Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Structural and functional insights into oligopeptide acquisition by the RagAB transporter from Porphyromonas gingivalis

Porphyromonas gingivalis, an asaccharolytic member of the Bacteroidetes, is a keystone pathogen in human periodontitis that may also contribute to the development of other chronic inflammatory diseases. P. gingivalis utilizes protease-generated peptides derived from extracellular proteins for growth, but how these peptides enter the cell is not clear. Here, we identify RagAB as the outer-membrane importer for these peptides. X-ray crystal structures show that the transporter forms a dimeric RagA2B2 complex, with the RagB substrate-binding surface-anchored lipoprotein forming a closed lid on the RagA TonB-dependent transporter. Cryo-electron microscopy structures reveal the opening of the RagB lid and thus provide direct evidence for a ‘pedal bin’ mechanism of nutrient uptake. Together with mutagenesis, peptide-binding studies and RagAB peptidomics, our work identifies RagAB as a dynamic, selective outer-membrane oligopeptide-acquisition machine that is essential for the efficient utilization of proteinaceous nutrients by P. gingivalis

Infection control in dentistry A practitioner's guide

Published as a supplement to British Dental Journal, 10 Jul 1993SIGLEAvailable from British Library Document Supply Centre- DSC:1871.6075(BDA-OP--2) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Les attentes face au counseling chez les étudiants de premier cycle au Canada : Comparaison des canadiens caucasiens et originaires de l’Asie de l’Est

This study investigated whether East Asians differ from Caucasian Canadians in their expectations about counselling. Participants in this study included 31 East Asian and 53 Caucasian Canadian university students. The East Asian participants were all first-generation East Asians living in Canada, originally from China, Korea, Japan, or Vietnam. The Caucasian Canadians were all born in Canada. All participants completed the Expectations about Counseling–Brief Form (Tinsley, Workman, & Kass, 1980), amongst other measures. Results indicated that Asians scored lower than Caucasians on client motivation and responsibility, but higher on the counsellor confrontation, directiveness, empathy, self-disclosure, expertise, and tolerance subscales. Clinical implications of these results and directions for future research are discussed.Cette recherche vise à déterminer s’il existe des différences dans les attentes face au counseling entre des participants originaires de l’Asie orientale et canadiens caucasiens. L’échantillon comprenait 31 participants originaires de l’Asie de l’Est et 53 participants canadiens caucasiens, tous étudiants universitaires. Les participants originaires de l’Asie orientale étaient tous des immigrants de première génération provenant de la Chine, la Corée, le Japon, ou le Vietnam et habitant au Canada. Les participants caucasiens étaient tous nés au Canada. Les participants complétèrent le Expectations about Counseling–Brief Form (Tinsley, Workman, & Kass, 1980), parmi d’autres mesures. Les résultats indiquent que les participants originaires de l’Asie orientale avaient des scores plus bas au niveau de la motivation et de la responsabilisation, mais plus élevés quant à l’indice de confrontation du conseiller, le contrôle, l’empathie, le dévoilement, l’expertise, et la tolérance. Les résultats sont discutés en tenant compte de considérations cliniques et des orientations de recherche à venir

Nurse-led multidisciplinary initiatives to improve outcomes and reduce hospital admissions for older adults: The care coordination through emergency department, residential aged care and Primary Health Collaboration project

Johnston-Devin, CM ORCiD: 0000-0003-2632-5383Objectives: This article describes the Care coordination through Emergency Department, Residential Aged Care and Primary Health Collaboration (CEDRiC) project. Methods: CEDRiC is designed to improve the health outcomes for older people with an acute illness. It attempts this via enhanced primary care in residential aged care facilities, focused and streamlined care in the emergency department and enhanced intersectoral communication and referral. Results: Implementing this approach has the potential to decrease inappropriate hospital admissions while improving care for older people in residential aged care and community settings. Conclusion: This article discusses an innovative way of caring for older adults in an ageing population utilising the existing evidence. A formal evaluation is currently underway. © 2018 AJA Inc

Care coordination through Emergency Department, Residential aged care and primary health Collaboration (CEDRiC) toolkit

Johnston-Devin, CM ORCiD: 0000-0003-2632-5383This toolkit provides information about an evidence-based model of care and includes preimplementation planning strategies and evaluation tools. This has been designed to assist RACF and ED clinicians, administrators and policy makers in the implementation of this model, either in its entirety (CEDRiC) or individually as HIPS or GEDI. Further information on the research underpinning this model of care may be found in the publications listed on the CEDRiC website: www.cedric.org.a

Nurse-led multidisciplinary initiatives to improve outcomes and reduce hospital admissions for older adults: The care coordination through emergency department, residential aged care and Primary Health Collaboration project

Objectives: This article describes the Care coordination through Emergency Department, Residential Aged Care and Primary Health Collaboration (CEDRiC) project. Methods: CEDRiC is designed to improve the health outcomes for older people with an acute illness. It attempts this via enhanced primary care in residential aged care facilities, focused and streamlined care in the emergency department and enhanced intersectoral communication and referral. Results: Implementing this approach has the potential to decrease inappropriate hospital admissions while improving care for older people in residential aged care and community settings. Conclusion: This article discusses an innovative way of caring for older adults in an ageing population utilising the existing evidence. A formal evaluation is currently underway. © 2018 AJA Inc

Structural basis for nutrient acquisition by dominant members of the human gut microbiota

The human large intestine is populated by a high density of microorganisms, collectively termed the colonic microbiota, which has an important role in human health and nutrition. The survival of microbiota members from the dominant Gram-negative phylum Bacteroidetes depends on their ability to degrade dietary glycans that cannot be metabolized by the host. The genes encoding proteins involved in the degradation of specific glycans are organized into co-regulated polysaccharide utilization loci, with the archetypal locus sus (for starch utilisation system) encoding seven proteins, SusA-SusG. Glycan degradation mainly occurs intracellularly and depends on the import of oligosaccharides by an outer membrane protein complex composed of an extracellular SusD-like lipoprotein and an integral membrane SusC-like TonB-dependent transporter. The presence of the partner SusD-like lipoprotein is the major feature that distinguishes SusC-like proteins from previously characterized TonB-dependent transporters. Many sequenced gut Bacteroides spp. encode over 100 SusCD pairs, of which the majority have unknown functions and substrate specificities. The mechanism by which extracellular substrate binding by SusD proteins is coupled to outer membrane passage through their cognate SusC transporter is unknown. Here we present X-ray crystal structures of two functionally distinct SusCD complexes purified from Bacteroides thetaiotaomicron and derive a general model for substrate translocation. The SusC transporters form homodimers, with each β-barrel protomer tightly capped by SusD. Ligands are bound at the SusC-SusD interface in a large solvent-excluded cavity. Molecular dynamics simulations and single-channel electrophysiology reveal a 'pedal bin' mechanism, in which SusD moves away from SusC in a hinge-like fashion in the absence of ligand to expose the substrate-binding site to the extracellular milieu. These data provide mechanistic insights into outer membrane nutrient import by members of the microbiota, an area of major importance for understanding human-microbiota symbiosis