Endothelial Dysfunction in Youth-Onset Type 2 Diabetes: A Clinical Translational Study.

BACKGROUND: Youth-onset type 2 diabetes (Y-T2D) is associated with increased risk for coronary atherosclerotic disease, but the timing of the earliest pathological features and evidence of cardiac endothelial dysfunction have not been evaluated in this population. Magnetic resonance imaging functional imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using cardiac magnetic resonance imaging functional imaging, we evaluated peripheral and coronary endothelial artery structure and function in young adults with Y-T2D diagnosed ≤5 years compared with age-matched healthy peers. We isolated and characterized plasma-derived small extracellular vesicles and evaluated their effects on inflammatory and signaling biomarkers in healthy human coronary artery endothelial cells to validate the imaging findings. METHODS: Right coronary wall thickness, coronary artery flow-mediated dilation, and brachial artery flow-mediated dilation were measured at baseline and during isometric handgrip exercise using a 3.0T magnetic resonance imaging. Human coronary artery endothelial cells were treated with Y-T2D plasma-derived small extracellular vesicles. Protein expression was measured by Western blot analysis, oxidative stress was measured using the redox-sensitive probe dihydroethidium, and nitric oxide levels were measured by 4-amino-5-methylamino-2',7'-difluororescein diacetate. RESULTS: Y-T2D (n=20) had higher hemoglobin A1c and high-sensitivity C-reactive protein, but similar total and LDL (low-density lipoprotein)-cholesterol compared with healthy peers (n=16). Y-T2D had greater coronary wall thickness (1.33±0.13 versus 1.22±0.13 mm; P=0.04) and impaired endothelial function: coronary artery flow-mediated dilation (-3.1±15.5 versus 15.9±17.3%; P<0.01) and brachial artery flow-mediated dilation (6.7±14.7 versus 26.4±15.2%; P=0.001). Y-T2D plasma-derived small extracellular vesicles reduced phosphorylated endothelial nitric oxide synthase expression and nitric oxide levels, increased reactive oxygen species production, and elevated ICAM (intercellular adhesion molecule)-mediated inflammatory pathways in human coronary artery endothelial cells. CONCLUSIONS: Coronary and brachial endothelial dysfunction was evident in Y-T2D who were within 5 years of diagnosis and did not have severe hyperglycemia or dyslipidemia. Plasma-derived small extracellular vesicles induced markers of endothelial dysfunction, which corroborated accelerated subclinical coronary atherosclerosis as an early feature in Y-T2D. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02830308.

The role of HIV as a risk modifier for coronary endothelial function in young adults.

BACKGROUND: People living with HIV have an increased risk of cardiovascular disease (CVD). Although coronary endothelial function (CEF) is an early direct indicator of CVD, only a few studies have been able to interrogate CEF directly. Most studies have examined vascular endothelial function through indirect assessment of brachial flow-mediated dilatation (FMD). However, peripheral arteries are significantly larger and manifest atherogenesis differently from the coronary arteries, and so produce conflicting results. Additionally, none of these studies focused on young adults who acquired HIV perinatally or in early childhood. OBJECTIVE: The present study investigates CEF in a unique population of young adults with lifelong HIV using direct magnetic resonance imaging (MRI) of coronary FMD (corFMD) with an in-house developed MRI-integrated isometric handgrip exercise system with continuous feedback and monitoring mechanisms (fmIHE). METHODS: Young adults who acquired HIV perinatally or in early childhood (n = 23) and group-matched healthy participants (n = 12) completed corFMD-MRI with fmIHE. CorFMD was measured as the coronary cross-sectional area response to the fmIHE. RESULTS: In univariable and multivariable regression analysis, HIV status was a significant risk modifier. CD8+ T-cell count and smoking pack-years and their interaction with HIV status were independently associated with impaired coronary artery response to fmIHE. In people living with HIV, corFMD was significantly inversely correlated with CD8+ T-cells and smoking pack-years. In a multivariable regression analysis adjusted for age and body mass index, CD8+ T-cells and smoking and their interaction with HIV status remained significant independent predictors of coronary endothelial dysfunction. DISCUSSION: In this unique population of young adults, HIV status was a significant risk modifier, and immune activation and smoking were associated with decreased CEF, directly measured from the coronary vascular response to fmIHE. CONCLUSIONS: Management of CVD risk factors such as smoking and developing strategies that target immune activation in people living with HIV are warranted.

Triglyceride Paradox Is Related to Lipoprotein Size, Visceral Adiposity and Stearoyl-CoA Desaturase Activity in Black Versus White Women.

RATIONALE: In black women, triglycerides are paradoxically normal in the presence of insulin resistance. This relationship may be explained by race-related differences in central adiposity and SCD (stearoyl-CoA desaturase)-1 enzyme activity index. OBJECTIVE: In a cross-sectional study, to compare fasting and postprandial triglyceride-rich lipoprotein particle (TRLP) concentrations and size in black compared with white pre- and postmenopausal women and determine the relationship between TRLP subfractions and whole-body insulin sensitivity, hepatic and visceral fat, and SCD-1 levels. METHODS AND RESULTS: In 122 federally employed women without diabetes mellitus, 73 black (58 African American and 15 African immigrant) and 49 white; age, 44±10 (mean±SD) years; body mass index, 30.0±5.6 kg/m2, we measured lipoprotein subfractions using nuclear magnetic resonance. Hepatic fat was measured by proton magnetic resonance spectroscopy, insulin sensitivity index calculated by minimal modeling from a frequently sampled intravenous glucose test, and red blood cell fatty acid profiles were measured by gas chromatography and were used to estimate SCD-1 indices. Hepatic fat, insulin sensitivity index, and SCD-1 were similar in black women and lower than in whites, regardless of menopausal status. Fasting and postprandial large, medium, and small TRLPs, but not very small TRLPs, were lower in black women. Fasting large, medium, and very small TRLPs negatively correlated with insulin sensitivity index and positively correlated with visceral and hepatic fat and SCD-1 activity in both groups. In multivariate models, visceral fat and SCD-1 were associated with total fasting TRLP concentrations (adjR2, 0.39; P=0.001). Black women had smaller postprandial changes in large (P=0.005) and medium TRLPs (P=0.007). CONCLUSIONS: Lower visceral fat and SCD-1 activity may contribute to the paradoxical association of lower fasting and postprandial TRLP subfractions despite insulin resistance in black compared with white pre- and postmenopausal women. Similar concentrations of very small TRLPs are related to insulin resistance and could be important mediators of cardiometabolic disease risk in women. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01809288.

Proton MR Spectroscopy Measurements of White and Brown Adipose Tissue in Healthy Humans: Relaxation Parameters and Unsaturated Fatty Acids.

Background Activation of brown adipose tissue (BAT) in rodents increases lipolysis in white adipose tissue (WAT) and improves glucose tolerance. Adult humans can have metabolically active BAT. Implications for diabetes and obesity in humans require a better characterization of BAT in humans. Purpose To study fat depots with localized proton MR spectroscopy relaxometry and to identify differences between WAT and fluorine 18 fluorodeoxyglucose (FDG) PET/CT proven cold-activated BAT in humans. Materials and Methods Participants were consecutively enrolled in this prospective study (ClinicalTrials.gov identifiers: NCT01568671 and NCT01399385) from August 2016 to May 2019. Supraclavicular potential BAT regions were localized with MRI. Proton densities, T1, and T2 were measured with localized MR spectroscopy in potential BAT and in subcutaneous WAT. FDG PET/CT after cold stimulation was used to retrospectively identify active supraclavicular BAT or supraclavicular quiescent adipose tissue (QAT) regions. MR spectroscopy results from BAT and WAT were compared with grouped and paired tests. Results Of 21 healthy participants (mean age, 36 years ± 16 [standard deviation]; 13 men) FDG PET/CT showed active BAT in 24 MR spectroscopy-targeted regions in 16 participants (eight men). Four men had QAT. The T2 for methylene protons was shorter in BAT (mean, 69 msec ± 6, 24 regions) than in WAT (mean, 83 msec ± 3, 18 regions, P < .01) and QAT (mean, 78 msec ± 2, five regions, P < .01). A T2 cut-off value of 76 msec enabled the differentiation of BAT from WAT or QAT with a sensitivity of 85% and a specificity of 95%. Densities of protons adjacent and between double bonds were 33% and 24% lower, respectively, in BAT compared with those in WAT (P = .01 and P = .03, respectively), indicating a lower content of unsaturated and polyunsaturated fatty acids, respectively, in BAT compared with WAT. Conclusion Proton MR spectroscopy showed shorter T2 and lower unsaturated fatty acids in brown adipose tissue (BAT) than that in white adipose tissue in healthy humans. It was feasible to identify BAT with MR spectroscopy without the use of PET/CT or cold stimulation. © RSNA, 2021 See also the editorial by Barker in this issue. Online supplemental material is available for this article.

X-ray microtomosynthesis of unstained pathology tissue samples.

In pathology protocols, a tissue block, such as one containing a mouse brain or a biopsy sample from a patient, can produce several hundred thin sections. Substantial time may be required to analyse all sections. In cases of uncertainty regarding which sections to focus on, noninvasive scout imaging of intact blocks can help in guiding the pathology procedure. The scouting step is ideally done in a time window of minutes without special sample preparation that may interfere with the pathology procedures. The challenge is to obtain some visibility of unstained tissue structures at sub-10 µm resolution. We explored a novel x-ray tomosynthesis method as a way to maximise contrast-to-noise ratio, a determinant of tissue visibility. It provided a z-stack of thousands of images at 7.3 µm resolution (10% contrast, half-period of 68.5 line pairs/mm), in scans of 5-15 minutes. When compared with micro-CT scans, the straight-line tomosynthesis scan did not need to rotate the sample, which allowed flat samples, such as paraffin blocks, to be kept as close as possible to the x-ray source. Thus, given the same hardware, scan time and resolution, this mode maximised the photon flux density through the sample, which helped in maximising the contrast-to-noise ratio. The tradeoff of tomosynthesis is incomplete 3D information. The microtomosynthesis scanner has scanned 110 unstained human and animal tissue samples as part of their respective pathology protocols. In all cases, the z-stack of images showed tissue structures that guided sectioning or provided correlative structural information. We describe six examples that presented different levels of visibility of soft tissue structures. Additionally, in a set of coronary artery samples from an HIV patient donor, microtomosynthesis made a new discovery of isolated focal calcification in the internal elastic lamina of coronary wall, which was the onset of medial calcific sclerosis in the arteries.

A microscopy version of the imaging method for 3D luggage screening has been adapted to image unstained pathology samples. Pathology tests of tissue samples are used for clinical diagnosis and for biomedical research. The tissue samples are often embedded in paraffin blocks and sectioned into many thin slices, which are then stained with the appropriate agents for light microscopy. Since each tissue block can produce several hundred thin sections, much time and labour is required to analyse all sections. Noninvasive scout imaging of intact blocks can help in guiding the pathology procedure. The scouting step is ideally done in a time window of minutes without special sample preparation that may interfere with the pathology procedures. The challenge is to obtain some visibility of unstained tissue structures at sufficient resolution. X-ray imaging is a promising tool to meet the challenge since x-rays can penetrate thick samples that are opaque to visible light. With x-ray imaging, a determinant of tissue visibility is the flux density of photons that illuminate the sample. We explored a novel x-ray tomosynthesis method as a way to maximise this factor. It provided a stack of thousands of cross-sectional images at 7.3 µm resolution (half-period of 68.5 line pairs/mm) in scans of 5-15 minutes. When compared with micro-CT scans (a widely used laboratory technology), this method did not need to rotate the sample, which allowed flat samples such as paraffin blocks to be kept as close as possible to the x-ray source. Thus, given the same hardware, scan time and resolution, this method maximised the photon flux density through the sample, which helped in improving the visibility of unstained tissue under x-ray. The tradeoff of the method is incomplete 3D information. Over 100 unstained human and animal tissue samples have been scanned with this method as part of their respective pathology protocols. In all cases, the stack of cross-sectional images showed tissue structures that guided pathology analysis or provided correlative structural information. We describe six examples that presented different levels of tissue visibility. Additionally, in a set of coronary artery samples from an HIV patient donor, microtomosynthesis made a new discovery of isolated focal calcification in the internal elastic lamina of coronary wall, which was the onset of medial calcific sclerosis in the arteries.

Coronary calcification in adults with Turner syndrome.

PurposeAdults with Turner syndrome (TS) have an increased predisposition to ischemic heart disease. The quantitative relationship between coronary atherosclerosis and TS has yet to be established.MethodsA total of 128 females (62 with TS) participated in this prospective study. Coronary computed tomography angiography was performed to measure coronary calcified plaque burden, and prevalent noncalcified plaque burden. Regression analysis was used to study the effects of TS and traditional cardiovascular disease risk factors on coronary plaque burden.ResultsAdults with TS were 63% more likely to have coronary calcifications than controls (odds ratio 1.63, 95% confidence interval: 1.02, 2.61, P = 0.04), with an age cutoff of 51.7 years for a probability of >50% for the presence of coronary calcifications, when compared to 55.7 years in female controls. The average age of TS patients with calcified plaques was significantly lower than that of controls with calcified plaques (51.5 ± 8.9 years vs. 60.5 ± 7.0 years, P < 0.001). Age increased the likelihood of coronary calcifications by 13% per year (odds ratio 1.13, confidence interval 95%: 1.07-1.19, P < 0.001).ConclusionThis study demonstrates a higher prevalence and earlier onset of calcified coronary plaques in TS. These findings have important implications for cardiovascular risk assessment and the management of patients with TS.

How healthy are the "Healthy volunteers"? Penetrance of NAFLD in the biomedical research volunteer pool.

Healthy volunteers are crucial for biomedical research. Inadvertent inclusion of subjects with nonalcoholic fatty liver disease (NAFLD) as controls can compromise study validity and subject safety. Given the rising prevalence of NAFLD in the general population, we sought to identify its prevalence and potential impact in volunteers for clinical trials. We conducted a cross-sectional study of subjects who were classified as healthy volunteers between 2011 and 2015 and had no known liver disease. Subjects were classified as presumed NAFLD (pNF; alanine aminotransferase [ALT] level ≥ 20 for women or ≥ 31 for men and body mass index [BMI] > 25 kg/m2 ), healthy non-NAFLD controls (normal ALT and BMI), or indeterminate. A total of 3160 subjects participated as healthy volunteers in 149 clinical trials (1-29 trials per subject); 1732 of these subjects (55%) had a BMI > 25 kg/m2 and 1382 (44%) had abnormal ALT. pNF was present in 881 subjects (27.9%), and these subjects were older than healthy control subjects and had higher triglycerides, low-density lipoprotein cholesterol, and HbA1c and lower high-density lipoprotein cholesterol (P < 0.001 for all). The 149 trials included 101 non-interventional, 33 interventional, and 15 vaccine trials. The impact on study validity of recruiting NAFLD subjects as controls was estimated as likely, probable, and unlikely in 10, 41, and 98 trials, respectively. The proportion of pNF subjects (28%-29%) did not differ by impact. Only 14% of trials used both BMI and ALT for screening. ALT cutoffs for screening were based on local reference values. Grade 3-4 ALT elevations during the study period were rare but more common in pNF subjects than in healthy control subjects (4 versus 1). CONCLUSION: NAFLD is common and often overlooked in volunteers for clinical trials, despite its potential impact on subject safety and validity of study findings. Increased awareness of NAFLD prevalence and stricter ALT cutoffs may ameliorate this problem. (Hepatology 2017;66:825-833).

Rheological determinants for simultaneous staging of hepatic fibrosis and inflammation in patients with chronic liver disease.

The purpose of this study is to investigate the use of fundamental rheological parameters as quantified by MR elastography (MRE) to measure liver fibrosis and inflammation simultaneously in humans. MRE was performed on 45 patients at 3 T using a vibration frequency of 56 Hz. Fibrosis and inflammation scores were obtained from liver biopsies. Biomechanical properties were quantified in terms of complex shear modulus G* as well as shear wave phase velocity c and shear wave attenuation α. A rheological fractional derivative order model was used to investigate the linear dependence of the free model parameters (dispersion slope y, intrinsic speed c0 , and intrinsic relaxation time τ) on histopathology. Leave-one-out cross-validation was then utilized to demonstrate the effectiveness of the model. The intrinsic speed c0 increases with hepatic fibrosis, while an increased relaxation time τ is reflective of more inflammation of the liver parenchyma. The dispersion slope y does not depend either on fibrosis or on inflammation. The proposed rheological model, given this specific parameterization, establishes the functional dependences of biomechanical parameters on histological fibrosis and inflammation. The leave-one-out cross-validation demonstrates that the model allows identification, from the MRE measurements, of the histology scores when grouped into low-/high-grade fibrosis and low-/high-grade inflammation with significance levels of P = 0.0004 (fibrosis) and P = 0.035 (inflammation). The functional dependences of intrinsic speed and relaxation time on fibrosis and inflammation, respectively, shed new light onto the impact hepatic pathological changes on liver tissue biomechanics in humans. The dispersion slope y appears to represent a structural parameter of liver parenchyma not impacted by the severity of fibrosis/inflammation present in this patient cohort. This specific parametrization of the well-established rheological fractional order model is valuable for the clinical assessment of both fibrosis and inflammation scores, going beyond the capability of the plain shear modulus measurement commonly used for MRE.

Severe cardiac iron toxicity in two adults with sickle cell disease.

BACKGROUND: Use of chronic blood transfusions as a treatment modality in patients with blood disorders places them at risk for iron overload. Since patients with ß-thalassemia major (TM) are transfusion-dependent, most studies on iron overload and chelation have been conducted in this population. While available data suggest that compared to TM, patients with sickle cell disease (SCD) have a lower risk of extrahepatic iron overload, significant iron overload can develop. Further, previous studies have demonstrated a direct relationship between iron overload and morbidity and mortality rates in SCD. However, reports describing the outcome for patients with SCD and cardiac iron overload are rare. STUDY DESIGN AND METHODS: We performed a retrospective analysis and identified two SCD patients with cardiac iron overload. We provide detailed descriptions of both cases and their outcomes. RESULTS: Serum ferritin levels ranged between 17,000 and 19,000 µg/L. Both had liver iron concentrations in excess of 35 mg of iron per gram of dried tissue as well as evidence of cardiac iron deposition on magnetic resonance imaging. One patient died of an arrhythmia and had evidence of severe multiorgan iron overload via autopsy. On the other hand, after appropriate therapy, a second patient had improvement in cardiac function. CONCLUSION: Improper treatment of iron overload in SCD can lead to a fatal outcome. Alternatively, iron overload may potentially be prevented or reversed with judicious use of blood transfusions and early use of chelation therapy, respectively.

Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial.

BACKGROUND: Chronic liver injury can result in fibrosis that may progress over years to end-stage liver disease. The most effective anti-fibrotic therapy is treatment of the underlying disease, however when not possible, interventions to reverse or slow fibrosis progression are needed. AIM: The aim of this study was to study the safety and tolerability of simtuzumab, a monoclonal antibody directed against lysyl oxidase-like 2 (LOXL2) enzyme, in subjects with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or HCV-HIV co-infection and advanced liver disease. METHODS: Eighteen subjects with advanced liver fibrosis received simtuzumab 700 mg intravenously every 2 weeks for 22 weeks. Transjugular liver biopsies were performed during screening and at the end of treatment to measure hepatic venous pressure gradient (HVPG) and to stage fibrosis. RESULTS: Treatment was well-tolerated with no discontinuations due to adverse events. No significant changes were seen in HVPG or liver biopsy fibrosis score after treatment. Exploratory transcriptional and protein profiling using paired pre- and post-treatment liver biopsy and serum samples suggested up-regulation of TGF-ß3 and IL-10 pathways with treatment. CONCLUSION: In this open-label, pilot clinical trial, simtuzumab treatment was well-tolerated in HCV- and HIV-infected subjects with advanced liver disease. Putative modulation of TGF-ß3 and IL-10 pathways during simtuzumab treatment merits investigation in future trials.

Nonalcoholic Steatohepatitis and Hepatic Fibrosis in HIV-1-Monoinfected Adults With Elevated Aminotransferase Levels on Antiretroviral Therapy.

BACKGROUND: Persistent aminotransferase elevations are common in human immunodeficiency virus (HIV)-infected patients on antiretroviral therapy (ART), including those without hepatitis B or C coinfection, but their clinical significance is unknown. METHODS: HIV-infected adults with aminotransferase levels elevated above the upper limit of normal for ≥6 months while receiving ART, and without chronic viral hepatitis or other known causes of chronic liver disease, underwent a detailed metabolic assessment and liver biopsy. RESULTS: Sixty-two HIV-infected subjects completed the study. Forty (65%) had clinically significant liver pathology, including 34 (55%) with nonalcoholic steatohepatitis (NASH) and 11 (18%) with bridging fibrosis, 10 of whom also had NASH. Nonspecific abnormalities alone were seen in 22 (35%) subjects, including mild steatosis, mild to moderate inflammation, and evidence of drug adaptation. Insulin resistance, obesity, and the presence of either of 2 minor alleles in the PNPLA3 gene were significantly associated with increased risk of NASH and fibrosis. NASH and/or fibrosis were not associated with duration of HIV infection or ART, specific antiretroviral drugs, history of opportunistic infection, immune status, or duration of aminotransferase elevation. CONCLUSIONS: HIV-infected adults with chronic aminotransferase elevations while receiving ART have a high rate of liver disease. Noninvasive testing can help identify liver disease in such patients, but liver biopsy is necessary to definitively identify those at risk for liver disease progression and complications. Longitudinal follow-up of this cohort will better characterize the natural history of aminotransferase elevations in this population and identify noninvasive biomarkers of liver disease progression.

Assessment of liver fibrosis using fast strain-encoded MRI driven by inherent cardiac motion.

PURPOSE: An external driver-free MRI method for assessment of liver fibrosis offers a promising noninvasive tool for diagnosis and monitoring of liver disease. Lately, the heart's intrinsic motion and MR tagging have been utilized for the quantification of liver strain. However, MR tagging requires multiple breath-hold acquisitions and substantial postprocessing. In this study, we propose the use of a fast strain-encoded (FSENC) MRI method to measure the peak strain (Sp ) in the liver's left lobe, which is in close proximity and caudal to the heart. Additionally, we introduce a new method of measuring heart-induced shear wave velocity (SWV) inside the liver. METHODS: Phantom and in vivo experiments (11 healthy subjects and 11 patients with liver fibrosis) were conducted. Reproducibility experiments were performed in seven healthy subjects. RESULTS: Peak liver strain, Sp , decreased significantly in fibrotic liver compared with healthy liver (6.46% ± 2.27% vs 12.49% ± 1.76%; P < 0.05). Heart-induced SWV increased significantly in patients compared with healthy subjects (0.15 ± 0.04 m/s vs 0.63 ± 0.32 m/s; P < 0.05). Reproducibility analysis yielded no significant difference in Sp (P = 0.47) or SWV (P = 0.56). CONCLUSION: Accelerated external driver-free noninvasive assessment of left liver lobe strain and SWV is feasible using strain-encoded MRI. The two measures significantly separate healthy subjects from patients with fibrotic liver. Magn Reson Med 74:106-114, 2015. © 2014 Wiley Periodicals, Inc.

Increased coronary vessel wall thickness in HIV-infected young adults.

BACKGROUND: Individuals with long-term human immunodeficiency virus (HIV) infection are at risk for premature vasculopathy and cardiovascular disease (CVD). We evaluated coronary vessel wall thickening, coronary plaque, and epicardial fat in patients infected with HIV early in life compared with healthy controls. METHODS: This is a prospective cross-sectional study of 35 young adults who acquired HIV in early life and 11 healthy controls, free of CVD. Time resolved phase-sensitive dual inversion recovery black-blood vessel wall magnetic resonance imaging (TRAPD) was used to measure proximal right coronary artery (RCA) wall thickness, and multidetector computed tomography (CT) angiography was used to quantify coronary plaque and epicardial fat. RESULTS: RCA vessel wall thickness was significantly increased in HIV-infected patients compared with sex- and race-matched controls (1.32 ± 0.21 mm vs 1.09 ± 0.14 mm, P = .002). No subject had discrete plaque on CT sufficient to cause luminal narrowing, and plaque was not related to RCA wall thickness. In multivariate regression analyses, smoking pack-years (P = .004) and HIV infection (P = .007) were independently associated with thicker RCA vessel walls. Epicardial fat did not differ between groups. Among the HIV-infected group, duration of antiretroviral therapy (ART) (P = .02), duration of stavudine exposure (P < .01), low-density lipoprotein cholesterol (P = .04), and smoking pack-years (P < .01) were positively correlated with RCA wall thickness. CONCLUSIONS: This investigation provides evidence of subclinical coronary vascular disease among individuals infected with HIV in early life. Increased duration of ART, hyperlipidemia, and smoking contributed to proximal RCA thickening, independent of atherosclerotic plaque quantified by CT. These modifiable risk factors appear to influence early atherogenesis as measured by coronary wall thickness and may be important targets for CVD risk reduction.

X chromosome parental origin and aortic stiffness in turner syndrome.

INTRODUCTION: Aortic abnormalities contribute to increased morbidity and mortality of women with Turner syndrome (TS). Impaired aortic stiffness may prove to have clinical prognostic value in TS as is the case in other diseases such as Marfan syndrome, diabetes and hypertension. Additionally, the parental origin of the X chromosome in TS may influence aortic stiffness. OBJECTIVE: To assess the relation between X chromosome parental origin and aortic stiffness in TS patients. METHODS: Twenty-four subjects with TS participated in this cross-sectional study at a tertiary care centre. The parental origin of the X chromosome was determined. Cardiac-gated multidetector computerized tomography (MDCT) was performed and distensibility of the ascending aorta (AA), a measure of aortic stiffness, was calculated. RESULTS: Fourteen women were Xm (maternal origin) and 10 were Xp (paternal origin) for their inheritance of the single X chromosome. Age, body size, blood pressure and AA areas were similar in the two groups. However, the calculated AA distensibility was significantly lower in the Xm group (2·8 ± 1·1 mm/Hg) than in the Xp group (4·1 ± 1·5 mm/Hg); P < 0·05. Conclusion This study demonstrates that TS subjects that inherit their single X chromosome from their mother (Xm) have a significantly stiffer aorta compared with the TS with a paternally originating X chromosome (Xp), consistent with a potentially greater risk for cardiovascular complications. These findings suggest that parental chromosomal analysis and aortic stiffness measurements would be useful for the risk assessment and clinical management of TS patients.

Optimization of free-breathing whole-heart 3-dimensional cardiac magnetic resonance imaging at 3 tesla to identify coronary vein anatomy and to compare with multidetector computed tomography.

OBJECTIVE: This study optimizes use of 3-T magnetic resonance imaging (MRI) to delineate coronary venous anatomy and compares 3-T MRI with multidetector computed tomography (MDCT) measurements. METHODS: The study population included 37 consecutive subjects (22 men, 19-71 years old). Whole-heart contrast-enhanced MRI images at 3 T were acquired using segmented k-space gradient echo with inversion recovery prepared technique. The MDCT images were obtained using nonionic iodinated contrast. RESULTS: The coronary sinus and great cardiac, posterior interventricular, and anterior interventricular veins were visualized in 100% of cases by both MRI and MDCT. Detection of the posterior vein of the left ventricle and the left marginal vein by MRI was 97% and 81%, respectively. Bland-Altman plots showed agreement in ostial diameter measured by both modalities with correlation coefficients ranging from 0.5 to 0.76. Vein length and distances also agreed closely. CONCLUSIONS: Free-breathing whole-heart 3-dimensional MRI at 3 T provides high-spatial-resolution images and could offer an alternative imaging technique instead of MDCT scans.

Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome.

BACKGROUND: Mutations in signal transducer and activator of transcription (STAT) 1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles) to mild disseminated mycobacterial disease (hypomorphic alleles) to chronic mucocutaneous candidiasis (CMC; hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity, and squamous cell cancers. OBJECTIVE: We sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC. METHODS: We initially screened patients with CMC and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T (Treg) cells. After our initial case identifications, we explored 2 large cohorts of patients with wild-type forkhead box protein 3 and an immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX)-like phenotype for STAT1 mutations. RESULTS: We identified 5 children with polyendocrinopathy, enteropathy, and dermatitis reminiscent of IPEX syndrome; all but 1 had a variety of mucosal and disseminated fungal infections. All patients lacked forkhead box protein 3 mutations but had uniallelic STAT1 mutations (c.629 G>T, p.R210I; c.1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M [2 patients]). STAT1 phosphorylation in response to IFN-γ, IL-6, and IL-21 was increased and prolonged. CD4(+) IL-17-producing T-cell numbers were diminished. All patients had normal Treg cell percentages in the CD4(+) T-cell compartment, and their function was intact in the 2 patients tested. Patients with cells available for study had normal levels of IL-2-induced STAT5 phosphorylation. CONCLUSIONS: Gain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells.

Association of Coronary Wall Thickening and Diminished Diastolic Function in Asymptomatic, Low Cardiovascular Disease-Risk Persons Living with HIV.

Purpose To assess early subclinical coronary artery disease (CAD) burden and its relation to myocardial function in asymptomatic persons living with HIV (PLWH) who are at low risk for cardiovascular disease (CVD). Materials and Methods In this prospective, HIPAA-compliant study (ClinicalTrials.gov NCT01656564 and NCT01399385) conducted from April 2010 to May 2013, 74 adult PLWH without known CVD and 25 matched healthy controls underwent coronary MRI to measure coronary vessel wall thickness (VWT) and echocardiography to assess left ventricular function. Univariable and multivariable linear regression analyses were used to evaluate statistical associations. Results For PLWH, the mean age was 49 years ± 11 (SD), and the median Framingham risk score was 3.2 (IQR, 0.5-6.6); for matched healthy controls, the mean age was 46 years ± 8 and Framingham risk score was 2.3 (IQR, 0.6-6.1). PLWH demonstrated significantly greater coronary artery VWT than did controls (1.47 mm ± 0.22 vs 1.34 mm ± 0.18; P = .006) and a higher left ventricular mass index (LVMI) (77 ± 16 vs 70 ± 13; P = .04). Compared with controls, PLWH showed altered association between coronary artery VWT and both E/A (ratio of left ventricular-filling peak blood flow velocity in early diastole [E wave] to that in late diastole [A wave]) (P = .03) and LVMI (P = .04). In the PLWH subgroup analysis, coronary artery VWT increase was associated with lower E/A (P < .001) and higher LVMI (P = .03), indicating restricted diastolic function. In addition, didanosine exposure was associated with increased coronary artery VWT and decreased E/A ratio. Conclusion Asymptomatic low-CVD-risk PLWH demonstrated increased coronary artery VWT in association with impaired diastolic function, which may be amenable to follow-up studies of coronary pathogenesis to identify potential effects on the myocardium and risk modification strategies. Keywords: Coronary Vessel Wall Thickness, Diastolic Function, HIV, MRI, Echocardiography, Atherosclerosis Clinical trial registration nos. NCT01656564 and NCT01399385 Supplemental material is available for this article. © RSNA, 2024.

Pulmonary vein morphology by free-breathing whole heart magnetic resonance imaging at 3 Tesla versus breathhold multi-detector computed tomography.

PURPOSE: To compare pulmonary vein and left atrial anatomy using three-dimensional free-breathing whole-heart magnetic resonance imaging (MR) at 3 Tesla (T) and multi-detector computed tomography (MDCT). MATERIALS AND METHODS: Thirty-three subjects (19 male, age 49 ± 12 years) underwent free-breathing 3T MR and contrast-enhanced MDCT during inspiratory breath hold. Pulmonary vein parameters (ostial areas, diameters, angles) were measured. RESULTS: All pulmonary veins and anomalies were identified by 3T MR and by MDCT. The right-sided pulmonary veins were directed more posteriorly, the right superior pulmonary vein more inferiorly, and the right inferior pulmonary vein more superiorly by 3T MR when compared with MDCT. The cross-sectional area, perimeters and minimum diameters of right-sided pulmonary vein ostia were significantly larger by MR, as were the maximum diameters of right and left inferior pulmonary veins. There were no significant differences between techniques in distance to first pulmonary vein branch. CONCLUSION: Pulmonary vein measurements demonstrated significant differences in angulations and dimensions when 3T MR is compared with MDCT. These differences likely represent hemodynamic and respiratory variation during free-breathing with MR versus breath-holding with MDCT. MR imaging at 3T during free-breathing offers an alternate method to define pulmonary vein and left atrial anatomy without exposure to radiation.

Computer-Based Simulators in Pharmacy Practice Education: A Systematic Narrative Review.

Computer-based simulations may represent an innovative, flexible, and cost-efficient training approach that has been underutilised in pharmacy practice education. This may need to change, with increasing pressure on clinical placement availability, COVID-19 restrictions, and economic pressures to improve teaching efficiency. This systematic narrative review summarises various computer-based simulations described in the pharmacy practice education literature, identifies the currently available products, and highlights key characteristics. Five major databases were searched (Medline, CINAHL, ERIC, Education Source and Embase). Authors also manually reviewed the publication section of major pharmacy simulator websites and performed a citation analysis. We identified 49 studies describing 29 unique simulators, which met the inclusion criteria. Only eight of these simulators were found to be currently available. The characteristics of these eight simulators were examined through the lens of eight main criteria (feedback type, grading, user play mode, cost, operational requirement, community/hospital setting, scenario sharing option, and interaction elements). Although a number of systems have been developed and trialled, relatively few are available on the market, and each comes with benefits and drawbacks. Educators are encouraged to consider their own institutional, professional and curriculum needs, and determine which product best aligns with their teaching goals.