Metal Catalysed Intermolecular Hydroacylation

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Evolutionary responses to acquiring a multidrug resistance plasmid are dominated by metabolic functions across diverse <i>Escherichia coli</i> lineages

Multidrug resistance (MDR) plasmids drive the spread of antibiotic resistance between bacterial lineages. The immediate impact of MDR plasmid acquisition on fitness and cellular processes varies among bacterial lineages, but how the evolutionary processes enabling the genomic integration of MDR plasmids vary is less well understood, particularly in clinical pathogens. Using diverse Escherichia coli lineages experimentally evolved for ~700 generations, we show that the evolutionary response to gaining the MDR plasmid pLL35 was dominated by chromosomal mutations affecting metabolic and regulatory functions, with both strain-specific and shared mutational targets. The expression of several of these functions, such as anaerobic metabolism, is known to be altered upon acquisition of pLL35. Interactions with resident mobile genetic elements, notably several IS-elements, potentiated parallel mutations, including insertions upstream of hns that were associated with its upregulation and the downregulation of the plasmid-encoded extended-spectrum beta-lactamase gene. Plasmid parallel mutations targeted conjugation-related genes, whose expression was also commonly downregulated in evolved clones. Beyond their role in horizontal gene transfer, plasmids can be an important selective force shaping the evolution of bacterial chromosomes and core cellular functions. IMPORTANCE Plasmids drive the spread of antimicrobial resistance genes between bacterial genomes. However, the evolutionary processes allowing plasmids to be assimilated by diverse bacterial genomes are poorly understood, especially in clinical pathogens. Using experimental evolution with diverse E. coli lineages and a clinical multidrug resistance plasmid, we show that although plasmids drove unique evolutionary paths per lineage, there was a surprising degree of convergence in the functions targeted by mutations across lineages, dominated by metabolic functions. Remarkably, these same metabolic functions show higher evolutionary rates in MDR-lineages in nature and in some cases, like anaerobic metabolism, their expression is directly manipulated by the plasmid. Interactions with other mobile elements resident in the genomes accelerated adaptation by disrupting genes and regulatory sequences that they inserted into. Beyond their role in horizontal gene transfer, plasmids are an important selective force driving the evolution of bacterial genomes and core cellular functions. </p

Mapping gene-by-gene single-nucleotide variation in 8,535 <i>Mycobacterium tuberculosis</i> genomes:a resource to support potential vaccine and drug development

Tuberculosis is an infectious disease caused by the bacterium Mycobacterium tuberculosisMycobacterium bovi

Early fluid bolus in adults with sepsis in the emergency department : a systematic review, meta-analysis and narrative synthesis

Background: Early intravenous fluids for patients with sepsis presenting with hypoperfusion or shock in the emergency department remains one of the key recommendations of the Surviving Sepsis Campaign guidelines to reduce mortality. However, compliance with the recommendation remains poor. While several interventions have been implemented to improve early fluid administration as part of sepsis protocols, the extent to which they have improved compliance with fluid resuscitation is unknown. The factors associated with the lack of compliance are also poorly understood. Methods: We conducted a systematic review, meta-analysis and narrative review to investigate the effectiveness of interventions in emergency departments in improving compliance with early fluid administration and examine the non-interventional facilitators and barriers that may influence appropriate fluid administration in adults with sepsis. We searched MEDLINE Ovid/PubMed, Ovid EMBASE, CINAHL, and SCOPUS databases for studies of any design to April 2021. We synthesised results from the studies reporting effectiveness of interventions in a meta-analysis and conducted a narrative synthesis of studies reporting non-interventional factors. Results: We included 31 studies out of the 825 unique articles identified in the systematic review of which 21 were included in the meta-analysis and 11 in the narrative synthesis. In meta-analysis, interventions were associated with a 47% improvement in the rate of compliance [(Random Effects (RE) Relative Risk (RR) = 1.47, 95% Confidence Interval (CI), 1.25–1.74, p-value < 0.01)]; an average 24 min reduction in the time to fluids [RE mean difference = − 24.11(95% CI − 14.09 to − 34.14 min, p value < 0.01)], and patients receiving an additional 575 mL fluids [RE mean difference = 575.40 (95% CI 202.28–1353.08, p value < 0.01)]. The compliance rate of early fluid administration reported in the studies included in the narrative synthesis is 48% [RR = 0.48 (95% CI 0.24–0.72)]. Conclusion: Performance improvement interventions improve compliance and time and volume of fluids administered to patients with sepsis in the emergency department. While patient-related factors such as advanced age, co-morbidities, cryptic shock were associated with poor compliance, important organisational factors such as inexperience of clinicians, overcrowding and inter-hospital transfers were also identified. A comprehensive understanding of the facilitators and barriers to early fluid administration is essential to design quality improvement projects

Identifying factors associated with intravenous fluid administration in patients with sepsis presenting to the emergency department : a retrospective cohort study

Background: Appropriate and timely administration of intravenous fluids to patients with sepsis-induced hypotension is one of the mainstays of sepsis management in the emergency department (ED), however, fluid resuscitation remains an ongoing challenge in ED. Our study has been undertaken with two specific aims: firstly, for patients with sepsis, to identify factors associated with receiving intravenous fluids while in the ED; and, secondly to identify determinants associated with the actual time to fluid administration. Methods: We conducted a retrospective multicentre cohort study of adult ED presentations between October 2018 and May 2019 in four metropolitan hospitals in Western Sydney, Australia. Patients meeting pre-specified criteria for sepsis and septic shock and treated with antibiotics within the first 24 h of presentation were included. Multivariable models were used to identify factors associated with fluid administration in sepsis. Results: Four thousand one hundred forty-six patients met the inclusion criteria, among these 2,300 (55.5%) patients with sepsis received intravenous fluids in ED. The median time to fluid administration from the time of diagnosis of sepsis was 1.6 h (Interquartile Range (IQR) 0.5 to 3.8), and the median volume of fluids administered was 1,100 mL (IQR 750 to 2058). Factors associated with patients receiving fluids were younger age (Odds Ratio (OR) 1.05, 95% Confidence Interval (CI (1.03 to 1.07), p < 0.001); lower systolic blood pressure (OR 1.11, 95% CI (1.08 to 1.13), p < 0.001); presenting to smaller hospital (OR 1.48, 95% CI (1.25 to 1.75, p < 0.001) and a Clinical Rapid Response alert activated (OR 1.64, 95% CI (1.28 to 2.11), p < 0.001). Patients with Triage Category 1 received fluids 101.22 min earlier (95% CI (59.3 to131.2), p < 0.001) and those with Category 2 received fluids 43.58 min earlier (95% CI (9.6 to 63.1), p < 0.001) compared to patients with Triage Category 3-5. Other factors associated with receiving fluids earlier included septic shock (-49.37 min (95% CI (-86.4 to -12.4), p < 0.001)); each mmol/L increase in serum lactate levels (-9.0 min, 95% CI (-15.7 to -2.3), p < 0.001) and presenting to smaller hospitals (-74.61 min, 95% CI (-94.0 to -55.3), p < 0.001). Conclusions: Younger age, greater severity of sepsis, and presenting to a smaller hospital increased the probability of receiving fluids and receiving it earlier. Recognition of these factors may assist in effective implementation of sepsis management guidelines which should translate into better patient outcomes. Future studies are needed to identify other associated factors that we have not explored

Control over microphase separation and dielectric properties via para-fluoro thiol click reaction

Herein, we have reported the facile para-fluoro thiol click reaction to control microphase separation and the dielectric properties of poly(pentafluorostyrene-b-acrylic acid) copolymers. The block copolymer of pentafluorostyrene and acrylic acid was synthesized resulting in high block incompatibility by Nitroxide Mediated Polymerisation. By using the para-fluoro thiol reaction, 1-dodecanethiol was precisely clicked to block copolymers in various ratios. The microphase structures were observed in cylindrical geometry and their directionality was changed from parallel to perpendicular with increasing click ratio, besides domain size was recorded as low as 5.5 nm. The dielectric constant of the copolymers decreases with increasing click ratio due to the low dielectric constant of dodecane pendant groups and reaches κ=2.4 (at 1000 Hz). This study provides insights on one-step control over phase and dielectric properties by using a facile and very effective click reaction strategy that can simplify the fabrication of novel polymers for next-generation capacitor films for use in directed energy and advanced integrated circuits with smaller feature sizes

Genetic import and phenotype specific alleles associated with hyper-invasion in Campylobacter jejuni

Background: Campylobacter jejuni is a major zoonotic pathogen, causing gastroenteritis in humans. Invasion is an important pathogenesis trait by which C. jejuni causes disease. Here we report the genomic analysis of 134 strains to identify traits unique to hyperinvasive isolates. Methods: A total of 134 C. jejuni genomes were used to create a phylogenetic tree to position the hyperinvasive strains. Comparative genomics lead to the identification of mosaic capsule regions. A pan genome approach led to the discovery of unique loci, or loci with unique alleles, to the hyperinvasive strains. Results: Phylogenetic analysis showed that the hyper-invasive phenotype is a generalist trait. Despite the fact that hyperinvasive strains are only distantly related based on the whole genome phylogeny, they all possess genes within the capsule region with high identity to capsule genes from C. jejuni subsp. doylei and C. lari. In addition there were genes unique to the hyper-invasive strains with identity to non-C. jejuni genes, as well as allelic variants of mainly pathogenesis related genes already known in the other C. jejuni. In particular, the sequence of flagella genes, flgD-E and flgL were highly conserved amongst the hyper-invasive strains and divergent from sequences in other C. jejuni. A novel cytolethal distending toxin (cdt) operon was also identified as present in all hyper-invasive strains in addition to the classic cdt operon present in other C. jejuni. Conclusions: Overall, the hyper-invasive phenotype is strongly linked to the presence of orthologous genes from other Campylobacter species in their genomes, notably within the capsule region, in addition to the observed association with unique allelic variants in flagellar genes and the secondary cdt operon which is unlikely under random sharing of accessory alleles in separate lineages.Peer reviewe

Terminology and Classification of Muscle Injuries in Sport: The Munich Consensus Statement

Objective: To provide a clear terminology and classification of muscle injuries in order to facilitate effective communication among medical practitioners and development of systematic treatment strategies. Methods: Thirty native English-speaking scientists and team doctors of national and first division professional sports teams were asked to complete a questionnaire on muscle injuries to evaluate the currently used terminology of athletic muscle injury. In addition, a consensus meeting of international sports medicine experts was established to develop practical and scientific definitions of muscle injuries as well as a new and comprehensive classification system. Results: The response rate of the survey was 63%. The responses confirmed the marked variability in the use of the terminology relating to muscle injury, with the most obvious inconsistencies for the term strain. In the consensus meeting, practical and systematic terms were defined and established. In addition, a new comprehensive classification system was developed, which differentiates between four types: functional muscle disorders (type 1: overexertion-related and type 2: neuromuscular muscle disorders) describing disorders without macroscopic evidence of fibre tear and structural muscle injuries (type 3: partial tears and type 4: (sub)total tears/tendinous avulsions) with macroscopic evidence of fibre tear, that is, structural damage. Subclassifications are presented for each type. Conclusions: A consistent English terminology as well as a comprehensive classification system for athletic muscle injuries which is proven in the daily practice are presented. This will help to improve clarity of communication for diagnostic and therapeutic purposes and can serve as the basis for future comparative studies to address the continued lack of systematic information on muscle injuries in the literature. What are the new things: Consensus definitions of the terminology which is used in the field of muscle injuries as well as a new comprehensive classification system which clearly defines types of athletic muscle injuries

Real-time sampling of travelers shows intestinal colonization by multidrug-resistant bacteria to be a dynamic process with multiple transient acquisitions

AbstractBackgroundAntimicrobial resistance (AMR) is highly prevalent in low- and middle-income countries (LMIC). International travel contributes substantially to the global spread of intestinal multidrug-resistant gram-negative (MDR-GN) bacteria. Of the 100 million annual visitors to LMIC, 30–70% become colonized by MDR-GN bacteria. The phenomenon has been well documented, but since sampling has only been conducted after travelers’ return home, data on the actual colonization process are scarce. We aimed to characterize colonization dynamics by exploring stool samples abroad on a daily basis while visiting LMIC.MethodsA group of 20 European volunteers visiting Lao People’s Democratic Republic for three weeks provided daily stool samples and filled in daily questionnaires. Acquisition of extended-spectrum beta-lactamase-producing gram-negative bacteria (ESBL-GN) was examined by selective stool cultures followed by whole-genome sequencing (WGS) of isolates.ResultsWhile colonization rates were 70% at the end of the study, daily sampling revealed that all participants had acquired ESBL-GN at some time point during their overseas stay, the colonization status varying day by day. WGS analysis ascribed the transient pattern of colonization to sequential acquisition of new strains, resulting in a loss of detectable colonization by the initial MDR-GN strains. All but one participant acquired multiple strains (n=2–7). Of the total of 83 unique strains identified (53 E. coli, 10 Klebsiella, 20 other ESBL-GN species), some were shared by as many as four subjects.ConclusionsThis is the first study to characterize in real time the dynamics of acquiring MDR-GN during travel. Our data show multiple transient colonization events indicative of constant microbial competition.</jats:sec