Ridinilazole: a novel, narrow‐spectrum antimicrobial agent targeting Clostridium ( Clostridioides ) difficile

Clostridium (Clostridioides) difficile infection (CDI) remains an urgent threat to patients in health systems worldwide. Recurrent CDI occurs in up to 30% of cases due to sustained dysbiosis of the gut microbiota which normally protects against CDI. Associated costs of initial and recurrent episodes of CDI impose heavy financial burdens on health systems. Vancomycin and metronidazole have been the mainstay of therapy for CDI for many years; however, these agents continue to cause significant disruption to the gut microbiota and thus carry a high risk of recurrence for CDI patients. Treatment regimens are now turning towards novel narrow spectrum antimicrobial agents which target C. difficile while conserving the commensal gut microbiota, thus significantly reducing risk of recurrence. One such agent, fidaxomicin, has been in therapeutic use for several years and is now recommended as a first-line treatment for CDI, as it is superior to vancomycin in reducing risk of recurrence. Another narrow spectrum agent, ridnilazole, was recently developed and is undergoing evaluation of its potential clinical utility. This review aimed to summarize experimental reports of ridinilazole and assess its potential as a first-line agent for treatment of CDI. Reported results from in vitro assessments, and from hamster models of CDI, show potent activity against C. difficile, non-inferiority to vancomycin for clinical cure and non-susceptibility among most gut commensal bacteria. Phase I and II clinical trials have been completed with ridinilazole showing high tolerability and efficacy in treatment of CDI, and superiority over vancomycin in reducing recurrence of CDI within 30 days of treatment completion. Phase III trials are currently underway, the results of which may prove its potential to reduce recurrent CDI and lessen the heavy health and financial burden C. difficile imposes on patients and healthcare systems

Service user leadership: training and development for service users to take the lead

Purpose – This paper outlines the concept of service user leadership and both describes and reflects on an accredited training programme that enables mental health service users to take a leadership role. Design/methodology/approach – The authors argue for a service user leadership approach and the training programme is reviewed by previous participants Findings – Service users can take on a leadership role if they are given suitable and relevant training and development opportunities. Service user led training can be transformational. Practical implications – Commissioners of mental health services should consider how to support service user leadership programmes, which can reach places and achieve outcomes that traditional mental health services are unable to attain. Originality/value – The concept of service user leadership is relatively new and the training programme described in this paper is both original and highly valued by participants with many significant outcomes. Keywords Service user leadership, Peer support, Empowerment, Service user involvement, Confidence, Wellbeing, Leadership, Trainin

Systematic Assessment of the Influence of Mo Concentration on the Oxygen Ingress in Ti–Mo System During High Temperature Oxidation

To understand the role of composition in the oxidation behavior of Ti–Mo system and to evaluate the extent of oxygen ingress into the metal substrate during high temperature exposure, a compositionally graded Ti–xMo specimen (0 ≤ x ≤ 12 wt% Mo) was prepared using an additive manufacturing technique, solutionized and then subjected to oxidation tests at 650 °C for different exposure times. The depth of oxygen diffusion, across the composition range, was assessed via change in the local hardness and the results were coupled with quantitative measurement of the oxygen concentration. The concentration of O in the α phase was reduced by 90 % after a short distance of 16 μm from the metal/oxide interface while it remained more or less the same in β phase. The solubility of Mo in α phase also approached zero near the surface as O changed the partition coefficient of this element between α and β phases. It was shown that the addition of Mo reduces the solubility of O in the metal substrate which in turn retards the transition point from parabolic to the linear oxidation stage

Genome analysis of Clostridium difficile PCR ribotype 014 lineage in Australian pigs and humans reveals a diverse genetic repertoire and signatures of long-range interspecies transmission

Clostridium difficile PCR ribotype (RT) 014 is well-established in both human and porcine populations in Australia, raising the possibility that C. difficile infection (CDI) may have a zoonotic or foodborne etiology. Here, whole genome sequencing and high-resolution core genome phylogenetics were performed on a contemporaneous collection of 40 Australian RT014 isolates of human and porcine origin. Phylogenies based on MLST (7 loci, STs 2, 13, and 49) and core orthologous genes (1260 loci) showed clustering of human and porcine strains indicative of very recent shared ancestry. Core genome single nucleotide variant (SNV) analysis found 42% of human strains showed a clonal relationship (separated by ≤2 SNVs in their core genome) with one or more porcine strains, consistent with recent inter-host transmission. Clones were spread over a vast geographic area with 50% of the human cases occurring without recent healthcare exposure. These findings suggest a persistent community reservoir with long-range dissemination, potentially due to agricultural recycling of piggery effluent. We also provide the first pan-genome analysis for this lineage, characterizing its resistome, prophage content, and in silico virulence potential. The RT014 is defined by a large “open” pan-genome (7587 genes) comprising a core genome of 2296 genes (30.3% of the total gene repertoire) and an accessory genome of 5291 genes. Antimicrobial resistance genotypes and phenotypes varied across host populations and ST lineages and were characterized by resistance to tetracycline [tetM, tetA(P), tetB(P) and tetW], clindamycin/erythromycin (ermB), and aminoglycosides (aph3-III-Sat4A-ant6-Ia). Resistance was mediated by clinically important mobile genetic elements, most notably Tn6194 (harboring ermB) and a novel variant of Tn5397 (harboring tetM). Numerous clinically important prophages (Siphoviridae and Myoviridae) were identified as well as an uncommon accessory gene regulator locus (agr3). Conservation in the pathogenicity locus and S-layer correlated with ST affiliation, further extending the concept of clonal C. difficile lineages. This study provides novel insights on the genetic variability and strain relatedness of C. difficile RT014, a lineage of emerging One Health importance. Ongoing molecular and genomic surveillance of strains in humans, animals, food, and the environment is imperative to identify opportunities to reduce the overall CDI burden

On the eutectoid transformation behavior of the Ti-Zn system and its metastable phases

To date, Zn has not been used as an alloying addition in structural Ti alloys. The main obstacle has been the disparity between their melting and vaporization temperatures. A novel processing technique was developed to create a Ti-Zn compound. The equilibrium phases and microstructures were studied by electron microscopy and x-ray diffraction techniques. Results show the presence of pearlitic domains of α-Ti (hexagonal closed packed crystal structure) and Ti2Zn (body center tetragonal structure) in regions that have a near eutectoid composition. Solutionizing and water quenching results in the formation of martensite along with intermetallic laths, suggesting that the eutectoid transformation is active

New concepts in the abstract format of the Compositional Interchange Format

The compositional interchange format for hybrid systems (CIF) supports inter-operability of a wide range of tools by means of model transformations to and from the CIF. Work on the CIF takes place in the FP7 Multiform project, and in several other European projects. The CIF consists of an abstract and a concrete format, used for defining a formal semantics and for modeling, respectively. This paper discusses the results of a redesign of the abstract format as previously published, leading to the following main changes: variables are introduced using scoping operators; the abstract language is made more orthogonal by providing an operator for each concept in the language; parallel composition has been defined in such a way that compositional verification (assume/guarantee reasoning) is supported; and the concept of urgent actions has been properly defined. As a result, the expressivity and semantics of the abstract language have been considerably improved

Clostridium difficile ribotype 017 – characterization, evolution and epidemiology of the dominant strain in Asia

Clostridium difficile ribotype (RT) 017 is an important toxigenic C. difficile RT which, due to a deletion in the repetitive region of the tcdA gene, only produces functional toxin B. Strains belonging to this RT were initially dismissed as nonpathogenic and circulated largely undetected for almost two decades until they rose to prominence following a series of outbreaks in the early 2000s. Despite lacking a functional toxin A, C. difficile RT 017 strains have been shown subsequently to be capable of causing disease as severe as that caused by strains producing both toxins A and B. While C. difficile RT 017 strains can be found in almost every continent today, epidemiological studies suggest that the RT is endemic in Asia and that the global spread of this MLST clade 4 lineage member is a relatively recent event. C. difficile RT 017 transmission appears to be mostly from human to human with only a handful of reports of isolations from animals. An important feature of C. difficile RT 017 strains is their resistance to several antimicrobials and this has been documented as a possible factor driving multiple outbreaks in different parts of the world. This review summarizes what is currently known regarding the emergence and evolution of strains belonging to C. difficile RT 017 as well as features that have allowed it to become an RT of global importance

Global evolutionary dynamics and resistome analysis of Clostridioides difficile ribotype 017

Clostridioides difficile PCR ribotype (RT) 017 ranks among the most successful strains of C. difficile in the world. In the past three decades, it has caused outbreaks on four continents, more than other ‘epidemic’ strains, but our understanding of the genomic epidemiology underpinning the spread of C. difficile RT 017 is limited. Here, we performed high-resolution phylogenomic and Bayesian evolutionary analyses on an updated and more representative dataset of 282 non-clonal C. difficile RT 017 isolates collected worldwide between 1981 and 2019. These analyses place an estimated time of global dissemination between 1953 and 1983 and identified the acquisition of the ermB-positive transposon Tn6194 as a key factor behind global emergence. This coincided with the introduction of clindamycin, a key inciter of C. difficile infection, into clinical practice in the 1960s. Based on the genomic data alone, the origin of C. difficile RT 017 could not be determined; however, geographical data and records of population movement suggest that C. difficile RT 017 had been moving between Asia and Europe since the Middle Ages and was later transported to North America around 1860 (95 % confidence interval: 1622–1954). A focused epidemiological study of 45 clinical C. difficile RT 017 genomes from a cluster in a tertiary hospital in Thailand revealed that the population consisted of two groups of multidrug-resistant (MDR) C. difficile RT 017 and a group of early, non-MDR C. difficile RT 017. The significant genomic diversity within each MDR group suggests that although they were all isolated from hospitalized patients, there was probably a reservoir of C. difficile RT 017 in the community that contributed to the spread of this pathogen

Subtraction terms at NNLO

Perturbative calculations at next-to-next-to-leading order for multi-particle final states require a method to cancel infrared singularities. I discuss the subtraction method at NNLO. As a concrete example I consider the leading-colour contributions to e+ e- --> 2 jets. This is the simplest example which exhibits all essential features. For this example, explicit subtraction terms are given, which approximate the four-parton and three-parton final states in all double and single unresolved limits, such that the subtracted matrix elements can be integrated numerically.Comment: 41 page

Sampled-data control of hybrid systems with discrete inputs and outputs

We address the control synthesis of hybrid systems with discrete inputs, disturbances and outputs. The control objective is to ensure that the events of the closed-loop system belong to the language of the control requirements. The controller is sampling-based and it is representable by a finite-state machine. We formalize the control problem and provide a theoretically sound solution. The solution is based on solving a discrete-event control problem for a finite-state abstraction of the plant. We propose a specific construction for the finite-state abstraction. This construction is not based on discretizing the state-space, but rather on converting the continuous-time hybrid system to a discrete-time one based on sampling. The construction works only for a specific class of hybrid systems. We describe this class of systems and we provide an example of such a system, inspired by an industrial use-case