Fertility, Living Arrangements, Care and Mobility

There are four main interconnecting themes around which the contributions in this book are based. This introductory chapter aims to establish the broad context for the chapters that follow by discussing each of the themes. It does so by setting these themes within the overarching demographic challenge of the twenty-first century – demographic ageing. Each chapter is introduced in the context of the specific theme to which it primarily relates and there is a summary of the data sets used by the contributors to illustrate the wide range of cross-sectional and longitudinal data analysed

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Characterization of the lipopolysaccharide O-antigen of Cronobacter turicensis HPB3287 as a polysaccharide containing a 5,7-diacetamido-3,5,7,9- tetradeoxy-d-glycero-d-galacto-non-2-ulosonic acid (legionaminic acid) residue

Cronobacter turicensis, previously known as Enterobacter sakazakii, is a Gram-negative opportunistic food-borne pathogen that has been reported as a cause of life-threatening neonatal infections. From chemical and physical analyses involving composition analysis, methylation, two-dimensional high-resolution nuclear magnetic resonance, and mass spectrometry methods, the antigenic O-polysaccharide in the smooth-type lipopolysaccharide of C. turicensis (strain HPB 3287) was determined to be a high molecular mass polymer of a repeating pentasaccharide unit composed of d-galactose, d-glucose, 2-acetamido-2-deoxy-d-galactose, and 5,7-diacetamido-3,5,7,9-tetradeoxy-d- glycero-d-galacto-non-2-ulosonic acid (legionaminic acid), in a molar ratio 2:1:1:1, and having the structure. \ua9 2011 Elsevier Ltd. All rights reserved.Peer reviewed: YesNRC publication: Ye

Structure of the O-antigen polysaccharide present in the lipopolysaccharide of Cronobacter dublinensis (subspecies lactaridi or lausannensis) HPB 3169

Cronobacter dublinensis (formerly Enterobacter sakazakii) HPB 3169 is a pathogenic Gram-negative bacterium that produces a smooth-type lipopolysaccharide in which the antigenic O-polysaccharide component was determined to be a repeating pentasaccharide unit composed of L-rhamnose; 2-acetamido-2-deoxy-D-glucose; 3,6-dideoxy-3-(R)-3-hydroxybutyramido-Dglucose; and 3-deoxy-manno-oct-2-ulosonic acid in the respective molar ratio 2:1:1:1. Chemical and 2D NMR analyses of the O-polysaccharide and a pentasaccharide derived by the mild acid hydrolysis of the ketosyl linkage of the Kdo (3-deoxy-D-manno-2-octulosonic acid) residue in the O-polysaccharide established that the O-antigen is a high molecular mass unbranched polymer of a repeating pentasaccharide unit and has the structure where Bu is a (R)-3-hydroxybutanoyl substituent. The O-antigen is structurally similar to that of the recently reported Cronobacter sakazakii strain G706 (designated as serotype O5), except that in strain G706 the D-Qui3N is in its N-acetyl form, in contrast to its presence as a 3-deoxy-3-(R)-3-hydroxybutyramido derivative in the C. sakazakii HPB 3169 strain O-antigen.Peer reviewed: YesNRC publication: Ye

Structure of the capsular polysaccharides and lipopolysaccharides from Haemophilus parasuis strains ER-6P (serovar 15) and Nagasaki (serovar 5)

Haemophilus parasuis is a Gram-negative bacterium from the family Pasteurellaceae and a swine pathogen. H. parasuis is found in the upper respiratory tract of piglets and produces Gl\ue4sser's disease, an invasive disease characterized by polyserositis. H. parasuis contains a short lipopolysaccharide (LPS) or lipooligosaccharide (LOS) reported to play a partial role in interaction with host cells. The presence of capsule has been phenotypically demonstrated in certain H. parasuis strains and its role in virulence has been suggested, but the chemical structure of the surface polysaccharides of this bacterium was unknown. The structure of capsular polysaccharide (CPS) and LOS from virulent strains ER-6P and Nagasaki was studied by NMR spectroscopy, mass spectrometry and chemical methods. CPS from both strains had the same main chain with disaccharide repeating unit, substituted with \u3b1-Neu5R-(2-3)-\u3b1-GalNAc-(1-P-(strain ER-6P) or \u3b1-Neu5R-(2-3)-\u3b1-Gal-(1-P-strain Nagasaki) side chains, where R is the N-acetyl or N-glycolyl group. Glycolyl-neuraminic acid is widely found in animal glycoproteins, but it apparently has not been found in bacteria before, and might be important for the biology of this microorganism. Ac and Gc were present in equal amounts in the strain ER-6P but Nagasaki contained only about 20% of Gc substituent. Both strains produced the same LPS of a rough type with a single phosphorylated Kdo linking core and lipid A parts. LOS structure was similar to some strains of H. influenzae and contained a globotetraose terminal sequence. Crown Copyright \ua9 2013 Published by Elsevier Ltd.Peer reviewed: YesNRC publication: Ye

Fluconazole distribution in rat dermis following intravenous and topical application: a microdialysis study.

The objective of this study was to investigate the skin distribution of fluconazole, a water-soluble antifungal agent, following intravenous (i.v.) and topical administration in the awake freely moving rat. Following i.v. bolus injection of fluconazole (10 mg/kg), a dual-site microdialysis sampling was performed in jugular vein and dermis in five rats. In addition, cutaneous absorption was studied by dermal microdialysis sampling following topical application of Diflucan Gel 0.5% to 12 rats. Fluconazole microdialysate concentrations were measured by on-line HPLC. To calibrate in vivo the probes, a fluorinated analog (UK-54737) of fluconazole was used as retrodialysis marker after demonstrating that recoveries were no different. Following i.v. bolus injection, fluconazole rapidly penetrates into the dermis. Cutaneous microdialysis sampling provided dermal concentrations of fluconazole, which were very similar to the unbound plasma concentrations determined by vascular microdialysis. The distribution equilibrium was rapidly achieved with a dermis-to-plasma partition coefficient of 1.02+/-0.04 (n=5). Following topical application of 0.5 g of Diflucan Gel containing 0.5% of fluconazole, active unbound concentrations in dermis were measured by cutaneous microdialysis for 11 h after application. The area under the curve (AUC) of fluconazole in dermal dialysate was relatively constant to an implantation depth of approximately 350 microm. Below this depth, the AUC progressively decreased with increasing implantation depth of the probe. Finally, this study shows that cutaneous microdialysis is an effective and minimally invasive tool to evaluate the dermal pharmacokinetics of fluconazole following intravenous or topical administration