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Ijeoma M Muo,1 Sandra D MacDonald,2 Ritu Madan,3 Sung-Jun Park,1 Ahmed M Gharib,4 Pedro E. Martinez,5 Mary F Walter,3 Shanna B Yang,6 Justin A Rodante,7 Amber B Courville,6 Peter J Walter,8 Hongyi Cai,8 Michael Glicksman,3 Gioia M Guerrieri,5 Rivka R Ben-Dor,9 Ronald Ouwerkerk,4 Stephanie Mao,1 Jay H Chung1 1Laboratory of Obesity and Aging Research NHLBI, National Institutes of Health, Bethesda, MD 20892, USA; 2NHLBI Pulmonary Branch, Laboratory of Chronic Airway Infections, National Institutes of Health, Bethesda, MD 20892, USA; 3Diabetes Endocrinology and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA; 4Biomedical and Metabolic Imaging Branch NIDDK, National Institutes of Health, Bethesda, MD 20892, USA; 5Section on Behavioral Endocrinology, NIMH, National Institutes of Health, Bethesda, MD 20892, USA; 6Clinical Center Nutrition Department, National Institutes of Health, Bethesda, MD 20892, USA; 7Laboratory of Inflammation and Cardiometabolic Diseases, NHLBI, National Institutes of Health, Bethesda, MD 20892, USA; 8Mass Spectrometry Clinical Core, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA; 9NIMH, National Institutes of Health, Bethesda, MD 20892, USA Purpose: Roflumilast (Daliresp, Daxas) is a FDA-approved phosphodiesterase 4 (PDE4) inhibitor for the treatment of moderate-to-severe chronic obstructive pulmonary disease. In mice and in limited human studies, this oral medication can cause weight loss and improve insulin sensitivity. We set out to determine the mechanism of its effect on insulin sensitivity. Patients and methods: Eight adults with overweight/obesity and prediabetes received roflumilast for 6 weeks. Before and after roflumilast, subjects underwent tests of insulin sensitivity, mixed meal test, body composition, markers of inflammation, and mitochondria function. Dietary intake and physical activity were also assessed. Our primary outcome was the change in peripheral insulin sensitivity, as assessed by the hyper-insulinemic euglycemic clamp. Results: This study was underpowered for the primary outcome. Pre- and post-roflumilast mean peripheral insulin sensitivity were 48.7 and 70.0 mg/g fat free mass/minute, respectively, (P-value=0.18), respectively. Among the mixed meal variables, roflumilast altered glucagon-like peptide 1 (GLP-1) hormone the most, although the average effect was not statistically significant (P=0.18). Roflumilast induced a trend toward significance in 1) decreased energy intake (from 11,095 KJ to 8,4555 KJ, P=0.07), 2) decreased fat mass (from 34.53 to 32.97 kg, P=0.06), 3) decreased total and LDL cholesterol (P=0.06 for both variables), and 4) increased plasma free fatty acids (from 0.40 to 0.50 mEq/L, P=0.09) The interval changes in adiposity and free fatty acid were significantly associated with the subject’s age (P-value range=

An ethnomedicinal expedition was conducted to collect and record indigenous knowledge about the use of medicinal plants by local inhabitants of four villages (Chittra, Topi, Pandi, and Kalri) of district Bagh, Azad Jammu and Kashmir. Ethnomedicinal data were obtained from 60 randomly selected local inhabitants of the study area through semi-structured questionnaires and interviews. These data were analyzed quantitatively through different ethnobotanical indices including family importance value, relative frequency of citation, use value (UV), fidelity level (FL), informant consensus factor (ICF), and Jaccard index (JI). our study reported 69 medicinal plants belonging to 39 families. Rosaceae (9 species) was a dominant family of the study area. Herb (54.83%) was dominant growth form of plants used for medicinal purpose. Leaves contributed maximum usage (44.29%) for curing diseases. Decoction (23 records) was most used mode of utilization. Relative frequency of citation and UV ranged from 0.03–0.85 and 0.05–1.17, respectively. There were 4 plant species with 100% FL. Highest ICF (0.88%) was found for gastrointestinal diseases. By comparing results with previous study, JI ranged from 0.54 to 24.43%. Our results found that there were 18 plant species not reported with ethnomedicinal aspect in previous studies from district Bagh region. The research of this study concludes that the area is rich with medicinal plants and the local inhabitant of this area still prefer medicinal plants over allopathic medicines for treating different ailments. Comparative analysis has shown some novel uses of plant species which may be due to cultural differences of the study area. However, awareness and pharmacological study are needed to conserve and unveil pharmaceutically important plants.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Albuminuria is the most sensitive marker for the early recognition of DN. Therefore, we aimed to study the risk factors of albuminuria as a marker of DN among diabetic patients. The study included 41 patients with type 2 diabetes mellitus (T2DM), 50 type 2 diabetic nephropathy (T2DN) patients with macroalbuminuria, 43 T2DN patients with microalbuminuria and 38 healthy controls. Logistic regression was used to detect the most significant risk factors for albuminuria. A high statistically significant difference was found between the groups regarding age, sex, body mass index (BMI), diabetes mellitus (DM) duration, glucose, glycated haemoglobin (HbA1c), creatinine, glomerular filtration rate (GFR), lipid profile, tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), the albumin–creatinine ratio (ACR), vitamin D, total parathyroid hormone (PTH), urea, total calcium and chemerin (p < 0.001). It was found that the duration of DM, BMI, glucose, GFR, total cholesterol (TC), low-density lipoprotein (LDL), TNF-α, IL-6, CRP, ACR, vitamin D, PTH and chemerin are significant albuminuria risk factors in DN. Vitamin D deficiency and associated inflammatory mediators such as chemerin, TNF-α, IL-6 and CRP are the most essential risk factors for albuminuria in T2DM patients.

Abstract Background The ideal screening test would be capable of identifying iron deficiency in the absence of anemia. We tried to detect role of urinary hepcidin-25 level in early prediction of iron deficiency in children. Methods This is a case control study performed on 100 children in Hematology Unit of Pediatric Department, Zagazig University Hospital, Egypt. Our study included 25 cases of iron deficiency (ID) stage-1 (iron depletion), 25 cases ID stage-2 (iron-deficient erythropoiesis), 25 cases ID stage-3 (iron deficiency anemia) and 25 healthy children as a control group. Estimation of iron status parameters was done. Urinary hepcidin-25 level was detected. Results Urinary hepcidin-25 level was significantly lower in all stages of iron deficiency than in control group, more significant reduction in its level was observed with the progress in severity of iron deficiency. Urinary hepcidin showed significant positive correlation with hemoglobin, mean corpuscular volume, hematocrit value, serum iron and ferritin and transferrin saturation. In contrary, it showed significant negative correlation with serum transferrin and total iron binding capacity. Urinary hepcidin at cutoff point ≤0.94 nmol/mmol Cr could Predict ID stage-1 with sensitivity 88% and specificity 88%. Cutoff point ≤0.42 nmol/mmol Cr could predict ID stage-2 with sensitivity 96% and specificity 92%. Cutoff point ≤0.08 nmol/mmol Cr could Predict ID stage-3 with Sensitivity 96% and specificity 100%. Conclusions We can conclude that detection of urinary hepcidin-25 level was a simple and non invasive test and could predict iron deficiency very early, before appearance of hematological affections.

Abstract Background Recently, hepcidin expression in adipose tissue has been described and shown to be increased in patients with severe obesity. We tried to assess the effect of obesity on hepcidin serum levels and treatment outcome of iron deficiency anemia in children. Methods This was a case control study included 70 children with iron deficiency anemia "IDA" (35 obese and 35 non-obese) and 30 healthy non-obese children with comparable age and sex(control group). Parameters of iron status (Serum iron, ferritin, transferrin, total iron binding capacity and transferrin saturation) and serum hepcidin levels were assessed initially and after 3 months of oral iron therapy for IDA. Results Compared to the control group, serum hepcidin was significantly lower in non-obese children with IDA(p < 0.01) and significantly higher in obese children with IDA (p < 0.01). Hepcidin increased significantly in non-obese children with IDA after 3 months of iron therapy (P < 0.01). On the other hand, obese children showed non-significant change in hepcidin level after iron therapy (p > 0.05). Although hepcidin showed significant positive correlations with Hb, serum iron and transferrin saturation in non-obese children with IDA, it showed significant negative correlations with Hb, serum iron and transferrin saturation in obese children with IDA (P < 0.05). Conclusions Obesity increased hepcidin levels and was associated with diminished response to oral iron therapy in childhood iron deficiency anemia.

Background: : Increasing student numbers and logistical challenges in pharmacy education limit patient counselling and clinical placement opportunities. Computer-based simulation (CBS) offers scalable, interactive learning but faces integration barriers., Objective: : To explore global perceptions of CBS implementation in pharmacy education among educators and students. Methods: An online cross-sectional survey was developed based on literature review and expert feedback. The survey was distributed globally through academic pharmacy organisations, social media, and the authors' networks. It included 20 questions targeting pharmacy educators and students., Results: : Responses from 152 educators across 38 countries and 392 students from 46 countries, spanning six WHO regions (AFRO, AMRO, EMRO, EURO, SEARO, and WPRO) were analysed using descriptive and inferential statistics. The majority of educators (90.1%, n = 137) and students (84.2%, n = 330) expressed comfort with using CBS and implementing it in their curriculum. Despite this, CBS was perceived as underutilised by 53.5% (n = 81) of educators and 63.7% (n = 250) of students. Students valued CBS for enhancing communication and problem-solving skills, while educators highlighted its relevance to community pharmacy practice. Both groups supported CBS use in assessments. All educators (100%) identified workload reduction as a key priority, hoped CBS could assist in this area. Educators also reported barriers such as financial constraints (56.6%, n = 86) and insufficient technical support (53.3%, n = 81). On the other hand, students were less optimistic about institutional support, with only a few (7.4%, n = 29) believed institutional leaders would actively support CBS adoption. Regional differences emerged, with SEARO (Southeast Asia) and AFRO (Africa) showing the lowest CBS usage rates. Educators in SEARO, AFRO, and EMRO (Eastern Mediterranean) raised concerns about technical support, while those in SEARO, AFRO, and WPRO (Western Pacific, including Australia, New Zealand, and Singapore) expressed financial concerns. Educators in AFRO and WPRO, however, reported being 100% comfortable with using CBS., Conclusion: : Both students and educators recognised the potential of CBS in pharmacy education, with strong support for its integration. Addressing barriers such as educator workload, financial constraints, and technical support is crucial for broader adoption. Improved resource allocation and targeted training for educators are essential to effectively incorporate CBS into the pharmacy curriculum., Competing Interests: The University of Tasmania owns the underlying Intellectual Property for Pharmacy Simulator and makes use of it in their Bachelor of Pharmacy program. This technology has been outlicensed for commercialisation and is being actively sold as Pharmacy Simulator by Imitated Environments Pty Ltd., Hobart, Australia. ABN 71 625 288 575. One of the authors, IB, is the director and major shareholder of Imitated Environments Pty Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Gharib, Bindoff, Peterson and Salahudeen.)

Background: At the University of Tasmania (UTAS), pharmacy education traditionally relies on placements to provide students with hands-on experience. However, these placements have become increasingly limited due to logistical challenges and growing student numbers. Computer-based simulation (CBS) has the potential to offer a scalable, effective alternative to enhance learning and critical thinking. However, integrating CBS in pharmacy education faces several barriers that must be addressed for successful implementation., Objective: To gain insight into pharmacy educators' and students' views regarding the barriers, and potential solutions, to integrating CBS in pharmacy practice education., Methods: This mixed-methods case study involved semi-structured interviews with pharmacy educators and quantitative surveys with pharmacy students. The data underwent thematic coding for interview transcripts and statistical analysis for survey responses. The findings were integrated by examining convergence, complementarity, and discrepancy, revealing insights into how pharmacy students and educators perceive implementation barriers and improvement strategies for CBS., Results: Ten interviews were conducted, and 75 survey responses were collected, with a 62.5% response rate. Key barriers to CBS integration included educators' heavy workload, scepticism about CBS's educational value, and general integration challenges. Students, however, showed high acceptance of CBS, with 70.7% agreeing that CBS could assess their knowledge, 69.3% emphasising its role in developing problem-solving skills, and 80% viewing CBS as a complement to classroom study. Proposed solutions for enhancing CBS uptake included additional institutional support by appointing dedicated simulation technicians, leveraging champions to advocate for CBS, and aligning CBS with educational objectives., Conclusion: A significant gap between students' readiness and educators' hesitancy to use CBS in pharmacy education was identified. While students are eager to adopt new technologies, educators expressed reservations, primarily due to workload concerns and uncertainties about the efficacy of CBS. The feedback from educators suggests that institutions may see improved uptake by employing dedicated support personnel and initiating targeted training programs. Future research should focus on exploring barriers and facilitators, using larger and more diverse samples, and gaining deeper insights into decision-makers' perspectives to enhance the integration and efficacy of CBS in pharmacy education., Competing Interests: The University of Tasmania owns the underlying Intellectual Property for Pharmacy Simulator and makes use of it in their Bachelor of Pharmacy program. This technology has been out-licensed for commercialisation and is being actively sold as Pharmacy Simulator by Imitated Environments Pty Ltd., Hobart, Australia. ABN 71625288575. One of the authors, Ivan Bindoff is the director and major shareholder of Imitated Environments Pty Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board members of Frontiers, (MS and GP) at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Gharib, Peterson, Bindoff and Salahudeen.)

Background: Analysis of free DNA molecules shed from tumour cells in plasma of patients referred as circulating tumour DNA (ctDNA) with reference to physiological circulating cell-free DNA (cfDNA) is nowadays exploited as liquid biopsy and is considered a new emerging promising biomarker for diagnosis, selection of proper treatment, and prognosis of cancer. DNA integrity index (DII) is assessed by calculating the ratio between the concentration of long cfDNA strands released from tumour cells (ALU247) and the short strands released from normal cells (ALU115). The aim of the current study was to evaluate DII as a potential diagnostic and prognostic biomarker of NSCLC., Methods: Our study included 48 NSCLC patients diagnosed as primary NSCLC before starting treatment, 30 COPD patients diagnosed clinically, radiologically, and subjected to chest high-resolution computerized tomography, and 40 healthy controls. cfDNA concentration and DII were measured by quantitative real-time polymerase chain reaction (qPCR)., Results: ALU115, ALU247, and DII were significantly higher in NSCLC compared to COPD patients (p < 0.0001) and controls (p < 0.0001) and in COPD patients compared to control subjects (p < 0.0001). DII positively correlated with the stage of tumour (p = 0.01), tumour metastasis (p = 0.004), and with adenocarcinoma compared to other histopathological types (p = 0.02). To evaluate clinical utility of DII in NSCLC, ROC curve analysis demonstrated an AUC of 0.91 at a cut-off value of 0.44 with total accuracy = 85.6%, sensitivity = 90%, specificity = 83%, PPV = 78.1%, and NPV = 92.1%., Conclusion: cfDNA and DII represent a promising diagnostic and prognostic tool in NSCLC. This type of noninvasive liquid biopsy revealed its chance in the screening, early diagnosis, and monitoring of NSCLC., (© 2024. The Author(s).)

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.

Computer-based simulation (CBS) is an interactive pedagogical training method that has seen increased interest, especially in recent years. There is some evidence that CBS in pharmacy education is not as widely adopted compared to other healthcare disciplines. Pharmacy education literature to date has not specifically discussed the potential barriers which may cause this uptake challenge. In this systematic narrative review, we attempted to explore and discuss potential barriers that may impact the integration of CBS in pharmacy practice education and provide our suggestions to overcome them. We searched five major databases and used the AACODS checklist for grey literature assessment. We identified 42 studies and four grey literature reports, published between 1 January 2000 and 31 August 2022, which met the inclusion criteria. Then, the specific approach of Braun and Clarke for thematic analysis was followed. The majority of the included articles were from Europe, North America, and Australasia. Although none of the included articles had a specific focus on barriers to implementation, thematic analysis was used to extract and discuss several potential barriers, such as resistance to change, cost, time, usability of software, meeting accreditation standards, motivating and engaging students, faculty experience, and curriculum constraints. Ad- dressing academic, process, and cultural barriers can be considered the first step in providing guidance for future implementation research for CBS in pharmacy education. The analysis suggests that to effectively overcome any possible barriers to implementing CBS, different stakeholders must engage in careful planning, collaboration, and investment in resources and training. The review indicates that additional research is required to offer evidence-based approach and strategies to prevent overwhelming or disengaging users from either learning or teaching process. It also guides further research into exploring potential barriers in different institutional cultures and regions.

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.

Regional soft tissue mechanical strain offers crucial insights into tissue's mechanical function and vital indicators for different related disorders. Tagging magnetic resonance imaging (tMRI) has been the standard method for assessing the mechanical characteristics of organs such as the heart, the liver, and the brain. However, constructing accurate artifact-free pixelwise strain maps at the native resolution of the tagged images has for decades been a challenging unsolved task. In this work, we developed an end-to-end deep-learning framework for pixel-to-pixel mapping of the two-dimensional Eulerian principal strains [Formula: see text] and [Formula: see text] directly from 1-1 spatial modulation of magnetization (SPAMM) tMRI at native image resolution using convolutional neural network (CNN). Four different deep learning conditional generative adversarial network (cGAN) approaches were examined. Validations were performed using Monte Carlo computational model simulations, and in-vivo datasets, and compared to the harmonic phase (HARP) method, a conventional and validated method for tMRI analysis, with six different filter settings. Principal strain maps of Monte Carlo tMRI simulations with various anatomical, functional, and imaging parameters demonstrate artifact-free solid agreements with the corresponding ground-truth maps. Correlations with the ground-truth strain maps were R = 0.90 and 0.92 for the best-proposed cGAN approach compared to R = 0.12 and 0.73 for the best HARP method for [Formula: see text] and [Formula: see text], respectively. The proposed cGAN approach's error was substantially lower than the error in the best HARP method at all strain ranges. In-vivo results are presented for both healthy subjects and patients with cardiac conditions (Pulmonary Hypertension). Strain maps, obtained directly from their corresponding tagged MR images, depict for the first time anatomical, functional, and temporal details at pixelwise native high resolution with unprecedented clarity. This work demonstrates the feasibility of using the deep learning cGAN for direct myocardial and liver Eulerian strain mapping from tMRI at native image resolution with minimal artifacts., (© 2021. The Author(s).)

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.

The carbohydrate-insulin model of obesity posits that high-carbohydrate diets lead to excess insulin secretion, thereby promoting fat accumulation and increasing energy intake. Thus, low-carbohydrate diets are predicted to reduce ad libitum energy intake as compared to low-fat, high-carbohydrate diets. To test this hypothesis, 20 adults aged 29.9 ± 1.4 (mean ± s.e.m.) years with body mass index of 27.8 ± 1.3 kg m -2 were admitted as inpatients to the National Institutes of Health Clinical Center and randomized to consume ad libitum either a minimally processed, plant-based, low-fat diet (10.3% fat, 75.2% carbohydrate) with high glycemic load (85 g 1,000 kcal -1 ) or a minimally processed, animal-based, ketogenic, low-carbohydrate diet (75.8% fat, 10.0% carbohydrate) with low glycemic load (6 g 1,000 kcal -1 ) for 2 weeks followed immediately by the alternate diet for 2 weeks. One participant withdrew due to hypoglycemia during the low-carbohydrate diet. The primary outcomes compared mean daily ad libitum energy intake between each 2-week diet period as well as between the final week of each diet. We found that the low-fat diet led to 689 ± 73 kcal d -1 less energy intake than the low-carbohydrate diet over 2 weeks (P < 0.0001) and 544 ± 68 kcal d -1 less over the final week (P < 0.0001). Therefore, the predictions of the carbohydrate-insulin model were inconsistent with our observations. This study was registered on ClinicalTrials.gov as NCT03878108 .

Background: Persons living with HIV (PLWH) are at an increased risk of myocardial dysfunction and metabolic disturbances represent one of several potential contributing factors. Adiponectin is an adipokine that enhances insulin sensitivity with potential cardioprotective effects. We therefore investigated the relationship between myocardial fibrosis, adiponectin, and related metabolic parameters to better understand the pathophysiologic mechanisms of myocardial injury in PLWH., Methods: This is a prospective, cross-sectional study of PLWH without known cardiovascular disease (n = 87) and 28 healthy matched controls. Diffuse myocardial fibrosis and epicardial adipose tissue (EAT) were evaluated using cardiac magnetic resonance imaging and cardiac computed tomography., Results: Myocardial fibrosis was increased in PLWH and was correlated with adiponectin (r = 0.26, P = 0.004) and EAT (r = -0.42, P < 0.0001). Myocardial fibrosis was not associated with smoking pack years or CD4/CD8 ratio. In multivariate analysis that included body mass index, HIV status (P = 0.04), female sex (P < 0.0001), higher adiponectin (P = 0.046) and lower EAT (P = 0.01) were independently associated with myocardial fibrosis., Conclusion: We describe a novel association between serum adiponectin and subclinical intramyocardial fibrosis, as well as a significant inverse relationship between intramyocardial fibrosis and EAT. Adiponectin may represent a target for preventing myocardial injury in the future; however, our findings reflect the complexity of the metabolic interactions of adiponectin and epicardial adipose as factors associated with the myocardial architecture.

Context: Radiological characterization of adrenal size in primary bilateral macronodular adrenocortical hyperplasia (PBMAH) has not been previously investigated., Objective: We hypothesized that volumetric modeling of adrenal gland size may correlate with biochemical disease severity in patients with PBMAH. Secondary analysis of patients with concurrent primary aldosteronism (PA) was performed., Design: A retrospective cross-sectional analysis of 44 patients with PBMAH was conducted from 2000 to 2019., Setting: Tertiary care clinical research center., Patients: Patients were diagnosed with PBMAH based upon clinical, genetic, radiographic and biochemical characteristics., Intervention: Clinical, biochemical, and genetic data were obtained. Computed tomography scans were used to create volumetric models by manually contouring both adrenal glands in each slice using Vitrea Core Fx v6.3 software (Vital Images, Minnetonka, Minnesota)., Main Outcome and Measures: 17-hydroxycorticosteroids (17-OHS), ARMC5 genetics, and aldosterone-to-renin ratio (ARR) were retrospectively obtained. Pearson test was used for correlation analysis of biochemical data with adrenal volume., Results: A cohort of 44 patients with PBMAH was evaluated, with a mean age (±SD) of 53 ± 11.53. Eight patients met the diagnostic criteria for PA, of whom 6 (75%) were Black. In the Black cohort, total adrenal volumes positively correlated with midnight cortisol (R = 0.76, P  = 0.028), urinary free cortisol (R = 0.70, P  = 0.035), and 17-OHS (R = 0.87, P  = 0.0045), with a more pronounced correlation with left adrenal volume alone. 17-OHS concentration positively correlated with total, left, and right adrenal volume in patients harboring pathogenic variants in ARMC5 (R = 0.72, P  = 0.018; R = 0.65, P  = 0.042; and R = 0.73, P  = 0.016, respectively)., Conclusions: Volumetric modeling of adrenal gland size may associate with biochemical severity in patients with PBMAH, with particular utility in Black patients., (Published by Oxford University Press on behalf of the Endocrine Society 2020.)

Oxidative stress (OS) in non-alcoholic fatty liver disease (NAFLD) promotes liver injury and inflammation. Treatment with vitamin E (α-tocopherol, αT), a lipid-soluble antioxidant, improves liver injury but also decreases steatosis, thought to be upstream of OS, through an unknown mechanism. To elucidate the mechanism, we combined a mechanistic human trial interrogating pathways of intrahepatic triglyceride (IHTG) accumulation and in vitro experiments. 50% of NAFLD patients (n = 20) treated with αT (200-800 IU/d) for 24 weeks had a ≥ 25% relative decrease in IHTG by magnetic resonance spectroscopy. Paired liver biopsies at baseline and week 4 of treatment revealed a decrease in markers of hepatic de novo lipogenesis (DNL) that strongly predicted week 24 response. In vitro, using HepG2 cells and primary human hepatocytes, αT inhibited glucose-induced DNL by decreasing SREBP-1 processing and lipogenic gene expression. This mechanism is dependent on the antioxidant capacity of αT, as redox-silenced methoxy-αT is unable to inhibit DNL in vitro. OS by itself was sufficient to increase S2P expression in vitro, and S2P is upregulated in NAFLD livers. In summary, we utilized αT to demonstrate a vicious cycle in which NAFLD generates OS, which feeds back to augment DNL and increases steatosis. Clinicaltrials.gov: NCT01792115., (Published by Elsevier B.V.)

De novo lipogenesis (DNL) plays a role in the development of hepatic steatosis. In humans with lipodystrophy, reduced adipose tissue causes lower plasma leptin, insulin resistance, dyslipidemia, and ectopic triglyceride (TG) accumulation. We hypothesized that recombinant leptin (metreleptin) for 6 months in 11 patients with lipodystrophy would reduce DNL by decreasing insulin resistance and glycemia, thus reducing circulating TG and hepatic TG. The percentage of TG in TG-rich lipoprotein particle (TRLP-TG) derived from DNL (%DNL) was measured by deuterium incorporation from body water into palmitate. At baseline, DNL was elevated, similar to levels previously shown in obesity-associated nonalcoholic fatty liver disease (NAFLD). After metreleptin, DNL decreased into the normal range. Similarly, absolute DNL (TRLP-TG × %DNL) decreased by 88% to near-normal levels. Metreleptin improved peripheral insulin sensitivity (hyperinsulinemic-euglycemic clamp) and lowered hemoglobin A1c and hepatic TG. Both before and after metreleptin, DNL positively correlated with insulin resistance, insulin doses, and hepatic TG, supporting the hypothesis that hyperinsulinemia stimulates DNL and that elevated DNL is integral to the pathogenesis of lipodystrophy-associated NAFLD. These data suggest that leptin-mediated improvement in insulin sensitivity increases clearance of blood glucose by peripheral tissues, reduces hepatic carbohydrate flux, and lowers insulinemia, resulting in DNL reductions and improvements in hepatic steatosis and dyslipidemia.

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/m 2 , 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.

Purpose: To demonstrate the association between coronary vessel wall thickness (VWT) measured at MRI and coronary artery disease (CAD) risk in asymptomatic groups at low and intermediate risk on the basis of Framingham score., Materials and Methods: A total of 131 asymptomatic adults were prospectively enrolled. All participants underwent CT angiography for scoring CAD, and coronary VWT was measured at 3.0-T MRI. Nonlinear single and multivariable regression analyses with consideration for interaction with sex were performed to investigate the association of traditional atherosclerotic risk factors and VWT with CT angiography-based CAD scores., Results: The analysis included 62 women and 62 men with low or intermediate Framingham score of less than 20%. Age (mean age, 45.0 years ± 14.5 [standard deviation]) and body mass index were not different between the groups. Age, sex, and VWT were individually significantly associated with all CT angiography-based CAD scores ( P < .05). Additionally, sex was a significant effect modifier of the associations with all CAD scores. In men, age was the only statistically significant independent risk factor of CAD; in women, VWT was the only statistically significant independent surrogate associated with increased CAD scores ( P < .05)., Conclusion: In asymptomatic women, VWT MRI was the primary independent surrogate of CAD, whereas age was the strongest risk factor in men. This study suggests that VWT may be used as a CAD surrogate in women at low or intermediate risk of CAD. Further longitudinal studies are required to determine the potential implication and use of this MRI technique for the preventative management of CAD in women.© RSNA, 2019., (2019 by the Radiological Society of North America, Inc.)

Objectives: Lipodystrophies are characterized by regional or generalized loss of adipose tissue and severe metabolic complications. The role of visceral adipose tissue (VAT) in the development of metabolic derangements in lipodystrophy is unknown. The study aim was to investigate VAT contribution to metabolic disease in lipodystrophy versus healthy controls., Methods: Analysis of correlations between VAT volume and biomarkers of metabolic disease in 93 patients and 93 age/sex-matched healthy controls., Results: Patients with generalized lipodystrophy ( n  = 43) had lower VAT compared with matched controls, while those with partial lipodystrophy ( n  = 50) had higher VAT versus controls. Both groups with lipodystrophy had lower leg fat mass versus controls ( p  < 0.05 for all; unpaired t -test). In both generalized and partial lipodystrophy, there was no correlation between VAT and glucose, triglycerides or high-density lipoprotein cholesterol ( p  > 0.05 for all; Spearman correlation). In controls matched to patients with generalized or partial lipodystrophy, VAT correlated with glucose ( R  = 0.42 and 0.36), triglycerides ( R  = 0.36 and 0.60) and high-density lipoprotein cholesterol ( R  = -0.34 and -0.64) ( p  < 0.05 for all; Spearman correlation)., Conclusions: In contrast to healthy controls, metabolic derangements in lipodystrophy did not correlate with VAT volume. These data suggest that, in lipodystrophy, impaired peripheral subcutaneous fat deposition may exert a larger effect than VAT accumulation on the development of metabolic complications. Interventions aimed at increasing functional subcutaneous adipose tissue may provide metabolic benefit., Competing Interests: The authors declared no conflict of interest.

Coronary plaque burden measured by coronary computerized tomography angiography (CCTA), independent of stenosis, is a significant independent predictor of coronary heart disease (CHD) events and mortality. Hence, it is essential to develop comprehensive CCTA plaque quantification beyond existing subjective plaque volume or stenosis scoring methods. The purpose of this study is to develop a framework for automated 3D segmentation of CCTA vessel wall and quantification of atherosclerotic plaque, independent of the amount of stenosis, along with overcoming challenges caused by poor contrast, motion artifacts, severe stenosis, and degradation of image quality. Vesselness, region growing, and two sequential level sets are employed for segmenting the inner and outer wall to prevent artifact-defective segmentation. Lumen and vessel boundaries are joined to create the coronary wall. Curved multiplanar reformation is used to straighten the segmented lumen and wall using lumen centerline. In-vivo evaluation included CCTA stenotic and non-stenotic plaques from 41 asymptomatic subjects with 122 plaques of different characteristics against the individual and consensus of expert readers. Results demonstrate that the framework segmentation performed robustly by providing a reliable working platform for accelerated, objective, and reproducible atherosclerotic plaque characterization beyond subjective assessment of stenosis; can be potentially applicable for monitoring response to therapy.

Objectives: To determine the types and to assess the role of auditory evoked potentials and otoacoustic emissions in early detection of hearing abnormalities in Behçet's disease (BD) patients. Their correlations with disease activity were also considered., Methods: Thirty patients with BD and thirty apparently sex- and age-matched healthy volunteers were included in this study. Auditory evaluation included pure tone audiometry (PTA), otoacoustic emissions (TEOAEs, DPOAE), auditory brainstem response test (ABR) and cortical auditory evoked potentials (tone and speech CAEPs) for all patients and control., Results: The highest abnormality of CAEP latencies elicited by (500Hz and 1000 Hz) as well as speech stimuli (da and ga) among our BD patients was delayed P1 and N1 waves at 80 dB with greater bilateral affection, as well as significant differences between patients and controls. All our BD patients had a smaller amplitude of distortion product OAE (DPOAE) and S/N ratio at 1, 2, 4, 6 kHZ compared with controls and the differences were highly statistically significant (p=0.0001)., Conclusions: Being one of the autoimmune inner ear diseases (AIED), BD has a definite hearing impairment, even in the presence of normal hearing sensitivity, as evidenced by PTA. BD patients had a sub-clinical cochlear pathology which was not affected by disease activity or different organ affection. DPOAE (S/N ratio) proved to be a sensitive test in detecting minimal changes in cochlear pathology and the latencies of CAEPs (tone and speech) measures were considered as sensitive indicators (100%) of early detection of hearing impairment in BD patients.

Black women, compared with White women, have high rates of whole-body insulin resistance but a lower prevalence of fasting hyperglycemia and hepatic steatosis. This dissociation of whole-body insulin resistance from fasting hyperglycemia may be explained by racial differences in gluconeogenesis, hepatic fat, or tissue-specific insulin sensitivity. Two groups of premenopausal federally employed women, without diabetes were studied. Using stable isotope tracers, [2H2O] and [6,62-H2]glucose, basal glucose production was partitioned into its components (gluconeogenesis and glycogenolysis) and basal whole-body lipolysis ([2H5]glycerol) was measured. Indices of insulin sensitivity, whole-body (SI), hepatic (HISIGPR), and adipose tissue, were calculated. Hepatic fat was measured by proton magnetic resonance spectroscopy. Black women had less hepatic fat and lower fractional and absolute gluconeogenesis. Whole-body SI, HISIGPR, and adipose tissue sensitivity were similar by race, but at any given level of whole-body SI, Black women had higher HISIGPR. Therefore, fasting hyperglycemia may be a less common early pathological feature of prediabetes in Black women compared with White women, because gluconeogenesis remains lower despite similar whole-body SI.

Background: Recombinant leptin (metreleptin) ameliorates hyperphagia and metabolic abnormalities in leptin-deficient humans with lipodystrophy. We aimed to determine whether metreleptin improves glucose and lipid metabolism in humans when food intake is held constant., Methods: Patients with lipodystrophy were hospitalized for 19 days, with food intake held constant by a controlled diet in an inpatient metabolic ward. In a nonrandomized, crossover design, patients previously treated with metreleptin (n = 8) were continued on metreleptin for 5 days and then taken off metreleptin for the next 14 days (withdrawal cohort). This order was reversed in metreleptin-naive patients (n = 14), who were reevaluated after 6 months of metreleptin treatment on an ad libitum diet (initiation cohort). Outcome measurements included insulin sensitivity by hyperinsulinemic-euglycemic clamp, fasting glucose and triglyceride levels, lipolysis measured using isotopic tracers, and liver fat by magnetic resonance spectroscopy., Results: With food intake constant, peripheral insulin sensitivity decreased by 41% after stopping metreleptin for 14 days (withdrawal cohort) and increased by 32% after treatment with metreleptin for 14 days (initiation cohort). In the initiation cohort only, metreleptin decreased fasting glucose by 11% and triglycerides by 41% and increased hepatic insulin sensitivity. Liver fat decreased from 21.8% to 18.7%. In the initiation cohort, changes in lipolysis were not independent of food intake, but after 6 months of metreleptin treatment on an ad libitum diet, lipolysis decreased by 30% (palmitate turnover) to 35% (glycerol turnover)., Conclusion: Using lipodystrophy as a human model of leptin deficiency and replacement, we show that metreleptin improves insulin sensitivity and decreases hepatic and circulating triglycerides and that these improvements are independent of its effects on food intake., Trial Registration: ClinicalTrials.gov NCT01778556FUNDING. This research was supported by the intramural research program of the NIDDK.

Histopathology protocols often require sectioning and processing of numerous microscopy slides to survey a sample. Trade-offs between workload and sampling density means that small features can be missed. Aiming to reduce the workload of routine histology protocols and the concern over missed pathology in skipped sections, we developed a prototype x-ray tomographic scanner dedicated to rapid scouting and identification of regions of interest in pathology specimens, thereby allowing targeted histopathology analysis to replace blanket searches. In coronary artery samples of a deceased HIV patient, the scanner, called Tomopath, obtained depth-resolved cross-sectional images at 15 µm resolution in a 15-minute scan, which guided the subsequent histological sectioning and microscopy. When compared to a commercial tabletop micro-CT scanner, the prototype provided several-fold contrast-to-noise ratio in 1/11 th the scan time. Correlated tomographic and histological images revealed two types of micro calcifications: scattered loose calcifications typically found in atherosclerotic lesions; isolated focal calcifications in one or several cells in the internal elastic lamina and occasionally in the tunica media, which we speculate were the initiation of medial calcification linked to kidney disease, but rarely detected at this early stage due to their similarity to particle contaminants introduced during histological processing, if not for the evidence from the tomography scan prior to sectioning. Thus, in addition to its utility as a scouting tool, in this study it provided complementary information to histological microscopy. Overall, the prototype scanner represents a step toward a dedicated scouting and complementary imaging tool for routine use in pathology labs.

Noncirrhotic portal hypertension (NCPH) is a rare disease that may lead to serious clinical consequences. Currently, noninvasive tools for the assessment of NCPH are absent. We investigated the utility of spleen and liver volumetrics as a marker of the presence and severity of portal hypertension in this population. A cohort of NCPH patients evaluated between 2003 and 2015 was retrospectively studied. The association of spleen and liver volumes with the hepatic venous pressure gradient (HVPG) level was evaluated using locally weighted scatterplot smoothing curves. A cohort of patients with viral hepatitis-related liver disease was used as controls. Of the 86 patients with NCPH evaluated during the study period, 75 (mean age, 35 ± 17; 73% males) were included in the final analysis. Patients with portal hypertension had significantly higher spleen and liver to body mass index (BMI) ratios compared to patients with HVPG <5 mm Hg (39.5 ± 27.9 versus 22.8 ± 10.6 cm 3 /kg/m 2 , P = 0.003; 91.1 ± 40.1 versus 71.4 ± 16.7 cm 3 /kg/m 2 , P = 0.014, for spleen/BMI and liver/BMI, respectively). In contrast to the patients with viral hepatitis, a positive linear correlation was observed in the NCPH cohort between spleen/BMI and liver/BMI (above a cutoff of 25 and 80 cm 3 /kg/m 2 , respectively) and HVPG level. Additionally, only in the NCPH cohort was an increase in spleen/BMI range quartile predictive of a higher prevalence of portal hypertension and clinically significant portal hypertension (trend, P = 0.014 and 0.031, respectively). Conclusion: Spleen and liver volumetrics may have utility in the assessment of NCPH as a noninvasive biomarker that can be performed using routine radiologic examinations. Further studies are needed to validate these findings. ( Hepatology Communications 2018; 00:000-000).

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.

Background: Current guidelines for the primary prevention of atherosclerotic cardiovascular disease are based on the estimation of a predicted 10-year cardiovascular disease risk and the average relative risk reduction estimates from statin trials. In the clinical setting, however, decision-making is better informed by the expected benefit for the individual patient, which is typically lacking. Consequently, a personalized statin benefit approach based on absolute risk reduction over 10 years (ARR10 benefit threshold ≥2.3%) has been proposed as a novel approach. However, how this benefit threshold relates with coronary plaque burden in asymptomatic individuals with low/intermediate cardiovascular disease risk is unknown., Aims: In this study, we compared the predicted ARR10 obtained in each individual with plaque burden detected by coronary computed tomography angiography., Methods and Results: Plaque burden (segment volume score, segment stenosis score, and segment involvement score) was assessed in prospectively recruited asymptomatic subjects (n = 70; 52% male; median age 56 years [interquartile range 51-64 years]) with low/intermediate Framingham risk score (< 20%). The expected ARR10 with statin in the entire cohort was 2.7% (1.5-4.6%) with a corresponding number needed to treat over 10 years of 36 (22-63). In subjects with an ARR10 benefit threshold ≥2.3% (vs. < 2.3%), plaque burden was significantly higher (p = 0.02)., Conclusion: These findings suggest that individuals with higher coronary plaque burden are more likely to get greater benefit from statin therapy even among asymptomatic individuals with low cardiovascular risk., (This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel.)

Background. Portal hypertension, an elevation in the hepatic venous pressure gradient (HVPG), can be used to monitor disease progression and response to therapy in cirrhosis. Since obtaining HVPG measurements is invasive, reliable noninvasive methods of assessing portal hypertension are needed. Methods. Noninvasive markers of fibrosis, including magnetic resonance elastography (MRE) shear wave velocity, were correlated with histologic fibrosis and HVPG measurements in hepatitis C (HCV) and/or HIV-infected patients with advanced liver disease enrolled in a clinical trial of treatment with simtuzumab, an anti-LOXL2 antibody. Results. This exploratory analysis includes 23 subjects: 9 with HCV monoinfection, 9 with HIV and HCV, and 5 with HIV and nonalcoholic steatohepatitis. Median Ishak fibrosis score was 4 (range 1-6); 11 subjects (48%) had cirrhosis. Median HVPG was 6 mmHg (range 3-16). Liver stiffness measured by MRE correlated with HVPG ( r = 0.64, p = 0.01), histologic fibrosis score ( r = 0.71, p = 0.004), noninvasive fibrosis indices, including APRI ( r = 0.81, p < 0.001), and soluble LOXL2 ( r = 0.82, p = 0.001). On stepwise multivariate regression analysis, MRE was the only variable independently associated with HVPG ( R 2 = 0.377, p = 0.02). Conclusions. MRE of the liver correlated independently with HVPG. MRE is a valid noninvasive measure of liver disease severity and may prove to be a useful tool for noninvasive portal hypertension assessment. Trial Registration Number . This trial is registered with NCT01707472.

Objective: We examined if chronic cannabis smoking is associated with hepatic steatosis, insulin resistance, reduced β-cell function, or dyslipidemia in healthy individuals., Research Design and Methods: In a cross-sectional, case-control study, we studied cannabis smokers (n = 30; women, 12; men, 18; 27 ± 8 years) and control subjects (n = 30) matched for age, sex, ethnicity, and BMI (27 ± 6). Abdominal fat depots and intrahepatic fat content were quantified by magnetic resonance imaging and proton magnetic resonance spectroscopy, respectively. Insulin-sensitivity indices and various aspects of β-cell function were derived from oral glucose tolerance tests (OGTT)., Results: Self-reported cannabis use was: 9.5 (2-38) years; joints/day: 6 (3-30) [median (range)]. Carbohydrate intake and percent calories from carbohydrates, but not total energy intake, were significantly higher in cannabis smokers. There were no group differences in percent total body fat, or hepatic fat, but cannabis smokers had a higher percent abdominal visceral fat (18 ± 9 vs. 12 ± 5%; P = 0.004). Cannabis smokers had lower plasma HDL cholesterol (49 ± 14 vs. 55 ± 13 mg/dL; P = 0.02), but fasting levels of glucose, insulin, total cholesterol, LDL cholesterol, triglycerides, or free fatty acids (FFA) were not different. Adipocyte insulin resistance index and percent FFA suppression during an OGTT was lower (P < 0.05) in cannabis smokers. However, oral glucose insulin sensitivity index, measures of β-cell function, or incretin concentrations did not differ between the groups., Conclusions: Chronic cannabis smoking was associated with visceral adiposity and adipose tissue insulin resistance but not with hepatic steatosis, insulin insensitivity, impaired pancreatic β-cell function, or glucose intolerance.

Background: Pulmonary arterial hypertension is a rare disorder associated with poor survival. Endothelial dysfunction plays a central role in the pathogenesis and progression of pulmonary arterial hypertension. Inflammation appears to drive this dysfunctional endothelial phenotype, propagating cycles of injury and repair in genetically susceptible patients with idiopathic and disease-associated pulmonary arterial hypertension. Therapy targeting pulmonary vascular inflammation to interrupt cycles of injury and repair and thereby delay or prevent right ventricular failure and death has not been tested. Spironolactone, a mineralocorticoid and androgen receptor antagonist, has been shown to improve endothelial function and reduce inflammation. Current management of patients with pulmonary arterial hypertension and symptoms of right heart failure includes use of mineralocorticoid receptor antagonists for their diuretic and natriuretic effects. We hypothesize that initiating spironolactone therapy at an earlier stage of disease in patients with pulmonary arterial hypertension could provide additional benefits through anti-inflammatory effects and improvements in pulmonary vascular function., Methods/design: Seventy patients with pulmonary arterial hypertension without clinical evidence of right ventricular failure will be enrolled in a randomized, double-blinded, placebo-controlled trial to investigate the effect of early treatment with spironolactone on exercise capacity, clinical worsening and vascular inflammation in vivo. Our primary endpoint is change in placebo-corrected 6-minute walk distance at 24 weeks and the incidence of clinical worsening in the spironolactone group compared to placebo. At a two-sided alpha level of 0.05, we will have at least 84% power to detect an effect size (group mean difference divided by standard deviation) of 0.9 for the difference in the change of 6-minute walk distance from baseline between the two groups. Secondary endpoints include the effect of spironolactone on the change in placebo-corrected maximal oxygen consumption; plasma markers of vascular inflammation and peripheral blood mononuclear cell gene expression profiles; sympathetic nervous system activation, renin-angiotensin-aldosterone system activation and sex hormone metabolism; and right ventricular structure and function using echocardiography and novel high-resolution magnetic resonance imaging-based techniques. Safety and tolerability of spironolactone will be assessed with periodic monitoring for hyperkalemia and renal insufficiency as well as the incidence of drug discontinuation for untoward effects., Trial Registration: ClinicalTrials.gov: NCT01712620.

Coronary bifurcations represent specific regions of the arterial tree that are susceptible to atherosclerotic lesions. While the effects of vessel compliance, curvature, pulsatile blood flow, and cardiac motion on coronary endothelial shear stress have been widely explored, the effects of myocardial contraction on arterial wall stress/strain (WS/S) and vessel stiffness distributions remain unclear. Local increase of vessel stiffness resulting from wall-strain stiffening phenomenon (a local process due to the nonlinear mechanical properties of the arterial wall) may be critical in the development of atherosclerotic lesions. Therefore, the aim of this study was to quantify WS/S and stiffness in coronary bifurcations and to investigate correlations with plaque sites. Anatomic coronary geometry and cardiac motion were generated based on both computed tomography and MRI examinations of eight patients with minimal coronary disease. Computational structural analyses using the finite element method were subsequently performed, and spatial luminal arterial wall stretch (LW(Stretch)) and stiffness (LW(Stiff)) distributions in the left main coronary bifurcations were calculated. Our results show that all plaque sites were concomitantly subject to high LW(Stretch) and high LW(Stiff), with mean amplitudes of 34.7 ± 1.6% and 442.4 ± 113.0 kPa, respectively. The mean LW(Stiff) amplitude was found slightly greater at the plaque sites on the left main coronary artery (mean value: 482.2 ± 88.1 kPa) compared with those computed on the left anterior descending and left circumflex coronary arteries (416.3 ± 61.5 and 428.7 ± 181.8 kPa, respectively). These findings suggest that local wall stiffness plays a role in the initiation of atherosclerotic lesions.

Turner syndrome is the most common chromosomal abnormality in female subjects, affecting 1 in 2000 live births. The condition is associated with a generalized vasculopathy as well as congenital cardiac and other defects. We report aneurysmal dilation of medium caliber arteries involving the celiac axis and coronary vessels in two women with Turner syndrome., (© 2011 Copyright the Authors. Congenital Heart Disease © 2011 Wiley Periodicals, Inc.)

Objective: To assess fetal and maternal outcomes of pregnancies in women with Turner syndrome (TS)., Design: Retrospective case series., Setting: Clinical research center., Patient(s): 276 adults with cytogenetically proven TS participating in an intramural natural history protocol., Intervention(s): None., Main Outcome Measure(s): Menstrual and obstetric histories, 50-cell karyotypes, and cardiovascular evaluation including aortic diameter measurements., Result(s): Our cohort included five women with spontaneous pregnancies and five with pregnancies using assisted reproduction (ART). All five women with spontaneous pregnancies had spontaneous puberty, despite 45,X in ≥90% of their 50-cell karyotype. Participants had a total of 13 pregnancies and 14 live births. One child had cerebral palsy; the others were chromosomally and developmentally normal. Delivery was by cesarean section in four out of seven spontaneous and six out of six ART-related pregnancies. One mother experienced preeclampsia in an ART-related twin pregnancy that required a preterm delivery; she has marked but stable aortic dilation years later., Conclusion(s): Approximately 2% of our study cohort experienced spontaneous pregnancies despite high-grade X monosomy, and a similar number achieved pregnancy via oocyte donation and ART. The potential for life-threatening cardiovascular complications warrants comprehensive screening before conception or single-embryo transfer, and caution regarding unintentional pregnancies for TS women., (Copyright © 2011. Published by Elsevier Inc.)

There are advantages to conducting cardiovascular magnetic resonance (CMR) studies at a field strength of 3.0 Telsa, including the increase in bulk magnetization, the increase in frequency separation of off-resonance spins, and the increase in T1 of many tissues. However, there are significant challenges to routinely performing CMR at 3.0 T, including the reduction in main magnetic field homogeneity, the increase in RF power deposition, and the increase in susceptibility-based artifacts.In this review, we outline the underlying physical effects that occur when imaging at higher fields, examine the practical results these effects have on the CMR applications, and examine methods used to compensate for these effects. Specifically, we will review cine imaging, MR coronary angiography, myocardial perfusion imaging, late gadolinium enhancement, and vascular wall imaging.

It is now recognized that prediction of the vulnerable coronary plaque rupture requires not only an accurate quantification of fibrous cap thickness and necrotic core morphology but also a precise knowledge of the mechanical properties of plaque components. Indeed, such knowledge would allow a precise evaluation of the peak cap-stress amplitude, which is known to be a good biomechanical predictor of plaque rupture. Several studies have been performed to reconstruct a Young's modulus map from strain elastograms. It seems that the main issue for improving such methods does not rely on the optimization algorithm itself, but rather on preconditioning requiring the best estimation of the plaque components' contours. The present theoretical study was therefore designed to develop: 1) a preconditioning model to extract the plaque morphology in order to initiate the optimization process, and 2) an approach combining a dynamic segmentation method with an optimization procedure to highlight the modulogram of the atherosclerotic plaque. This methodology, based on the continuum mechanics theory prescribing the strain field, was successfully applied to seven intravascular ultrasound coronary lesion morphologies. The reconstructed cap thickness, necrotic core area, calcium area, and the Young's moduli of the calcium, necrotic core, and fibrosis were obtained with mean relative errors of 12%, 4% and 1%, 43%, 32%, and 2%, respectively.

Fibrous cap thickness is often considered as diagnostic of the degree of plaque instability. Necrotic core area (Core(area)) and the arterial remodeling index (Remod(index)), on the other hand, are difficult to use as clinical morphological indexes: literature data show a wide dispersion of Core(area) thresholds above which plaque becomes unstable. Although histopathology shows a strong correlation between Core(area) and Remod(index), it remains unclear how these interact and affect peak cap stress (Cap(stress)), a known predictor of rupture. The aim of this study was to investigate the change in plaque vulnerability as a function of necrotic core size and plaque morphology. Cap(stress) value was calculated on 5,500 idealized atherosclerotic vessel models that had the original feature of mimicking the positive arterial remodeling process described by Glagov. Twenty-four nonruptured plaques acquired by intravascular ultrasound on patients were used to test the performance of the associated idealized morphological models. Taking advantage of the extensive simulations, we investigated the effects of anatomical plaque features on Cap(stress). It was found that: 1) at the early stages of positive remodeling, lesions were more prone to rupture, which could explain the progression and growth of clinically silent plaques and 2) in addition to cap thickness, necrotic core thickness, rather than area, was critical in determining plaque stability. This study demonstrates that plaque instability is to be viewed not as a consequence of fibrous cap thickness alone but rather as a combination of cap thickness, necrotic core thickness, and the arterial remodeling index.

We present a tool for tracking coronary vessels in MRI scans of the human heart to aid in the screening of heart diseases. The vessels are identified through a single click inside each vessel present in a standard orthogonal view. The vessel identification results from a series of computational steps including eigenvalue analysis of the Hessian of the MRI image followed by a level set-based extraction of the vessel centerline. All identified vessels are highlighted using a virtual contrast agent and displayed simultaneously in a spherical curved reformation view. In cases of over segmentation, the vessel traces can be shortened by a click on each vessel end point. Intermediate analysis results of the vessel computation steps can be displayed as well. We successfully validated the tool on 40 MRI scans demonstrating accuracy and significant time savings over manual vessel tracing.

Molecular imaging may be defined as spatially localized and/or temporally resolved sensing of molecular and cellular processes in vivo. An imageable molecular event may be the result of the overexpression of a gene that produces a specific messenger RNA. The overexpressed protein could be an enzyme or could be incorporated into cell-surface transporters or receptors. Any step of this process is a potential target for molecular imaging. Current molecular imaging modalities include magnetic resonance imaging, nuclear imaging, ultrasound, and optical imaging. Nuclear medicine has been at the forefront of molecular imaging because of the relatively high sensitivity to detect nanomolar or picomolar quantities of the radiolabeled imaging probe. Imaging has had a central role in the diagnosis of hepatocellular carcinoma (HCC), which is considered the fifth most frequent malignancy worldwide. Nuclear imaging was one of the earlier modalities used for liver imaging. Traditional tracers included technetium 99m ( 99m Tc) sulfur colloid, gallium 67, and 99m Tc iminodiacetate acid analogues. Other less traditional probes include 99m Tc diethylenetriamine pentaacetic acid-galactosyl-human serum albumin for evaluation of functional liver volume and 99m Tc-labeled tetrofosmin and methoxisobutylisonitrile for detecting drug resistance. Fluorodeoxyglucose is the most widely used probe for positron emission tomography (PET) tumor imaging; however, carbon 11-labeled acetate appears to show improved sensitivity and specificity for HCC. Oxygen 15 PET imaging allows for the measurement of hepatic and tumor blood flow. Difficulties developing specific imaging methods for HCC are caused by the lack of obvious specific molecular targets, problems with drug delivery, and poor contrast-to-noise. No magic molecular imaging method exists today to accurately detect, characterize, and monitor HCC in vivo.

Accumulation of oxidative damage to mitochondria, protein, and nucleic acid in the brain may lead to neuronal and cognitive dysfunction. The effects on cognitive function, brain mitochondrial structure, and biomarkers of oxidative damage were studied after feeding old rats two mitochondrial metabolites, acetyl-l-carnitine (ALCAR) [0.5% or 0.2% (wt/vol) in drinking water], and/or R-alpha-lipoic acid (LA) [0.2% or 0.1% (wt/wt) in diet]. Spatial memory was assessed by using the Morris water maze; temporal memory was tested by using the peak procedure (a time-discrimination procedure). Dietary supplementation with ALCAR and/or LA improved memory, the combination being the most effective for two different tests of spatial memory (P < 0.05; P < 0.01) and for temporal memory (P < 0.05). Immunohistochemical analysis showed that oxidative damage to nucleic acids (8-hydroxyguanosine and 8-hydroxy-2'-deoxyguanosine) increased with age in the hippocampus, a region important for memory. Oxidative damage to nucleic acids occurred predominantly in RNA. Dietary administration of ALCAR and/or LA significantly reduced the extent of oxidized RNA, the combination being the most effective. Electron microscopic studies in the hippocampus showed that ALCAR and/or LA reversed age-associated mitochondrial structural decay. These results suggest that feeding ALCAR and LA to old rats improves performance on memory tasks by lowering oxidative damage and improving mitochondrial function.