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ObjectivesTo evaluate the added value of deep learning (DL) analysis of the left ventricular myocardium (LVM) in resting coronary CT angiography (CCTA) over determination of coronary degree of stenosis (DS), for identification of patients with functionally significant coronary artery stenosis.MethodsPatients who underwent CCTA prior to an invasive fractional flow reserve (FFR) measurement were retrospectively selected. Highest DS from CCTA was used to classify patients as having non-significant (≤ 24% DS), intermediate (25–69% DS), or significant stenosis (≥ 70% DS). Patients with intermediate stenosis were referred for fully automatic DL analysis of the LVM. The DL algorithm characterized the LVM, and likely encoded information regarding shape, texture, contrast enhancement, and more. Based on these encodings, features were extracted and patients classified as having a non-significant or significant stenosis. Diagnostic performance of the combined method was evaluated and compared to DS evaluation only. Functionally significant stenosis was defined as FFR ≤ 0.8 or presence of angiographic high-grade stenosis (≥ 90% DS).ResultsThe final study population consisted of 126 patients (77% male, 59 ± 9 years). Eighty-one patients (64%) had a functionally significant stenosis. The proposed method resulted in improved discrimination (AUC = 0.76) compared to classification based on DS only (AUC = 0.68). Sensitivity and specificity were 92.6% and 31.1% for DS only (≥ 50% indicating functionally significant stenosis), and 84.6% and 48.4% for the proposed method.ConclusionThe combination of DS with DL analysis of the LVM in intermediate-degree coronary stenosis may result in improved diagnostic performance for identification of patients with functionally significant coronary artery stenosis.Key Points• Assessment of degree of coronary stenosis on CCTA has consistently high sensitivity and negative predictive value, but has limited specificity for identifying the functional significance of a stenosis.• Deep learning algorithms are able to learn complex patterns and relationships directly from the images without prior specification of which image features represent presence of disease, and thereby may be more sensitive to subtle changes in the LVM caused by functionally significant stenosis.• Addition of deep learning analysis of the left ventricular myocardium to the evaluation of degree of coronary artery stenosis improves diagnostic performance and increases specificity of resting CCTA. This could potentially decrease the number of patients undergoing invasive coronary angiography.

More than 240 genetic risk loci have been associated with inflammatory bowel disease (IBD), but little is known about how they contribute to disease development in involved tissue. Here, we hypothesized that host genetic variation affects gene expression in an inflammation-dependent way, and investigated 299 snap-frozen intestinal biopsies from inflamed and non-inflamed mucosa from 171 IBD patients. RNA-sequencing was performed, and genotypes were determined using whole exome sequencing and genome wide genotyping. In total, 28,746 genes and 6,894,979 SNPs were included. Linear mixed models identified 8,881 independent intestinal cis- expression quantitative trait loci ( cis -eQTLs) (FDR < 0.05) and interaction analysis revealed 190 inflammation-dependent intestinal cis -eQTLs (FDR < 0.05), including known IBD-risk genes and genes encoding immune-cell receptors and antibodies. The inflammation-dependent cis -eQTL SNPs (eSNPs) mainly interact with prevalence of immune cell types. Inflammation-dependent intestinal cis -eQTLs reveal genetic susceptibility under inflammatory conditions that can help identify the cell types involved in and the pathways underlying inflammation, knowledge that may guide future drug development and profile patients for precision medicine in IBD. Inflammatory bowel diseases are heterogeneous, and little is known about how underlying genetic variation can affect their development. Here, the authors report that intestinal inflammation modulates the effect of host genetics on the gut mucosal expression of 190 genes in the context of inflammatory bowel diseases.

Background Anti-tumour necrosis factor alpha (TNFα) therapy is widely used in the management of Crohn’s disease (CD) and ulcerative colitis (UC). However, up to a third of patients do not respond to induction therapy and another third of patients lose response over time. To aid patient stratification, polygenetic risk scores have been identified as predictors of response to anti-TNFα therapy. We aimed to replicate the association between polygenetic risk scores and response to anti-TNFα therapy in an independent cohort of patients, to establish its clinical validity. Materials and methods Primary non-response, primary response, durable response and loss of response to anti-TNFα therapy was retrospectively assessed for each patient using stringent definitions. Genome wide genotyping was performed and previously described polygenetic risk scores for primary non-response and durable response were calculated. We compared polygenetic risk scores between patients with primary response and primary non-response, and between patients with durable response and loss of response, using separate analyses for CD and UC. Results Out of 334 patients with CD, 15 (4%) patients met criteria for primary non-response, 221 (66%) for primary response, 115 (34%) for durable response and 35 (10%) for loss of response. Out of 112 patients with UC, 12 (11%) met criteria for primary non-response, 68 (61%) for primary response, 19 (17%) for durable response and 20 (18%) for loss of response. No significant differences in polygenetic risk scores were found between primary non-responders and primary responders, and between durable responders and loss of responders. Conclusions We could not replicate the previously reported association between polygenetic risk scores and response to anti-TNFα therapy in an independent cohort of patients with CD or UC. Currently, there is insufficient evidence to use polygenetic risk scores to predict response to anti-TNFα therapy in patients with IBD.

Gene-microbiome interactions are important in aetiology and pathogenesis of inflammatory bowel disease, a chronic inflammatory disorder of the gastrointestinal tract consisting of Crohn's disease and ulcerative colitis. Scarce studies on gene-microbiome interactions show very little overlap in their results. Therefore, it is of utmost importance that gene-microbiome studies are repeated. We aimed to replicate the association between the SLC39A8 [Thr]391 risk allele and gut microbiome composition in patients with inflammatory bowel disease and healthy controls. We collected faecal samples, peripheral blood and extensive phenotype data from 291 patients with inflammatory bowel disease and 476 healthy controls. Carrier status information was obtained from whole exome sequencing data, generated using the Illumina HiSeq. The gut microbiome composition was determined by tag-sequencing the 16S rRNA gene. Associations between carrier status and disease were tested using the Wilcoxon-Mann-Whitney test. Associations between carriers and gut microbiome composition were determined using principal coordinate analyses, variance explained, alpha diversity and additive general linear models in inflammatory bowel disease, healthy controls and all groups combined. Crohn's disease patients were more often carriers of the missense variant (21/171, 12.3%) than controls (30/476, 6.3%) (OR = 2.1, P = 0.01). We could not identify associations between carrier status and overall gut microbiome composition and microbial richness in all tested groups after correcting for potential confounding factors. We did identify 37 different operational taxonomical units to be associated with carrier status among the tested groups. Two of these 37 were identified before in the discovery study. We could confirm the genetic association of the SLC39A8 [Thr]391 risk allele with Crohn's disease but we could only limited replicate the association in gut microbiome composition. Independent replication of gene-microbiome studies is warranted to identify true biological mechanisms.

Heart failure with preserved left ventricular ejection fraction (HFPEF) affects about half of all patients diagnosed with heart failure. The pathophysiological aspect of this complex disease state has been extensively explored, yet it is still not fully understood. Since the sympathetic nervous system is related to the development of systolic HF, we hypothesized that an increased sympathetic nerve activation (SNA) is also related to the development of HFPEF. This review summarizes the available literature regarding the relation between HFPEF and SNA. Electronic databases and reference lists through April 2014 were searched resulting in 7722 unique articles. Three authors independently evaluated citation titles and abstracts, resulting in 77 articles reporting about the role of the sympathetic nervous system and HFPEF. Of these 77 articles, 15 were included for critical appraisal: 6 animal and 9 human studies. Based on the critical appraisal, we selected 9 articles (3 animal, 6 human) for further analysis. In all the animal studies, isoproterenol was administered to mimic an increased sympathetic activity. In human studies, different modalities for assessment of sympathetic activity were used. The studies selected for further evaluation reported a clear relation between HFPEF and SNA. Current literature confirms a relation between increased SNA and HFPEF. However, current literature is not able to distinguish whether enhanced SNA results in HFPEF, or HFPEF results in enhanced SNA. The most likely setting is a vicious circle in which HFPEF and SNA sustain each other.

[...]in-hospital mortality after ACS has been reduced to approximately 5% [1]. [...]about 20% of ACS survivors experience an ischaemic cardiovascular event within 2 years after ACS and 5‑year mortality is still around 20% [2]. Besides the percutaneous treatment of coronary artery disease (CAD), secondary prevention in these patients has become one of the cornerstones of cardiovascular care. [...]42% still had blood pressure ≥ 140/90 mm Hg (≥ 140/85 mm Hg if diabetic), 71% had low-density lipoprotein cholesterol ≥ 1.8 mmol/l (≥ 70 mg/dl), and 29% reported having diabetes.

Cerebral perforating artery flow velocity and pulsatility can be measured using 7 tesla (T) MRI. Enabling these flow metrics on more widely available 3T systems would make them more employable. It is currently unknown whether these measurements can be performed at 3T MRI due to the lower signal-to-noise ratio (SNR). Therefore, the aim of this study is to investigate if flow velocity and pulsatility in the perforating arteries of the basal ganglia (BG) can be measured at 3T MRI and assess the agreement with 7T MRI measurements as reference. Twenty-nine subjects were included, of which 14 patients with aortic coarctation [median age 29 years (21–72)] and 15 controls [median age 27 years (22–64)]. Using a cardiac-gated 2D phase-contrast MRI sequence BG perforating arteries were imaged at 3T and 7T MRI and perforating artery density (N density , #/cm 2 ), flow velocity (V mean , cm/s) and pulsatility index (PI) were determined. Agreement between scanner modalities was assessed using correlation and difference plots with linear regression. A p -value ≤ 0.05 indicated statistical significance. It was shown that perforating artery flow velocity and pulsatility can be measured at 3T MRI (N density = 0.21 ± 0.11; V mean = 6.04 ± 1.27; PI = 0.49 ± 0.19), although values differed from 7T MRI measurements (N density = 0.95 ± 0.21; V mean = 3.89 ± 0.56; PI = 0.28 ± 0.08). The number of detected arteries was lower at 3T (5 ± 3) than 7T MRI (24 ± 6), indicating that 3T MRI is on average a factor 4.8 less sensitive to detect cerebral perforating arteries. Comparison with 7T MRI as reference showed some agreement in N density , but little to no agreement for V mean and PI. Equalizing the modalities’ sensitivity by comparing the detected arteries on 7T MRI with the highest velocity with all vessels detected on 3T MRI, showed some improvement in agreement for PI, but not for V mean . This study shows that it is possible to measure cerebral perforating artery flow velocity and pulsatility at 3T MRI, although an approximately fivefold sample size is needed at 3T relative to 7T MRI for a given effect size, and the measurements should be performed with equal scanner field strength and protocol.

Anti-tumour necrosis factor alpha (TNF[alpha]) therapy is widely used in the management of Crohn's disease (CD) and ulcerative colitis (UC). However, up to a third of patients do not respond to induction therapy and another third of patients lose response over time. To aid patient stratification, polygenetic risk scores have been identified as predictors of response to anti-TNF[alpha] therapy. We aimed to replicate the association between polygenetic risk scores and response to anti-TNF[alpha] therapy in an independent cohort of patients, to establish its clinical validity. Primary non-response, primary response, durable response and loss of response to anti-TNF[alpha] therapy was retrospectively assessed for each patient using stringent definitions. Genome wide genotyping was performed and previously described polygenetic risk scores for primary non-response and durable response were calculated. We compared polygenetic risk scores between patients with primary response and primary non-response, and between patients with durable response and loss of response, using separate analyses for CD and UC. Out of 334 patients with CD, 15 (4%) patients met criteria for primary non-response, 221 (66%) for primary response, 115 (34%) for durable response and 35 (10%) for loss of response. Out of 112 patients with UC, 12 (11%) met criteria for primary non-response, 68 (61%) for primary response, 19 (17%) for durable response and 20 (18%) for loss of response. No significant differences in polygenetic risk scores were found between primary non-responders and primary responders, and between durable responders and loss of responders. We could not replicate the previously reported association between polygenetic risk scores and response to anti-TNF[alpha] therapy in an independent cohort of patients with CD or UC. Currently, there is insufficient evidence to use polygenetic risk scores to predict response to anti-TNF[alpha] therapy in patients with IBD.

BackgroundPrevious research on congenital aortic stenosis (AS) mainly focused on children, while data on long-term outcomes in adults is scarce. Therefore, this study aims to evaluate outcomes in adult patients with congenital AS and identify prognostic markers for aortic valve replacement (AVR).MethodsIn this multicentre study, patients aged 18–55 years with congenital AS (peak velocity ≥2.5 m/s) registered in the Dutch CONCOR (Congential Cor Vitia) registry from expert centres for congenital heart disease between 2001 and 2019 were included. Exclusion criteria were severe aortic regurgitation (AR) or prior AVR. Associations with the composite endpoint of all-cause mortality and AVR were assessed with multivariable Cox regression.ResultsOf the 427 included patients (median age 26 years, 62.5% male) median aortic peak velocity was 3.1 (IQR 2.7–3.6) m/s, 35% had moderate AR and 29% showed signs of left ventricular (LV) remodelling. During a median follow-up period of 7.9 (IQR 4.1–12.6) years, 7 patients died (1.6%) and 177 patients underwent AVR (41.5%). LV systolic dysfunction was the primary indication for AVR in three patients (1.7%). Peak velocity at baseline (HR 3.17, 95% CI 2.29 to 4.39), non-sinus rhythm (HR 3.12, 95% CI 1.62 to 6.02) and concentric LV geometry (HR 1.64, 95% CI 1.04 to 2.58) were associated with the primary endpoint beside age. Significant male–female differences were observed in prognostic factors for the primary endpoint.ConclusionAVR was often indicated in adult patients with congenital AS, even if the stenosis at baseline was mild. Moreover, monitoring LV remodelling alongside severity of AS is more important than focusing on systolic LV dysfunction.

BackgroundSupravalvular aortic stenosis (SVAS) is a rare condition with limited data on patients beyond childhood. This study aims to investigate the clinical course and outcomes of SVAS in adults.MethodsAll adult (≥18 years) patients with SVAS, prospectively registered in the Dutch Congenital Cor Vitia database between 2001 and 2019, were included. Survival and event-free survival were assessed. Evolution of peak velocity was analysed using linear mixed models. Differences in previous operated state, sex and Williams-Beuren syndrome were explored.Results65 patients were included (age: 23 (IQR: 20, 31) years, 31% female, 46% previous SVAS correction, 47% Williams-Beuren syndrome). The peak velocity was 2.3±1.0 m/s at inclusion. Median follow-up time was 13 (IQR: 10, 17) years. Four patients died (one patient after cardiac surgery, two of non-cardiac causes and in one patient the cause of death was unknown) resulting in a 10-year survival of 95% (95% CI 90% to 100%) and event-free survival of 83% (95% CI 74% to 93%). There were no differences in event-free survival between previous operated state (p=0.2), sex (p=0.48) or Williams-Beuren syndrome (p=0.85). 31 cardiovascular events occurred in 15 patients, with the majority being arrhythmias. All SVAS-related interventions (three surgeries in two patients) occurred in unoperated patients (7 (95% CI 2 to 21)/1000 patient years). Although no patient showed fast progression (≥0.3 m/s/year), the peak velocity evolution over time increased faster in females compared with males (first time spline: 0.8 m/s, p=0.017).ConclusionIn adulthood, SVAS patients showed a stable clinical course without rapid progression. While cardiovascular events occurred in this young cohort, they were mostly obsereved in those with additional congenital heart defects, suggesting a more optimistic view for SVAS itself. No significant differences in outcomes were observed in patients with/without Williams-Beuren syndrome. Overall, SVAS tends to follow a more benign course in adulthood compared with childhood, potentially allowing for less intensive follow-up- though follow-up should still be individualised based on associated congenital heart defects and cardiovascular risks.