Metabolic-associated fatty liver disease and hepatocellular carcinoma: a prospective study of characteristics and response to therapy.

BACKGROUND AND AIM: The rising incidence of hepatocellular carcinoma (HCC) in Australia is related to increasing rates of metabolic-associated fatty liver disease (MAFLD). This study aimed to prospectively characterize the metabolic profile, lifestyle, biometric features, and response to treatment of HCC patients in an Australian population. METHOD: Multicenter prospective cohort analysis of newly diagnosed HCC patients at six multidisciplinary team meetings over a 2-year period. RESULTS: Three hundred and thirteen (313) newly diagnosed HCC patients with MAFLD (n = 77), MAFLD plus other liver disease (n = 57) (the "mixed" group), and non-MAFLD (n = 179) were included in the study. Alcohol-associated liver disease (ALD) (43%) and MAFLD (43%) were the most common underlying liver diseases. MAFLD-HCC patients were older (73 years vs 67 years vs 63 years), more likely to be female (40% vs 14% vs 20%), less likely to have cirrhosis (69% vs 88% vs 85%), showed higher ECOG, and were less likely to be identified by screening (29% vs 53% vs 45%). Metabolic syndrome was more prevalent in the MAFLD and mixed groups. The severity of underlying liver disease and HCC characteristics were the same across groups. While the MAFLD population self-reported more sedentary lifestyles, reported dietary patterns were no different across the groups. Dyslipidemia was associated with tumor size, and those taking statins had a lower recurrence rate. CONCLUSION: Equal to ALD, MAFLD is now the most common underlying liver disease seen in HCC patients in Australia. Future HCC prevention screening and treatment strategies need to take this important group of patients into consideration.

Non-Centrosymmetric Sr2IrO4 Obtained Under High Pressure.

Sr2IrO4 with strong spin-orbit coupling and Hubbard repulsion (U) hosts Mott insulating states. The similar crystal structure and magnetic and electronic properties, particularly the d-wave gap observed in Sr2IrO4 enhanced the analogies to the cuprate high-Tc superconductor, La2CuO4. The incomplete analogy was due to the lack of broken inversion symmetry phases observed in Sr2IrO4. Here, under high-pressure and high-temperature conditions, we report a noncentrosymmetric Sr2IrO4. The crystal structure and its noncentrosymmetric character were determined by single-crystal X-ray diffraction and high-resolution scanning transmission electron microscopy. The magnetic characterization confirms the Ir4+ with S = 1/2 at low temperature in Sr2IrO4 with magnetic ordering occurring at around 86 K, where a larger moment is observed than the ambient pressure Sr2IrO4. Moreover, the resistivity measurement shows three-dimensional Mott variable-range hopping (VRH) existed in the system. This noncentrosymmetric Sr2IrO4 phase appears to be a unique material that offers a further understanding of high-Tc superconductivity.

Epidemiology and outcomes of primary sclerosing cholangitis: an Australian multicentre retrospective cohort study.

BACKGROUND AND AIMS: Little is known regarding the epidemiology and outcomes of patients with primary sclerosing cholangitis (PSC) in Australia. We, therefore, evaluated the epidemiology and clinical outcomes of PSC in a large cohort of Australian patients and compared these to the general population. METHODS: We conducted a multicentre, retrospective cohort study of PSC patients at nine tertiary liver centers across three Australian states, including two liver transplant centers. RESULTS: A total of 413 PSC patients with 3,285 person-years of follow-up were included. Three hundred and seventy-one (90%) patients had large duct PSC and 294 (71%) had associated inflammatory bowel disease. A total of 168 (41%) patients developed cirrhosis (including 34 at the time of PSC diagnosis) after a median of 15.8 (95% CI 12.4, NA) years. The composite endpoint of death or liver transplantation occurred in 49 (12%) and 78 (19%) patients, respectively, with a median transplant-free survival of 13.4 (95% CI 12.2-15) years. Compared to the general population, PSC accounted for a 240-fold increased risk of development of cholangiocarcinoma (CCA) and CCA-related death. CCA risk was increased with older age of PSC diagnosis, presence of dominant stricture and colectomy. Compared to same-aged counterparts in the general population, PSC patients who were diagnosed at an older age or with longer disease duration had reduced relative survival. CONCLUSION: In this large retrospective cohort study of PSC patients in Australia, increased age and time from diagnosis was associated with increased mortality and morbidity particularly from CCA and development of cirrhosis, necessitating need for liver transplant.

Irreversible Electroporation For Hepatocellular Carcinoma: Longer-Term Outcomes At A Single Centre.

BACKGROUND AND AIMS: Irreversible electroporation (IRE) is a non-thermal ablation technique for unresectable hepatocellular carcinoma (HCC) not amenable to standard thermal ablation. The aim of this study was to report our longer-term outcomes using this treatment modality. METHOD: We identified all patients at our institution who underwent IRE for HCC between December 2008 and October 2019 as recommended after multi-disciplinary team review. Demographic, clinical, tumour response and survival data up until 1 March, 2020 were analysed. The primary outcome was local recurrence-free survival (LRFS) in patients who had a complete response (CR). Secondary outcomes included CR rates, procedure-related complications and the incidence of death or liver transplantation. RESULTS: A total of 23 patients (78% males, median age 65.2 years) received IRE therapy to 33 HCC lesions during the study period with the median tumour size being 2.0 cm (range 1.0-5.0 cm). Twenty-nine (87.9%) lesions were successfully ablated after one (n = 26) or two (n = 3) procedures. The median follow-up time for these lesions was 20.4 months. The median overall LRFS was 34.5 (95% CI 24.8 -) months with a 6- and 12-month LRFS of 87.9% (95% CI 75.8-100) and 83.6% (95% CI 70.2-99.7), respectively. Tumours < 2 cm had a 12-month LRFS of 100% (95% CI 100-100). CONCLUSION: IRE appears to be an efficacious local ablative method for early stage HCC not amenable to standard ablative techniques, with very good CR rates and longer-term LRFS, particularly for smaller lesions. Further studies comparing this technique to more widely accepted ablative methods such as radiofrequency and microwave ablation are warranted.

Low SAR 31 P (multi-echo) spectroscopic imaging using an integrated whole-body transmit coil at 7T.

Phosphorus (31 P) MRSI provides opportunities to monitor potential biomarkers. However, current applications of 31 P MRS are generally restricted to relatively small volumes as small coils are used. Conventional surface coils require high energy adiabatic RF pulses to achieve flip angle homogeneity, leading to high specific absorption rates (SARs), and occupy space within the MRI bore. A birdcage coil behind the bore cover can potentially reduce the SAR constraints massively by use of conventional amplitude modulated pulses without sacrificing patient space. Here, we demonstrate that the integrated 31 P birdcage coil setup with a high power RF amplifier at 7 T allows for low flip angle excitations with short repetition time (TR ) for fast 3D chemical shift imaging (CSI) and 3D T1 -weighted CSI as well as high flip angle multi-refocusing pulses, enabling multi-echo CSI that can measure metabolite T2 , over a large field of view in the body. B1+ calibration showed a variation of only 30% in maximum B1 in four volunteers. High signal-to-noise ratio (SNR) MRSI was obtained in the gluteal muscle using two fast in vivo 3D spectroscopic imaging protocols, with low and high flip angles, and with multi-echo MRSI without exceeding SAR levels. In addition, full liver MRSI was achieved within SAR constraints. The integrated 31 P body coil allowed for fast spectroscopic imaging and successful implementation of the multi-echo method in the body at 7 T. Moreover, no additional enclosing hardware was needed for 31 P excitation, paving the way to include larger subjects and more space for receiver arrays. The increase in possible number of RF excitations per scan time, due to the improved B1+ homogeneity and low SAR, allows SNR to be exchanged for spatial resolution in CSI and/or T1 weighting by simply manipulating TR and/or flip angle to detect and quantify ratios from different molecular species.

Dynamical Structure Factor of the Three-Dimensional Quantum Spin Liquid Candidate NaCaNi_{2}F_{7}.

We study the dynamical structure factor of the spin-1 pyrochlore material NaCaNi_{2}F_{7}, which is well described by a weakly perturbed nearest-neighbour Heisenberg Hamiltonian, Our three approaches-molecular dynamics simulations, stochastic dynamical theory, and linear spin wave theory-reproduce remarkably well the momentum dependence of the experimental inelastic neutron scattering intensity as well as its energy dependence with the exception of the lowest energies. We discuss two surprising aspects and their implications for quantum spin liquids in general: the complete lack of sharp quasiparticle excitations in momentum space and the success of the linear spin wave theory in a regime where it would be expected to fail for several reasons.

Community-based provision of direct-acting antiviral therapy for hepatitis C: study protocol and challenges of a randomized controlled trial.

BACKGROUND: To achieve the World Health Organization hepatitis C virus (HCV) elimination targets, it is essential to increase access to treatment. Direct-acting antiviral (DAA) treatment can be provided in primary healthcare services (PHCS), improving accessibility, and, potentially, retention in care. Here, we describe our protocol for assessing the effectiveness of providing DAAs in PHCS, and the impact on the HCV care cascade. In addition, we reflect on the challenges of conducting a model of care study during a period of unprecedented change in HCV care and treatment. METHODS: Consenting patients with HCV infection attending 13 PHCS in Australia or New Zealand are randomized to receive DAA treatment at the local tertiary institution (standard care arm), or their PHCS (intervention arm). The primary endpoint is the proportion commenced on DAAs and cured. Treatment providers at the PHCS include: hepatology nurses, primary care practitioners, or, in two sites, a specialist physician. All PHCS offer opioid substitution therapy. DISCUSSION: The Prime Study is the first real-world, randomized, model of care study exploring the impact of community provision of DAA therapy on HCV-treatment uptake and cure. Although the study has faced challenges unique to this period of time characterized by changing treatment and service delivery, the data gained will be of critical importance in shaping health service policy that enables the elimination of HCV. TRIAL REGISTRATION: ClinicalTrials.gov , ID: NCT02555475 . Registered on 15 September 2015.

Systematic review and meta-analysis: non-invasive detection of non-alcoholic fatty liver disease related fibrosis in the obese.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a significant disease burden in obesity. Liver fibrosis is an important prognostic factor in NAFLD, and detection is vital. The pathophysiological changes of obesity can alter the accuracy of non-invasive NAFLD tests. We aimed to review current evidence for common non-invasive tests for NAFLD-related fibrosis in obesity. METHODS: We systematically searched for studies assessing the diagnostic accuracy of 11 biomarker panels and elastography techniques for NAFLD-related fibrosis in obesity. Meta-analyses were performed where possible. RESULTS: Thirty-eight studies were identified assessing the selected tests in obese populations. Simple biomarker panels (e.g. NAFLD fibrosis score) were the most validated. Evidence showed better accuracy of complex biomarker panels (NAFLD fibrosis score: summary receiver operator characteristic [SROC] 0.795-0.813 vs. enhanced liver fibrosis: SROC 0.962); however, these were poorly validated in obesity. Elastography techniques were better studied and had high diagnostic accuracy (transient elastography: SROC 0.859; magnetic resonance elastography: SROC 0.965) but were limited by BMI-dependent failure. Limited evidence was found to validate the accuracy of any test in exclusively obese populations. CONCLUSION: In obese subjects, complex biomarker panels and elastography have been reasonable to good accuracy for NAFLD-related fibrosis; however, these methods have not been well validated. Further study in this high-risk population is needed.

Preoperative indication for systemic therapy extended to patients with early-stage breast cancer using multiparametric 7-tesla breast MRI.

PURPOSE: To establish a preoperative decision model for accurate indication of systemic therapy in early-stage breast cancer using multiparametric MRI at 7-tesla field strength. MATERIALS AND METHODS: Patients eligible for breast-conserving therapy were consecutively included. Patients underwent conventional diagnostic workup and one preoperative multiparametric 7-tesla breast MRI. The postoperative (gold standard) indication for systemic therapy was established from resected tumor and lymph-node tissue, based on 10-year risk-estimates of breast cancer mortality and relapse using Adjuvant! Online. Preoperative indication was estimated using similar guidelines, but from conventional diagnostic workup. Agreement was established between preoperative and postoperative indication, and MRI-characteristics used to improve agreement. MRI-characteristics included phospomonoester/phosphodiester (PME/PDE) ratio on 31-phosphorus spectroscopy (31P-MRS), apparent diffusion coefficients on diffusion-weighted imaging, and tumor size on dynamic contrast-enhanced (DCE)-MRI. A decision model was built to estimate the postoperative indication from preoperatively available data. RESULTS: We included 46 women (age: 43-74yrs) with 48 invasive carcinomas. Postoperatively, 20 patients (43%) had positive, and 26 patients (57%) negative indication for systemic therapy. Using conventional workup, positive preoperative indication agreed excellently with positive postoperative indication (N = 8/8; 100%). Negative preoperative indication was correct in only 26/38 (68%) patients. However, 31P-MRS score (p = 0.030) and tumor size (p = 0.002) were associated with the postoperative indication. The decision model shows that negative indication is correct in 21/22 (96%) patients when exempting tumors larger than 2.0cm on DCE-MRI or with PME>PDE ratios at 31P-MRS. CONCLUSIONS: Preoperatively, positive indication for systemic therapy is highly accurate. Negative indication is highly accurate (96%) for tumors sized ≤2,0cm on DCE-MRI and with PME≤PDE ratios on 31P-MRS.

Redox reactions and weak buffering capacity lead to acidification in the Chesapeake Bay.

The combined effects of anthropogenic and biological CO2 inputs may lead to more rapid acidification in coastal waters compared to the open ocean. It is less clear, however, how redox reactions would contribute to acidification. Here we report estuarine acidification dynamics based on oxygen, hydrogen sulfide (H2S), pH, dissolved inorganic carbon and total alkalinity data from the Chesapeake Bay, where anthropogenic nutrient inputs have led to eutrophication, hypoxia and anoxia, and low pH. We show that a pH minimum occurs in mid-depths where acids are generated as a result of H2S oxidation in waters mixed upward from the anoxic depths. Our analyses also suggest a large synergistic effect from river-ocean mixing, global and local atmospheric CO2 uptake, and CO2 and acid production from respiration and other redox reactions. Together they lead to a poor acid buffering capacity, severe acidification and increased carbonate mineral dissolution in the USA's largest estuary.The potential contribution of redox reactions to acidification in coastal waters is unclear. Here, using measurements from the Chesapeake Bay, the authors show that pH minimum occurs at mid-depths where acids are produced via hydrogen sulfide oxidation in waters mixed upward from anoxic depths.

Impact of viral hepatitis aetiology on survival outcomes in hepatocellular carcinoma: A large multicentre cohort study.

While HBV and HCV are risk factors for HCC, uncertainty exists as to whether these viral infections have prognostic significance in HCC. Thus, we compared the overall survival of patients with HBV, HCV and nonviral HCC, and evaluated whether the presence of HBV and HCV predicts patient outcomes. We conducted a multicentre study of HCC cases diagnosed at six Melbourne tertiary hospitals between Jan 2000-Dec 2014. Patient demographics, liver disease and tumour characteristics and patient outcomes were obtained from hospital databases, computer records and the Victorian Death Registry. Survival outcomes were compared between HBV, HCV and nonviral hepatitis cases and predictors of survival determined using Cox proportional hazards regression. There were 1436 new HCC cases identified including 776 due to viral hepatitis (HBV 235, HCV 511, HBV-HCV 30) and 660 from nonviral causes. The median survival of HBV, HCV and nonviral HCC patients was 59.1, 28.4 and 20.9 months, respectively (P<.0001). On multivariate analysis, independent risk factors for survival included HCC aetiology, gender, BCLC stage, serum AFP, total number and size of lesions, and serum creatinine and albumin. After adjusting for these and method of detection, HBV remained an independent predictor of improved overall survival when compared to both nonviral (HR 0.60%, 95% CI 0.35-0.98; P=.03) and HCV-related HCC (HR 0.51%, 95% CI 0.30-0.85; P=.01). In this large multicentre study, HBV is independently associated with improved overall survival compared with HCV and nonviral-related HCC. Further studies are needed to determine the underlying factor(s) responsible.

Whole-body radiofrequency coil for (31) P MRSI at 7 T.

Widespread use of ultrahigh-field (31) P MRSI in clinical studies is hindered by the limited field of view and non-uniform radiofrequency (RF) field obtained from surface transceivers. The non-uniform RF field necessitates the use of high specific absorption rate (SAR)-demanding adiabatic RF pulses, limiting the signal-to-noise ratio (SNR) per unit of time. Here, we demonstrate the feasibility of using a body-sized volume RF coil at 7 T, which enables uniform excitation and ultrafast power calibration by pick-up probes. The performance of the body coil is examined by bench tests, and phantom and in vivo measurements in a 7-T MRI scanner. The accuracy of power calibration with pick-up probes is analyzed at a clinical 3-T MR system with a close to identical (1) H body coil integrated at the MR system. Finally, we demonstrate high-quality three-dimensional (31) P MRSI of the human body at 7 T within 5 min of data acquisition that includes RF power calibration. Copyright © 2016 John Wiley & Sons, Ltd.

Scattering continuum and possible fractionalized excitations in α-RuCl(3).

The combination of electronic correlation and spin-orbit coupling is thought to precipitate a variety of highly unusual electronic phases in solids, including topological and quantum spin liquid states. We report a Raman scattering study that provides evidence for unconventional excitations in α-RuCl_{3}, a spin-orbit coupled Mott insulator on the honeycomb lattice. In particular, our measurements reveal unusual magnetic scattering, typified by a broad continuum. The temperature dependence of this continuum is evident over a large scale compared to the magnetic ordering temperature, suggestive of frustrated magnetic interactions. This is confirmed through an analysis of the phonon linewidths, which show a related anomaly due to spin-phonon coupling. These observations are in line with theoretical expectations for the Heisenberg-Kitaev model and suggest that α-RuCl_{3} may be close to a quantum spin liquid ground state.

Portal hypertension: pathophysiology, diagnosis and management.

Portal hypertension is an important complication of liver disease. As a result of elevated pressures within the portal vein several complications can arise, including the development of oesophageal and gastric varices, ascites, hepatic encephalopathy as well as complications secondary to circulatory dysfunction, such as hepatorenal syndrome, portopulmonary syndrome and hepatopulmonary syndrome. This review outlines the pathogenesis and diagnosis of portal hypertension and outlines the management of these various important clinical sequelae. The management of oesophageal and gastric varices is particularly important, and both the emergency management together with prophylactic management of this condition are described.

Increased sensitivity of 31P MRSI using direct detection integrated with multi-echo polarization transfer (DIMEPT).

Here, we show that the sensitivity of (31)P MRSI of (31)P spins J-coupled to protons can be increased by almost a factor of three when compared with an optimal direct detection free induction decay. By direct detection integrated with multi-echo polarization transfer (DIMEPT), multiple signals from polarization transfer and direct detection can be acquired in one repetition time, with minimal mutual interference, provided that the number of refocusing pulses in the multi-echo polarization transfer part is even. The DIMEPT sequence was implemented on a 7-T body scanner and tested on a phantom and on the breasts of five healthy volunteers. The in vivo signal-to-noise ratio (SNR) enhancement for the J-coupled phosphomonoesters was 270% when compared with an Ernst angle pulse-acquire sequence. However, the phosphodiester signals, presumably mainly mobile phospholipids, had T2 values that were too short to be enhanced. Uncoupled (31)P spins, with sufficiently long T2 values, such as inorganic phosphate, were SNR enhanced by a factor of 1.9 relative to an Ernst-angle excitation pulse-acquire sequence by multi-echo direct detection.

Extended hypoxia in the alfalfa leafcutting bee, Megachile rotundata, increases survival but causes sub-lethal effects.

Many insects are tolerant of hypoxic conditions, but survival may come at a cost to long-term health. The alfalfa leaf-cutting bee, Megachile rotundata, develops in brood cells inside natural cavities, and may be exposed to hypoxic conditions for extended periods of time. Whether M. rotundata is tolerant of hypoxia, and whether exposure results in sub-lethal effects, has never been investigated. Overwintering M. rotundata prepupae were exposed to 10%, 13%, 17%, 21% and 24% O2 for 11 months. Once adults emerged, five indicators of quality - emergence weight, body size, feeding activity, flight performance, and adult longevity, - were measured to determine whether adult bees that survived past exposure to hypoxia were competent pollinators. M. rotundata prepupae are tolerant of hypoxic condition and have higher survival rates in hypoxia, than in normoxia. Under hypoxia, adult emergence rates did not decrease over the 11 months of the experiment. In contrast, bees reared in normoxia had decreased emergence rates by 8 months, and were dead by 11 months. M. rotundata prepupae exposed to extended hypoxic conditions had similar emergence weight, head width, and cross-thorax distance compared to bees reared in standard 21% oxygen. Despite no significant morphological differences, hypoxia-exposed bees had lower feeding rates and shorter adult lifespans. Hypoxia may play a role in post-diapause physiology of M. rotundata, with prepupae showing better survival under hypoxic conditions. Extended exposure to hypoxia, while not fatal, causes sub-lethal effects in feeding rates and longevity in the adults, indicating that hypoxia tolerance comes at a cost.

(31)P magnetic resonance spectroscopy of the breast and the influence of the menstrual cycle.

Phosphorus metabolite ratios are potential biomarkers in breast cancer diagnosis and treatment monitoring. Our purpose was to investigate the metabolite ratios phosphomonoester to phosphodiester, phosphoethanolamine (PE) to glycerophosphoethanolamine (GPE), and phosphocholine (PC) to glycerophosphocholine (GPC) in glandular breast tissue, and the potential effect of the menstrual cycle, using (31)P magnetic resonance spectroscopy (MRS) at 7T. Seven women with regular menstrual cycles each underwent four examinations using a 3D (31)P multi-echo magnetic resonance spectroscopic imaging sequence. Peak integrals were assessed using IDL and JMRUI software. First, T2 relaxation times were calculated using multi-echo data pooled across subjects and time points. Subsequent, metabolite ratios were calculated for each phase of the menstrual cycle using the calculated T2 values to account for when combining the free induction decay and all five echoes. The metabolite ratios were calculated both on group level and individually. T2 decay fits resulted in a T2 relaxation time for PE of 154 ms (95 % CI 144-164), for PC of 173 ms (95 % CI 148-205), for Pi of 188 ms (95 % CI 182-193), for GPE of 48 ms (95 % CI 44-53), and for GPC of 23 ms (95 % CI 21-26). The metabolite ratios analyzed on group level showed negligible variation throughout the menstrual cycle. Individual results did show an apparent intra-individual variation; however, not significant due to the measurements' uncertainty. To conclude, phospholipids in glandular tissue as measured with (31)P MRS at 7 T are not significantly affected by the menstrual cycle.