A Functional and Immunologic Point of View on Corneal Endothelial Transplantation: A Systematic Review and Meta-Analysis.

Background: To systematically review and meta-analyze the immunologic aspects and outcomes of various endothelial keratoplasty (EK) techniques, specifically comparing Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK), Ultra-Thin Descemet's Stripping Automated Endothelial Keratoplasty (UT-DSAEK), and Descemet's Membrane Endothelial Keratoplasty (DMEK). Methods: Systematic review and meta-analysis. Main outcomes were the proportion of patients achieving a best spectacle-corrected visual acuity (BSCVA) of 20/20 at 6 months after keratoplasty, rejection rate one year after surgery, BSCVA at last follow up, and postoperative immunomodulating regimen. Results: A higher proportion of DMEK patients achieved a BSCVA of 20/20 after 6 months. UT-DSAEK and DMEK showed similar rejection rates with a lower risk of re-bubbling for UT-DSAEK (4% vs. 20%). Conclusions: DMEK showed faster visual recovery than UT-DSAEK but a similar rejection rate and long-term visual acuity. One-year postoperative slow tapering steroid regimen has a positive but not (yet) significant effect on rejection risk and visual outcomes.

Clinical outcomes and phenotypes of respiratory failure in older subjects admitted to an acute care geriatric hospital ward.

Respiratory failure (RF) is frequent in hospitalized older patients, but was never systematically investigated in large populations of older hospitalized patients. We conducted a retrospective administrative study based on hospitalizations of a Geriatrics Unit regarding 2014, 2015, and 2016. Patients underwent daily screening for hypoxia. Hospital discharge records were coded through a standardized methodology. RF, defined as documented hypoxia on room air, was always coded, whenever present. We investigated how RF affected clinical outcomes, whether RF grouped into specific comorbidity phenotypes, and how phenotypes associated with the outcomes. RF was coded in 48.6% of the 1,810 hospitalizations. RF patients were older and more frequently had congestive heart failure (CHF: 49 vs 23%), chronic obstructive pulmonary disease (COPD: 27 vs 6%), pneumonia (14 vs 4%), sepsis (12 vs 7%), and pleural effusion (6 vs 3%), than non-RF patients. RF predicted longer length of stay (a-Beta 2.05, 95% CI 1.4-2.69; p < 0.001) and higher in-hospital death/intensive care units (ICU) need (aRR 7.12, 5-10.15; p < 0.001) after adjustment for confounders (linear and Poisson regression with robust error variance). Among RF patients, cerebrovascular disease, cancer, electrolyte disturbances, sepsis, and non-invasive ventilation predicted increased, while CHF and COPD predicted decreased in-hospital death/ICU need. The ONCO (cancer) and Mixed (cerebrovascular disease, dementia, pneumonia, sepsis, electrolyte disturbances, bedsores) phenotypes displayed higher in-hospital death/ICU need than CARDIO (CHF) and COPD phenotypes. In this study, RF predicted increased hospital death/ICU need and longer hospital stay, but also reflected diverse underlying conditions and clinical phenotypes that accounted for different clinical courses.

Acoustic Radiation Forced Impulse of the Liver and the Spleen, Combined with Spleen Dimension and Platelet Count in New Ratio Scores, Identifies High-Risk Esophageal Varices in Well-Compensated Cirrhotic Patients.

Acoustic radiation forced impulse (ARFI) is an integrated ultrasound method, measuring stiffness by point shear wave elastography. To evaluate the diagnostic performance of the ARFI of the liver and the spleen, combined with spleen dimension and platelet count, in predicting high-risk esophageal varices (HRVs) in cirrhotic patients, a prospective and cross-sectional study was conducted between February 2017 and February 2021. The following ratio scores were calculated based on ARFI measurements: ALSDP (ARFI Liver-Spleen Diameter-to-Platelet Ratio Score), ASSDP (ARFI Spleen-Spleen Diameter-to-Platelet Ratio Score), ASSAP (ARFI Spleen-Spleen Area-to-Platelet Ratio Score), and ALSAP (ARFI Liver-Spleen Area-to-Platelet Ratio Score). In 100 enrolled subjects, spleen ARFI, ASSDP, and ASSAP were significantly associated with HRVs in the prospective short- and long-term follow-ups and in the cross-sectional study (p < 0.05), while ALSDP and ALSAP were associated with HRVs only in the prospective long-term follow-up and cross-sectional study (p< 0.05). ASSAP was the best ARFI ratio score for HRVs at the long-term follow-up [value of area under curve (AUC) = 0.88], although all the ARFI ratio scores performed better than individual liver and spleen ARFI (AUC > 0.7). In our study, ARFI ratio scores can predict, in well-compensated cirrhotic patients, the risk of developing HVRs in short- and long-term periods.

Poor accuracy and sustainability of the first-step FIB4 EASL pathway for stratifying steatotic liver disease risk in the general population.

BACKGROUND AND AIMS: The European Association for the Study of the Liver introduced a clinical pathway (EASL CP) for screening significant/advanced fibrosis in people at risk of steatotic liver disease (SLD). We assessed the performance of the first-step FIB4 EASL CP in the general population across different SLD risk groups (MASLD, Met-ALD and ALD) and various age classes. METHODS: We analysed a total of 3372 individuals at risk of SLD from the 2017-2018 National Health and Nutrition Examination Survey (NHANES17-18), projected to 152.3 million U.S. adults, 300,329 from the UK Biobank (UKBB) and 57,644 from the Biobank Japan (BBJ). We assessed liver stiffness measurement (LSM) ≥8 kPa and liver-related events occurring within 3 and 10 years (3/10 year-LREs) as outcomes. We defined MASLD, MetALD, and ALD according to recent international recommendations. RESULTS: FIB4 sensitivity for LSM ≥ 8 kPa was low (27.7%), but it ranged approximately 80%-90% for 3-year LREs. Using FIB4, 22%-57% of subjects across the three cohorts were identified as candidates for vibration-controlled transient elastography (VCTE), which was mostly avoidable (positive predictive value of FIB4 ≥ 1.3 for LSM ≥ 8 kPa ranging 9.5%-13% across different SLD categories). Sensitivity for LSM ≥ 8 kPa and LREs increased with increasing alcohol intake (ALD>MetALD>MASLD) and age classes. For individuals aged ≥65 years, using the recommended age-adjusted FIB4 cut-off (≥2) substantially reduced sensitivity for LSM ≥ 8 kPa and LREs. CONCLUSIONS: The first-step FIB4 EASL CP is poorly accurate and feasible for individuals at risk of SLD in the general population. It is crucial to enhance the screening strategy with a first-step approach able to reduce unnecessary VCTEs and optimise their yield.

Appropriateness of direct oral anticoagulant prescribing in older subjects with atrial fibrillation discharged from acute medical wards.

AIMS: Knowledge on the prescriptive practice of direct oral anticoagulants (DOACs) in older subjects with atrial fibrillation (AF) hospitalized in acute medical wards is limited. This study aimed to evaluate the prevalence and appropriateness of DOAC prescriptions in hospitalized older subjects with AF, discharged from acute medical wards. METHODS: We analysed a cohort of 609 subjects with AF, aged ≥65 years (mean age 85 years) enrolled from 39 geriatric and nephrology wards in Italy. DOAC prescriptive appropriateness was evaluated according to the summary of product characteristics (smPC), 2019 Beers and STOPP criteria, and drug-drug interactions (DDIs). RESULTS: At hospital discharge, 33% of patients with AF were prescribed with DOAC, 26% with vitamin-K antagonist, while 41% did not receive any anticoagulant. Among subjects on DOAC therapy, 31% presented a violation of the smPC criteria (mainly underdosage-17%), while 48% and 18% presented a Beers/STOPP inappropriate prescription, or a DDI, respectively. Older age, lower body mass index (BMI), cancer and higher estimated glomerular filtration rate (eGFR) were independently associated with DOAC underdosage or missed prescription (age: adjusted odds ratio [aOR] 1.06, 95% confidence interval [95% CI] 1.00-1.12 for underdosage; eGFR: aOR 1.04, 95% CI 1.02-1.07 for underdosage; BMI: aOR 0.95, 95% CI 0.91-0.99 for missed prescription; cancer: aOR 1.93, 95% CI 1.19-3.13 for missed prescription). CONCLUSIONS: This study showed a suboptimal DOAC prescriptive practice in older in-patients, with frequent missed prescription and DOAC underdosage. Contrary to current recommendations, physicians appear overly concerned by bleeding risk in real-life older and frailer subjects. Strategies should be developed to promote appropriate DOAC prescription in the hospital setting.

Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses an excess of triglycerides in the liver, which can lead to cirrhosis and liver cancer. While there is solid epidemiological evidence of MASLD coexisting with cardiometabolic disease, several leading genetic risk factors for MASLD do not increase the risk of cardiovascular disease, suggesting no causal relationship between MASLD and cardiometabolic derangement. In this work, we leveraged measurements of visceral adiposity and identified 27 novel genetic loci associated with MASLD. Among these loci, we replicated 6 in several independent cohorts. Next, we generated two partitioned polygenic risk scores (PRS) based on the mechanism of genetic association with MASLD encompassing intra-hepatic lipoprotein retention. The two PRS suggest the presence of at least two distinct types of MASLD, one confined to the liver resulting in a more aggressive liver disease and one that is systemic and results in a higher risk of cardiometabolic disease.

Microarray-Based Detection of Critical Overexpressed Genes in the Progression of Hepatic Fibrosis in Non-Alcoholic Fatty Liver Disease: A Protein-Protein Interaction Network Analysis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a prevalent cause of chronic liver disease and encompasses a broad spectrum of disorders, including simple steatosis, steatohepatitis, fibrosis, cirrhosis, and liver cancer. However, due to the global epidemic of NAFLD, where invasive liver biopsy is the gold standard for diagnosis, it is necessary to identify a more practical method for early NAFLD diagnosis with useful therapeutic targets; as such, molecular biomarkers could most readily serve these aims. To this end, we explored the hub genes and biological pathways in fibrosis progression in NAFLD patients. METHODS: Raw data from microarray chips with GEO accession GSE49541 were downloaded from the Gene Expression Omnibus database, and the R package (Affy and Limma) was applied to investigate differentially expressed genes (DEGs) involved in the progress of low- (mild 0-1 fibrosis score) to high- (severe 3-4 fibrosis score) fibrosis stage NAFLD patients. Subsequently, significant DEGs with pathway enrichment were analyzed, including gene ontology (GO), KEGG and Wikipathway. In order to then explore critical genes, the protein-protein interaction network (PPI) was established and visualized using the STRING database, with further analysis undertaken using Cytoscape and Gephi software. Survival analysis was undertaken to determine the overall survival of the hub genes in the progression of NAFLD to hepatocellular carcinoma. RESULTS: A total of 311 significant genes were identified, with an expression of 278 being upregulated and 33 downregulated in the high vs. low group. Gene functional enrichment analysis of these significant genes demonstrated major involvement in extracellular matrix (ECM)-receptor interaction, protein digestion and absorption, and the AGE-RAGE signaling pathway. The PPI network was constructed with 196 nodes and 572 edges with PPI enrichment using a p-value < 1.0 e-16. Based on this cut-off, we identified 12 genes with the highest score in four centralities: Degree, Betweenness, Closeness, and Eigenvector. Those twelve hub genes were CD34, THY1, CFTR, COL3A1, COL1A1, COL1A2, SPP1, THBS1, THBS2, LUM, VCAN, and VWF. Four of these hub genes, namely CD34, VWF, SPP1, and VCAN, showed significant association with the development of hepatocellular carcinoma. CONCLUSIONS: This PPI network analysis of DEGs identified critical hub genes involved in the progression of fibrosis and the biological pathways through which they exert their effects in NAFLD patients. Those 12 genes offer an excellent opportunity for further focused research to determine potential targets for therapeutic applications.

Development and Validation of a Score for Fibrotic Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: Noninvasive assessment of histological features of nonalcoholic fatty liver disease (NAFLD) has been an intensive research area over the last decade. Herein, we aimed to develop a simple noninvasive score using routine laboratory tests to identify, among individuals at high risk for NAFLD, those with fibrotic nonalcoholic steatohepatitis (NASH) defined as NASH, NAFLD activity score ≥4, and fibrosis stage ≥2. METHODS: The derivation cohort included 264 morbidly obese individuals undergoing intraoperative liver biopsy in Rome, Italy. The best predictive model was developed and internally validated using a bootstrapping stepwise logistic regression analysis (2000 bootstrap samples). Performance was estimated by the area under the receiver operating characteristic curve (AUROC). External validation was assessed in 3 independent European cohorts (Finland, n = 370; Italy, n = 947; England, n = 5368) of individuals at high risk for NAFLD. RESULTS: The final predictive model, designated as Fibrotic NASH Index (FNI), combined aspartate aminotransferase, high-density lipoprotein cholesterol, and hemoglobin A1c. The performance of FNI for fibrotic NASH was satisfactory in both derivation and external validation cohorts (AUROC = 0.78 and AUROC = 0.80-0.95, respectively). In the derivation cohort, rule-out and rule-in cutoffs were 0.10 for sensitivity ≥0.89 (negative predictive value, 0.93) and 0.33 for specificity ≥0.90 (positive predictive value, 0.57), respectively. In the external validation cohorts, sensitivity ranged from 0.87 to 1 (negative predictive value, 0.99-1) and specificity from 0.73 to 0.94 (positive predictive value, 0.12-0.49) for rule-out and rule-in cutoff, respectively. CONCLUSION: FNI is an accurate, simple, and affordable noninvasive score which can be used to screen for fibrotic NASH in individuals with dysmetabolism in primary health care.

Length of Hospital Stay after Total Knee Arthroplasty: A Correlation Study on 1200 Patients.

In countries with a high average population age, total knee arthroplasty is still carried out in an inpatient setting. The roadmap to performing major surgery on an outpatient basis passes through the understanding of those perioperative features that correlate with higher lengths of hospital stay (LOS). A retrospective database of 1200 patients was reviewed for retrieving preoperative and perioperative factors including anthropometric and demographic data, comorbidities, preoperative laboratory assessment, and surgical time. Considering the LOS as a discrete series, data were analyzed by means of logistic regression with multiple univariate and multivariate models. The results showed a median length of hospital stay of 3 (IQR 3, 4) days. According to multiple univariate analysis, arterial hypertension (p = 0.008), diabetes mellitus (p = 0.028), CCI score (p < 0.001), ASA score (p = 0.006), surgical time (p < 0.001) and intraoperative blood loss (p < 0.001) were significantly associated with the duration of hospital stay in days. Moreover, preoperative hemoglobin value was inversely correlated to the LOS (p = 0.008). Multivariate analysis showed a significant correlation between LOS and surgical time and intraoperative blood loss. Many factors influence the permanence of the inpatient and acting on those variables, by stabilizing comorbidities and optimizing laboratory values, may reduce the overall healthcare burden.

A Genetic and Metabolic Staging System for Predicting the Outcome of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is an emerging cause of liver-related events (LREs). Here, we have assessed the ability of a composite score based on clinical features, metabolic comorbidities, and genetic variants to predict LREs. A total of 546 consecutive patients with NAFLD were recruited and stratified according to the fibrosis-4 (FIB-4) index. LREs were defined as occurrence of hepatocellular carcinoma or hepatic decompensation. Cox regression multivariate analysis was used to identify baseline variables associated with LREs. The UK Biobank was used as the validation cohort, and severe liver disease (incidence of cirrhosis, decompensated liver disease, hepatocellular carcinoma, and/or liver transplantation) was used as the outcome. LREs were experienced by 58 patients, only one of whom was in the cohort of patients with a FIB-4 score < 1.3. Multivariate Cox regression analysis of 229 patients with a FIB-4 score ≥ 1.3 highlighted clinical variables independently associated with the development of LREs, including older age, low platelet count, low albumin, low high-density lipoprotein cholesterol, certain genetic factors, and interactions between genetic factors and sex or diabetes. The area under the curve (AUC) for the model was 0.87 at 1, 3, and 5 years. Our novel Genetic and Metabolic Staging (GEMS) scoring system was derived from the Cox model linear predictor, ranked from 0 to 10, and categorized into five classes (0-5, 5-6, 6-7, 7-8, and 8-10). The risk of LREs increased from 4% in patients in the best class (GEMS score 0-5) to 91% in the worst (GEMS score 8-10). GEMS score was associated with incident severe liver disease in the study population (hazard ratio, 1.56; 95% confidence interval, 1.48-1.65; P < 0.001) as well as in the UK Biobank cohort where AUCs for prediction of severe liver disease at 1, 3, and 5 years were 0.70, 0.69, and 0.67, respectively. Conclusion: The novel GEMS scoring system has an adequate ability to predict the outcome of patients with NAFLD.

Sarcopenia in Hepatocellular Carcinoma: Pathogenesis and Management.

BACKGROUND: Sarcopenia is almost constantly observed in patients with cirrhosis and hepatocellular carcinoma (HCC). SUMMARY: Chronic liver disease represents a unique pathophysiological scenario in which sarcopenia develops and all factors involved in the pathogenesis should be taken into account for an appropriate management of the disease. No properly designed intervention studies on this topic are available and, thus, no effective strategies have been developed for clinical practice. Apart from any targeted intervention, treatment, and optimization of liver disease is crucial. KEY MESSAGES: In patients with cirrhosis and HCC, nutritional support to maintain and restore nutrition status, a targeted use of branched-chain amino acids and a guided physical exercise, should all be an integral part of the multidimensional assessment and tailored interventions.

Metabolic and genetic determinants for progression to severe liver disease in subjects with obesity from the UK Biobank.

BACKGROUND: Obesity is among the main determinants of nonalcoholic fatty liver disease progression towards severe liver disease (SLD). However, risk factors for SLD in individuals with obesity have not been examined. OBJECTIVES: To identify the independent risk factors for SLD among participants with obesity from the UK Biobank. METHODS: A total of 80,224 UK Biobank participants with obesity (body mass index[BMI] > 30 kg/m2) and 242,822 without obesity, of European descent without clinical history of liver disease and liver cancer were prospectively followed for the onset of SLD, defined as a composite diagnosis of cirrhosis, decompensated liver disease, hepatocellular carcinoma and/or liver transplantation. Risk factors for incident SLD were assessed by Cox proportional hazards models. Different clinical phenotypes were derived by latent class analysis (LCA). RESULTS: Obesity conferred a 2.6-fold increased risk for SLD that was abolished after the inclusion of waist circumference (WC) in the model. Among individuals with obesity, age (adjusted hazard ratio [aHR] 1.05, 95%CI 1.03-1.07, p = 3.9 * 10-7), type 2 diabetes (aHR 2.18, 95%CI 1.55-3.05, p = 6.2 * 10-6), PNPLA3 rs738409 (aHR 1.59, 95%CI 1.33-1.9, p = 3.1 * 10-7) and WC (aHR 1.04, 95%CI 1.02-1.06, p = 8.5 * 10-6) were independent predictors of SLD. BMI category-specific WC thresholds allowed a better risk stratification compared to traditional ones. By LCA, the clinical phenotype at highest risk for SLD was that with BMI < 35 kg/m2 and WC above BMI-category specific thresholds. CONCLUSIONS: Age, WC, type 2 diabetes, and the PNPLA3 variant are the main risk factors for SLD in individuals with obesity. WC is the principal mediator of SLD risk conveyed by increased BMI. BMI category-specific WC-thresholds may refine the SLD risk more accurately than traditional thresholds.

A Polygenic Risk Score to Refine Risk Stratification and Prediction for Severe Liver Disease by Clinical Fibrosis Scores.

BACKGROUND & AIMS: A polygenic risk score based on well-known genetic variants in PNPLA3, TM6SF2, MBOAT7, and GCKR predicts hepatic fat content (polygenic risk score-hepatic fat content [PRS-HFC]). Here, we hypothesized that the addition of PRS-HFC to clinical fibrosis scores may improve risk stratification and prediction of severe liver disease (SLD). METHODS: We used data from 266,687 individuals in the UK Biobank, evaluating the incidence of cirrhosis, decompensated liver disease, hepatocellular carcinoma, and/or liver transplantation during a median follow-up period of 9 years. Nonalcoholic fatty liver disease fibrosis score, Fibrosis-4, aspartate aminotransferase-to-platelet ratio, BARD, and Forns scores, and PRS-HFC, were computed. All analyses were stratified according to the presence of diabetes, obesity, and a positive fatty liver index (≥60). RESULTS: Unfavorable genetics (PRS-HFC, ≥0.396) further stratified the risk of SLD in subjects in intermediate-/high-risk classes of fibrosis scores, with a higher effect in those with metabolic risk factors, and the prediction was improved by integrating PRS-HFC (areas under the receiver operating characteristic increased for all scores with a P value of approximately 10-2 to 10-4, except for the aspartate aminotransferase-to-platelet ratio in the overall population and in subjects with obesity). PRS-HFC improved diagnostic accuracies and positive predictive values for SLD in intermediate-high clinical score risk classes. Risk stratification and prediction were not affected or were poorly affected by unfavorable genetics in subjects without metabolic risk factors. CONCLUSIONS: Integration of genetics with clinical fibrosis scores refines individual risk and prediction for SLD, mainly in individuals at risk for nonalcoholic fatty liver disease. These data provide evidence from a prospective cohort that common genetic variants capture additional prognostic insights not conveyed by validated clinical/biochemical parameters.

Accuracy of controlled attenuation parameter for assessing liver steatosis in individuals with morbid obesity before bariatric surgery.

BACKGROUND & AIMS: The ultrasound-based controlled attenuation parameter (CAP) is a non-invasive tool widely validated for assessing liver steatosis across different etiologies. However, few studies, with liver biopsy available, have investigated its performance in individuals with morbid obesity. Herein, we aimed to evaluate the diagnostic accuracy of CAP in participants with morbid obesity from the MAFALDA study before bariatric surgery. METHODS: A total of 120 individuals with valid examinations within three months from bariatric surgery were included. Clinical, laboratory, FibroScan® (XL probe), and liver biopsy data were collected using standardized procedures. The overall accuracy of CAP for detecting liver steatosis was estimated by the area under the receiver-operating characteristics curve (AUROC). Optimal cut-offs were chosen at points with the highest Youden index. RESULTS: The AUROCs of CAP for detecting S ≥ S1, S ≥ S2, and S = S3 were 0.91 (95% CI 0.86-0.97), 0.83 (95% CI 0.76-0.90), and 0.86 (95% CI 0.79-0.94), respectively. The best CAP cut-offs for S ≥ S1, S ≥ S2, and S = S3 were 300 dB/m (95% CI 275-316), 328 dB/m (95% CI 296-345), and 344 dB/m (95% CI 343-352), respectively. CAP values were independently influenced by steatosis grade (estimate 20.60, 95% CI 12.70-28.40, P = 1.05 × 10-6 ). The AUROC of FibroScan-AST (FAST) score for detecting progressive non-alcoholic steatohepatitis was 0.76 (95% CI 0.66-0.86). CONCLUSIONS: In individuals with morbid obesity, CAP measured by XL probe is an accurate non-invasive tool for grading liver steatosis. Measurement of liver fat content by CAP may help identify those eligible for bariatric procedures and estimate the effect of bariatric surgery on hepatic steatosis. LAY SUMMARY: The ultrasound-based controlled attenuation parameter (CAP) by using the XL probe has an excellent performance for grading liver steatosis among individuals with morbid obesity. CAP may represent an accurate tool for the non-invasive assessment of liver steatosis among individuals with morbid obesity before and after bariatric surgery.

Combined evaluation of aminotransferases improves risk stratification for overall and cause-specific mortality in older patients.

BACKGROUND: Recent studies identified low levels of alanine aminotransferase (ALT) as strong predictors of mortality in older people. AIMS: Here we verified if the combined evaluation of aminotransferases may improve risk stratification for adverse outcomes in older patients. METHODS: Data are from 761 participants aged more than 65 years from a prospective population-based database (InCHIANTI study), without known baseline chronic liver disease or malignancies. Associations between aminotransferase levels and the risk of all-cause, cardiovascular- and cancer-death were assessed by Cox-models with time-dependent covariates. RESULTS: The association of ALT and aspartate aminotransferase (AST) with mortality was non-linear, mirroring a J- and a U-shaped curve, respectively. Based on quintiles of transaminase activities and on their association with overall mortality, low, intermediate (reference group) and high levels were defined. Having at least one transaminase in the low range [aHR 1.76 (1.31-2.36), p < 0.001], mainly if both [(aHR 2.39 (1.81-3.15), p < 0.001], increased the risk of overall mortality, as well as having both enzymes in the high range [aHR 2.14 (1.46-3.15), p < 0.001]. While similar trends were confirmed with respect to cardiovascular mortality, subjects with the highest risk of cancer mortality were those with both enzymes in the high range [aHR 3.48 (1.43-8.44), p = 0.006]. Low levels of transaminases were associated with frailty, sarcopenia and disability, while high levels did not capture any known proxy of adverse outcome. Conclusions and discussion The prognostic information is maximized by the combination of the 2 liver enzymes. While both aminotransferases in low range are characteristically found in the most fragile phenotype, both enzymes in high range are more likely to identify new-onset vascular/infiltrative diseases with adverse outcome.

Inborn and acquired risk factors for severe liver disease in Europeans with type 2 diabetes from the UK Biobank.

BACKGROUND & AIMS: Type 2 diabetes is a major driver of fatty liver disease and its long-term complications. The aim of this study was to investigate the individual contribution of inborn and acquired risk factors for severe liver disease in individuals with type 2 diabetes from the UK Biobank study. METHODS: A total of 22,812 UK Biobank participants of European descent without clinical history of liver disease and liver cancer were prospectively followed for the development of severe liver disease, defined as a composite diagnosis of cirrhosis, decompensated liver disease, hepatocellular carcinoma, and/or liver transplantation from the National Health Service records. The contribution of inborn and acquired risk factors to the risk of incident severe liver disease was assessed by Cox proportional hazards models. RESULTS: During a median follow-up of 8.9 years (IQR 8.1-9.6), there were 279 individuals with severe liver disease, including 255 with cirrhosis and/or decompensated liver disease, 47 with hepatocellular carcinoma, and 5 with liver transplantation; death from severe liver disease occurred in 83 individuals. Risk factors independently associated with increased risk of incident severe liver disease included abnormal aspartate aminotransferase (adjusted hazard ratio [aHR] 4.85, 95% CI 2.76-8.54), decrease in serum albumin (aHR 2.39, 95% CI 1.76-3.24) and platelet count (aHR 1.12, 95% CI 1.09-1.16), cardiovascular disease (aHR 1.86, 95% CI 1.23-2.79), microalbuminuria (aHR 1.55, 95% CI 1.04-2.30), PNPLA3 rs738409 (aHR 1.67, 95% CI 1.27-2.18) and TM6SF2 rs58542926 (aHR 1.63, 95% CI 1.12-2.39), while the net effect of male sex was protective (aHR 0.49, 95% CI 0.26-0.94). CONCLUSIONS: These findings may help in clinical care to identify individuals with type 2 diabetes at risk of severe liver disease, in turn leading to personalised risk prediction and prevention strategies. LAY SUMMARY: Type 2 diabetes is a key driver of severe liver disease, namely cirrhosis, hepatocellular carcinoma, and liver-related mortality. In Europeans with type 2 diabetes from the prospective UK Biobank study, abnormal liver function, cardiovascular disease, microalbuminuria, and genetic variants in PNPLA3 and TM6SF2 genes are the major independent risk factors for severe liver disease. These findings may contribute in clinical care to identify and closely monitor individuals with type 2 diabetes at risk of developing severe liver disease, requiring more intensive follow-up strategies.

Non-alcoholic fatty liver disease and steatohepatitis: State of the art on effective therapeutics based on the gold standard method for diagnosis.

OBJECTIVE: The prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NAFLD/NASH) is increasing. NAFLD/NASH may progress to cirrhosis and hepatocellular carcinoma. However, most patients with NAFLD/NASH will die from a vascular cause. There are no approved pharmacological treatments for NASH/NAFLD. Many clinical trials have been, or are being, undertaken; however, the challenge is the assessment of the clinical endpoint. The main objective of this narrative review was to evaluate the efficacy of drugs used in clinical trials for the treatment of NAFLD/NASH that included a liver biopsy as the gold standard. METHODS: A literature search was conducted using 3 databases (PubMed, Scopus, and Google Scholar) to identify the clinical trials that included liver biopsy assessment before and after treatment. RESULTS: Interventional clinical trials (n = 33) involving 18 different agents, alone and in combination, were identified. Pioglitazone is the only agent that has shown consistent benefit and efficacy in clinical trials. Pentoxifylline, rosiglitazone, and ursodeoxycholic acid had both positive and negative results from clinical trials. There is also evidence for vitamin E and metformin. Other drugs, including bicyclol, cysteamine bitartrate, l-carnitine, liraglutide, obeticholic acid, oligofructose, selonsertib, silymarin, and statins, each had a single clinical study. CONCLUSIONS: In summary, the available molecules demonstrated a significant improvement in NASH and/or liver fibrosis in a minority of patients; thus, other drugs should be identified, possibly those acting on alternative pathophysiological pathways, and tested for their safety and efficacy.

Return to Sport Activity in the Elderly Patients after Unicompartmental Knee Arthroplasty: A Systematic Review and Meta-Analysis.

In patients with knee osteoarthritis, when only medial or lateral compartment of the knee is involved, unicompartimental knee arthroplasty (UKA) is a reliable option for addressing the symptoms and restore function. The main aim of the present review is to systematically collect the available evidence concerning the return to sport activity in the elderly patients after UKA. An electronic search was carried out on the following databases; Pubmed-Medline, Cochrane central, and Scopus, searching for randomized controlled trials, prospective cohort studies, retrospective case-control studies, and case series. Data concerning the evaluation of the return to sport (RTS) and of functional outcomes in the elderly patients after UKA surgery. MINORS score was used to assess the risk of methodological biases. Odds ratios and raw proportions were used to report the pooled effect of UKA on the return to sport in comparative and non-comparative studies, respectively. Same level RTS in elderly patients was of 86% (pooled return proportion 0.86, 95%CI 0.78, 0.94), showing also better relative RTS and time to RTS of patients undergoing UKA, in comparison to those undergoing TKA. Sport-specific RTS showed that higher return rates were observed for low-impact sports, whereas high-impact sports prevented a full return to activities. UKA is a valid and reliable option for elderly patients to satisfactorily resume their sport practice, especially for low impact activities. The rate of return to sports following UKA is higher than TKA.

Voltammetric analysis for distinguishing portal hypertension-related from malignancy-related ascites: A proof of concept study.

BACKGROUND: Serum-ascites albumin gradient (SAAG) remains the most sensitive and specific marker for the differentiation of ascites due to portal hypertension from ascites due to other causes. SAAG has some limitations and may fail in selected conditions. Voltammetric analysis (VA) has been used for the detection of electroactive species of biological significance and has proven effective for detection infections in biological fluids. AIMS: In this study, we compared the accuracy of voltammetric analysis (VA) with that of SAAG to differentiate ascites due to portal hypertension from that having a different origin. METHODS: 80 ascites samples were obtained from patients undergoing paracentesis at the Campus Bio-Medico Hospital of Rome. VA was performed using the BIONOTE device. The ability of VA to discriminate ascitic fluid etiology and biochemical parameters was evaluated using Partial Least Square Discriminant Analysis (PLS-DA), with ten-fold cross-validations. RESULTS: Mean age was 68.6 years (SD 12.5), 58% were male. Ascites was secondary to only portal hypertension in 72.5% of cases (58 subjects) and it was secondary to a baseline neoplastic disease in 27.5% of cases (22 subjects). Compared to SAAG≥1.1, e-tongue predicted ascites from portal hypertension with a better accuracy (92.5% Vs 87.5%); sensitivity (98.3% Vs 94.8%); specificity (77.3% Vs 68.2%); predictive values (PPV 91.9% Vs 88.7% and NPV 94.4% Vs 83.3%). VA correctly classified ascites etiology in 57/58 (98.2%) of cases with portal hypertension and in 17/22 (77.2%) of cases with malignancy. Instead, VA showed poor predictive capacities towards total white blood count and polymorphonuclear cell count. CONCLUSIONS: According to this proof of concept study, VA qualifies as a promising low-cost and easy method to discriminate between ascites secondary to portal hypertension and ascites due to malignancy.

Management of hip fracture in the older people: rationale and design of the Italian consensus on the orthogeriatric co-management.

BACKGROUND: Hip fracture (HF) is a burdening health problem in older people. The orthogeriatric approach has been shown to favour functional recovery and reduce mortality, but its implementation in clinical practice cannot rely upon shared management protocols and greatly varies among different healthcare systems. Here, we present the rationale and design of the Italian consensus document on the management of HF in older people. METHODS: A panel of multidisciplinary experts from ten Italian scientific societies involved in the care of HF and including geriatricians, orthopaedics, anaesthesiologists, physiatrists and general practitioners, will join to establish the content validity of a list of statements. A Delphi consensus methodology will be applied to obtain the opinions of the panel and to provide the final recommendations. OBJECTIVES: The document will include indications on the following relevant topics: (1) optimal care path of older subjects with HF; (2) management of comorbidities and pre-operative alteration of physiological parameters; (3) management of selected categories of patients at expected increased risk of adverse outcomes; (4) continuity of care out of hospital; (5) screening and correction of risk factors for HF in older subjects; (6) information and divulgation of shared management strategies. The objective of the consensus will be to inform clinicians, patients, researchers, and health policy makers about the best management strategies for HF in older people and their inherent limitations, thus facilitating communication between stakeholders and promoting the most cost/effective models of care.