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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.

Culex pipiens mosquitoes are the primary vector of the West Nile virus worldwide and have a wide distribution. To avoid the development of resistance in insect pests to conventional synthetic pesticides, there have been many attempts to study botanical pesticides. The increasing resistance of insect pests to synthetic pesticides is a threat to the diversity of ecosystems, which makes the study of botanical pesticides all the more important. The study aimed to determine the efficacy of Thuja orientalis essential oil irradiated with 1, 3 and 5 KGy compared to unirradiated T. orientalis as larvicidal agents against the third instar larvae of C. pipiens using six different concentrations (15, 20, 25, 30, 35 and 40 ppm) and as an adulticidal agent against approximately three-day-old female adults 0.2, 0.4, 0.6, 1 and 2%. The results generally showed that the irradiated essential oil with 5 KGy had the highest efficacy by LC 50 (20.16 ppm) followed by essential oil irradiated with 3 and 1 KGy (LC 50 , 23.16 and 26.00 ppm, respectively) compared to unirradiated ones (LC 50 , 27.28 ppm) after 24 h from the exposure for the third instar larvae. The knockdown effect for adults increased significantly with higher concentrations of the oil, across different exposure times ranging from 5 to 60 min. The time to knock down 100% of mosquito population to Thuja orientalis essential oils at the highest concentration 2% were 20 min at 0, 1, and 3 KGy and 10 min at 5 KGy. Our results indicate that gamma irradiation of T. orientalis fruit improves the efficacy of their essential oil against Culex pipiens and the irradiated oil could be successfully used for management of these insects. The head capsule, antenna, and the last abdominal segments of the 3rd instar larvae exposed to the essential oil of unirradiated or irradiated Thuja orientalis unripe were examined by the scanning electron microscope (SEM)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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: 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. Endothelial function magnetic resonance imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using endothelial function magnetic resonance imaging, we evaluated peripheral and coronary artery structure and endothelial 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: lower 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 and NCT01399385., Competing Interests: None.

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.

Coronary artery disease (CAD) risk and plaque scores are often subjective and biased, particularly in mid-age asymptomatic women, whose CAD risk assessment has been historically underestimated. In this study, a new automatic ascending aorta time-to-peak-distention (TPD) analysis was developed for fast screening and as an independent surrogate for subclinical atherosclerosis in asymptomatic women. CCTA was obtained in 50 asymptomatic adults. Plaque burden segment involvement score (SIS) and automatic TPD were obtained from all subjects. Logistic regression analyses were performed to investigate the association between CAD risk scores and TPD with severe coronary plaque burden (SIS>5). TPD, individually, was found to be a significant predictor of SIS>5. Additionally, sex was a significant effect modifier of TPD, with a stronger statistically significant association with women. Four-dimensional aortic time-to-peak distention could supplement conventional CCTA analysis and offer a quick objective screening tool for plaque burden severity and CAD risk stratification, especially in women., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

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., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

Objectives: Three-dimensional (3D) magnetic resonance elastography (MRE) measures liver fibrosis and inflammation but requires several breath-holds that hamper clinical acceptance. The aim of this study was to evaluate the technical and clinical feasibility of a single breath-hold 3D MRE sequence as a means of measuring liver fibrosis and inflammation in obese patients., Methods: From November 2020 to December 2021, subjects were prospectively enrolled and divided into 2 groups. Group 1 included healthy volunteers (n = 10) who served as controls to compare the single breath-hold 3D MRE sequence with a multiple-breath-hold 3D MRE sequence. Group 2 included liver patients (n = 10) who served as participants to evaluate the clinical feasibility of the single breath-hold 3D MRE sequence in measuring liver fibrosis and inflammation. Controls and participants were scanned at 60 Hz mechanical excitation with the single breath-hold 3D MRE sequence to retrieve the magnitude of the complex-valued shear modulus (|G*| [kPa]), the shear wave speed (Cs [m/s]), and the loss modulus (G" [kPa]). The controls were also scanned with a multiple-breath-hold 3D MRE sequence for comparison, and the participants had histopathology (Ishak scores) for correlation with Cs and G"., Results: For the 10 controls, 5 were female, and the mean age and body mass index were 33.1 ± 9.5 years and 23.0 ± 2.1 kg/m 2 , respectively. For the 10 participants, 8 were female, and the mean age and body mass index were 45.1 ± 16.5 years and 33.1 ± 4.0 kg/m 2 (obese range), respectively. All participants were suspected of having nonalcoholic fatty liver disease. Bland-Altman analysis of the comparison in controls shows there are nonsignificant differences in |G*|, Cs, and G" below 6.5%, suggesting good consensus between the 2 sequences. For the participants, Cs and G" correlated significantly with Ishak fibrosis and inflammation grades, respectively ( ρ = 0.95, P < 0.001, and ρ = 0.84, P = 0.002)., Conclusion: The single breath-hold 3D MRE sequence may be effective in measuring liver fibrosis and inflammation in obese patients., Competing Interests: Conflicts of interest and sources of funding: Omar Darwish is a PhD candidate, and their university tuitions fees are covered by Siemens Healthineers. Dr Radhouene Neji is an employee of Siemens Healthineers United Kingdom, Dr Daniel Stäb is an employee of Siemens Healthcare Australia, and Dr Peter Speier is an employee of Siemens Healthcare Germany. For the remaining authors, none were declared. Sources of funding: CRUK City of London Centre Award (C7893/A26233), CRUK (EDDCPGM/100001), Siemens Healthineers, ITMO Aviesan 2020 (DESP/PB n°241), National Institutes of Health intramural fund, and by US Agency for International Development (USAID) and National Academy of Sciences through Subaward 2000012771 (any opinions, findings, conclusions, or recommendations expressed are those of the authors alone, and do not necessarily reflect the views of USAID or National Academy of Sciences)., (Copyright © 2023 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

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.

Background: Partial lipodystrophy (PL) syndromes involve deficiency of adipose tissue, causing severe insulin resistance and hypertriglyceridemia. Apolipoprotein C-III (apoC-III) is elevated in PL and is thought to contribute to hypertriglyceridemia by inhibiting lipoprotein lipase (LPL)., Objective: We hypothesized that volanesorsen, an antisense oligonucleotide to apoC-III, would decrease apoC-III, increase LPL activity, and lower triglycerides in PL., Methods: Five adults with PL enrolled in a 16-week placebo-controlled, randomized, double blind study of volanesorsen, 300 mg weekly, followed by 1-year open label extension., Results: Within-subject effects of volanesorsen before and after 16 weeks of active drug are reported due to small sample size. From week 0 to 16, apoC-III decreased from median (25 th , 75 th %ile) 380 (246, 600) to 75 (26, 232) ng/mL, and triglycerides decreased from 503 (330, 1040) to 116 (86, 355) mg/dL while activation of LPL by subjects' serum increased from 21 (20, 25) to 36 (29, 42) nEq/mL*min. Although, A1c did not change, peripheral and hepatic insulin sensitivity (glucose disposal and suppression of glucose production during hyperinsulinemic clamp) increased and palmitate turnover decreased. After 32-52 weeks of volanesorsen, liver fat decreased. Common adverse events included injection site reactions and decreased platelets., Conclusions: In PL, volanesorsen decreased apoC-III and triglycerides, in part through an LPL dependent mechanism, and may improve insulin resistance and hepatic steatosis., Competing Interests: Declaration of Competing Interest In-kind research support for this study (including study drug, analysis of pharmacokinetics and lipids, database management, patient remuneration and visiting nurse support) were provided by Ionis Pharmaceuticals and Akcea Therapeutics. All authors have declared that no conflict of interest exists., (Copyright © 2022. Published by Elsevier Inc.)

Background: Visual vertigo (VV) is a condition at which there is worsening or triggering of vestibular symptoms in certain visual environments with large size (full field) repetitive or moving visual patterns as shopping malls., Purpose: This work was designed to study effect of virtual reality and optokinetic stimulation on rehabilitation of VV., Method: A total of 60 subjects divided into 2 groups that were simply randomized by the concealed envelope method: Group I consisted of 30 VV patients underwent vestibular rehabilitation using virtual reality. Group II consisted of 30 VV patients underwent vestibular rehabilitation using optokinetic stimulation., Results: Significant improvement in performance in the two groups after rehabilitation with no statistically significant difference when comparing both groups., Conclusions: A combined intense rehabilitation program including OPK stimulation or VR rehabilitation combined with home-based exercises appeared to be equally effective for management of patients with VV and improving their quality of life., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Assessment of regional myocardial function at native pixel-level resolution can play a crucial role in recognizing the early signs of the decline in regional myocardial function. Extensive data processing in existing techniques limits the effective resolution and accuracy of the generated strain maps. The purpose of this study is to compute myocardial principal strain maps ε p1 and ε p2 from tagged MRI (tMRI) at the native image resolution using deep-learning local patch convolutional neural network (CNN) models (DeepStrain)., Methods: For network training, validation, and testing, realistic tMRI datasets were generated and consisted of 53,606 cine images simulating the heart, the liver, blood pool, and backgrounds, including ranges of shapes, positions, motion patterns, noise, and strain. In addition, 102 in-vivo image datasets from three healthy subjects, and three Pulmonary Arterial Hypertension patients, were acquired and used to assess the network's in-vivo performance. Four convolutional neural networks were trained for mapping input tagging patterns to corresponding ground-truth principal strains using different cost functions. Strain maps using harmonic phase analysis (HARP) were obtained with various spectral filtering settings for comparison. CNN and HARP strain maps were compared at the pixel level versus the ground-truth and versus the least-loss in-vivo maps using Pearson correlation coefficients (R) and the median error and Inter-Quartile Range (IQR) histograms., Results: CNN-based local patch DeepStrain maps at a phantom resolution of 1.1mm × 1.1 mm and in-vivo resolution of 2.1mm × 1.6 mm were artifact-free with multiple fold improvement with ε p1 ground-truth median error of 0.009(0.007) vs. 0.32(0.385) using HARP and ε p2 ground-truth error of 0.016(0.021) vs. 0.181(0.08) using HARP. CNN-based strain maps showed substantially higher agreement with the ground-truth maps with correlation coefficients R > 0.91 for ε p1 and ε p2 compared to R < 0.21 and R < 0.82 for HARP-generated maps, respectively., Conclusion: CNN-generated Eulerian strain mapping permits artifact-free visualization of myocardial function at the native image resolution., (Copyright © 2021. Published by Elsevier Ltd.)

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).)

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., (© 2021 The Authors. Journal of Microscopy published by JohnWiley & Sons Ltd on behalf of Royal Microscopical Society.)

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.

This study aimed to evaluate liver involvement in patients with Carney complex (CNC) based on a large cohort and to analyze any germline PRKAR1A genotype-phenotype association of liver disease. The study included 83 patients with CNC, followed between 1995 and 2018 at a tertiary research center. We reviewed liver images, recorded types and number of lesions and analyzed per genotype: all patients were sequenced for the PRKAR1A gene. A total of 29/83 patients (24.0%) had liver radiological findings. Patients with liver lesion had a significantly higher rate of pathogenic variants detected in the PRKAR1A gene (72.4 vs 38.9%, P = 0.005, respectively). Patients with a pathogenic variant detected on germline PRKAR1A analysis had a higher risk for having a liver lesion compared with patients with wild-type (WT) PRKAR1A alleles (21/42 (50.0%) vs 8/41 (19.5%), respectively, P = 0.004). Among patients with liver lesions, those with a nonsense PRKAR1A pathogenic-variant had more liver lesions (7/7) than among those with other pathogenic-variant types (8/22, P = 0.001). In multivariable analysis, detection of liver lesion(s) was associated with an odds ratio of 5.2 for cardiac myxomas (95% CI 1.55-17.49, P = 0.008). In conclusion, patients with CNC, particularly with a PRKAR1A pathogenic variant, have a higher rate of liver lesions. Additionally, liver lesions are associated with a high risk for cardiac myxomas in this population.

Context: Pheochromocytomas/paragangliomas (PPGLs) are neuroendocrine tumors that can secrete norepinephrine (NE). Brown adipose tissue (BAT) activation is mediated through the action of NE on β-adrenoceptors (β-ARs). In some malignancies, BAT activation is associated with higher cancer activity., Objective: To study the relationship between BAT activation and PPGL clinical outcomes., Design: A retrospective case-control study that included 342 patients with PPGLs who underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (18F-FDG PET/CT) imaging at the National Institutes of Health (NIH). We excluded all patients with parasympathetic tumors and those who underwent 18F-FDG PET/CT after PPGL resection. Scans of 205 patients were reviewed by 2 blinded nuclear medicine physicians; 16 patients had BAT activation on 18F-FDG PET/CT [7.80%; age 27.50 (15.00-45.50) years; 10 female/6 male; body mass index [BMI] 24.90 [19.60-25.35] kg/m2). From the remaining 189 patients, we selected 36 matched controls (age 34.4 [25.4-45.5] years; 21 female/15 male; BMI 25.0 [22.0-26.0] kg/m2)., Primary Outcome Measure: Overall survival., Results: The presence of active BAT on 18F-FDG PET/CT was associated with decreased overall survival when compared with the control group (HRz 5.80; 95% CI, 1.05-32.05; P = 0.02). This association remained significant after adjusting for the SDHB mutation. Median plasma NE in the BAT group was higher than the control group [4.65 vs 0.55 times above the upper limit of normal; P < 0.01]. There was a significant association between higher plasma NE levels and mortality in PPGLs in both groups., Conclusions: Our findings suggest that the detection of BAT activity in PPGL patients is associated with higher mortality. We suggest that BAT activation could either be reflecting or contributing to a state of increased host stress that may predict poor outcome in metastatic PPGL., (Published by Oxford University Press on behalf of the Endocrine Society 2020.)

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.

Measuring coronary artery distensibility can determine the arterial remodeling type, arterial wall inflammation, and atherosclerotic plaques in early stage even before any observed narrowing in the lumen. This is crucial to promote an appropriate, preventive, and effective treatment. This study introduces a framework for calculating the 3D distensibility of the left coronary artery (LCA) from time-resolved coronary computerized tomography angiography (CCTA) images. Vesselness, region growing, and level sets are utilized for segmenting the LCA lumen in the systole and diastole CCTA time frames. The segmented arteries are then analyzed and registered using computational geometry to calculate the changes in the lumen cross-section areas between both time frames. In-vivo validation of the framework performance was accomplished against that of two radiologists and their consensus. Results demonstrate that the framework was accurate and reliable tool for measuring the coronary arteries distensibility.

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.

Context: Postprandial hyperinsulinemia might be an important cardiometabolic risk determinant in black compared with white women. However, the contributions of insulin clearance and β-cell function to racial differences in postprandial insulin response are unknown., Objective: To compare, by race and menopause, early insulin response to oral and intravenous glucose and to measure postprandial intact glucagon-like peptide 1 (GLP-1) concentrations, insulin clearance, and β-cell function., Design and Participants: 119 federally employed women without diabetes [87 premenopausal (52 black, 35 white) and 32 postmenopausal (19 black, 13 white)] underwent an oral glucose tolerance test, insulin-modified frequently sampled intravenous glucose test (IM-FSIGT), and mixed meal tolerance test (MMTT)., Outcome Measures: Early insulin response was measured as follows: (i) insulinogenic index (oral glucose tolerance test); (ii) acute insulin response to glucose (IM-FSIGT); and (iii) ratio of incremental insulin/glucose area under the curve in the first 30 minutes of the MMTT. Insulin clearance was assessed during the IM-FSIGT and MMTT. During the MMTT, intact GLP-1 was measured and β-cell function assessed using the insulin secretion rate and β-cell responsivity indexes., Results: Black pre-menopausal and postmenopausal women had a greater insulin response and lower insulin clearance and greater dynamic β-cell responsivity (P ≤ 0.05 for all). No differences were found in the total insulin secretion rates or intact GLP-1 concentrations., Conclusions: Greater postprandial hyperinsulinemia in black pre-menopausal and postmenopausal women was associated with lower hepatic insulin clearance and heightened β-cell capacity to rapid changes in glucose, but not to higher insulin secretion. The relationship of increased β-cell secretory capacity, reduced insulin clearance, and ambient hyperinsulinemia to the development of cardiometabolic disease requires further investigation.

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.

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 c 0 , 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 c 0 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., (© 2018 John Wiley & Sons, Ltd.)

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.

Introduction: Subjects with unilateral hearing loss (UHL) report difficulties in speech understanding in noise. Speech-evoked auditory brainstem response (S-ABR) provides cues for temporal and spectral encoding of speech in the brainstem. S-ABR recording in noise increases its sensitivity in evaluating the auditory processing and related disorders., Objectives: Study speech encoding at the level of brainstem when the auditory system relies on one ear and to study the effect of noise on this encoding., Subjects and Method: This study included two groups: control group consisted of 15 adults with normal hearing sensitivity and study group consisted of 30 adults with UHL. The study group was further subdivided into two subgroups: study subgroup A (SG A) consisted of 15 adults with right functioning ears and study subgroup B (SG B) consisted of 15 adults with left functioning ears. S-ABR in quiet and with ipsilateral noise was recorded in both the groups using complex ABR advanced auditory research module., Results: In UHL, there was a statistically significant delay in the S-ABR onset and offset in noise compared to quiet. Moreover, quiet-noise (+5 SNR) correlation was significantly low compared to NH. Furthermore, pitch representation (F0 amplitude) was significantly degraded with noise. In addition, there was a statistically significant noise-induced phase shift in the transition region of speech syllable in these subjects., Conclusion: In monaural processing, pitch representation (F0 amplitude) and cross-phaseogram were the main affected domains. Speech phonemes of transient origin can be confused in subjects with UHL.

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.)