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Background: Previous studies have demonstrated important geographic variations in peripheral artery disease (PAD) management despite existing guidelines. We assessed differences in patient characteristics, procedural technique, and outcomes for PAD interventions in Canada versus United States., Methods: The Vascular Quality Initiative (VQI) was used to identify all patients who underwent endovascular intervention or surgical bypass for PAD between 2010 and 2019 in Canada and United States. Independent t-test and chi-square test were performed to assess differences between countries in terms of demographic, clinical, and procedural characteristics. The primary outcome was the percentage of interventions performed for claudication versus chronic limb-threatening ischemia (CLTI). Perioperative outcomes were in-hospital mortality and index limb amputation. The long-term outcome was 1-year amputation-free survival. Univariate/multivariate logistic regression and Cox proportional hazards analysis were performed to investigate associations between region and outcomes., Results: A total of 246,770 US patients and 3,467 Canadian patients underwent revascularization for PAD during the study period. There was a higher proportion of endovascular interventions in the US (75.9% vs. 69.2%, OR 1.41 [95% CI 1.31-1.51], P< 0.001). American patients were younger with more comorbidities, including hypertension, diabetes, and coronary artery disease. The percentage of interventions performed for claudication was significantly higher in the US (42.3% vs. 35.7%, OR 1.31 [95% CI 1.22-1.44], P< 0.001). This persisted after controlling for demographic, clinical, and procedural characteristics (adjusted OR 1.05 [95% CI 1.01-1.10], P = 0.02). Perioperative outcomes were similar between countries after adjustment for baseline differences: in-hospital mortality (adjusted OR 1.07 [95% CI 0.69-1.62], P= 0.75) and index limb amputation (adjusted OR 0.67 [95% CI 0.43-1.07], P= 0.09). However, 1-year amputation-free survival was higher in the US (84.1% vs. 71.0%, HR 1.61 [95% CI 1.47-1.76], P< 0.001). Multivariable Cox proportional hazards analysis demonstrated that the factor most strongly associated with index limb amputation or death at 1-year was intervention for CLTI (HR 1.56 [95% CI 1.54-1.58], P< 0.001)., Conclusions: There are significant variations in PAD management between US and Canada. In particular, a higher proportion of interventions are performed for claudication rather than CLTI in the US compared to Canada. This is an important contributor to the higher 1-year amputation-free survival rate in US patients. Reasons for these differences should be assessed by future studies and evidence-based care may be standardized by targeted quality improvement projects., (Copyright © 2021. Published by Elsevier Inc.)

Background: Previous studies have demonstrated significant geographic variations in the management of carotid artery stenosis despite standard guidelines. To further characterize these practice variations, we assessed differences in patient selection, operative technique, and outcomes for carotid endarterectomy (CEA) in Canada vs. United States., Methods: The Vascular Quality Initiative (VQI) was used to identify all patients who underwent CEA between 2010 and 2019 in Canada and United States. Demographic, clinical, and procedural characteristics were recorded and differences between countries were assessed using independent t-test and chi-square test. The primary outcome was the percentage of CEA performed for asymptomatic versus symptomatic disease. The secondary outcomes were 30-day and long-term stroke or death. Associations between country and outcomes were assessed using univariate/multivariate logistic regression and Cox proportional hazards analysis., Results: During the study period, 131,411 US patients and 701 Canadian patients underwent CEA in VQI sites. Patients from the US were older with more comorbidities including hypertension, diabetes, congestive heart failure, and chronic kidney disease. The use of a shunt, patch, drain, or protamine was less common in the US. Most patients had 70 - 99% stenosis, with no difference between regions. The percentage of CEA performed for asymptomatic disease was significantly higher in the US even after adjusting for demographic, clinical, and procedural characteristics (72.4% vs. 30.7%, adjusted OR 3.91 [95% CI 3.21 - 4.78], p < 0.001). Thirty-day stroke/death was low (1.8% vs. 1.9%) and 1-year stroke/death was similar between groups (HR 0.98 [95% CI 0.69 - 1.39], P = 0.89). The similarities in 1-year stroke/death persisted in asymptomatic patients (HR 0.70 [95% CI 0.37 - 1.30], P = 0.26) and symptomatic patients (HR 1.14 [95% CI 0.74 - 1.73], P = 0.56)., Conclusions: There are significant variations in CEA practice between Canada and US. In particular, most US patients are treated for asymptomatic disease, whereas most Canadian patients are treated for symptomatic disease. Furthermore, adjunctive procedures including shunting, patch use, and protamine administration are performed less commonly in the US. Despite these differences, perioperative and 1-year stroke/death rates are similar between countries. Future studies should investigate reasons for these variations and quality improvement projects are needed to standardize care., Competing Interests: Declarations Of Interest None., (Copyright © 2021. Published by Elsevier Inc.)

Background: Previous studies have demonstrated significant geographic variations in the management of abdominal aortic aneurysms (AAA) despite standard guidelines. Differences in patient selection, operative technique, and outcomes for AAA repair in Canada versus United States were assessed., Methods: The Vascular Quality Initiative was used to identify all patients who underwent elective endovascular or open AAA repair between 2010 and 2019 in Canada and the United States. Demographic, clinical, and procedural characteristics were recorded and differences between countries were assessed using independent t test and χ 2 test. The primary outcome was the percentage of AAA repaired below recommended diameter thresholds (men, <5.5 cm; women, <5.0 cm). The secondary outcomes were in-hospital and 1-year mortality rates. Associations between region and outcomes were assessed using univariate/multivariate logistic regression and Cox proportional hazards analysis., Results: There were 51,455 U.S. patients and 1451 Canadian patients who underwent AAA repair in Vascular Quality Initiative sites during the study period. There was a higher proportion of endovascular repairs in the United States (83.7% vs 68.4%; odds ratio [OR], 2.38; 95% confidence interval [CI], 2.13-2.63; P < .001). U.S. patients had more comorbidities, including hypertension, congestive heart failure, chronic kidney disease, and prior revascularization. The percentage of AAA repaired below recommended thresholds was significantly higher in the United States (38.8% vs 15.2%; OR, 3.57; 95% CI, 3.03-4.17; P < .001). This difference persisted after controlling for demographic, clinical, and procedural characteristics (adjusted OR, 3.57; 95% CI, 2.63-4.17; P < .001). Factors that predicted AAA repair below recommended thresholds were U.S. region (adjusted OR, 3.57; 95% CI, 3.03-4.17), male sex (adjusted OR, 2.89; 95% CI, 2.72-3.07), and endovascular repair (adjusted OR, 2.08; 95% CI, 1.95-2.21). The in-hospital mortality rate was low (1.0% vs 0.8%) and the 1-year rate mortality was similar between countries (hazard ratio, 0.96; 95% CI, 0.70-1.31; P = .79)., Conclusions: There are significant variations in AAA management between Canada and the United States. A greater proportion of U.S. patients underwent AAA repair below the recommended diameter thresholds. This finding is partly driven by a higher percentage of endovascular repairs. Despite these differences, the perioperative and 1-year mortality rates are similar. Future studies should investigate reasons for these variations and quality improvement projects are needed to standardize care., (Copyright © 2021 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

αβ-TCRs expressed at the CD8(+) T-cell surface interact with short peptide fragments (p) bound to MHC class I molecules (pMHCI). The TCR/pMHCI interaction is pivotal in all aspects of CD8(+) T-cell immunity. However, the rules that govern the outcome of TCR/pMHCI engagement are not entirely understood, and this is a major barrier to understanding the requirements for both effective immunity and vaccination. In the present study, we discovered an unexpected feature of the TCR/pMHCI interaction by showing that any given TCR exhibits an explicit preference for a single MHCI-peptide length. Agonists of nonpreferred length were extremely rare, suboptimal, and often entirely distinct in sequence. Structural analysis indicated that alterations in peptide length have a major impact on antigenic complexity, to which individual TCRs are unable to adapt. This novel finding demonstrates that the outcome of TCR/pMHCI engagement is determined by peptide length in addition to the sequence identity of the MHCI-bound peptide. Accordingly, the effective recognition of pMHCI Ag, which is a prerequisite for successful CD8(+) T-cell immunity and protective vaccination, can only be achieved by length-matched Ag-specific CD8(+) T-cell clonotypes.

C-protein is a major component of skeletal and cardiac muscle thick filaments. Mutations in the gene encoding cardiac C-protein [cardiac myosin binding protein-C (cMyBP-C)] are one of the principal causes of hypertrophic cardiomyopathy. cMyBP-C is a string of globular domains including eight immunoglobulin-like and three fibronectin-like domains termed C0-C10. It binds to myosin and titin, and probably to actin, and may have both a structural and a regulatory role in muscle function. To help to understand the pathology of the known mutations, we have solved the structure of the immunoglobulin-like C1 domain of MyBP-C by X-ray crystallography to a resolution of 1.55 A. Mutations associated with hypertrophic cardiomyopathy are clustered at one end towards the C-terminus, close to the important C1C2 linker, where they alter the structural integrity of this region and its interactions.

Carbohydrate recognition by monocot mannose-binding lectins was studied via the crystal structure determination of daffodil (Narcissus pseudonarcissus) lectin. The lectin was extracted from daffodil bulbs, and crystallised in the presence of alpha-1,3 mannobiose. Molecular replacement methods were used to solve the structure using the partially refined model of Hippeastrum hybrid agglutinin as a search model. The structure was refined at 2.0 A resolution to a final R -factor of 18.7 %, and Rfreeof 26.7 %. The main feature of the daffodil lectin structure is the presence of three fully occupied binding pockets per monomer, arranged around the faces of a triangular beta-prism motif. The pockets have identical topology, and can bind mono-, di- or oligosaccharides. Strand exchange forms tightly bound dimers, and higher aggregation states are achieved through hydrophobic patches on the surface, completing a tetramer with internal 222-symmetry. There are therefore 12 fully occupied binding pockets per tetrameric cluster. The tetramer persists in solution, as shown with small-angle X-ray solution scattering. Extensive sideways and out-of-plane interactions between tetramers, some mediated via the ligand, make up the bulk of the lattice contacts.A fourth binding site was also observed. This is unique and has not been observed in similar structures. The site is only partially occupied by a ligand molecule due to the much lower binding affinity. A comparison with the Galanthus nivalis agglutinin/mannopentaose complex suggests an involvement of this site in the recognition mechanism for naturally occurring glycans., (Copyright 1999 Academic Press.)

Maltoporin (LamB) facilitates the diffusion of maltodextrins across the outer membrane of E. coli. The structural basis for the specificity of the channel is investigated by X-ray structure analysis of maltoporin in complex with the disaccharides sucrose, trehalose, and melibiose. The sucrose complex, determined to 2.4 A resolution, shows that the glucosyl moiety is partly inserted into the channel constriction, while the bulky fructosyl residue appears to be hindered to enter the constriction, thus interfering with its further translocation. One of the glucosyl moieties of trehalose is found in a similar position as the glucosyl moiety of sucrose, whereas melibiose appears disordered when bound to maltoporin. A comparison with the previously reported maltoporin-maltose complex sheds light on the basis for sugar discrimination, and explains the different permeation rates observed for the saccharides., (Copyright 1997 Academic Press Limited.)

The mannose transporter from Escherichia coli is a member of the phosphoenolpyruvate-dependent phosphotransferase system. The multi-subunit complex couples translocation across the bacterial inner membrane with phosphorylation of the solute. A functional fragment (IIA(Man), residues 2 to 133) of the membrane-associated IIAB(Man) subunit of the mannose transporter was expressed as a selenomethionine protein, and the unphosphorylated molecule was crystallized and its structure solved by X-ray crystallography. The protein consists of a central five-stranded beta-sheet covered by helices on either face. The order of the secondary structure elements is (beta alpha)4, alpha beta. Four beta-strands are arranged in a parallel manner with strand order 2134 and are linked by helices forming right-handed cross-over connections. The fifth strand that forms one edge of the sheet and runs antiparallel to the others is swapped between the subunits of the dimeric structure. Helices D and E form a helical hairpin. Histidine 10, which is transiently phosphorylated during catalysis, is located at the topological switch-point of the structure, close to the subunit interface. Its imidazole ring is hydrogen bonded to the buried side-chain of Asp67. It is likely that Asp67 acts as a general base and thus increases the nucleophilicity of the histidine. Modeling suggests that the covalently bound phosphoryl group would be stabilized by the macrodipole of helix C. Putative interactions between IIA(Man) and the histidine-containing phosphocarrier protein are discussed.

The NADP(+)-dependent hexameric glutamate dehydrogenase from Escherichia coli has been crystallized as the apo-enzyme and also in the presence of its substrates 2-oxoglutarate, glutamate or NADP+, using either pulsed equilibrium microdialysis, or the hanging drop method of vapour diffusion. Three non-isomorphous, but related, crystal forms have been obtained, all of which belong to the orthorhombic system and are most likely to be in space group P2(1)2(1)2(1). One crystal form is grown from ammonium sulphate, includes the apoenzyme and the binary complexes with 2-oxoglutarate or NADP+, and has cell dimensions a = 157.5 A, b = 212.5 A, c = 101.0 A with a hexamer in the asymmetric unit. Crystallizations using glutamate as the precipitant produced two further crystal forms, which show significant changes in the b and c cell dimensions with respect to the apo-enzyme crystals, with parameters a = 160.0 A, b = 217.5 A c = 92.4 A and a = 160.0 A, b = 223.0 A c = 92.4 A, respectively. X-ray diffraction photographs taken with synchrotron radiation show measurable reflections to beyond 3.0 A resolution.