Hepatic steatosis: Ultrasound assessment using attenuation imaging (ATI) with liver biopsy correlation.

INTRODUCTION: Hepatic steatosis duration and severity are risk factors for liver fibrosis and cardiometabolic disease. We assessed the diagnostic accuracy of attenuation imaging (ATI), compared with histologic hepatosteatosis grading in adults with varied suspected liver pathologies. METHODS: Liver biopsy was performed on 76 patients (51 women, 25 men) with non-malignant diffuse parenchymal liver disease, within 4 weeks of multiparametric liver ultrasound including attenuation imaging (ATI). Skin-liver capsule distance (SCD) and body mass index (BMI) were measured. Histologic steatosis was graded none (S0), mild (S1), moderate (S2) or severe (S3). We compared histology and sonographic parameters. RESULTS: The median patient age was 50.5 (range 18-83) years and BMI 28.9 kg/m2 (interquartile range 24.0-33.3). The distribution of histologic steatosis grade was S0 (44%), S1(17%), S2(30%) and S3(9%). Median ATI value for each biopsy steatosis grade was 0.60 (IQR: 0.52-0.65), 0.65 (IQR: 0.6-0.71), 0.83 (IQR: 0.74-0.90) and 0.90 (IQR: 0.82-1.01) dB/cm/MHz for S0, S1, S2 and S3, respectively. The AUC of ATI for detection of any steatosis (S1-S3) and moderate to severe steatosis (S2-S3) was 0.85 (95% CI: 0.75-0.91) and 0.91 (95% CI: 0.83-0.99) with cut-offs of 0.55 and 0.62 dB/cm/MHz. ATI threshold of 0.74 dB/cm/MHz was able to discriminate between S0-S1 and S2-3 with accuracy, CI and kappa statistic of 0.8889, 0.65-0.98 and 0.7534. CONCLUSION: We found a good correlation between ATI and steatosis grade. The most accurate discrimination was between none to mild (S0-1) and moderate to severe (S2-3) steatosis.

Cooperative Sorption on Heterogeneous Surfaces.

Heterogeneous adsorbents, those composed of multiple surface and pore types, can result in stepwise isotherms that have been difficult to model. The complexity of these systems has often led to appealing to empirical equations without physical insights, unrealistic assumptions with many parameters, or applicability limited to a particular class of isotherms. Here, we present a statistical thermodynamic approach to model stepwise isotherms, those consisting of either an initial rise followed by a sigmoid or multiple sigmoidal steps, founded on the rigorous statistical thermodynamic theory of sorption. Our only postulates are (i) the finite ranged nature of the interface and (ii) the existence of several different types of microscopic interfacial subsystems that act independently in sorption. These two postulates have led to the superposition scheme of simple surface (i.e., Langmuir type) and cooperative isotherms. Our approach has successfully modeled the adsorption on micro-mesoporous carbons, gate-opening adsorbents, and hydrogen-bonded organic frameworks. In contrast to the previous models that start with a priori assumptions on sorption mechanisms, the advantages of our approach are that it can be applied universally under the above two postulates and that all of the fitting parameters can be interpreted with statistical thermodynamics, leading to clear insights on sorption mechanisms.

Correlation between hepatorenal index and attenuation imaging for assessing hepatic steatosis.

Introduction: Hepatic steatosis screening is required to assess high-risk populations, identify those for intervention, monitor response and prevent disease progression and complications. Liver biopsy and magnetic resonance imaging proton density fat fraction are current gold standards, but are limited by biopsy risk factors, patient tolerance and cost. Non-invasive, cost-effective, semi-quantitative and quantitative ultrasound assessment exists. The aim of this study was to assess the correlation between the semi-quantitative hepatorenal index (HRI) to assess hepatic steatosis using the quantitative attenuation imaging (ATI) as a reference standard, in adults with varied suspected liver pathologies. Methods: Data were collected prospectively between April 2019 and March 2020 at a tertiary institution on any patient >18 years referred to US assessment of suspected liver pathology. The only exclusion criteria were absent or invalid HRI or ATI measurements. Three hundred fifty eight patients were included. Results: There was a significant weak positive correlation between HRI and ATI (r = 0.351, P < 0.001) and between HRI steatosis grade (SG) and ATI SG (r = 0.329, P < 0.001), using previously established cut-off values. With ATI as the reference standard, there was no significant correlation between HRI and hepatic steatosis within steatosis grades, nor for no (SG = 0) or any (SG > 0) hepatic steatosis. Conclusions: Our study in a typical heterogeneous clinical population suggests the semi-quantitative HRI is of limited use in hepatic steatosis imaging. As HRI is the objective measure of the subjective brightness (B)-mode assessment, this imaging feature may not be as reliable as previously thought. Quantitative ATI may be the preferred non-invasive technique for hepatic steatosis assessment.

Clinical relevance of shear wave elastography compared with transient elastography and other markers of liver fibrosis.

BACKGROUND: Early and accurate non-invasive diagnosis of liver fibrosis is important for reducing the burden of cirrhosis and related complications. AIM: This cross-sectional study compares shear wave elastography (SWE), transient elastography (TE) and clinical markers of chronic liver disease in patients with various liver disorders. METHODS: Liver ultrasound with SWE was performed on 421 adult patients, 227 of whom also had TE. Patient age, gender, body mass index (BMI), liver disease aetiology and laboratory results were recorded. Associations between SWE, TE and other tests for liver fibrosis and chronic liver disease severity were sought. Advanced liver fibrosis was defined as liver stiffness measurement (LSM) equivalent to ≥F3 using Metavir staging. RESULTS: Patients were predominantly male (68%), with mean (standard deviation) age 54 (13) years, BMI 28 (6) kg/m2 and serum alanine aminotransferase (ALT) 39 (27) U/L. Liver disorders were predominantly non-alcoholic fatty liver disease (NAFLD), chronic hepatitis B (CHB), chronic hepatitis C (CHC) and alcohol-related liver disease. The median (interquartile range) LSM was 10 (6-20) kPa with SWE and 9.2 (6-21) kPa with TE. Advanced liver fibrosis was associated with older age, higher BMI, model for end-stage liver disease score, aspartate aminotransferase (AST), AST/ALT ratio, AST to platelet ratio index, fibrosis-4 index and Hepascore. SWE and TE LSM were positively correlated, particularly for NAFLD and CHC. SWE LSM predicted ultrasound and endoscopy-diagnosed portal hypertension and oesophageal varices. CONCLUSIONS: Across various liver diseases, SWE is at least comparable with TE and other non-invasive tests of liver fibrosis. SWE is accurate for predicting liver-related portal hypertension.

Objective quantification of burn scar stiffness using shear-wave elastography: Initial evidence of validity.

Shear-wave elastography (SWE) is an ultrasound based technology that can provide reliable measurements (velocity) of scar stiffness. The aim of this research was to evaluate the concurrent validity of using both the measured velocity and the calculated difference in velocity between scars and matched controls, in addition to evaluating potential patient factors that may influence the interpretation of the measurements. METHODS: A cross-sectional study of 32 participants, with 48 burn scars and 48 matched contralateral control sites were evaluated with SWE, the Vancouver Scar Scale (VSS) and the Patient and Observer Scar Assessment Scale (POSAS) tactile sub-scores. RESULTS: Spearman's rho demonstrated high correlations (r > 0.7) between the measured scar velocity and both the POSAS and VSS pliability sub-scores, whereas moderate correlations (r > 0.6) were found with the calculated difference in velocity. Regression analysis indicated that the association of increased velocity in scars, varied by length of time after burn injury and gender. Body location and Fitzpatrick skin type also demonstrated significant associations with velocity, whereas age did not. CONCLUSION: SWE shows potential as a novel tool to quantify burn scar stiffness, however patient factors need to be considered when interpreting results. Further research is recommended on a larger variety of scars to support the findings.

A Novel, Reliable Protocol to Objectively Assess Scar Stiffness Using Shear Wave Elastography.

The aim of this research was to investigate the use of shear wave elastography as a novel tool to quantify and visualize scar stiffness after a burn. Increased scar stiffness is indicative of pathologic scarring which is associated with persistent pain, chronic itch and restricted range of movement. Fifty-five participants with a total of 96 scars and 69 contralateral normal skin sites were evaluated. A unique protocol was developed to enable imaging of the raised and uneven burn scars. Intra-rater and inter-rater reliability was excellent (intra-class correlation coefficient >0.97), and test-retest reliability was good (intra-class correlation coefficient >0.85). Shear wave elastography was able to differentiate between normal skin, pathologic scars and non-pathologic scars, with preliminary cutoff values identified. Significant correlations were found between shear wave velocity and subjective clinical scar assessment (r = 0.66). Shear wave elastography was able to provide unique information associated with pathologic scarring and shows promise as a clinical assessment and research tool.

HELLP syndrome: An ultrasound case of geographically altered liver parenchymal echogenicity with shear wave elastography, shear wave dispersion and attenuation imaging correlation.

HELLP syndrome is a rare, potentially life threatening obstetric condition that is diagnosed by the combination of Haemolysis, Elevated Liver enzyme levels, and Low Platelets (Pregnancy Hypertens, 1, 164, 2011). HELLP affects between 0.5% and 0.9% of all pregnancies (BMC Pregnancy Childbirth, 9, 8, 2009), however less than 0.5% of HELLP syndrome cases demonstrate any imaging abnormalities (Am J Roentgenol 185, 1205, 2005). This case report outlines the use of three new liver ultrasound technologies - shear wave elastography (SWE), shear wave dispersion (SWD) and attenuation imaging (ATI) in the evaluation of a patient with HELLP syndrome. The ultrasound applications were used to examine temporal changes of the disease with corresponding biochemical variations. The SWE and SWD values correlated with B mode ultrasound imaging and the clinical findings of HELLP.

Quantifying non-specific interactions via liquid chromatography.

Determinations of solute-cosolute interactions from chromatography have often resulted in problems, such as the "antibinding" (or a negative binding constant) between the solute and micelle in micellar liquid chromatography (MLC) or indeterminacy of salt-ligand binding strength in high-performance affinity chromatography (HPAC). This shows that the stoichiometric binding models adopted in many chromatographic analyses cannot capture the non-specific nature of solvation interactions. In contrast, an approach using statistical thermodynamics handles these complexities without such problems and directly links chromatographic data to, for example, solubility data via a universal framework based on Kirkwood-Buff integrals (KBI) of the radial distribution functions. The chromatographic measurements can now be interpreted within this universal theoretical framework that has been used to rationalize small solute solubility, biomolecular stability, binding, aggregation and gelation. In particular, KBI analysis identifies key solute-cosolute interactions, including excluded volume effects. We present (i) how KBI can be obtained directly from the cosolute concentration dependence of the distribution coefficient, (ii) how the classical binding model, when used solely as a fitting model, can yield the KBIs directly from the literature data, and (iii) how chromatography and solubility measurements can be compared in the unified theoretical framework provided via KBIs without any arbitrary assumptions about the stationary phase. To perform our own analyses on multiple datasets we have used an "app". To aid readers' understanding and to allow analyses of their own datasets, the app is provided with many datasets and is freely available on-line as an open-source resource.

Quantifying non-specific interactions between flavour and food biomolecules.

The ways in which flavour molecules interact with proteins in foods have an impact on flavour and aroma and on the (in)stability of the proteins. There is a long history of analysing these interactions using a "specific binding model" that gives values for the number of molecules, n, bound to the proteins with a binding constant Kb. However, recent progress in molecular thermodynamics forced us to reconsider this approach. In addition, there are a number of methods for determining these values and it is not at all clear whether the various assumptions behind the various methods allow legitimate comparisons between techniques. By adopting an assumption-free molecular thermodynamics approach, Kirkwood-Buff theory, we find that we gain a welcome universality, simplicity and deep understanding of what is happening at the molecular level. Here we look at three different methods for examining flavour-protein interactions (vapour pressure, dialysis equilibrium and melting temperature changes), show how historical data can be re-cast into the universal language of Kirkwood-Buff and provide a free, open-source app that can both re-analyze historical data and be a platform for analyzing fresh data. In each case, the fundamental theory is described along with a pragmatic implementation accepting the realities of experimentation. One key insight is that the n and Kb parameters of the classical binding models can be turned directly, via simple arithmetic, into the Kirkwood-Buff integrals that accurately capture non-specific flavour-protein interactions.

The validity and reliability of using ultrasound elastography to measure cutaneous stiffness, a systematic review.

BACKGROUND: Ultrasound elastography is an imaging technology which can objectively and non-invasively assess tissue stiffness. It is emerging as a useful marker for disease diagnosis, progression and treatment efficacy. OBJECTIVE: To examine current, published research evaluating the use of ultrasound elastography for the measurement of cutaneous or subcutaneous stiffness and to determine the level of validity and reliability, recommended methodologies and limitations. METHODS: MEDLINE, Web of science and Scopus were systematically searched in August 2016 to identify original articles evaluating the use of ultrasound elastography to assess cutaneous stiffness. Relevant studies were then quality evaluated using the Quality Assessment of Diagnostic Accuracy Studies v 2 (QUADAS-2) tool and the Quality Appraisal of Reliability Studies (QAREL). RESULTS: From a total of 688 articles, 14 met the inclusion criteria for full review. Within the 14 studies, elastography was used to evaluate tumors, systemic sclerosis, lymphedema, abscess, and post-radiation neck fibrosis. Only three robust studies demonstrated good interrater reliability, whereas all validity studies had low sample sizes and demonstrated risks of bias. CONCLUSION: Robust evidence supporting the use of ultrasound elastography as a diagnostic tool in cutaneous conditions is low, however, initial indicators support further research to establish the utility of ultrasound elastography in dermatology.

How Entrainers Enhance Solubility in Supercritical Carbon Dioxide.

Supercritical carbon dioxide (scCO2) on its own can be a relatively poor solvent. However, the addition at relatively modest concentration of "entrainers", simple solvent molecules such as ethanol or acetone, can provide a significant boost in solubility, thereby enabling its industrial use. However, how entrainers work is still under debate; without an unambiguous explanation, it is hard to optimize entrainers for any specific solute. This paper demonstrates that a fundamental, assumption-free statistical thermodynamic theory, the Kirkwood-Buff (KB) theory, can provide an unambiguous explanation of the entrainer effect through an analysis of published experimental data. The KB theory shows that a strong solute-entrainer interaction accounts for the solubility enhancement, while CO2 density increase and/or CO2-entrainer interactions, which have been assumed widely in the literature, do not account for solubilization. This conclusion, despite the limited completeness of available data, is demonstrably robust; this can be shown by an order-of-magnitude analysis based upon the theory, and can be demonstrated directly through a public-domain "app", which has been developed to implement the theory.

Hydrotrope accumulation around the drug: the driving force for solubilization and minimum hydrotrope concentration for nicotinamide and urea.

Nicotinamide is an effective non-micellar hydrotrope (solubilizer) for drugs with low aqueous solubility. To clarify the molecular basis of nicotinamide's hydrotropic effectiveness, we present here a rigorous statistical thermodynamic theory, based on the Kirkwood-Buff theory of solutions, and our recent application of it to hydrotropy. We have shown that (i) nicotinamide self-association reduces solubilization efficiency, contrary to the previous hypothesis which claimed that self-association drives solubilization and (ii) the minimum hydrotrope concentration (MHC), namely, the threshold concentration above which solubility suddenly increases, is caused not by the bulk-phase self-association of nicotinamides as has been postulated previously, but by the enhancement of nicotinamide-nicotinamide interaction around the drug molecules. We have thus established a new view of hydrotropy - it is nicotinamide's non-stoichiometric accumulation around the drug that is the basis of solubility increase above MHC.

Correction: Using Hansen solubility parameters to study the encapsulation of caffeine in MOFs.

Correction for 'Using Hansen solubility parameters to study the encapsulation of caffeine in MOFs' by Lorena Paseta et al., Org. Biomol. Chem., 2015, DOI: 10.1039/c4ob01898b.

Using Hansen solubility parameters to study the encapsulation of caffeine in MOFs.

Hansen solubility parameters (HSP) have found their greatest use in the evaluation of solvent-polymer chemical interactions. Given their great interest among the scientific community, host-guest interactions in metal-organic frameworks (MOFs), with organic and inorganic moieties, could benefit from a HSP approach. In this work we have initiated the application of HSP to the study of caffeine encapsulation in MOFs ZIF-8 and NH2-MIL-88B(Fe). However, the availability of HSP for MOFs is nearly zero. As a first step to evaluating the potential of HSP for rational design we have made the simplifying assumption that the HSP distance of the caffeine-ligand interaction (i.e. ignoring the metal and the MOF structure) dominates the ability to form a MOF host-guest system. Although much work remains to be done, the first indications are that this approach has much potential.

Hydrotropy: binding models vs. statistical thermodynamics.

Hydrophobic drugs can often be solubilized by the addition of hydrotropes. We have previously shown that preferential drug-hydrotrope association is one of the major factors of increased solubility (but not "hydrotrope clustering" or changes in "water structure"). How, then, can we understand this drug-hydrotrope interaction at a molecular level? Thermodynamic models based upon stoichiometric solute-water and solute-hydrotrope binding have long been used to understand solubilization microscopically. Such binding models have shown that the solvation numbers or coordination numbers of the water and hydrotrope molecules around the drug solute is the key quantity for solute-water and solute-hydrotrope interaction. However, we show that a rigorous statistical thermodynamic theory (the fluctuation solution theory originated by Kirkwood and Buff) requires the total reconsideration of such a paradigm. Here we show that (i) the excess solvation number (the net increase or decrease, relative to the bulk, of the solvent molecules around the solute), not the coordination number, is the key quantity for describing the solute-hydrotrope interaction; (ii) solute-hydrotrope binding is beyond the reach of the stoichiometric models because long-range solvation structure plays an important role.

Vibration arthrometry: a critical review.

The clinical value of sounds and vibrations produced by biological joints in motion has been studied extensively since 1902, aimed at developing a technology to aid the interpretation of recorded joint vibration signals. Such technology would have clear advantages to current medical imaging systems, e.g. MRI, in speed, cost, and non-invasiveness. However, it has yet to achieve routine clinical use. This review aims to provide a balanced analysis of past and present attempts to progress vibration arthrometry. The literature reveals significant barriers to successful implementation of vibration arthrometry. From a technical standpoint, accounting for the intense variability within recorded signals caused by shifting characteristics of contacting joint surfaces and forces during motion is the primary issue. Additionally, understandable scepticism in the clinical community as to the reliability of vibration arthrometry represents a significant barrier to adoption. In conclusion, until the variability issue is shown to be adequately dealt with, and clear transparent evidence of clinical usefulness to orthopedic medicine demonstrated, it will be difficult to move the field forward. Future work should lead toward proving value to clinicians, and be transparent about how the variability issue has been resolved.

Mechanism of hydrophobic drug solubilization by small molecule hydrotropes.

Drugs that are poorly soluble in water can be solubilized by the addition of hydrotropes. Albeit known for almost a century, how they work at a molecular basis is still controversial due to the lack of a rigorous theoretical basis. To clear up this situation, a combination of experimental data and Fluctuation Theory of Solutions (FTS) has been employed; information on the interactions between all the molecular species present in the solution has been evaluated directly. FTS has identified two major factors of hydrotrope-induced solubilization: preferential hydrotrope-solute interaction and water activity depression. The former is dominated by hydrotrope-solute association, and the latter is enhanced by ionic dissociation and hindered by the self-aggregation of the hydrotropes. Moreover, in stark contrast to previous hypotheses, neither the change of solute hydration nor the water structure accounts for hydrotropy. Indeed, the rigorous FTS poses serious doubts over the other common hypothesis: self-aggregation of the hydrotrope hinders, rather than promotes, solubilization.