Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells.

Susceptibility and protection against human autoimmune diseases, including type I diabetes, multiple sclerosis, and Goodpasture disease, is associated with particular human leukocyte antigen (HLA) alleles. However, the mechanisms underpinning such HLA-mediated effects on self-tolerance remain unclear. Here we investigate the molecular mechanism of Goodpasture disease, an HLA-linked autoimmune renal disorder characterized by an immunodominant CD4+ T-cell self-epitope derived from the α3 chain of type IV collagen (α3135-145). While HLA-DR15 confers a markedly increased disease risk, the protective HLA-DR1 allele is dominantly protective in trans with HLA-DR15 (ref. 2). We show that autoreactive α3135-145-specific T cells expand in patients with Goodpasture disease and, in α3135-145-immunized HLA-DR15 transgenic mice, α3135-145-specific T cells infiltrate the kidney and mice develop Goodpasture disease. HLA-DR15 and HLA-DR1 exhibit distinct peptide repertoires and binding preferences and present the α3135-145 epitope in different binding registers. HLA-DR15-α3135-145 tetramer+ T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (Tconv) that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-α3135-145 tetramer+ T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4+Foxp3+ regulatory T cells (Treg cells) expressing tolerogenic cytokines. HLA-DR1-induced Treg cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15+ and HLA-DR1+ healthy human donors display altered α3135-145-specific T-cell antigen receptor usage, HLA-DR15-α3135-145 tetramer+ Foxp3- Tconv and HLA-DR1-α3135-145 tetramer+ Foxp3+CD25hiCD127lo Treg dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded α3135-145-specific CD4+ T-cell repertoire. Accordingly, we provide a mechanistic basis for the dominantly protective effect of HLA in autoimmune disease, whereby HLA polymorphism shapes the relative abundance of self-epitope specific Treg cells that leads to protection or causation of autoimmunity.

Outcomes of intravascular ultrasound versus optical coherence tomography guided percutaneous coronary angiography: A meta regression-based analysis.

BACKGROUND: Studies comparing clinical outcomes with intravascular ultrasound (IVUS) versus optical coherence tomography (OCT) guidance for percutaneous coronary intervention (PCI) in patients presenting with coronary artery disease, including stable angina or acute coronary syndrome, are limited. METHODS: We performed a detailed search of electronic databases (PubMed, Embase, and Cochrane) for randomized controlled trials and observational studies that compared cardiovascular outcomes of IVUS versus OCT. Data were aggregated for the primary outcome measure using the random-effects model as pooled risk ratio (RR). The primary outcome of interest was major adverse cardiac events (MACE), cardiac mortality, and all-cause mortality. Secondary outcomes included myocardial infarction (MI), stent thrombosis (ST), target lesion revascularization (TLR), and stroke. RESULTS: A total of seven studies met the inclusion criteria, comprising 5917 patients (OCT n = 2075; IVUS n = 3842). OCT-PCI versus IVUS-guided PCI comparison yielded no statistically significant results for all the outcomes; MACE (RR 0.78; 95% confidence interval [CI], 0.57-1.09; p = 0.14), cardiac mortality (RR 0.97; 95% CI, 0.27-3.46; p = 0.96), all-cause mortality (RR 0.74; 95% CI, 0.39-1.39; p = 0.35), MI (RR 1.27; 95% CI, 0.52-3.07; p = 0.60), ST (RR 0.70; 95% CI, 0.13-3.61; p = 0.67), TLR (RR 1.09; 95% CI, 0.53-2.25; p = 0.81), and stroke (RR 2.32; 95% CI, 0.42-12.90; p = 0.34). Furthermore, there was no effect modification on meta-regression including demographics, comorbidities, lesion location, lesion length, and stent type. CONCLUSIONS: In this meta-analysis, OCT-guided PCI was associated with no difference in clinical outcomes compared with IVUS-guided PCI.

Performance of the academic research consortium high-bleeding risk criteria in patients undergoing PCI for acute myocardial infarction.

Patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) are at increased risk for thrombotic and bleeding complications compared to patients with chronic coronary syndrome (CCS). The academic research consortium (ARC) recently suggested a set of criteria to identify patients at high bleeding risk (HBR). We sought to evaluate the performance of the ARC-HBR criteria among patients undergoing PCI according to clinical presentation. We included all consecutive patients undergoing PCI at a tertiary-care center. Patients were deemed at HBR if they fulfilled ≥ 1 major or ≥ 2 minor ARC-HBR criteria. The primary bleeding endpoint was a composite of in-hospital or post-discharge bleeding at 1-year follow-up. Secondary outcomes included all-cause death and myocardial infarction. Out of 6068 patients, 1391 (22.9 %) presented with AMI and were more often at HBR than those with CCS (46.9 % vs. 43.0 %, p = 0.01). HBR patients had a higher risk for the primary bleeding endpoint than non-HBR, irrespective of the clinical indication for PCI (AMI: 19.5 % vs. 5.5 %; HR 3.86, 95 % CI 2.63-5.69; CCS: 6.8 % vs. 2.6 %; HR 2.65, 95 % CI 1.92-3.68; p-interaction = 0.11). Secondary outcomes followed a similar trend. After multivariable adjustment, AMI presentation remained significantly associated with increased risk for bleeding at 1 year (HR 1.64, 95 % CI 1.13-2.38, p = 0.01). The ARC-HBR criterion associated with the highest bleeding risk was severe/end-stage chronic kidney disease in AMI and moderate/severe anemia in CCS. The ARC-HBR framework successfully identified AMI and CCS patients with increased risk for bleeding complications at 1 year post-PCI. Figure prepared with BioRender.

An Exploration of Recent Intelligent Image Analysis Techniques for Visual Pavement Surface Condition Assessment.

Road pavement condition assessment is essential for maintenance, asset management, and budgeting for pavement infrastructure. Countries allocate a substantial annual budget to maintain and improve local, regional, and national highways. Pavement condition is assessed by measuring several pavement characteristics such as roughness, surface skid resistance, pavement strength, deflection, and visual surface distresses. Visual inspection identifies and quantifies surface distresses, and the condition is assessed using standard rating scales. This paper critically analyzes the research trends in the academic literature, professional practices and current commercial solutions for surface condition ratings by civil authorities. We observe that various surface condition rating systems exist, and each uses its own defined subset of pavement characteristics to evaluate pavement conditions. It is noted that automated visual sensing systems using intelligent algorithms can help reduce the cost and time required for assessing the condition of pavement infrastructure, especially for local and regional road networks. However, environmental factors, pavement types, and image collection devices are significant in this domain and lead to challenging variations. Commercial solutions for automatic pavement assessment with certain limitations exist. The topic is also a focus of academic research. More recently, academic research has pivoted toward deep learning, given that image data is now available in some form. However, research to automate pavement distress assessment often focuses on the regional pavement condition assessment standard that a country or state follows. We observe that the criteria a region adopts to make the evaluation depends on factors such as pavement construction type, type of road network in the area, flow and traffic, environmental conditions, and region's economic situation. We summarized a list of publicly available datasets for distress detection and pavement condition assessment. We listed approaches focusing on crack segmentation and methods concentrating on distress detection and identification using object detection and classification. We segregated the recent academic literature in terms of the camera's view and the dataset used, the year and country in which the work was published, the F1 score, and the architecture type. It is observed that the literature tends to focus more on distress identification ("presence/absence" detection) but less on distress quantification, which is essential for developing approaches for automated pavement rating.

Radial versus femoral access for coronary interventions: An updated systematic review and meta-analysis of randomized trials.

OBJECTIVE: It is still debated if benefits associated with radial versus femoral access for coronary angiography and percutaneous coronary interventions (PCI) are due to the access site selection itself, operator expertise or other underlying mechanisms. METHODS: We searched PubMed, Embase, and meeting abstracts for randomized trials comparing radial versus femoral access site for coronary angiography and PCI. Primary safety endpoint was major bleeding. Coprimary efficacy endpoints were stroke and myocardial infarction (MI). This study is registered with PROSPERO. RESULTS: We identified 31 trials (30,096 patients, PCI performed in 21,225 patients). Radial compared to femoral access was associated with a significant risk reduction in major bleeding (OR 0.53, 95%CI 0.42-0.66, I2  = 3.3%). Findings were consistent regardless of clinical characteristics or whether coronary angiography was performed with or without PCI. The benefit of radial access was significantly increased in studies published before 2010 and in patients with chronic coronary syndrome. Risk for stroke (OR 1.11, 95%CI 0.76-1.64, I2  = 0%) and MI (OR 0.90, 95%CI 0.79-1.04, I2  = 0%) were comparable between the groups. Risk for mortality and vascular complications were significantly lower with radial than femoral access. CONCLUSION: In patients undergoing coronary angiography and PCI, radial access is associated with a significant risk reduction in bleeding, vascular complications, and mortality compared to femoral access. The risk of stroke or MI were comparable in patients with radial or femoral access.

Impact of anemia on short-term outcomes after TAVR: A subgroup analysis from the BRAVO-3 randomized trial.

OBJECTIVES: To determine the prognostic impact of anemia in patients randomized to bivalirudin or unfractionated heparin (UFH) during transcatheter aortic valve replacement (TAVR). BACKGROUND: Whether the periprocedural use of bivalirudin as compared with UFH in anemic patients undergoing TAVR has an impact on outcomes remains unknown. METHODS: The BRAVO-3 trial compared the use of bivalirudin versus UFH in 802 high risk patients undergoing transfemoral TAVR for severe symptomatic aortic stenosis. Patients were stratified according to the presence (defined as hemoglobin levels <13 g/dl in men and <12 g/dl in women) or absence of anemia. The primary outcomes were net adverse cardiac events (NACE; a composite of all-cause mortality, myocardial infarction, stroke, or bleeding) and major bleeding (Bleeding Academic Research Consortium ≥3b) at 30 days. RESULTS: Among 798 patients with available baseline hemoglobin levels, 427 (54%) were anemic of whom 221 (52%) received bivalirudin. There were no significant differences in NACE and major bleeding at 30 days between patients with and without anemia, irrespective of the type of anticoagulant used (pinteraction  = 0.71 for NACE, pinteraction  = 1.0 for major bleeding). However, anemic patients had a higher risk of major vascular complications (adjusted OR 2.43, 95% CI 1.42-4.16, p = 0.001), and acute kidney injury (adjusted OR 1.74, 95% CI 1.16-2.59, p = 0.007) compared to non-anemic patients at 30 days. CONCLUSIONS: Anemia was not associated with a higher risk of NACE or major bleeding at 30 days after TAVR without modification of the treatment effects of periprocedural anticoagulation with bivalirudin versus UFH.

Impact of target vessel choice on outcomes following percutaneous coronary intervention in patients with a prior coronary artery bypass graft.

OBJECTIVES: To evaluate and compare characteristics and clinical outcomes of percutaneous coronary intervention (PCI) among target vessel types in patients with a prior coronary artery bypass graft (CABG) surgery. BACKGROUND: Patients with a prior CABG often require repeat revascularization with PCI. Graft PCI has been associated with worse outcomes compared to native vessel PCI, yet the optimal PCI strategy in prior CABG patients remains unknown. METHODS: We stratified prior CABG patients who underwent PCI at a tertiary-care center between 2009 and 2017 by target vessel type: native vessel, venous graft, and arterial graft. The primary outcome of major adverse cardiac events (MACE) was a composite of all-cause death, myocardial infarction, stent thrombosis, or target vessel revascularization up to 1 year post-PCI. RESULTS: Prior CABG patients (n = 3983) represented 19.5% of all PCI interventions during the study period. PCI was most frequently performed on native vessels (n = 2928, 73.5%) followed by venous (n = 883, 22.2%) and arterial grafts (n = 172, 4.3%). Procedural success and complications were similar among the groups; however, slow- and no-reflow phenomenon was more common in venous graft PCI compared to native vessel PCI (OR 4.78; 95% CI 2.56-8.95; p < 0.001). At 1 year, there were no significant differences in MACE or in its individual components. CONCLUSIONS: Target vessel choice did not appear to affect MACE at 1 year in a large cohort of patients with prior CABG undergoing PCI. Whether PCI of surgical grafts versus native arteries truly results in similar outcomes warrants further investigation in randomized controlled trials.

Preprocedural anemia in females undergoing transcatheter aortic valve implantation: Insights from the WIN-TAVI registry.

OBJECTIVES: To assess the impact of anemia on clinical outcomes in female patients enrolled in the Women's InterNational transcatheter aortic valve implantation (WIN-TAVI) registry. BACKGROUND: Anemia is highly prevalent among females who constitute half of TAVI candidates, yet, its clinical significance remains poorly investigated. METHODS: Patients were divided into three groups according to preprocedural hemoglobin (Hb) level: (1) no anemia (Hb ≥12 g/dl), (2) mild-to-moderate anemia (10 ≤ Hb <12 g/dl), and (3) severe anemia (Hb <10 g/dl). The primary outcome was the occurrence of Valve Academic Research Consortium (VARC)-2 efficacy endpoint, a composite of mortality, stroke, myocardial infarction (MI), hospitalization for valve-related symptoms or heart failure or valve-related dysfunction at 1-year follow-up. RESULTS: Hemoglobin level was available in 877 (86.1%) patients: 412 (47.0%) had no anemia, 363 (41.4%) had mild-to-moderate anemia, and 102 (11.6%) had severe anemia. The latter group had a higher prevalence of cardiovascular risk factors. Compared with patients without anemia, severe anemia was associated with a greater risk of VARC-2 efficacy endpoint (adj HR 1.71, 95% CI: 1.02-2.87, p = .04), all-cause death (adj HR 2.36, 95% CI: 1.31-4.26, p = .004) and a composite of death, MI or stroke (adj HR 1.88, 95% CI: 1.10-3.22, p = .02) at 1 year. Moreover, an increased risk of late mortality (adj HR 1.15, 95% CI: 1.02-1.30, p = .03) was observed with every 1 g/dl decrease in hemoglobin level. CONCLUSION: Severe anemia in females undergoing TAVI was independently associated with increased rates of VARC-2 efficacy endpoint and mortality at 1 year.

First principles characterisation of bio-nano interface.

Nanomaterials possess a wide range of potential applications due to their novel properties and exceptionally high activity as a result of their large surface to volume ratios compared to bulk matter. The active surface may present both advantage and risk when the nanomaterials interact with living organisms. As the overall biological impact of nanomaterials is triggered and mediated by interactions at the bio-nano interface, an ability to predict those from the atomistic descriptors, especially before the material is produced, can present enormous advantage for the development of nanotechnology. Fast screening of nanomaterials and their variations for specific biological effects can be enabled using computational materials modelling. The challenge lies in the range of scales that needs to be crossed from the material-specific atomistic representation to the relevant length scales covering typical biomolecules (proteins and lipids). In this work, we present a systematic multiscale approach that allows one to evaluate crucial interactions at the bionano interface from the first principles without any prior information about the material and thus establish links between the details of the nanomaterials structure to protein-nanoparticle interactions. As an example, an advanced computational characterization of titanium dioxide nanoparticles (6 different surfaces of rutile and anatase polymorphs) has been performed. We computed characteristics of the titanium dioxide interface with water using density functional theory for electronic density, used these parameters to derive an atomistic force field, and calculated adsorption energies for essential biomolecules on the surface of titania nanoparticles via direct atomistic simulations and coarse-grained molecular dynamics. Hydration energies, as well as adsorption energies for a set of 40 blood proteins are reported.

Serum potassium abnormalities in chronic kidney disease: prevalence, patient characteristics and clinical outcomes.

BACKGROUND: Abnormalities in serum potassium are a well known complication of chronic kidney disease (CKD), but little is known about their impact on inpatient outcomes. AIMS: To better understand the role of dyskalaemia in hospital in-patients, we assessed the epidemiology of potassium disorders among CKD patients, and the association between admission potassium and inpatient mortality or intensive care unit (ICU) requirement. METHODS: This retrospective hospital-based cohort study (n = 11 156) included patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 admitted to Austin Health between 2014 and 2018 and who had an admission potassium value. Dialysis patients or those with a renal transplant were excluded. Multivariate logistic analysis was conducted to identify factors associated with hyperkalaemia (≥5.5 mmol/L) and hypokalaemia (<3.5 mmol/L). Odds ratios for inpatient mortality and ICU admission between potassium categories were obtained by multivariate regression with adjustments for demographics, renal function and comorbidities. RESULTS: Hyperkalaemia and hypokalaemia were present in 6.86% and 2.94% of hospital admissions respectively. In multivariate regression male sex, lower eGFR, diabetes and cardiac failure were associated with higher odds of hyperkalaemia. Thiazide diuretics, loop diuretics, infectious disease and endocrine pathology were associated with higher odds of hypokalaemia. A U-shaped association was noted between potassium and inpatient mortality. Potassium <4.0 mmol/L and ≥5.0 mmol/L was associated with increased mortality. Only patients with potassium ≥5.5 mmol/L had increased ICU admission risk. CONCLUSION: Derangements in potassium frequently occur in CKD inpatients and are independently associated with higher mortality and ICU requirement. Further studies are required to determine whether interventions to maintain normokalaemia improve outcomes in this population.

Dialysis and driving: an anonymous survey of patients receiving dialysis for end-stage kidney disease.

BACKGROUND: Driving is a complex task requiring multiple cognitive domains and the musculoskeletal system. Cognitive dysfunction is associated with driving impairment. Dialysis patients are known to have a high prevalence of cognitive impairment and other comorbidities, and may be at risk of driving impairment. No Australian guidelines address driving safety in dialysis patients. AIMS: To estimate the proportion of dialysis patients who were driving and those at risk of driving impairment, and to investigate the agreement between objective and subjective markers of risk. METHODS: This single-centre study involved dialysis patients voluntarily completing two questionnaires relating to risk of driving impairment; the first questionnaire focussed on objective markers, and the second questionnaire focussed on subjective markers. Risk of driving impairment was established using pre-determined criteria, and the agreement between objective and subjective markers was estimated using Cohen kappa. RESULTS: A total of 44.8% (99/221) of patients participated; 76.8% (76/99) of participants were driving, and 76.3% (58/76) of drivers were at risk of driving impairment. Factors associated with at-risk driving included post dialysis dizziness, leg weakness or numbness, falling asleep while driving and hypoglycaemia. Sixteen patients reported collisions since commencing dialysis. The questionnaires displayed slight agreement (Cohen kappa = 0.20) between objective and subjective markers. CONCLUSIONS: Dialysis patients are at risk of driving impairment based on self-reported questionnaire responses. Discrepancies between patients' perceptions and objective markers were apparent. Further research into appropriate risk assessments, as well as development of guidelines to aid in determining driving safety in dialysis patients, is needed.

The importance of the Heart Team evaluation before transcatheter aortic valve replacement: Results from the BRAVO-3 trial.

BACKGROUND/OBJECTIVES: Clinicians use validated scores to risk-stratify patients undergoing transcatheter aortic valve replacement (TAVR). However, evaluation by the Heart Team often deems patients to be at higher risk than their formal scores suggest. We sought to assess clinical outcomes of TAVR patients defined as high-risk by the Heart Team's assessment versus the patient's logistic EuroSCORE (LES). METHODS: The BRAVO-3 trial randomized patients at high risk (LES ≥ 18, or deemed inoperable by the Heart Team) to TAVR with periprocedural anticoagulation with unfractionated heparin versus bivalirudin. Endpoints included net adverse cardiac events (NACE: the composite of all-cause mortality, MI, stroke, or bleeding), major adverse cardiovascular events (MACE: death, MI, or stroke), the individual components of MACE, major vascular complications, BARC ≥ 3b bleeding and VARC life-threatening bleeding at 30 days. We compared patients deemed high-risk based on LES ≥ 18 versus high-risk by the Heart Team despite lower LES. RESULTS: A total of 467/800 (58.4%) patients were deemed high-risk by the Heart Team despite LES < 18. After multivariable analysis, there were no differences in the odds of endpoints between groups (NACE, ORLES≥18 : 1.32, 95% CI 0.86-2.02, p = .21; MACE, ORLES≥18 : 1.27, 95% CI 0.72-2.25, p = .41; major vascular complications, ORLES≥18 : 0.97, 95% CI 0.65-1.44, p = .88; BARC ≥3b, ORLES≥18 : 1.38, 95% CI 0.82-2.33, p = .23; and VARC life-threatening bleeding, ORLES≥18 : 0.99, 95% CI 0.69-1.41, p = .95). CONCLUSION: Patients undergoing TAVR and labeled high-risk by LES ≥ 18 or Heart Team assessment despite LES < 18 have comparable short-term outcomes. Assignment of high-risk status to over 50% of patients is attributable to Heart Team's clinical assessment.

Diagnostic application of kidney allograft-derived absolute cell-free DNA levels during transplant dysfunction.

Graft-derived cell-free DNA (donor-derived cell-free DNA) is an emerging marker of kidney allograft injury. Studies examining the clinical validity of this biomarker have previously used the graft fraction, or proportion of total cell-free DNA that is graft-derived. The present study evaluated the diagnostic validity of absolute measurements of graft-derived cell-free DNA, as well as calculated graft fraction, for the diagnosis of graft dysfunction. Plasma graft-derived cell-free DNA, total cell-free DNA, and graft fraction were correlated with biopsy diagnosis as well as individual Banff scores. Sixty-one samples were included in the analysis. For the diagnosis of antibody mediated rejection, the receiver-operator characteristic area under the curves of graft-derived cell-free DNA and graft fraction were 0.91 (95% CI 0.82-0.98) and 0.89 (95% CI 0.79-0.98), respectively. Both measures did not diagnose borderline or type 1A cellular mediated rejection. Graft fraction was associated with a broader range of Banff lesions, including lesions associated with cellular mediated rejection, while graft-derived cell-free DNA appeared more specific for antibody mediated rejection. Limitations of this study include a small sample size and lack of a validation cohort. The capacity for absolute quantification, and lower barriers to implementation of this methodology recommend it for further study.

Absence of the ß1 subunit of AMP-activated protein kinase reduces myofibroblast infiltration of the kidneys in early diabetes.

Activation of the heterotrimeric energy-sensing kinase AMP-activated protein kinase (AMPK) has been reported to improve experimental diabetic kidney disease. We examined the effect of type 1 diabetes in wild-type (WT) mice and mice lacking the ß1 subunit of AMPK (AMPK ß1-/- mice), which have reduced AMPK activity in kidneys and other organs. Diabetes was induced using streptozotocin (STZ) and the animals followed up for 4 weeks. Hyperglycaemia was more severe in diabetic AMPK ß1-/- mice, despite the absence of any difference in serum levels of insulin, adiponectin and leptin. There was no change in AMPK activity in the kidneys of diabetic WT mice by AMPK activity assay, or phosphorylation of either the αT172 activation site on the α catalytic subunit of AMPK or the AMPK-specific phosphosite S79 on acetyl CoA carboxylase 1 (ACC1). Phosphorylation of the inhibitory αS485 site on the α subunit of AMPK was significantly increased in the WT diabetic mice compared to non-diabetic controls. Despite increased plasma glucose levels in the diabetic AMPK ß1-/- mice, there were fewer myofibroblasts in the kidneys compared to diabetic WT mice, as evidenced by reduced α-smooth muscle actin (α-SMA) protein by Western blot, mRNA by qRT-PCR and fewer α-SMA-positive cells by immunohistochemical staining. Albuminuria was also reduced in the AMPK ß1-/- mice. In contrast to previous studies, therefore, myofibroblasts were reduced in the kidneys of AMPK ß1-/- diabetic mice compared to diabetic WT mice, despite increased circulating glucose, suggesting that AMPK can worsen renal fibrosis in type 1 diabetes.

Impact of percutaneous closure device type on vascular and bleeding complications after TAVR: A post hoc analysis from the BRAVO-3 randomized trial.

BACKGROUND/OBJECTIVE: Prostar XL (PS) and ProGlide (PG) are common vascular closure devices (VCD) used in TAVR via transfemoral vascular approach. The impact of these VCD on vascular and bleeding complications remains unclear. METHODS: The BRAVO-3 trial randomized 802 patients undergoing transfemoral TAVR. We stratified patients according to type of VCD used and examined the 30-day incidence of major or minor vascular complications, major bleeding (BARC ≥3b), AKI and major adverse cardiac and cerebrovascular events (MACCE; death, myocardial infarction or stroke). RESULTS: A total of 746 (93%) patients were treated with either PS (n = 352, 47%) or PG (n = 394, 53%) VCD, without significant differences in successful deployment rate (PS 322 [91.2%] vs. PG 373 [94.2%] respectively, p = .20). PG was associated with a significantly lower incidence of major or minor vascular complications, compared to PS (adjusted OR: 0.54; 95% CI: 0.37-0.80; p < .01). Rates of acute kidney injury were also lower with the PG device. There was no significant difference between bleeding, MACCE, and death. CONCLUSIONS: Compared to PS, the PG VCD was associated with a lower rate of major or minor vascular complications and lower rates of AKI after transfemoral TAVR.

Case-control study of end-of-life treatment preferences and costs following advance care planning for adults with end-stage kidney disease.

AIM: The aim of the present study was to examine the efficacy of advance care planning (ACP) to improve the likelihood that end-stage kidney disease (ESKD) patient's preferences will be known and adhered to at end-of-life. METHODS: A case-control study of a nurse-led ACP programme in adults with ESKD from a major tertiary hospital. The primary outcome was the proportion of patients whose preferences were known (by substitute decision maker and/or clinicians) and adhered to by their treating doctors. Secondary measures were health system resource use and costs ($AUD) for a nurse-led ACP intervention in the last 12-months of life. RESULTS: In total, 57 cases (38 men, mean age 73.8 years) and 57 historical controls (38 men, mean age 74.0 years) were included. Cases (38/57, 67%) were significantly more likely than controls (15/57, 26%) to have their preferences known and adhered to by their treating doctor at end-of-life (P < 0.001). Cases (33/40, 83%) were also significantly more likely to withdraw from dialysis in accordance with their preferences than controls (11/33, 33%) (P < 0.001). For cases, the average hospital costs in the last 12 months of life was AUD $99 077 (SD = $71 002) per patient. The total cost of the ACP programme in 2010/2011 was AUD $26 821. CONCLUSION: Advance care planning was associated with improvements in end-of-life care preferences being known and adhered to for people with ESKD.

Phosphorylation of Acetyl-CoA Carboxylase by AMPK Reduces Renal Fibrosis and Is Essential for the Anti-Fibrotic Effect of Metformin.

BACKGROUND: Expression of genes regulating fatty acid metabolism is reduced in tubular epithelial cells from kidneys with tubulointerstitial fibrosis (TIF), thus decreasing the energy produced by fatty acid oxidation (FAO). Acetyl-CoA carboxylase (ACC), a target for the energy-sensing AMP-activating protein kinase (AMPK), is the major controller of the rate of FAO within cells. Metformin has a well described antifibrotic effect, and increases phosphorylation of ACC by AMPK, thereby increasing FAO. METHODS: We evaluated phosphorylation of ACC in cell and mouse nephropathy models, as well as the effects of metformin administration in mice with and without mutations that reduce ACC phosphorylation. RESULTS: Reduced phosphorylation of ACC on the AMPK site Ser79 occurred in both tubular epithelial cells treated with folate to mimic cellular injury and in wild-type (WT) mice after induction of the folic acid nephropathy model. When this effect was exaggerated in mice with knock-in (KI) Ser to Ala mutations of the phosphorylation sites in ACC, lipid accumulation and fibrosis increased significantly compared with WT. The effect of ACC phosphorylation on fibrosis was confirmed in the unilateral ureteric obstruction model, which showed significantly increased lipid accumulation and fibrosis in the KI mice. Metformin use was associated with significantly reduced fibrosis and lipid accumulation in WT mice. In contrast, in the KI mice, the drug was associated with worsened fibrosis. CONCLUSIONS: These data indicate that reduced phosphorylation of ACC after renal injury contributes to the development of TIF, and that phosphorylation of ACC is required for metformin's antifibrotic action in the kidney.

The personalities of most medical students are suited to rural practice: Implications for rural education program recruitment.

Introduction: The success of rural longitudinal integrated clerkship (LIC) programs has contributed to our understanding of selecting and training students for rural practice. Studies have explored the personality traits of students who participate in rural LICs although few have compared them with classmates who have not. The purpose is to compare personalities of four successive cohorts of students in the LIC Rural Physician Associate Program (RPAP) with their non-RPAP classmates. Methods: In a longitudinal cross-sectional design, medical students RPAP and non-RPAP, from 2013 to 2017 completed identical questionnaires comprising measures of personality, perfectionism, ambiguity tolerance, and resilience. T-tests, ANOVA, and post-hoc tests compared groups. K-means cluster analysis identified profiles of traits. Results: Total sample 286; RPAP = 128; non-RPAP = 158. Gender and age proportions were not different between groups. RPAP students were significantly lower in levels of perfectionism and higher in cooperativeness compared to non-RPAP classmates. Similar proportions of both groups were distributed across three personality profiles detected. Conclusions: Lower perfectionism implies advantages for rural practice. Nevertheless, similarities between groups suggest that most students would be successful in rural practice. More encouragement to all students may improve uptake of rural LICs. Greater attention to issues that affect decisions to explore rural medical education, particularly for our next generation of students, is required.

To Pay or Not to Pay Community Preceptors? That Is a Question .

Phenomenon: Pairing medical students with community-based preceptors has provided unique medical education advantages. However, due to an increase in the number of M.D.-granting medical schools and medical school class sizes, academic medical institutions have struggled to recruit community preceptors to teach their students. This task has been made more difficult due to rising pressures upon institutions and clinicians-for example, increased productivity demands, greater volume and oversight of electronic health record documentation, and competition for community preceptors from both D.O. and non-U.S.-based medical schools. Although academic institutions have historically relied largely on altruistic motives and intrinsic rewards to actively engage and retain community-based preceptors, alternative models have arisen, chiefly those in which community-based preceptors are explicitly compensated for teaching. Approach: To study this phenomenon, representatives of the Alliance for Clinical Education developed and deployed a 31-item survey accompanied with a subset of free text questions to the collective membership of its 8-member constituent organizations. Survey questions explored if community preceptors were compensated indirectly or directly and what types of compensation were provided, if any. There were 188 surveys analyzed, with an estimated response rate of 18.2%. Findings: Twenty-six percent of respondents indicated they compensate community preceptors directly and/or indirectly. Respondents discussed their motivations for payment (or nonpayment), mechanisms for paying, aspirations to pay, and expectations of the recipient. No statistically significant association was found when comparing responses of paid versus not paid by region. Free text responses provided additional insight regarding payment considerations, institutional competition, recruitment/retention, recognition, and education issues. Insights: Increasingly, medical schools are finding it necessary to provide funding for community preceptors in order to retain them. New creative forms of compensation to community preceptors may prove important in the future for this vital aspect of medical student education.

A Systematic Review and Meta-analysis of Thrombotic Events Following Endovenous Thermal Ablation of the Great Saphenous Vein.

OBJECTIVES: A systematic review and meta-analysis was performed to determine the incidence of thrombotic events following great saphenous vein (GSV) endovenous thermal ablation (EVTA). METHODS: MEDLINE, Embase and conference abstracts were searched. Eligible studies were randomised controlled trials and case series that included at least 100 patients who underwent GSV EVTA (laser ablation or radiofrequency ablation [RFA]) with duplex ultrasound (DUS) within 30 days. The systematic review focused on the complications of endovenous heat induced thrombosis (EHIT), deep venous thrombosis (DVT), and pulmonary embolism (PE). The primary outcome for the meta-analysis was deep venous thrombotic events which were defined as DVT or EHIT Type 2, 3, or 4. Secondary outcomes for the meta-analysis were EHIT Type 2, 3, or 4, DVT and PE. Subgroup analyses were performed for both the RFA and EVLA groups. Pooled proportions were calculated using random effects modelling. RESULTS: Fifty-two studies (16,398 patients) were included. Thrombotic complications occurred infrequently. Deep venous thrombotic events occurred in 1.7% of cases (95% CI 0.9-2.7%) (25 studies; 10,012 patients; 274 events). EHIT Type 2, 3, or 4 occurred in 1.4% of cases (95% CI 0.8-2.3%) (26 studies; 10,225 patients; 249 events). DVT occurred in 0.3% of cases (95% CI = 0.2%-0.5%) (49 studies; 15,676 patients; 48 events). PE occurred in 0.1% of cases (95% CI = 0.1-0.2%) (29 studies; 8223 patients; 3 events). Similar results were found when the RFA and EVLA groups were analysed separately. CONCLUSION: Thrombotic events occur infrequently following GSV EVTA. Given the large numbers of procedures worldwide and the potential for serious consequences, further research is needed on the burden of these complications and their management.