Qualitative interviews to understand methods and systems used to collect ethnicity information in health administrative data sources in England.

Background: This article is one of a series aiming to inform analytical methods to improve comparability of estimates of ethnic health disparities based on different sources. This article explores the quality of ethnicity data and identifies potential sources of bias when ethnicity information is collected in three key NHS data sources. Future research can build on these findings to explore analytical methods to mitigate biases. Methods: Thematic analysis of semi-structured qualitative interviews to explore potential sources of error and bias in the process of collecting ethnicity information across three NHS data sources: General Practice Extraction Service (GPES) Data for Pandemic Planning and Research (GDPPR), Hospital Episode Statistics (HES) and Improving Access to Psychological Therapies (IAPT). The study included feedback from 22 experts working on different aspects of health admin data collection for England (including staff from NHS Digital, IT system suppliers and relevant healthcare service providers). Results: Potential sources of error and bias were identified across data collection, data processing and quality assurance processes. Similar issues were identified for all three sources. Our analysis revealed three main themes which can result in bias and inaccuracies in ethnicity data recorded: data infrastructure challenges, human challenges, and institutional challenges. Conclusions: Findings highlighted that analysts using health admin data should be aware of the main sources of potential error and bias in health admin data, and be mindful that the main sources of error identified are more likely to affect the ethnicity data for ethnic minority groups. Where possible, analysts should describe and seek to account for this bias in their research.

Structural and biochemical insights into the disulfide reductase mechanism of DsbD, an essential enzyme for neisserial pathogens.

The worldwide incidence of neisserial infections, particularly gonococcal infections, is increasingly associated with antibiotic-resistant strains. In particular, extensively drug-resistant Neisseria gonorrhoeae strains that are resistant to third-generation cephalosporins are a major public health concern. There is a pressing clinical need to identify new targets for the development of antibiotics effective against Neisseria-specific processes. In this study, we report that the bacterial disulfide reductase DsbD is highly prevalent and conserved among Neisseria spp. and that this enzyme is essential for survival of N. gonorrhoeae DsbD is a membrane-bound protein that consists of two periplasmic domains, n-DsbD and c-DsbD, which flank the transmembrane domain t-DsbD. In this work, we show that the two functionally essential periplasmic domains of Neisseria DsbD catalyze electron transfer reactions through unidirectional interdomain interactions, from reduced c-DsbD to oxidized n-DsbD, and that this process is not dictated by their redox potentials. Structural characterization of the Neisseria n- and c-DsbD domains in both redox states provides evidence that steric hindrance reduces interactions between the two periplasmic domains when n-DsbD is reduced, thereby preventing a futile redox cycle. Finally, we propose a conserved mechanism of electron transfer for DsbD and define the residues involved in domain-domain recognition. Inhibitors of the interaction of the two DsbD domains have the potential to be developed as anti-neisserial agents.

Production, biophysical characterization and initial crystallization studies of the N- and C-terminal domains of DsbD, an essential enzyme in Neisseria meningitidis.

The membrane protein DsbD is a reductase that acts as an electron hub, translocating reducing equivalents from cytoplasmic thioredoxin to a number of periplasmic substrates involved in oxidative protein folding, cytochrome c maturation and oxidative stress defence. DsbD is a multi-domain protein consisting of a transmembrane domain (t-DsbD) flanked by two periplasmic domains (n-DsbD and c-DsbD). Previous studies have shown that DsbD is required for the survival of the obligate human pathogen Neisseria meningitidis. To help understand the structural and functional aspects of N. meningitidis DsbD, the two periplasmic domains which are required for electron transfer are being studied. Here, the expression, purification and biophysical properties of n-NmDsbD and c-NmDsbD are described. The crystallization and crystallographic analysis of n-NmDsbD and c-NmDsbD are also described in both redox states, which differ only in the presence or absence of a disulfide bond but which crystallized in completely different conditions. Crystals of n-NmDsbDOx, n-NmDsbDRed, c-NmDsbDOx and c-NmDsbDRed diffracted to 2.3, 1.6, 2.3 and 1.7 Šresolution and belonged to space groups P213, P321, P41 and P1211, respectively.

HN, N, Cα and Cß assignments of the two periplasmic domains of Neisseria meningitidis DsbD.

DsbD is a disulfide bond reductase present in the inner membrane of many Gamma-Proteobacteria. In the human pathogen Neisseria meningitidis, DsbD is required for viability and represents a potential target for the development of antibiotics. Here we report the chemical shift assignments (HN, N, Cα and Cß) for the reduced and oxidized forms of the two periplasmic domains of N. meningitidis DsbD, n-NmDsbD and c-NmDsbD. The backbone amide resonances in all four forms were completely assigned, and the secondary structures for the core regions of the proteins were calculated using 13Cαß shifts. The reduced and oxidized forms of each domain have similar secondary shifts suggesting they retain the same fold. We anticipate that these data will provide an important basis for studying the interaction between n-NmDsbD and c-NmDsbD, which is required for electron transfer across the bacterial cytoplasmic membrane.

An Updated Protocol for Evaluating Chest Pain and Managing Acute Coronary Syndromes.

Clinical pathways can optimize care both across and within institutions, but regular updates to these pathways based on new clinical trials, professional guidelines, and Food and Drug Administration approvals are essential. Herein we describe the most recent revisions to the New York-Presbyterian Hospital (Columbia University Medical Center and Weill Cornell Medical Center) clinical pathway for acute coronary syndromes and chest pain, which incorporates novel data regarding the timing and administration of P2Y12 inhibition (including the intravenous P2Y12 inhibitor cangrelor) and the appropriateness of prolonged (>1 year) dual antiplatelet therapy for the secondary prevention of ischemic events.

Targeting Bacterial Dsb Proteins for the Development of Anti-Virulence Agents.

Recent years have witnessed a dramatic increase in bacterial antimicrobial resistance and a decline in the development of novel antibiotics. New therapeutic strategies are urgently needed to combat the growing threat posed by multidrug resistant bacterial infections. The Dsb disulfide bond forming pathways are potential targets for the development of antimicrobial agents because they play a central role in bacterial pathogenesis. In particular, the DsbA/DsbB system catalyses disulfide bond formation in a wide array of virulence factors, which are essential for many pathogens to establish infections and cause disease. These redox enzymes are well placed as antimicrobial targets because they are taxonomically widespread, share low sequence identity with human proteins, and many years of basic research have provided a deep molecular understanding of these systems in bacteria. In this review, we discuss disulfide bond catalytic pathways in bacteria and their significance in pathogenesis. We also review the use of different approaches to develop inhibitors against Dsb proteins as potential anti-virulence agents, including fragment-based drug discovery, high-throughput screening and other structure-based drug discovery methods.

Repair renal tubular cells: a potential false-positive diagnosis in urine cytology.

To study the cytopathology of repair renal tubular cells (RRTCs), the Papanicolaou-stained urine sediments of 371 patients with mild and moderate renal tubular injuries were reviewed. In 46 cases, the urine sediments showed, in addition to a mild or moderate increase in number of RTCs, a few isolated and clustered RRTCs that displayed well- or ill-defined, variably abundant, granular or vacuolated cytoplasm; slightly pleomorphic nuclei; and conspicuous or prominent nucleoli. A spectrum of nuclear changes ranging from mild to moderate atypias and/or severe atypia were present in many cases. These RRTCs stained strongly positively with vimentin antibody in 92.3% of the cases.