Implementation of the TALK© clinical self-debriefing tool in operating theatres: a single-centre interventional study.

Background: Debriefing in operating theatre environments leads to benefits in mortality, efficiency, productivity, and safety culture; however, it is still not regularly performed. TALK© is a simple and widely applicable team self-debriefing method to collaboratively learn and improve.

Methods: An interventional study introducing TALK© for voluntary clinical debriefing was carried out in operating theatre environments in a UK National Health Service hospital over 18 months.

A Hybrid Architecture (CO-CONNECT) to Facilitate Rapid Discovery and Access to Data Across the United Kingdom in Response to the COVID-19 Pandemic: Development Study.

Background: COVID-19 data have been generated across the United Kingdom as a by-product of clinical care and public health provision, as well as numerous bespoke and repurposed research endeavors. Analysis of these data has underpinned the United Kingdom's response to the pandemic, and informed public health policies and clinical guidelines. However, these data are held by different organizations, and this fragmented landscape has presented challenges for public health agencies and researchers as they struggle to find relevant data to access and interrogate the data they need to inform the pandemic response at pace.

Simulated laryngoscopy with supraglottic high-pressure source ventilation: an in vitro study of tracheal airflow to determine optimal positioning of laryngoscope and jet ventilation cannula.

Purpose: To investigate how variations in positioning of laryngoscope and location of jet cannula on the laryngoscope body influence tracheal airflow during simulated high-pressure source supraglottic (HPSV) jet ventilation laryngoscopy using an anatomical model.

Methods: A Broncho Boy Bronchoscopy model was modified to allow recording of tracheal airflow. A laryngoscope was suspended and positioned to simulate laryngoscopy.

A narrative systematic review of randomised controlled trials that compare cannulation techniques for haemodialysis.

Background: Cannulation of arteriovenous access for haemodialysis affects longevity of the access, associates with complications and affects patients' experiences of haemodialysis. Buttonhole and rope ladder techniques were developed to reduce complications. However, studies that compare these two techniques report disparate results.

A real-world, cross-sectional, community survey of symptoms and health-related quality of life of adults with acute myeloid leukemia.

We used Adelphi Real World Disease-Specific Programme data to characterize adults with newly diagnosed or relapsed/refractory acute myeloid leukemia (AML). Community-practice hematologists/oncologists completed patient record forms for their regular AML patients. Patients were invited to complete patient self-completion forms including 3-Level EuroQol 5-Dimensions (EQ-5D-3L) and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) questionnaires.

Real-World Impact of Cardiovascular Disease and Anemia on Quality of Life and Productivity in Patients with Non-Dialysis-Dependent Chronic Kidney Disease.

Introduction: Patients with chronic kidney disease (CKD) have an increased risk of comorbid conditions, including cardiovascular disease (CVD). Anemia is prevalent in the CKD population and worsens as kidney function declines, resulting in a diminished quality of life and increased morbidity/mortality. The purpose of this secondary analysis was to determine the real-world prevalence of CVD among patients with non-dialysis-dependent CKD (NDD-CKD), with and without comorbid anemia, and to assess the impact of these conditions on quality of life (QoL) and work productivity.

Perception of simulation training in emergencies for dental sedation practitioners.

Background: Simulation education is an important part of health care education and training. There is growing evidence to support the usefulness of simulation, especially in training for infrequently occurring situations, such as medical emergencies seen by dental practitioners. There are, however, few data on the longer term effects of simulation, including usefulness, relevance, emotional effect and ability to affect changes to daily practice.

Fragment-based discovery of DNA gyrase inhibitors targeting the ATPase subunit of GyrB.

Inhibitors of the ATPase function of bacterial DNA gyrase, located in the GyrB subunit and its related ParE subunit in topoisomerase IV, have demonstrated antibacterial activity. In this study we describe an NMR fragment-based screening effort targeting Staphylococcus aureus GyrB that identified several attractive and novel starting points with good ligand efficiency. Fragment hits were further characterized using NMR binding studies against full-length S.

Analysis of Streptomyces coelicolor phosphopantetheinyl transferase, AcpS, reveals the basis for relaxed substrate specificity.

The transfer of the phosphopantetheine chain from coenzyme A (CoA) to the acyl carrier protein (ACP), a key protein in both fatty acid and polyketide synthesis, is catalyzed by ACP synthase (AcpS). Streptomyces coelicolor AcpS is a doubly promiscuous enzyme capable of activation of ACPs from both fatty acid and polyketide synthesis and catalyzes the transfer of modified CoA substrates. Five crystal structures have been determined, including those of ligand-free AcpS, complexes with CoA and acetyl-CoA, and two of the active site mutants, His110Ala and Asp111Ala.

Structural and spectroscopic consequences of hexacoordination of a bacteriochlorophyll cofactor in the Rhodobacter sphaeroides reaction center .

The structural and functional consequences of changing the coordination state of one of the bacteriochlorophyll (BChl) cofactors in the purple bacterial reaction center have been explored. A combination of steady state spectroscopy and X-ray crystallography was used to demonstrate that mutagenesis of residue 181 of the L-polypeptide from Phe to Arg (FL181R) causes the BChl at the accessory (B(B)) position on the so-called inactive cofactor branch to become hexacoordinated, with no significant changes to the structure of the surrounding protein. This change was accompanied by the appearance of a distinctive absorbance band at 631 nm in the room-temperature absorbance spectrum.

Structure of insoluble rat sperm glyceraldehyde-3-phosphate dehydrogenase (GAPDH) via heterotetramer formation with Escherichia coli GAPDH reveals target for contraceptive design.

Sperm glyceraldehyde-3-phosphate dehydrogenase has been shown to be a successful target for a non-hormonal contraceptive approach, but the agents tested to date have had unacceptable side effects. Obtaining the structure of the sperm-specific isoform to allow rational inhibitor design has therefore been a goal for a number of years but has proved intractable because of the insoluble nature of both native and recombinant protein. We have obtained soluble recombinant sperm glyceraldehyde-3-phosphate dehydrogenase as a heterotetramer with the Escherichia coli glyceraldehyde-3-phosphate dehydrogenase in a ratio of 1:3 and have solved the structure of the heterotetramer which we believe represents a novel strategy for structure determination of an insoluble protein.

Cloning and characterisation of dihydrodipicolinate synthase from the pathogen Neisseria meningitidis.

Neisseria meningitidis is an obligate commensal bacterium of humans, and also an important human pathogen. To facilitate future drug studies, we report here the biochemical and structural characterisation of a key enzyme in (S)-lysine biosynthesis, dihydrodipicolinate synthase (DHDPS), from N. meningitidis (NmeDHDPS).

Structure of bacterial glutathione-S-transferase maleyl pyruvate isomerase and implications for mechanism of isomerisation.

Maleyl pyruvate isomerase (MPI) is a bacterial glutathione S-transferase (GST) from the pathway for degradation of naphthalene via gentisate that enables the bacterium Ralstonia to use polyaromatic hydrocarbons as a sole carbon source. Genome sequencing projects have revealed the presence of large numbers of GSTs in bacterial genomes, often located within gene clusters encoding the degradation of different aromatic compounds. This structure is therefore an example of this under-represented class of enzymes.

Crystal structure of Pseudomonas aeruginosa SPM-1 provides insights into variable zinc affinity of metallo-beta-lactamases.

Metallo-beta-lactamases (mbetals) confer broad-spectrum resistance to beta-lactam antibiotics upon host bacteria and escape the action of existing beta-lactamase inhibitors. SPM-1 is a recently discovered mbetal that is distinguished from related enzymes by possession of a substantial central insertion and by sequence variation at positions that maintain active site structure. Biochemical data show SPM-1 to contain two Zn2+ sites of differing affinities, a phenomenon that is well documented amongst mbetals but for which a structural explanation has proved elusive.

Design, synthesis and analysis of inhibitors of bacterial aspartate semialdehyde dehydrogenase.

Unsaturated and fluorinated analogues of aspartyl-beta-phosphate were synthesised as potential inhibitors of the bacterial enzyme aspartate semialdehyde dehydrogenase (ASA-DH). Acetylenic and Z-olefinic analogues showed competitive inhibition, but an E-olefinic analogue was inactive. A monofluoromethylene phosphonate competed poorly, but showed time-dependent inhibition of ASA-DH in the absence of phosphate.

The crystal structure of the actIII actinorhodin polyketide reductase: proposed mechanism for ACP and polyketide binding.

We have determined the 2.5 angstroms crystal structure of an active, tetrameric Streptomyces coelicolor type II polyketide ketoreductase (actIII) with its bound cofactor, NADP+. This structure shows a Rossman dinucleotide binding fold characteristic of SDR enzymes.

Expression, purification and preliminary X-ray diffraction analysis of a ketoreductase from a type II polyketide synthase.

Polyketide metabolites produced by bacteria and other organisms include antibiotics, anticancer and antifungal compounds. In type II polyketide synthesis, three enzymes are sufficient to form a polyketide product of the requisite chain length, although the fidelity of the first cyclization is variable. Addition of ketoreductase (KR) to this system results in the formation of a product with correct cyclization and reduction.

Difluoromethylene analogues of aspartyl phosphate: the first synthetic inhibitors of aspartate semi-aldehyde dehydrogenase.

The difluoromethylene analogue of aspartyl phosphate 6 has been prepared by the fluoride catalysed coupling of diethyl trimethylsilyldifluoromethyl phosphonate with an appropriate aldehyde followed by Dess-Martin oxidation and deprotection; the deprotected compound inhibited (KI 95 microM) aspartate semi-aldehyde dehydrogenase, a key enzyme involved in bacterial amino acid and peptidoglycan biosynthesis.

Active site analysis of the potential antimicrobial target aspartate semialdehyde dehydrogenase.

Aspartate-beta-semialdehyde dehydrogenase (ASADH) lies at the first branch point in the biosynthetic pathway through which bacteria, fungi, and the higher plants synthesize amino acids, including lysine and methionine and the cell wall component diaminopimelate from aspartate. Blocks in this biosynthetic pathway, which is absent in mammals, are lethal, and inhibitors of ASADH may therefore serve as useful antibacterial, fungicidal, or herbicidal agents. We have determined the structure of ASADH from Escherichia coli by crystallography in the presence of its coenzyme and a substrate analogue that acts as a covalent inhibitor.

Carcinoembryonic antigens are targeted by diverse strains of typable and non-typable Haemophilus influenzae.

Haemophilus influenzae (Hi), a commensal of the human respiratory mucosa, is an important cause of localized and systemic infections. We show that distinct strains belonging to typable (THi) and non-typable (NTHi) H. influenzae target human carcinoembryonic antigens (the membrane associated CEA family of cell adhesion molecules, are now termed CEACAMs).

Analysis of three structurally related antiviral compounds in complex with human rhinovirus 16.

Rhinoviruses are a frequent cause of the common cold. A series of antirhinoviral compounds have been developed that bind into a hydrophobic pocket in the viral capsid, stabilizing the capsid and interfering with cell attachment. The structures of a variety of such compounds, complexed with rhinovirus serotypes 14, 16, 1A, and 3, previously have been examined.

Critical determinants of host receptor targeting by Neisseria meningitidis and Neisseria gonorrhoeae: identification of Opa adhesiotopes on the N-domain of CD66 molecules.

The human pathogens Neisseria meningitidis and Neisseria gonorrhoeae express a family of variable outer membrane opacity-associated (Opa) proteins that recognize multiple human cell surface receptors. Most Opa proteins target the highly conserved N-terminal domain of the CD66 family of adhesion molecules, although a few also interact with heparan sulphate proteoglycans. In this study, we observed that at least two Opa proteins of a N.

Structure of aspartate-beta-semialdehyde dehydrogenase from Escherichia coli, a key enzyme in the aspartate family of amino acid biosynthesis.

Aspartate beta-semialdehyde dehydrogenase (ASADH) lies at the first branch point in an essential aspartic biosynthetic pathway found in bacteria, fungi and the higher plants. Mutations in the asd gene encoding for ASADH that produce an inactive enzyme are lethal, which suggests that ASADH may be an effective target for antibacterial, herbicidal and fungicidal agents. We have solved the crystal structure of the Escherichia coli enzyme to 2.