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Summary: Background: Recently, a panel of multi‐society experts proposed steatotic liver disease (SLD) as an alternative terminology for metabolic dysfunction‐associated fatty liver disease (MAFLD) or nonalcoholic fatty liver disease (NAFLD). Aims: We compared the impact of SLD, subtype of SLD, MAFLD and NAFLD on all‐cause and cause‐specific mortality. Methods: A total of 7811 individuals in the third National Health and Nutrition Examination Survey and linked mortality through 2019 were analysed. SLD was defined based on ultrasonographic hepatic steatosis. SLD, subtype of SLD and MAFLD were defined using the proposed definitions. The Cox proportional hazard model assessed all‐cause/cause‐specific mortality. Results: During a median follow‐up of 27.1 years, individuals with SLD and MAFLD experienced approximately 13%–23% higher risk of all‐cause mortality (hazard ratio [HR]: 1.15, 95% confidence interval [CI]: 1.02–1.29 for SLD; HR: 1.23, 95% CI: 1.09–1.38 for MAFLD; HR: 1.13, 95% CI: 1.01–1.27 for metabolic dysfunction‐associated steatotic liver disease [MASLD]). Individuals with MetALD demonstrated a higher risk of all‐cause (HR: 1.68, 95% CI: 1.10–2.57) and cancer‐related mortality (HR: 2.40, 95% CI: 1.23–4.66). MASLD with advanced fibrosis had an increased risk of all‐cause mortality compared to MASLD without advanced fibrosis. Conclusions: SLD, especially MASLD and MetALD, is associated with increased all‐cause mortality among adults in the US. Given this significant association between SLD or subtype of SLD (MASLD and MetALD) and all‐cause mortality, adopting the proposed SLD criteria may help identify a sub‐group of individuals with SLD who are at an increased risk for all‐cause mortality. [ABSTRACT FROM AUTHOR]

Summary Background Aim Methods Results Conclusions Economic hardship associated with chronic liver disease (CLD) may delay timely access to healthcare.To estimate the national burden of financial hardship across the spectrum of CLD in the United States (US) during the coronavirus disease 2019 (COVID‐19) pandemic.A cross‐sectional analysis was performed using the 2020–2021 US National Health Interview Survey database. The questionnaire defined financial hardship from medical bills and cost‐related nonadherence to medications in patients with CLD. We used weighted survey analysis to obtain the national estimates.While 6.9% (95% confidence interval [CI]: 6.7%–7.2%) out of 60,689 US adults (weighted sample: 251 million) reported financial hardship and inability to pay medical bills; 10.6% (95% CI: 8.3%–13.4%), 18.2% (95% CI: 14.5%–22.6%), 22.6% (95% CI: 11.0%–41.0%) with hepatitis, CLD/cirrhosis, and liver cancer experienced an inability to pay their medical bills due to financial hardship, respectively. 19.8% (95% CI: 15.9%–24.5%) and 23.3% (95% CI: 12.5%–39.3%) with CLD/cirrhosis and liver cancer, respectively experienced cost‐related nonadherence to medications, compared to a tenth of US adults (10.7%, 95% CI: 10.3%–11.2%). CLD/cirrhosis demonstrated an independent association with financial hardship from medical bills and cost‐related nonadherence to medications. Overall, these disparities were more pronounced in individuals aged <65 years old. In addition, over 40% of individuals with CLD/cirrhosis reported difficulties accessing medical care during the COVID‐19 pandemic. CLD/cirrhosis showed an independent association with difficulties accessing medical care due to COVID‐19.Financial hardship from medical bills and cost‐related nonadherence to medication can negatively impact individuals with CLD and need further evaluation. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Verma et al papers. To view these articles, visit https://doi.org/10.1111/apt.17891 and https://doi.org/10.1111/apt.17913 [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: Patients with pre‐existing cirrhosis and exposure to coronavirus disease‐19 (COVID‐19) may portend a poor prognosis. We evaluated the temporal trends in aetiology‐based hospitalisations and potential predictors of in‐hospital mortality in hospitalisation with cirrhosis before and during the COVID‐19 pandemic. Methods: Based on the US National Inpatient Sample 2019–2020, we determined quarterly trends in aetiology‐based hospitalisations with cirrhosis and decompensated cirrhosis and identified predictors of in‐hospital mortality in hospitalisation with cirrhosis. Results: We analysed 316,418 hospitalisations, representing 1,582,090 hospitalisations with cirrhosis. Hospitalisations for cirrhosis increased at a relatively higher rate during the COVID‐19 era. Hospitalisation rates for alcohol‐related liver disease (ALD)‐related cirrhosis increased significantly (quarterly percentage change [QPC]: 3.6%, 95% CI: 2.2%–5.1%), with a notably higher rate during the COVID‐19 era. In contrast, hospitalisation rates for hepatitis C virus (HCV)‐related cirrhosis decreased steadily with a trend of −1.4% of QPC (95% CI: −2.5% to −0.1%). Quarterly trends in the proportion of ALD‐ (QPC: 1.7%, 95% CI: 0.9%–2.6%) and nonalcoholic fatty liver disease‐related (QPC: 0.7%, 95% CI: 0.1%–1.2%) hospitalisations with cirrhosis increased significantly but declined steadily for viral hepatitis. The COVID‐19 era and COVID‐19 infection were independent predictors of in‐hospital mortality during hospitalisation with cirrhosis and decompensated cirrhosis. Compared with HCV‐related cirrhosis, ALD‐related cirrhosis was associated with a 40% higher risk of in‐hospital mortality. Conclusion: In‐hospital mortality in cirrhosis was higher in the COVID‐19 era than in the pre‐COVID‐19 era. ALD is the leading aetiology‐specific cause of in‐hospital mortality in cirrhosis with an independent detrimental impact of the COVID‐19 infection. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Gawrieh et al papers. To view these articles, visit https://doi.org/10.1111/apt.17849 and https://doi.org/10.1111/apt.17886 [ABSTRACT FROM AUTHOR]

Summary: Background: Non‐alcoholic fatty liver disease (NAFLD) affects obese and non‐obese individuals. However, mechanisms underlying non‐obese non‐alcoholic steatohepatitis (NASH) remain unclear. Aims: To attempt to identify metabolic perturbations associated with non‐obese and obese NAFLD using a lipidomics approach. Methods: A cross‐sectional analysis of 361 subjects with biopsy‐proven NAFLD (157 NAFL and 138 NASH) and healthy controls (n = 66) was performed. Individuals were categorised as obese or non‐obese based on the Asian cut‐off for body mass index. Circulating lipidomic profiling of sera was performed based on the histological severity of NAFLD. Circulating lipidomic alterations were validated with an independent validation set (154 NAFLD subjects [93 NAFL and 61 NASH] and 21 healthy controls). Results: Saturated sphingomyelin (SM) species were significantly associated with visceral adiposity in non‐obese NAFLD (SM d38:0; P < 0.001) but not in obese NAFLD. Additionally, SM levels were significantly associated with systemic and adipose tissue insulin resistance (SM d38:0; P = 0.002 and <0.001, respectively). Five potential lipid metabolites for non‐obese subjects and seven potential lipids for obese subjects were selected to predict NAFLD and NASH. These lipid combinations showed good diagnostic performance for non‐obese (area under the curve [AUC] for NAFLD/NASH = 0.916/0.813) and obese (AUC for NAFLD/NASH = 0.967/0.812) subjects. Moreover, distinctly altered patterns of diacylglycerol (DAG), triacylglycerol (TAG) and SM levels were confirmed in the validation set depending on the histological severity of NAFLD. Conclusion: Non‐obese and obese NAFLD subjects exhibit unique circulating lipidomic signatures, including DAGs, TAGs and SMs. These lipid combinations may be useful biomarkers for non‐obese and obese NAFLD patients. [ABSTRACT FROM AUTHOR]

Summary: Background: Currently, the relationship between depression and non‐alcoholic fatty liver disease (NAFLD) is not clearly defined. Aim: To determine whether depression is associated with NAFLD and NAFLD‐related advanced fibrosis in a large population sample. Methods: We performed a cross‐sectional analysis using the 2007‐2016 National Health and Nutrition Examination Survey database among adults (20 years or older) in the United States (US). Depression and functional impairment due to depression were assessed with the Patient Health Questionnaire (PHQ‐9). NAFLD was defined by utilising the US fatty liver index (USFLI), hepatic steatosis index (HSI) and the fatty liver index (FLI) in the absence of other causes of chronic liver disease. The presence and absence of advanced fibrosis in NAFLD were defined by Fibrosis‐4 score. Results: Of the 10 484 subjects (mean age 47.0 years; 48.8% men), the prevalence of depression and functional impairment due to depression was higher in subjects with NAFLD than in those without. Compared to subjects without depression, those with depression were 1.6‐2.2‐fold more likely to have NAFLD. In our multivariate analyses, depression_med was associated with increased risk of NAFLD using USFLI (odds ratio [OR] 1.48 95% confidence interval [CI] 1.17‐1.87), HSI (OR 1.51 95% CI 1.04‐2.19) and FLI (OR 2.01 95% CI 1.65‐2.48), respectively. The addition of diabetes, obesity and lipid profile to the model reduced the ORs for depression, but the significance persisted. Depression was not associated with NAFLD‐related advanced fibrosis. Conclusions: In a nationally representative sample of US adults, depression was independently associated with NAFLD. [ABSTRACT FROM AUTHOR]

Summary: Background: Long term renal safety of antiviral agents against hepatitis B virus (HBV) has been debated. Aim: To compare longitudinal trends of renal function among HBV mono‐infected patients receiving entecavir (ETV), tenofovir disoproxil fumarate (TDF), and adefovir (ADV) in comparison to untreated subjects. Methods: A retrospective cohort consisting of 815 patients with chronic HBV infection was constructed. Serial estimated glomerular filtration rate (eGFR) was compared to the expected rate of age‐dependent decline in eGFR, derived from the National Health and Nutrition Examination Survey (NHANES) data. Generalised estimating equations and linear mixed‐effects models were used to compare trends in eGFR (in mL/min/1.73m2 as a "unit"). Results: In NHANES data (n = 23 051), each year of age was associated with a 0.86 unit decrease in eGFR in subjects without hypertension and 0.96 units with hypertension. The Stanford cohort consisted of patients who received ETV (n = 207), TDF (n = 191), ADV (n = 46) or no therapy (n = 371). After a median follow‐up 4.0 (interquartile range: 1.9‐6.5) years, there was no significant difference in the expected and observed rates of eGFR decline in untreated HBV patients. Patients receiving antiviral treatment experienced steeper reduction in renal function than expected. In the multivariable model, ETV was associated with eGFR loss at 1.81 units per year (P = 0.06, compared to untreated patients). TDF‐ and ADV‐treated patients experienced significantly higher rate of eGFR loss at 2.21 and 2.63 units per year, respectively (both P < 0.01). Conclusion: In this longitudinal cohort study, HBV patients receiving antiviral therapy, particularly TDF and ADV, experienced more rapid loss in eGFR. [ABSTRACT FROM AUTHOR]

Key points: We studied the role of the large‐conductance Ca2+‐activated K+ channel (BK) and voltage‐dependent K+ channels (Kv) on [Ca2+]i responses to a wide range of hypoxia at different resting cell membrane potential (Em). BK/Kv were mostly closed at rest in normoxia. BK/Kv became basally active when cells were depolarized by elevated [KCl]o (>12 m m). Regardless of whether BK/Kv were closed or basally open, hypoxia‐induced elevation of [Ca2+]i was enhanced 2‐ to 3‐fold by inhibitors of BK/Kv. Hypoxia‐induced elevation of [Ca2+]i was enhanced ∼2‐fold by an inhibitor of Kv2, a major Kv in rat glomus cells. Hypoxia did not inhibit BK in inside‐out patches. Our study supports a scheme in which activation of BK/Kv strongly limits the magnitude of hypoxia‐induced [Ca2+]i rise, with Kv having a much greater effect than BK. Abstract: Large‐conductance KCa (BK) and other voltage‐dependent K+ channels (Kv) are highly expressed in carotid body (CB) glomus cells, but their role in hypoxia‐induced excitation is still not well defined and remains controversial. We addressed this issue by studying the effects of inhibitors of BK (IBTX) and BK/Kv (TEA/4‐AP) on [Ca2+]i responses to a wide range of hypoxia at different levels of resting cell membrane potential (Em). IBTX and TEA/4‐AP did not affect the basal [Ca2+]i in isolated glomus cells bathed in 5 m m KClo, but elicited transient increases in [Ca2+]i in cells that were moderately depolarized (11–20 mV) by elevation of [KCl]o (12–20 m m). Thus, BK and Kv were mostly closed at rest and activated by depolarization. Four different levels of hypoxia (mild, moderate, severe, anoxia) were used to produce a wide range of [Ca2+]i elevation (0–700 n m). IBTX did not affect the rise in [Ca2+]i, but TEA/4‐AP strongly (∼3‐fold) enhanced [Ca2+]i rise by moderate and severe levels of hypoxia. Guangxitoxin, a Kv2 blocker, inhibited the whole‐cell current by ∼50%, and enhanced 2‐fold the [Ca2+]i rise elicited by moderate and severe levels of hypoxia. Anoxia did not directly affect BK, but activated BK via depolarization. Our findings do not support the view that hypoxia inhibits BK/Kv to initiate or maintain the hypoxic response. Rather, our results show that BK/Kv are activated as glomus cells depolarize in response to hypoxia, which then limits the rise in [Ca2+]i. Inhibition of Kv may provide a mechanism to enhance the chemosensory activity of the CB and ventilation. [ABSTRACT FROM AUTHOR]

Key points Hypoxia is thought to depolarize glomus cells by inhibiting the outward K+ current, which sets in motion a cascade of ionic events that lead to transmitter secretion, increased afferent carotid sinus nerve activity and increased ventilation., Our study of Na+-permeable channels in glomus cells has revealed that hypoxia not only inhibits TASK background K+ channels but also indirectly activates a non-selective cation channel with a single channel conductance of 20 pS. Under physiological conditions, the reversal potential of the cation channel is ∼ -28 mV, indicating that Na+ influx is also involved in hypoxia-induced excitation of glomus cells., Activation of the 20 pS cation channel is present when the O2 content is 5% or less, indicating that Na+ influx occurs during moderate to severe hypoxia (<5% O2), but not mild hypoxia (>5% O2)., The 20 pS cation channel is directly activated by a rise in intracellular Ca2+. Thus, factors that elevate intracellular Ca2+ such as hypoxia, extracellular acidosis and high external KCl all activate the cation channel. A feed-forward mechanism may be present in which an initial depolarization-induced rise in intracellular Ca2+ opens the Na+-permeable cation channel, and the Na+ influx causes additional depolarization and influx of Ca2+ into glomus cells., Abstract The current model of O2 sensing by carotid body chemoreceptor (glomus) cells is that hypoxia inhibits the outward K+ current and causes cell depolarization, Ca2+ influx via voltage-dependent Ca2+ channels and a rise in intracellular [Ca2+] ([Ca2+]i). Here we show that hypoxia (<5% O2), in addition to inhibiting the two-pore domain K+ channels TASK-1/3 (TASK), indirectly activates an ∼20 pS channel in isolated glomus cells. The 20 pS channel was permeable to K+, Na+ and Cs+ but not to Cl− or Ca2+. The 20 pS channel was not sensitive to voltage. Inhibition of TASK by external acid, depolarization of glomus cells with high external KCl (20 m m) or opening of the Ca2+ channel with FPL64176 activated the 20 pS channel when 1 m m Ca2+ was present in the external solution. Ca2+ (10 μ m) applied to the cytosolic side of inside-out patches activated the 20 pS channel. The threshold [Ca2+]i for activation of the 20 pS channel in cell-attached patches was ∼200 n m. The reversal potential of the 20 pS channel was estimated to be −28 mV. Our results reveal a sequential mechanism in which hypoxia (<5% O2) first inhibits the K+ conductance and then activates a Na+-permeable, non-selective cation channel via depolarization-induced rise in [Ca2+]i. Our results suggest that inhibition of K+ efflux and stimulation of Na+ influx both contribute to the depolarization of glomus cells during moderate to severe hypoxia. [ABSTRACT FROM AUTHOR]

Carotid body (CB) glomus cells from rat express a TASK-like background K+ channel that is believed to play a critical role in the regulation of excitability and hypoxia-induced increase in respiration. Here we studied the kinetic behaviour of single channel openings from rat CB cells to determine the molecular identity of the ‘TASK-like’ K+ channels. In outside-out patches, the TASK-like background K+ channel in CB cells was inhibited >90% by a reduction of pHo from 7.3 to 5.8. In cell-attached patches with 140 mm KCl and 1 mm Mg2+ in the bath and pipette solutions, two main open levels with conductance levels of ∼14 pS and ∼32 pS were recorded at a membrane potential of −60 mV. The K+ channels showed kinetic properties similar to TASK-1 (∼14 pS), TASK-3 (∼32 pS) and TASK-1/3 heteromer (∼32 pS). The presence of three TASK isoforms was tested by reducing [Mg2+]o to ∼0 mm, which had no effect on the conductance of TASK-1, but increased those of TASK-1/3 and TASK-3 to 42 pS and 74 pS, respectively. In CB cells, the reduction of [Mg2+]o to ∼0 mm also caused the appearance of ∼42 pS (TASK-1/3-like) and ∼74 pS (TASK-3-like) channels, in addition to the ∼14 pS (TASK-1-like) channel. The 42 pS channel was the most abundant, contributing ∼75% of the current produced by TASK-like channels. Ruthenium red (5 μm) had no effect on TASK-1 and TASK-1/3, but inhibited TASK-3 by 87%. In CB cells, ruthenium red caused ∼12% inhibition of TASK-like activity. Methanandamide reduced the activity of all three TASKs by 80–90%, and that of TASK-like channels in CB cell also by ∼80%. In CB cells, hypoxia caused inhibition of TASK-like channels, including TASK-1/3-like channels. These results show that TASK-1, TASK-1/3 and TASK-3 are all functionally expressed in isolated CB cells, and that the TASK-1/3 heteromer provides the major part of the oxygen-sensitive TASK-like background K+ conductance. [ABSTRACT FROM AUTHOR]

TREK-2 expressed in mammalian cells exhibits small (∼52 pS) and large (∼220 pS) unitary conductance levels. Here we tested the role of the N-terminus (69 amino acids long) in the control of the unitary conductance, and role of the alternative translation initiation as a mechanism that produces isoforms of TREK-2 that show different conductance levels. Deletion of the first half (Δ1–36) of the N-terminus had no effect. However, deletion of most of the N-terminus (Δ1–66) resulted in the appearance of only the large-conductance channel (∼220 pS). In support of the critical function of the distal half of the N-terminus, the deletion mutants Δ1–44 and Δ1–54 produced ∼90 pS and 188 pS channels, respectively. In Western blot analysis, TREK-2 antibody detected two immunoreactive bands at ∼54 kDa and ∼60 kDa from cells expressing wild-type TREK-2 that has three potential translation initiation sites (designated M1M2M3) within the N-terminus. Mutation of the second and third initiation sites from Met to Leu (M1L2L3) produced only the ∼60 kDa isoform and the small-conductance channel (∼52 pS). Mutants designed to produce translation from the second (M2L3) or third (M3) initiation site produced the ∼54 kDa isoform, and the large conductance channel (∼185–224 pS). M1L2L3, M2L3 and M3 were relatively selectively permeable to K+, as judged by the 51–55 mV shifts in reversal potential following a 10-fold change in [K+]o. PNa/ PK values were also similar for M1L2L3 (∼0.02), M2L3 (∼0.02) and M3 (∼0.03). Arachidonic acid, proton and membrane stretch activated, whereas dibutyryl-cAMP inhibited all three isoforms of TREK-2, indicating that deletion of the N-terminus does not abolish modulation. These results show that the small and large conductance TREK-2 channels are produced as a result of alternative translation initiation, producing isoforms with long and short N-termini, and that the distal half of the N-terminus controls the unitary conductance. [ABSTRACT FROM AUTHOR]

TREK-2 (K2P10.1), a member of the two-pore domain K+ (K2P) channel family, provides the background K+ conductance in many cell types, and is a target of neurotransmitters that act on receptors coupled to Gs and Gq. We report here that TREK-2 exhibits small (TREK-2S) and large (TREK-2L) conductance phenotypes when expressed in mammalian cell lines (COS-7, HEK293, HeLa) and in Xenopus oocytes. TREK-2S phenotype shows a noisy open state with a mean conductance of 54 pS (+40 mV). TREK-2L phenotype shows a full open state (202 pS) with several short-lived sub-conductance levels. Both phenotypes were strongly activated by arachidonic acid, membrane stretch (−40 mmHg) and intracellular acidification (pH 6.4). Phosphorylation of TREK-2 produced by treatment of cells with activators of protein kinases A and C, and okadaic acid (a serine/threonine phosphatase inhibitor) decreased the current contributed by TREK-2S and TREK-2L, and caused partial switching of conductance levels from those of TREK-2S and TREK-2L to more intermediate values. Under this condition, TREK-2 exhibited six conducting levels and one closed level. TREK-2 mutants in which putative protein kinases A and C phosphorylation sites were mutated to alanines (S326A, S359A, S326A/S359A) displayed mostly TREK-2S and TREK-2L phenotypes. However, S326D and S359D mutants (as well as the double mutants) that mimic the phosphorylated state showed all six conducting levels and low channel activity. The S326A and S359A mutants did not significantly affect the intrinsic voltage dependence of TREK-2 in Mg2+-free solution. Phenotypes resembling TREK-2S and TREK-2L were also observed in cerebellar granule neurons that express TREK-2 mRNA. These results show that TREK-2 exhibits two primary modes of gating that give rise to two channel phenotypes under dephosphorylated conditions, and that its phosphorylation shifts the gating mode to include intermediate conducting levels. This represents a novel mechanism by which receptor agonists modulate the function of a K+ channel to alter cell excitability. [ABSTRACT FROM AUTHOR]

TASK-1 and TASK-3 are functional members of the tandem-pore K+ (K2P) channel family, and mRNAs for both channels are expressed together in many brain regions. Although TASK-1 and TASK-3 subunits are able to form heteromers when their complementary RNAs are injected into oocytes, whether functional heteromers are present in the native tissue is not known. Using cultured cerebellar granule (CG) neurones that express mRNAs of both TASK-1 and TASK-3, we studied the presence of heteromers by comparing the sensitivities of cloned and native K+ channels to extracellular pH (pHo) and ruthenium red. The single-channel conductance of TASK-1, TASK-3 and a tandem construct (TASK-1/TASK-3) expressed in COS-7 cells were 14.2 ± 0.4, 37.8 ± 0.7 and 38.1 ± 0.7 pS (-60 mV), respectively. TASK-3 and TASK-1/TASK-3 (and TASK-3/TASK-1) displayed nearly identical single-channel kinetics. TASK-3 and TASK-l/ TASK-3 expressed in COS-7 cells were inhibited by 26 ± 4 and 36 ± 2%, respectively, when pHo was changed from 8.3 to 7.3. In outside-out patches from CG neurones, the K+ channel with single channel properties similar to those of TASK-3 was inhibited by 31 ± 7% by the same reduction in pHo. TASK-3 and TASK- 1/TASK-3 expressed in COS-7 cells were inhibited by 78 ± 7 and 3 ± 4%, respectively, when µM ruthenium red was applied to outside-out patches. In outside-out patches from CG neurones containing a 38 pS channel, two types of responses to ruthenium red were observed. Ruthenium red inhibited the channel activity by 77 ± 5% in 42% of patches (range: 72-82%) and by 5 ± 4% (range: 0-9%) in 58% of patches. When patches contained more than three 38 pS channels, the average response to ruthenium red was 47 ± 6% inhibition (n = 5). These electrophysiological studies show that native 38 pS K+ channels of the TASK family in... [ABSTRACT FROM AUTHOR]

The author discusses the potential endocytosis as another pathway in receptor Gq-TASK signalling. He cites a study which indicates that muscarine can cause a rapid, clathrin-mediated endocytosis which was dependent on protein kinase C (PKC). The author explains the outcome of the study and suggests the need for investigators to repeat studies using more than one cell type to show pathways in receptor-Gq-TASK signalling and indeed cell type specific.