Silver diamine fluoride and oral health-related quality of life: A review and network meta-analysis.

Objective: Silver diamine fluoride (SDF) is an effective non-surgical treatment for dental caries which may also impact oral health-related quality of life (OHRQoL). The objective of this study was to conduct a network meta-analysis of SDF versus other standard of care therapies on OHRQoL.

Data Sources: Studies published in PubMed/MEDLINE, Scopus, or Web of Science through July 2021 with no date or language restrictions.

Functional Genomic Identification of Predictors of Sensitivity and Mechanisms of Resistance to Multivalent Second-Generation TRAIL-R2 Agonists.

Multivalent second-generation TRAIL-R2 agonists are currently in late preclinical development and early clinical trials. Herein, we use a representative second-generation agent, MEDI3039, to address two major clinical challenges facing these agents: lack of predictive biomarkers to enable patient selection and emergence of resistance. Genome-wide CRISPR knockout screens were notable for the lack of resistance mechanisms beyond the canonical TRAIL-R2 pathway (caspase-8, FADD, BID) as well as p53 and BAX in TP53 wild-type models, whereas a CRISPR activatory screen identified cell death inhibitors MCL-1 and BCL-XL as mechanisms to suppress MEDI3039-induced cell death.

Rapid implementation of virtual clinics due to COVID-19: report and early evaluation of a quality improvement initiative.

Background: The COVID-19 outbreak has placed the National Health Service under significant strain. Social distancing measures were introduced in the UK in March 2020 and virtual consultations (via telephone or video call) were identified as a potential alternative to face-to-face consultations at this time.

Local Problem: The Royal National Orthopaedic Hospital (RNOH) sees on average 11 200 face-to-face consultations a month.

Discovery of potent and stable conformationally constrained analogues of the MCH R1 antagonist SB-568849.

A strategy of systematically targeting more rigid analogues of the known MCH R1 receptor antagonist, SB-568849, serendipitously uncovered a binding mode accessible to N-aryl-phthalimide ligands. Optimisation to improve the stability of this compound class led to the discovery of novel N-aryl-quinazolinones, benzotriazinones and thienopyrimidinones as selective ligands with good affinity for human melanin-concentrating hormone receptor 1.

SAR of biphenyl carboxamide ligands of the human melanin-concentrating hormone receptor 1 (MCH R1): discovery of antagonist SB-568849.

We report here the discovery of a class of MCH R1 ligands based on a biphenyl carboxamide template. A docked-in model is presented indicating key interactions in the putative binding site of the receptor. Parallel high throughput synthetic techniques were utilised to allow rapid exploration of the structure-activity relationship around this template, leading to compound SB-568849 which possessed good receptor affinity and selectivity.

Thomas Hastie Bryce (1862-1946)--a lesson in the power of observation.

Thomas Hastie Bryce was Regius Professor of Anatomy at the University of Glasgow from 1909 to 1935. In Anatomy, he is remembered as an embryologist and as an editor of the 11th edition of Quain's Elements of Anatomy. His most-lasting scientific contribution, however, was in archaeology where he defined the Clyde Group of Neolithic cairns in south-west Scotland.

S-alkyl dithioformates as 1,3-dipolarophiles. Generation of C(2)-unsubstituted penems.

S-Alkyl dithioformates, generated by a cycloreversion process, react as 1,3-dipolarophiles with beta-lactam-based azomethine ylids to provide, after (net) elimination of MeSH, C(2)-unsubstituted penems. The overall cycloreversion/cycloaddition sequence was accelerated by microwave irradiation. [reaction: see text]

Using patient stories to inspire quality improvement within the NHS Modernization Agency collaborative programmes.

The importance of obtaining the opinions of service users has long been recognized and, traditionally, most contact has focused on measuring their satisfaction with the services they receive. However, there is little evidence that this has had much impact on improving care. The Discovery Interview Process, a technique for listening to patients and carers and using their narratives to improve care, is discussed in this article.

Coordination geometries of metal ions in d- or l-captopril-inhibited metallo-beta-lactamases.

d- and l-captopril are competitive inhibitors of metallo-beta-lactamases. For the enzymes from Bacillus cereus (BcII) and Aeromonas hydrophila (CphA), we found that the mononuclear enzymes are the favored targets for inhibition. By combining results from extended x-ray absorption fine structure, perturbed angular correlation of gamma-rays spectroscopy, and a study of metal ion binding, we derived that for Cd(II)1-BcII, the thiolate sulfur of d-captopril binds to the metal ion located at the site defined by three histidine ligand residues.

Identification of a series of tricyclic natural products as potent broad-spectrum inhibitors of metallo-beta-lactamases.

This work describes the discovery and characterization of a novel series of tricyclic natural product-derived metallo-beta-lactamase inhibitors. Natural product screening of the Bacillus cereus II enzyme identified an extract from a strain of Chaetomium funicola with inhibitory activity against metallo-beta-lactamases. SB236050, SB238569, and SB236049 were successfully extracted and purified from this extract.

Characterization of monomeric L1 metallo-beta -lactamase and the role of the N-terminal extension in negative cooperativity and antibiotic hydrolysis.

The L1 metallo-beta-lactamase from Stenotrophomonas maltophilia is unique among this class of enzymes because it is tetrameric. Previous work predicted that the two regions of important intersubunit interaction were the residue Met-140 and the N-terminal extensions of each subunit. The N-terminal extension was also implicated in beta-lactam binding.

beta-Lactamase epidemiology and the utility of established and novel beta-lactamase inhibitors.

beta-Lactamase inhibitor:beta-lactam combinations remain one of the most successful strategies for the treatment of bacterial infections. Over the last 20 years the number and diversity of serine and metallo active site beta-lactamases has increased dramatically. This review highlights some of the new additions to the beta-lactamase arena and discusses how the commercially available beta-lactamase inhibitors are keeping pace with the changing epidemiology of beta-lactamases.

Voltage-gated potassium channels in human ductus arteriosus.

We studied tone in the human ductus arteriosus and show that the constriction to oxygen is due to inhibition of voltage-gated potassium channels and, in the acute phase, is independent of endothelin-1.

Minocycline-induced staining of the adult permanent dentition: a review of the literature and report of a case.

Tetracycline staining of teeth during tooth development is well documented. We report here the rarer condition of tetracycline staining of adult teeth. This occurrence appears to involve enamel surface demineralization/remineralization and can produce staining clinically indistinguishable from that occurring during tooth development.

Crystal structure of the zinc-dependent beta-lactamase from Bacillus cereus at 1.9 A resolution: binuclear active site with features of a mononuclear enzyme.

The structure of the zinc-dependent beta-lactamase II from Bacillus cereus has been determined at 1.9 A resolution in a crystal form with two molecules in the asymmetric unit and 400 waters (space group P3121; Rcryst = 20.8%).

Nucleotide and amino acid sequences of the metallo-beta-lactamase, ImiS, from Aeromonas veronii bv. sobria.

The Aeromonas veronii bv. sobria metallo-beta-lactamase gene, imiS, was cloned. The imiS open reading frame extends for 762 bp and encodes a protein of 254 amino acids with a secreted modified protein of 227 amino acids and a predicted pI of 8.

Inhibition of metallo-beta-lactamases by a series of thiol ester derivatives of mercaptophenylacetic acid.

A series of mercaptophenylacetic acid thiol esters bearing a phenyl substituent adjacent to the carboxylic acid function has been shown to be inhibitors of metallo-beta-lactamases. The inhibition of the Bacteroides fragilis CfiA and Bacillus cereus II metallo-beta-lactamases was Zn2- dependent, greater inhibition being observed at 1 microM ZnSO4 than at 100 microM ZnSO4. Despite this Zn2+ dependency, isothermal titration calorimetry studies illustrated that representative compounds had no detectable affinity for Zn2+ (K > 1 mM).

Inhibition of metallo-beta-lactamases by a series of mercaptoacetic acid thiol ester derivatives.

A series of mercaptoacetic acid thiol esters have been identified as metallo-beta-lactamase inhibitors. Electrospray mass spectrometry (ESMS) has shown that irreversible inhibition of the Bacillus cereus II metallo-beta-lactamase by SB214751, SB214752, and SB213079 was concomitant with a 90-Da increase in mass of the enzyme. Tryptic digestion of the B.

Phosphonamidate analogues of dipeptides with carboxypeptidase A and beta-lactamase-inhibitory activity: elucidation of the mechanism of beta-lactamase inhibition by electrospray mass spectrometry.

A series of phosphonamidate compounds with different P1' amino acid residues have been shown to be irreversible inactivators of the serine beta-lactamase from Enterobacter cloacae P99. The efficiency of inhibition (based on k2/K values) of P99 by these derivatives, ordered in decreasing potency, is: beta-phenyl-beta-Ala > L-Phe > beta-Ala > Gly > D-Phe > D-Pro > D-thiazolidine. The D- and L-Phe compounds also inhibit carboxypeptidase A.

Rapid identification of metallo- and serine beta-lactamases.

Simple methods to detect, identify, and differentiate metallo- and serine beta-lactamases were developed and used to differentiate enzymes produced by 17 clinical isolates of Xanthomonas maltophilia. All isolates exhibited beta-lactamase activity, and in 16 strains this was induced by imipenem. All but one isolate hydrolyzed imipenem (and meropenem), and in all cases this activity was inhibited by 1 mM EDTA.