Parkinson's disease-related perfusion and glucose metabolic brain patterns identified with PCASL-MRI and FDG-PET imaging

AbstractIntroductionUnder normal conditions, the spatial distribution of resting cerebral blood flow and cerebral metabolic rate of glucose are closely related. A relatively new magnetic resonance (MR) technique, pseudo-continuous arterial spin labeling (PCASL), can be used to measure regional brain perfusion. We identified a Parkinson's disease (PD)-related perfusion and metabolic covariance pattern in the same patients using PCASL and FDG-PET imaging and assessed (dis)similarities in the disease-related pattern between perfusion and metabolism in PD patients.MethodsNineteen PD patients and seventeen healthy controls underwent [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging. Of 14 PD patients and all healthy controls PCASL-MRI could be obtained. Data were analyzed using scaled subprofile model/principal component analysis (SSM/PCA).ResultsUnique Parkinson's disease-related perfusion and metabolic covariance patterns were identified using PCASL and FDG-PET in the same patients. The PD-related metabolic covariance brain pattern is in high accordance with previously reports. Also our disease-related perfusion pattern is comparable to the earlier described perfusion pattern. The most marked difference between our perfusion and metabolic patterns is the larger perfusion decrease in cortical regions including the insula.ConclusionWe identified PD-related perfusion and metabolic brain patterns using PCASL and FDG-PET in the same patients which were comparable with results of existing research. In this respect, PCASL appears to be a promising addition in the early diagnosis of individual parkinsonian patients

Early childhood educator's implementation readiness and intervention fidelity: Findings from a person-centered study

Research has indicated that early educators’ intervention fidelity is a significant predictor of children's responsiveness to classroom interventions. To improve understanding of predictors of intervention fidelity in early childhood settings, this study adopted a person-centered approach to identify profiles of “implementation readiness” in 1,192 Danish educators, and to examine relations with implementation fidelity. Multilevel latent profile analyses including setting-level characteristics as well as characteristics particular to the individual educator, showed reliable profiles of general and intervention-specific implementation readiness, which were associated with proportion of fulltime educators, employees with a teaching-related pre-service education, and investment in professional development. Higher and more positive implementation readiness predicted implementation dosage and adherence to early childhood interventions

Accounting for Breakout in Britain: The Industrial Revolution Through a Malthusian Lens

Over the past few years non-cardiac surgery has been recognised as a serious circulatory stress test which may trigger cardiovascular events such as myocardial infarction, in particular in patients at high risk. Detection of these postoperative cardiovascular events is difficult as clinical symptoms often go unnoticed. To improve detection, guidelines advise to perform routine postoperative assessment of cardiac troponin. Troponin elevation – or postoperative myocardial injury – can be caused by myocardial infarction. However, also non-coronary causes, such as cardiac arrhythmias, sepsis and pulmonary embolism, may play a role in a considerable number of patients with postoperative myocardial injury. It is crucial to acquire more knowledge about the underlying mechanisms of postoperative myocardial injury because effective prevention and treatment options are lacking. Preoperative administration of beta-blockers, aspirin, statins, clonidine, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and preoperative revascularisation have all been investigated as preventive options. Of these, only statins should be considered as the initiation or reload of statins may reduce the risk of postoperative myocardial injury. There is also not enough evidence for intraoperative measures such blood pressure optimisation or intensified medical therapy once patients have developed postoperative myocardial injury. Given the impact, better preoperative identification of patients at risk of postoperative myocardial injury, for example using preoperatively measured biomarkers, would be helpful to improve cardiac optimisation

Current and Future Use of Long Axial Field-of-View Positron Emission Tomography/Computed Tomography Scanners in Clinical Oncology

The latest technical development in the field of positron emission tomography/computed tomography (PET/CT) imaging has been the extension of the PET axial field-of-view. As a result of the increased number of detectors, the long axial field-of-view (LAFOV) PET systems are not only characterized by a larger anatomical coverage but also by a substantially improved sensitivity, compared with conventional short axial field-of-view PET systems. In clinical practice, this innovation has led to the following optimization: (1) improved overall image quality, (2) decreased duration of PET examinations, (3) decreased amount of radioactivity administered to the patient, or (4) a combination of any of the above. In this review, novel applications of LAFOV PET in oncology are highlighted and future directions are discussed.</p

Effect of Adding Ticagrelor to Standard Aspirin on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting (POPular CABG) A Randomized, Double-Blind, Placebo-Controlled Trial

BACKGROUND: Approximately 15% of saphenous vein grafts (SVGs) occlude during the first year after coronary artery bypass graft surgery (CABG) despite aspirin use. The POPular CABG trial (The Effect of Ticagrelor on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting Surgery) investigated whether ticagrelor added to standard aspirin improves SVG patency at 1 year after CABG. METHODS: In this investigator-initiated, randomized, double-blind, placebo-controlled, multicenter trial, patients with ≥1 SVGs were randomly assigned (1:1) after CABG to ticagrelor or placebo added to standard aspirin (80 mg or 100 mg). The primary outcome was SVG occlusion at 1 year, assessed with coronary computed tomography angiography, in all patients that had primary outcome imaging available. A generalized estimating equation model was used to perform the primary analysis per SVG. The secondary outcome was 1-year SVG failure, which was a composite of SVG occlusion, SVG revascularization, myocardial infarction in myocardial territory supplied by a SVG, or sudden death. RESULTS: Among 499 randomly assigned patients, the mean age was 67.9±8.3 years, 87.1% were male, the indication for CABG was acute coronary syndrome in 31.3%, and 95.2% of procedures used cardiopulmonary bypass. Primary outcome imaging was available in 220 patients in the ticagrelor group and 223 patients in the placebo group. The SVG occlusion rate in the ticagrelor group was 10.5% (51 of 484 SVGs) versus 9.1% in the placebo group (43 of 470 SVGs), odds ratio, 1.29 [95% CI, 0.73-2.30]; P=0.38. SVG failure occurred in 35 (14.2%) patients in the ticagrelor group versus 29 (11.6%) patients in the placebo group (odds ratio, 1.22 [95% CI, 0.72-2.05]). CONCLUSIONS: In this randomized, placebo-controlled trial, the addition of ticagrelor to standard aspirin did not reduce SVG occlusion at 1 year after CABG. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02352402

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Common Variants in the Type 2 Diabetes KCNQ1 Gene Are Associated with Impairments in Insulin Secretion During Hyperglycaemic Glucose Clamp

Background: Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients. Methodology: The KCNQ1 variants rs151290, rs2237892, and rs2237895 were genotyped in a total of 4620 type 2 diabetes patients and 5285 healthy controls from the Netherlands. Data on macrovascular complications, nephropathy and retinopathy were available in a subset of diabetic patients. Association between genotype and insulin secretion/action was assessed in the additional sample of 335 individuals who underwent a hyperglycaemic clamp. Principal Findings: We found that all the genotyped KCNQ1 variants were significantly associated with type 2 diabetes in our Dutch population, and the association of rs151290 was the strongest (OR 1.20, 95% CI 1.07-1.35, p = 0.002). The risk C-allele of rs151290 was nominally associated with reduced first-phase glucose-stimulated insulin secretion, while the non-risk T-allele of rs2237892 was significantly correlated with increased second-phase glucose-stimulated insulin secretion (p = 0.025 and 0.0016, respectively). In addition, the risk C-allele of rs2237892 was associated with higher LDL and total cholesterol levels (p = 0.015 and 0.003, respectively). We found no evidence for an association of KCNQ1 with diabetic complications. Conclusions: Common variants in the KCNQ1 gene are associated with type 2 diabetes in a Dutch population, which can be explained at least in part by an effect on insulin secretion. Furthermore, our data suggest that KCNQ1 is also associated with lipid metabolism