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Background and Aims Methods Results Conclusions This study sought to assess the capabilities of large language models (LLMs) in identifying clinically significant metabolic dysfunction‐associated steatotic liver disease (MASLD).We included individuals from NHANES 2017–2018. The validity and reliability of MASLD diagnosis by GPT‐3.5 and GPT‐4 were quantitatively examined and compared with those of the Fatty Liver Index (FLI) and United States FLI (USFLI). A receiver operating characteristic curve was conducted to assess the accuracy of MASLD diagnosis via different scoring systems. Additionally, GPT‐4V's potential in clinical diagnosis using ultrasound images from MASLD patients was evaluated to provide assessments of LLM capabilities in both textual and visual data interpretation.GPT‐4 demonstrated comparable performance in MASLD diagnosis to FLI and USFLI with the AUROC values of .831 (95% CI .796–.867), .817 (95% CI .797–.837) and .827 (95% CI .807–.848), respectively. GPT‐4 exhibited a trend of enhanced accuracy, clinical relevance and efficiency compared to GPT‐3.5 based on clinician evaluation. Additionally, Pearson's r values between GPT‐4 and FLI, as well as USFLI, were .718 and .695, respectively, indicating robust and moderate correlations. Moreover, GPT‐4V showed potential in understanding characteristics from hepatic ultrasound imaging but exhibited limited interpretive accuracy in diagnosing MASLD compared to skilled radiologists.GPT‐4 achieved performance comparable to traditional risk scores in diagnosing MASLD and exhibited improved convenience, versatility and the capacity to offer user‐friendly outputs. The integration of GPT‐4V highlights the capacities of LLMs in handling both textual and visual medical data, reinforcing their expansive utility in healthcare practice. [ABSTRACT FROM AUTHOR]

Background: In patients with metabolic dysfunction-associated steatotic liver disease (MASLD), there are limited data on how changes in FIB4 and liver stiffness measurement (LSM) correlate in non-biopsy cohorts. Aims: Our objective was to evaluate associations between changes in FIB4 and LSM in MASLD patients. Methods: We included MASLD patients with serial VCTE from 2015–2022. The primary predictors were change in FIB4 and presence of diabetes, obesity, and high alanine aminotransferase (ALT). The primary outcome, applied only to patients with LSM1 < 8 kPa, was incident significant fibrosis (SF) defined as a ≥ 20% increase in LSM2 vs. LSM1 and LSM2 ≥ 8 kPa. A secondary outcome was LSM progression with a similar definition but applied to all participants, not only those with LSM1 < 8 kPa. Results: Of 285 included patients, 216 had LSM1 < 8 kPa and were included in the primary analysis; of these, 34 (16%) had incident SF. Changes in FIB4 correlated with changes in LSM (R = 0.16, p = 0.016). Independent predictors of incident SF included comorbid diabetes mellitus (OR 2.43, 95% CI 1.04–6.56), obesity (OR 3.88, 95% CI 1.63–9.25), and baseline ALT ≥ 30 (OR 8.55, 95% CI 1.10–66.29). A model including ALT, diabetes, and obesity outperformed a model with FIB4 change alone. Conclusion: Among patients with MASLD, changes in FIB4 correlated with changes in LSM but more significant correlates of incident significant fibrosis included diabetes mellitus, obesity, and high baseline ALT. [ABSTRACT FROM AUTHOR]

Agile scores, including liver stiffness measurements (LSM) and routine clinical/laboratory biomarkers, have been developed for advanced fibrosis (F≥3) and cirrhosis (F4), respectively, in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). We independently validated the diagnostic accuracy of these scores in MASLD, alcohol-related liver disease (ALD) and chronic hepatitis B or C (CHB/C) and assessed them in clinical algorithms with FIB-4 and LSM. We included 4,243 patients (MASLD: 912, ALD: 386, CHB: 597, CHC: 2,348) with LSM, liver biopsy and laboratory tests within 6 months. FIB-4, Agile 3+ and Agile 4 scores were calculated. For F≥3, the diagnostic accuracy of Agile 3+ and LSM were similar in MASLD (AUC: 0.86 vs. 0.86, p = 0.831) and ALD (0.92 vs. 0.94, p = 0.123). For cirrhosis, Agile 4 was similar to LSM in MASLD (0.89 vs. 0.90, p = 0.412) and ALD (0.94 vs. 0.95, p = 0.513). Agile 3+/4 performed worse than LSM in CHB/C. Using predefined dual thresholds of 90% sensitivity/specificity, correct classification rates in MASLD were 66% vs. 61% using Agile 3+ vs. LS dual cut-offs and 71% vs. 67% in ALD, respectively. When using Agile 3+ or LSM as a second step after FIB-4 >1.3, correct classification rates were higher with Agile 3+ than LSM, both for MASLD (75% vs. 71%) and ALD (76% vs. 72%), with fewer indeterminate results. Positive agreement of LSM and Agile 3+/4 significantly increased the specificity of a diagnosis of advanced fibrosis/cirrhosis. Agile 3+ and Agile 4 have equal diagnostic accuracy with LSM in both MASLD and ALD but result in fewer indeterminate results. Sequential use of FIB-4 and Agile 3+/4 or concurrent Agile 3+/4 and LSM can be used to further optimize F≥3 diagnosis. As of today, it is accepted that there will be no single non-invasive test or an isolated cut-off for identifying patients with advanced chronic liver disease. Here, we confirmed that Agile 3+ and Agile 4 scores are useful alternatives to simple liver stiffness measurement in diagnosing advanced fibrosis/cirrhosis in steatotic liver disease, but they do not perform as well in chronic viral hepatitis. Agile scores can help optimize the diagnosis of advanced fibrosis/cirrhosis in a dual cut-off strategy by reducing the number of indeterminate results either alone or in a sequential strategy after FIB-4. The combination of Agile scores and liver stiffness measurement can further increase our confidence in a positive diagnosis of advanced fibrosis/cirrhosis. These novel combination strategies can be useful tools to predict the likelihood of advanced stages of liver disease with the highest possible accuracy in a secondary/tertiary healthcare setting. [Display omitted] • Agile 3+ and Agile 4 have equal diagnostic accuracy with LSM in both MASLD and ALD but offer no benefit in viral hepatitis. • By selecting optimal dual cut-offs, more patients are correctly classified with Agile 3+ and 4 than with LSM alone. • More importantly, fewer patients remain with indeterminate results when using Agile 3+ and 4. • Using Agile scores as a second step (instead of LSM) in patients with indeterminate FIB-4 further improves risk stratification. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction‐associated steatohepatitis (MASH), a severe form of metabolic dysfunction‐associated steatotic liver disease (MASLD), poses a significant threat to global health. Despite extensive research efforts over the past decade, only one drug has received market approval under accelerated pathways. In this review, we summarise the pathogenesis of MASH and present a comprehensive overview of recent advances in phase 2–3 clinical trials targeting MASH. These trials have highlighted considerable challenges, including low response rates to drugs, limitations of current surrogate histological endpoints, and inadequacies in the design of MASH clinical trials, all of which hinder the progress of MASH pharmacotherapy. We also explored the potential of non‐invasive tests to enhance clinical trial design. Furthermore, given the strong association between MASLD and cardiometabolic disorders, we advocate for an integrated approach to disease management to improve overall patient outcomes. Continued investigation into the mechanisms and pharmacology of combination therapies may offer valuable insights for developing innovative MASH treatments. [ABSTRACT FROM AUTHOR]

Abstract The quality and freshness of eggs deteriorate during storage, impacting their role as a crucial dietary and industrial component. This study utilizes transmittance spectroscopy (200–1000 nm) to predict the S-ovalbumin content and to identify optimal wavelengths for assessing egg freshness levels. Three hundred fresh eggs were evaluated over 21 days of storage at ambient (25 ± 2 °C, 45 ± 5% R.H.) and refrigerated (5 ± 0.5 °C, 75 ± 5% R.H.) conditions by measuring quality indicators (Haugh unit, air cell height, yolk index, S-ovalbumin, and albumin/yolk pH). The samples were divided into several clusters using the fuzzy C-means algorithm based on these parameters. The changes in the S-ovalbumin concentration increased significantly (p

The PNPLA3‐rs738409‐G variant was the first common variant associated with hepatic fat accumulation and progression of metabolic dysfunction‐associated steatotic liver disease (MASLD). Nevertheless, to date, the clinical translation of this discovery has been minimal because it has not yet been clearly demonstrated where the genetic information may play an independent and additional role in clinical risk prediction. In this mini‐review, we will discuss the most relevant evidence regarding the potential integration of the PNPLA3 variant into scores and algorithms for liver disease diagnostics and risk stratification, specifically focusing on MASLD but also extending to liver diseases of other etiologies. The PNPLA3 variant adds little in diagnosing the current state of the disease, whether in terms of presence/absence of metabolic dysfunction‐associated steatohepatitis or the stage of fibrosis. While it can play an important role in prediction, allowing for the early definition of risk profiles that enable tailored monitoring and interventions over time, this is most valuable when applied to populations with relatively high pre‐test probability of having significant fibrosis based on either non‐invasive tests (e.g. Fibrosis‐4) or demographics (e.g. diabetes). Indeed, in this context, integrating FIB4 with the PNPLA3 genotype can refine risk stratification, though there is still no evidence that genetic information adds to liver stiffness determined by elastography. Similarly, in patients with known liver cirrhosis, knowing the PNPLA3 genotype can play a role in predicting the risk of hepatocellular carcinoma, while more doubts remain about the risk of decompensation. [ABSTRACT FROM AUTHOR]

Purpose of Review: The increasing global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) underscores the urgent need for a reliable non-invasive test (NIT) to phenotype and stratify risk in affected individuals. This narrative review aims to provide clinicians with an understanding of vibration-controlled transient elastography (VCTE). We focus on the clinical significance of key VCTE-derived parameters: the controlled attenuation parameter (CAP), liver stiffness measurement (LSM), and spleen stiffness measurement (SSM). Recent Findings: VCTE enables simultaneous assessment of hepatic steatosis, fibrosis, and the severity of portal hypertension by measuring CAP, LSM, and SSM, respectively. Furthermore, combination scores improve diagnostic accuracy by reducing values in the indeterminate range. Changes in CAP, LSM, or SSM over time may serve as biomarkers of disease activity. Summary: CAP, LSM, and SSM, as NITs obtained through VCTE, play pivotal roles in disease phenotyping risk prognostication and monitoring disease progression or treatment response. It is hoped that VCTE-based parameters will minimize or obviate the need for invasive liver biopsy. [ABSTRACT FROM AUTHOR]

The rising prevalence of liver diseases related to obesity and excessive use of alcohol is fuelling an increasing demand for accurate biomarkers aimed at community screening, diagnosis of steatohepatitis and significant fibrosis, monitoring, prognostication and prediction of treatment efficacy. Breakthroughs in omics methodologies and the power of bioinformatics have created an excellent opportunity to apply technological advances to clinical needs, for instance in the development of precision biomarkers for personalised medicine. Via omics technologies, biological processes from the genes to circulating protein, as well as the microbiome – including bacteria, viruses and fungi, can be investigated on an axis. However, there are important barriers to omics-based biomarker discovery and validation, including the use of semi-quantitative measurements from untargeted platforms, which may exhibit high analytical, inter- and intra-individual variance. Standardising methods and the need to validate them across diverse populations presents a challenge, partly due to disease complexity and the dynamic nature of biomarker expression at different disease stages. Lack of validity causes lost opportunities when studies fail to provide the knowledge needed for regulatory approvals, all of which contributes to a delayed translation of these discoveries into clinical practice. While no omics-based biomarkers have matured to clinical implementation, the extent of data generated has enabled the hypothesis-free discovery of a plethora of candidate biomarkers that warrant further validation. To explore the many opportunities of omics technologies, hepatologists need detailed knowledge of commonalities and differences between the various omics layers, and both the barriers to and advantages of these approaches. [ABSTRACT FROM AUTHOR]

Background & Aims: Elevated liver stiffness has been associated with atrial fibrillation (AFib) in the general population. The mechanism underlying this association is unclear. Methods: Participants were recruited from the general population and prospectively enrolled with follow-up for 5 years. The fibrosis-4 (FIB-4) index was used as a surrogate marker for liver fibrosis. Proteomics analysis was performed using the 92-target Olink inflammation panel. Validation was performed using the NAFLD fibrosis score (NFS), aspartate aminotransferase to platelet index (APRI), and repeat confirmation proteomics. Results: A sample of 11,509 participants with a mean age of 54.0 ± 11.1 years, 51.3% women, and a median FIB-4 index of 0.85 (0.65/1.12), was used. The FIB-4 index was predictive for prevalent (FIB-4 index adjusted odds ratio (aOR) per SD: 1.100 with 95% CI 1.011-1.196; p = 0.026), but not incident AFib (log[FIB-4 index]) adjusted hazard ratio: 1.125 with 95% CI 0.943-1.342, p = 0.19). Elastic net regularized regression identified CCL20, DNER, and CXCL10 for prevalent AFib, and AXIN1, CXCL10, and Flt3L for the log(FIB-4 index) (per SD) as most important in common regulated proteins. The relationship between the FIB-4 index, the identified proteins, and AFib was relevant and reproduced at the 5-year follow-up for CXCL10 after adjusting for confounders (log[FIB-4 index] per SD - CXCL10 [per SD] adjusted β 0.160 with 95% CI 0.127-0.194, p

Summary: Background: The liver–heart axis potentially influences the risk of mortality in patients with heart failure. We aimed to identify the clinical utility of the fibrosis-4 (FIB-4) index in patients with heart failure for predicting mortality in the context of metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: Patients with heart failure and a subsample of healthy participants were enrolled in the MyoVasc study (NCT04064450) and followed for nine years. Participants with excessive alcohol consumption were excluded. The Fatty Liver Index (FLI) and FIB-4 index were used to classify MASLD and hepatic fibrosis, respectively. Data were adjusted for potential confounders. The primary endpoint was all-cause mortality. Findings: 2726 participants, including 172 healthy individuals, were included in the study. The participants had a mean age of 64.4 ± 11.2 years and a median FIB-4 index of 1.59 (interquartile range [1.17; 2.17]). There were 532 deaths. The FIB-4 index was predictive for all-cause mortality (hazard ratio (HR) 1.341, 95% confidence interval (CI) [1.273; 1.412], p

Background & aimsNon-invasive tests (NITs) offer a practical solution for advanced fibrosis identification in non-alcoholic fatty liver disease (NAFLD). Despite increasing implementation, their use is not standardised, which can lead to inconsistent interpretation and risk stratification. We aimed to assess the types of NITs and the corresponding cut-offs used in a range of healthcare settings.MethodsA survey was distributed to a convenience sample of liver health experts who participated in a global NAFLD consensus statement. Respondents provided information on the NITs used in their clinic with the corresponding cut-offs and those used in established care pathways in their areas.ResultsThere were 35 respondents from 24 countries, 89% of whom practised in tertiary level settings. A total of 14 different NITs were used, and each respondent reported using at least one (median = 3). Of the respondents, 80% reported using FIB-4 and liver stiffness by vibration-controlled transient elastography (Fibroscan®), followed by the NAFLD fibrosis score (49%). For FIB-4, 71% of respondents used a low cut-off of 7.5 to >20 kPa, respectively).ConclusionsThe cut-offs used for the same NITs for NAFLD risk stratification vary between clinicians. As cut-offs impact test performance, these findings underscore the heterogeneity in risk-assessment and support the importance of establishing consistent guidelines on the standardised use of NITs in NAFLD management.Lay summaryOwing to the high prevalence of non-alcoholic fatty liver disease (NAFLD) in the general population it is important to identify those who have more advanced stages of liver fibrosis, so that they can be properly treated. Non-invasive tests (NITs) provide a practical way to assess fibrosis risk in patients. However, we found that the cut-offs used for the same NITs vary between clinicians. As cut-offs impact test performance, these findings highlight the importance of establishing consistent guidelines on the standardised use of NITs to optimise clinical management of NAFLD.

Background: Non-alcoholic fatty liver disease (NAFLD) encompasses a heterogeneous spectrum ranging from simple steatosis to fibrosis and cirrhosis. Fibrosis, associated with long-term overall mortality and liver-related events, requires evaluation. Traditionally, liver biopsy has been the gold standard for diagnosing fibrosis. However, its invasive nature, potential complications, and sampling variability limit widespread use. Consequently, various non-invasive tests have been developed as alternatives for diagnosing fibrosis in NAFLD patients. Aim: This study aimed to compare the accuracy of non-invasive tests (NITs) and evaluate the diagnostic accuracy of acoustic radiation force impulse (ARFI), one of the point shear wave techniques, compared to conventional methods, assessing its effective role in diagnosis. Methods: This is a retrospective study; a total of 136 patients diagnosed with fatty liver disease through ultrasonography were enrolled. The anthropometric data of the patients were collected on the day of admission and blood tests, measurements of ARFI, and a point shear test were conducted using abdominal ultrasound; a biopsy was performed the following day. In addition, we calculated the aspartate aminotransferase-to-platelet ratio index (APRI) index based on four factors (FIB-4) and the NAFLD fibrosis score (NFS). Subsequently, we assessed the diagnostic accuracy of NITs within various subgroups based on the extent of obesity, steatosis, or NAFLD activity score. Results: ARFI has been shown to have the highest diagnostic value among various NITs, with AUROC values of 0.832, 0.794, 0.767, and 0.696 for ARFI, APRI, FIB-4, and NFS, respectively. In the morbidly obese subgroup, the AUROC values of ARFI, APRI, FIB-4, and NFS were 0.805, 0.769, 0.736, and 0.674. In the group with severe steatosis or non-alcoholic steatohepatitis (NASH), the AUROC values were 0.679, 0.596, 0.661, and 0.612, respectively, for severe steatosis and 0.789, 0.696, 0.751, and 0.691, respectively, for NASH. Conclusions: In conclusion, ARFI is not affected by various factors and maintains diagnostic accuracy compared to serum NITs. Therefore, we can recommend ARFI as a valuable diagnostic test to screen for advanced fibrosis in patients with NAFLD. [ABSTRACT FROM AUTHOR]

Propose further indicators for helping to detect hand osteoarthritis (HOA) using either active or functional ranges of motion (AROM or FROM). Hand kinematics data of 16 hand joint angles from previous studies were used, taken from healthy participants and HOA patients with differently affected joints and distinct levels of compromise. Data consisted of: (i) AROM (extreme values and ranges); (ii) FROM while performing the Sollerman Hand Function Test (mean, extreme percentiles and ranges). Two linear discriminant analyses (stepwise method) were conducted, one per dataset (AROM and FROM), with condition (healthy/patient) as the grouping variable. The potential predictors were the data from the joints with significant differences between samples for each analysis (A-predictors and F-predictors). Good sensitivity-specificity values of 85.2–90.9% and 93.8–93.9% for F-predictors and A-predictors, respectively. Sets of predictors corresponded to the joints more commonly affected by HOA. F-predictors: lower maximal flexion of carpometacarpal and interphalangeal thumb joints, higher maximal flexion of thumb metacarpal joint, lower flexion/extension range of ring proximal interphalangeal joint and higher maximal little finger adduction. A-predictors: narrower flexion/extension range of the thumb carpometacarpal joint, lesser extension of the ring metacarpophalangeal joint; lower flexion of the middle finger proximal interphalangeal joint along with a narrower palmar arch range. Both sets of predictors provide discrimination capacity of HOA with good sensitivity-specificity, slightly better for A-predictors. The AROM measurement is technically less demanding and can be clinically applied even with manual goniometry. Range of motion is affected by hand osteoarthritis even before joint deformity is noticeable. Active (AROM) or functional (FROM) ranges of motion can help to identify potential hand osteoarthritis and opening up the possibility of applying rehabilitation treatments to improve quality of life. The AROM measurement is technically less demanding and can be clinically applied even with manual goniometry. [ABSTRACT FROM AUTHOR]

A novel ternary heterojunction material In2O3/In2S3/ZnIn2S4 was synthesized, and a photoelectrochemical sensor was fabricated for the non-invasive test of dopamine (DA) in sweat. In2O3 multihollow microtubules were synthesized and then In2S3 was formed on their surface to construct a type-I heterojunction between In2S3 and In2O3. ZnIn2S4 was further introduced to form a Z-scheme heterojunction between In2S3/ZnIn2S4. Under photoexcitation, the photogenerated holes of In2O3 transferred to the valence band of In2S3, superimposed with the holes produced by In2S3, leads to a significantly higher photocatalytic oxidation capacity of In2O3/In2S3/ZnIn2S4 ternary composites than that of In2O3/In2S3. The Z-scheme heterojunction accelerates the transfer of photogenerated electrons accumulated on the type-I heterojunction. In the presence of DA, it is rapidly oxidized into polydopamine (PDA) by In2O3/In2S3, and the benzoquinone groups of PDA compete for the photogenerated electrons to reduce the current in the external circuit, whereby DA determination is achieved. Owing to the combination of type-I and Z-scheme heterojunction, the sensor showed extremely high sensitivity, with a detection limit of 3.94 × 10−12 mol/L. It is one of the most sensitive methods for DA detection reported and has been applied to the determination of DA in human sweat. [ABSTRACT FROM AUTHOR]

In vitro detection of small molecules in the human circulatory system contributes a lot to prompt personalized healthcare and early disease diagnose. The precise detection requires to select target molecules for real‐time noninvasive identifications, which remains a challenge derived from the lack of both molecule‐sieving techniques and rapid detection tools. Herein, positively charged polymer chains into graphene oxide membranes are seeded to tune their interlayer spacing precisely and persistently within a range of 8.67–13.75 Å. The adaptive yet stable nanocapillaries allow membranes to sieve small molecules with fitted sizes, for example, salts and biomarkers. The molecule‐sieving membranes with organic electrochemical transistors, further achieving an in vitro detection of lactate and uric acid with a high accuracy, are coupled. Based on this finding, a wearable sweat lactate rapid test kit, which detects sweat lactate secreted from human body within a few minutes, is demonstrated. [ABSTRACT FROM AUTHOR]

Objective: The recent World Endoscopy Organization (WEO) guidelines now recognize precursor lesions of colorectal cancer (CRC) as legitimate screening targets. However, an optimal screening method for detecting advanced adenoma (AA), a significant precursor lesion, remains elusive. Methods: We employed five machine learning methods, using clinical and laboratory data, to develop and validate a diagnostic model for identifying patients with AA (569 AAs vs. 3228 controls with normal colonoscopy). The best-performing model was selected based on sensitivity and specificity assessments. Its performance in recognizing adenoma-carcinoma sequence was evaluated in line with guidelines, and adjustable thresholds were established. For comparison, the Fecal Occult Blood Test (FOBT) was also selected. Results: The XGBoost model demonstrated superior performance in identifying AA, with a sensitivity of 70.8% and a specificity of 83.4%. It successfully detected 42.7% of non-advanced adenoma (NAA) and 80.1% of CRC. The model-transformed risk assessment scale provided diagnostic performance at different positivity thresholds. Compared to FOBT, the XGBoost model better identified AA and NAA, however, was less effective in CRC. Conclusion: The XGBoost model, compared to FOBT, offers improved accuracy in identifying AA patients. While it may not meet the recommendations of some organizations, it provides value for individuals who are unable to use FOBT for various reasons. [ABSTRACT FROM AUTHOR]

Strategies to reduce liver biopsy (LB) screen failures through better patient selection are needed for clinical trials. Standard fibrosis biomarkers were not derived to detect "at-risk" metabolic dysfunction-associated steatohepatitis (MASH; MASH with metabolic dysfunction-associated steatotic liver disease score ≥4 and fibrosis stage ≥2). We compared the performance of screening pathways that incorporate NIS2+™, an optimized version of the blood-based NIS4® technology designed to identify at-risk MASH, with those incorporating fibrosis (FIB)-4 within the RESOLVE-IT clinical trial (NCT02704403), aiming for optimized selection of patients for LB. A retrospective simulation analysis was conducted in the RESOLVE-IT screening pathway (RSP) cohort. LB failure rate (LBFR), number of patients needed to screen, and overall cost estimations of different pathways were calculated for a range of NIS2+™ and FIB-4 cut-offs and compared with those of the RSP, which relied on investigators' local practices. An analysis of potential recruitment bias based on histology, sex, age, or comorbidities was performed. The analysis cohort included 1,929 patients, 765 (40%) with at-risk MASH. The NIS2+™ pathway resulted in a significantly lower LBFR (39%) compared with the FIB-4 pathway (58%) or the RSP (60%) when using cost-optimized cut-offs (NIS2+™, 0.53; FIB-4, 0.58). For every 1,000 inclusions, NIS2+™ significantly reduced unnecessary LBs (632 vs. 1,522; -58%) and screening costs (US$12.7 million vs. US$15.0 million) vs. the RSP, while the number of patients needed to screen increased moderately (3,220 to 4,033). NIS2+™ alone is better than FIB-4 alone or combined with FIB-4. This analysis demonstrated that patient selection for LB using NIS2+™ significantly reduced unnecessary biopsies and screening costs, which could greatly improve the feasibility of MASH clinical trials. Simple and accurate non-invasive strategies to optimize the selection of patients who should be referred for liver biopsy for inclusion in MASH clinical trials is critical to reduce the high liver biopsy failure rates. While the use of the Fibrosis-4 index alone did not lead to a significant improvement of the screening process, selecting patients using NIS2+™, a recently developed optimization of the NIS4® technology for the detection of at-risk MASH, showed improved performance by simultaneously reducing liver biopsy failure rates and the overall cost of the trial, while maintaining the number of patients needed to screen at a manageable level and not generating any bias in included patients' characteristics. This makes NIS2+™ an accurate and reliable screening tool that could improve the recruitment of patients in future MASH clinical trials, and would lead to increased patient comfort and security, ensuring timely and cost-efficient trial completion. [Display omitted] • The liver biopsy failure rate in MASH clinical trials is unacceptably high. • We used NIS2+™, a two-biomarker test, to refer patients with at-risk MASH for liver biopsy. • NIS2+™ reduced liver biopsy failure rates and screening costs. • NIS2+™ screening performance was superior to that of FIB-4. • The profile of patients included with NIS2+™ screening pathway was not impacted. [ABSTRACT FROM AUTHOR]

Background: The prognosis of metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with liver fibrosis. We aimed to investigate whether liver stiffness measurement (LSM) and changes in LSM (ΔLSM) on magnetic resonance elastography (MRE) can predict clinical events in patients with MASLD. Methods: We included 405 patients with MASLD who underwent at least two MREs. The patients were divided into five groups corresponding to fibrosis stages (0–4) based on initial LSM and classified as progressors (ΔLSM ≥ 19%) or non-progressors (ΔLSM < 19%) based on the difference between the first and last LSM. Results: The mean follow-up period was 72.6 months, and the mean interval between MREs was 23.5 months. There were 52 (12.8%) progressors and 353 (87.2%) non-progressors. The initial LSM was significantly associated with the cumulative probabilities of decompensated cirrhosis, hepatocellular carcinoma (HCC), liver-related events, extrahepatic malignancies, and overall mortality but not with cardiovascular disease. Progressors had significantly higher hazard ratios (HRs) for decompensated cirrhosis, HCC, and liver-related events but not for extrahepatic malignancies, cardiovascular disease, or overall mortality. Among patients without cirrhosis, the HR for developing cirrhosis among progressors was 60.15. Progressors had a significantly higher risk of liver-related events, even in the low initial LSM (fibrosis stage 0–2) subgroups. Conclusions: Both initial LSM and ΔLSM can predict liver-related events in patients with MASLD, even for low initial LSM. This integrated assessment can allow more detailed risk stratification compared with single LSM assessments and identify high-risk patients with MASLD among those previously considered as low risk. [ABSTRACT FROM AUTHOR]

In vitro detection of small molecules in the human circulatory system contributes a lot to prompt personalized healthcare and early disease diagnose. The precise detection requires to select target molecules for real‐time noninvasive identifications, which remains a challenge derived from the lack of both molecule‐sieving techniques and rapid detection tools. Herein, positively charged polymer chains into graphene oxide membranes are seeded to tune their interlayer spacing precisely and persistently within a range of 8.67–13.75 Å. The adaptive yet stable nanocapillaries allow membranes to sieve small molecules with fitted sizes, for example, salts and biomarkers. The molecule‐sieving membranes with organic electrochemical transistors, further achieving an in vitro detection of lactate and uric acid with a high accuracy, are coupled. Based on this finding, a wearable sweat lactate rapid test kit, which detects sweat lactate secreted from human body within a few minutes, is demonstrated.

Background: Non-alcoholic fatty liver disease (NAFLD) encompasses a heterogeneous spectrum ranging from simple steatosis to fibrosis and cirrhosis. Fibrosis, associated with long-term overall mortality and liver-related events, requires evaluation. Traditionally, liver biopsy has been the gold standard for diagnosing fibrosis. However, its invasive nature, potential complications, and sampling variability limit widespread use. Consequently, various non-invasive tests have been developed as alternatives for diagnosing fibrosis in NAFLD patients. Aim: This study aimed to compare the accuracy of non-invasive tests (NITs) and evaluate the diagnostic accuracy of acoustic radiation force impulse (ARFI), one of the point shear wave techniques, compared to conventional methods, assessing its effective role in diagnosis. Methods: This is a retrospective study; a total of 136 patients diagnosed with fatty liver disease through ultrasonography were enrolled. The anthropometric data of the patients were collected on the day of admission and blood tests, measurements of ARFI, and a point shear test were conducted using abdominal ultrasound; a biopsy was performed the following day. In addition, we calculated the aspartate aminotransferase-to-platelet ratio index (APRI) index based on four factors (FIB-4) and the NAFLD fibrosis score (NFS). Subsequently, we assessed the diagnostic accuracy of NITs within various subgroups based on the extent of obesity, steatosis, or NAFLD activity score. Results: ARFI has been shown to have the highest diagnostic value among various NITs, with AUROC values of 0.832, 0.794, 0.767, and 0.696 for ARFI, APRI, FIB-4, and NFS, respectively. In the morbidly obese subgroup, the AUROC values of ARFI, APRI, FIB-4, and NFS were 0.805, 0.769, 0.736, and 0.674. In the group with severe steatosis or non-alcoholic steatohepatitis (NASH), the AUROC values were 0.679, 0.596, 0.661, and 0.612, respectively, for severe steatosis and 0.789, 0.696, 0.751, and 0.691, respectively, for NASH. Conclusions: In conclusion, ARFI is not affected by various factors and maintains diagnostic accuracy compared to serum NITs. Therefore, we can recommend ARFI as a valuable diagnostic test to screen for advanced fibrosis in patients with NAFLD.

The non-invasive identification of liver fibrosis related to Non-Alcoholic Fatty Liver Disease is crucial for risk-stratification of patients. Currently, the reference standard to stage hepatic fibrosis relies on liver biopsy, but multiple approaches are developed to allow for non-invasive diagnosis and risk stratification. Non-invasive tests, including blood-based scores and vibration-controlled transient elastography, have been widely validated and represent a good surrogate for risk stratification according to recent European and American guidelines. Novel approaches are based on 'liquid' biomarkers of liver fibrogenesis, including collagen-derived markers (PRO-C3 or PRO-C6), or 'multi-omics' technologies (e.g. proteomic-based molecules or miRNA testing), bearing the advantage of tailoring the intrahepatic disease activity. Alternative approaches are based on 'dry' biomarkers, including magnetic resonance-based tools (including proton density fat fraction, magnetic resonance elastography, or corrected T1), which reach similar accuracy of liver histology and will potentially help identify the best candidates for pharmacological treatment of fibrosing non-alcoholic steatohepatitis. In the near future, the sequential use of non-invasive tests, as well as the complimentary use of liquid and dry biomarkers according to the clinical need (diagnosis, risk stratification, and prognosis, or treatment response) will guide and improve the management of this liver disease. [ABSTRACT FROM AUTHOR]

Introduction: Torque teno virus (TTV) replication is controlled by immune status, mirroring a degree of immunosuppression after solid organ transplantation. TTV viraemia (TTVv) was associated with acute cellular rejection and infection within the first year after liver transplantation (LT). Long-term data on TTV after LT and correlation with graft injury from protocol biopsies are limited. Methods: One hundred plasma samples paired with graft biopsies from a prospective single-center biorepository were analyzed. Results: The median time post-LT was 23 months (range, 2-298). TTVv was detectable in 97%. TTVv decreased over time after LT and showed a significant decline from year 1 to later time points. Hence, TTVv correlated negatively with histologic liver fibrosis (liver allograft fibrosis and Ishak scores) and positively with the overall immunosuppression degree quantified by an immunosuppression score in the first year after LT. There was no association with dosages or trough levels of single immunosuppressants. The pharmacodynamic marker TTVv did not correlate with pharmacokinetic assessments of immunosuppression degree [calcineurin inhibitor (CNI) trough levels or immunosuppressant dosages]--our clinical gold standards to guide immunosuppressive therapy. TTVv was independently associated with histologically proven liver fibrosis after LT in the first year after LT in multivariate analysis. Discussion: The independent association of histological graft fibrosis with lower TTVv in year 1 underscores that a pharmacodynamic marker would be preferable to individualize immunosuppression after LT. However, a high variability of TTVv at the low immunosuppression doses given after the first year precludes TTV as a clinically useful marker after LT in the long-term liver transplant recipients. [ABSTRACT FROM AUTHOR]

Background: The evaluation of liver fibrosis is essential in the management of patients with autoimmune hepatitis (AIH). We aimed to establish and validate an easy-to-use nomogram to identify AIH patients with advanced liver fibrosis. Methods: AIH patients who underwent liver biopsies were included and randomly divided into a training set and a validation set. The least absolute shrinkage and selection operator (LASSO) regression was used to select independent predictors of advanced liver fibrosis from the training set, which were utilized to establish a nomogram. The performance of the nomogram was evaluated using the receiver characteristic curve (ROC), calibration curve, and decision curve analysis (DCA). Results: The median age of 235 patients with AIH was 54 years old, with 83.0% of them being female. Six independent factors associated with advanced fibrosis, including sex, age, red cell distribution width, platelets, alkaline phosphatase, and prothrombin time, were combined to construct a predictive AIH fibrosis (AIHF)- nomogram. The AIHF-nomogram showed good agreement with real observations in the training and validation sets, according to the calibration curve. The AIHF-nomogram performed significantly better than the fibrosis-4 and aminotransferase-to-platelet ratio scores in the training and validation sets, with an area under the ROCs for predicting advanced fibrosis of 0.804 in the training set and 0.781 in the validation set. DCA indicated that the AIHFInomogram was clinically useful. The nomogram will be available at http://ndth-zzy.shinyapps.io/AIHF-nomogram/as a web-based calculator. Conclusions: The novel, easy-to-use web-based AIHF-nomogram model provides an insightful and applicable tool to identify AIH patients with advanced liver fibrosis. [ABSTRACT FROM AUTHOR]

IntroductionTorque teno virus (TTV) replication is controlled by immune status, mirroring a degree of immunosuppression after solid organ transplantation. TTV viraemia (TTVv) was associated with acute cellular rejection and infection within the first year after liver transplantation (LT). Long-term data on TTV after LT and correlation with graft injury from protocol biopsies are limited. MethodsOne hundred plasma samples paired with graft biopsies from a prospective single-center biorepository were analyzed.ResultsThe median time post-LT was 23 months (range, 2–298). TTVv was detectable in 97%. TTVv decreased over time after LT and showed a significant decline from year 1 to later time points. Hence, TTVv correlated negatively with histologic liver fibrosis (liver allograft fibrosis and Ishak scores) and positively with the overall immunosuppression degree quantified by an immunosuppression score in the first year after LT. There was no association with dosages or trough levels of single immunosuppressants. The pharmacodynamic marker TTVv did not correlate with pharmacokinetic assessments of immunosuppression degree [calcineurin inhibitor (CNI) trough levels or immunosuppressant dosages]—our clinical gold standards to guide immunosuppressive therapy. TTVv was independently associated with histologically proven liver fibrosis after LT in the first year after LT in multivariate analysisDiscussionThe independent association of histological graft fibrosis with lower TTVv in year 1 underscores that a pharmacodynamic marker would be preferable to individualize immunosuppression after LT. However, a high variability of TTVv at the low immunosuppression doses given after the first year precludes TTV as a clinically useful marker after LT in the long-term liver transplant recipients.

Background. Assessment of liver fibrosis is essential to guide treatment in autoimmune hepatitis (AIH), but non-invasive tests (NITs) showed poor accuracy. Our study aims to evaluate the performance of NITs among different AIH presentations. Methods. Monocentric retrospective study among 122 AIH patients. NITs were compared to histological grading of liver fibrosis. We performed an accuracy analysis among acute (jaundice and/or transaminases > 10 times upper limit of normal) and non-acute patients. Results. A significant difference in the distribution of NIT values for each Ishak stage was found for spleen-diameter-to-platelet-count ratio (SD/PC) (p < 0.001), fibrosis-4-score (FIB-4) (p = 0.002), AST-to-ALT ratio (AAR) (p = 0.002), red-blood-cell-width-distribution-to-platelet-count ratio (RDW/PC) (p = 0.008) and AST-to-platelet-count ratio (APRI) (p = 0.029). The AUC for advanced fibrosis of SD/PC, FIB-4, RDW/PC, APRI and AAR were, respectively, 0.814, 0.770, 0.768, 0.708 and 0.694. The AUC of SD/PC, FIB-4 and APRI in non-acute subgroup were 0.902, 0.834 and 0.758, while in acute patients they were 0.754, 0.724 and 0.716. RDW/PC and AAR weren’t different among the two subgroups. Conclusions. For SD/PC, FIB-4 and APRI, diagnostic accuracy is higher in patients with non-acute presentation. In this context, SD/PC and FIB-4 showed an overall performance that could be of interest in clinical practice alongside other non-invasive techniques.

Abstract Background The main epigenetic event occurring during the bladder carcinogenesis process is DNA methylation, affecting genes involved in various metabolic pathways and cell regulation. The use of biological fluids such as urine sediments could be used as a non-invasive approach to enhance bladder cancer management. In this study, we aim to determine the promoter methylation status of a panel of genes in bladder cancer on tumor biopsies and urine sediments to evaluate the usefulness of urine samples as a non-invasive approach for methylation status assessment. Methods Using the methylation-specific PCR technique, we explored the promoter methylation status of hTERT, TWIST1, VIM and NID2 genes in 40 tumor biopsies and their paired urine samples from Moroccan bladder cancer patients. Results In this study, bladder tumors showed promoter hypermethylation frequency of individual genes as 90%, 85%, 62.5% and 72.5% in TWIST1, hTERT, NID2 and VIM genes, respectively. Interestingly, the specificity of methylation detection in urine samples was 100% and the sensitivity to detect hypermethylation of TWIST1, hTERT, NID2 and VIM genes reached 91.7%; 97.1%; 84% and 82.8%, respectively. Conclusions Our results clearly show that the assessment of promoter hypermethylation in urine samples is highly specific and has high sensitivity. Furthermore, urine sediments would be a useful approach to detect the DNA methylation status of genes and its potential association with bladder cancer development.

Currently available non-invasive tests, including fibrosis-4 index (FIB-4) and liver stiffness measurement (LSM by VCTE), are highly effective at excluding advanced fibrosis (AF) (F ≥3) or cirrhosis in people with non-alcoholic fatty liver disease (NAFLD), but only have moderate ability to rule-in these conditions. Our objective was to develop and validate two new scores (Agile 4 and Agile 3+) to identify cirrhosis or AF, respectively, with optimized positive predictive value and fewer indeterminate results, in individuals with NAFLD attending liver clinics. This international study included seven adult cohorts with suspected NAFLD who underwent liver biopsy, LSM and blood sampling during routine clinical practice or screening for trials. The population was randomly divided into a training set and an internal validation set, on which the best-fitting logistic regression model was built, and performance and goodness of fit were assessed, respectively. Furthermore, both scores were externally validated on two large cohorts. Cut-offs for high sensitivity and specificity were derived in the training set to rule-out and rule-in cirrhosis or AF and then tested in the validation set and compared to FIB-4 and LSM. Each score combined LSM, AST/ALT ratio, platelets, sex and diabetes status, as well as age for Agile 3+. Calibration plots for Agile 4 and Agile 3+ indicated satisfactory to excellent goodness of fit. Agile 4 and Agile 3+ outperformed FIB-4 and LSM in terms of AUROC, percentage of patients with indeterminate results and positive predictive value to rule-in cirrhosis or AF. The two novel non-invasive scores improve identification of cirrhosis or AF among individuals with NAFLD attending liver clinics and reduce the need for liver biopsy in this population. Non-invasive tests currently used to identify patients with advanced fibrosis or cirrhosis, such as fibrosis-4 index and liver stiffness measurement by vibration-controlled transient elastography, have high negative predictive values but high false positive rates, while results are indeterminate for a large number of cases. This study provides scores that will help the clinician diagnose advanced fibrosis or cirrhosis. These new easy-to-implement scores will help liver specialists to better identify (1) patients who need more intensive follow-up, (2) patients who should be referred for inclusion in therapeutic trials, and (3) which patients should be treated with pharmacological agents when effective therapies are approved. [Display omitted] • Non-invasive tests' ability to rule-in advanced fibrosis and cirrhosis is moderate. • Consequently, two new FibroScan-based scores are proposed: Agile 3+ and Agile 4. • They demonstrate fewer indeterminate results and higher positive predictive value. • Clinical performances are globally validated in two large independent cohorts. • Use of these scores in clinical practice could reduce the need for liver biopsy. [ABSTRACT FROM AUTHOR]

Background & Aims: Clinically significant portal hypertension (CSPH) is a landmark in the natural history of cirrhosis, influencing clinical decisions in patients with hepatocellular carcinoma (HCC). Previous small series suggested that splanchnic volume measurements may predict portal hypertension. We aimed to evaluate whether volumetry obtained by standard multidetector computerised tomography (MDCT) can predict CSPH in patients with HCC. Methods: We included 175 patients with HCC, referred for hepatic venous pressure gradient (HVPG) evaluation, in whom contemporary MDCT was available. Liver volume, spleen volume (SV) and liver segmental volume ratio (LSVR: volume of the segments I-III/volume of the segments IV-VIII) were calculated semi-automatically from MDCT. Other non-invasive tests (NITs) were also employed. Results: Volume parameters could be measured in almost 100% of cases with an excellent inter-observer agreement (intraclass correlation coefficient >0.950). SV and LSVR were independently associated with CSPH (HVPG ≥10 mmHg) and did not interact with aetiology. The volume Index (VI), calculated as the product of SV and LSVR, predicted CSPH (AUC 0.83; 95% CI 0.77–0.89). Similar results were observed in an external cohort (n = 23) (AUC 0.87; 95% CI 0.69–1.00). Setting a sensitivity and specificity of 98%, VI could have avoided 35.9% of HVPG measurements. The accuracy of VI was similar to that of other NITs. VI also accurately predicted HVPG greater than 12, 14, 16 and 18 mmHg (AUC 0.81 [95% CI 0.74–0.88], 0.84 [95% CI 0.77–0.91], 0.85 [95% CI 0.77–0.92] and 0.87 [95% CI 0.79–0.94], respectively). Conclusions: Quantification of liver and spleen volumes by MDCT is a simple, accurate and reliable method of CSPH estimation in patients with compensated cirrhosis and HCC. Impact and implications: An increase in portal pressure strongly impacts outcomes after surgery in patients with early hepatocellular carcinoma (HCC). Direct measurement through hepatic vein catheterization remains the reference standard for portal pressure assessment, but its invasiveness limits its application. Therefore, we evaluated the ability of CT scan-based liver and spleen volume measurements to predict portal hypertension in patients with HCC. Our results indicate that the newly described index, based on quantification of liver and spleen volume, accurately predicts portal hypertension. These results suggest that a single imaging test may be used to diagnose and stage HCC, while providing an accurate estimation of portal hypertension, thus helping to stratify surgical risks.

Background & Aims: The accuracy of non-invasive tests (NITs) should be ≥80% (EASL recommendation). We aimed to compare the accuracies of the recommended NITs for advanced fibrosis in MASLD and improve NIT accuracy., Methods: 1051 MASLD patients were allocated to derivation (n=637) and validation (n=414) sets. The main outcome (Kleiner F3+F4) was primarily evaluated by accuracy. Conventional NITs were FIB-4, Fibrotest, FibroMeter, liver stiffness measurement (LSM by Fibroscan), Elasto-FibroMeter (FibroMeter-LSM combination), and ELF in 396 patients. We used machine-learning-optimized multitargeting to develop new NITs: FIB-9 (including 9 usual biomarkers), FIB-11 (adding 2 specialized blood markers) and FIB-12 (adding LSM)., Results: In the whole population, the accuracies of recommended NITs were insufficient, Fibrotest: 68.0%, FIB-4: 71.2%, FibroMeter: 75.1%, LSM: 75.9%, Elasto-FibroMeter: 78.6%. Therefore, new NITs (FIB-9, FIB-11, FIB-12) were developed in the derivation set. In the validation set, AUROCs were, FIB-4: 0.757, Fibrotest: 0.766, FibroMeter: 0.850, LSM: 0.852, FIB-9: 0.863, FIB-11: 0.880, Elasto-FibroMeter: 0.894, FIB-12: 0.912 (p<0.001). The FIB-12 AUROC was superior to the ELF AUROC (0.906 vs 0.865, p=0.039). Accuracies were, FIB-4: 68.8%, Fibrotest: 68.6%, LSM: 75.4%, FibroMeter: 76.3%, FIB-9: 78.7%, Elasto-FibroMeter: 79.7%, FIB-11: 80.2%, FIB-12: 83.3% (p<0.001 between all NITs). Scores were segmented by ≥90% sensitivity and specificity cut-offs or NIT match, which individualized subgroups with NIT accuracies ≥80%, e.g. for FIB-9: 85.8% in 68.1% of patients using two cut-offs and 83.2% in 71.7% of patients where FIB-9 agreed with FIB-4., Conclusions: Recommended NITs had accuracies <80% for advanced fibrosis in MASLD. Several NIT segmentations individualized subgroups with accuracies ≥80%. New NITs further improved accuracy. The simple FIB-9 (available via a free calculator) provided accuracy equaling or surpassing recommended NITs. FIB-12 outperformed other NITs., Impact and Implications: Currently recommended non-invasive tests (NITs) have insufficient accuracy (<80%) for the diagnosis of advanced fibrosis in MASLD. Therefore, we developed three new NITs with new statistical techniques. Thus, FIB-9 (available via a free calculator), including nine usual blood markers, equaled the performance of patented NITs. FIB-11, adding two specialized blood markers, and FIB-12, adding liver stiffness, had accuracy >80%. FIB-12, outperformed all other NITs. FIB-9 is suitable for screening and FIB-11 or FIB-12 for diagnosis., Competing Interests: Declaration of Competing Interest Paul Calès: inventor of FibroMeters Clémence M Canivet: none Charlotte Costentin: Intercept, Gilead, Ipsen Adrien Lannes: none Frédéric Oberti: Astra, Ipsen Isabelle Fouchard: none Gilles Hunault: SATT Victor de Lédinghen: AbbVie, Gilead, Orphalan, Astra Zeneca, Alfasigma, Escopics, BMS, GSK, Bayer, Janssen Jérôme Boursier: Diafir, Intercept, Siemens, BMS, Gilead, Pfizer, Echosens, Inventiva, (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Detection of patients with early cirrhosis is of importance to prevent the occurrence of complications and improve prognosis. The SEAL program aimed at evaluating the usefulness of a structured screening procedure to detect cirrhosis as early as possible. SEAL was a prospective cohort study with a control cohort from routine care data. Individuals participating in the general German health check-up after the age of 35 ("Check-up 35") at their primary care physicians were offered a questionnaire, liver function tests (aspartate and alanine aminotransferase [AST and ALT]), and follow-up. If AST/ALT levels were elevated, the AST-to-platelet ratio index (APRI) score was calculated, and patients with a score >0.5 were referred to a liver expert in secondary and/or tertiary care. A total of 11,859 participants were enrolled and available for final analysis. The control group comprised 349,570 participants of the regular Check-up 35. SEAL detected 488 individuals with elevated APRI scores (4.12%) and 45 incident cases of advanced fibrosis/cirrhosis. The standardized incidence of advanced fibrosis/cirrhosis in the screening program was slightly higher than in controls (3.83‰ vs. 3.36‰). The comparison of the chance of fibrosis/cirrhosis diagnosis in SEAL vs. in standard care was inconclusive (marginal odds ratio 1.141, one-sided 95% CI 0.801, +Inf). Of note, when patients with decompensated cirrhosis at initial diagnosis were excluded from both cohorts in a post hoc analysis, SEAL was associated with a 59% higher chance of early cirrhosis detection on average than routine care (marginal odds ratio 1.590, one-sided 95% CI 1.080, +Inf; SEAL 3.51‰, controls: 2.21‰). The implementation of a structured screening program may increase the early detection rate of cirrhosis in the general population. In this context, the SEAL pathway represents a feasible and potentially cost-effective screening program. DRKS00013460 Detection of patients with early liver cirrhosis is of importance to prevent the occurrence of complications and improve prognosis. This study demonstrates that the implementation of a structured screening program using easily obtainable measures of liver function may increase the early detection rate of cirrhosis in the general population. In this context, the 'SEAL' pathway represents a feasible and potentially cost-effective screening program. [Display omitted] • The detection of patients with early cirrhosis is important to improve prognosis. • The SEAL algorithm evaluates the utility of population-based screening to detect cirrhosis as early as possible. • Excluding patients with decompensated cirrhosis at initial diagnosis, SEAL was associated with a 60% higher chance of early cirrhosis detection. • Only 50% of the patients identified by SEAL in primary care utilized specialist assessment. [ABSTRACT FROM AUTHOR]

• GP73 shows promise as a biomarker for liver fibrosis, with elevated levels correlating to disease severity. • Modulating GP73 synthesis could potentially prevent or reverse liver fibrosis. • GP73's clinical use is limited by assay variability and individual differences, needing more research for reliable validation. Golgi protein 73 (GP73) is implicated in key pathogenic processes, particularly those related to inflammation and fibrogenesis. In the last years, its measurement has emerged as a promising biomarker for detection of liver fibrosis (LF), a common consequence of chronic liver disease that can progress to cirrhosis and eventually hepatocellular carcinoma. GP73 concentrations in blood appear significantly increased in LF patients, correlating with disease severity, making this biomarker a possible non-invasive alternative for detecting and monitoring this condition regardless of etiology. Understanding the molecular mechanisms involving GP73 expression could also lead to new therapeutic strategies aimed at modulating its synthesis or function to prevent or reverse LF. Despite its clinical potential, GP73 as a LF biomarker faces several challenges. The lack of demonstrated comparability among different assays as well as the lack of knowledge of individual variability can make difficult the result interpretation. Further research is therefore needed focusing on robust clinical validation of GP73 as a LF biomarker. Addressing analytical, biological, and clinical limitations will be critical to exploiting its potential for improving detection and monitoring of advanced LF. [ABSTRACT FROM AUTHOR]

Abstract Background and aims Alcohol use disorders (AUD) cause 7.2% of UK hospital admissions/year. Most are not managed by hepatologists and liver disease may be missed. We used the Enhanced Liver Fibrosis (ELF) test to investigate prevalence and associations of occult advanced liver fibrosis in AUD patients not known to have liver fibrosis. Methods Liver fibrosis was assessed using ELF in prospective patients referred to the Royal Free Hospital Alcohol Specialist Nurse (November 2018–December 2019). Known cases of liver disease were excluded. Patient demographics, blood tests, imaging data and alcohol histories recorded. Advanced fibrosis was categorised as ELF ≥ 10.5. Results The study included 99 patients (69% male, mean age 53.1 ± 14.4) with median alcohol intake 140 units/week (IQR 80.9–280), and a mean duration of harmful drinking of 15 years (IQR 10–27.5). The commonest reason for admission was symptomatic alcohol withdrawal (36%). The median ELF score was 9.62, range 6.87–13.78. An ELF score ≥ 10.5 was recorded in 28/99 (29%) patients, of whom 28.6% had normal liver tests. Within previous 5-years, 76% had attended A&E without assessment of liver disease. The ELF score was not associated with recent alcohol intake (p = 0.081), or inflammation (p = 0.574). Conclusion Over a quarter of patients with AUD had previously undetected advanced liver fibrosis assessed by ELF testing. ELF was not associated with liver inflammation or recent alcohol intake. The majority had recent missed opportunities for investigating liver disease. We recommend clinicians use non-invasive tests to assess liver fibrosis in patients admitted to hospital with AUD.

Human diversity is one of the main pitfalls in the development of robust worldwide biomarkers in oncology. Epigenetic variability across human populations is associated with different genetic backgrounds, as well as variable lifestyles and environmental exposures, each of which should be investigated. To identify potential non‐invasive biomarkers of sporadic breast cancer in the Uruguayan population, we studied genome‐wide DNA methylation using Illumina methylation arrays in leukocytes of 22 women with sporadic breast cancer and 10 healthy women in a case–control study. We described a panel of 38 differentially methylated CpG positions that was able to cluster breast cancer patients (BCP) and controls, and that also recapitulated methylation differences in 12 primary breast tumors and their matched normal breast tissue. Moving forward, we simplified the detection method to improve its applicability in a clinical setting and used an independent well‐characterized cohort of 80 leukocyte DNA samples from BCP and 80 healthy controls to validate methylation results at specific cancer‐related genes. Our investigations identified methylation at CYFIP1 as a novel epigenetic biomarker candidate for sporadic breast cancer in the Uruguayan population. These results provide a proof‐of‐concept for the design of larger studies aimed at validating biomarker panels for the Latin American population.

Introduction This study aimed to reveal the utility of age-platelet (AP) index and aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR), which are non-invasive markers, in patients with chronic Hepatitis C virus (HCV) infection in prediction of fibrosis and evaluate whether viral markers could be used for that purpose or not. Methods A total of treatment-naïve 49 patients with chronic HCV who underwent liver biopsy were included in this retrospective study. Anti-HCV S/CO and HCV-RNA viral load (copy/ml) values measured simultaneously with biopsy were determined. AP index and AAR score were calculated and compared. Results Staging of liver biopsy samples of 49 HCV patients was assessed. Comparable diagnostic accuracies of AP index and AAR in prediction of significant fibrosis (F≥2) were showed with ROC curve analysis. The areas under the ROC (AUROCs) were 0.713 and 0.506 respectively. Diagnostic accuracy of API in prediction of significant fibrosis was superior to that of AAR (p=0.03). AUROC of HCV-RNA viral load in prediction of F≥2 was 0.531. Anti-HCV S/CO value (AUROC=0.464) was not found as a suitable marker in prediction of fibrosis. Conclusions AP index, AAR score and HCV viral load among non-invasive markers assessed in this study were useful in predicting significant fibrosis. Especially API was the most useful test in predicting significant fibrosis. AP index can be preferred in patients with near normal ALT values.

The pulmonary circulation and the right ventricle play a pivotal role in the global hemodynamics of human beings, so much so that their close interaction is encapsulated in the concept of a "morpho-functional unit". In this review we aim to pinpoint the strengths and weaknesses of various noninvasive established techniques. The goal is to detect early morphologic and/or functional changes in the pulmonary circulation and right ventricular unit, which is crucial for tailoring treatments and prognostic assessments. The scope of this review includes resting and stress echocardiography, cardiopulmonary exercise testing, computed tomography, and cardiac magnetic resonance in characterizing the pulmonary circulation-right ventricular unit both morphologically and functionally., Competing Interests: Disclosure The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: In patients with non‐alcoholic fatty liver disease (NAFLD), the impact of the severity of steatosis and inflammatory activity on the accuracy of liver stiffness measurement (LSM) by transient elastography (TE) and by two‐dimensional shear wave elastography (2D‐SWE) in staging liver fibrosis is still debated and scarce. We aimed to focus on this aspect. Methods: We prospectively studied 104 patients requiring biopsy for the assessment of NAFLD. We used ordinary least squares regression to test for differences in the association between fibrosis and LSM by TE and 2D‐SWE when other factors (steatosis and inflammatory activity) are considered. Results: Among 104 patients, 102 had reliable LSM by TE, and 88 had valid LSM by 2D‐SWE. The association between fibrosis based on histology and LSM was significantly stronger when 2D‐SWE assessed LSM compared to TE (Spearman's correlation coefficient of.71; P <.001 vs.51, P <.001; Z = 2.21, P =.027). Inflammatory activity was an independent predictor of LSM by TE but not of LSM by 2D‐SWE. After controlling for fibrosis, age, sex and body mass index, the inflammatory activity and the interaction between inflammatory activity and fibrosis independently explained 11% and 13% of variance in LSM by TE respectively. Steatosis did not affect the association of fibrosis and LSM by either method. Conclusion: Inflammatory activity on histology significantly affects LSM by TE, but not LSM by 2D‐SWE in NAFLD. LSM by 2D‐SWE reflects liver fibrosis more accurately than LSM by TE. Furthermore, the severity of steatosis on histology did not influence the association of LSM and fibrosis by either elastography method. [ABSTRACT FROM AUTHOR]

Abstract Background The diagnostic accuracy of CT-derived fractional flow reserve (CT-FFR) in clinical application has been well validated. This advanced technology focus on evaluating anatomical stenosis and functional ischemia simultaneously. However, the effect of CT-FFR on the management of decision making has not been fully evaluated in randomized controlled design. Method/design TARGET study is a pragmatic, multicenter, prospective, open-label, and randomized controlled trial evaluating the effect of a CCTA/CT-FFR strategy (group A) versus usual care (group B) on intermediate-to-high risk patients with suspected CAD who undergo clinically indicated diagnostic evaluation. A total sample size of 1216 subjects will be enrolled and followed up for 12 months. This study will be performed in 6 Chinese hospitals, and the primary endpoint is the planned ICA without significant obstructive CAD within 90 days. The secondary endpoints include MACE, quality of life, medical expenditure, and cumulative radiation exposure during 1-year follow-up. Discussion The study will provide information to patients, health care providers, and other stakeholders in China about which strategy could be more effective in the management of intermediate-to-high risk patients with suspect CAD. Trial registration ClinicalTrials.gov NCT03901326 . Registered on 3 April 2019.

Background: In an earlier monocentric study, we have developed a novel non-invasive test system for the prediction of renal allograft rejection, based on the detection of a specific urine metabolite constellation. To further validate our results in a large real-world patient cohort, we designed a multicentric observational prospective study (PARASOL) including six independent European transplant centers. This article describes the study protocol and characteristics of recruited better patients as subjects.Methods: Within the PARASOL study, urine samples were taken from renal transplant recipients when kidney biopsies were performed. According to the Banff classification, urine samples were assigned to a case group (renal allograft rejection), a control group (normal renal histology), or an additional group (kidney damage other than rejection).Results: Between June 2017 and March 2020, 972 transplant recipients were included in the trial (1,230 urine samples and matched biopsies, respectively). Overall, 237 samples (19.3%) were assigned to the case group, 541 (44.0%) to the control group, and 452 (36.7%) samples to the additional group. About 65.9% were obtained from male patients, the mean age of transplant recipients participating in the study was 53.7 ± 13.8 years. The most frequently used immunosuppressive drugs were tacrolimus (92.8%), mycophenolate mofetil (88.0%), and steroids (79.3%). Antihypertensives and antidiabetics were used in 88.0 and 27.4% of the patients, respectively. Approximately 20.9% of patients showed the presence of circulating donor-specific anti-HLA IgG antibodies at time of biopsy. Most of the samples (51.1%) were collected within the first 6 months after transplantation, 48.0% were protocol biopsies, followed by event-driven (43.6%), and follow-up biopsies (8.5%). Over time the proportion of biopsies classified into the categories Banff 4 (T-cell-mediated rejection [TCMR]) and Banff 1 (normal tissue) decreased whereas Banff 2 (antibody-mediated rejection [ABMR]) and Banff 5I (mild interstitial fibrosis and tubular atrophy) increased to 84.2 and 74.5%, respectively, after 4 years post transplantation. Patients with rejection showed worse kidney function than patients without rejection.Conclusion: The clinical characteristics of subjects recruited indicate a patient cohort typical for routine renal transplantation all over Europe. A typical shift from T-cellular early rejections episodes to later antibody mediated allograft damage over time after renal transplantation further strengthens the usefulness of our cohort for the evaluation of novel biomarkers for allograft damage.

Background & Aims: Elevated liver stiffness has been associated with atrial fibrillation (AFib) in the general population. The mechanism underlying this association is unclear., Methods: Participants were recruited from the general population and prospectively enrolled with follow-up for 5 years. The fibrosis-4 (FIB-4) index was used as a surrogate marker for liver fibrosis. Proteomics analysis was performed using the 92-target Olink inflammation panel. Validation was performed using the NAFLD fibrosis score (NFS), aspartate aminotransferase to platelet index (APRI), and repeat confirmation proteomics., Results: A sample of 11,509 participants with a mean age of 54.0 ± 11.1 years, 51.3% women, and a median FIB-4 index of 0.85 (0.65/1.12), was used. The FIB-4 index was predictive for prevalent (FIB-4 index adjusted odds ratio (aOR) per SD: 1.100 with 95% CI 1.011-1.196; p  = 0.026), but not incident AFib (log[FIB-4 index]) adjusted hazard ratio: 1.125 with 95% CI 0.943-1.342, p  = 0.19). Elastic net regularized regression identified CCL20, DNER, and CXCL10 for prevalent AFib, and AXIN1, CXCL10, and Flt3L for the log(FIB-4 index) (per SD) as most important in common regulated proteins. The relationship between the FIB-4 index, the identified proteins, and AFib was relevant and reproduced at the 5-year follow-up for CXCL10 after adjusting for confounders (log[FIB-4 index] per SD - CXCL10 [per SD] adjusted β 0.160 with 95% CI 0.127-0.194, p <0.0001; CXCL10 [per SD] - AFib aOR 1.455 with 95% CI 1.217-1.741, p <0.0001), reproduced using the NFS and APRI, and corresponding to increased serum levels., Conclusions: CXCL10 is linked to liver fibrosis, as determined by the FIB-4 index, and to prevalent AFib., Impact and Implications: How elevated liver stiffness relates to atrial fibrillation in the general population remains to be clarified. We hypothesized that systemic inflammation against a background of liver fibrosis produced from metabolic dysfunction-associated steatotic liver disease (MASLD), is involved in the pathophysiology of atrial fibrillation. Using large-scale targeted proteomics, we found that CXCL10 is related to both liver fibrosis, as defined by the fibrosis-4 index, and to atrial fibrillation. These results can aid evidence-based drug development for patients with atrial fibrillation and MASLD-related liver fibrosis., (© 2024 The Author(s).)

Ventricular tachycardia (VT) may lead to syncope and sudden cardiac death. Implantable loop recorders (ILR) are recommended in the clinical work-up of patients with unexplained syncope. Our aim was to evaluate if echocardiographic parameters assessed prior to ILR implantation in patients with unexplained syncope may aid in identifying individuals with an increased risk of VT. The present study included 288 ambulatory patients (mean age 58 ± 19 years, 51% women) with syncope (90%) and presyncope (10%) who had an ILR implanted in the diagnostic workup. All patients underwent an echocardiographic examination prior to device implantation (median 3 months [IQR 1 to 6 months]). We examined incident VT, defined as a first-time episode of VT (> 30 s) or non-sustained VT (< 30 s) detected by the ILR. During median follow-up of 2.9 years [IQR 1.3 to 3.5 years] of continuous rhythm monitoring, 36 patients (13%) were diagnosed with incident VT (n = 25 non-sustained VT, n = 11 sustained VT). In unadjusted Cox proportional hazards models, left ventricular (LV) mass index (HR: 1.04 per 1 g/m2 increase [1.00 to 1.08], P = 0.047), mean LV wall thickness (HR: 1.36 per 1 mm increase [1.08 to 1.71], P = 0.009), and global longitudinal strain (HR: 1.15 per 1% decrease [1.05 to 1.25], P = 0.002) were significantly associated with VT. After adjusting for age, sex, implantable loop recorder indication and known heart failure, the above-mentioned parameters remained significantly associated with incident VT. LV mass index, LV wall thickness, and GLS may aid in identifying patients with increased risk of incident VT among patients with syncope. Echocardiography may potentially help select patients who can benefit from ILR. [ABSTRACT FROM AUTHOR]

Background and Aim: Mortality of alcohol‐related liver disease (ArLD) is increasing, and liver fibrosis stage is the best mortality predictor. Non‐invasive tests (NITs) are increasingly used to detect fibrosis, but their value as prognostic tests in chronic liver disease, and in particular in ArLD, is less well recognized. We aimed to describe the prognostic performance of four widely used NITs (Fibrosis 4 test [FIB4], Enhanced Liver Fibrosis [ELF] test, FibroScan, and FibroTest) in ArLD. Methods: Applying systematic review methodology, we searched four databases from inception to May 2020. Inclusion/exclusion criteria were applied to search using Medical Subject Heading terms and keywords. The first and second reviewers independently screened results, extracted data, and performed risk‐of‐bias assessment using Quality in Prognosis Studies tool. Results: Searches produced 25 088 articles. After initial screening, 1020 articles were reviewed independently by both reviewers. Eleven articles remained after screening for eligibility: one on ELF, four on FibroScan, four on FIB4, one on FIB4 + FibroScan, and one on FibroTest + FIB4. Area under the receiver operating characteristic curves for outcome prediction ranged from 0.65 to 0.76 for FibroScan, 0.64 to 0.83 for FIB4, 0.69 to 0.79 for FibroTest, and 0.72 to 0.85 for ELF. Studies scored low–moderate risk of bias for most domains but high risk in confounding/statistical reporting domains. The results were heterogeneous for outcomes and reporting, making pooling of data unfeasible. Conclusions: This systematic review returned 11 papers, six of which were conference abstracts and one unpublished manuscript. While the heterogeneity of studies precluded direct comparisons of NITs, each NIT performed well in individual studies in predicting prognosis in ArLD (area under the receiver operating characteristic curves >0.7 in each NIT category) and may add value to prognostication in clinical practice. [ABSTRACT FROM AUTHOR]

AimsNon-alcoholic fatty liver disease (NAFLD) has a dynamic disease course, therefore repeated measurements of NAFLD status could have benefits rather than single one. The aim of this study was to investigate the effects of persistent NAFLD on the incidence of myocardial infarction (MI) and stroke and all-cause mortality by using repeated measurement of fatty liver index (FLI).MethodsAbout 3 million subjects who had undergone the health screening four times from 2009 until 2013 were included. NAFLD was defined as an FLI ≥60. FLI points were defined as the number of times participants meeting the criteria of NAFLD (0–4). Outcomes included all-cause mortality, MI, and stroke.ResultsThe higher the FLI points, the higher the risk of all-cause mortality, MI, and stroke (P for trend

Background and Aims: Alcohol use disorders (AUD) cause 7.2% of UK hospital admissions/year. Most are not managed by hepatologists and liver disease may be missed. We used the Enhanced Liver Fibrosis (ELF) test to investigate prevalence and associations of occult advanced liver fibrosis in AUD patients not known to have liver fibrosis.Methods: Liver fibrosis was assessed using ELF in prospective patients referred to the Royal Free Hospital Alcohol Specialist Nurse (November 2018-December 2019). Known cases of liver disease were excluded. Patient demographics, blood tests, imaging data and alcohol histories recorded. Advanced fibrosis was categorised as ELF ≥ 10.5.Results: The study included 99 patients (69% male, mean age 53.1 ± 14.4) with median alcohol intake 140 units/week (IQR 80.9-280), and a mean duration of harmful drinking of 15 years (IQR 10-27.5). The commonest reason for admission was symptomatic alcohol withdrawal (36%). The median ELF score was 9.62, range 6.87-13.78. An ELF score ≥ 10.5 was recorded in 28/99 (29%) patients, of whom 28.6% had normal liver tests. Within previous 5-years, 76% had attended A&E without assessment of liver disease. The ELF score was not associated with recent alcohol intake (p = 0.081), or inflammation (p = 0.574).Conclusion: Over a quarter of patients with AUD had previously undetected advanced liver fibrosis assessed by ELF testing. ELF was not associated with liver inflammation or recent alcohol intake. The majority had recent missed opportunities for investigating liver disease. We recommend clinicians use non-invasive tests to assess liver fibrosis in patients admitted to hospital with AUD. [ABSTRACT FROM AUTHOR]

Aims: Non-alcoholic fatty liver disease (NAFLD) has a dynamic disease course, therefore repeated measurements of NAFLD status could have benefits rather than single one. The aim of this study was to investigate the effects of persistent NAFLD on the incidence of myocardial infarction (MI) and stroke and all-cause mortality by using repeated measurement of fatty liver index (FLI). Methods: About 3 million subjects who had undergone the health screening four times from 2009 until 2013 were included. NAFLD was defined as an FLI ≥60. FLI points were defined as the number of times participants meeting the criteria of NAFLD (0–4). Outcomes included all-cause mortality, MI, and stroke. Results: The higher the FLI points, the higher the risk of all-cause mortality, MI, and stroke (P for trend <0.001, all). Subjects with four FLI points had a higher risk of all-cause mortality (aHR, 1.86; 95% CI, 1.75–1.98; P < 0.001), incidence of MI (aHR, 1.3; 95% CI, 1.21–1.40; P < 0.001), and stroke (aHR, 1.27; 95% CI, 1.19–1.37; P < 0.001) after adjustment for age, sex, smoking, alcohol consumption, income, hypertension, dyslipidemia, diabetes, body mass index, and physical activity. When the 1st and the last FLI were compared, the "incident NAFLD" group had a higher risk for death compared to the "no NAFLD" group (aHR, 1.46; 95% CI, 1.37–1.55), and the "regression of NAFLD" group had a decreased risk for death compared to the "persistent NAFLD" group (aHR, 0.83; 95% CI, 0.77–0.89). Conclusion: Repeated evaluations of NAFLD status based on FLI measurements could help physicians identify higher-risk groups in terms of mortality, MI, and stroke. The association between FLI worsening or improvement and outcomes also suggests clinical benefits of the prevention and treatment of NAFLD. [ABSTRACT FROM AUTHOR]

Human diversity is one of the main pitfalls in the development of robust worldwide biomarkers in oncology. Epigenetic variability across human populations is associated with different genetic backgrounds, as well as variable lifestyles and environmental exposures, each of which should be investigated. To identify potential non‐invasive biomarkers of sporadic breast cancer in the Uruguayan population, we studied genome‐wide DNA methylation using Illumina methylation arrays in leukocytes of 22 women with sporadic breast cancer and 10 healthy women in a case–control study. We described a panel of 38 differentially methylated CpG positions that was able to cluster breast cancer patients (BCP) and controls, and that also recapitulated methylation differences in 12 primary breast tumors and their matched normal breast tissue. Moving forward, we simplified the detection method to improve its applicability in a clinical setting and used an independent well‐characterized cohort of 80 leukocyte DNA samples from BCP and 80 healthy controls to validate methylation results at specific cancer‐related genes. Our investigations identified methylation at CYFIP1 as a novel epigenetic biomarker candidate for sporadic breast cancer in the Uruguayan population. These results provide a proof‐of‐concept for the design of larger studies aimed at validating biomarker panels for the Latin American population. [ABSTRACT FROM AUTHOR]