Meta-analysis of type 2 Diabetes in African Americans Consortium

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe

Retrospective study of first-generation drug-eluting stents, second-generation drug-eluting stents and non-drug eluting stent methods in the treatment of native vessel in-stent restenosis in real-world clinical practice

Background: The efficacy of second-generation drug-eluting stents (DES) in treating in-stent restenosis (ISR) compared to first-generation DES and non-DES treatment methods in real-world cohorts has not yet been adequately addressed. This research intends to examine optimum treatment of in-stent restenosis, considering first-generation DES, second-generation DES and non-DES treatment methods in a real-world cohort. Methods: Retrospective analysis was performed on 114 patients treated for native-vessel BMS or DES ISR. Thirty-two were treated with a first-generation DES (81% sirolimus, 19% paclitaxel), 32 with a second-generation DES (72% everolimus, 28% zotarolimus) and 28 with non-DES methods (32% bare-metal stent, 39% balloon angioplasty, 29% cutting balloon). The composite primary endpoint was total adverse cardiac events, recurrent stable angina, unstable angina, myocardial infarction (MI), target vessel revascularisation (TVR) and cardiac death at minimum clinical follow-up of six months. Results: Primary endpoint rates were significantly higher in the non-DES and second-generation DES treatment groups than in first-generation DES (42.9%, 25.9%, 6.2%; p = 0.004). Rates of MI and TVR were significantly higher in the non-DES treatment group, compared to first and second-generation DES (MI: 17.9%, 0%, 5.6%; p = 0.018; TLR: 21.4%, 3.1%, 7.4%; p = 0.041). Conclusions: First-generation DES may be superior to second-generation DES and non-DES in treating BMS or DES ISR with regard to overall adverse cardiac events

The effect of X-ray beam distortion on the Edwards Sapien XT™ trans-catheter aortic valve replacement prosthesis

Introduction: Profiling the Aortic root perpendicular to the fluoroscopic image plane will achieve a more successful implant position for trans-catheter aortic valve replacement (TAVR). This study aimed to investigate whether the divergent nature of the X-ray beam from the C-arm altered the appearance of the TAVR device. Methods: Under bench-top testing, a 23, 26 and 29 mm Edwards Sapien XT valve was positioned coaxially at the bottom of a fluoroscopic image utilising 22 and 32 cm fields of view (FOV). The table was then moved so that the valve was positioned at the top of the image. The valve's appearance was scored using a previously published three tier classification tool (excellent, satisfactory and poor) and quantified with measurements. The number of degrees of C-arm rotation that were required to bring the valve back to a coaxial appearance was recorded. Results: When using the 32 cm FOV, the valve's appearance changes from excellent to satisfactory. When a 22 cm FOV was used, the change is less marked. More C-arm rotation is required to bring the appearance back to coaxial with the 32 cm FOV. Conclusion: Not maintaining the valve in the centre of the image can distort the valves appearance. This has the potential to affect the final implantation depth

Confirmation of specific binding of the 18 kDa translocator protein (TSPO) radioligand [18F]GE-180: a blocking study using XBD173 in multiple sclerosis normal appearing white and grey matter

Purpose: Positron emission tomography (PET) ligands exhibit different levels of non-displaceable binding in vivo. In the case of ligands for the 18 kDa translocator protein (TSPO), the component of non-displaceable binding for the most widely used radiotracer, [11C]-(R)-PK11195, is relatively high compared to that for newer TSPO ligands. Non-displaceable binding is not often quantified in humans in vivo, partially due to a lack of available ligands that are known to be safe with which to displace binding to the target receptor. Recently, however, a technique has been developed to quantify the non-displaceable binding of TSPO tracers in vivo, by blocking the receptor with the TSPO ligand XBD173 and comparing the total volume of distribution ( ) pre and post-blockade. Here, we used an occupancy plot to quantify the non-displaceable binding ( ) of the TSPO PET tracers [18F]GE-180 and [11C]PBR28 in cohorts of people with multiple sclerosis (MS). We also compared plots of subjects carrying both high and mixed binding affinity polymorphisms of TSPO to estimate while potentially avoiding the need for receptor blockade. Procedures: Twelve people with multiple sclerosis (MS) and high (HAB) or mixed (MAB) affinity binding for TSPO underwent baseline MRI and 90-minute dynamic [18F]GE-180 PET (n=6; 3 HAB and 3 MAB) or [11C]PBR28 PET (n=6; 3 HAB, 3 MAB). Either one week later ([18F]GE-180) or the same afternoon ([11C]PBR28), participants had repeat PET following a 90mg dose of XBD173. PET images were co-registered with T1 MR volumetric images and regions of interest (ROIs) were defined using the 83-region Hammers atlas. Arterial blood sampling was used to generate plasma input functions for the two-tissue compartment model to quantify . The non-displaceable fraction of the total volume of distribution ( ) was calculated using two independent methods: the occupancy plot (by modelling the differences in signal post XBD173), and the polymorphism plot (by modelling the differences in signal across presence and absence of rs6971 genotypes). Results: Whole brain (mean ± standard deviation) was 0.29±0.17 ml.cm-3 for [18F]GE-180 and 5.01±1.88 ml.cm-3 for [11C]PBR28. for [18F]GE-180 was 0.11 ml.cm-3 (95% CI: 0.02, 0.16) using the constrained occupancy plot and 0.20 ml.cm-3 (0.16, 0.34) using the polymorphism plot. accounted for, on average, 55% of in the whole brain. Equivalent values for [11C]PBR28 were 3.81 ml.cm-3 (3.02, 4.21) and 3.49 (1.38, 4.27), with accounting for 67% of average whole brain . Conclusions: Although the of [18F]GE-180 is low, indicating low brain penetration, half of the signal shown by MS subjects reflected specific TSPO binding. The of [11C]PBR28 was higher and two thirds of the binding was non-specific. No brain ROIs were devoid of specific signal, further confirming that true reference tissue approaches are potentially problematic for estimates of TSPO levels

Factors contributing to acute kidney injury and the impact on mortality in patients undergoing transcatheter aortic valve replacement

Background: Transcatheter aortic valve replacement (TAVR) patients are at a high risk of acute kidney injury (AKI). This study aimed to investigate AKI and the relationship with iodinated contrast media (ICM), whether there are significant pre- or peri- procedural variables predicting AKI, and whether AKI impacts on hospital length of stay and mortality. Methods: Serum creatinine (SC) levels pre- and post- (peak) TAVR were recorded in 209 consecutive TAVR patients. AKI was defined by the Valve Academic Research Consortium 2 (VARC2) criteria. Baseline characteristics, procedural variables, hospital length of stay (LOS) and mortality at 72 hours, 30 days and one year were analysed. Results: Eighty-two of 209 (39%) patients suffered AKI. Mean ICM volume was 228cc, with no difference between patients with AKI and those with no AKI (227cc (213-240(95%CI)) vs 231cc (212-250) p=0.700)). Univariate and multivariate analysis demonstrated that chronic kidney disease, respiratory failure, previous stroke, the need for blood transfusion and valve repositioning were all predictors of AKI. Acute kidney injury increased LOS (5.6 days (3.8 - 7.5) vs 3.2 days (2.6 - 3.9) no AKI (P=0.004)) but was not linked to increased mortality. Mortality rates did increase with AKI severity. Conclusion: Acute kidney injury is a common complication of TAVR. The severity of AKI is important in determining mortality. Acute kidney injury appears to be independent of ICM use but pre-existing renal impairment and respiratory failure were predictors for AKI. Transcatheter aortic valve replacement device repositioning or retrieval was identified as a new risk factor impacting on AKI

Using DynaCT for the assessment of ilio-femoral arterial calibre, calcification and tortuosity index in patients selected for trans-catheter aortic valve replacement

Adequate vascular access for femoral transcatheter aortic valve replacement is fundamental to the success of the procedure. Assessment of vascular calibre, tortuosity and calcification is performed by angiography and multi-slice computed tomography (MSCT). Can DynaCT provide the same information as MSCT? 15 Patients underwent MSCT, angiography and DynaCT. Vessel diameter measurements were taken in three positions of the left and right ilio-femoral arteries. Tortuosity was assessed using an index of the direct distance and the distance taken by the artery between two points. Calcification was assessed in MSCT and DynaCT using a simple scoring system. Concordance correlation coefficient of arterial calibre between angiography and MSCT was 0.96 (95 % CI 0.94-0.97). DynaCT and angiography was 0.94 (95 % CI 0.91-0.96) and Dyna CT and MSCT, 0.95 (95 % CI 0.92-0.97). Bland-Altman tests demonstrate a mean difference between the angiogram and the MSCT of 0.06 mm (+0.97, -1.42), angiogram and DynaCT, 0.13 mm, (+1.00, -0.87), DynaCT and MSCT, 0.2 mm, (+1.15, -0.76). Tortuosity comparisons gave a median tortuosity index for MSCT 1.29 and DynaCT 1.23 (p = 0.472). Calcification comparisons of MSCT and DynaCT using correlation coefficients demonstrate a correlation of 0.245 (p = 0.378). Effective radiation doses were: DynaCT; 3.63 ± 0.65 mSv and angiography; 0.57 ± 0.72 mSv, MSCT; 7.15 ± 2.58 mSv. DynaCT is equal to MSCT and angiography in assessing femoral artery calibre. Like MSCT, it can assess tortuosity and can produce 3D images but is inferior in the assessment of calcification