Entanglement on an optical atomic-clock transition.

State-of-the-art atomic clocks are based on the precise detection of the energy difference between two atomic levels, which is measured in terms of the quantum phase accumulated over a given time interval1-4. The stability of optical-lattice clocks (OLCs) is limited both by the interrupted interrogation of the atomic system by the local-oscillator laser (Dick noise5) and by the standard quantum limit (SQL) that arises from the quantum noise associated with discrete measurement outcomes. Although schemes for removing the Dick noise have been recently proposed and implemented4,6-8, performance beyond the SQL by engineering quantum correlations (entanglement) between atoms9-20 has been demonstrated only in proof-of-principle experiments with microwave clocks of limited stability. The generation of entanglement on an optical-clock transition and operation of an OLC beyond the SQL represent important goals in quantum metrology, but have not yet been demonstrated experimentally16. Here we report the creation of a many-atom entangled state on an OLC transition, and use it to demonstrate a Ramsey sequence with an Allan deviation below the SQL after subtraction of the local-oscillator noise. We achieve a metrological gain of [Formula: see text] decibels over the SQL by using an ensemble consisting of a few hundred ytterbium-171 atoms, corresponding to a reduction of the averaging time by a factor of 2.8 ± 0.3. Our results are currently limited by the phase noise of the local oscillator and Dick noise, but demonstrate the possible performance improvement in state-of-the-art OLCs1-4 through the use of entanglement. This will enable further advances in timekeeping precision and accuracy, with many scientific and technological applications, including precision tests of the fundamental laws of physics21-23, geodesy24-26 and gravitational-wave detection27.

Efficacy and safety of infliximab in patients with autoimmune hepatitis.

BACKGROUND AND AIMS: A limited number of drugs are used as standard or alternative therapies in autoimmune hepatitis (AIH). No specific recommendations are available for patients failing to respond to these therapies. We analyzed the efficacy and safety of infliximab in patients with AIH. APPROACH AND RESULTS: We performed a retrospective study of 42 patients with AIH who received infliximab at 21 liver centers in 12 countries. Patients were categorized according to the reason for infliximab therapy. Patients in group 1 (n=20) had failed standard, second-line (mycophenolate mofetil and 6-mercaptopurine) or third-line (tacrolimus or cyclosporine) therapy. In group 2 (n=22), infliximab was given for treatment of concomitant extrahepatic autoimmune diseases. Patients received a median of 17 (range: 3-104) infliximab infusions. Complete biochemical response (CR) was achieved or maintained in 33 (78%) patients during infliximab therapy. In group 1, infliximab induced CR in 11 of 20 (55%) patients. In group 2, 16 patients with CR prior to infliximab maintained remission, and the remaining 6 patients with active AIH (5 on standard and 1 on both second-line and third-line therapy) showed CR following infliximab therapy. Infliximab led to CR in 75% (6/8) of nonresponders to second-line and in 46% (6/13) of failing third-line therapy. Overall, 65% (17/26) of the patients with active AIH achieved CR on infliximab. Infliximab was discontinued in 3 patients of group 1. One patient had a severe allergic reaction and 2 developed anti-infliximab autoantibodies. CONCLUSIONS: Our study suggests that infliximab may be an effective and safe rescue therapy in AIH.

Epstein-Barr virus nuclear antigen 2 extensively rewires the human chromatin landscape at autoimmune risk loci.

The interplay between environmental and genetic factors plays a key role in the development of many autoimmune diseases. In particular, the Epstein-Barr virus (EBV) is an established contributor to multiple sclerosis, lupus, and other disorders. Previously, we showed that the EBV nuclear antigen 2 (EBNA2) transactivating protein occupies up to half of the risk loci for a set of seven autoimmune disorders. To further examine the mechanistic roles played by EBNA2 at these loci on a genome-wide scale, we globally examined gene expression, chromatin accessibility, chromatin looping, and EBNA2 binding in a B cell line that was (1) uninfected, (2) infected with a strain of EBV lacking EBNA2, or (3) infected with a strain that expresses EBNA2. We identified more than 400 EBNA2-dependent differentially expressed human genes and more than 5000 EBNA2 binding events in the human genome. ATAC-seq analysis revealed more than 2000 regions in the human genome with EBNA2-dependent chromatin accessibility, and HiChIP data revealed more than 1700 regions where EBNA2 altered chromatin looping interactions. Autoimmune genetic risk loci were highly enriched at the sites of these EBNA2-dependent chromatin-altering events. We present examples of autoimmune risk genotype-dependent EBNA2 events, nominating genetic risk mechanisms for autoimmune risk loci such as ZMIZ1 Taken together, our results reveal important interactions between host genetic variation and EBNA2-driven disease mechanisms. Further, our study highlights a critical role for EBNA2 in rewiring human gene regulatory programs through rearrangement of the chromatin landscape and nominates these interactions as components of genetic mechanisms that influence the risk of multiple autoimmune diseases.

Bright ultra-broadband fiber-based biphoton source.

In this Letter, we report a first, to the best of our knoqledge, experimental realization of a bright ultra-broadband (180 THz) fiber-based biphoton source with widely spectrally separated signal and idler photons. Such a two-photon source is realized due to the joint use of a broadband two-loop phase-matching of interacting light waves and high optical nonlinearity of a silica-core photonic crystal fiber. The high performance of the developed fiber source identifies it as an important and useful tool for a wide range of optical quantum applications.

Conformity Experiment on Inelastic Scattering Exponent of Electrons in Two Dimensions.

The quantum Hall (QH) effect is one of the most widely studied physical phenomenon in two dimensions. The plateau-plateau transition within this effect can be comprehensively described by the scaling theory, which encompasses three pivotal exponents: the critical exponent κ, the inelastic scattering exponent p, and the universal exponent γ. Prior studies have focused on measuring κ and estimating γ, assuming a constant p value of 2 across magnetic fields. Here, our work marks a significant advancement by measuring all three exponents within a single graphene device and a conventional two-dimensional electron system. This study uniquely determines p at low magnetic fields (weak localization region and well outside the QH regime) and high magnetic fields (in the vicinity of the QH regime). Employing a comprehensive analytical approach that includes weak localization, plateau-plateau transitions, and variable range hopping, we have directly determined κ, p, and γ. Our findings reveal a distinct variation in p, shifting from 1 in the low magnetic field regime to 2 in the QH regime in graphene.

Achievement of Target Gain Larger than Unity in an Inertial Fusion Experiment.

On December 5, 2022, an indirect drive fusion implosion on the National Ignition Facility (NIF) achieved a target gain G_{target} of 1.5. This is the first laboratory demonstration of exceeding "scientific breakeven" (or G_{target}>1) where 2.05 MJ of 351 nm laser light produced 3.1 MJ of total fusion yield, a result which significantly exceeds the Lawson criterion for fusion ignition as reported in a previous NIF implosion [H. Abu-Shawareb et al. (Indirect Drive ICF Collaboration), Phys. Rev. Lett. 129, 075001 (2022)PRLTAO0031-900710.1103/PhysRevLett.129.075001]. This achievement is the culmination of more than five decades of research and gives proof that laboratory fusion, based on fundamental physics principles, is possible. This Letter reports on the target, laser, design, and experimental advancements that led to this result.

Transitioning from Subtyping to Precision Medicine in Parkinson's Disease: A Purpose-Driven Approach.

The International Parkinson and Movement Disorder Society (MDS) created a task force (TF) to provide a critical overview of the Parkinson's disease (PD) subtyping field and develop a guidance on future research in PD subtypes. Based on a literature review, we previously concluded that PD subtyping requires an ultimate alignment with principles of precision medicine, and consequently novel approaches were needed to describe heterogeneity at the individual patient level. In this manuscript, we present a novel purpose-driven framework for subtype research as a guidance to clinicians and researchers when proposing to develop, evaluate, or use PD subtypes. Using a formal consensus methodology, we determined that the key purposes of PD subtyping are: (1) to predict disease progression, for both the development of therapies (use in clinical trials) and prognosis counseling, (2) to predict response to treatments, and (3) to identify therapeutic targets for disease modification. For each purpose, we describe the desired product and the research required for its development. Given the current state of knowledge and data resources, we see purpose-driven subtyping as a pragmatic and necessary step on the way to precision medicine. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

High histamine levels are associated with acute-on-chronic liver failure and liver-related death in patients with advanced chronic liver disease.

BACKGROUND AND AIMS: The role of histamine in advanced chronic liver disease (ACLD) is poorly understood. We investigated plasma histamine levels across ACLD stages and their prognostic value. METHODS: We included patients with evidence of ACLD, defined by portal hypertension (hepatic venous pressure gradient [HVPG] ≥6 mmHg) and/or a liver stiffness measurement by transient elastography ≥10 kPa, who underwent HVPG measurement between 2017 and 2020. Acute-on-chronic liver failure (ACLF) and/or liver-related death were defined as composite endpoint. RESULTS: Of 251 patients, 82.5% had clinically significant portal hypertension (median HVPG: 17 mmHg [interquartile range (IQR) 12-21]) and 135 patients (53.8%) were decompensated at baseline. Median plasma histamine was 8.5 nmol/L (IQR: 6.4-11.5), 37.1% of patients showed elevated values (>9.9 nmol/L). Histamine levels did not differ significantly across Child-Turcotte-Pugh (CTP) stages nor strata of model for end-stage liver disease (MELD) or HVPG. Histamine levels correlated with markers of circulatory dysfunction (i.e. sodium, renin and aldosterone). During a median follow-up of 29.2 months, 68 patients developed ACLF or liver-related death. In univariate as well as in multivariate analysis (adjusting for age, sex, HVPG as well as either MELD, clinical stage, and serum albumin or CTP and serum sodium), elevated histamine levels remained associated with the composite endpoint. CTP-based multivariate model adjusted sub-distribution hazard ratio (asHR): 1.010 (95% CI: 1.004-1.021), p < .001; MELD-based multivariate model asHR: 1.030 (95% CI: 1.017-1.040), p < .001. CONCLUSION: High levels of histamine were linked to circulatory dysfunction in ACLD patients and independently associated with increased risks of ACLF or liver-related death. Further mechanistic studies on the link between histamine signalling and development of hyperdynamic circulation and ACLF are warranted.

One-pot Synthesis and Photophysical Studies of Α-cycloamino-substituted 5-aryl-2,2'-bipyridines.

A series of α-cycloamine substituted 2,2'-bipyridines 3ae'-3ce' was obtained via the one-pot approach based on ipso-substitution of a cyano-group in 1,2,4-triazines, followed by aza-Diels-Alder reaction in good yields. Photophysical properties, including fluorosolvatochromism, were studied for 3ae'-3ce' and were compared with α-unsubstituted 2,2'-bipyridines. In addition, dipole moments differences in ground and excited states were calculated by both Lippert-Mataga equation and DFT studies and were compared to each other. The correlation between the size of cycloamine unit and the dipole moments differences value (based on Lippert-Mataga equation) was observed. In addition charge transfer indices (DCT, Λ, H and t) were calculated to demonstrate influence of molecular structure on the intramolecular charge transfer degree.

Theoretical investigation of (La4O6)n, (La2Ce2O7)n, and (Ce4O8)n nanoclusters (n = 10, 18): Temperature effects and O-vacancy formation.

We report a theoretical investigation of temperature, size, and composition effects on the structural, energetic, and electronic properties of the (La4O6)n, (La2Ce2O7)n, and (Ce4O8)n nanoclusters (NCs) for n = 10, 18. Furthermore, we investigated the single O vacancy formation energy as a function of the geometric location within the NC. Our calculations are based on the combination of force-field molecular dynamics (MD) simulations and density functional theory calculations. We identified a phase transition from disordered to ordered structures for all NCs via MD simulations and structural analysis, e.g., radius changes, radial distribution function, common neighbor analysis, etc. The transition is sharp for La36Ce36O126, La20Ce20O70, and Ce72O144 due to the crystalline domains in the core and less abrupt for Ce40O80, La40O60, and La72O108. As expected, radius changes are abrupt at the transition temperature, as are morphological differences between NCs located below and above the transition temperature. We found a strong dependence on the O vacancy formation energy (Evac) and its location within the NCs. For example, for La40O60, Evac decreases almost linearly as the distance from the geometric center increases; however, the same trend was not observed for Ce40O80, while there are large deviations from the linear trend for La20Ce20O70. Evac has smaller values for Ce40O80 and higher values for La40O60, that is, almost three times, while Evac has intermediate values for mixed oxides, as expected from weighted averages. Therefore, the mixture of one formula unit of La2O3 with two formula units of CeO2 has the effect of increasing the stability of CeO2 (binding energy), which increases the magnitude of the formation energy of the O vacancy.

Atomistic insights from DFT calculations into the catalytic properties on ceria-lanthanum clusters for methane activation.

Improving the catalytic performance of materials based on cerium oxide (CeO2) for the activation of methane (CH4) can be achieved through the following strategies: mixture of CeO2 with different oxides (e.g., CeO2-La2O3) and the use of particles with different sizes. In this study, we present a theoretical investigation of the initial CH4 dehydrogenation on (La2Ce2O7)n clusters, where n = 2, 4, and 6. Our framework relies on density functional theory calculations combined with the unity bond index-quadratic exponential potential approximation. Our results indicate that chemical species arising from the first dehydrogenation of CH4, that is, CH3 and H, bind through the formation of C-O and H-O bonds with the clusters, respectively. The coordination of the adsorption site and the chemical environment plays a crucial role in the magnitude of the adsorption energy; for example, species adsorb more strongly in the low-coordinated topO sites located close to the La atoms. Thus, it affects the activation energy barrier, which tends to be lower in configurations where the adsorption of the chemical species is stronger. During CH4 dehydrogenation, the CH3 radical can be present in a planar or tetrahedral configuration. Its conformation changes as a function of the charge transference between the molecule and the cluster, which depends on the CH3-cluster distance. Finally, we analyze the effects of the Hubbard effective parameter (Ueff) on adsorption properties, as the magnitude of localization of Ce f-states affects the hybridization of the interaction between the molecule and the clusters and hence the magnitude of the adsorption energies. We obtained a linear decrease in the adsorption energies by increasing the Ueff parameter; however, the activation energy is only slightly affected.

Perspectives of Implementation of Closed-Loop Deep Brain Stimulation: From Neurological to Psychiatric Disorders.

BACKGROUND: Deep brain stimulation (DBS) is a highly efficient, evidence-based therapy to alleviate symptoms and improve quality of life in movement disorders such as Parkinson's disease, essential tremor, and dystonia, which is also being applied in several psychiatric disorders, such as obsessive-compulsive disorder and depression, when they are otherwise resistant to therapy. SUMMARY: At present, DBS is clinically applied in the so-called open-loop approach, with fixed stimulation parameters, irrespective of the patients' clinical state(s). This approach ignores the brain states or feedback from the central nervous system or peripheral recordings, thus potentially limiting its efficacy and inducing side effects by stimulation of the targeted networks below or above the therapeutic level. KEY MESSAGES: The currently emerging closed-loop (CL) approaches are designed to adapt stimulation parameters to the electrophysiological surrogates of disease symptoms and states. CL-DBS paves the way for adaptive personalized DBS protocols. This review elaborates on the perspectives of the CL technology and discusses its opportunities as well as its potential pitfalls for both clinical and research use in neuropsychiatric disorders.

Development of a Topological-Insulator-Based Quantum Resistance Standard.

This paper describes the characterization of the quantum anomalous Hall (QAH) effect resistor with Chromium-doped Bismuth Antimony Telluride with the efforts in coupling directly to a programmable Josephson voltage standard (PJVS) at zero magnetic field. The precision measurement of the QAH resistance was performed under the presence of microwave signal biased to the PJVS. Understanding such effect will help to improve the experimental set-up for integrating multiple quantum electrical standards in a single system.

Carvedilol Achieves Higher Hemodynamic Response and Lower Rebleeding Rates Than Propranolol in Secondary Prophylaxis.

BACKGROUND & AIMS: Carvedilol induces stronger decreases in hepatic venous pressure gradient (HVPG) than conventional nonselective ß-blockers (ie, propranolol). Limited data exist on the efficacy of carvedilol in secondary prophylaxis of variceal bleeding. METHODS: Patients undergoing paired HVPG measurements for guiding secondary prophylaxis with either carvedilol or propranolol were included in this retrospective analysis. All patients also underwent band ligation. Changes in HVPG and systemic hemodynamics were compared between the 2 groups. Long-term follow-up data on rebleeding, acute kidney injury, nonbleeding decompensation, and liver-related death were analyzed applying competing risk regression. RESULTS: Eighty-seven patients (carvedilol/propranolol, n = 45/42) were included in our study. The median baseline HVPG was 21 mm Hg (interquartile range, 18-24 mm Hg), and 39.1%/48.3%/12.6% had Child-Turcotte-Pugh A/B/C cirrhosis, respectively. Upon nonselective ß-blocker initiation, HVPG decreased more strongly in carvedilol users (median relative decrease, -20% [interquartile range: -29% to -10%] vs -11% [-22% to -5%] for propranolol; P = .027), who also achieved chronic HVPG response more often (53.3% vs 28.6%; P = .034). Cumulative incidences for rebleeding (Gray test, P = .027) and liver-related death (P = .036) were significantly lower in patients taking carvedilol compared with propranolol. Notably, ascites development/worsening also was observed less commonly in carvedilol patients (P = .012). Meanwhile, acute kidney injury rates did not differ between the 2 groups (P = .255). Stratifying patients by HVPG response status yielded similar results. The prognostic value of carvedilol intake was confirmed in competing risk regression models. CONCLUSIONS: Carvedilol induces more marked reductions in HVPG than propranolol in secondary prophylaxis of variceal bleeding, and thus is associated with lower rates of rebleeding, liver-related death, and further nonbleeding decompensation.

Topological Properties of Floquet Winding Bands in a Photonic Lattice.

The engineering of synthetic materials characterized by more than one class of topological invariants is one of the current challenges of solid-state based and synthetic materials. Using a synthetic photonic lattice implemented in a two-coupled ring system we engineer an anomalous Floquet metal that is gapless in the bulk and shows simultaneously two different topological properties. On the one hand, this synthetic lattice presents bands characterized by a winding number. The winding emerges from the breakup of inversion symmetry, and it directly relates to the appearance of Bloch suboscillations within its bulk. On the other hand, the Floquet nature of the lattice results in well-known anomalous insulating phases with topological edge states. The combination of broken inversion symmetry and periodic time modulation studied here enriches the variety of topological phases available in lattices subject to Floquet driving and suggests the possible emergence of novel phases when periodic modulation is combined with the breakup of spatial symmetries.

A neural network for tics: insights from causal brain lesions and deep brain stimulation.

Brain lesions are a rare cause of tic disorders. However, they can provide uniquely causal insights into tic pathophysiology and can also inform on possible neuromodulatory therapeutic targets. Based on a systematic literature review, we identified 22 cases of tics causally attributed to brain lesions and employed 'lesion network mapping' to interrogate whether tic-inducing lesions would be associated with a common network in the average human brain. We probed this using a normative functional connectome acquired in 1000 healthy participants. We then examined the specificity of the identified network by contrasting tic-lesion connectivity maps to those seeding from 717 lesions associated with a wide array of neurological and/or psychiatric symptoms within the Harvard Lesion Repository. Finally, we determined the predictive utility of the tic-inducing lesion network as a therapeutic target for neuromodulation. Specifically, we collected retrospective data of 30 individuals with Tourette disorder, who underwent either thalamic (n = 15; centromedian/ventrooralis internus) or pallidal (n = 15; anterior segment of globus pallidus internus) deep brain stimulation and calculated whether connectivity between deep brain stimulation sites and the lesion network map could predict clinical improvements. Despite spatial heterogeneity, tic-inducing lesions mapped to a common network map, which comprised the insular cortices, cingulate gyrus, striatum, globus pallidus internus, thalami and cerebellum. Connectivity to a region within the anterior striatum (putamen) was specific to tic-inducing lesions when compared with control lesions. Connectivity between deep brain stimulation electrodes and the lesion network map was predictive of tic improvement, regardless of the deep brain stimulation target. Taken together, our results reveal a common brain network involved in tic generation, which shows potential as a therapeutic target for neuromodulation.

Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease.

Gaucher disease is caused by mutations in GBA1, which encodes the lysosomal enzyme glucocerebrosidase (GCase). GBA1 mutations drive extensive accumulation of glucosylceramide (GC) in multiple innate and adaptive immune cells in the spleen, liver, lung and bone marrow, often leading to chronic inflammation. The mechanisms that connect excess GC to tissue inflammation remain unknown. Here we show that activation of complement C5a and C5a receptor 1 (C5aR1) controls GC accumulation and the inflammatory response in experimental and clinical Gaucher disease. Marked local and systemic complement activation occurred in GCase-deficient mice or after pharmacological inhibition of GCase and was associated with GC storage, tissue inflammation and proinflammatory cytokine production. Whereas all GCase-inhibited mice died within 4-5 weeks, mice deficient in both GCase and C5aR1, and wild-type mice in which GCase and C5aR were pharmacologically inhibited, were protected from these adverse effects and consequently survived. In mice and humans, GCase deficiency was associated with strong formation of complement-activating GC-specific IgG autoantibodies, leading to complement activation and C5a generation. Subsequent C5aR1 activation controlled UDP-glucose ceramide glucosyltransferase production, thereby tipping the balance between GC formation and degradation. Thus, extensive GC storage induces complement-activating IgG autoantibodies that drive a pathway of C5a generation and C5aR1 activation that fuels a cycle of cellular GC accumulation, innate and adaptive immune cell recruitment and activation in Gaucher disease. As enzyme replacement and substrate reduction therapies are expensive and still associated with inflammation, increased risk of cancer and Parkinson disease, targeting C5aR1 may serve as a treatment option for patients with Gaucher disease and, possibly, other lysosomal storage diseases.

HCC risk stratification after cure of hepatitis C in patients with compensated advanced chronic liver disease.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality in patients with advanced chronic liver disease (ACLD) caused by chronic hepatitis C who have achieved sustained virologic response (SVR). We developed risk stratification algorithms for de novo HCC development after SVR and validated them in an independent cohort. METHODS: We evaluated the occurrence of de novo HCC in a derivation cohort of 527 patients with pre-treatment ACLD and SVR to interferon-free therapy, in whom alpha-fetoprotein (AFP) and non-invasive surrogates of portal hypertension including liver stiffness measurement (LSM) were assessed pre-/post-treatment. We validated our results in 1,500 patients with compensated ACLD (cACLD) from other European centers. RESULTS: During a median follow-up (FU) of 41 months, 22/475 patients with cACLD (4.6%, 1.45/100 patient-years) vs. 12/52 decompensated patients (23.1%, 7.00/100 patient-years, p <0.001) developed de novo HCC. Since decompensated patients were at substantial HCC risk, we focused on cACLD for all further analyses. In cACLD, post-treatment-values showed a higher discriminative ability for patients with/without de novo HCC development during FU than pre-treatment values or absolute/relative changes. Models based on post-treatment AFP, alcohol consumption (optional), age, LSM, and albumin, accurately predicted de novo HCC development (bootstrapped Harrel's C with/without considering alcohol: 0.893/0.836). Importantly, these parameters also provided independent prognostic information in competing risk analysis and accurately stratified patients into low- (~2/3 of patients) and high-risk (~1/3 of patients) groups in the derivation (algorithm with alcohol consumption; 4-year HCC-risk: 0% vs. 16.5%) and validation (3.3% vs. 17.5%) cohorts. An alternative approach based on alcohol consumption (optional), age, LSM, and albumin (i.e., without AFP) also showed a robust performance. CONCLUSIONS: Simple algorithms based on post-treatment age/albumin/LSM, and optionally, AFP and alcohol consumption, accurately stratified patients with cACLD based on their risk of de novo HCC after SVR. Approximately two-thirds were identified as having an HCC risk <1%/year in both the derivation and validation cohort, thereby clearly falling below the cost-effectiveness threshold for HCC surveillance. LAY SUMMARY: Simple algorithms based on age, alcohol consumption, results of blood tests (albumin and α-fetoprotein), as well as liver stiffness measurement after the end of hepatitis C treatment identify a large proportion (approximately two-thirds) of patients with advanced but still asymptomatic liver disease who are at very low risk (<1%/year) of liver cancer development, and thus, might not need to undergo 6-monthly liver ultrasound.

Decreasing von Willebrand Factor Levels Upon Nonselective Beta Blocker Therapy Indicate a Decreased Risk of Further Decompensation, Acute-on-chronic Liver Failure, and Death.

BACKGROUND & AIMS: Nonselective beta blockers (NSBBs) exert beneficial effects beyond lowering hepatic venous pressure gradient (HVPG), which may be particularly relevant in patients with decompensated cirrhosis (DC), in whom bacterial translocation and bacterial-induced systemic inflammation drive the development of complications such as acute-on-chronic liver failure (ACLF). We evaluated whether NSBB-related changes in von Willebrand factor (VWF) may serve as a biomarker for these effects. METHODS: In this retrospective analysis, 159 prospectively characterized patients with clinically stable DC (ie, without acute decompensation) who underwent paired HVPG/VWF assessments before/on NSBB therapy were classified as 'VWF-responders' (as defined by a ≥5% decrease in VWF) versus 'VWF-non-responders.' RESULTS: There were no major differences in baseline characteristics between VWF-responders (61%) and VWF-non-responders. VWF-responders showed more pronounced decreases in inflammation (procalcitonin), whereas rates of HVPG-response were similar. In line, NSBB-related changes in VWF correlated with the dynamics of bacterial translocation/inflammation (lipopolysaccharide-binding protein, C-reactive protein, and procalcitonin), rather than those of HVPG. Interestingly, VWF-responders also showed less pronounced NSBB-related decreases in mean arterial pressure, suggesting an amelioration of systemic vasodilatation. Finally, VWF-response was associated with decreased risks of further decompensation (adjusted hazard ratio [aHR], 0.555; 95% confidence interval [CI], 0.337-0.912; P = .020), ACLF (aHR, 0.302; 95% CI, 0.126-0.721; P = .007), and liver-related death (aHR, 0.332; 95% CI, 0.179-0.616; P < .001) in Cox regression models adjusted for prognostic factors including changes in HVPG. CONCLUSIONS: Decreases in VWF upon NSBB therapy reflect their anti-inflammatory activity, are accompanied by less pronounced adverse effects on systemic hemodynamics, and are independently associated with a decreased risk of further decompensation, ACLF, and death. VWF-response may discriminate between decompensated patients who benefit from NSBB treatment and have a favorable prognosis versus patients with poor outcomes.

Noninvasive Risk Stratification After HCV Eradication in Patients With Advanced Chronic Liver Disease.

BACKGROUND AND AIMS: Risk stratification after cure from hepatitis C virus (HCV) infection remains a clinical challenge. We investigated the predictive value of noninvasive surrogates of portal hypertension (liver stiffness measurement [LSM] by vibration-controlled transient elastography and von Willebrand factor/platelet count ratio [VITRO]) for development of hepatic decompensation and hepatocellular carcinoma in patients with pretreatment advanced chronic liver disease (ACLD) who achieved HCV cure. APPROACH AND RESULTS: A total of 276 patients with pretreatment ACLD and information on pretreatment and posttreatment follow-up (FU)-LSM and FU-VITRO were followed for a median of 36.6 months after the end of interferon-free therapy. FU-LSM (area under the receiver operating characteristic curve [AUROC]: 0.875 [95% confidence interval [CI]: 0.796-0.954]) and FU-VITRO (AUROC: 0.925 [95% CI: 0.874-0.977]) showed an excellent predictive performance for hepatic decompensation. Both parameters provided incremental information and were significantly associated with hepatic decompensation in adjusted models. A previously proposed combined approach (FU-LSM < 12.4 kPa and/or FU-VITRO < 0.95) to rule out clinically significant portal hypertension (CSPH, hepatic venous pressure gradient ≥10 mm Hg) at FU assigned most (57.3%) of the patients to the low-risk group; none of these patients developed hepatic decompensation. In contrast, in patients in whom FU-CSPH was ruled in (FU-LSM > 25.3 kPa and/or FU-VITRO > 3.3; 25.0% of patients), the risk of hepatic decompensation at 3 years following treatment was high (17.4%). Patients within the diagnostic gray-zone for FU-CSPH (17.8% of patients) had a very low risk of hepatic decompensation during FU (2.6%). The prognostic value of this algorithm was validated in an internal (n = 86) and external (n = 162) cohort. CONCLUSION: FU-LSM/FU-VITRO are strongly and independently predictive of posttreatment hepatic decompensation in HCV-induced ACLD. An algorithm combining these noninvasive markers not only rules in or rules out FU-CSPH, but also identifies populations at negligible versus high risk for hepatic decompensation. FU-LSM/FU-VITRO are readily accessible and enable risk stratification after sustained virological response, and thus facilitate personalized management.