A comparison of bolus track and test bolus computed tomography pulmonary angiography and the implications on pulmonary and aortic vessel enhancement, effective dose and suboptimal scan rate.

INTRODUCTION: Bolus track and test bolus are the most commonly used contrast timing protocols to undertake computed tomography pulmonary angiography (CTPA). The aim of this study was to compare test bolus and bolus track contrast enhancement protocols in terms of enhancement of the pulmonary vessels and aorta, radiation dose and suboptimal scan rate to determine the optimal technique for CTPA. METHODS: A total of 200 CTPA examinations (100 using each protocol) performed between January and February 2021 were assessed retrospectively. All scans were performed on a 2x128 Dual Source Siemens Drive Scanner. CT attenuation was measured in Hounsfield Units (HU), with measurements taken from the main pulmonary trunk, right pulmonary artery and left pulmonary artery, ascending and descending aorta. The mean effective dose was calculated from the dose-length product (DLP). The suboptimal scan rate was calculated as the percentage of examinations below 210HU. RESULTS: The average HU of the pulmonary arteries was 358 HU ± SD 129.2 in the test bolus group and increased to 394 HU ± SD 133.9 in the bolus track group with a P value of ≤0.05. The average HU of the aorta was 235 HU ± SD 82.8 in the test bolus group and increased to 319 HU ± SD 91.8 in the bolus track group with a P value of <0.001. Although not statistically significant, the mean effective dose was reduced by 4.2% for the bolus track protocol (2.4 mSv vs. 2.5 mSv, P > 0.05). Fewer suboptimal scans were performed with the bolus track protocol (5 scans <210HU Bolus Track vs. 9 scans <210HU Test Bolus). CONCLUSION: The bolus track protocol results in increased enhancement of the pulmonary arteries and aorta, with the added benefits of a lower suboptimal scan rate and lower effective dose.

Data-Driven Dietary Patterns, Nutrient Intake and Body Weight Status in a Cross-Section of Singaporean Children Aged 6-12 Years.

Pattern analysis of children's diet may provide insights into chronic disease risk in adolescence and adulthood. This study aimed to assess dietary patterns of young Singaporean children using cluster analysis. An existing dataset included 15,820 items consumed by 561 participants (aged 6-12 years) over 2 days of dietary recall. Thirty-seven food groups were defined and expressed as a percentage contribution of total energy. Dietary patterns were identified using k-means cluster analysis. Three clusters were identified, "Western", "Convenience" and "Local/hawker", none of which were defined by more prudent dietary choices. The "Convenience" cluster group had the lowest total energy intake (mean 85.8 ± SD 25.3% of Average Requirement for Energy) compared to the other groups (95.4 ± 25.9% for "Western" and 93.4 ± 25.3% for "Local/hawker", p < 0.001) but also had the lowest calcium intake (66.3 ± 34.7% of Recommended Dietary Allowance), similar to intake in the "Local/hawker" group (69.5 ± 38.9%) but less than the "Western" group (82.8 ± 36.1%, p < 0.001). These findings highlight the need for longitudinal analysis of dietary habit in younger Singaporeans in order to better define public health messaging targeted at reducing risk of major noncommunicable disease.

Dietary substitution of SFA with MUFA within high-fat diets attenuates hyperinsulinaemia and pancreatic islet dysfunction.

Preliminary evidence has suggested that high-fat diets (HFD) enriched with SFA, but not MUFA, promote hyperinsulinaemia and pancreatic hypertrophy with insulin resistance. The objective of this study was to determine whether the substitution of dietary MUFA within a HFD could attenuate the progression of pancreatic islet dysfunction seen with prolonged SFA-HFD. For 32 weeks, C57BL/6J mice were fed either: (1) low-fat diet, (2) SFA-HFD or (3) SFA-HFD for 16 weeks, then switched to MUFA-HFD for 16 weeks (SFA-to-MUFA-HFD). Fasting insulin was assessed throughout the study; islets were isolated following the intervention. Substituting SFA with MUFA-HFD prevented the progression of hyperinsulinaemia observed in SFA-HFD mice (P < 0·001). Glucose-stimulated insulin secretion from isolated islets was reduced by SFA-HFD, yet not fully affected by SFA-to-MUFA-HFD. Markers of ß-cell identity (Ins2, Nkx6.1, Ngn3, Rfx6, Pdx1 and Pax6) were reduced, and islet inflammation was increased (IL-1ß, 3·0-fold, P = 0·007; CD68, 2·9-fold, P = 0·001; Il-6, 1·1-fold, P = 0·437) in SFA-HFD - effects not seen with SFA-to-MUFA-HFD. Switching to MUFA-HFD can partly attenuate the progression of SFA-HFD-induced hyperinsulinaemia, pancreatic inflammation and impairments in ß-cell function. While further work is required from a mechanistic perspective, dietary fat may mediate its effect in an IL-1ß-AMP-activated protein kinase α1-dependent fashion. Future work should assess the potential translation of the modulation of metabolic inflammation in man.

Potential Interplay between Dietary Saturated Fats and Genetic Variants of the NLRP3 Inflammasome to Modulate Insulin Resistance and Diabetes Risk: Insights from a Meta-Analysis of 19 005 Individuals.

SCOPE: Insulin resistance (IR) and inflammation are hallmarks of type 2 diabetes (T2D). The nod-like receptor pyrin domain containing-3 (NLRP3) inflammasome is a metabolic sensor activated by saturated fatty acids (SFA) initiating IL-1ß inflammation and IR. Interactions between SFA intake and NLRP3-related genetic variants may alter T2D risk factors. METHODS: Meta-analyses of six Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 19 005) tested interactions between SFA and NLRP3-related single-nucleotide polymorphisms (SNPs) and modulation of fasting insulin, fasting glucose, and homeostasis model assessment of insulin resistance. RESULTS: SFA interacted with rs12143966, wherein each 1% increase in SFA intake increased insulin by 0.0063 IU mL-1 (SE ± 0.002, p = 0.001) per each major (G) allele copy. rs4925663, interacted with SFA (ß ± SE = -0.0058 ± 0.002, p = 0.004) to increase insulin by 0.0058 IU mL-1 , per additional copy of the major (C) allele. Both associations are close to the significance threshold (p < 0.0001). rs4925663 causes a missense mutation affecting NLRP3 expression. CONCLUSION: Two NLRP3-related SNPs showed potential interaction with SFA to modulate fasting insulin. Greater dietary SFA intake accentuates T2D risk, which, subject to functional validation, may be further elaborated depending on NLRP3-related genetic variants.

Weighted Gene Co-Expression Network Analysis Identifies Gender Specific Modules and Hub Genes Related to Metabolism and Inflammation in Response to an Acute Lipid Challenge.

SCOPE: Inflammation is characteristic of diet-related diseases including obesity and type 2 diabetes (T2D). However, biomarkers of inflammation that reflect the early stage metabolic derangements are not optimally sensitive. Lipid challenges elicit postprandial inflammatory and metabolic responses. Gender-specific transcriptomic networks of the peripheral blood mononuclear cell (PBMC) were constructed in response to a lipid challenge. METHODS AND RESULTS: Eighty-six adult males and females of comparable age, anthropometric, and biochemical profiles completed an oral lipid tolerance test (OLTT). PBMC transcriptome was profiled following OLTT. Weighted gene coexpression networks were constructed separately for males and females. Functional ontology analysis of network modules was performed and hub genes identified. Two modules of interest were identified in females-an "inflammatory" module and an "energy metabolism" module. NLRP3, which plays a central role in inflammation and STARD3 that is involved in cholesterol metabolism, were identified as hub genes for the respective modules. CONCLUSION: The OLTT induced some gender-specific correlations of gene coexpression network modules. In females, biological processes relating to energy metabolism and inflammation pathways were evident. This suggests a gender specific link between inflammation and energy metabolism in response to lipids. In contrast, G-protein coupled receptor protein signaling pathway was common to both genders.

Intermittent hypoxia in obstructive sleep apnoea mediates insulin resistance through adipose tissue inflammation.

Obstructive sleep apnoea (OSA) is increasingly associated with insulin resistance. The underlying pathophysiology remains unclear but intermittent hypoxia (IH)-mediated inflammation and subsequent dysfunction of the adipose tissue has been hypothesised to play a key role.We tested this hypothesis employing a comprehensive translational approach using a murine IH model of lean and diet-induced obese mice, an innovative IH system for cell cultures and a tightly controlled patient cohort.IH led to the development of insulin resistance in mice, corrected for the degree of obesity, and reduced insulin-mediated glucose uptake in 3T3-L1 adipocytes, associated with inhibition of the insulin-signalling pathway and downregulation of insulin-receptor substrate-1 mRNA. Providing mechanistic insight, IH induced a pro-inflammatory phenotype of visceral adipose tissue in mice with pro-inflammatory M1 macrophage polarisation correlating with the severity of insulin resistance. Complimentary in vitro analysis demonstrated that IH led to M1 polarisation of THP1-derived macrophages. In subjects without comorbidities (n=186), OSA was independently associated with insulin resistance. Furthermore, we found an independent correlation of OSA severity with the M1 macrophage inflammatory marker sCD163.This study provides evidence that IH induces a pro-inflammatory phenotype of the adipose tissue, which may be a crucial link between OSA and the development of insulin resistance.

High-Density Lipoprotein Proteomic Composition, and not Efflux Capacity, Reflects Differential Modulation of Reverse Cholesterol Transport by Saturated and Monounsaturated Fat Diets.

BACKGROUND: Acute inflammation impairs reverse cholesterol transport (RCT) and reduces high-density lipoprotein (HDL) function in vivo. This study hypothesized that obesity-induced inflammation impedes RCT and alters HDL composition, and investigated if dietary replacement of saturated (SFA) for monounsaturated (MUFA) fatty acids modulates RCT. METHODS AND RESULTS: Macrophage-to-feces RCT, HDL efflux capacity, and HDL proteomic profiling was determined in C57BL/6j mice following 24 weeks on SFA- or MUFA-enriched high-fat diets (HFDs) or low-fat diet. The impact of dietary SFA consumption and insulin resistance on HDL efflux function was also assessed in humans. Both HFDs increased plasma (3)H-cholesterol counts during RCT in vivo and ATP-binding cassette, subfamily A, member 1-independent efflux to plasma ex vivo, effects that were attributable to elevated HDL cholesterol. By contrast, ATP-binding cassette, subfamily A, member 1-dependent efflux was reduced after both HFDs, an effect that was also observed with insulin resistance and high SFA consumption in humans. SFA-HFD impaired liver-to-feces RCT, increased hepatic inflammation, and reduced ABC subfamily G member 5/8 and ABC subfamily B member 11 transporter expression in comparison with low-fat diet, whereas liver-to-feces RCT was preserved after MUFA-HFD. HDL particles were enriched with acute-phase proteins (serum amyloid A, haptoglobin, and hemopexin) and depleted of paraoxonase-1 after SFA-HFD in comparison with MUFA-HFD. CONCLUSIONS: Ex vivo efflux assays validated increased macrophage-to-plasma RCT in vivo after both HFDs but failed to capture differential modulation of hepatic cholesterol trafficking. By contrast, proteomics revealed the association of hepatic-derived inflammatory proteins on HDL after SFA-HFD in comparison with MUFA-HFD, which reflected differential hepatic cholesterol trafficking between groups. Acute-phase protein levels on HDL may serve as novel biomarkers of impaired liver-to-feces RCT in vivo.

Monounsaturated fatty acid-enriched high-fat diets impede adipose NLRP3 inflammasome-mediated IL-1ß secretion and insulin resistance despite obesity.

Saturated fatty acid (SFA) high-fat diets (HFDs) enhance interleukin (IL)-1ß-mediated adipose inflammation and insulin resistance. However, the mechanisms by which different fatty acids regulate IL-1ß and the subsequent effects on adipose tissue biology and insulin sensitivity in vivo remain elusive. We hypothesized that the replacement of SFA for monounsaturated fatty acid (MUFA) in HFDs would reduce pro-IL-1ß priming in adipose tissue and attenuate insulin resistance via MUFA-driven AMPK activation. MUFA-HFD-fed mice displayed improved insulin sensitivity coincident with reduced pro-IL-1ß priming, attenuated adipose IL-1ß secretion, and sustained adipose AMPK activation compared with SFA-HFD-fed mice. Furthermore, MUFA-HFD-fed mice displayed hyperplastic adipose tissue, with enhanced adipogenic potential of the stromal vascular fraction and improved insulin sensitivity. In vitro, we demonstrated that the MUFA oleic acid can impede ATP-induced IL-1ß secretion from lipopolysaccharide- and SFA-primed cells in an AMPK-dependent manner. Conversely, in a regression study, switching from SFA- to MUFA-HFD failed to reverse insulin resistance but improved fasting plasma insulin levels. In humans, high-SFA consumers, but not high-MUFA consumers, displayed reduced insulin sensitivity with elevated pycard-1 and caspase-1 expression in adipose tissue. These novel findings suggest that dietary MUFA can attenuate IL-1ß-mediated insulin resistance and adipose dysfunction despite obesity via the preservation of AMPK activity.

Interactions between differential fatty acids and inflammatory stressors-impact on metabolic health.

Current interest in obesity has established a clear link between diets high in fat and metabolic complications such as Type 2 Diabetes. Dietary fats and their metabolites act as stressors to induce a pro-inflammatory immune response which dysregulates many essential metabolic functions. Recent research suggests that different dietary fats may have varying inflammatory potentials. However the molecular mechanisms involved in the cross talk between dietary fat composition and the 'immuno-metabolism' remain enigmatic. It is probable that lipids, and their derivatives, differentially regulate IL-1ß activation and inflammatory signaling via the NLRP3 inflammasome complex. Also from the translational perspective, certain nutrient sensitive genotypes and potential gene nutrient interactions offer the possibility to reduce inflammation through personalized nutrition approaches.

Improving comprehension in adolescents with severe receptive language impairments: a randomized control trial of intervention for coordinating conjunctions.

BACKGROUND: Little evidence exists for the effectiveness of therapy for children with receptive language difficulties, particularly those whose difficulties are severe and persistent. AIMS: To establish the effectiveness of explicit speech and language therapy with visual support for secondary school-aged children with language impairments focusing on comprehension of coordinating conjunctions in a randomized control trial with an assessor blind to group status. METHODS & PROCEDURES: Fourteen participants (aged 11;3-16;1) with severe RELI (mean standard scores: CELF4 ELS = 48, CELF4 RLS = 53 and TROG-2 = 57), but higher non-verbal (Matrices = 83) and visual perceptual skills (Test of Visual Perceptual Skills (TVPS) = 86) were randomly assigned to two groups: therapy versus waiting controls. In Phase 1, the therapy group received eight 30-min individual sessions of explicit teaching with visual support (Shape Coding) with their usual SLT. In Phase 2, the waiting controls received the same therapy. The participants' comprehension was tested pre-, post-Phase 1 and post-Phase 2 therapy on (1) a specific test of the targeted conjunctions, (2) the TROG-2 and (3) a test of passives. OUTCOMES & RESULTS: After Phase 1, the therapy group showed significantly more progress than the waiting controls on the targeted conjunctions (d = 1.6) and overall TROG-2 standard score (d = 1.4). The two groups did not differ on the passives test. After Phase 2, the waiting controls made similar progress to those in the original therapy group, who maintained their previous progress. Neither group showed progress on passives. When the two groups were combined, significant progress was found on the specific conjunctions (d = 1.3) and TROG-2 raw (d = 1.1) and standard scores (d = 0.9). Correlations showed no measures taken (including Matrices and TVPS) correlated significantly with progress on the targeted conjunctions or the TROG-2. CONCLUSIONS & IMPLICATIONS: Four hours of Shape Coding therapy led to significant gains on comprehension of coordinating conjunctions which were maintained after 4 months. Given the significant progress at a group level and the lack of reliable predictors of progress, this approach could be offered to other children with similar difficulties to the participants. However, the intervention was delivered one-to-one by speech and language therapists, thus the effectiveness of this therapy method with other methods of delivery remains to be evaluated.

A retrospective analysis of the use of C-reactive protein assays in the management of acute medical admissions.

AIMS: In this study, we analysed the frequency of C-reactive protein (CRP) use in the management of acute medical admissions, the clinical reasoning behind it, and its contribution (if any) to clinical management. Our aim was to gauge the current clinical criteria used for the ordering of CRP. METHODS: We performed a retrospective analysis of a representative sample of 171 patients who had C-reactive protein assays ordered. We compiled criteria whereby each order could be deemed either clinically indicated or inappropriate. RESULTS: In these patients, 264 orders for CRP were made. Of these 133 (50.38%) were deemed inappropriate to the clinical scenario. The reasons for the order being inappropriate were: clinically obvious infections where the result made no difference to treatment choice (47.37%); serial measurements in patients who were clinically improving (33.58%); and CRP measurements in patients presenting with symptoms unlikely due to an infective or inflammatory processes (19.55%). CONCLUSION: 50.38% of C-reactive protein assays ordered in this study were clinically unnecessary, representing not only poor clinical judgement but also poor use of laboratory time and expenditure.