Introdution and aim The most important determinant of the progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) and fibrosis is insulin resistance (IR). Interferon gamma-induced protein 10 (IP-10), a proinflammatory chemokine, plays a crucial role in inflammatory diseases but its interaction with IR in the setting of NAFLD is not clear. Methods We analysed data from 200 patients with biopsy proven NAFLD (M/F 121/79; mean age 47±12). A subgroup of 46 non-diabetic NAFLD subjects underwent tracers studies (6,6-D2-glucose and [2H5 ]glycerol). Tracers enrichment was determined by GC-MS and data were used to calculate hepatic (Hep)-IR and adipose tissue (AT)-IR components. Serum IP-10 levels were assessed by Bio-Plex (BioRad Laboratories). Results Overall, 81/200 (40.5%) patients had F≥2 and 151/200 (75.5%) had NASH. The prevalence of type 2 diabetes was 27.5% and 47.5% of the patients were obese. IP-10 levels significantly increased across lean to overweight to obese subjects (p=0.009), showed a stepwise increase according to the stages of hepatic fibrosis (p=0.006) and were significantly higher in patients with NASH compared to those with NAFL (457pg/ml vs 383pg/ml, p=0.039). Moreover, IP-10 levels were increased in diabetic compared to non-diabetic patients (491pg/ml vs 393pg/ml, p=0.021) and showed a significant correlation with HOMA-IR (r=0.30, p=0.006). In the subgroup of non-obese, non-diabetic NAFLD patients who underwent tracers' studies, IP-10 levels showed a significant correlation with both Hep-IR and AT-IR (r=0.32, p=0.030 and r=0.33, p=0.049, respectively). At multivariate analysis, IP-10 was independently associated to the degree of hepatic fibrosis (rp=0.3, p=0.05). Conclusions IP-10 may be involved in the complex pathogenesis of NAFLD. Further studies are needed to demonstrate its causality in determining liver damage. This research has been supported by the Italian MIUR under the programme "Dipartimenti di Eccellenza 2018-2022", n.D15D18000410001 and by EU/EFPIA-IMI2 under g.a. no.777377, LITMUS The most important determinant of the progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) and fibrosis is insulin resistance (IR). Interferon gamma-induced protein 10 (IP-10), a proinflammatory chemokine, plays a crucial role in inflammatory diseases but its interaction with IR in the setting of NAFLD is not clear. We analysed data from 200 patients with biopsy proven NAFLD (M/F 121/79; mean age 47±12). A subgroup of 46 non-diabetic NAFLD subjects underwent tracers studies (6,6-D2-glucose and [2H5 ]glycerol). Tracers enrichment was determined by GC-MS and data were used to calculate hepatic (Hep)-IR and adipose tissue (AT)-IR components. Serum IP-10 levels were assessed by Bio-Plex (BioRad Laboratories). Overall, 81/200 (40.5%) patients had F≥2 and 151/200 (75.5%) had NASH. The prevalence of type 2 diabetes was 27.5% and 47.5% of the patients were obese. IP-10 levels significantly increased across lean to overweight to obese subjects (p=0.009), showed a stepwise increase according to the stages of hepatic fibrosis (p=0.006) and were significantly higher in patients with NASH compared to those with NAFL (457pg/ml vs 383pg/ml, p=0.039). Moreover, IP-10 levels were increased in diabetic compared to non-diabetic patients (491pg/ml vs 393pg/ml, p=0.021) and showed a significant correlation with HOMA-IR (r=0.30, p=0.006). In the subgroup of non-obese, non-diabetic NAFLD patients who underwent tracers' studies, IP-10 levels showed a significant correlation with both Hep-IR and AT-IR (r=0.32, p=0.030 and r=0.33, p=0.049, respectively). At multivariate analysis, IP-10 was independently associated to the degree of hepatic fibrosis (rp=0.3, p=0.05). IP-10 may be involved in the complex pathogenesis of NAFLD. Further studies are needed to demonstrate its causality in determining liver damage.

Intro: Tuberculosis infection control (TBIC) is one of the main pillars of tuberculosis control programs. The objectives of this study were to evaluate the implementation of TBIC and identify the barriers hindering the implementation of TBIC in TB healthcare facilities in Mogadishu, Somalia. Methods: A cross-sectional study with direct observations using the WHO Checklist for Periodic Evaluation of TBIC in TB Health-Care Facilities was conducted between April 2021 and July 2022 in 10/12 TB health facilities in Mogadishu, Somalia. 1/10 (10%) private and 9/10 (90%) public TB health facilities participated in this study. Findings: Managerial infection control measures: only 4/10 (40%) facilities demonstrated available TBIC guidelines. All facilities 10/10 (100%) were unable to demonstrate a designated TBIC focal-person or committee; budget allocation and documented training on TBIC for clinical staff. Administrative infection control measures: all facilities 10/10 (100%) provided cough guidance and sufficient TB transmission and prevention information for patients. Environmental infection control measures: all facilities 10/10 (100%) had a well- ventilated waiting area; patients were not overcrowded, and Sputum samples were collected in a well-ventilated area. Only 3/10 (30%) and 4/10 (40%) of the facilities had the capacity to group patients according to their drug sensitivity status or had a properly designed facility respectively. All facilities, 10/10 (100%) had sufficient Personal Protective Equipment (PPE) including N95 respirators, and their staff was trained on proper usage of PPE. Regarding the barriers to implementation of TBIC, 10/10 (100%) and 8/10 (80%) of the facilities identified lack of funding or lack of training, enforcement, and motivation respectively as barriers to TBIC in their facilities. Discussion: Proper implementation of TBIC measures in the TB facilities in Mogadishu was low. Conclusion: We recommend a similar country-level study in Somalia; the rollout and training of TB staff on Somalia's national TBIC guidelines and allocation of funds and resources for TBIC implementation.

Hepatocellular carcinoma (HCC) represents a relevant disease burden in cirrhotic patients with non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the prognostic value of simple non-invasive tests (NITs) (AAR, APRI, BARD, FIB-4) for the stratification of HCC risk development in a cohort of 122 consecutive cirrhotic individuals with NAFLD. Over a median follow up of 5.9 (3.2-9.3) years, 13 (10.7%) developed HCC. Only FIB-4 was associated with HCC risk (HR = 1.27, 95% CI 1.03-1.58, p = 0.027). After evaluating different established FIB-4 cut-offs, the lowest cut-off of 1.45 allowed the ruling out of a greater number of patients with a minimal risk of HCC than the 1.3 cut-off (23 vs. 18 patients). Conversely, the cumulative incidence of HCC using the highest cut-off of 3.25 (rule in) was distinctly higher than the 2.67 cut-off (19.4% vs. 13.3%). After multivariate Cox regression analysis, these cut-offs were independently associated with HCC after adjusting for sex, BMI and T2DM (HR = 6.40, 95% CI 1.71-24.00, p = 0.006). In conclusion, FIB-4 values of <1.3 and >3.25 could allow for the optimal stratification of long-term HCC risk in cirrhotic individuals with NAFLD.

Late chronotype, the individual’s aptitude to perform daily activities late in the day, has been associated with low adherence to the Mediterranean diet (MedDiet) and metabolic syndrome. The aim of this work was to investigate the potential association of chronotype and adherence to the MedDiet with the liver fibrosis risk in patients with non-alcoholic fatty liver disease (NAFLD). Liver stiffness was assessed in 126 patients by FibroScan®530. Significant (F ≥ 2) and advanced (F ≥ 3) hepatic fibrosis were defined according to liver stiffness values ≥7.1 kPa and ≥8.8 kPa, respectively. Chronotype (MSFsc) was defined by the Munich Chronotype Questionnaire, and adherence to the MedDiet was defined by the Mediterranean diet score (MDS). Overall, the median age was 55 (46–63) years, and 57.9% of participants were male. The principal comorbidities were type-2 diabetes mellitus (T2DM) (26.1%), arterial hypertension (53.1%), dyslipidaemia (63.4%), obstructive sleep apnoea (5.5%) and depression (5.5%). Most subjects (65.0%) had intermediate + late chronotype and showed higher mid-sleep on workdays (p < 0.001) and on work-free days (p < 0.001) compared to those with early chronotype. In the logistic regression model, intermediate + late chronotype (p = 0.024), MDS (p = 0.019) and T2DM (p = 0.004) were found to be significantly and independently associated with the risk of both F ≥ 2 And F ≥ 3. We observed that the intermediate + late chronotype and low adherence to the MedDiet were associated with both significant and advanced liver fibrosis in patients with NAFLD.

Background and aims: Non-invasive tests (NITs) are needed in clinical practice to replace histology for the identification of liver fibrosis and prognostication in Non-Alcoholic Fatty Liver Disease (NAFLD). Novel collagen-derived fibrogenesis markers including N-terminal type III collagen pro-peptide (PRO-C3) are among the most promising tools in this field. The aim of this study was to assess the diagnostic accuracy of PRO-C3, the derivative ADAPT score, and other NITs for the identification of advanced fibrosis (stages 3–4) and changes over 12 months of follow-up. Methods: In this longitudinal study, 96 patients with biopsy-proven NAFLD were evaluated at baseline, of which 50 underwent a follow-up visit after 12 months. Clinical-biochemical parameters, liver stiffness (LS) by transient elastography, PRO-C3, and other NITs (ADAPT, FIB-4, NFS, APRI) were collected at baseline and follow-up. Results: LS showed the best accuracy for the identification of advanced fibrosis, with Area under the Receiving Operator Curve (AUROC) 0.82 (0.73–0.89) for a cut-off value of 9.4 kPa. Among the other NITs, the ADAPT score showed the best accuracy, with AUROC 0.80 (0.71–0.88) for a cut-off of 5.02 (Se 62%, Sp 89%, PPV 74%, NPV 83%). The comparison between the AUROC of LS with that of ADAPT was not statistically different (DeLong test p value 0.348). At follow-up, LS was slightly reduced, whilst PRO-C3 displayed a significant increase from baseline median 11.2 ng/mL to 13.9 ng/mL at follow-up (p = 0.017). Accordingly, ADAPT score increased from median 5.3 to 6.1 (p = 0.019). The other NITs did not significantly change over 12 months. Conclusions: The ADAPT score shows the best performance among non-invasive scores for the identification of advanced fibrosis, not different from LS. Collagen-derived biomarker PRO-C3 and the derivative score ADAPT display significant changes over time, and may be useful tools for monitoring the progression of liver disease or assessing responses to treatments.

Introduction Individuals with Non-Alcoholic Fatty Liver Disease (NAFLD) have abnormal myocardial energy metabolism and reduced coronary functional capacity, even in the absence of risk factors for cardiovascular disease (CVD). Aim We aimed to evaluate diastolic and systolic function in NAFLD individuals with preserved ejection fraction without overt CVD. Material and Method We prospectively included 95 patients (median age 53.0 [IQR 44.5-62.5] years, male sex 44.6%) with ultrasound-diagnosed NAFLD undergoing echocardiographic evaluation, which included speckle tracking analysis with left ventricular global longitudinal strain (GLS) measurement (Philips, Andover, US). Diastolic dysfunction was defined by mitral E/E'>9 and systolic dysfunction was defined by GLS >-18. Significant liver fibrosis (SLF) was defined by Fibrosis-4 (FIB-4) score>1.3. Results Obesity, type 2 diabetes (T2D), arterial hypertension and dyslipidemia were present in 43.3%, 21.1%, 46.2% and 57.8% of cases, while median FIB-4 was 0.97 [0.67-1.24]. SLF, diastolic and systolic dysfunction were found in 20%, 17% and 18.3% of the total. Higher FIB-4 levels were found in both diastolic and systolic dysfunction (p=0.003 and p=0.001). SLF was associated with diastolic dysfunction (OR 6.8 [95%CI 1.8-25.5], p=0.004), showing an Area Under the Curve of 0.76 (Se 76.9%, Sp 72.2%, PPV 33.3%, NPV 94.5%). In a multiple stepwise logistic regression model including T2D, obesity, arterial hypertension, dyslipidemia, male sex and SLF, both SLF and T2D were significantly and independently associated with diastolic dysfunction (aOR of SLF 6.2 [95%CI 1.5-25.1, p=0.011). In the same regression model for systolic dysfunction, only T2D showed a significant association (aOR 4.6 [95%CI 1.3-16.8], p=0.021). Conclusion In NAFLD patients with preserved ejection fraction, SLF by FIB-4 is associated with diastolic dysfunction independently of major risk factors for CVD. Screening echocardiography may be recommended in this population. Funding: the Italian Ministry for Education, University and Research (MIUR) under the programme "Dipartimenti di Eccellenza 2018-2022" Project code D15D18000410001.

Introduction Hepatocellular Carcinoma (HCC) represents a major clinical event in the cirrhotic population, leading to a significant incidence of morbidity and mortality. Aim To assess the prognostic value of simple non-invasive tests (NITs) for the stratification of the risk of HCC development in a Non-Alcoholic Fatty Liver Disease (NAFLD) cirrhotic population on long-term follow-up (FU). Materials and Methods A total of 122 patients with NAFLD-cirrhosis (median age: 62 years; males 52.5%; median BMI 30.5 kg/m2; prevalence of type-2 diabetes: 57.4%) were retrospectively analyzed. Cirrhosis diagnosis was achieved by either liver histology, instrumental findings and/or clinical evidence of portal hypertension. Clinical and biochemical data were collected at the time of diagnosis; the following NITs were calculated: FIB-4, AST to Platelet Ratio Index (APRI) gamma-glutamyl transpeptidase-to-platelet ratio (GPR), BARD. Results During a median FU of 6 (IQR 3.2-9.3) years, 13 (10.7%) patients developed HCC. Baseline FIB-4 (HR=1.27, 95%CI 1.03–1.58, p=0.027) and GPR (HR=1.44, 95%CI 1.11–1.85, p=0.005) values resulted significantly associated to HCC occurrence. Conversely, no association was observed for APRI and BARD. Conventional FIB-4 cut-off values allowed a proper patients' stratification into 3 risk categories with different HCC incidence: FIB-4<1.3 = 0/18 (0%), FIB-4 between 1.3–3.25 = 7/73 (9.6%), and FIB-4>3.25 = 6/31 (19.4%) (Log-rank test: p=0.009). Likewise, the cumulative HCC incidence according to GPR tertiles risk groups was: 3/41 (7.3%), 4/40 (10.0%) and 6/41 (14.6%) (Log-rank test: p=0.041). Conclusions Baseline FIB-4 could stratify patients with NAFLD-cirrhosis on long-term FU according to their individual risk of HCC development. In such patients, this simple NIT may be useful to optimize tailored HCC surveillance strategies.

Introduction&Aim Low adherence to the Mediterranean Diet (MedDiet) has been associated with an increased risk of metabolic associated fatty liver disease (MAFLD), a clinical condition characterized by low grade chronic inflammation. The aim of this study was to assess whether the adherence to the Mediterranean diet is associated with biomarkers of inflammation in patients with MAFLD. Method A total of 40 patients with MAFLD were evaluated. Liver fibrosis was assessed by transient electrography (Fibroscan®530). Anthropometric, clinical and biochemical parameters were collected at enrolment. We measured the soluble CD163 (sCD163) levels by ELISA as indirect biomarker of both hepatic inflammation and fibrosis. Adherence to the MedDiet was assessed using a validated 14-item Mediterranean diet adherence questionnaire; low and high adherence were defined by the median value of the final score. Results Overall, the median age was 51 years (IQR 44;62), 52.00% of subjects were female and 32.00% had diabetes. Median liver stiffness was 6.6 (IQR 4.9;8.8), while sCD163 levels were 657 (IQR 553.5;813.5). Consistently, liver stiffness was significantly correlated to both MedDiet adherence and sCD163 concentrations (MedDiet: r= -0.38, p=0.006; sCD163: r=0.66, p<0.001, respectively). In addition, in patients with a low adherence to MedDiet significantly higher levels of sCD163 were observed (771.3 vs. 629.0, p=0.035). Interestingly, at multiple regression analysis, both low adherence to MedDiet adherence and sCD163 values (750-1303 ng/mL) were significantly associated with liver stiffness independently of age, sex, body mass index and diabetes. Conclusion In conclusion, in subjects with MAFLD low adherence to MedDiet is associated to a pro-inflammatory profile and is associated with the degree of hepatic fibrosis. This work has received support from the EU/EFPIA Innovative Medicines Initiaive 2 Joint Undertaking (LITMUS grant no. 777377).

Coronavirus disease 2019 (COVID-19) has afflicted tens of millions of people, fostering and unprecedent effort in vaccine development and distribution. Healthcare workers (HCW) play a key role in vaccine promotion and patient guidance, and it is likely that hesitancy among this population will have a major impact on the adoption of a successful immunization policy. To investigate HCW attitudes towards anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccination, we developed an anonymous online cross-sectional survey. 1723 Italian HCW responded. Overall, 1155 (67%) intended to be vaccinated, while 443 (26%) were not sure and 125 (7%) declared refusal. In multivariate analysis, factors associated with hesitancy were using Facebook as the main information source and being a non-physician HCW, while predictors of acceptance included younger age, being in close contact with high-risk groups and having received flu vaccination during the 2019–2020 season. Reasons for hesitancy included lack of trust in vaccine safety (85%) and receiving little (78%) or conflicting (69%) information about vaccines. According to our results, adequate investment in vaccine education for healthcare personnel appears to be urgently needed, prioritizing non-physicians and information quality spread through social media. We hope that our data could help governments and policy-makers to target communication in the ongoing COVID-19 vaccination campaign.

The response to treatment with biologic drugs, in patients with Crohn’s disease, could be associated with changes in gut microbiota composition. The aim of our study was to analyse the modification of microbiota during adalimumab therapy in patients with Crohn’s disease. We performed a prospective study in patients with Crohn’s disease analysing gut microbiota before start of adalimumab therapy (T0) and after six months of therapy (T1). Among the 20 included patients, the phylum Proteobacteria fell from 15.7 ± 3.5% at T0 to 10.3 ± 3.4% at T1 (p = 0.038). Furthermore, the trend in relation to therapeutic success was analysed. Regarding bacterial phyla, Proteobacteria decreased in patients in whom therapeutic success was obtained, passing from a value of 15.8% (± 4.6%) to 6.8 ± 3.1% (p = 0.049), while in non-responder patients, percentages did not change (T0 = 15.6 ± 5.7%, T1 = 16.8 ± 7.6%, p = 0.890). Regarding the Lachnospiraceae family, in patients with normalization of C reactive protein six 6 months of adalimumab therapy, it increased from 16.6 ± 3.1% at T0 to 23.9 ± 2.6% at T1 (p = 0.049). In conclusion, in patients who respond to Adalimumab therapy by decreasing inflammation, there is a trend of intestinal eubiosis being restored.