Study protocol for locoregional precision treatment of hepatocellular carcinoma with transarterial chemoembolisation (TACTida), a clinical study:idarubicin dose selection, tissue response and survival

INTRODUCTION: Hepatocellular carcinoma (HCC) is a common cause of cancer-related death, often detected in the intermediate stage. The standard of care for intermediate-stage HCC is transarterial chemoembolisation (TACE), where idarubicin (IDA) is a promising drug. Despite the fact that TACE has been used for several decades, treatment success is unpredictable. This clinical trial has been designed believing that further improvement might be achieved by increasing the understanding of interactions between local pharmacology, tumour targeting, HCC pathophysiology, metabolomics and molecular mechanisms of drug resistance. METHODS AND ANALYSIS: The study population of this single-centre clinical trial consists of adults with intermediate-stage HCC. Each tumour site will receive TACE with two different IDA doses, 10 and 15 mg, on separate occasions. Before and after each patient's first TACE blood samples, tissue and liquid biopsies, and positron emission tomography (PET)/MRI will be performed. Blood samples will be used for pharmacokinetics (PK) and liver function evaluation. Tissue biopsies will be used for histopathology analyses, and culturing of primary organoids of tumour and non-tumour tissue to measure cell viability, drug response, multiomics and gene expression. Multiomics analyses will also be performed on liquid biopsies. PET/MRI will be used to evaluate tumour viability and liver metabolism. The two doses of IDA will be compared regarding PK, antitumour effects and safety. Imaging, molecular biology and multiomics data will be used to identify HCC phenotypes and their relation to drug uptake and metabolism, treatment response and survival. ETHICS AND DISSEMINATION: Participants give informed consent. Personal data are deidentified. A patient will be withdrawn from the study if considered medically necessary, or if it is the wish of the patient. The study has been approved by the Swedish Ethical Review Authority (Dnr. 2021-01928) and by the Medical Product Agency, Uppsala, Sweden. TRIAL REGISTRATION NUMBER: EudraCT number: 2021-001257-31

The Transcription Factors SOX9 and SOX10 Are Vitiligo Autoantigens in Autoimmune Polyendocrine Syndrome Type I

Vitiligo is common in the hereditary disorder autoimmune polyendocrine syndrome type I (APS I). Patients with APS I are known to have high titer autoantibodies directed against various tissue-specific antigens. Using sera from APS I patients for immunoscreening of a cDNA library from human scalp, we identified the transcription factors SOX9 and SOX10 as novel autoantigens related to this syndrome. Immunoreactivity against SOX9 was found in 14 (15%) and against SOX10 in 20 (22%) of the 91 APS I sera studied. All patients reacting with SOX9 displayed reactivity against SOX10, suggesting shared epitopes. Among the 19 patients with vitiligo, 12 (63%) were positive for SOX10 (p0.0001). Furthermore, three of 93 sera from patients with vitiligo unrelated to APS I showed strong reactivity against SOX10, which may indicate a more general role of SOX10 as an autoantigen in vitiligo

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Circulating fatty acids from high-throughput metabolomics platforms as potential biomarkers of dietary fatty acids

Background Some fatty acids, i.e. n-3 and n-6 polyunsaturated fatty acids (PUFA), from metabolomics platforms based on nuclear magnetic resonance imaging (NMR) or liquid chromatography mass-spectrometry (LC-MS) are suggested to reflect dietary exposure. NMR and LC-MS are both relatively fast and cheap, however few studies have investigated their validity. Linoleic acid (LA) and docosahexaenoic acid (DHA), measured using gas chromatography (GC), are established biomarkers of dietary n-6 and n-3 PUFA intake, respectively. Objective To examine if circulating fatty acids derived from two commonly applied metabolomics platforms (using NMR and LC-MS) provide similar information compared to GC in two pooled population-based cohorts, one patient cohort, and in a randomized controlled trial (RCT). Methods Spearman rank correlations were conducted between LA and DHA in cholesteryl esters (CE) from GC and whole serum/plasma LA and DHA from the metabolomics platforms in a pooled population-based cohort of men and women (n ˜ 1100) (primary analysis). Secondary correlation analyses included fatty acid classes such as n-3 PUFA, n-6 PUFA, saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and total PUFA. Additionally, correlations were investigated for LA, DHA and the five fatty acid classes in phospholipids (PL), triacylglycerols (TAG) and non-esterified fatty acids (NEFA) in a RCT of n = 60 as well as in a population with biopsy-verified non-alcoholic fatty liver disease (NAFLD) (n = 59). Misclassification was examined using cross-tabulation and visualized using alluvial plots. Results Moderate to strong correlations (r = 0.51–0.81) were observed for LA and DHA in multiple lipid fractions in all cohorts using the NMR platform. For the pooled cohort, LA (r = 0.67, P < 0.0001) and DHA (r = 0.68, P < 0.0001) assessed in CE were strongly correlated with LA and DHA derived using NMR. Nearly half (49%) were correctly classified into their respective quartiles. Using LC-MS, only DHA (r = 0.44, P < 0.0001) demonstrated moderate correlations with DHA from GC. Conclusions Unless fatty acid data from GC analysis is available or feasible, NMR-based technology might be a better option than a LC-MS-based platform, at least for certain PUFA. This should be taken into account in future studies aiming to use circulating fatty acids as dietary biomarkers for the investigation of diet-disease relationships

Accumulation of cadmium in pancreatic β cells is similar to that of calcium in being stimulated by both glucose and high potassium

The transport of Cd 2+ and the effects of this ion on secretory activity and metabolism were investigated in β cell-rich pancreatic islets isolated from obese-hyperglycemic mice. The endogenous cadmium content was 2.5 μmol/kg dry wt. After 60 min of incubation in a Ca 2+-deficient medium containing 2.5 μM Cd 2+ the islet cadmium content increased to 0.18 mmol/kg dry wt. This uptake was reduced by approx. 50% in the presence of 1.28 mM Ca 2+. The incorporation of Cd 2+ was stimulated either by raising the concentration of glucose to 20 mM or K + to 30.9 mM. Whereas D-600 suppressed the stimulatory effect of glucose by 75%, it completely abolished that obtained with high K +. Only about 40% of the incorporated cadmium was mobilized during 60 min of incubation in a Cd 2+-free medium containing 0.5 mM EGTA. It was possible to demonstrate a glucose-induced suppression of Cd 2+ efflux into a Ca 2+-deficient medium. Concentrations of Cd 2+ up to 2.5 μM did not affect glucose oxidation, whereas, there was a progressive inhibition when the Cd 2+ concentration was above 10 μM. Basal insulin release was stimulated by 5 μM Cd 2+. At a concentration of 160 μM, Cd 2+ did not affect basal insulin release but significantly inhibited the secretory response to glucose. It is concluded that the β cell uptake of Cd 2+ is facilitated by the activation of voltage-dependent Ca 2+ channels. Apparently, the accumulation of Cd 2+ mimics that of Ca 2+ also involving a component of intracellular sequestration promoted by glucose

Feeling safe or falling through the cracks-Patients' experiences of healthcare in cirrhosis illness: A qualitative study.

IntroductionPatients with cirrhosis have a long-lasting relationship with medical personnel. Hierarchy in the healthcare contacts and feeling stigmatised may affect the patient's interactions with these care providers. Despite healthcare professionals' awareness of patients' increased self-care needs, patients report getting insufficient information and support. The patients' expectations and experiences of interacting with healthcare professionals in cirrhosis care is hence a research area that needs further investigation.PurposeTo capture patients' descriptions of healthcare experiences in relation to cirrhosis illness.Material and methodsData comprise semi-structured interviews (N = 18) and open-ended questionnaire responses (N = 86) of patients with cirrhosis. Braun and Clarke's thematic analysis process was used, including both semantic and inductive elements. The study is reported following the COREQ guidelines.FindingsThe analysis resulted in two themes: 1) Struggle to be in a dialogue and 2) Being helped or harmed. Six sub-themes were identified concerning aspects of experiences within each theme during the analysis. These sub-themes included: 'getting information', 'being involved', 'being perceived as a person', 'enduring care', 'feeling lost in the healthcare organisation', and 'not being taken care of'.ConclusionsPatients with cirrhosis express concerns regarding where to turn in the continuum of cirrhosis care. They emphasise the importance of being involved in the dialogue with the healthcare professional, to be perceived as a person with a unique need to be informed. The healthcare organisation and continuity of care are either viewed as confusing or as helping to shape a safe and trustful contact, which was an important difference in feeling helped or harmed. Hence, patients wished for improved collaboration with healthcare professionals and to receive increased information about their disease. Person-centred communication in nurse-led clinics may increase patient satisfaction and prevent patients from falling through the cracks

Liver cirrhosis turns life into an unpredictable roller-coaster : A qualitative interview study

Aim: To explore how persons living with liver cirrhosis experience day-to-day life. Background: Liver cirrhosis is the sixth most common cause of death among adults in Western countries. Persons with advanced liver cirrhosis report poor quality of life, in comparison with other chronic diseases. However, knowledge regarding day-to-day life during earlier stages of the disease is lacking. In other chronic diseases, the suffering process is well explored, while in liver cirrhosis suffering is insufficiently investigated. Design: An exploratory study, with a qualitative inductive interview approach. Methods: A purposive maximum variation sample of 20 informants with liver cirrhosis aged 25-71, from two gastroenterology outpatient clinics in mid-Sweden, were interviewed from September 2016 to October 2017. Interview data were analysed inductively with qualitative content analysis. Reporting followed the COREQ guidelines. Results: The experiences of day-to-day life living with liver cirrhosis comprised four sub-themes. Living with liver cirrhosis implied varying levels of deterioration, the most apparent being exhaustion or tiredness. The informants had to find ways of adapting to a new life situation. The insecurity of future health evoked existential reflections such as feeling emotionally and existentially distressed. Shame and guilt were reasons for feeling stigmatised. These sub-themes emerged into one overarching theme of meaning: life turns into an unpredictable roller-coaster. This is based on experiences of liver cirrhosis as an unpredictable disease with fluctuating symptoms, worries and disease progression. Conclusion: Living with cirrhosis implies an unpredictable condition with a progressive, stigmatising disease. The fluctuating symptoms and deep concerns about future life pose an increased personal suffering. Relevance to clinical practice: Within healthcare, knowledge of the person's experience is vital to enable and fulfil the person's healthcare needs. Clinical registered nurses need a person-centred approach to strengthen their patients to cope with their new life situation

Patient perceived quality of cirrhosis care- adjunctive nurse-based care versus standard medical care : a pragmatic multicentre randomised controlled study

BACKGROUND: Cirrhosis treatment implies prevention and alleviation of serious disease events. Healthcare providers may, however, fail to meet patients' expectations of collaboration and specific needs of information and support. Individualised nursing care could meet patients' needs. The aim was thus to measure patient-perceived quality of care after adjunctive registered nurse-based intervention Quality Liver Nursing Care Model (QLiNCaM) compared with standard medical care. METHODS: This pragmatic multicentre study consecutively randomised patients to either adjunctive registered nurse-based care, or standard medical care for 24 months (ClinicalTrials.gov NCT02957253). Patients were allocated to either group at an equal ratio, at six Swedish outpatient clinics during 2016-2022. Using the questionnaire 'Quality of care from the patient's perspective', patients rated their perceived lack of quality for the adjunctive registered nurse-based intervention compared with the control group at 12 and 24 months, respectively. RESULTS: In total, 167 patients were recruited. Seven out of 22 items in the questionnaire supported the finding that 'lacking quality' decreased with adjunctive registered nurse-based care (p < 0.05) at 12 months follow-up; however, these differences could not be established at 24 months. CONCLUSION: Additional structured registered nurse-based visits in the cirrhosis outpatient team provided support for improved patient-perceived quality of care during the first 12 months. Registered nurses increase patient involvement and present easy access to cirrhosis outpatient care. Patients express appreciation for personalised information. This study reinforces registered nurses' role in the outpatient cirrhosis team, optimising patient care in compensated and decompensated cirrhosis. TRIAL REGISTRATION: Registered at Clinical Trials 18th of October 2016, [ https://www. CLINICALTRIALS: gov ], registration number: NCT02957253

Transient Simulation of Microwave SiC MESFETs With Improved Trap Models

Measured and simulated transient characteristics of a SiC metal–semiconductor field-effect transistor are compared. Self-heating, gate tunneling, substrate, and surface traps are taken into account in the simulations. By explicitly filling surface traps at the vicinity of the gate during pinchoff, close correspondence between simulated and measured gate lags is achieved