G 
Published: November 2020

Background and purposeCombining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models.Basic proceduresWe used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib—dosed orally at 5, 10 or 20 mg/kg daily—combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer.Main findingsRegorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (Rag1-deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10—a ligand for CXCR3 expressed on tumor-infiltrating lymphocytes—in murine HCC and in blood of patients with HCC. UsingCxcr3-deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy.Principal conclusionsJudicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells.
Neurodegenerative diseases among miners in Ontario, Canada, using a linked cohort
Authors: Zeng Xiaoke , DeBono Nathan L , Harris Anne M , Arrandale Victoria H , Demers Paul A 
Published: November 2020

ObjectivesWe examined employment in mining occupations and industries and its association with neurological disease incidence in a linkage cohort from Ontario, Canada. Outcomes included Alzheimer’s disease (alone and with other dementias), Parkinson’s disease, parkinsonism, motor neuron disease and amyotrophic lateral sclerosis (ALS).MethodsThe Occupational Disease Surveillance System cohort was created by linking workers’ compensation data and healthcare usage records. This analysis included over 1.1 million male workers, followed between 1999 and 2016. Neurological diseases were ascertained using physician billing and hospital discharge records. Adjusted Poisson regression models were used to estimate incidence rate ratios (RR) comparing mining to non-mining workers overall and by ore (industry) and occupation group.ResultsSuggested elevations in incidence rates were observed for ALS among workers of metal mines (RR 2.21, 95% CI 1.04 to 4.69) and for motor neuron disease among those employed in mining occupations within metal mining industries (RR 1.96, 95% CI 1.01 to 3.79), though these were based on relatively few cases. In miscellaneous metal mines, workers who held mining occupations had an elevated rate of Alzheimer’s disease (RR 1.27, 95% CI 0.92 to 1.77). Parkinson’s disease rate was elevated among workers with rock and soil drilling occupations (RR 1.60, 95% CI 1.04 to 2.45).ConclusionsMining hazards may be associated with elevated rates of neurodegenerative diseases among workers in mining occupations and industries. More work is needed to better understand mining exposures and their associations with neurodegenerative diseases.
Hormonal contraception and the risk of severe asthma exacerbation: 17-year population-based cohort study
Authors: Nwaru Bright I , Tibble Holly , Shah Syed A , Pillinger Rebecca , McLean Susannah , Ryan Dermot P , Critchley Hilary , Price David B , Hawrylowicz Catherine M , Simpson Colin R , Soyiri Ireneous N , Appiagyei Francis , Sheikh Aziz 
Published: November 2020

BackgroundLongitudinal studies investigating impact of exogenous sex steroids on clinical outcomes of asthma in women are lacking. We investigated the association between use of hormonal contraceptives and risk of severe asthma exacerbation in reproductive-age women with asthma.MethodsWe used the Optimum Patient Care Research Database, a population-based, longitudinal, anonymised primary care database in the UK, to construct a 17-year (1 January 2000–31 December 2016) retrospective cohort of reproductive-age (16–45 years, n=83 084) women with asthma. Using Read codes, we defined use, subtypes and duration of use of hormonal contraceptives. Severe asthma exacerbation was defined according to recommendations of the European Respiratory Society/American Thoracic Society as asthma-related hospitalisation, accident and emergency department visits due to asthma and/or oral corticosteroid prescriptions. Analyses were done using multilevel mixed-effects Poisson regression with QR decomposition.ResultsThe 17-year follow-up resulted in 456 803 person-years of follow-up time. At baseline, 34% of women were using any hormonal contraceptives, 25% combined (oestrogen/progestogen) and 9% progestogen-only contraceptives. Previous (incidence rate ratio (IRR) 0.94, 95% CI 0.92 to 0.97) and current (IRR 0.96, 95% CI 0.94 to 0.98) use of any, previous (IRR 0.92, 95% CI 0.87 to 0.97) and current use of combined (IRR 0.93, 95% CI 0.91 to 0.96) and longer duration of use (3–4 years: IRR 0.94, 95% CI 0.92 to 0.97; 5+ years: IRR 0.91, 95% CI 0.89 to 0.93) of hormonal contraceptives, but not progestogen-only contraceptives, were associated with reduced risk of severe asthma exacerbation compared with non-use.ConclusionsUse of hormonal contraceptives may reduce the risk of severe asthma exacerbation in reproductive-age women. Mechanistic studies investigating the biological basis for the influence of hormonal contraceptives on clinical outcomes of asthma in women are required.Protocol registration numberEuropean Union electronic Register of Post-Authorisation Studies (EUPAS22967).
Hierarchically nanostructured thermoelectric materials: challenges and opportunities for improved power factors
Authors: Neophytou Neophytos , Vargiamidis Vassilios , Foster Samuel , Graziosi Patrizio , de Sousa Oliveira Laura , Chakraborty Dhritiman , Li Zhen , Thesberg Mischa , Kosina Hans , Bennett Nick , Pennelli Giovanni , Narducci Dario 
Published: November 2020

AbstractThe field of thermoelectric materials has undergone a revolutionary transformation over the last couple of decades as a result of the ability to nanostructure and synthesize myriads of materials and their alloys. TheZTfigure of merit, which quantifies the performance of a thermoelectric material has more than doubled after decades of inactivity, reaching values larger than two, consistently across materials and temperatures. Central to thisZTimprovement is the drastic reduction in the material thermal conductivity due to the scattering of phonons on the numerous interfaces, boundaries, dislocations, point defects, phases, etc., which are purposely included. In these new generation of nanostructured materials, phonon scattering centers of different sizes and geometrical configurations (atomic, nano- and macro-scale) are formed, which are able to scatter phonons of mean-free-paths across the spectrum. Beyond thermal conductivity reductions, ideas are beginning to emerge on how to use similar hierarchical nanostructuring to achieve power factor improvements. Ways that relax the adverse interdependence of the electrical conductivity and Seebeck coefficient are targeted, which allows power factor improvements. For this, elegant designs are required, that utilize for instance non-uniformities in the underlying nanostructured geometry, non-uniformities in the dopant distribution, or potential barriers that form at boundaries between materials. A few recent reports, both theoretical and experimental, indicate that extremely high power factor values can be achieved, even for the same geometries that also provide ultra-low thermal conductivities. Despite the experimental complications that can arise in having the required control in nanostructure realization, in this colloquium, we aim to demonstrate, mostly theoretically, that it is a very promising path worth exploring. We review the most promising recent developments for nanostructures that target power factor improvements and present a series of design ‘ingredients’ necessary to reach high power factors. Finally, we emphasize the importance of theory and transport simulations for materialoptimization, and elaborate on the insight one can obtain from computational tools routinely used in the electronic device communities.Graphical abstract
Proving highly-concurrent traversals correct
Authors: Feldman Yotam M. Y. , Khyzha Artem , Enea Constantin , Morrison Adam , Nanevski Aleksandar , Rinetzky Noam , Shoham Sharon 
Published: November 2020

Modern highly-concurrent search data structures, such as search trees, obtain multi-core scalability and performance by having operations traverse the data structure without any synchronization. As a result, however, these algorithms are notoriously difficult to prove linearizable, which requires identifying a point in time in which the traversal's result is correct. The problem is that traversing the data structure as it undergoes modifications leads to complex behaviors, necessitating intricate reasoning about all interleavings of reads by traversals and writes mutating the data structure.
In this paper, we present a general proof technique for proving unsynchronized traversals correct in a significantly simpler manner, compared to typical concurrent reasoning and prior proof techniques. Our framework relies only on sequential properties of traversals and on a conceptually simple and widely-applicable condition about the ways an algorithm's writes mutate the data structure. Establishing that a target data structure satisfies our condition requires only simple concurrent reasoning, without considering interactions of writes and reads. This reasoning can be further simplified by using our framework.
To demonstrate our technique, we apply it to prove several interesting and challenging concurrent binary search trees: the logical-ordering AVL tree, the Citrus tree, and the full contention-friendly tree. Both the logical-ordering tree and the full contention-friendly tree are beyond the reach of previous approaches targeted at simplifying linearizability proofs.
Statically verified refinements for multiparty protocols
Authors: Zhou Fangyi , Ferreira Francisco , Hu Raymond , Neykova Rumyana , Yoshida Nobuko 
Published: November 2020

With distributed computing becoming ubiquitous in the modern era, safe distributed programming is an open challenge. To address this, multiparty session types (MPST) provide a typing discipline for message-passing concurrency, guaranteeing communication safety properties such as deadlock freedom.
While originally MPST focus on the communication aspects, and employ a simple typing system for communication payloads, communication protocols in the real world usually contain constraints on the payload. We introduce refined multiparty session types (RMPST), an extension of MPST, that express data dependent protocols via refinement types on the data types.
We provide an implementation of RMPST, in a toolchain called Session*, using Scribble, a toolchain for multiparty protocols, and targeting F*, a verification-oriented functional programming language. Users can describe a protocol in Scribble and implement the endpoints in F* using refinement-typed APIs generated from the protocol. The F* compiler can then statically verify the refinements. Moreover, we use a novel approach of callback-styled API generation, providing static linearity guarantees with the inversion of control. We evaluate our approach with real world examples and show that it has little overhead compared to a naive implementation, while guaranteeing safety properties from the underlying theory.
Compiling symbolic execution with staging and algebraic effects
Authors: Wei Guannan , Bračevac Oliver , Tan Shangyin , Rompf Tiark 
Published: November 2020

Building effective symbolic execution engines poses challenges in multiple dimensions: an engine must correctly model the program semantics, provide flexibility in symbolic execution strategies, and execute them efficiently.
This paper proposes a principled approach to building correct, flexible, and efficient symbolic execution engines, directly rooted in the semantics of the underlying language in terms of a high-level definitional interpreter. The definitional interpreter induces algebraic effects to abstract over semantic variants of symbolic execution, e.g., collecting path conditions as a state effect and path exploration as a nondeterminism effect. Different handlers of these effects give rise to different symbolic execution strategies, making execution strategies orthogonal to the symbolic execution semantics, thus improving flexibility. Furthermore, by annotating the symbolic definitional interpreter with binding-times and specializing it to the input program via the first Futamura projection, we obtain a "symbolic compiler", generating efficient instrumented code having the symbolic execution semantics. Our work reconciles the interpretation- and instrumentation-based approaches to building symbolic execution engines in a uniform framework.
We illustrate our approach on a simple imperative language step-by-step and then scale up to a significant subset of LLVM IR. We also show effect handlers for common path selection strategies. Evaluating our prototype's performance shows speedups of 10~30x over the unstaged counterpart, and ~2x over KLEE, a state-of-the-art symbolic interpreter for LLVM IR.