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Penetrating injury to the head and neck accounts for a minority of trauma but significant morbidity in the US civilian population. The 3-zone anatomical framework has historically guided evaluation and management; however, the most current evidence-based protocols favor a no-zone, systems-based approach. In stable patients, a thorough physical examination and noninvasive imaging should be prioritized, with surgical exploration of the head and neck reserved for certain circumstances. Diagnostic and management decisions should be tailored to the mechanism of injury, history, physical examination, experience of personnel, availability of equipment, and clinical judgment.

This study evaluated the impact of cell debris and 7-day room temperature storage on the quality and yield of transrenal DNA. Archived urine specimens collected from five hepatocellular carcinoma (HCC) patients and two pregnant women carrying male fetuses were used to assess the impact of cell debris on urine cell-free DNA (ucfDNA) isolation as measured by quantitative PCR for Y-chromosome DNA, or HCC-associated mutation and methylation markers, and by capillary electrophoresis. Prospectively collected urine from 21 HCC patients was aliquoted after collection for paired immediate freezing versus 7-day room temperature storage followed by freezing for further analysis. Cell debris contained more Y-chromosome DNA than supernatant in three of the six urine specimens tested from pregnant women, suggesting that cell debris can be associated with 20.6% to 84.9% of transrenal ucfDNA. Ninety-five percent (20 of 21) of frozen and room temperature urine pairs had overlapping DNA size distribution. ucfDNA quantity determined by quantitative PCR for TP53, CTNNB1, TERT, and HCC-associated urine circulating tumor DNA markers were statistically similar between room temperature and frozen samples. This suggests no significant difference in DNA degradation between the groups. The association of transrenal ucfDNA with cell debris and HCC circulating DNA stability at room temperature is significant to further the understanding of transrenal circulating tumor DNA pre-analytical handling for HCC screening.

Elevated triglycerides and non-high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an RNA interference therapy that targets angiopoietin-like protein 3 (ANGPTL3), a regulator of lipoprotein metabolism. This first-in-human, phase 1, randomized, placebo-controlled, open-label trial investigated single and repeat ARO-ANG3 doses in four cohorts of fifty-two healthy participants and one cohort of nine participants with hepatic steatosis, part of a basket trial. Safety (primary objective) and pharmacokinetics (in healthy participants) and pharmacodynamics (secondary objectives) of ARO-ANG3 were evaluated. ARO-ANG3 was generally well tolerated, with similar frequencies of treatment-emergent adverse events in active and placebo groups. Systemic absorption of ARO-ANG3 in healthy participants was rapid and sustained, with a mean Tmaxof 6.0–10.5 h and clearance from plasma within 24–48 h after dosing with a mean t½of 3.9–6.6 h. In healthy participants, ARO-ANG3 treatment reduced ANGPTL3 (mean −45% to −78%) 85 days after dose. Reductions in triglyceride (median −34% to −54%) and non-HDL-C (mean −18% to −29%) (exploratory endpoints) concentrations occurred with the three highest doses. These early-phase data support ANGPTL3 as a potential therapeutic target for ASCVD treatment. ClinicalTrials.gov identifier: NCT03747224

Background: The arteriovenous fistula (AVF) is the preferred vascular access for End Stage Renal Disease, having superior patency and lower infection risks than prosthetic graft and catheter access. When AVF dysfunction or delayed maturation does occur, the gold standard for diagnosis is the fistula angiogram (a.k.a. fistulogram). 3D ultrasound is available for obstetrical and other specialized uses, but it is cost prohibitive and has a field of view that is too small to cover the region of interest for the dialysis fistula application. We sought to develop a point of care 3D solution using freehand 2D ultrasound data acquisition.Methods: We developed open-source software for 3D image reconstruction and projection of an angiogram-like image of the vascular access using a 2D freehand ultrasound scanner. We evaluated this software by comparing the ultrasound “sono-angiogram” images to fistulogram images in five subjects, using visual inspection and by applying the Percent of Exact Match (PEM) as a statistic test.Results: The sono-angiograms showed identifiable characteristics that matched the fistulogram results in all five subjects. The PEM ranged between 42.8% and 77.0%, with Doppler and grayscale ultrasound data, showing complementary advantages and disadvantages when used for sono-angiogram image construction. Motion from freehand ultrasound acquisition was a significant source of mismatch. 3D image generation is a potential advantage with ultrasound data.Conclusions: While further work is needed to improve the accuracy with free hand scanning, fistulogram-like “sono-angiograms” can be generated using point of care 2D ultrasound. Methods such as these may be able to assist in point-of-care diagnosis in the future. The software is open-source, and importantly, the ultrasound data used are non-proprietary and available from any standard ultrasound machine. The simplicity and accessibility of this approach warrant further study.

The development of transgenic mouse models that express genes of interest in specific cell types has transformed our understanding of basic biology and disease. However, generating these models is time- and resource-intensive. Here we describe a model system, SELective Expression and Controlled Transduction In Vivo (SELECTIV), that enables efficient and specific expression of transgenes by coupling adeno-associated virus (AAV) vectors with Cre-inducible overexpression of the multi-serotype AAV receptor, AAVR. We demonstrate that transgenic AAVR overexpression greatly increases the efficiency of transduction of many diverse cell types, including muscle stem cells, which are normally refractory to AAV transduction. Superior specificity is achieved by combining Cre-mediated AAVR overexpression with whole-body knockout of endogenous Aavr, which is demonstrated in heart cardiomyocytes, liver hepatocytes and cholinergic neurons. The enhanced efficacy and exquisite specificity of SELECTIV has broad utility in development of new mouse model systems and expands the use of AAV for gene delivery in vivo.

The article focuses on the importance of systems thinking in healthcare leadership to improve quality, safety, and overall performance. It highlights the need for a holistic approach to address complex problems and encourages leaders to break down silos and promote collaboration among different systems in healthcare organizations.

The article presents the discussion on healthcare organizations as well international students representing healthcare. Topics include meeting staffing needs, the use of agency staffing, management communication, and onboarding of staff and physicians containing proper orientation; and management of telephonic communication, tackling system work related problems or just the lack of demonstrated management ability.

To investigate the feasibility of ultrasound elastography for assessing the symmetry in stiffness values and movements of both false vocal folds (FVFs). After Institutional Review Board's approval and written informed consent obtained, we measured ultrasound strain and shear wave velocity (SWV) of the bilateral FVF in vocal fold abduction and adduction in 30 participants using a linear array transducer (4–10 MHz). Twenty‐eight participants met inclusion criteria as healthy subjects for analysis. Mean strain of FVF produced by FVF movement from abduction to adduction was analyzed using 2D speckle‐tracking software offline. A SWV ratio ([SWVadduction– SWabduction]/SWabduction) was developed to test the contractibility of FVF. Statistical analysis included one‐way ANOVA to test the difference in mean strain, SWV (adduction and abduction), and SWV ratio among the three age groups; linear regression to analyze correlations of stiffness and movement between the right and left FVF; and intraclass correlation coefficient (ICC) to examine intra‐ and interobserver reliability in performing shear wave elastography (SWE) of FVF. The 28 healthy participants were divided into 3 age groups (10 of young 20–44 years; 9 of mid‐age 45–64 years; and 9 of senior ≥65 years). The SWV in FVF abduction was higher and the SWV ratio was lower in seniors compared to young participants (P< .05). Good to excellent correlation of mean strain and SWV between both FVFs (R2> 0.89). The reliability of performing SWE of FVF was moderate to excellent. Ultrasound elastography is feasible to assess the stiffness, dynamic movement, and symmetry of adult FVF, and healthy seniors may exhibit increased FVF stiffness.

Introduction: Dialysis vascular access, preferably an autogenous arteriovenous fistula, remains an end stage renal disease (ESRD) patient’s lifeline providing a means of connecting the patient to the dialysis machine. Once an access is created, the current gold standard of care for maintenance of vascular access is angiography and angioplasty to treat stenosis. While point of care 2D ultrasound has been used to detect access problems, we sought to reproduce angiographic results comparable to the gold standard angiogram (fistulogram) using ultrasound data acquired from a conventional 2D ultrasound scanner.Methods: A 2D ultrasound probe was used to acquire a series of cross sectional images of the vascular access including arteriovenous anastomosis of a subject with a radio-cephalic fistula. These 2D B-mode images were used for 3D vessel reconstruction by binary thresholding to categorize vascular versus non-vascular structures followed by standard image segmentation to select the structure representative of dialysis vascular access and morphologic filtering. Image processing was done using open source Python Software.Results: The open source software was able to: (1) view the gold standard fistulogram images, (2) reconstruct 2D planar images of the fistula from ultrasound data as viewed from the top, analogous to computerized tomography images, and (3) construct a 2D representation of vascular access similar to the angiogram.Conclusion: We present a simple approach to obtain an angiogram-like representation of the vascular access from readily available, non-proprietary 2D ultrasound data in the point of care setting. While the sono-angiogram is not intended to replace angiography, it may be useful in providing 3D imaging at the point of care in the dialysis unit, outpatient clinic, or for pre-operative planning for interventional procedures. Future work will focus on improving the robustness and quality of the imaging data while preserving the straightforward freehand approach used for ultrasound data acquisition.

Ultrasound is useful in predicting arteriovenous fistula (AVF) maturation, which is essential for hemodialysis in end‐stage renal disease patients. We developed ultrasound software that measures circumferential vessel wall strain (distensibility) using conventional ultrasound Digital Imaging and Communications in Medicine (DICOM) data. We evaluated user‐induced variability in measurement of arterial wall distensibility and upon finding considerable variation we developed and tested 2 methods for semiautomated measurement. Ultrasound scanning of arteries of 10 subjects scheduled for AVF surgery were performed. The top and bottom of the vessel wall were tracked using the Kanade‐Lucas‐Tomasi (KLT) feature‐tracking algorithm over the stack of images in the DICOM cine loops. The wall distensibility was calculated from the change of vessel diameter over time. Two semiautomated methods were used for comparison. The location of points selected by users for the cine loops varied significantly, with a maximum spread of up to 120 pixels (7.8 mm) for the top and up to 140 pixels (9.1 mm) for the bottom of the vessel wall. This variation in users' point selection contributed to the variation in distensibility measurements (ranging from 5.63 to 41.04%). Both semiautomated methods substantially reduced variation and were highly correlated with the median distensibility values obtained by the 10 users. Minimizing user‐induced variation by standardizing point selection will increase reproducibility and reliability of distensibility measurements. Our recent semiautomated software may help expand use in clinical studies to better understand the role of vascular wall compliance in predicting the maturation of fistulas.

Isolated communities are located far from major electrical networks and sources (i.e., bulk interconnected power systems) and, therefore, grid connection to these sources may not be practical or economically justified. Electricity in isolated remote areas is generated and consumed locally within an arrangement of electrical components deployed to supply, transfer, and consume local electricity. Such networks are called isolated power systems (IPSs), which, subject to their specific application, can have different compositions and configurations.

Mitochondria generate heat due to H+leak (IH) across their inner membrane1. IHresults from the action of long-chain fatty acids on uncoupling protein 1 (UCP1) in brown fat2–6and ADP/ATP carrier (AAC) in other tissues1,7–9, but the underlying mechanism is poorly understood. As evidence of pharmacological activators of IHthrough UCP1 and AAC is lacking, IHis induced by protonophores such as 2,4-dinitrophenol (DNP) and cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP)10,11. Although protonophores show potential in combating obesity, diabetes and fatty liver in animal models12–14, their clinical potential for treating human disease is limited due to indiscriminately increasing H+conductance across all biological membranes10,11and adverse side effects15. Here we report the direct measurement of IHinduced by DNP, FCCP and other common protonophores and find that it is dependent on AAC and UCP1. Using molecular structures of AAC, we perform a computational analysis to determine the binding sites for protonophores and long-chain fatty acids, and find that they overlap with the putative ADP/ATP-binding site. We also develop a mathematical model that proposes a mechanism of uncoupler-dependent IHthrough AAC. Thus, common protonophoric uncouplers are synthetic activators of IHthrough AAC and UCP1, paving the way for the development of new and more specific activators of these two central mediators of mitochondrial bioenergetics.

This study presents an edge detection and speckle tracking (EDST) based algorithm to calculate distensibility as percentage of change of vessel diameter during cardiac cycles. Canny edge detector, Vandermonde matrix representation, Kanade Lucas Tomasi algorithm with pyramidal segmentation, and penalized least squares technique identifies the vessel lumen edge, track the vessel diameter, detrend the signal and find peaks and valleys when the vessel is fully distended or contracted. An upper extremity artery from 10 patients underwent an ultrasound examination as part of preoperative evaluation before arteriovenous fistula surgery. Three studies were performed to evaluate EDST with automatic peak and valley selection versusmanual speckle selection of expert users using manual peak and valley selection. Results demonstrate the effectiveness of the proposed methodology, to obtain comparable results as those obtained by expert-users, and considerably reducing the variability associated with external factors such as excessive motion, fluctuations in stroke volume, beat-to-beat blood pressure changes, breathing cycles, and arm-transducer pressure.

Maintaining dialysis vascular access is a source of considerable morbidity in patients with end-stage renal disease (ESRD). High-resolution radiofrequency (RF) ultrasound vascular strain imaging has been applied experimentally in the vascular access setting to assist in diagnosis and management. Unfortunately, high-resolution RF data are not routinely accessible to clinicians. In contrast, the standard DICOM formatted B-mode ultrasound data are widely accessible. However, B-mode, representing the envelope of the RF signal, is of much lower resolution. If strain imaging could use open-source B-mode data, these imaging techniques could be more broadly investigated. We conducted experiments to detect wall strain signals with submillimeter tracking resolutions ranging from 0.2 mm (3 pixels) to 0.65 mm (10 pixels) using DICOM B-mode data. We compared this submillimeter tracking to the overall vascular distensibility as the reference measurements to see if high-strain resolution strain could be detected using open-source B-Mode data. We measured the best-fit coefficient of determination between signals, expressed as the percentage of strain waveforms that exhibited a correlation with a pvalue of 0.05 or less. The lowest percentage was 86.7%, and most were 90% and higher. This indicates high-resolution strain signals can be detected within the vessel wall using B-mode DICOM data.

We used novel open source software, based on an ultrasound speckle tracking algorithm, to examine the distensibility of the vessel wall of the inflow artery, anastomosis, and outflow vein before and after two procedures. An 83-year-old white man with a poorly maturing radio-cephalic fistula received an angioplasty at the anastomosis followed by branch ligation 28 days later. Duplex Doppler measurements corroborated the blood flow related changes anticipated from the interventions. The experimental distensibility results showed that it is technically feasible to measure subtle vessel wall motion changes with high resolution (sub-millimeter) using standard Digital Imaging and Communications in Medicine (DICOM) ultrasound data, which are readily available on conventional ultrasound scanners. While this methodology was originally developed using high resolution radiofrequency from ultrasound data, the goal of this study was to use DICOM data, which makes this technology accessible to a wide range of users.

Liver transplantation (LT) from donors‐with‐HIV to recipients‐with‐HIV (HIV D+/R+) is permitted under the HOPE Act. There are only three international single‐case reports of HIV D+/R+ LT, each with limited follow‐up. We performed a prospective multicenter pilot study comparing HIV D+/R+ to donors‐without‐HIV to recipients‐with‐HIV (HIV D−/R+) LT. We quantified patient survival, graft survival, rejection, serious adverse events (SAEs), human immunodeficiency virus (HIV) breakthrough, infections, and malignancies, using Cox and negative binomial regression with inverse probability of treatment weighting. Between March 2016–July 2019, there were 45 LTs (8 simultaneous liver‐kidney) at 9 centers: 24 HIV D+/R+, 21 HIV D−/R+ (10 D− were false‐positive). The median follow‐up time was 23 months. Median recipient CD4 was 287 cells/µL with 100% on antiretroviral therapy; 56% were hepatitis C virus (HCV)‐seropositive, 13% HCV‐viremic. Weighted 1‐year survival was 83.3% versus 100.0% in D+ versus D− groups (p= .04). There were no differences in one‐year graft survival (96.0% vs. 100.0%), rejection (10.8% vs. 18.2%), HIV breakthrough (8% vs. 10%), or SAEs (all p> .05). HIV D+/R+ had more opportunistic infections, infectious hospitalizations, and cancer. In this multicenter pilot study of HIV D+/R+ LT, patient and graft survival were better than historical cohorts, however, a potential increase in infections and cancer merits further investigation. A multicenter study of HIV+ donor to HIV+ recipient liver transplantation under the HOPE Act shows that patient and graft survival were better than historical cohorts, but the possible increased incidence of infections and cancer merits further investigation.

Background and aimsAcute-on-chronic liver failure (ACLF) is characterised by acute decompensation of cirrhosis associated with organ failures. We systematically evaluated the geographical variations of ACLF across the world in terms of prevalence, mortality, aetiology of chronic liver disease (CLD), triggers and organ failures.MethodsWe searched EMBASE and PubMed from 3/1/2013 to 7/3/2020 using the ACLF-EASL-CLIF (European Association for the Study of the Liver-Chronic Liver Failure) criteria. Two investigators independently conducted the abstract selection/abstraction of the aetiology of CLD, triggers, organ failures and prevalence/mortality by presence/grade of ACLF. We grouped countries into Europe, East/South Asia and North/South America. We calculated the pooled proportions, evaluated the methodological quality using the Newcastle-Ottawa Scale and statistical heterogeneity, and performed sensitivity analyses.ResultsWe identified 2369 studies; 30 cohort studies met our inclusion criteria (43 206 patients with ACLF and 140 835 without ACLF). The global prevalence of ACLF among patients admitted with decompensated cirrhosis was 35% (95% CI 33% to 38%), highest in South Asia at 65%. The global 90-day mortality was 58% (95% CI 51% to 64%), highest in South America at 73%. Alcohol was the most frequently reported aetiology of underlying CLD (45%, 95% CI 41 to 50). Infection was the most frequent trigger (35%) and kidney dysfunction the most common organ failure (49%). Sensitivity analyses showed regional estimates grossly unchanged for high-quality studies. Type of design, country health index, underlying CLD and triggers explained the variation in estimates.ConclusionsThe global prevalence and mortality of ACLF are high. Region-specific variations could be explained by the type of triggers/aetiology of CLD or grade. Health systems will need to tailor early recognition and treatment of ACLF based on region-specific data.

ObjectiveWe examined the serological, virological (in serum and liver) and histological profiles in chronic hepatitis B virus (HBV) patients during and after completion of multiple dose (MD) ARC-520.DesignThe present phase 1b study was a multidose, open-label extension cohort of patients that had received single dose ARC-520 in our previous study. Eight patients received 4–9 4 weekly doses of MD ARC-520 and entecavir. Liver biopsies were performed in six patients. Intrahepatic and serum HBV DNA, HBV RNA and viral antigens were measured.ResultsAll patients had 28.9–30.4 months of follow-up after the last MD. All three hepatitis B e antigen (HBeAg)-positive patients had profound reductions in hepatitis B surface antigen (HBsAg), HBeAg, hepatitis B core-related antigen and HBV RNA with two undergoing HBeAg seroconversion. One further achieved HBsAg seroconversion (anti-HBs level of 25.1 IU/L) and the remaining two had HBsAg reductions of −1.7 and −3.5 log IU/mL >30 months after MD. Among the five HBeAg-negative patients, four had modest HBsAg reduction >29 months after completion of MD and one achieved HBsAg seroconversion (anti-HBs level of 152.5 IU/L) and was negative for liver HBsAg staining. Entecavir was successfully stopped in this patient 12 months after HBsAg seroconversion. Temporally related alanine aminotransferase elevations preceded by HBsAg reductions were observed in three patients suggesting immune activation. HBcAg staining was negative in all six biopsied patients. Two patients with <10% HBsAg positive staining of hepatocytes had correspondingly low serum HBsAg levels of 1.5 and 11.5 IU/mL.ConclusionsMD ARC-520 therapy achieved sustained and profound reductions of viral antigens and HBV RNA. HBsAg seroclearance was achievable.Trial registration numberNCT02065336.

Wilson disease (WND) is caused by inactivation of the copper transporter ATP7B and copper accumulation in tissues. WND presentations vary from liver steatosis to inflammation, fibrosis, and liver failure. Diets influence the liver phenotype in WND, but findings are inconsistent. To better understand the impact of excess calories on liver phenotype in WND, the study compared C57BL/6J Atp7b−/−and C57BL/6J mice fed for 12 weeks with Western diet or normal chow. Serum and liver metabolites, body fat content, liver histology, hepatic proteome, and copper content were analyzed. Wild-type and Atp7b−/−livers showed striking similarities in their responses to Western diet, most notably down-regulation of cholesterol biosynthesis, altered nuclear receptor signaling, and changes in cytoskeleton. Western diet increased body fat content and induced liver steatosis in males and females regardless of genotype; however, the effects were less pronounced in Atp7b−/−mice compared with those in the wild type mice. Although hepatic copper remained elevated in Atp7b−/−mice, liver inflammation was reduced. The diet diminished signaling by Rho GTPases, integrin, IL8, and reversed changes in cell cycle machinery and cytoskeleton. Overall, high calories decreased inflammatory response in favor of steatosis without improving markers of cell viability. Similar changes of cellular pathways during steatosis development in wild-type and Atp7b−/−mice explain histologic overlap between WND and non-alcoholic fatty liver disease despite opposite copper changes in these disorders.

AbstractIn this article James Hamilton, Research Principal at the Society of Writers to HM Signet in Edinburgh, describes the history of the Signet Library as it approaches its 300thanniversary. He writes about some of the changes that have taken place over those three centuries and he also mentions some of the challenges for the library as the nature of the legal profession has altered, not least those presented recently by the Covid-19 pandemic.

AbstractAdverse childhood experiences (ACEs) are associated with a high risk of developing chronic diseases and decreased life expectancy, but no ACE epigenetic biomarkers have been identified until now. The latter may result from the interaction of multiple factors such as age, sex, degree of adversity, and lack of transcriptional effects of DNA methylation changes. We hypothesize that DNA methylation changes are related to childhood adversity levels and current age, and these markers evolve as aging proceeds. Two Gene Expression Omnibus datasets, regarding ACE, were selected (GSE72680 and GSE70603), considering raw- and meta-data availability, including validated ACE index (Childhood Trauma Questionnaire (CTQ) score). For DNA methylation, analyzed probes were restricted to those laying within promoters and first exons, and samples were grouped by CTQ scores terciles, to compare highly (ACE) with non-abused (control) cases. Comparison of control and ACE methylome profile did not retrieve differentially methylated CpG sites (DMCs) after correcting by false discovery rate < 0.05, and this was also observed when samples were separated by sex. In contrast, grouping by decade age ranges (i.e., the 20s, 30s, 40s, and 50s) showed a progressive increase in the number of DMCs and the intensity of changes, mainly related with hypomethylation. Comparison with transcriptome data for ACE subjects in the 40s, and 50s showed a similar age-dependent effect. This study provides evidence that epigenetic markers of ACE are age-dependent, but not defined in the long term. These differences among early, middle, and late adulthood epigenomic profiles suggest a window for interventions aimed to prevent the detrimental effects of ACE.

Nonalcoholic fatty liver disease (NAFLD) has become one of the most common causes of chronic liver disease worldwide. The prevalence of NAFLD has grown proportionally with the rise in obesity, sedentary lifestyle, unhealthy dietary patterns, and metabolic syndrome. Currently, in the absence of approved pharmacologic treatment, the keystone of treatment is lifestyle modification focused on achieving a weight loss of 7%–10%, cardiovascular exercise, and improving insulin sensitivity. The primary aim of this review is to outline the effect of different dietetic approaches against NAFLD and highlight the important micronutrient components in the management of NAFLD.

Australia’s waste management is heavily dependent on landfill. The Australian Bureau of Statistics predicts that as Australia’s population and economy grow, there will be a significant increase in the magnitude of waste output. Concentrated solar driven pyrolysis has been identified as a promising means in creating renewable liquid fuel and improving waste management. This technology is based on the upgrading of waste into a valuable commodity. This is of interest to city councils, communities and stakeholders, as both Australia’s annual waste generation and energy demands are growing rapidly. This paper provides a case for the implementation of solar-driven pyrolysis for biofuel production in the Australian state of Victoria as well as a comparative analysis of different Renewable Energy Sources and biomass reactions to justify the combination of Concentrated Solar Power with pyrolysis. This study is the first to assess the solar-driven pyrolysis under a Victorian setting. Victoria was chosen due to the comprehensive and readily available waste data kept by its government. The review concluded that a combination of Fresnel Reflector CSP and pyrolysis are best suited for regional Victorian environment. Fresnel reflector technology was found to complement slow pyrolysis well due to its 250–500◦C operating temperature, while regional Victoria was found to be a good trade-off between feedstock distance and DNI exposure. These requirements were important because feedstock transportation was found to cost $AUD 96 per 500km, and it was observed that there could be up to 1200 kWh/m2solar exposure difference between Victorian rural and metropolitan locations. This study provides a comprehensive framework of technical requirements pertaining to a Victorian solar-driven pyrolysis system, which will then act as a guidance for future designers.

Membrane-bound proteins have been proposed to mediate the transport of long-chain FA (LCFA) transport through the plasma membrane (PM). These proposals are based largely on reports that PM transport of LCFAs can be blocked by a number of enzymes and purported inhibitors of LCFA transport. Here, using the ratiometric pH indicator (2′,7′-bis-(2-carboxyethyl)-5-(and-6-)-carboxyfluorescein and acrylodated intestinal FA-binding protein-based dual fluorescence assays, we investigated the effects of nine inhibitors of the putative FA transporter protein CD36 on the binding and transmembrane movement of LCFAs. We particularly focused on sulfosuccinimidyl oleate (SSO), reported to be a competitive inhibitor of CD36-mediated LCFA transport. Using these assays in adipocytes and inhibitor-treated protein-free lipid vesicles, we demonstrate that rapid LCFA transport across model and biological membranes remains unchanged in the presence of these purported inhibitors. We have previously shown in live cells that CD36 does not accelerate the transport of unesterified LCFAs across the PM. Our present experiments indicated disruption of LCFA metabolism inside the cell within minutes upon treatment with many of the “inhibitors” previously assumed to inhibit LCFA transport across the PM. Furthermore, using confocal microscopy and a specific anti-SSO antibody, we found that numerous intracellular and PM-bound proteins are SSO-modified in addition to CD36. Our results support the hypothesis that LCFAs diffuse rapidly across biological membranes and do not require an active protein transporter for their transmembrane movement.

Angiopoietin-like protein 3 (ANGPTL3) inhibits lipid clearance and is a promising target for managing cardiovascular disease. Here we investigated the effects of a high-sugar (high-fructose) diet on circulating ANGPTL3 concentrations in rhesus macaques. Plasma ANGPTL3 concentrations increased ∼30% to 40% after 1 and 3 months of a high-fructose diet (both P< 0.001 vs. baseline). During fructose-induced metabolic dysregulation, plasma ANGPTL3 concentrations were positively correlated with circulating indices of insulin resistance [assessed with fasting insulin and the homeostatic model assessment of insulin resistance (HOMA-IR)], hypertriglyceridemia, adiposity (assessed as leptin), and systemic inflammation [C-reactive peptide (CRP)] and negatively correlated with plasma levels of the insulin-sensitizing hormone adropin. Multiple regression analyses identified a strong association between circulating APOC3 and ANGPTL3 concentrations. Higher baseline plasma levels of both ANGPTL3 and APOC3 were associated with an increased risk for fructose-induced insulin resistance. Fish oil previously shown to prevent insulin resistance and hypertriglyceridemia in this model prevented increases of ANGPTL3 without affecting systemic inflammation (increased plasma CRP and interleukin-6 concentrations). ANGPTL3RNAi lowered plasma concentrations of ANGPTL3, triglycerides (TGs), VLDL-C, APOC3, and APOE. These decreases were consistent with a reduced risk of atherosclerosis. In summary, dietary sugar-induced increases of circulating ANGPTL3 concentrations after metabolic dysregulation correlated positively with leptin levels, HOMA-IR, and dyslipidemia. Targeting ANGPTL3 expression with RNAi inhibited dyslipidemia by lowering plasma TGs, VLDL-C, APOC3, and APOE levels in rhesus macaques.

Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH.

Background/Objectives: Coffee consumption has been found to be associated with reduced risk of chronic conditions such as liver disease. However, less is known about the association between coffee and liver-related hospitalizations and deaths. Subjects/Methods: We conducted a prospective analysis on 14,208 participants aged 45–64 years from the Atherosclerosis Risk in Communities (ARIC) study. Coffee consumption (cups/day) was assessed using food frequency questionnaires at visit 1 (1987–89) and visit 3 (1993–95). Liver-related hospitalizations were defined as a hospitalization with any International Classification of Diseases, Ninth Revision (ICD-9) code related to liver disease identified through cohort surveillance. Liver-related death was defined as any death with a liver disease ICD-9 code listed anywhere on the death certificate form. Results: There were 833 incident cases of liver-related hospitalizations over a median follow-up of 24 years and 152 liver-related deaths over a median follow-up of 25 years. Participants who were in the highest category of coffee consumption (=?3 cups/day) were more likely to be men, whites, current smokers, and current alcohol drinkers. In our fully adjusted model, consuming =?3 cups/day of coffee was significantly associated with a reduced risk of liver-related hospitalizations compared with never drinkers (hazard ratio: 0.79, 95% CI: 0.63–0.99). There were no significant associations between coffee consumption and liver-related deaths after adjusting for covariates. Conclusions: Coffee drinkers may be at lower risk for liver-related hospitalizations. This supports current evidence that low and moderate levels of coffee may be protective to the liver.

Background:Hepatocellular carcinoma (HCC) is now the second-highest cause of cancer death worldwide. Recent studies have discovered a wide range of somatic mutations in HCC. These mutations involve various vital signaling pathways such as: Wnt/β-Catenin, p53, telome­rase reverse transcriptase (TERT), chromatin remodeling, RAS/MAPK signaling, and oxidative stress. However, fusion transcripts have not been broadly explored in HCC. Methods:To identify novel fusion transcripts in HCC, in the first phase of our study, we performed targeted RNA sequencing (in HCC and paired non-HCC tissues) on 6 patients with a diagnosis of HCC undergoing liver transplantation. Results:As a result of these studies, we discovered the novel fusion transcript, VTI1A-CFAP46. In the second phase of our study, we measured the expression of wild-type VTI1A in 21 HCC specimens, which showed that 10 of 21 exhibited upregulation of wild-type VTI1A in their tumors. VTI1A (Vesicle Transport via Interaction with t-SNARE homolog 1A) is a member of the Soluble N-ethylmaleimide-Sensitive Factor (NSF) attachment protein receptor (SNARE) gene family, which is essential for membrane trafficking and function in endocytosis, autophagy, and Golgi transport. Notably, it is known that autophagy is involved in HCC. Conclusions:The link between novel fusion transcript VTI1A-CFAP46 and autophagy as a potential therapeutic target in HCC patients deserves further investigation. Moreover, this study shows that fusion transcripts are worthy of additional exploration in HCC.

Dyslipidemia and insulin resistance are significant adverse outcomes of consuming high-sugar diets. Conversely, dietary fish oil (FO) reduces plasma lipids. Diet-induced dyslipidemia in a rhesus model better approximates the pathophysiology of human metabolic syndrome (MetS) than rodent models. Here, we investigated relationships between metabolic parameters and hypertriglyceridemia in rhesus macaques consuming a high-fructose diet (n = 59) and determined the effects of FO supplementation or RNA interference (RNAi) on plasma ApoC3 and triglyceride (TG) concentrations. Fructose supplementation increased body weight, fasting insulin, leptin, TGs, and large VLDL particles and reduced adiponectin concentrations (all P< 0.001). In multiple regression analyses, increased plasma ApoC3 was the most consistent and significant variable related to diet-induced hypertriglyceridemia. FO supplementation, which attenuated increases of plasma TG and ApoC3 concentrations, reversed fructose-induced shifts of lipoprotein particle size toward IDL and VLDL, a likely mechanism contributing to beneficial metabolic effects, and reduced hepatic expression of genes regulated by the SREBP pathway, particularly acetyl-CoA carboxylase. Furthermore, RNAi-mediated ApoC3 inhibition lowered plasma TG concentrations in animals with diet-induced hypertriglyceridemia. In summary, ApoC3 is an important independent correlate of TG-rich lipoprotein concentrations in rhesus macaques consuming a high-fructose diet. ApoC3 is a promising therapeutic target for hypertriglyceridemia in patients with MetS and diabetes.

This article demonstrates a method of cultural–historical analysis in which digital archives of magazines and newspapers play a central role. It addresses the formation of broadcasting as a particular complex of social relationships and, further, that can be addressed by investigating changes in the concept of broadcasting itself. Primary sources include digital archives of newspapers and magazines, supplemented by appropriate additional primary and secondary sources. The key question is how a late-1700s agricultural conception of broadcasting as the hand-spreading of seeds in a field emerged in the 1920s radio era and beyond as the indiscriminate electronic distribution of messages. The study documents a gradual, sedimented, radically historical process of mystification and naturalization, in which broadcasting is transmogrified from a human practice of agriculture (an intrinsically human activity) into the electromagnetic basis of modern media systems (a phenomenon of nature and thus by definition outside human control and beyond question or change). The article concludes with reflections about the research process described here, as well as about the value more generally of critical commentary regarding historical methods.

The chief of surgery of a 264-bed acute care facility and clinic system in Topeka, KS, USA, gives a chronology that illustrates the rapid and profound clinical, economic, and emotional impact of the SARS-CoV-2 outbreak on his hospital and community. In his view, the pandemic has laid bare the weaknesses of several factors basic to the modern US health care system and the resulting economic crisis: just-in-time supply chain technology; foreign sourcing of masks, gowns, and critical equipment, all at critical shortages during the crisis; rural hospital closings; lack of excess capacity through maximization of utilization for efficiency; and an overreliance on high revenue elective procedures and tests. His team was tested by an emergency operation for bowel obstruction that put all the isolation protocols into action. Despite their readiness and the success of the operation and the potential for telemedicine as an alternative to in-person evaluations and outpatient visits, the forced cancellation of all elective operations have led to the loss of revenue for both hospital system and providers, furlough and termination of workers, and financial hardship and uncertainty.

ABSTRACTWe describe the treatment of a preadolescent who presented with nonepileptic seizures. He had received a diagnosis of conversion disorder from the referring provider. We implemented a treatment strategy that construed a negative reinforcer of the absence of seizure-like behaviors (restricting then reintroducing screen time contingent upon seizure-free status) as an active neurological treatment (resting his brain) for his seizures. His seizures abated immediately and had not returned at 1-month or 1-year follow-up. The case illustrates the importance of providing face-saving ways for patients to relinquish the sick role. We also discuss possible alternative approaches to diagnosis in cases like this one. Specifically, we address negative consequences of biases in the Diagnostic and Statistical Manual of Mental Disordersthat promote the view that excessive illness behavior is the product of unconscious processes and that discourage recognition that the illness behavior may be intentional and strategic.

ARC-520 Injection, an RNA interference drug for the treatment of hepatitis B that targets cccDNA-derived viral mRNA transcripts with high specificity, effectively reduces the production of viral proteins and HBV DNA. In this phase 1 randomized, double-blind, placebo-controlled study, 54 healthy volunteers (half male, half female) received a single, intravenous dose of 0.01–4.0 mg/kg ARC-520 Injection (n = 36) or placebo (n = 18). Assessments included safety, tolerability, pharmacokinetics, and pharmacodynamics (cytokines and complement). Pharmacokinetics of the siRNA and peptide excipient components contained in ARC-520 Injection showed a relatively short half-life of 3–5 and 8–10 hours, respectively. Dose exposure linearity was demonstrated within the dose range. ARC-520 Injection was well tolerated, with adverse-event frequency the same as placebo and no serious adverse events. ARC-520 Injection was initially found to induce histamine release through mast cell degranulation, resulting in 2 moderate hypersensitivity reactions. However, after initiation of pretreatment with oral antihistamine, no further hypersensitivity reactions occurred. Low-level, transient complement induction and sporadic, mild, and transient elevations of several cytokines were observed but not associated with any symptoms. ARC-520 Injection showed a favorable tolerability profile in this single-dose study in healthy volunteers. Oral antihistamine pretreatment is recommended in the future to offset mast cell degranulation stimulation.

Telomere syndromes have their most common manifestation in idiopathic pulmonary fibrosis and emphysema. The short telomere defect in these patients may manifest systemically as bone marrow failure and liver disease. We sought to understand the causes of dyspnea in telomerase and telomere gene mutation carriers who have no parenchymal lung disease.

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