Conceptual and practical challenges for implementing the communities of practice model on a national scale - a Canadian cancer control initiative

<p>Abstract</p> <p>Background</p> <p>Cancer program delivery, like the rest of health care in Canada, faces two ongoing challenges: to coordinate a pan-Canadian approach across complex provincial jurisdictions, and to facilitate the rapid translation of knowledge into clinical practice. Communities of practice, or CoPs, which have been described by Etienne Wenger as a collaborative learning platform, represent a promising solution to these challenges because they rely on bottom-up rather than top-down social structures for integrating knowledge and practice across regions and agencies. The communities of practice model has been realized in the corporate (e.g., Royal Dutch Shell, Xerox, IBM, etc) and development (e.g., World Bank) sectors, but its application to health care is relatively new. The Canadian Partnership Against Cancer (CPAC) is exploring the potential of Wenger's concept in the Canadian health care context. This paper provides an in-depth analysis of Wenger's concept with a focus on its applicability to the health care sector.</p> <p>Discussion</p> <p>Empirical studies and social science theory are used to examine the utility of Wenger's concept. Its value lies in emphasizing learning from peers and through practice in settings where innovation is valued. Yet the communities of practice concept lacks conceptual clarity because Wenger defines it so broadly and sidelines issues of decision making within CoPs. We consider the implications of his broad definition to establishing an informed nomenclature around this specific type of collaborative group. The CoP Project under CPAC and communities of practice in Canadian health care are discussed.</p> <p>Summary</p> <p>The use of communities of practice in Canadian health care has been shown in some instances to facilitate quality improvements, encourage buy in among participants, and generate high levels of satisfaction with clinical leadership and knowledge translation among participating physicians. Despite these individual success stories, more information is required on how group decisions are made and applied to the practice world in order to leverage the potential of Wenger's concept more fully, and advance the science of knowledge translation within an accountability framework.</p

Site-specific perturbations of alpha-synuclein fibril structure by the Parkinson's disease associated mutations A53T and E46K.

PMCID: PMC3591419This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Parkinson's disease (PD) is pathologically characterized by the presence of Lewy bodies (LBs) in dopaminergic neurons of the substantia nigra. These intracellular inclusions are largely composed of misfolded α-synuclein (AS), a neuronal protein that is abundant in the vertebrate brain. Point mutations in AS are associated with rare, early-onset forms of PD, although aggregation of the wild-type (WT) protein is observed in the more common sporadic forms of the disease. Here, we employed multidimensional solid-state NMR experiments to assess A53T and E46K mutant fibrils, in comparison to our recent description of WT AS fibrils. We made de novo chemical shift assignments for the mutants, and used these chemical shifts to empirically determine secondary structures. We observe significant perturbations in secondary structure throughout the fibril core for the E46K fibril, while the A53T fibril exhibits more localized perturbations near the mutation site. Overall, these results demonstrate that the secondary structure of A53T has some small differences from the WT and the secondary structure of E46K has significant differences, which may alter the overall structural arrangement of the fibrils

Chronic intermittent hypoxia induces local inflammation of the rat carotid body via functional upregulation of proinflammatory cytokine pathways

Maladaptive changes in the carotid body (CB) induced by chronic intermittent hypoxia (IH) account for the pathogenesis of cardiovascular morbidity in patients with sleep-disordered breathing. We postulated that the proinflammatory cytokines, namely interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, and cytokine receptors (IL-1r1, gp130 and TNFr1) locally expressed in the rat CB play a pathophysiological role in IH-induced CB inflammation. Results showed increased levels of oxidative stress (serum 8-isoprostane and nitrotyrosine in the CB) in rats with 7-day IH treatment resembling recurrent apneic conditions when compared with the normoxic control. Local inflammation shown by the amount of ED1-containing cells (macrophage infiltration) and the gene transcripts of NADPH oxidase subunits (gp91phox and p22phox) and chemokines (MCP-1, CCR2, MIP-1α, MIP-1β and ICAM-1) in the CB were significantly more in the hypoxic group than in the control. In addition, the cytokines and receptors were expressed in the lobules of chemosensitive glomus cells containing tyrosine hydroxylase and the levels of expressions were significantly increased in the hypoxic group. Exogenous cytokines elevated the intracellular calcium ([Ca2+]i) response to acute hypoxia in the dissociated glomus cells. The effect of cytokines on the [Ca2+]i response was significantly greater in the hypoxic than in the normoxic group. Moreover, daily treatment of IH rats with anti-inflammatory drugs (dexamethasone or ibuprofen) attenuated the levels of oxidative stress, gp91phox expression and macrophage infiltration in the CB. Collectively, these results suggest that the upregulated expression of proinflammatory cytokine pathways could mediate the local inflammation and functional alteration of the CB under chronic IH conditions

Proteomic analysis of the action of the Mycobacterium ulcerans toxin mycolactone: targeting host cells cytoskeleton and collagen

Buruli ulcer (BU) is a neglected tropical disease caused by Mycobacterium ulcerans. The tissue damage characteristic of BU lesions is known to be driven by the secretion of the potent lipidic exotoxin mycolactone. However, the molecular action of mycolactone on host cell biology mediating cytopathogenesis is not fully understood. Here we applied two-dimensional electrophoresis (2-DE) to identify the mechanisms of mycolactone's cellular action in the L929 mouse fibroblast proteome. This revealed 20 changed spots corresponding to 18 proteins which were clustered mainly into cytoskeleton-related proteins (Dync1i2, Cfl1, Crmp2, Actg1, Stmn1) and collagen biosynthesis enzymes (Plod1, Plod3, P4ha1). In line with cytoskeleton conformational disarrangements that are observed by immunofluorescence, we found several regulators and constituents of both actin- and tubulin-cytoskeleton affected upon exposure to the toxin, providing a novel molecular basis for the effect of mycolactone. Consistent with these cytoskeleton-related alterations, accumulation of autophagosomes as well as an increased protein ubiquitination were observed in mycolactone-treated cells. In vivo analyses in a BU mouse model revealed mycolactone-dependent structural changes in collagen upon infection with M. ulcerans, associated with the reduction of dermal collagen content, which is in line with our proteomic finding of mycolactone-induced down-regulation of several collagen biosynthesis enzymes. Our results unveil the mechanisms of mycolactone-induced molecular cytopathogenesis on exposed host cells, with the toxin compromising cell structure and homeostasis by inducing cytoskeleton alterations, as well as disrupting tissue structure, by impairing the extracellular matrix biosynthesis.The research leading to these results has received funding from the European Community's Seventh Framework Program (FP7/2007-2013) under grant agreement Nu 241500 (BuruliVac), from Fundacao Calouste Gulbenkian and from Projeto Estrategico - LA 26 - 2013-2014 (PEst-C/SAU/LA0026/2013). JBG, TGM and AGF had a personal grant from the Portuguese Science and Technology Foundation (FCT) (SFRH/BD/33573/2009, SFRH/BD/41598/2007 and SFRH/BPD/68547/2010, respectively). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Dietary and other lifestyle correlates of serum folate concentrations in a healthy adult population in Crete, Greece: a cross-sectional study

BACKGROUND: Folate has emerged as a key nutrient for optimising health. Impaired folate status has been identified as a risk factor for cardiovascular disease, various types of cancers, and neurocognitive disorders. The study aimed at examining the distribution and determinants of serum folate concentrations in a healthy adult population in Crete, Greece. METHODS: A cross-sectional sample of 486 healthy adults (250 men, 236 women) aged 39 ± 14 years, personnel of the Medical School and the University Hospital of Crete in Greece, was examined. Serum folate and vitamin B(12 )concentrations were measured by microbiological assay, and total homocysteine was determined fluorometrically and by high-pressure liquid chromatography. Lifestyle questionnaires were completed, and nutrient intakes and food consumption were assessed by 24-h dietary recalls. Multivariate analyses were performed using SPSS v10.1. RESULTS: The geometric mean (95% confidence interval) concentrations of serum folate were 15.6 μmol/l (14.6–16.8) in men and 19.2 μmol/l (17.9–20.7) in women (p < 0.001). Inadequate folate levels (≤7 nmol/l) were present in 6.8% of men and 2.1% of women (p < 0.001). Approximately 76% of men and 87% of women did not meet the reference dietary intake for folate (400 μg/day). Serum folate was inversely related to total homocysteine levels (p < 0.001). Increased tobacco and coffee consumption were associated with lower folate concentrations (p < 0.05 for both) but these associations disappeared after controlling for nutrient intakes. In multivariate analysis, intakes of MUFA, fibre, calcium, magnesium, folate, and vitamins A, E, C, B(1), and B(6 )were positively associated with serum folate. Consumption of potatoes, legumes, fruits, and vegetables were favourably related to the serum folate status. CONCLUSION: Serum folate concentrations were associated with various demographic, lifestyle and dietary factors in healthy Cretan adults. Large-scale epidemiological studies should be conducted within the general Greek adult population to assess the prevalence of impaired folate status and further examine associations with dietary patterns and chronic disease risk. Considering the importance of folate in health maintenance, it is important to increase the public's awareness of modifiable lifestyle patterns and diet and tobacco use in particular, which may be associated with improved folate status

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 &gt;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

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Studies of new Higgs boson interactions through nonresonant HH production in the b¯bγγ fnal state in pp collisions at √s = 13 TeV with the ATLAS detector

A search for nonresonant Higgs boson pair production in the b ¯bγγ fnal state is performed using 140 fb−1 of proton-proton collisions at a centre-of-mass energy of 13 TeV recorded by the ATLAS detector at the CERN Large Hadron Collider. This analysis supersedes and expands upon the previous nonresonant ATLAS results in this fnal state based on the same data sample. The analysis strategy is optimised to probe anomalous values not only of the Higgs (H) boson self-coupling modifer κλ but also of the quartic HHV V (V = W, Z) coupling modifer κ2V . No signifcant excess above the expected background from Standard Model processes is observed. An observed upper limit µHH &lt; 4.0 is set at 95% confdence level on the Higgs boson pair production cross-section normalised to its Standard Model prediction. The 95% confdence intervals for the coupling modifers are −1.4 &lt; κλ &lt; 6.9 and −0.5 &lt; κ2V &lt; 2.7, assuming all other Higgs boson couplings except the one under study are fxed to the Standard Model predictions. The results are interpreted in the Standard Model efective feld theory and Higgs efective feld theory frameworks in terms of constraints on the couplings of anomalous Higgs boson (self-)interactions

Measurement of the H → γ γ and H → ZZ∗ → 4 cross-sections in pp collisions at √s = 13.6 TeV with the ATLAS detector

The inclusive Higgs boson production cross section is measured in the di-photon and the Z Z∗ → 4 decay channels using 31.4 and 29.0 fb−1 of pp collision data respectively, collected with the ATLAS detector at a centre of-mass energy of √s = 13.6 TeV. To reduce the model dependence, the measurement in each channel is restricted to a particle-level phase space that closely matches the chan nel’s detector-level kinematic selection, and it is corrected for detector effects. These measured fiducial cross-sections are σfid,γ γ = 76+14 −13 fb, and σfid,4 = 2.80 ± 0.74 fb, in agreement with the corresponding Standard Model predic tions of 67.6±3.7 fb and 3.67±0.19 fb. Assuming Standard Model acceptances and branching fractions for the two chan nels, the fiducial measurements are extrapolated to the full phase space yielding total cross-sections of σ (pp → H) = 67+12 −11 pb and 46±12 pb at 13.6 TeV from the di-photon and Z Z∗ → 4 measurements respectively. The two measure ments are combined into a total cross-section measurement of σ (pp → H) = 58.2±8.7 pb, to be compared with the Stan dard Model prediction of σ (pp → H)SM = 59.9 ± 2.6 p