Functionality of primary hepatic non-parenchymal cells in a 3D spheroid model and contribution to acetaminophen hepatotoxicity.

In addition to hepatocytes, the liver comprises a host of specialised non-parenchymal cells which are important to consider in the development of in vitro models which are both physiologically and toxicologically relevant. We have characterized a 3D co-culture system comprising primary human hepatocytes (PHH) and non-parenchymal cells (NPC) and applied it to the investigation of acetaminophen-induced toxicity. Firstly, we titrated ratios of PHH:NPC and confirmed the presence of functional NPCs via both immunohistochemistry and activation with both LPS and TGF-β. Based on these data we selected a ratio of 2:1 PHH:NPC for further studies. We observed that spheroids supplemented with NPCs were protected against acetaminophen (APAP) toxicity as determined by ATP (up to threefold difference in EC50 at day 14 compared to hepatocytes alone) and glutathione depletion, as well as miR-122 release. APAP metabolism was also altered in the presence of NPCs, with significantly lower levels of APAP-GSH detected. Expression of several CYP450 enzymes involved in the bioactivation of APAP was also lower in NPC-containing spheroids. Spheroids containing NPCs also expressed higher levels of miRNAs which have been implicated in APAP-induced hepatotoxicity, including miR-382 and miR-155 which have potential roles in liver regeneration and inflammation, respectively. These data indicate that the interaction between hepatocytes and NPCs can have significant metabolic and toxicological consequences important for the correct elucidation of hepatic safety mechanisms

Utilizing Weak-to-Strong Consistency for Semi-Supervised Glomeruli Segmentation

Accurate segmentation of glomerulus instances attains high clinical significance in the automated analysis of renal biopsies to aid in diagnosing and monitoring kidney disease. Analyzing real-world histopathology images often encompasses inter-observer variability and requires a labor-intensive process of data annotation. Therefore, conventional supervised learning approaches generally achieve sub-optimal performance when applied to external datasets. Considering these challenges, we present a semi-supervised learning approach for glomeruli segmentation based on the weak-to-strong consistency framework validated on multiple real-world datasets. Our experimental results on 3 independent datasets indicate superior performance of our approach as compared with existing supervised baseline models such as U-Net and SegFormer.Comment: accepted to MIDL'2

Biomarkers of Kidney Failure and All-Cause Mortality in CKD

Background: Chronic kidney disease (CKD) carries a variable risk for multiple adverse outcomes, highlighting the need for a personalised approach. This study evaluated several novel biomarkers linked to key disease mechanisms to predict the risk of kidney failure (first event of eGFR <15 ml/min/1.73m2 or kidney replacement therapy), all-cause mortality, and a composite of both.Methods: We included 2,884 adults with non-dialysis CKD from 16 nephrology centres across the UK. Twenty-one biomarkers associated with kidney damage, fibrosis, inflammation, and cardiovascular disease were analysed in urine, plasma, or serum. Cox proportional hazards models were used to assess biomarker associations and develop risk prediction models.Results: Participants had mean age 63 (15) years, 58% were male and 87% White. Median eGFR 35 (25, 47) ml/min/1.73m2, and median urinary albumin-to-creatinine ratio (UACR) 197 (32, 895) mg/g. During median 48 (33, 55) months follow-up, 680 kidney failure events and 414 all-cause mortality events occurred. For kidney failure, a model combining three biomarkers (sTNFR1, sCD40, UCOL1A1) showed good discrimination (c-index 0.86, 95% CI: 0.83-0.89) but was outperformed by a model using established risk factors (age, sex, ethnicity, eGFR, UACR; c-index 0.90, 95% CI: 0.88-0.92). For all-cause mortality, a model using three biomarkers (hs-cTnT, NT-proBNP, suPAR) demonstrated equivalent discrimination (c-index 0.80, 95% CI: 0.75-0.84) to an established risk factor model (c-index 0.80, 95% CI: 0.76-0.84).For the composite outcome, the biomarker model discrimination (C-index 0.78, 95% CI: 0.76, 0.81) was numerically higher than for established risk factors (C-index 0.77, 95% CI: 0.74, 0.80), and the addition of biomarkers to the established risk factors led to a small but statistically significant improvement in discrimination (C-index 0.80, 95% CI: 0.77, 0.82; p value < 0.01).Conclusions: Risk prediction models incorporating novel biomarkers showed comparable discrimination to established risk factors for kidney failure and all-cause mortality

Rapid Identification of Bio-Molecules Applied for Detection of Biosecurity Agents Using Rolling Circle Amplification

Detection and identification of pathogens in environmental samples for biosecurity applications are challenging due to the strict requirements on specificity, sensitivity and time. We have developed a concept for quick, specific and sensitive pathogen identification in environmental samples. Target identification is realized by padlock- and proximity probing, and reacted probes are amplified by RCA (rolling-circle amplification). The individual RCA products are labeled by fluorescence and enumerated by an instrument, developed for sensitive and rapid digital analysis. The concept is demonstrated by identification of simili biowarfare agents for bacteria (Escherichia coli and Pantoea agglomerans) and spores (Bacillus atrophaeus) released in field

Firm-level inefficiency and its determinants in the Swedish water and wastewater sector

The Swedish Water and Wastewater (WW) utilities are subject to a cost-of-service regulation with no regulatory incentives to reduce costs. An estimation of firm-level inefficiency using stochastic frontier models on a cross-sectional sample of 148 utilities from 2006 suggests that overall the sector has at least a 15% cost reduction potential. Utilities can increase efficiency by reducing network losses. The cost frontier shifts to a higher level when (1) two or more municipalities merge their WW operations and when (2) utilities receive tax subsidies.

Welfare-Maximising Investors? – Utility Firm Performance with Heterogeneous Quality Preferences and Endogenous Ownership

We model the endogenous ownership of a monopoly utility by either investors or the firm's customers. Ownership arises endogenously based on customers' quality preference, which affects each ownership type's viability. Customer ownership arises when quality preference falls below the threshold for profitable entry by investors, but above that for entry by customer-owners. When quality preferences diverge sufficiently, a profitmaximising investor-owned utility produces higher welfare than a welfare-maximising customer-owned firm, despite its higher prices. Otherwise, a customer-owned utility produces greater efficiency, quality and welfare, despite having lower-value customers. These predictions agree with empirical findings for US utilities, and find direct support using data from Electricity Distribution Businesses in New Zealand. To reflect ownership endogeneity, we instrument for ownership changes using the staggered rollout of regional air quality regulations. Our findings suggest that performance comparisons of customer- and investor-owned utilities should account for ownership endogeneity. This has implications for ownership debates, efficiency study specification, and the development of regulatory screens

Public interest versus regulatory capture in the Swedish electricity market

This article tests the public interest and regulatory capture hypotheses, in the context of the Swedish electricity market, by studying the factors influencing the Swedish Energy Agency’s decision to replace decision-makers it employs to hear customer complaints against utilities. The study covers the period from the beginning of 1996, when a series of regulatory reforms were introduced to improve consumer protection, until the end of 2008. The study concludes that decision-makers who find in favor of customers have had a statistically lower probability of being removed, consistent with public interest theory. A transitory effect of favoring utilities can be observed for the period from 2 to 6 years following the reforms. In this period, government and public scrutiny of the regulator, which had been high in the immediate aftermath of the reforms, had waned and there were few precedents decided by the courts that the regulator was required to follow. This vacuum created an opportunity for the utilities to increase their influence over the regulator. Once the courts started establishing precedents in relatively large numbers, the supervisory role of the courts ensured that the actions of the regulator were scrutinized. This development has served a similar function to government and public scrutiny in the years immediately following the reforms in promoting the public interest.