Fibroblast growth factor 21 is a hepatokine involved in MASLD progression.

AIM: We aimed to assess the role of FGF21 in metabolic dysfunction-associated steatotic liver disease (MASLD) at a multi-scale level. METHODS: We used human MASLD pathology samples for FGF21 gene expression analyses (qPCR and RNAseq), serum to measure circulating FGF21 levels and DNA for genotyping the FGF21 rs838133 variant in both estimation and validation cohorts. A hepatocyte-derived cell line was exposed to free fatty acids at different timepoints. Finally, C57BL/6J mice were fed a high-fat and choline-deficient diet (CDA-HFD) for 16 weeks to assess hepatic FGF21 protein expression and FGF21 levels by ELISA. RESULTS: A significant upregulation in FGF21 mRNA expression was observed in the liver analysed by both qPCR (fold change 5.32 ± 5.25 vs. 0.59 ± 0.66; p = 0.017) and RNA-Seq (3.5 fold; FDR: 0.006; p < 0.0001) in MASLD patients vs. controls. Circulating levels of FGF21 were increased in patients with steatohepatitis vs. bland steatosis (386.6 ± 328.9 vs. 297.9 ± 231.5 pg/mL; p = 0.009). Besides, sex, age, A-allele from FGF21, GG genotype from PNPLA3, ALT, type 2 diabetes mellitus and BMI were independently associated with MASH and significant fibrosis in both estimation and validation cohorts. In vitro exposure of Huh7.5 cells to high concentrations of free fatty acids (FFAs) resulted in overexpression of FGF21 (p < 0.001). Finally, Circulating FGF21 levels and hepatic FGF21 expression were found to be significantly increased (p < 0.001) in animals under CDA-HFD. CONCLUSIONS: Hepatic and circulating FGF21 expression was increased in MASH patients, in Huh7.5 cells under FFAs and in CDA-HFD animals. The A-allele from the rs838133 variant was also associated with an increased risk of steatohepatitis and significant and advanced fibrosis in MASLD patients.

Hepatic venous pressure gradient predicts risk of hepatic decompensation and liver-related mortality in patients with MASLD.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of advanced chronic liver disease (ACLD). Portal hypertension drives hepatic decompensation and is best diagnosed by hepatic venous pressure gradient (HVPG) measurement. Here we investigate the prognostic value of HVPG in compensated (cACLD) MASLD. METHODS: This European multicentre study included MASLD-cACLD patients characterised by HVPG at baseline. Hepatic decompensation (variceal bleeding/ ascites/hepatic encephalopathy) and liver-related mortality were considered the primary events of interest. RESULTS: 340 MASLD-cACLD patients [56.2% men; age: 62 (55-68) years; MELD: 8 (7-9); 71.2% diabetes] were included. Clinically significant portal hypertension (CSPH; i.e., HVPG ≥10 mmHg) was found in 209 patients (61.5%). During a median follow-up of 41.5 (27.5-65.8) months, 65 patients developed hepatic decompensation with a cumulative incidence of 10.0% after 2 years (2Y) and 30.7% after 5 years (5Y) in MASLD-cACLD with CSPH, compared to 2.4% after 2Y and 9.4% after 5Y in patients without CSPH. Variceal bleeding did not occur without CSPH. CSPH (subdistribution hazard ratio, SHR:5.13; p<0.001) was associated with an increased decompensation risk and a higher HVPG remained an independent risk factor in the multivariable model (aSHR per mmHg:1.12; p<0.001). Liver-related mortality occurred in 37 patients with a cumulative incidence of 3.3% after 2Y and 21.4% after 5Y in CSPH. Without CSPH, the incidence after 5Y was 0.8%. Accordingly, a higher HVPG was also independently associated with a higher risk of liver-related death (aSHR per mmHg:1.20; p<0.001). CONCLUSION: HVPG measurement is of high prognostic value in MASLD-cACLD. While MASLD-cACLD patients without CSPH show a very low short-term risk of decompensation and liver-related mortality is rare, the presence of CSPH substantially increases both risks. IMPACT AND IMPLICATIONS: While the incidence of compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide, insights into the impact of clinically significant portal hypertension (CSPH) on the risk of liver-related events in MASLD-cACLD remain limited. Based on the findings of this European multicentre study including 340 MASLD-cACLD, we could show that increasing HVPG values and the presence of CSPH in particular were associated with a significantly higher risk of first hepatic decompensation and liver-related mortality. In contrast, the short-term incidence of decompensation in MASLD-cACLD patients without CSPH was low and the risk of liver-mortality remained negligible. Thus, HVPG measurements can provide important prognostic information for individualised risk-stratification in MASLD-cACLD and may help facilitate the study of novel and promising treatment possibilities for MASLD.

Metabolic-associated fatty liver voxel-based quantification on CT images using a contrast adapted automatic tool.

BACKGROUND & AIMS: Metabolic-dysfunction associated fatty liver disease (MAFLD) is highly prevalent and can lead to liver complications and comorbidities, with non-invasive tests such as vibration-controlled transient elastography (VCTE) and invasive liver biopsies being used for diagnosis The aim of the present study was to develop a new fully automatized method for quantifying the percentage of fat in the liver based on a voxel analysis on computed tomography (CT) images to solve previously unconcluded diagnostic deficiencies either in contrast (CE) or non-contrast enhanced (NCE) assessments. METHODS: Liver and spleen were segmented using nn-UNet on CE- and NCE-CT images. Radiodensity values were obtained for both organs for defining the key benchmarks for fatty liver assessment: liver mean, liver-to-spleen ratio, liver-spleen difference, and their average. VCTE was used for validation. A classification task method was developed for detection of suitable patients to fulfill maximum reproducibility across cohorts and highlight subjects with other potential radiodensity-related diseases. RESULTS: Best accuracy was attained using the average of all proposed benchmarks being the liver-to-spleen ratio highly useful for CE and the liver-to-spleen difference for NCE. The proposed whole-organ automatic segmentation displayed superior potential when compared to the typically used manual region-of-interest drawing as it allows to accurately obtain the percent of fat in liver, among other improvements. Atypical patients were successfully stratified through a function based on biochemical data. CONCLUSIONS: The developed method tackles the current drawbacks including biopsy invasiveness, and CT-related weaknesses such as lack of automaticity, dependency on contrast agent, no quantification of the percentage of fat in liver, and limited information on region-to-organ affectation. We propose this tool as an alternative for individualized MAFLD evaluation by an early detection of abnormal CT patterns based in radiodensity whilst abording detection of non-suitable patients to avoid unnecessary exposure to CT radiation. Furthermore, this work presents a surrogate aid for assessing fatty liver at a primary assessment of MAFLD using elastography data.

Phenotypes of Metabolic Dysfunction-Associated Steatotic Liver Disease-Associated Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) typically develops as a consequence of liver cirrhosis, but HCC epidemiology has evolved drastically in recent years. Metabolic dysfunction-associated steatotic liver disease (MASLD), including metabolic dysfunction-associated steatohepatitis, has emerged as the most common chronic liver disease worldwide and a leading cause of HCC. A substantial proportion of MASLD-associated HCC (MASLD-HCC) also can develop in patients without cirrhosis. The specific pathways that trigger carcinogenesis in this context are not elucidated completely, and recommendations for HCC surveillance in MASLD patients are challenging. In the era of precision medicine, it is critical to understand the processes that define the profiles of patients at increased risk of HCC in the MASLD setting, including cardiometabolic risk factors and the molecular targets that could be tackled effectively. Ideally, defining categories that encompass key pathophysiological features, associated with tailored diagnostic and treatment strategies, should facilitate the identification of specific MASLD-HCC phenotypes. In this review, we discuss MASLD-HCC, including its epidemiology and health care burden, the mechanistic data promoting MASLD, metabolic dysfunction-associated steatohepatitis, and MASLD-HCC. Its natural history, prognosis, and treatment are addressed specifically, as the role of metabolic phenotypes of MASLD-HCC as a potential strategy for risk stratification. The challenges in identifying high-risk patients and screening strategies also are discussed, as well as the potential approaches for MASLD-HCC prevention and treatment.

Extraction of 5-Hydroxymethylfurfural and Furfural in Aqueous Biphasic Systems: A COSMO-RS Guided Approach to Greener Solvent Selection.

5-Hydroxymethylfurfural (HMF) and furfural (Fur) are promising biobased platform chemicals, derived from the dehydration of carbohydrate feedstocks, normally conducted in an aqueous phase. Plagued by side-reactions in such phase, such as the rehydration to levulinic acid (LA) and formic acid (FA) or self-condensation to humins, HMF and Fur necessitates diversification from monophasic aqueous reaction systems toward biphasic systems to mitigate undesired side-reactions. Here, a methodology based on the COnductor-like Screening MOdel for Real Solvents (COSMO-RS) method was used to screen solvent candidates based on the predicted partition coefficients (Ki). Hansen solubility parameters in conjunction with excess thermodynamic quantities determined by COSMO-RS were employed to assess solvent compatibility. Experimental validation of the COSMO-RS values highlighted only minor deviations from the predictions with root-mean-square-error (RMSE) values of HMF and Fur at 0.76 and 5.32, respectively, at 298 K. The combined effort suggested cyclohexanone, isophorone, and methyl isobutyl ketone (MIBK) as the best candidates. Finally, extraction solvent reuse demonstrated cyclohexanone suitability for HMF extraction with KHMF of 3.66 and MIBK for Fur with KFur 7.80 with consistent partitioning across four total runs. Both solvents are classified as recommended by the CHEM21 solvent selection guide, hence adding to the sustainability of the process.

Introducing Design Strategies to Preserve N-Heterocycles Throughout the On-Surface Synthesis of Graphene Nanostructures.

Despite the impressive advances in the synthesis of atomically precise graphene nanostructures witnessed during the last decade, advancing in compositional complexity faces major challenges. The concept of introducing the desired functional groups or dopants in the molecular precursor often fails due to their lack of stability during the reaction path. Here, a study on the stability of different pyridine and pyrimidine moieties during the on-surface synthesis of graphene nanoribbons on Au(111) is presented. Combining bond-resolved scanning tunneling microscopy with X-ray photoelectron spectroscopy, the thermal evolution of the nitrogen dopants throughout the whole reaction sequence is tracked. A comparative experimental and ab initio electronic characterization confirms the presence of dopants in the final structures, revealing also that the pyridinic nitrogen leads to a significant band downshift. The results demonstrate that, by using synthetic strategies to lower the reaction temperatures, one can preserve specific N-heterocycles throughout all the reaction steps of the synthesis of graphene nanoribbons and beyond the interibbon coupling reaction that leads to nanoporous graphene.

Prevalence and Risk Factors of MASLD and Liver Fibrosis amongst the Penitentiary Population in Catalonia: The PRISONAFLD Study.

BACKGROUND AND AIMS: The prevalence of chronic non-communicable diseases, particularly metabolic syndrome (MetS), has increased among the prison population. Nevertheless, we have limited data on metabolic dysfunction-associated steatotic liver disease (MASLD), the hepatic manifestation of this syndrome. We aimed to investigate the prevalence and risk factors of MASLD and MASLD-associated liver fibrosis in the penitentiary population in Catalonia, Spain. METHOD: A cross-sectional observational study involving eight penitentiary centers. Participants had at least one metabolic disorder and were at a closed-regimen penitentiary. Individuals with concomitant liver diseases and/or alcohol risk consumption were excluded. Significant fibrosis and MASLD were defined as liver stiffness ≥8 kPa and a controlled attenuation parameter ≥275 dB/m by vibration-controlled transient elastography (VCTE), respectively. After exclusions, metabolic inmates with VCTE were analyzed. Logistic regression analysis was performed to identify predictors of MASLD and MASLD-associated significant fibrosis. RESULTS: Out of the 4338 inmates studied, 1290 (29.7%) had metabolic disorders, and 646 (14.9%) underwent VCTE. The mean age was 48.0 years (SD 12.1), and 89.5% were male. MASLD prevalence was 33.9%. Significant fibrosis and MASLD-associated significant fibrosis were found in 16.4% and 9.4% of inmates, respectively. In the multivariate analysis, T2D, waist circumference, MetS, and higher ALT values were identified as independent risk factors for MASLD and MASLD-associated significant fibrosis amongst the prison population. CONCLUSIONS: Metabolic disorders including MASLD are highly prevalent among inmates. The prevalence of significant fibrosis seems notably higher than that of the general population, underscoring the need for targeted screening programs and therapeutic interventions in the incarcerated population.

Accuracy of a sequential algorithm based on FIB-4 and ELF to identify high-risk advanced liver fibrosis at the primary care level.

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, and liver fibrosis is the strongest predictor of morbimortality. We aimed to assess the performance of a sequential algorithm encompassing the Fibrosis 4 (FIB-4) and Enhanced Liver Fibrosis (ELF) scores for identifying patients at risk of advanced fibrosis. This cross-sectional study included one hospital-based cohort with biopsy-proven NAFLD (n = 140) and two primary care cohorts from different clinical settings: Type 2 Diabetes (T2D) follow-up (n = 141) and chronic liver disease (CLD) initial study (n = 138). Logistic regression analysis was performed to assess liver fibrosis diagnosis models based on FIB-4 and ELF biomarkers. The sequential algorithm retrieved the following accuracy parameters in predicting stages F3-4 in the biopsy-confirmed cohort: sensitivity (85%), specificity (73%), negative predictive value (79%) and positive predictive value (81%). In both T2D and CLD cohorts, a total of 28% of patients were classified as stages F3-4. Furthermore, of all F3-4 classified patients in the T2D cohort, 80% had a diagnosis of liver disease and 44% were referred to secondary care. Likewise, of all F3-4 classified patients in the CLD cohort, 71% had a diagnosis of liver disease and 44% were referred to secondary care. These results suggest the potential utility of this algorithm as a liver fibrosis stratifying tool in primary care, where updating referral protocols to detect high-risk F3-4 is needed. FIB-4 and ELF sequential measurement is an efficient strategy to prioritize patients with high risk of F3-4 in populations with metabolic risk factors.

Prediction of clinical events by liver stiffness and chronic kidney disease by NAFLD in patients with type-2 diabetes / Predicción de eventos clínicos por elasticidad hepática y enfermedad renal crónica por EHMet en pacientes con diabetes tipo 2

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is associated with poorer glycemic control and a higher risk of type-2 diabetes (T2D) complications, extrahepatic and cardiovascular disease (CVD). Our study aim was to evaluate the association between NAFLD, T2D complications, and the development of overall clinical events (OCE) (CV, liver-related, and mortality) in patients with T2D. Methods: Prospective single-center study comprising T2D subjects with no history of CVD and non-T2D matched controls. Patients were selected from the Outpatient Diabetes Clinic of Vall d’Hebron Hospital and related primary care centers. Results: 186 diabetics and 57 controls were included. Amongst T2D, 124/186 subjects had NAFLD (66.6%). T2D-NAFLD subjects showed a heavier metabolic burden and higher median liver stiffness (5.6kPa [4.5–7.3] vs 4.8 [4.2–5.8]; p=0.004) compared to non-NAFLD diabetics. During a median follow-up of 5.6 years, 33 (17.7%) T2D patients developed OCE vs 4 (7.0%) controls (p=0.049). No differences were found for OCE between NAFLD and non-NAFLD diabetics (16.9% vs 19.4%; p=0.68). CV was the most reported outcome and only one liver event occurred. NAFLD diabetics showed more often chronic kidney disease (CKD), whereas T2D complications and subclinical CVD rates were similar. A higher liver stiffness, older age, and male gender were independently associated with OCE amongst the entire T2D population and NAFLD diabetics. Conclusions: NAFLD and liver stiffness were associated with CKD and clinical outcomes in diabetics, respectively. A hepatic evaluation is recommended to identify high-risk T2D patients that would benefit from early referral to specialized care. (AU)

Antecedentes y objetivos: La esteatosis hepática metabólica (EHMet) se asocia con un peor control glucémico y un mayor riesgo de complicaciones de la diabetes tipo 2 (DM2), enfermedad extrahepática y cardiovascular (CV). El objetivo fue evaluar la asociación entre EHMet, complicaciones microvasculares y el desarrollo de eventos clínicos globales (ECG) (CV, hepáticos y mortalidad) en diabéticos. Métodos: Estudio unicéntrico prospectivo que incluye diabéticos sin historia de CV y controles sin DM2. Se seleccionaron pacientes de la consulta de Diabetes del Hospital Vall d’Hebron y centros de atención primaria asociados. Resultados: Se incluyeron 186 diabéticos y 57 controles. Entre los diabéticos, 124/186 presentaron EHMet (66,6%). Los pacientes DM2 con EHMet presentaron mayor carga metabólica y una elasticidad hepática superior (5,6kPa [4,5-7,3] vs. 4,8 [4,2-5,8]; p=0,004) a los diabéticos sin EHMet. Durante una mediana de seguimiento de 5,6 años, 33 (17,7%) diabéticos desarrollaron ECG vs. 4 (7,0%) controles (p=0,049). No hubo diferencias en ECG entre diabéticos con y sin EHMet (16,9% vs. 19,4%; p=0,68). El evento más reportado fue CV y solamente se produjo un evento hepático. La enfermedad renal crónica (ERC) fue más frecuente en diabéticos con EHMet, mientras que los ratios de complicaciones microvasculares y enfermedad CV silente fueron similares. El género masculino, una mayor edad y elasticidad hepática se asociaron de forma independiente a ECG para el total de diabéticos y para aquellos con EHMet. Conclusiones: La EHMet y la elasticidad hepática se asociaron a ERC y eventos clínicos en diabéticos. Se recomienda una evaluación hepática para identificar pacientes diabéticos de riesgo que se beneficiarían de una derivación precoz al especialista. (AU)

Point-of-Care Noninvasive Prediction of Liver-Related Events in Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Individual risk prediction of liver-related events (LRE) is needed for clinical assessment of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) patients. We aimed to provide point-of-care validated liver stiffness measurement (LSM)-based risk prediction models for the development of LRE in patients with NAFLD, focusing on selecting patients for clinical trials at risk of clinical events. METHODS: Two large multicenter cohorts were evaluated, 2638 NAFLD patients covering all LSM values as the derivation cohort and 679 more advanced patients as the validation cohort. We used Cox regression to develop and validate risk prediction models based on LSM alone, and the ANTICIPATE and ANTICIPATE-NASH models for clinically significant portal hypertension. The main outcome of the study was the rate of LRE in the first 3 years after initial assessment. RESULTS: The 3 predictive models had similar performance in the derivation cohort with a very high discriminative value (c-statistic, 0.87-0.91). In the validation cohort, the LSM-LRE alone model had a significant inferior discrimination (c-statistic, 0.75) compared with the other 2 models, whereas the ANTICIPATE-NASH-LRE model (0.81) was significantly better than the ANTICIPATE-LRE model (0.79). In addition, the ANTICIPATE-NASH-LRE model presented very good calibration in the validation cohort (integrated calibration index, 0.016), and was better than the ANTICIPATE-LRE model. CONCLUSIONS: The ANTICIPATE-LRE models, and especially the ANTICIPATE-NASH-LRE model, could be valuable validated clinical tools to individually assess the risk of LRE at 3 years in patients with NAFLD/NASH.

Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis.

Progressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS-/-) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS-/- mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS-/- livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.

Morbilidad metabólica en la población penitenciaria de Cataluña / Metabolic morbidity in the prison population of Catalonia, Spain

Objetivo: Investigar la prevalencia de la morbilidad metabólica (MM) en población penitenciaria. Diseño: Estudio observacional, transversal y multicéntrico. Emplazamiento: Los 9 centros penitenciarios de Cataluña. Participantes: Reclusos que no están en «régimen abierto» y, por consiguiente, dependen sanitariamente de los equipos de atención primaria penitenciaria (EAPP). Intervenciones: Se consideraron internos con MM los que presentaban al menos un componente del síndrome metabólico: obesidad, hipertensión arterial, diabetes tipo2 y/o dislipidemia. Se estudiaron variables antropométricas, antecedentes clínicos y parámetros analíticos asociados a la MM. Fuente de información: Sistema de Información de los Servicios de Atención Primaria de Cataluña (SISAP). Mediciones principales: Cálculo de prevalencia de la MM, total y por categorías. Para estudiar variables asociadas se realizó un análisis de regresión logística multivariante, calculándose la odds ratio ajustada (ORA) con intervalo de confianza del 95%. Resultados: Un total de 4.338 internos estudiados: el 93,9% hombres, edad media 38,4años, 51,7% de la Unión Europea y 6,7% (8,2% de los analizados) infectados por VIH. Presentaron más MM los de más edad y las personas infectadas por VIH y menos los europeos de países no miembros de la Unión Europea, los del Magreb y los del África subsahariana. Conclusiones: La prevalencia de MM es alta en presos, aun siendo una población joven, especialmente en reclusos de mayor edad y en infectados por VIH. La prevalencia varía mucho según el origen geográfico. Es conveniente que la MM sea detectada precozmente para evitar complicaciones. La prevención, la detección y el manejo terapéutico deben ser actividades prioritarias de la atención primaria penitenciaria.(AU)

Objective: To investigate the prevalence of metabolic morbidity (MM) amongst prison inmates. Design: Multicentric, cross-sectional observational study. Setting: All (nine) prisons in Catalonia. Participants: Convicted inmates that are not in an «open regime», whose healthcare relies on the Prison Primary Care Teams. Interventions: MM was defined as the presence of at least one component of the metabolic syndrome, i.e., obesity, arterial hypertension, type2 diabetes, and/or dyslipidemia. The variables collected included anthropometric measurements, medical history and laboratory values related to MM. The source of information was the Catalan Primary Healthcare Services Information System (SISAP). Main measurements: The prevalence of MM, overall and by several participant subcategories, was calculated. To investigate the risk factors associated to a higher prevalence of MM, a multivariable logistic regression analysis was carried out and expressed as adjusted odds ratios and 95% confidence intervals. Results: 4338 inmates were studied, of whom 93.9% were male. Mean age was 38.4years, 51.7% were born in European Union countries, and 6.7% were infected by HIV. The variables associated with a significantly increased risk of presenting MM were older age and HIV infection, whereas certain geographical origins (i.e., non-UE European countries, Maghreb and Sub-Saharan Africa) were associated with lower risk of MM. Conclusions: In spite of being an overall young population, prison inmates present high rates of MM. Older age, HIV infection and geographic origin appear as the most strongly associated factors with MM in the prison population. MM should be detected early in order to prevent complications. Prevention, screening and treatment of MM ought to be considered a priority in the clinical routine of prison healthcare professionals.(AU)

Ultratrace PFAS Detection Using Amplifying Fluorescent Polymers.

Per- and poly(fluoroalkyl) substances (PFAS) are environmentally persistent pollutants that are of growing concern due to their detrimental effects at ultratrace concentrations (ng·L-1) in human and environmental health. Suitable technologies for on-site ultratrace detection of PFAS do not exist and current methods require complex and specialized equipment, making the monitoring of PFAS in distributed water infrastructures extremely challenging. Herein, we describe amplifying fluorescent polymers (AFPs) that can selectively detect perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) at concentrations of ng·L-1. The AFPs are highly fluorinated and have poly(p-phenylene ethynylene) and polyfluorene backbones bearing pyridine-based selectors that react with acidic PFAS via a proton-transfer reaction. The fluorinated regions within the polymers partition PFAS into polymers, whereas the protonated pyridine units create lower-energy traps for the excitons, and emission from these pyridinium sites results in red-shifting of the fluorescence spectra. The AFPs are evaluated in thin-film and nanoparticle forms and can selectively detect PFAS concentrations of ∼1 ppb and ∼100 ppt, respectively. Both polymer films and nanoparticles are not affected by the type of water, and similar responses to PFAS were found in milliQ water, DI water, and well water. These results demonstrate a promising sensing approach for on-site detection of aqueous PFAS in the ng·L-1 range.

[Metabolic morbidity in the prison population of Catalonia, Spain]. / Morbilidad metabólica en la población penitenciaria de Cataluña.

OBJECTIVE: To investigate the prevalence of metabolic morbidity (MM) amongst prison inmates. DESIGN: Multicentric, cross-sectional observational study. SETTING: All (nine) prisons in Catalonia. PARTICIPANTS: Convicted inmates that are not in an «open regime¼, whose healthcare relies on the Prison Primary Care Teams. INTERVENTIONS: MM was defined as the presence of at least one component of the metabolic syndrome, i.e., obesity, arterial hypertension, type2 diabetes, and/or dyslipidemia. The variables collected included anthropometric measurements, medical history and laboratory values related to MM. The source of information was the Catalan Primary Healthcare Services Information System (SISAP). MAIN MEASUREMENTS: The prevalence of MM, overall and by several participant subcategories, was calculated. To investigate the risk factors associated to a higher prevalence of MM, a multivariable logistic regression analysis was carried out and expressed as adjusted odds ratios and 95% confidence intervals. RESULTS: 4338 inmates were studied, of whom 93.9% were male. Mean age was 38.4years, 51.7% were born in European Union countries, and 6.7% were infected by HIV. The variables associated with a significantly increased risk of presenting MM were older age and HIV infection, whereas certain geographical origins (i.e., non-UE European countries, Maghreb and Sub-Saharan Africa) were associated with lower risk of MM. CONCLUSIONS: In spite of being an overall young population, prison inmates present high rates of MM. Older age, HIV infection and geographic origin appear as the most strongly associated factors with MM in the prison population. MM should be detected early in order to prevent complications. Prevention, screening and treatment of MM ought to be considered a priority in the clinical routine of prison healthcare professionals.

Uncovering the NAFLD burden in people living with HIV from high- and middle-income nations: a meta-analysis with a data gap from Subsaharan Africa.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) has become a significant concern among people living with HIV (PLHIV), albeit its burden remains unclear. The primary objective of this systematic review (SR) and meta-analysis (MA) was to estimate the prevalence of NAFLD and significant fibrosis in PLHIV. The secondary objective was to determine the risk factors for NAFLD among PLHIV. METHODS: We searched MEDLINE and Scopus from inception to 30 December 2022 for peer-reviewed studies that included PLHIV and reported the prevalence of NAFLD. MA of proportions was used to estimate the pooled prevalence of NAFLD and significant fibrosis. MA of pre-calculated effect estimates examined risk factors for NAFLD in PLHIV. RESULTS: We included 24 articles published between 2009 and 2022, encompassing 6326 PLHIV. The pooled prevalence of NAFLD was 38% (95% CI: 31-45%) with high heterogeneity (I2 = 96.3%). The pooled prevalence of significant fibrosis was 13% (95% CI: 8-18%) with high heterogeneity (I2 = 92.09%). Subgroup analyses showed a NAFLD prevalence of 40% (95% CI: 24-57%) in the United States, 33% (95% CI: 31-36) in Asia, 42% (95% CI: 24-61%) in Europe and 33% (95% CI: 29-37) in South America. When stratifying by income level, NAFLD was 39% (95% CI: 31-48) prevalent in PLHIV from high-income economies and 34% in both upper-middle-income (95% CI: 31-37%) and lower-middle-income economies (95% CI: 28-41%). Higher body mass index (BMI) (OR = 1.32, 95% CI: 1.13-1.55; I2 = 89.9%), increasing triglycerides (OR = 1.48, 95% CI: 1.22-2.79; I2 = 27.2%) and dyslipidaemia (OR = 1.89, 95% CI: 1.32-2.71; I2 = 15.5%) were all associated with higher risk-adjusted odds of NAFLD in PLHIV. DISCUSSION: The burden of NAFLD and significant fibrosis in PLHIV is significant. Therefore, targeted efforts to screen and diagnose NAFLD in this population are needed. Health services for PLHIV could include ways to target NAFLD risk factors, screen for liver disease and implement interventions to treat those with significant fibrosis or more advanced stages of liver disease. Taking no action to address NAFLD in PLHIV should not be an option. CONCLUSIONS: This SR and MA found a 38% NAFLD and 13% significant fibrosis prevalence in PLHIV. Increasing triglyceride levels, higher BMI values and dyslipidaemia were associated with higher risk-adjusted odds of NAFLD among PLHIV.

Review article: The need for more efficient and patient-oriented drug development pathways in NASH-setting the scene for platform trials.

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) constitutes a significant unmet medical need with a burgeoning field of clinical research and drug development. Platform trials (PT) might help accelerate drug development while lowering overall costs and creating a more patient-centric environment. This review provides a comprehensive and nuanced assessment of the NASH clinical development landscape. METHODS: Narrative review and expert opinion with insight gained during the EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project. RESULTS: Although NASH represents an opportunity to use adaptive trial designs, including master protocols for PT, there are barriers that might be encountered owing to distinct and sometimes opposing priorities held by these stakeholders and potential ways to overcome them. The following aspects are critical for the feasibility of a future PT in NASH: readiness of the drug pipeline, mainly from large drug companies, while there is not yet an FDA/EMA-approved treatment; the most suitable design (trial Phase and type of population, e.g., Phase 2b for non-cirrhotic NASH patients); the operational requirements such as the scope of the clinical network, the use of concurrent versus non-concurrent control arms, or the re-allocation of participants upon trial adaptations; the methodological appraisal (i.e. Bayesian vs. frequentist approach); patients' needs and patient-centred outcomes; main regulatory considerations and the funding and sustainability scenarios. CONCLUSIONS: PT represent a promising avenue in NASH but there are a number of conundrums that need addressing. It is likely that before a global NASH PT becomes a reality, 'proof-of-platform' at a smaller scale needs to be provided.

Non-Alcoholic Fatty Liver Disease in Patients with Polycystic Ovary Syndrome: A Systematic Review, Meta-Analysis, and Meta-Regression.

BACKGROUND: The metabolic effects of polycystic ovary syndrome (PCOS) may increase the risk of non-alcoholic fatty liver disease (NAFLD). However, the burden of NAFLD in PCOS has not been unequivocally defined. This systematic review (SR), meta-analysis (MA) assessed NAFLD's prevalence, and risk factors in patients with PCOS. METHODS: A literature search was performed in MEDLINE, Scopus, and Scielo. First, we performed a MA of proportions to estimate the prevalence of NAFLD in PCOS. Second, we performed meta-analyses of precalculated adjusted odds ratios to examine NAFLD risk factors. Finally, we performed a meta-regression to model how the estimated prevalence changed with changes in prespecified variables. RESULTS: We identified 817 articles from the database searches. Thirty-six were included. MA of proportions found a pooled NAFLD prevalence of 43% (95% CI, 35-52%) with high heterogeneity (I2 = 97.2%). BMI, waist circumference, ALT values, HOMA-IR values, free androgen index levels, hyperandrogenism, and triglycerides were associated with significantly higher risk-adjusted odds of NAFLD among patients with PCOS. Meta-regression showed that rises in NAFLD prevalence were mediated through increases in metabolic syndrome prevalence and higher levels of HOMA-IR, free androgen index, and total testosterone. CONCLUSION: The prevalence of NAFLD (43%) among PCOS patients is high despite their average young age, with several metabolic and PCOS-specific factors influencing its occurrence. Screening programs may aid in detecting metabolic-associated fatty liver disease and prevent its consequences. Further work is required to establish the burden of liver-related outcomes once NAFLD has progressed in the PCOS population.

On-Surface Synthesis of Nanographenes and Graphene Nanoribbons on Titanium Dioxide.

The formation of two types of nanographenes from custom designed and synthesized molecular precursors has been achieved through thermally induced intramolecular cyclodehydrogenation reactions on the semiconducting TiO2(110)-(1×1) surface, confirmed by the combination of high-resolution scanning tunneling microscopy (STM) and spectroscopy (STS) measurements, and corroborated by theoretical modeling. The application of this protocol on differently shaped molecular precursors demonstrates the ability to induce a highly efficient planarization reaction both within strained pentahelicenes as well as between vicinal phenyl rings. Additionally, by the combination of successive Ullmann-type polymerization and cyclodehydrogenation reactions, the archetypic 7-armchair graphene nanoribbons (7-AGNRs) have also been fabricated on the titanium dioxide surface from the standard 10,10'-dibromo-9,9'-bianthryl (DBBA) molecular precursors. These examples of the effective cyclodehydrogenative planarization processes provide perspectives for the rational design and synthesis of molecular nanostructures on semiconductors.