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The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panellists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms “nonalcoholic” and “fatty” were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction–associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction–associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction–associated steatotic liver disease, who consume greater amounts of alcohol per week (140–350 g/wk and 210–420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and non-stigmati

PURPOSE: To assess the literature on men's preferences and perceptions regarding prostate cancer radiation therapy. METHODS: A scoping review was undertaken as per JBI guidelines. Searches were conducted in PubMed, CINAHL, Scopus and Science Direct with search terms including "prostate cancer," "radiotherapy," "radiation therapy," "radiation oncology," "patient preferences," "patient perceptions" and "patient experience." The resultant studies were mapped and grouped according to the emergent themes and pathway stages. RESULTS: A total of 779 titles and abstracts were screened by two independent reviewers. Fifty-two full-text studies were reviewed, with 27 eligible for inclusion. There were 4 pre-treatment, 13 during treatment and 10 post-treatment studies covering broad themes of information needs (n = 3), preferences and decisions (n = 6), general experiences (n = 8), side effects (n = 6), and support (n = 4). There were a mix of methodologies, including 11 qualitative, 14 quantitative (including four preference studies), one mixed methods and one narrative review. CONCLUSION: There were only four preference studies, with the remaining 23 reporting on perceptions. Overall, there is a paucity of literature regarding patient preferences and perceptions of prostate cancer radiation therapy, particularly when considering how many clinical and technical studies are published in the area. This highlights opportunities for future research.

Intensive care unit (ICU) patients with end-organ failure will require specialised machines or extracorporeal therapies to support the failing organs that would otherwise lead to death. ICU patients with severe acute kidney injury may require renal replacement therapy (RRT) to remove fluid and wastes from the body, and patients with severe cardiorespiratory failure will require extracorporeal membrane oxygenation (ECMO) to maintain adequate oxygen delivery whilst the underlying pathology is evaluated and managed. The presence of ECMO and RRT machines can further augment the existing pharmacokinetic (PK) alterations during critical illness. Significant changes in the apparent volume of distribution (Vd) and drug clearance (CL) for many important drugs have been reported during ECMO and RRT. Conventional antimicrobial dosing regimens rarely consider the impact of these changes and consequently, are unlikely to achieve effective antimicrobial exposures in critically ill patients receiving ECMO and/or RRT. Therefore, an in-depth understanding on potential PK changes during ECMO and/or RRT is required to inform antimicrobial dosing strategies in patients receiving ECMO and/or RRT. In this narrative review, we aim to discuss the potential impact of ECMO and RRT on the PK of antimicrobials and antimicrobial dosing requirements whilst receiving these extracorporeal therapies. The potential benefits of therapeutic drug monitoring (TDM) and dosing software to facilitate antimicrobial therapy for critically ill patients receiving ECMO and/or RRT are also reviewed and highlighted.

Improving muscle function has great potential to improve the quality of life. To identify novel regulators of skeletal muscle metabolism and function, we performed a proteomic analysis of gastrocnemius muscle from 73 genetically distinct inbred mouse strains, and integrated the data with previously acquired genomics and >300 molecular/phenotypic traits via quantitative trait loci mapping and correlation network analysis. These data identified thousands of associations between protein abundance and phenotypes and can be accessed online (https://muscle.coffeeprot.com/) to identify regulators of muscle function. We used this resource to prioritize targets for a functional genomic screen in human bioengineered skeletal muscle. This identified several negative regulators of muscle function including UFC1, an E2 ligase for protein UFMylation. We show UFMylation is up-regulated in a mouse model of amyotrophic lateral sclerosis, a disease that involves muscle atrophy. Furthermore, in vivo knockdown of UFMylation increased contraction force, implicating its role as a negative regulator of skeletal muscle function.

OBJECTIVE: Paediatric status epilepticus (SE) has potential for long-term sequelae. Existing data demonstrate delays to aspects of care. The objective of the present study was to examine the feasibility of collecting data on children with paediatric SE and describe current management strategies in pre-hospital and in-hospital settings. METHODS: A pilot, prospective, observational cohort study of children 4 weeks to 16 years of age with SE, in four EDs in Australia. Clinical details including medications administered, duration of seizure and short-term outcomes were collected. Follow up occurred by telephone at 1 month. RESULTS: We enrolled 167 children with SE. Mean age was 5.4 years (standard deviation [SD] 4.1), and 81 (49%) male. Median seizure duration was 10 min (interquartile range 7-30). Midazolam was the first medication administered in 87/100 (87%) instances, mean dose of 0.21 mg/kg (SD 0.13). The dose of midazolam was adequate in 30 (35%), high (>0.2 mg/kg) in 44 (51%) and low (<0.1 mg/kg) in 13 (15%). For second-line agents, levetiracetam was administered on 33/55 (60%) occasions, whereas phenytoin and phenobarbitone were administered on 11/55 (20%) occasions each. Mean dose of levetiracetam was 26.4 mg/kg (SD 13.5). One hundred and four (62%) patients were admitted to hospital, with 13 (8%) admitted to ICU and seven (4%) intubated. CONCLUSION: In children presenting with SE in Australia medical management differed from previous reports, with midazolam as the preferred benzodiazepine, and levetiracetam replacing phenytoin as the preferred second-line agent. This pilot study indicates the feasibility of a paediatric SE registry and its utility to understand and optimise practice.

PURPOSE: With increasing rates of cancer survival due to advances in screening and treatment options, the costs of breast cancer diagnoses are attracting interest. However, limited research has explored the costs to the Australian healthcare system associated with breast cancer. We aimed to describe the cost to hospital funders for hospital episodes and emergency department (ED) presentations for Queensland women with breast cancer, and whether costs varied by demographic characteristics. METHODS: We used a linked administrative dataset, CancerCostMod, limited to all breast cancer diagnoses aged 18 years or over in Queensland between July 2011 and June 2015 (n = 13,285). Each record was linked to Queensland Health Admitted Patient Data Collection and Emergency Department Information Systems records between July 2011 and June 2018. The cost of hospital episodes and ED presentations were determined, with mean costs per patient modelled using generalised linear models with a gamma distribution and log link function. RESULTS: The total cost to the Queensland healthcare system from hospital episodes for female breast cancer was AUD$309 million and AUD$12.6 million for ED presentations during the first 3 years following diagnosis. High levels of costs and service use were identified in the first 6 months following diagnosis. Some significant differences in cost of hospital and ED episodes were identified based on demographic characteristics, with Indigenous women and those from lower socioeconomic backgrounds having higher costs. CONCLUSION: Hospitalisation costs for breast cancer in Queensland exert a high burden on the healthcare system. Costs are higher for women during the first 6 months from diagnosis and for Indigenous women, as well as those with underlying comorbidities and lower socioeconomic position.

INTRODUCTION: There are several options for real-time prostate monitoring during radiation therapy including fiducial markers (FMs) and transperineal ultrasound (TPUS). However, the patient experience for these procedures is very different. This study aimed to determine patient preferences around various aspects of prostate image-guidance, focusing on FMs and TPUS. METHODS: A discrete choice experiment (DCE) was conducted, describing the image-guidance approach by: pain, cost, accuracy, side effects, additional appointments, and additional time. Participants were males with prostate cancer (PCa) and from the general Australian population. A DCE survey required participants to make hypothetical choices in each of 8 choice sets. Multinomial logit modelling and Latent Class Analysis (LCA) were used to analyse the responses. Marginal willingness to pay (mWTP) was calculated. RESULTS: 476 respondents completed the survey (236 PCa patients and 240 general population). The most important attributes for both cohorts were pain, cost and accuracy (p < 0.01). PCa patients were willing to pay more to avoid the worst pain than the general population, and willing to pay more for increased accuracy. LCA revealed 3 groups: 2 were focused more on the process-related attributes of pain and cost, and the third was focused on the clinical efficacy attributes of accuracy and side effects. CONCLUSION: Both cohorts preferred less cost and pain and improved accuracy, with men with PCa valuing accuracy more than the general population. In addition to the clinical and technical evidence, radiation oncology centres should consider the preferences of patients when considering choice of image-guidance techniques.

Many cell surface and secreted proteins are modified by the covalent addition of glycans that play an important role in the development of multicellular organisms. These glycan modifications enable communication between cells and the extracellular matrix via interactions with specific glycan-binding lectins and the regulation of receptor-mediated signaling. Aberrant protein glycosylation has been associated with the development of several muscular diseases, suggesting essential glycan- and lectin-mediated functions in myogenesis and muscle development, but our molecular understanding of the precise glycans, catalytic enzymes, and lectins involved remains only partially understood. Here, we quantified dynamic remodeling of the membrane-associated proteome during a time-course of myogenesis in cell culture. We observed wide-spread changes in the abundance of several important lectins and enzymes facilitating glycan biosynthesis. Glycomics-based quantification of released N-linked glycans confirmed remodeling of the glycome consistent with the regulation of glycosyltransferases and glycosidases responsible for their formation including a previously unknown digalactose-to-sialic acid switch supporting a functional role of these glycoepitopes in myogenesis. Furthermore, dynamic quantitative glycoproteomic analysis with multiplexed stable isotope labeling and analysis of enriched glycopeptides with multiple fragmentation approaches identified glycoproteins modified by these regulated glycans including several integrins and growth factor receptors. Myogenesis was also associated with the regulation of several lectins, most notably the upregulation of galectin-1 (LGALS1). CRISPR/Cas9-mediated deletion of Lgals1 inhibited differentiation and myotube formation, suggesting an early functional role of galectin-1 in the myogenic program. Importantly, similar changes in N-glycosylation and the upregulation of galectin-1 during postnatal skeletal muscle development were observed i

OBJECTIVE: CRISPR/Cas9 technology has revolutionized gene editing and fast tracked our capacity to manipulate genes of interest for the benefit of both research and therapeutic applications. Whilst many advances have, and continue to be made in this area, perhaps the most utilized technology to date has been the generation of knockout cells, tissues and animals. The advantages of this technology are many fold, however some questions still remain regarding the effects that long term expression of foreign proteins such as Cas9, have on mammalian cell function. Several studies have proposed that chronic overexpression of Cas9, with or without its accompanying guide RNAs, may have deleterious effects on cell function and health. This is of particular concern when applying this technology in vivo, where chronic expression of Cas9 in tissues of interest may promote disease-like phenotypes and thus confound the investigation of the effects of the gene of interest. Although these concerns remain valid, no study to our knowledge has yet to demonstrate this directly. METHODS: In this study we used the lox-stop-lox (LSL) spCas9 ROSA26 transgenic (Tg) mouse line to generate four tissue-specific Cas9-Tg models that express Cas9 in the heart, liver, skeletal muscle or adipose tissue. We performed comprehensive phenotyping of these mice up to 20-weeks of age and subsequently performed molecular analysis of their organs. RESULTS: We demonstrate that Cas9 expression in these tissues had no detrimental effect on whole body health of the animals, nor did it induce any tissue-specific effects on whole body energy metabolism, liver health, inflammation, fibrosis, heart function or muscle mass. CONCLUSIONS: Our data suggests that these models are suitable for studying the tissue specific effects of gene deletion using the LSL-Cas9-Tg model, and that phenotypes observed utilizing these models can be confidently interpreted as being gene specific, and not confounded by the chronic overexpr

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.

Purpose: There is currently little evidence assessing the repeatability and accuracy of central corneal thickness measurements using the devices Tonoref III and RS-3000. This study aims to compare these devices against measurements by ultrasound pachymetry. Methods: Central corneal thicknesses were measured on 50 eyes. Measurements from two non-contact devices—Tonoref III (NIDEK CO., LTD, Gamagori, Japan) and RS-3000 (NIDEK CO., LTD, Gamagori, Japan)—were compared against ultrasound pachymetry, the gold standard. Ultrasound measurements were obtained using a ‘Pachmate’ device (DGH Technology, Inc, Exton, PA, USA). Repeatability was defined as the value that the difference between two consecutive measurements falls below 95% of the time. The within-subject standard deviation and repeatability values were calculated for Pachmate and Tonoref III by one-way ANOVA. Repeatability of RS-3000 was determined by nonparametric analysis. Agreement between Tonoref III and Pachmate was assessed by a Bland–Altman plot. Agreement between RS-3000 and Pachmate was assessed by nonparametric analysis. Results: The Pachmate, Tonoref III and RS-3000 had repeatability values of 16, 7.4 and 5 µm, respectively. The mean difference between Tonoref III and Pachmate was − 15 µm (95% LoAs − 31 to + 0 µm). The median value for the difference between RS-3000 and Pachmate was − 4 µm (95% of values within − 24 and + 4 µm). Conclusion: The Tonoref III and RS-3000 showed good repeatability when compared to ultrasound pachymetry. However, neither instrument agreed interchangeably with CCT measurements by ultrasound pachymetry. Practitioners should determine whether the level of agreement is sufficient to meet their clinical needs.