‘It's like the bad guy in a movie who just doesn't die’ : a qualitative exploration of young people's adaptation to eczema and implications for self‐care

Background Eczema is a common childhood inflammatory skin condition, affecting more than one in five children. A popular perception is that children ‘outgrow eczema’, although epidemiological studies have shown that, for many, eczema follows a lifelong episodic course. Objectives To explore the perceptions of young people about the nature of their eczema and how these perceptions relate to their self‐care and adapting to living with eczema. Methods This is a secondary inductive thematic analysis of interviews conducted for Healthtalk.org. In total 23 interviews with young people with eczema were included. Of the 23 participants, 17 were female and six male, ranging from 17 to 25 years old. Results Participants generally experienced eczema as an episodic long‐term condition and reported a mismatch between information received about eczema and their experiences. The experience of eczema as long term and episodic had implications for self‐care, challenging the process of identifying triggers of eczema flare‐ups and evaluating the success of treatment regimens. Participants’ experiences of eczema over time also had implications for adaptation and finding a balance between accepting eczema as long term and hoping it would go away. This linked to a gradual shift in treatment expectations from ‘cure’ to ‘control’ of eczema. Conclusions For young people who continue to experience eczema beyond childhood, a greater focus on self‐care for a long‐term condition may be helpful. Greater awareness of the impact of early messages around ‘growing out of’ eczema and provision of high‐quality information may help patients to manage expectations and support adaptation to treatment regimens

Lipophagy and Alcohol-Induced Fatty Liver

This review describes the influence of ethanol consumption on hepatic lipophagy, a selective form of autophagy during which fat-storing organelles known as lipid droplets (LDs) are degraded in lysosomes. During classical autophagy, also known as macroautophagy, all forms of macromolecules and organelles are sequestered in autophagosomes, which, with their cargo, fuse with lysosomes, forming autolysosomes in which the cargo is degraded. It is well established that excessive drinking accelerates intrahepatic lipid biosynthesis, enhances uptake of fatty acids by the liver from the plasma and impairs hepatic secretion of lipoproteins. All the latter contribute to alcohol-induced fatty liver (steatosis). Here, our principal focus is on lipid catabolism, specifically the impact of excessive ethanol consumption on lipophagy, which significantly influences the pathogenesis alcohol-induced steatosis. We review findings, which demonstrate that chronic ethanol consumption retards lipophagy, thereby exacerbating steatosis. This is important for two reasons: (1) Unlike adipose tissue, the liver is considered a fat-burning, not a fat-storing organ. Thus, under normal conditions, lipophagy in hepatocytes actively prevents lipid droplet accumulation, thereby maintaining lipostasis; (2) Chronic alcohol consumption subverts this fat-burning function by slowing lipophagy while accelerating lipogenesis, both contributing to fatty liver. Steatosis was formerly regarded as a benign consequence of heavy drinking. It is now recognized as the first hit in the spectrum of alcohol-induced pathologies that, with continued drinking, progresses to more advanced liver disease, liver failure, and/or liver cancer. Complete lipid droplet breakdown requires that LDs be digested to release their high-energy cargo, consisting principally of cholesteryl esters and triacylglycerols (triglycerides). These subsequently undergo lipolysis, yielding free fatty acids that are oxidized in mitochondria to generate energy. Our review will describe recent findings on the role of lipophagy in LD catabolism, how continuous heavy alcohol consumption affects this process, and the putative mechanism(s) by which this occurs

Development of novel clinical examination scales for the measurement of disease severity in Creutzfeldt-Jakob disease

OBJECTIVE: To use a robust statistical methodology to develop and validate clinical rating scales quantifying longitudinal motor and cognitive dysfunction in sporadic Creutzfeldt-Jakob disease (sCJD) at the bedside. METHODS: Rasch analysis was used to iteratively construct interval scales measuring composite cognitive and motor dysfunction from pooled bedside neurocognitive examinations collected as part of the prospective National Prion Monitoring Cohort study, October 2008-December 2016.A longitudinal clinical examination dataset constructed from 528 patients with sCJD, comprising 1030 Motor Scale and 757 Cognitive Scale scores over 130 patient-years of study, was used to demonstrate scale utility. RESULTS: The Rasch-derived Motor Scale consists of 8 items, including assessments reliant on pyramidal, extrapyramidal and cerebellar systems. The Cognitive Scale comprises 6 items, and includes measures of executive function, language, visual perception and memory. Both scales are unidimensional, perform independently of age or gender and have excellent inter-rater reliability. They can be completed in minutes at the bedside, as part of a normal neurocognitive examination. A composite Examination Scale can be derived by averaging both scores. Several scale uses, in measuring longitudinal change, prognosis and phenotypic heterogeneity are illustrated. CONCLUSIONS: These two novel sCJD Motor and Cognitive Scales and the composite Examination Scale should prove useful to objectively measure phenotypic and clinical change in future clinical trials and for patient stratification. This statistical approach can help to overcome obstacles to assessing clinical change in rapidly progressive, multisystem conditions with limited longitudinal follow-up

Alcoholic vs non-alcoholic fatty liver in rats: distinct differences in endocytosis and vesicle trafficking despite similar pathology

Background: Non-alcoholic and alcoholic fatty liver disease (NAFLD and AFLD, respectively) are major health problems, as patients with either condition can progress to hepatitis, fibrosis, and cirrhosis. Although histologically similar, key differences likely exist in these two models. For example, altered content of several vesicle trafficking proteins have been identified in AFLD, but their content in NAFLD is unknown. In this study, we compared select parameters in NAFLD and AFLD in a rat model. Methods: We fed either Lieber- DeCarli liquid control or alcohol-containing (35 % as calories) diet (AFLD model) or lean or high-fat (12 or 60 % derived from fat, respectively) pellets (NAFLD model) for 8–10 weeks, n = 8 in each model. Serum, hepatocytes and liver tissue were analyzed. Liver injury markers were measured in serum, triglyceride content and endocytosis (binding and internalization of 125I- asialoorosomucoid) was measured in isolated hepatocytes, and content of selected trafficking proteins (Rab3D, Rab7 and Rab18) were determined in whole liver tissue. Results: Although liver injury markers and triglyceride content were similar in both models, binding and internalization of 125I- asialoorosomucoid was significantly impaired in the hepatocytes from AFLD, but not NAFLD, animals. In addition, protein content of the asialoglycoprotein receptor (ASGPR) and three trafficking proteins, Rab3D, Rab7and Rab18, were significantly decreased after alcohol, but not high-fat feeding. Levels of protein carbonylation, amount of glutathione stores, and lipid peroxidation were similar irrespective of the insult to the livers that resulted in fatty liver. Conclusion: Impairments in protein trafficking in AFLD are likely a direct result of alcohol administration, and not a function of fatty liver

Taking charge of eczema self-management : a qualitative interview study with young people with eczema

Objectives: To explore young people’s experiences of eczema self-management and interacting with health professionals. Design: Secondary qualitative data analysis of data sets from two semistructured interview studies. Data were analysed using inductive thematic analysis. Setting: Participants were recruited from the UK primary care, dermatology departments and a community-based sample (eg, patient representative groups, social media). Participants: Data included 28 interviews with young people with eczema aged 13–25 years (mean age=19.5 years; 20 female). Results: Although topical treatments were generally perceived as effective, young people expressed doubts about their long-term effectiveness, and concerns around the safety and an over-reliance on topical corticosteroids. Participants welcomed the opportunity to take an active role in their eczema management, but new roles and responsibilities also came with initial apprehension and challenges, including communicating their treatment concerns and preferences with health professionals, feeling unprepared for transition to an adult clinic and obtaining treatments. Decisions regarding whether to engage in behaviours that would exacerbate their eczema (eg, irritants/triggers, scratching) were influenced by young people’s beliefs regarding negative consequences of these behaviours, and perceived control over the behaviour and its negative consequences. Conclusions: Behavioural change interventions must address the treatment concerns of young people and equip them with the knowledge, skills and confidence to take an active role in their own eczema management

Public attitudes to inequality in water distribution: Insights from preferences for water reallocation from irrigators to Aboriginal Australians

Water allocation regimes that adjudicate between competing uses are in many countries under pressure to adapt to increasing demands, climate‐driven shortages, expectations for equity of access, as well as societal changes in values and priorities. International authorities expound standards for national allocation regimes that include robust processes for addressing the needs of ‘new entrants' and for varying existing entitlements within sustainable limits. The claims of Indigenous peoples to water represents a newly recognised set of rights and interests that will test the ability of allocation regimes to address the global water governance goal of equity. No study has sought to identify public attitudes or willingness to pay for a fairer allocation of water rights between Indigenous and non‐Indigenous people. We surveyed households from the jurisdictions of Australia's Murray‐Darling Basin, a region undergoing a historic government‐led recovery of water, and found that 69.2% of respondents support the principle of reallocating a small amount of water from irrigators to Aboriginal people via the water market. Using contingent valuation, we estimated households are willing to pay A$21.78 in a one‐off levy. The aggregate value calculated for households in the basin's jurisdictions was A$74.5 million, which is almost double a recent government commitment to fund the acquisition of entitlements for Aboriginal nations of this basin. Results varied by state of residency and affinity with environmental groups. An information treatment that presented narrative accounts from Aboriginal people influenced the results. Insights from this study can inform water reallocation processes

Development of prognostic models for survival and care status in sporadic Creutzfeldt-Jakob disease

This is the final version. Available on open access from Oxford University Press via the DOI in this recordData availability: Patient data from the National Prion Monitoring Cohort are owned by University College London. This patient data are not currently publicly available. For researchers interested in accessing this data, further information can be found at https://www.ucl.ac.uk/national-prion-clinic/national-prion-monitoring-cohort-npmc.Sporadic Creutzfeldt-Jakob disease, the most common human prion disease, typically presents as a rapidly progressive dementia and has a highly variable prognosis. Despite this heterogeneity, clinicians need to give timely advice on likely prognosis and care needs. No prognostic models have been developed that predict survival or time to increased care status from the point of diagnosis. We aimed to develop clinically useful prognostic models with data from a large prospective observational cohort study. Five hundred and thirty-seven patients were visited by mobile teams of doctors and nurses from the National Health Service National Prion Clinic within 5 days of notification of a suspected diagnosis of sporadic Creutzfeldt-Jakob disease, enrolled to the study between October 2008 and March 2020, and followed up until November 2020. Prediction of survival over 10-, 30- and 100-day periods was the main outcome. Escalation of care status over the same time periods was a secondary outcome for a subsample of 113 patients with low care status at initial assessment. Two hundred and eighty (52.1%) patients were female and the median age was 67.2 (interquartile range 10.5) years. Median survival from initial assessment was 24 days (range 0-1633); 414 patients died within 100 days (77%). Ten variables were included in the final prediction models: sex; days since symptom onset; baseline care status; PRNP codon 129 genotype; Medical Research Council Prion Disease Rating Scale, Motor and Cognitive Examination Scales; count of MRI abnormalities; Mini-Mental State Examination score and categorical disease phenotype. The strongest predictor was PRNP codon 129 genotype (odds ratio 6.65 for methionine homozygous compared with methionine-valine heterozygous; 95% confidence interval 3.02-14.68 for 30-day mortality). Of 113 patients with lower care status at initial assessment, 88 (78%) had escalated care status within 100 days, with a median of 35 days. Area under the curve for models predicting outcomes within 10, 30 and 100 days was 0.94, 0.92 and 0.91 for survival, and 0.87, 0.87 and 0.95 for care status escalation, respectively. Models without PRNP codon 129 genotype, which is not immediately available at initial assessment, were also highly accurate. We have developed a model that can accurately predict survival and care status escalation in sporadic Creutzfeldt-Jakob disease patients using clinical, imaging and genetic data routinely available in a specialist national referral service. The utility and generalizability of these models to other settings could be prospectively evaluated when recruiting to clinical trials and providing clinical care

The role of clathrin in post-golgi trafficking in toxoplasma gondii

Apicomplexan parasites are single eukaryotic cells with a highly polarised secretory system that contains unique secretory organelles (micronemes and rhoptries) that are required for host cell invasion. In contrast, the role of the endosomal system is poorly understood in these parasites. With many typical endocytic factors missing, we speculated that endocytosis depends exclusively on a clathrin-mediated mechanism. Intriguingly, in Toxoplasma gondii we were only able to observe the endogenous clathrin heavy chain 1 (CHC1) at the Golgi, but not at the parasite surface. For the functional characterisation of Toxoplasma gondii CHC1 we generated parasite mutants conditionally expressing the dominant negative clathrin Hub fragment and demonstrate that CHC1 is essential for vesicle formation at the trans-Golgi network. Consequently, the functional ablation of CHC1 results in Golgi aberrations, a block in the biogenesis of the unique secretory microneme and rhoptry organelles, and of the pellicle. However, we found no morphological evidence for clathrin mediating endocytosis in these parasites and speculate that they remodelled their vesicular trafficking system to adapt to an intracellular lifestyle