bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of VigiBase reports on tinnitus associated with bisoprolol—An exploratory and descriptive study
Authors: Watson Sarah , Taavola Henric , Attalla Marian , Kaminsky Elenor , Yue Quin‐Ying
Published: May 2021

The aim of this descriptive and explorative study was to assess individual case safety reports of bisoprolol associated with tinnitus and investigate their added value in information about adverse drug reactions (ADRs) in relation to information provided in medicine labels. The global reports from VigiBase, the WHO database of individual case safety reports, as of May 3, 2020, were analyzed for information about bisoprolol associated with tinnitus as an ADR affecting the quality of life of the patients. There were 123 reports of the ADR tinnitus reported with intake of bisoprolol in VigiBase. These described experiences of tinnitus and how this impacted on patients’ daily life, for example, it could be long‐lasting and may have negative impact on sleeping, and even ability to work and keep a job. There were also reports describing the management of the reaction, for example, recovery upon stopping the treatment, and improvement of the symptoms following a decreased dose or change of medicine batch. Based on reports in VigiBase, the ADR tinnitus associated with bisoprolol suggests vigilance for the onset of the event and that, if it occurs, a dose reduction or stopping the treatment could be necessary. The information provided in the reports shows the value of individual case safety reports collected post marketing, in providing descriptive information of the experience and management of the ADR.
A phase I, single and continuous dose administration study on the safety, tolerability, and pharmacokinetics of neorudin, a novel recombinant anticoagulant protein, in healthy subjects
Authors: Liu Yubin , Wang Meixia , Dong Xiaona , He Jia , Zhang Lin , Zhou Ying , Xia Xia , Dou Guifang , Wu Chu‐tse , Jin Jide
Published: May 2021

The aim of this study was to evaluate the tolerability, safety, and pharmacokinetics of single and continuous dose administration of recombinant neorudin (EPR‐hirudin, EH) by intravenous administration in healthy subjects, and to provide a safe dosage range for phase II clinical research. Forty‐four subjects received EH as a single dose of between 0.2 and 2.0 mg/kg by intravenous bolus and drip infusion. In addition, 18 healthy subjects were randomly divided into three dose groups (0.15, 0.30, and 0.45 mg/kg/h) with 6 subjects in each group for the continuous administration trial. Single or continuous doses of neorudin were generally well tolerated by healthy adult subjects. There were no serious adverse events (SAEs), and all adverse events (AEs) were mild to moderate. Moreover, no subjects withdrew from the trial because of AEs. There were no clinically relevant changes in physical examination results, clinical chemistry, urinalysis, or vital signs. The incidence of adverse events was not significantly related to drug dose or systemic exposure. After single‐dose and continuous administration, the serum EH concentration reached its peak at 5 min, and the exposure increased with the increase in the administered dose. The mean half‐life (T1/2), clearance (Cl), and apparent volume of distribution (Vd) of EH ranged from 1.7 to 2.5 h, 123.9 to 179.7 ml/h/kg, and 402.7 to 615.2 ml/kg, respectively. The demonstrated safety, tolerability, and pharmacokinetic characteristics of EH can be used to guide rational drug dosing and choose therapeutic regimens in subsequent clinical studies.

Clinical trial registration: Chinadrugtrials.org identifier: CTR20160444.
Pharmacokinetic/pharmacodynamic modeling of drug interactions at the P2Y12 receptor between selatogrel and oral P2Y12 antagonists
Authors: Henrich Andrea , Claussen Christian Hove , Dingemanse Jasper , Krause Andreas
Published: May 2021

Selatogrel is a potent and reversible P2Y12 receptor antagonist developed for subcutaneous self‐administration by patients with suspected acute myocardial infarction. After single‐dose emergency treatment with selatogrel, patients are switched to long‐term treatment with oral P2Y12 receptor antagonists. Selatogrel shows rapid onset and offset of inhibition of platelet aggregation (IPA) to overcome the critical initial time after acute myocardial infarction. Long‐term benefit is provided by oral P2Y12 receptor antagonists such as clopidogrel, prasugrel, and ticagrelor. A population pharmacokinetic (PK)/pharmacodynamic (PD) model based on data from 545 subjects in 4 phase I and 2 phase II studies well described the effect of selatogrel on IPA alone and in combination with clopidogrel, prasugrel, and ticagrelor. The PK of selatogrel were described by a three‐compartment model. The PD model included a receptor‐pool compartment to which all drugs can bind concurrently, reversibly or irreversibly, depending on their mode of action. Furthermore, ticagrelor and its active metabolite can bind to the selatogrel‐receptor complex allosterically, releasing selatogrel from the binding site. The model provided a framework for predicting the effect on IPA of selatogrel followed by reversibly and irreversibly binding oral P2Y12 receptor antagonists for sustained effects. Determining the timepoint for switching from emergency to maintenance treatment is critical to achieve sufficient IPA at all times. Simulations based on the interaction model showed that loading doses of clopidogrel and prasugrel administered 15 h and 4.5 h after selatogrel, respectively, provide sustained IPA with clinically negligible drug interaction.

Study Highlights

WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Selatogrel is a potent reversible P2Y12 receptor antagonist developed for subcutaneous self‐administration by patients in case of suspected acute myocardial infarction. Transition to oral P2Y12 receptor antagonists without drug interaction and sufficient inhibition of platelet aggregation must be assured at all times.

WHAT QUESTION DID THIS STUDY ADDRESS?

The pharmacokinetic/pharmacodynamic model semimechanistically describes the effect of selatogrel on platelet inhibition alone and in combination with the oral P2Y12 receptor antagonists clopidogrel, prasugrel, and ticagrelor.

WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Model‐based simulations showed that loading doses of clopidogrel and prasugrel can be administered from 15 h and 4.5 h after selatogrel, respectively.

HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These results support guiding the clinical transition from selatogrel emergency treatment to oral maintenance therapy in a safe and efficacious way.
A wavefunction model to chemical bonding
Authors: Náray‐Szabó Gábor , Mezey Paul G.
Published: May 2021

In this paper we give a brief survey on some specific aspects of a wavefunction model for chemical bonding which are connected to or have been motivated in part by the work of the late István Mayer and colleagues. After a brief description of the early wavefunction models as reflected in Mayer's works, naturally leading to electron densities, we discuss localized molecular orbitals, and summarize some of the early initiatives and applications. The concept of the Chemical Hamiltonian, as introduced by Mayer, its extensions and some classical and some more advanced connections will be discussed. The twofold motivating role of Mayer in the development of the earliest, ab initio level macromolecular linear scaling methods, giving proven “ab initio quality” protein energy results by the adjustable density matrix assembler method, and in some other molecular fragment advances will be also pointed out.
Current and future deep learning algorithms for tandem mass spectrometry (MS/MS)‐based small molecule structure elucidation
Authors: Liu Youzhong , De Vijlder Thomas , Bittremieux Wout , Laukens Kris , Heyndrickx Wouter
Published: May 2021

Rationale

Structure elucidation of small molecules has been one of the cornerstone applications of mass spectrometry for decades. Despite the increasing availability of software tools, structure elucidation from tandem mass spectrometry (MS/MS) data remains a challenging task, leaving many spectra unidentified. However, as an increasing number of reference MS/MS spectra are being curated at a repository scale and shared on public servers, there is an exciting opportunity to develop powerful new deep learning (DL) models for automated structure elucidation.

Architectures

Recent early‐stage DL frameworks mostly follow a “two‐step approach” that translates MS/MS spectra to database structures after first predicting molecular descriptors. The related architectures could suffer from: (1) computational complexity because of the separate training of descriptor‐specific classifiers, (2) the high dimensional nature of mass spectral data and information loss due to data preprocessing, (3) low substructure coverage and class imbalance problem of predefined molecular fingerprints. Inspired by successful DL frameworks employed in drug discovery fields, we have conceptualized and designed hypothetical DL architectures to tackle the above issues. For (1), we recommend multitask learning to achieve better performance with fewer classifiers by grouping structurally related descriptors. For (2) and (3), we introduce feature engineering to extract condensed and higher‐order information from spectra and structure data. For instance, encoding spectra with subtrees and pre‐calculated spectral patterns add peak interactions to the model input. Encoding structures with graph convolutional networks incorporates connectivity within a molecule. The joint embedding of spectra and structures can enable simultaneous spectral library and molecular database search.

Conclusions

In principle, given enough training data, adapted DL architectures, optimal hyperparameters and computing power, DL frameworks can predict small molecule structures, completely or at least partially, from MS/MS spectra. However, their performance and general applicability should be fairly evaluated against classical machine learning frameworks.
From Water Solutions to Ionic Liquids with Solid State Nanopores as a Perspective to Study Transport and Translocation Phenomena
Authors: Marion Sanjin , Vučemilović‐Alagić Nataša , Špadina Mario , Radenović Aleksandra , Smith Ana‐Sunčana
Published: May 2021

Solid state nanopores are single‐molecular devices governed by nanoscale physics with a broad potential for technological applications. However, the control of translocation speed in these systems is still limited. Ionic liquids are molten salts which are commonly used as alternate solvents enabling the regulation of the chemical and physical interactions on solid–liquid interfaces. While their combination can be challenging to the understanding of nanoscopic processes, there has been limited attempts on bringing these two together. While summarizing the state of the art and open questions in these fields, several major advances are presented with a perspective on the next steps in the investigations of ionic‐liquid filled nanopores, both from a theoretical and experimental standpoint. By analogy to aqueous solutions, it is argued that ionic liquids and nanopores can be combined to provide new nanofluidic functionalities, as well as to help resolve some of the pertinent problems in understanding transport phenomena in confined ionic liquids and providing better control of the speed of translocating analytes.
Ambient Air Blade‐Coating Fabrication of Stable Triple‐Cation Perovskite Solar Modules by Green Solvent Quenching
Authors: Vesce Luigi , Stefanelli Maurizio , Herterich Jan Philipp , Castriotta Luigi Angelo , Kohlstädt Markus , Würfel Uli , Di Carlo Aldo
Published: May 2021

Although halide perovskite solar cell (PSC) technology reaches, in few years, efficiencies greater than 25%, the cost‐ceffective perspective is achievable only if scalable processes in real manufacturing conditions (i.e., pilot line and/or plant factory) are designed and optimized for the full device stack. Herein, a full semiautomatic scalable process based on the blade‐coating technique is demonstrated to fabricate perovskite solar modules in ambient conditions. An efficient and stable triple‐cation cesium methylammonium formamidinium (CsMAFA) perovskite is deposited in ambient air with a two‐step process assisted by air and green anti‐solvent quenching. The developed industry compatible coating process enables the fabrication of several highly reproducible small‐area cells on module size substrate with an efficiency exceeding 17% and with high reproducibility. Corresponding reproducible modules (less than 2% variability) with a 90% geometrical fill factor achieve an efficiency larger than 16% and T
80 = 750 h in light‐soaking condition at maximum power point and room temperature/ambient after encapsulation. Film deposition properties are assessed by different characterization techniques, namely, scanning electron microscopy, profilometry, UV–vis and photoluminescence (PL) spectroscopy, and PL and electroluminescence imaging. The techniques confirm less defects and local coating variations of the ambient air/bladed devices with respect to the nitrogen air/spinned devices.
A method of constructing optimal sliced uniform designs under discrete discrepancy
Authors: Yin Changming , Huang Hengzhen
Published: May 2021

Sliced uniform designs are useful for generating experimental data with batch structures. In this paper, we employ the discrete discrepancy as the measure of uniformity to construct sliced uniform designs. The construction method is based on an important class of combinatorial configurations, namely, resolvable balanced incomplete block designs; hence, the construction method does not require any computer search. Through resolvable balanced incomplete block designs, under the discrete discrepancy, several infinite classes of new sliced uniform designs are obtained. The obtained design is optimal in the sense that not only the design as a whole but also each of its slices attain the lower bound of the discrete discrepancy. The design parameters are explicitly given, from which experimenters may choose an optimal sliced uniform design with the most suitable run size for their experiment.
Typification of Dactylis ibizensis (Poaceae) and inference of the ploidy level of the type specimen
Authors: Rosselló Josep A. , Maravilla Alexis J. , Rosato Marcela , Torres Nèstor , Ferrer‐Gallego P. Pablo
Published: May 2021

Dactylis ibizensis (Poaceae) is lectotypified based on a specimen at W. Anatomical and macromorphological data from karyologically verified individuals strongly support that the lectotype comprises exclusively diploid plants. This allows for preservation of the name in current use for the Balearic cocksfoot restricted to the islands of Formentera and Ibiza.
A novel (ATC)n microsatellite locus is associated with litter size in an indigenous Chinese pig
Authors: Wu Guofang , Shen Wenjuan , Xue Xingxing , Wang Lei , Ma Yuhong , Zhou Jiping
Published: May 2021

Simple sequence repeats (SSRs) are an important part of the genome and have become powerful auxiliary DNA markers in animal breeding using marker‐assisted selection (MAS). Based on previous sequencing data of Qinghai Bamei pigs, a total of three novel candidate SSR loci were analysed in this study. Time‐of‐flight mass spectrometry (TOF‐MS) was used for SSR genotyping, and association analyses between SSRs and the litter size of Qinghai Bamei sows was also performed. The results of genotyping showed that the (ATC)n‐P1, (AC)n‐P2 and (AC)n‐P3 loci had 2, 3 and 18 genotypes, respectively; 2, 3 and 8 alleles were also identified at these loci. Except for the (AC)n‐P2 locus, the polymorphism information content (PIC) values of other loci were greater than 0.25. Association analyses indicated that only the (ATC)n‐P1 locus was significantly associated with the litter size of Qinghai Bamei sows (p = .047). Compared to 189‐/189‐ genotype, individuals with the 189‐/195‐ genotype had the senior litter size, which was 9.04 ± 0.21. Our results enrich the data on SSRs in Qinghai Bamei pigs and indicate that (ATC)n‐P1 is a candidate locus for MAS in the pig industry.
Seroprevalence of Coxiella burnetii in patients presenting with acute febrile illness at Marigat District Hospital, Baringo County, Kenya
Authors: Lemtudo Allan P. , Mutai Beth K. , Mwamburi Lizzy , Waitumbi John N.
Published: May 2021

Q fever is not routinely diagnosed in Kenyan hospitals. This study reports on Q fever in patients presenting at Marigat District Hospital, Kenya, with febrile illness. ELISA was used to detect Coxiella burnetii phase antigens. Of 406 patients, 45 (11.1%) were judged to have acute disease (phase II IgM or IgG > phase I IgG), 2 (0.5%) were chronic (phase I IgG titer >800 or phase I IgG > phase II IgG), while 26 (6.4%) had previous exposure (phase I IgG titer <800). Age (6–10 years, p = 0.002) and contact with goats (p = 0.014) were significant risk factors. Compared to immunofluorescence antibody test, the sensitivity and specificity for phase I IgG were 84% and 98%, respectfully, 46% and 100% for phase II IgG and 35% and 89% for phase II IgM. It is concluded that the low sensitivity of phase II ELISA underestimated the true burden of acute Q fever in the study population.
Bacterial pathogens identified from houseflies in different human and animal settings: A systematic review and meta‐analysis
Authors: Monyama Maropeng C. , Onyiche Emmanuel T. , Taioe Moeti O. , Nkhebenyane Jane S. , Thekisoe Oriel M. M.
Published: May 2021

Housefly (Musca domestica) is an excellent candidate for the distribution of susceptible and resistant bacterial strains that potentially threaten public health. To date, there is a paucity of information on the global distribution of pathogenic bacteria of medical and veterinary importance from diverse environmental settings. Therefore, this study was undertaken to conduct a systemic review and meta‐analysis to estimate occurrence of various bacterial species of medical and veterinary importance harboured by houseflies around the world. Published articles from 1980 to 2020 were retrieved from electronic databases and assessed for eligibility according to Preferred Reporting Items for Systemic Reviews and Meta‐Analysis guidelines. Seventy‐eight studies were included in the review with only 44 studies being eligible for meta‐analysis. Results indicated that eligible studies used in this review were from four continents, i.e., Asia (47.4%) America (23.1%), Africa (20.5%) and Europe (8.9%). The majority of the studies (56.4%) used the culture method for the identification of bacterial pathogens, while 30.7% used both culture and PCR techniques. For meta‐analysis, we focused on five pathogenic bacterial species including Escherichia coli, Enterococcus faecium, Klebsiella pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus. High heterogeneity was found among studies investigating different pathogens including E. coli (Q = 10,739.55; I2 = 99.60; Q‐p 0.0001), E. faecium (Q = 317.61; I2 = 86.46; Q‐p < 0.0001), K. pneumonia (Q = 1,576.61; I2 = 97.27; Q‐p < 0.0001), S. aureus (Q = 2,439.12; I2 = 98.24; Q‐p < 0.0001) and P. aeruginosa (Q = 1,283.0; I2 = 96.65; Q‐p < 0.0001). Furthermore, it was observed that houseflies carried a considerable number of susceptible and antibiotic‐resistant bacterial strains that pose considerable threats to public health. Findings from this study have provided more insight on the vectoral potential of houseflies in the transmission of significant bacterial pathogens from different regions across the world. Further investigation is required to quantify the bacterial contamination and dissemination by houseflies.
Prevalence, aetiology and risk factors of mastitis of dairy cows kept under extensive management system in west Wollega, western Oromia, Ethiopia
Authors: Kitila Gutu , Kebede Bedaso , Wakgari Moti
Published: May 2021

Introduction

Mastitis is an inflammation of the mammary gland that could either be clinical or subclinical, and can be caused by infectious agents. It has different aetiological pathogens such as Staphylococcus aureus, Streptococcus agalactiae, Escherichia coli that pose different economic and health impacts. In Ethiopia, previous studies on mastitis have been focused on semi‐intensive and intensive dairy production system. The objectives of this study were therefore to estimate prevalence, aetiology of causative pathogens and identify different risk factors of mastitis in extensive management systems. A total of 532 lactating cows were randomly selected for a cross‐sectional study carried out in four districts of west Wollega, western Oromia, Ethiopia.

Result

Based on the clinical examination and California mastitis test, 39.67% overall prevalence of mastitis on cow level was recorded. Of them, 16.70% and 22.70% were clinical and subclinical mastitis, respectively. Among 2,128 quarters examined 210 were blind teats. The associated risk factors age ≥8 years (16.35%), parity 1–3 calving (27.63%), milk yield 1–2 litres (21.98%), lactation stage <4 months (18.04%) and tick infestation (26.70%) were significantly associated in the occurrence of mastitis. Staphylococcus spp. (15.60%) were the dominant bacteria isolated from collected mastitic milk.

Conclusion

Mastitis is an important disease for dairy cows kept under an extensive management system. Its occurrence is determined by risk factors like age, parity, milk yield, lactation stage and tick infestation. This study is indicated Staphylococcus species as the major bacteria isolated from mastitic milk. This study warrants further study on the prevalence, aetiology, economic impact and potential risk factors of mastitis in dairy cows kept in extensive production system.
Introduction: Citizens, Markets, and Turkey
Authors: Ark-Yıldırım Ceren , Smyrl Marc
Published: May 2021

The concept of citizenship is typically divided into distinct components. Following the pioneering work of T.H. Marshall, we focus on social and economic citizenship. We ask in particular whether the “basic equality of membership” at the heart of Marshall’s definition of citizenship can be advanced by market-centered policies such as social cash transfer, even in cases such as that of forced migrants in which political or civil elements of citizenship are not present. Contemporary Turkey provides an ideal setting in which to investigate this question.
The Turkish Context
Authors: Ark-Yıldırım Ceren , Smyrl Marc
Published: May 2021

In Chap. 2, we traced the emergence of a new and controversial model of citizenship centered on the market. We turn now to the national case that is the focus of this book, Turkey. The central question of this chapter is whether the transition to a market-based model of citizenship much studied in Europe and North America can be applied to countries like Turkey, typified by late industrialization and a distinct social welfare model. To this end, we consider the evolution of the operational content and context of social and economic citizenship in Turkey. In a final section, we expand the scope of reflection to discuss the situation of migrants, and the evolution of the Turkish “incorporation regime.”
Cash Transfer with Turkish Characteristics: Two Local Examples
Authors: Ark-Yıldırım Ceren , Smyrl Marc
Published: May 2021

Having discussed the emergence of cash transfer (CT) as an instrument not only for economic assistance but potentially for inclusion in a market-centered society, and the policy environment of contemporary Turkey, we now bring these together through examination of two case studies of CT programs designed and implemented at the local level. By proceeding in this way, we are explicitly eschewing any claim to providing a universal treatment of social policy, or even of CT programs, in contemporary Turkey. Rather, we consider these cases with a view to highlighting the elements that seem most closely tied to particular outcomes, and then to generalizing these in the form of hypotheses applicable beyond Turkey.
Cash Transfer and Humanitarian Assistance
Authors: Ark-Yıldırım Ceren , Smyrl Marc
Published: May 2021

In this chapter, we turn our attention to cash transfer (CT) as an instrument of humanitarian assistance for forced migrants in Turkey. We first consider the emergence of CT as a priority instrument for humanitarian assistance in the twenty-first century. We then sketch the political background of humanitarian assistance in Turkey for persons displaced by internal conflicts in Syria focusing in particular on the EU–Turkey agreements that led to the establishment of the Facility for Refugees in Turkey (FRiT) in 2016. In a final section we focus on the establishment as part of FRiT of the Emergency Social Safety Net (ESSN), the largest humanitarian CT program ever established by the European Union. We discuss in particular the program’s institutional complexity and the resulting risk of ambiguous consensus and conflicts of interest among the agencies involved in its design and implementation.
The Consequences of Ambiguity: Designing and Implementing the ESSN
Authors: Ark-Yıldırım Ceren , Smyrl Marc
Published: May 2021

The stated purpose of the Emergency Social Safety Net (ESSN) was to contribute to meeting the basic needs of the most vulnerable refugees in Turkey. In the context of this book’s argument, we ask whether it achieved this goal but also whether and to what extent it contributed to extending elements of market citizenship to forced migrants. We conclude that while the ESSN’s CT program made a limited contribution to meeting basic needs and empowering displaced persons as consumers, other elements of market citizenship, or even “denizenship,” are lacking. With regard to its explicit targets, the effectiveness of ESSN was limited by the ambiguities of its design, linked to the different priorities of the agencies involved, which exclude some vulnerable persons from the program. More broadly, very limited access to the formal labor market remained an obstacle to fuller market citizenship.
Does Cash Transfer Promote Market Citizenship?
Authors: Ark-Yıldırım Ceren , Smyrl Marc
Published: May 2021

The most obvious conclusion of this book is that there is no single Turkish experience. Nor can we reach definitive once-and-for-all conclusions about the impact of CT as an instrument of social assistance. Comparison among our cases highlights variables grounded in local conditions and policy design that help determine the outcome of CT projects, and whose relevance extends far beyond Turkey. Among these are human and financial resources, but also of the capacity for local knowledge. When these allow consistent and appropriate targeting, CT can provide an important step in the direction of inclusion and equality in a market context. It would be misleading, however, to believe that this instrument on its own is sufficient. At the core of market citizenship is the dignity conferred not only by paying one’s own way, but also by earning one’s own way: CT instruments work best as a complement to, not replacement for, access to the official labor market.
Dark scalars and heavy neutral leptons at DarkQuest
Authors: Batell Brian , Evans Jared A. , Gori Stefania , Rai Mudit
Published: May 2021

Abstract

The proposed DarkQuest beam dump experiment, a modest upgrade to the existing SeaQuest/SpinQuest experiment, has great potential for uncovering new physics within a dark sector. We explore both the near-term and long-term prospects for observing two distinct, highly-motivated hidden sector benchmark models: heavy neutral leptons and Higgs-mixed scalars. We comprehensively examine the particle production and detector acceptance at DarkQuest, including an updated treatment of meson production, and light scalar production through both bremsstrahlung and gluon-gluon fusion. In both benchmark models, DarkQuest will provide an opportunity to probe previously inaccessible interesting regions of parameter space on a fairly short timescale when compared to other proposed experiments.
Cutibacterium modestum and “Propionibacterium humerusii” represent the same species that is commonly misidentified as Cutibacterium acnes
Authors: Goldenberger Daniel , Søgaard Kirstine K. , Cuénod Aline , Seth-Smith Helena , de Menezes Daniel , Vandamme Peter , Egli Adrian
Published: May 2021

Cutibacterium spp. play an increasing role in soft tissue and implant-associated infections. We isolated a novel Cutibacterium spp. from an implant and investigated this isolate using multiple identification approaches. Correct identification was hampered by inconsistent reference data. The isolate was characterised using conventional methods such as Gram stain, MALDI-TOF MS, and antimicrobial susceptibility testing against multiple antimicrobials. Partial 16S rRNA gene sequencing and whole genome sequencing were also performed. In addition, we summarised the available published sequence data and compared prior data to our strain. Conventional phenotypic identification of our isolate resulted in Cutibacterium spp. After analysis of 16S rRNA gene and genome sequences, our isolate was identified as C. modestum, a very recently described species. The 16S rRNA gene analysis was hampered by three incorrect nucleotides within the 16S rRNA gene reference sequence of C. modestum M12T (accession no. LC466959). We also clearly demonstrate that this novel species is identical to tentatively named “Propionibacterium humerusii”. Retrospective data analysis indicates that C. modestum is a clinically important Cutibacterium species often misidentified as C. acnes. The isolation and identification of Cutibacterium spp. is still a challenge. The correct description of very recently named C. modestum and the availability of a correct 16S rRNA sequence of the type strain may help to clarify the taxonomical uncertainty concerning “P. humerusii”. The novel C. modestum is an additional, clinically important species within the genus Cutibacterium and may represent a new member of the human skin microbiome.
Effects of surface impedance on current density in a piezoelectric resonator for impedance distribution sensing
Authors: Liu Jing , Du Jianke , Wang Ji , Yang Jiashi
Published: May 2021

We study the relationship between the surface mechanical load represented by distributed acoustic impedance and the current density distribution in a shear mode piezoelectric plate acoustic wave resonator. A theoretical analysis based on the theory of piezoelectricity and trigonometric series is performed. In the specific and basic case when the surface load is due to a local mass layer, numerical results show that the current density concentrates under the mass layer and is sensitive to the physical as well as geometric parameters of the mass layer such as its location and size. This provides the theoretical foundation for predicting the surface impedance pattern from the current density distribution, which is fundamental to the relevant acoustic wave sensors.
Complex response analysis of a non-smooth oscillator under harmonic and random excitations
Authors: Ma Shichao , Ning Xin , Wang Liang , Jia Wantao , Xu Wei
Published: May 2021

It is well-known that practical vibro-impact systems are often influenced by random perturbations and external excitation forces, making it challenging to carry out the research of this category of complex systems with non-smooth characteristics. To address this problem, by adequately utilizing the stochastic response analysis approach and performing the stochastic response for the considered non-smooth system with the external excitation force and white noise excitation, a modified conducting process has proposed. Taking the multiple nonlinear parameters, the non-smooth parameters, and the external excitation frequency into consideration, the steady-state stochastic P-bifurcation phenomena of an elastic impact oscillator are discussed. It can be found that the system parameters can make the system stability topology change. The effectiveness of the proposed method is verified and demonstrated by the Monte Carlo (MC) simulation. Consequently, the conclusions show that the process can be applied to stochastic non-autonomous and non-smooth systems.
Complex community responses underpin biodiversity change following invasion
Authors: Kortz Alessandra R. , Magurran Anne E.
Published: May 2021

How do invasive species change native biodiversity? One reason why this long-standing question remains challenging to answer could be because the main focus of the invasion literature has been on shifts in species richness (a measure of α-diversity). As the underlying components of community structure—intraspecific aggregation, interspecific density and the species abundance distribution (SAD)—are potentially impacted in different ways during invasion, trends in species richness provide only limited insight into the mechanisms leading to biodiversity change. In addition, these impacts can be manifested in distinct ways at different spatial scales. Here we take advantage of the new Measurement of Biodiversity (MoB) framework to reanalyse data collected in an invasion front in the Brazilian Cerrado biodiversity hotspot. We show that, by using the MoB multi-scale approach, we are able to link reductions in species richness in invaded sites to restructuring in the SAD. This restructuring takes the form of lower evenness in sites invaded by pines relative to sites without pines. Shifts in aggregation also occur. There is a clear signature of spatial scale in biodiversity change linked to the presence of an invasive species. These results demonstrate how the MoB approach can play an important role in helping invasion ecologists, field biologists and conservation managers move towards a more mechanistic approach to detecting and interpreting changes in ecological systems following invasion.
The Synthesis of Biarylmonophosphonates via Palladium-Catalyzed Phosphonation, Iridium-Catalyzed C-H Borylation, Palladium-Catalyzed Suzuki–Miyaura Cross-Coupling
Authors: Doherty Simon , Knight Julian G. , Tran Tina S. T. , Alharbi Hussam Y. , Perry Daniel O.
Published: May 2021

The iridium-catalyzed C-H borylation of diethyl phenylphosphonate results in nonselective mono and bisborylation to afford a near statistical mixture of 3-, 3,5- and 4-boryl substituted aryl phosphonates whereas 3-substituted aryl phosphonates undergo highly regioselective C-H borylation to afford the corresponding meta-phosphonate substituted arylboronic esters as the sole product; the resulting boronic esters were used as nucleophilic reagents in a subsequent palladium-catalyzed Suzuki–Miyaura cross-coupling to generate a range of biarylmonophosphonates. Gratifyingly, the Suzuki–Miyaura cross-coupling can be conducted without purifying the boronic ester which greatly simplifies the synthetic procedure.

Graphical Abstract
Mendelian randomisation for mediation analysis: current methods and challenges for implementation
Authors: Carter Alice R. , Sanderson Eleanor , Hammerton Gemma , Richmond Rebecca C. , Davey Smith George , Heron Jon , Taylor Amy E. , Davies Neil M. , Howe Laura D.
Published: May 2021

Mediation analysis seeks to explain the pathway(s) through which an exposure affects an outcome. Traditional, non-instrumental variable methods for mediation analysis experience a number of methodological difficulties, including bias due to confounding between an exposure, mediator and outcome and measurement error. Mendelian randomisation (MR) can be used to improve causal inference for mediation analysis. We describe two approaches that can be used for estimating mediation analysis with MR: multivariable MR (MVMR) and two-step MR. We outline the approaches and provide code to demonstrate how they can be used in mediation analysis. We review issues that can affect analyses, including confounding, measurement error, weak instrument bias, interactions between exposures and mediators and analysis of multiple mediators. Description of the methods is supplemented by simulated and real data examples. Although MR relies on large sample sizes and strong assumptions, such as having strong instruments and no horizontally pleiotropic pathways, our simulations demonstrate that these methods are unaffected by confounders of the exposure or mediator and the outcome and non-differential measurement error of the exposure or mediator. Both MVMR and two-step MR can be implemented in both individual-level MR and summary data MR. MR mediation methods require different assumptions to be made, compared with non-instrumental variable mediation methods. Where these assumptions are more plausible, MR can be used to improve causal inference in mediation analysis.
Approximation and application of the Riesz-Caputo fractional derivative of variable order with fixed memory
Authors: Blaszczyk Tomasz , Bekus Krzysztof , Szajek Krzysztof , Sumelka Wojciech
Published: May 2021

In this paper, the Riesz-Caputo fractional derivative of variable order with fixed memory is considered. The studied non-integer differential operator is approximated by means of modified basic rules of numerical integration. The three proposed methods are based on polynomial interpolation: piecewise constant, piecewise linear, and piecewise quadratic interpolation. The errors generated by the described methods and the experimental rate of convergence are reported. Finally, an application of the Riesz-Caputo fractional derivative of space-dependent order in continuum mechanics is depicted.
Neurostructural and Neurophysiological Correlates of Multiple Sclerosis Physical Fatigue: Systematic Review and Meta-Analysis of Cross-Sectional Studies
Authors: Ellison Paula M. , Goodall Stuart , Kennedy Niamh , Dawes Helen , Clark Allan , Pomeroy Valerie , Duddy Martin , Baker Mark R. , Saxton John M.
Published: May 2021

Fatigue is one of the most debilitating symptoms for people with multiple sclerosis (PwMS). By consolidating a diverse and conflicting evidence-base, this systematic review and meta-analysis aimed to gain new insights into the neurobiology of MS fatigue. MEDLINE, ProQuest, CINAHL, Web of Science databases and grey literature were searched using Medical Subject Headings. Eligible studies compared neuroimaging and neurophysiological data between people experiencing high (MS-HF) versus low (MS-LF) levels of perceived MS fatigue, as defined by validated fatigue questionnaire cut-points. Data were available from 66 studies, with 46 used for meta-analyses. Neuroimaging studies revealed lower volumetric measures in MS-HF versus MS-LF for whole brain (­22.74 ml; 95% CI: -37.72 to -7.76 ml; p = 0.003), grey matter (­18.81 ml; 95% CI: ­29.60 to ­8.03 ml; p < 0.001), putamen (­0.40 ml; 95% CI: ­0.69 to ­0.10 ml; p = 0.008) and acumbens (­0.09 ml; 95% CI: ­0.15 to ­0.03 ml; p = 0.003) and a higher volume of T1-weighted hypointense lesions (1.10 ml; 95% CI: 0.47 to 1.73 ml; p < 0.001). Neurophysiological data showed reduced lower-limb maximum voluntary force production (­19.23 N; 95% CI: ­35.93 to ­2.53 N; p = 0.02) and an attenuation of upper-limb (­5.77%; 95% CI:­8.61 to ­2.93%; p < 0.0001) and lower-limb (­2.16%; 95% CI:­4.24 to ­0.07%; p = 0.04) skeletal muscle voluntary activation, accompanied by more pronounced upper-limb fatigability (­5.61%; 95% CI: -9.57 to -1.65%; p = 0.006) in MS-HF versus MS-LF. Results suggest that MS fatigue is characterised by greater cortico-subcortical grey matter atrophy and neural lesions, accompanied by neurophysiological decrements, which include reduced strength and voluntary activation.

Prospero registration Prospero registration number: CRD42016017934
Evaluation of the similarity between drought indices by correlation analysis and Cohen's Kappa test in a Mediterranean area
Authors: Vergni L. , Todisco F. , Di Lena B.
Published: May 2021

In the literature, numerous papers report comparative analyses of drought indices. In these types of studies, the similarity between drought indices is usually evaluated using the Pearson correlation coefficient, r, calculated between corresponding severity time series. However, it is well known that the correlation does not describe the strength of agreement between two variables. Two drought indices can exhibit a high degree of correlation but can, at the same time, disagree substantially, for example, if one index is consistently higher than the other. From an operational point of view, two indices can be considered in agreement when they indicate the same severity category for a given period (e.g. moderate drought). In this work, we compared six meteorological drought indices based on both correlation analysis and Cohen's Kappa test. This test is typically used in medical or social sciences to obtain a quantitative assessment of the degree of agreement between different methods or analysts. The indices considered are five timescale-dependent indices, i.e. the Percent of Normal Index, the Deciles Index, the Percentile Index, the Rainfall Anomaly Index, and the Standardised Precipitation Index, computed at the 1-, 3-, and 6-month timescales, and the Effective Drought Index, a relatively new index, which has a self-defined timescale. The indices were calculated for 15 stations in the Abruzzo region (central Italy) during 1951–2018. We found that the strength of agreement depends on both the criteria of drought severity classification and the different indices' calculation method. The Cohen's Kappa test indicates a prevailing moderate or fair agreement among the indices considered, despite the generally very high correlation between the corresponding severity times series. The results demonstrate that the Cohen's Kappa test is more effective than the correlation analysis in discriminating the actual strength of agreement/disagreement between drought indices.
Structurally Diverse Sesquiterpenoids with Anti-neuroinflammatory Activity from the Endolichenic Fungus Cryptomarasmius aucubae
Authors: Zhai Yi-Jie , Li Jian-Nan , Gao Yu-Qi , Gao Lin-Lin , Wang Da-Cheng , Han Wen-Bo , Gao Jin-Ming
Published: May 2021

Two new sterpurane sesquiterpenoids named sterpurol D (1) and sterpurol E (2), and one skeletally new sesquiterpene, cryptomaraone (3), bearing a 5,6-fused bicyclic ring system, along with five known ones, sterpurol A (4), sterpurol B (5), paneolilludinic Acid (6), murolane-2α, 9β-diol-3-ene (7) and (–)-10,11-dihydroxyfarnesol (8) were isolated from an endolichenic fungus Cryptomarasmius aucubae. The structures of the new compounds were elucidated by analysis of NMR spectroscopic spectra and HRESIMS data. The absolute configurations of 1 and 2 were established by spectroscopic data analysis and comparison of specific optical rotation, as well as the biosynthetic consideration. Additionally, compounds 1, 2, 4–6, and 8 showed significant nitric oxide (NO) production inhibition in Lipopolysaccharide (LPS)-induced BV-2 microglial cells with the IC50 values ranging from 9.06 to 14.81 μM.

Graphic Abstract
Subthalamic nucleus deep brain stimulation and impulsivity in Parkinson’s disease: a descriptive review
Authors: Lo Buono Viviana , Lucà Trombetta Marietta , Palmeri Rosanna , Bonanno Lilla , Cartella Emanuele , Di Lorenzo Giuseppe , Bramanti Placido , Marino Silvia , Corallo Francesco
Published: May 2021

Standard treatment of Parkinson’s disease involves the dopaminergic medications. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an important neurosurgical intervention often used as alternative treatment to drug therapy; however, it can be associated with increase of impulsive behaviors. This descriptive review focused on studies investigating the correlation between Deep brain stimulation of the subthalamic nucleus and impulsivity in Parkinson’s disease patients, arguing, the action’s mechanism and the specific role of the subthalamic nucleus. We searched on PubMed and Web of Science databases and screening references of included studies and review articles for additional citations. From initial 106 studies, only 15 met the search criteria. Parkinson’s Disease patients with and without Deep Brain Stimulation were compared with healthy controls, through 16 different tasks that assessed some aspects of impulsivity. Both Deep brain stimulation of the subthalamic nucleus and medication were associated with impulsive behavior and influenced decision-making processes. Moreover, findings demonstrated that: Impulse Control Disorders (ICDs) occurred soon after surgery, while, in pharmacological treatment, they appeared mainly after the initiation of treatment or the increase in dosage, especially with dopamine agonists. The subthalamic nucleus plays a part in the fronto-striato-thalamic-cortical loops mediating motor, cognitive, and emotional functions: this could explain the role of the Deep Brain Stimulation in behavior modulation in Parkinson’s Disease patients. Indeed, increase impulsivity has been reported also after deep brain stimulation of the subthalamic nucleus independently by dopaminergic medication status.
The Laws of Alfred
Authors: Jurasinski Stefan , Oliver Lisi
Published: May 2021

Alfred the Great's domboc ('book of laws') is the longest and most ambitious legal text of the Anglo-Saxon period. Alfred places his own laws, dealing with everything from sanctuary to feuding to the theft of bees, between a lengthy translation of legal passages from the Bible and the legislation of the West-Saxon King Ine (r. 688–726), which rival his own in length and scope. This book is the first critical edition of the domboc published in over a century, as well as a new translation. Five introductory chapters offer fresh insights into the laws of Alfred and Ine, considering their backgrounds, their relationship to early medieval legal culture, their manuscript evidence and their reception in later centuries. Rather than a haphazard accumulation of ordinances, the domboc is shown to issue from deep reflection on the nature of law itself, whose effects would permanently alter the development of early English legislation.
Laboratory-based evaluation of a simplified point-of-care test intended to support treatment decisions in non-severe bovine clinical mastitis
Authors: Malcata Francisco B. , Pepler P. Theo , Zadoks Ruth N. , Viora Lorenzo
Published: May 2021

To limit the use of antimicrobials in dairy cattle, farmers are increasingly encouraged to adopt targeted treatment decisions based on knowledge of the pathogens causing clinical mastitis (CM), whereby treatment of non-severe CM is generally recommended for gram-positive mastitis but not for gram-negative or culture-negative mastitis. The objectives of this study were to conduct a laboratory-based evaluation of the performance of a simplified slide test as a tool to differentiate gram-positive CM from other cases of CM, and to compare its performance against a commercially available on-farm test that is commonly used in our area (VétoRapid). Test outcomes after 24–48 h incubation were compared to results from bacteriological culture and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-ToF MS). Milk samples (n = 156) were obtained from cases of severe and non-severe CM on seven farms and collected by farm personnel. After removal of small numbers of contaminated samples and organisms with unknown species identity, the simplified slide test showed high sensitivity and accuracy (>80%), similar to the comparator test. For most outcomes of interest (culture positive, Escherichia coli, or gram-positive growth), the specificity of the slide test was higher than the specificity of the comparator test. When considering non-severe cases of CM only, and interpreting detection of gram-positive organisms as indicative of the need for antimicrobial treatment, the simplified test had higher specificity (77.4% v. 60.4%) and higher positive predictive value (79.7% v. 70.0%) than the comparator test and similar sensitivity (83.9% v. 87.5%). The proportion of sampled CM cases, contaminated samples and gram-positive mastitis cases – which affects the positive and negative predictive value, the economic value of diagnostic testing and its potential to reduce antimicrobial use – differed between farms. The simplicity and accuracy of the slide test could make it an attractive tool for farmers to target antimicrobial treatment of non-severe clinical mastitis.