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Abstract Background Alcohol consumption causes a spectrum of liver abnormalities and leads to over 3 million deaths per year. Alcoholic hepatitis (AH) is a florid presentation of alcoholic liver disease characterized by liver failure in the context of recent and heavy alcohol consumption. The aim of this study is to explore the potential benefits of the IL-1β antibody, canakinumab, in the treatment of AH. Methods This is a multicentre, double-blind, randomised placebo-controlled trial. Participants will be diagnosed with AH using clinical criteria. Liver biopsy will then confirm that all histological features of AH are present. Up to 58 participants will be recruited into two groups from 15 centres in the UK. Patients will receive an infusion of Canakinumab or matched placebo by random 1:1 allocation. The primary outcome is the difference between groups in the proportion of patients demonstrating histological improvement and will compare histological appearances at baseline with appearances at 28 days to assign a category of “improved” or “not improved”. Patients with evidence of ongoing disease activity will receive a second infusion of canakinumab or placebo. Participants will be followed up for 90 days. Secondary outcomes include mortality and change in MELD score at 90 days. Discussion This phase II study will explore the benefits of the IL-1β antibody, canakinumab, in the treatment of AH to provide proof of concept that inhibition of IL-1β signalling may improve histology and survival for patients with AH. Trial registration EudraCT 2017-003724-79 . Prospectively registered on 13 April 2018.

Background and Aims: Short-term mortality in alcohol-related hepatitis (AH) is high, and no current therapy results in durable benefit. A role for interleukin (IL)-1β has been demonstrated in the pathogenesis of alcohol-induced steatohepatitis. This study explored the safety and efficacy of canakinumab (CAN), a monoclonal antibody targeting IL-1β, in the treatment of patients with AH., Methods: Participants with biopsy-confirmed AH and discriminant function ≥32 but Model for End-Stage Liver Disease ≤27 were randomly allocated 1:1 to receive either CAN 3 mg/kg or placebo (PBO). Liver biopsies were taken before and 28 days after treatment. The primary endpoint was the overall histological improvement in inflammation analyzed by the modified intention-to-treat principle., Results: Fifty-seven participants were randomized: 29 to CAN and 28 to PBO. Two participants had histology that did not corroborate the clinical diagnosis. Of the remaining 55 participants, paired histology data were evaluable from 48 participants. In CAN-treated participants, 14 (58%) of 24 demonstrated histological improvement compared with 10 (42%) of 24 in the PBO group (P = .25). There was no improvement in prognostic scores of liver function. Four (7%) of the 55 participants died within 90 days, 2 in each group. The number of serious adverse events was similar between CAN vs PBO. In post hoc exploratory analyses after adjustment for baseline prognostic factors, CAN therapy was associated with overall histological improvement (P = .04)., Conclusions: CAN therapy in severe AH participants with Model for End-Stage Liver Disease ≤27 did not alter biochemical or clinical outcomes compared with PBO. Nonsignificant histological improvements did not translate into clinical benefit. EudraCT, Number: 2017-003724-79; ClinicalTrials.gov, Number: NCT03775109., (Copyright © 2024. Published by Elsevier Inc.)

Perovskite crystals-with their exceptional nonlinear optical properties, lasing and waveguiding capabilities-offer a promising platform for integrated photonic circuitry within the strong-coupling regime at room temperature. Here we demonstrate a versatile template-assisted method to efficiently fabricate large-scale waveguiding perovskite crystals of arbitrarily predefined geometry such as microwires, couplers and splitters. We non-resonantly stimulate a condensate of waveguided exciton-polaritons resulting in bright polariton lasing from the transverse interfaces and corners of our perovskite microstructures. Large blueshifts with excitation power and high mutual coherence between the different edge and corner lasing signals are detected in the far-field photoluminescence, implying that a spatially extended condensates of coherent polaritons has formed. The condensate polaritons are found to propagate over long distances in the wires from the excitation spot and can couple to neighbouring wires through large air gaps, making our platform promising for integrated polaritonic circuitry and on-chip optical devices with strong nonlinearities., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Alcohol consumption causes a spectrum of liver abnormalities and leads to over 3 million deaths per year. Alcoholic hepatitis (AH) is a florid presentation of alcoholic liver disease characterized by liver failure in the context of recent and heavy alcohol consumption. The aim of this study is to explore the potential benefits of the IL-1β antibody, canakinumab, in the treatment of AH., Methods: This is a multicentre, double-blind, randomised placebo-controlled trial. Participants will be diagnosed with AH using clinical criteria. Liver biopsy will then confirm that all histological features of AH are present. Up to 58 participants will be recruited into two groups from 15 centres in the UK. Patients will receive an infusion of Canakinumab or matched placebo by random 1:1 allocation. The primary outcome is the difference between groups in the proportion of patients demonstrating histological improvement and will compare histological appearances at baseline with appearances at 28 days to assign a category of "improved" or "not improved". Patients with evidence of ongoing disease activity will receive a second infusion of canakinumab or placebo. Participants will be followed up for 90 days. Secondary outcomes include mortality and change in MELD score at 90 days., Discussion: This phase II study will explore the benefits of the IL-1β antibody, canakinumab, in the treatment of AH to provide proof of concept that inhibition of IL-1β signalling may improve histology and survival for patients with AH., Trial Registration: EudraCT 2017-003724-79 . Prospectively registered on 13 April 2018., (© 2021. The Author(s).)

The influence of microgeometries on the Secondary Electron Yield (SEY) of surfaces is investigated. Laser written structures of different aspect ratio (height to width) on a copper surface tuned the SEY of the surface and reduced its value to less than unity. The aspect ratio of microstructures was methodically controlled by varying the laser parameters. The results obtained corroborate a recent theoretical model of SEY reduction as a function of the aspect ratio of microstructures. Nanostructures - which are formed inside the microstructures during the interaction with the laser beam - provided further reduction in SEY comparable to that obtained in the simulation of structures which were coated with an absorptive layer suppressing secondary electron emission.

Objectives: To investigate plasma levels of buprenorphine and norbuprenorphine and their relationship to respiratory depression., Materials and Methods: Opioid-dependent subjects were randomized 2 : 1 to novel lyophilized rapid-disintegrating tablet ("bup-lyo") or standard sublingual buprenorphine tablet ("bup-SL"). Measurements included oximetry scores and linked plasma buprenorphine and norbuprenorphine levels., Results: Respiratory depression (cumulative duration of SpO 2 < 90% over 30-minute periods) increased with corresponding exposure levels (AUC 30 min ) of buprenorphine and particularly with norbuprenorphine. A lower buprenorphine/norbuprenorphine ratio was predictive of respiratory depression. The mean (SD) observed ratio was significantly higher for "bup-lyo" (3.4 (2.8)) compared to "bup-SL" (1.7 (0.77)), p < 0.0001., Conclusion: Exploratory investigation found respiratory depression more strongly associated with norbuprenorphine than with buprenorphine. This accords with animal studies.
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Aims: To test the safety of new buprenorphine oral lyophilisate wafer ("bup-lyo") versus standard sub-lingual buprenorphine ("bup-SL")., Design: Randomised (2:1) open-label study; opioid-dependent subjects; subsequent partial cross-over., Settings: Specialised clinical trials facility and addictions treatment facility., Participants: Opioid-dependent subjects (n = 36) commencing buprenorphine maintenance (personalised dose-titration) including patients co-using alcohol, cocaine and benzodiazepines (below thresholds)., Measurements: Respiratory function (respiratory rate, pulse-oximetry); medication hold and dose adequacy; opiate withdrawal signs and symptoms; tablet disintegration times; treatment retention. Pharmacokinetics (PK) for plasma buprenorphine and norbuprenorphine (n = 11)., Findings: Oral lyophilised buprenorphine ("bup-lyo") completely dissolved within 2 min for 58 vs. 5% for "bup-SL." Dose titration resulted in similar maintenance dosing (10.8 vs. 9.6 mg). There were no significant between-group differences in opiate-withdrawal phenomena, craving, adequacy of "hold," respiratory function. No serious adverse events (AEs), nor "severe" AEs, although more AEs and Treatment-Emergent AEs with "bup-lyo" (mostly "mild"). PK found greater bioavailability of buprenorphine with "bup-lyo" (but not norbuprenorphine)., Conclusions: Orally disintegrating buprenorphine oral lyophilisate wafer disintegrated rapidly. No increased respiratory depression was found and clinically no difference between medications was observed. PK found substantially increased bioavailability of buprenorphine (but not of nor-buprenorphine) with "bup-lyo" relative to "bup-SL." In supervised dosing contexts, rapidly disintegrating formulations may enable wider buprenorphine prescribing., (© 2017 S. Karger AG, Basel.)

Introduction: The presence of obesity and the features of metabolic syndrome plays a predictive role in cardiovascular diseases (CVD) in adults. It seems reasonable to seek new risk factors in the development of CVD. Defining the genetic background of obesity could help to select patients from a high risk group and help to introduce prevention and treatment, which, in consequence, lead to the lowering of morbidity and mortality. One of the genes probably related to the body weight is the Fat Mass and Obesity Associated Gene (FTO)., The Aim: of the study was an attempt to assess the relationship between the FTO polymorphism rs9939609 and body mass index in children from Podlaskie voievodship., Material and Methods: 405 children aged 4-18 were selected for the study. The examination included body mass index, waist circumference, blood pressure and lipid profile analysis. FTO rs9939609 polymorphism was assessed using a discrimination allele method with the application of ABI 7900HT Fast Real-Time PCR System., Results: FTO rs9939609 polymorphism was related to the standarized body mass index and the AA genotype carriers had a higher risk of obesity. This polymorphism was also associated with waist circumference, systolic blood pressure and triglycerides concentration. It was not correlated with diastolic blood pressure and total HDL- and LDL-cholesterol concentrations., Conclusions: Our results demonstrate that rs9939609 FTO gene polymorphism is related to the body mass index in children. Our results should be confirmed in studies on a large cohort of healthy Polish children.