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Introduction: Acute kidney injury (AKI) is a commonly seen condition in the natural course of cirrhosis. The aim of this study was to evaluate the pooled incidence and risk factors of AKI in different clinical stages and situations in patients with cirrhosis. Methods: Search was conducted on 13 December 2023 across MEDLINE (PubMed), Embase, and Cochrane databases. Meta-analysis was performed using a generalized linear mixed model. Results: In total, 73 studies with 5,202,232 patients were finally enrolled in the meta-analysis. AKI commonly occurs among hospitalized cirrhotics experiencing any decompensation event (29%) as well as among stable outpatients (28%) throughout a 1-year follow-up period. On admission, patients with infection or sepsis/septic shock had the highest AKI rate (47%), followed by those with hepatic encephalopathy (41%). Furthermore, the severity of liver disease proved to be a substantial driver for AKI development, while patients at intensive care unit had the greatest AKI incidence (61%). Conclusions: Both hospitalized patients and stable outpatients with cirrhosis exhibited an elevated susceptibility to AKI. Patients at intensive care unit and those with severe liver disease, infection, sepsis/septic shock, hepatic encephalopathy, or acute on chronic liver failure upon admission are at higher risk for AKI. Trial registration: PROSPERO, registered 09/12/23, CRD42023487736 [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) and liver cirrhosis are clinical entities that frequently coexist, but glucose‐lowering medication options are limited in cirrhotic patients. Sodium–glucose linked transporter 2 (SGLT2) inhibitors are a class of glucose‐lowering medication that act independently of insulin, by causing glycosuria in the proximal convoluted tubule. In this review, we aimed to briefly present the main data and to provide insight into the pathophysiology and potential usefulness of SGLT2 inhibitors in cirrhotic patients with or without T2DM. SGLT2 inhibitors have been proven useful as antidiabetic treatment in patients with metabolic liver disease, with most robust data from patients with metabolic dysfunction‐associated steatotic liver disease (MASLD), where they also showed improvement in liver function parameters. Moreover, it has been suggested that SGLT2 inhibitors may have effects beyond their antidiabetic action. Accordingly, they have exhibited cardioprotective effects, expanding their indication in patients with heart failure without T2DM. Since decompensated liver cirrhosis and congestive heart failure share common pathophysiological features, namely renin–angiotensin–aldosterone axis and sympathetic nervous system activation as well as vasopressin secretion, SGLT2 inhibitors could also be beneficial in patients with decompensated cirrhosis, even in the absence of T2DM. [ABSTRACT FROM AUTHOR]

Administration of sedation by non-anesthesiologists during gastrointestinal endoscopy remains highly controversial in Greece. The aim of this set of 16 position statements prepared by experts in the field on behalf of the Hellenic Society of Gastroenterology is to aid gastroenterologists in their everyday clinical practice and provide evidence for the best use of drugs for the sedation of patients who undergo an endoscopy. The statements address issues such as the level of sedation required, the best drugs used, their mode of action, their side-effects and possible ways to counter their action, and were adopted if at least 80% of all participants agreed upon them. [ABSTRACT FROM AUTHOR]

Undernutrition is widely prevalent in patients with cirrhosis and affects prognosis. Given the lack of data regarding the dietary intake (DI) and habits of patients with cirrhosis, the aim of the present study was to evaluate them by assessing diet's adequacy compared to the new guidelines, and the association of DI with nutritional status indicators. One hundred and eighty-seven patients (57.8% male, 59.9 ± 10.9 years old, 44.9% decompensated ones) with cirrhosis of various etiologies were enrolled. The patients' DI was assessed using three 24 h recalls, which were analyzed regarding macronutrients' intake, food groups consumption, adherence to the Mediterranean diet and meal patterns. The Goldberg cut-off limits for the ratio of energy intake to resting energy expenditure were used to evaluate dietary underreporting and patients were accordingly classified as low or adequate energy reporters (LERs and AERs). Among the AERs (n = 91, 48.7%) only 29.7% and 31.9% met current recommendations regarding energy and protein intake, accordingly. Patients reported low intake of several healthy food groups and low adherence to the Mediterranean diet. They reported a median of 4.3 eating episodes per day and they frequently omitted late evening snack. Nevertheless, no statistically significant associations were found between parameters of DI and annual and two-year survival. Low energy reporting was very frequent in this sample of patients with liver cirrhosis. Diet quality was rather poor, whereas energy and protein intakes were lower than those recommended. [ABSTRACT FROM AUTHOR]

Background Peptic ulcer disease (PUD) is more prevalent in cirrhotics and this may aggravate prognosis. We investigated the prevalence of PUD in cirrhotics and its potential association with Helicobacter pylori (H. pylori) infection, the underlying etiology and severity of liver disease, and other manifestations of portal hypertension (PH). Methods We enrolled consecutive asymptomatic cirrhotic patients who underwent screening endoscopy in a tertiary hospital during a 12-month period. We recorded the presence of PUD and the endoscopic findings associated with PH. H. pylori infection was documented through either histology or CLO-test. The diagnosis of cirrhosis was based on elastography, liver biopsy or a combination of clinical, biochemical and imaging data. Results One hundred patients (M/F: 54/46, mean age: 61±14 years) were included in the analysis. Viral hepatitis (37%) and alcohol (22%) were the most common causes of cirrhosis. Child-Pugh stage was A/B/C: 60/35/5. PUD was found in 19 patients (14 gastric, 5 duodenal). H. pylori infection was diagnosed in 54%. Varices were detected in 59% (39% needed treatment). PH gastropathy was present in 81% (severe in 33%). The presence of PUD was unrelated to the etiology and the severity of liver disease or to other endoscopic manifestations of PH. No correlation was found between PUD and H. pylori infection. Conclusions A high prevalence of PUD was observed in our cirrhotic patients, although they were asymptomatic and had no known risk factors of ulcerogenicity. The value of screening endoscopy for the early diagnosis and treatment of PUD in cirrhotics deserves further investigation. [ABSTRACT FROM AUTHOR]

Background It is estimated that 17,000 people who inject drugs (PWID) in Greece have hepatitis C virus (HCV) viremia. The aim of our study was to explore the characteristics of the HCVinfected, direct acting antiviral (DAA)-naïve PWID. Methods This is a retrospective analysis of PWID with HCV infection. We selected data from six liver clinics during the period from 1st May 2014 to 31st May 2017 in order to record the characteristics of infected PWID. Results We included 800 PWID with HCV infection (78.5% male, mean age 42±10 years) who had not received DAAs before 1st June 2017. One third of the patients had comorbidities (diabetes mellitus, arterial hypertension and psychological disorders); 70% were smokers, 27% alcohol users, 67% unemployed, 29% married, and 34% had education >12 years; 65% were attending addiction programs; 57% were receiving methadone and 36% buprenorphine. Sporadic or systemic drug use was reported by 37% while 1.4% and 2.9% had HIV and HBV coinfection, respectively. The genotype distribution was 20.5%, 4.6%, 3.3%, 61% and 10% for genotypes 1a, 1b, 2, 3 and 4, respectively. Mean (±SD) liver stiffness was 9±7 kPa and 21% of the patients had cirrhosis. Half of the patients were in the F0-F1 stage of liver disease, defined as stiffness =7 kPa. Conclusions Our real-life data suggest that HCV genotype 3 remains the predominant genotype among PWID. One third of PWID had comorbidities and one-fifth cirrhosis. Half of PWID had earlystage liver disease and remained without access to DAAs according to the Greek prioritization criteria. [ABSTRACT FROM AUTHOR]

Background: The aim of our study was to evaluate the safety and efficacy of triple therapy using boceprevir (BOC) with pegylated interferon (pIFN)/ribavirin (RBV) in chronic hepatitis C (CHC) genotype 1 (G1) treatment-experienced patients with advanced fibrosis or compensated cirrhosis. Methods: We report the Greek experience on the first CHC patients who received BOC-based regimen. From September 2011 to June 2012, 26 treatment-experienced CHC patients and G1 with bridging fibrosis or compensated cirrhosis received 48 weeks of BOC+pIFN+RBV antiviral therapy. Data on complete blood counts and HCV RNA levels were obtained prior to therapy, at treatment weeks 4, 8, 12, 24, 36, 48 and 24 weeks after the end of treatment. Results: A full set analysis was performed in 25 of 26 patients. Nine patients (36%) achieved sustained viral response (SVR). Ten patients (40%) stopped the therapy because of futility rules and 3 (12%) due to adverse events. Four patients (16%) developed a virological breakthrough (3 of those presented futility rules as well) and 2 (8%) relapse. All patients who achieved SVR had G 1b, 6 (67%) were non-cirrhotic and 5 (55%) had >1 log decline in baseline HCV RNA levels at week 4 of the treatment. There were no deaths, while two patients were hospitalized due to side eff ects. Conclusion: The triple therapy with BOC+pIFN+RBV in this cohort of real-life treatmentexperienced CHC G1 patients and advanced liver disease was safe off ering cure in the majority of those who could tolerate and complete treatment under a close monitoring. [ABSTRACT FROM AUTHOR]

Background/aim Patients with HBV-related decompensated cirrhosis (HBV-DeCi) should be treated with potent nucleos(t)ide analogues (NA)[entecavir (ETV) or tenofovir (TDF)]. The aim was the evaluation of safety and efficacy in terms of changes in liver disease course in HBV-DeCi patients treated with ETV or TDF. Methods In 52 HBV-DeCi patients clinical and laboratory data, including glomerular filtration rates (GFR), were recorded. The changes in MELD (DMELD) and Child-Pugh (DCTP) scores between baseline and after 6 months of treatment were evaluated. The independent factors associated with survival were evaluated. Results 31 patients under TDF and 21 under ETV were evaluated. During a median follow-up of 22.5 months (range: 6-68), there were no differences between the two groups in GFR and serum phosphate levels. At the end of follow up, in the TDF group, 2 patients died and 3 received liver transplantations (LT), while in the ETV group, 1 patient died and 3 received LT. In multivariable Cox regression analysis, DMELD was independently associated with the outcome in the total cohort (HR: 1.78, 95%C.I.:1.12-2.79, P=0.013) as well as in the subgroup of naïve (n=37) patients (HR: 1.8, 95%C.I.:1.19-4.5, P=0.03). Finally, in the non-hepatocellular carcinoma patients, the DCTP score was independently associated with the outcome in the total cohort (HR: 2.64, 95%C.I.: 1.21-7.29, P=0.015). Conclusions TDF and ETV appear to have similar renal safety profile in HBV-DeCi patients. DMELD score in the total cohort and DCTP score in non-HCC patients were independently associated with the outcome; these findings need confirmation in larger studies. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Ambulatory 24-h pH-impedance monitoring can be used to assess the relationship of persistent symptoms and reflux episodes, despite proton pump inhibitor (PPI) therapy. Using this technique, we aimed to identify patients with hypersensitive esophagus and evaluate the effect of selective serotonin reuptake inhibitors (SSRIs) on their symptoms.METHODS:Patients with normal endoscopy and typical reflux symptoms (heartburn, chest pain, and regurgitation), despite PPI therapy twice daily, underwent 24-h pH-impedance monitoring. Distal esophageal acid exposure (% time pH <4) was measured and reflux episodes were classified into acid or non-acid. A positive symptom index (SI) was declared if at least half of the symptom events were preceded by reflux episodes. Patients with a normal distal esophageal acid exposure time, but with a positive SI were classified as having hypersensitive esophagus and were randomized to receive citalopram 20 mg or placebo once daily for 6 months.RESULTS:A total of 252 patients (150 females (59.5%); mean age 55 (range 18-75) years) underwent 24-h pH-impedance monitoring. Two hundred and nineteen patients (86.9%) recorded symptoms during the study day, while 105 (47.9%) of those had a positive SI (22 (20.95%) with acid, 5 (4.76%) with both acid and non-acid, and 78 (74.29%) with non-acid reflux). Among those 105 patients, 75 (71.4%) had normal distal esophageal acid exposure time and were randomized to receive citalopram 20 mg (group A, n=39) or placebo (group B, n=36). At the end of the follow-up period, 15 out of the 39 patients of group A (38.5%) and 24 out of the 36 patients of group B (66.7%) continue to report reflux symptoms (P=0.021).CONCLUSIONS:Treatment with SSRIs is effective in a select group of patients with hypersensitive esophagus. [ABSTRACT FROM AUTHOR]

A recent study in Asian patients with chronic hepatitis B (CHB) reported that the incidence of hepatocellular carcinoma (HCC) was lower in patients treated with tenofovir disoproxil fumarate (TDF) than entecavir (ETV), but this finding remains controversial. We aimed to identify any differences in HCC incidence, or other patient outcomes, between patients receiving TDF or ETV in the well monitored, multicenter European PAGE-B cohort. We included 1,935 Caucasians with CHB, with or without compensated cirrhosis, treated with ETV (n = 772) or TDF (n = 1,163) monotherapy. Mean follow-up was 7.1 ± 3.0 years from ETV/TDF onset. The 5-year cumulative HCC incidence was 5.4% in ETV- and 6.0% in TDF-treated patients (log-rank, p = 0.321), with no significant difference in any patient subgroup (with or without cirrhosis, naïve or experienced to oral antiviral(s) [total, with or without cirrhosis]). In multivariable Cox regression analyses, the hazard of HCC was similar between ETV- and TDF-treated patients after adjustment for several HCC risk factors. ETV- and TDF-treated patients had similar rates of on-therapy biochemical and virological remission, HBsAg loss, liver transplantation and/or death. Elastographic reversion of cirrhosis at year 5 (liver stiffness <12 kPa) was observed in 245/347 (70.6%) patients with pretreatment cirrhosis, being more frequent in TDF- than ETV- treated patients (73.8% vs. 61.5%, p = 0.038). In Caucasian patients with CHB, with or without cirrhosis, long-term ETV or TDF monotherapy is associated with similar HCC risk, rates of biochemical/virological remission, HBsAg loss and liver transplantation or death, but elastographic reversion of cirrhosis at year 5 was more frequent with TDF. In a large cohort of Caucasians with chronic hepatitis B treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF) monotherapy, cumulative rates of hepatocellular carcinoma did not differ (up to 12 years). Nor did rates of biochemical/virological remission, HBsAg loss and liver transplantation or death. However, elastographic reversion of cirrhosis at year 5 was more frequent in TDF- than ETV-treated patients with pretreatment cirrhosis. • Caucasians with chronic hepatitis B treated with entecavir vs. tenofovir had: • Similar rates of hepatocellular carcinoma up to 12 years • Similar rates of biochemical/virological response, HBsAg loss and mortality • Less frequent elastographic reversion of cirrhosis at year 5 [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) may develop in patients with chronic hepatitis (CHB) even after 5 years of oral therapy and cannot be easily predicted. We assessed predictors of HCC development and the need for HCC surveillance in this setting. Of 1,951 adult Caucasians with CHB included in the PAGE-B cohort, 1,427 (73%) had completed >5 years of follow-up under therapy without developing HCC by year 5. Median follow-up was 8.4 years from treatment onset. Points-based risk scores were developed to predict HCC risk after year 5. In years 5–12, HCC was diagnosed in 33/1,427 (2.3%) patients with cumulative incidences of 2.4%, 3.2% and 3.8% at 8, 10 and 12 years, respectively. Older age or age >50 years, baseline cirrhosis and liver stiffness (LSM) ≥12 kPa at year 5 were independently associated with increased HCC risk. The HCC incidence was lower in non-cirrhotics than cirrhotics at baseline with year-5 LSM <12; among cirrhotics at baseline, it was lower in those with year-5 LSM <12 than ≥12 kPa. CAGE-B score was based on age at year 5 and baseline cirrhosis in relation to LSM at year 5 and SAGE-B score was based only on age and LSM at year 5 (c-index = 0.809–0.814, 0.805–0.806 after bootstrap validation). Both scores offered 100% negative predictive values for HCC development in their low risk groups. In Caucasians with CHB, the HCC risk after the first 5 years of antiviral therapy depends on age, baseline cirrhosis status and LSM at year 5. CAGE-B and particularly SAGE-B represent simple and reliable risk scores for HCC prediction and surveillance beyond year 5 of therapy. In Caucasians with chronic hepatitis B, the risk of hepatocellular carcinoma after the first 5 years of entecavir or tenofovir therapy depends on age, baseline cirrhosis status and liver stiffness at year 5, which can provide simple and reliable risk scores for hepatocellular carcinoma prediction and surveillance beyond year 5. In patients with cirrhosis at baseline, liver stiffness <12 kPa at year 5 is associated with lower HCC risk, but surveillance may be still required. • Study conducted in Caucasians with chronic hepatitis B, with or without cirrhosis, after 5 years of entecavir/tenofovir. • Age >50 years, baseline cirrhosis and liver stiffness ≥12 kPa at year 5 were independently associated with increased risk of HCC. • CAGE-B score based on age at year 5 and baseline cirrhosis in relation to LSM at year 5 reliably predicted HCC risk >5 years. • SAGE-B score based only on age and LSM at year 5 was also a reliable predictor of HCC incidence >5 years. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Tenofovir-associated Fanconi syndrome in patients with chronic hepatitis B monoinfection," by D. M. Gracey and colleagues in the 2013 issue.

Background: Increased gut permeability and bacterial translocation play an important role in liver cirrhosis. Zonulin is a recently recognized protein involved in the disintegration of the intestinal barrier., Aim: To investigate possible differences in serum zonulin levels among patients with different cirrhosis stages and their potential prognostic implications., Methods: Consecutive cirrhotic patients who attended our liver clinic were included in the study. Serum zonulin levels, clinical, radiological and biochemical data were collected at baseline. Patients who accepted participation in a regular surveillance program were followed-up for at least 12 mo., Results: We enrolled 116 cirrhotics [mean Child-Turcotte-Pugh (CTP) score: 6.2 ± 1.6; model for end-stage liver disease score: 11 ± 3.9]. The causes of cirrhosis were viral hepatitis (39%), alcohol (30%), non-alcoholic fatty liver disease (17%), and other (14%). At baseline, 53% had decompensated cirrhosis, 48% had ascites, and 32% had history of hepatic encephalopathy. Mean zonulin levels were significantly higher in patients with CTP-B class than CTP-A class (4.2 ± 2.4 ng/dL vs 3.5 ± 0.9 ng/dL, P = 0.038), with than without ascites ( P = 0.006), and with than without history of encephalopathy ( P = 0.011). Baseline serum zonulin levels were independently associated with the probability of decompensation at 1 year ( P = 0.039), with an area under the receiving operating characteristic of 0.723 for predicting hepatic decompensation. Higher CTP score ( P = 0.021) and portal vein diameter ( P = 0.022) were independent predictors of mortality., Conclusion: Serum zonulin levels are higher in patients with more advanced chronic liver disease and have significant prognostic value in identifying patients who will develop decompensation., Competing Interests: Conflict-of-interest statement: The authors declare having no real or potential conflicts to disclose., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: It is estimated that 17,000 people who inject drugs (PWID) in Greece have hepatitis C virus (HCV) viremia. The aim of our study was to explore the characteristics of the HCV-infected, direct acting antiviral (DAA)-naïve PWID., Methods: This is a retrospective analysis of PWID with HCV infection. We selected data from six liver clinics during the period from 1 st May 2014 to 31 st May 2017 in order to record the characteristics of infected PWID., Results: We included 800 PWID with HCV infection (78.5% male, mean age 42±10 years) who had not received DAAs before 1 st June 2017. One third of the patients had comorbidities (diabetes mellitus, arterial hypertension and psychological disorders); 70% were smokers, 27% alcohol users, 67% unemployed, 29% married, and 34% had education >12 years; 65% were attending addiction programs; 57% were receiving methadone and 36% buprenorphine. Sporadic or systemic drug use was reported by 37% while 1.4% and 2.9% had HIV and HBV coinfection, respectively. The genotype distribution was 20.5%, 4.6%, 3.3%, 61% and 10% for genotypes 1a, 1b, 2, 3 and 4, respectively. Mean (±SD) liver stiffness was 9±7 kPa and 21% of the patients had cirrhosis. Half of the patients were in the F0-F1 stage of liver disease, defined as stiffness ≤7 kPa., Conclusions: Our real-life data suggest that HCV genotype 3 remains the predominant genotype among PWID. One third of PWID had comorbidities and one-fifth cirrhosis. Half of PWID had early-stage liver disease and remained without access to DAAs according to the Greek prioritization criteria., Competing Interests: Conflict of Interest: Gilead Sciences

Background: The remission rates after stopping antivirals in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) vary among studies, while reliable predictors of relapse have not been identified. This prospective study assessed rates and predictors of relapse and retreatment in 57 non-cirrhotic hepatitis B surface antigen (HBsAg)-positive patients with HBeAg-negative CHB who discontinued effective ≥4-year entecavir or tenofovir disoproxil fumarate (TDF) therapy., Methods: A total of 57 patients discontinued therapy after median virological remission of 5.3 years and remained under close follow-up. They were retreated with entecavir/TDF if they fulfilled predetermined criteria., Results: During median follow-up of 18 months, no patient died, developed jaundice or liver decompensation. The cumulative relapse rates varied according to HBV DNA and alanine aminotransferase cutoffs; for HBV DNA >2,000 IU/ml, they were 56%, 70% and 72% at 3, 12 and 18 months after stopping entecavir/TDF. The cumulative probability of retreatment was 18% and 26% at 3 and 12 months being significantly affected only by pretreatment fibrosis severity (adjusted relative hazard: 3.43; P=0.015). Cumulative rates of HBsAg loss were 5%, 16% and 25% at 6, 12 and 18 months being higher in patients with lower HBsAg levels at treatment discontinuation., Conclusions: Our prospective study shows that effective ≥4-year entecavir/TDF therapy can be safely discontinued in non-cirrhotic HBeAg-negative CHB patients. The probability of relapse decreased after month 6. Despite common virological relapses, most patients, particularly those with mild-moderate pretreatment fibrosis, remain without retreatment, at least in the first 18 months, as a substantial proportion of them clear HBsAg and the majority eventually enters into an inactive carrier state.

Aim: To evaluate the utility of fecal calprotectin (FC) in predicting relapse and endoscopic activity during follow-up in an inflammatory bowel disease (IBD) cohort., Methods: All FC measurements that were obtained during a 3-year period from patients with inflammatory bowel disease in clinical remission were identified. Data regarding the short-term (6 mo) course of the disease were extracted from the medical files. Exclusion criteria were defined as: (1) An established flare of the disease at the time of FC measurement, (2) Loss to follow up within 6 mo from baseline FC measurement, and, (3) Insufficient data on file. Statistical analysis was performed to evaluate whether baseline FC measurement could predict the short term clinical relapse and/or the presence of mucosal healing., Results: We included 149 [Crohn's disease (CD) = 113, Ulcerative colitis (UC) = 36, male = 77] IBD patients in our study. Within the determined 6-month period post-FC measurement, 47 (31.5%) had a disease flare. Among 76 patients who underwent endoscopy, 39 (51.3%) had mucosal healing. Baseline FC concentrations were significantly higher in those who had clinical relapse compared to those who remained in remission during follow up (481.0 μg/g, 286.0-600.0 vs 89.0, 36.0-180.8, P < 0.001). The significant predictive value of baseline median with IQR FC for clinical relapse was confirmed by multivariate Cox analysis [HR for 100μg/g: 1.75 (95%CI: 1.28-2.39), P = 0.001]. Furthermore, lower FC baseline values significantly correlated to the presence of mucosal healing in endoscopy (69.0 μg/g, 30.0-128.0 vs 481.0, 278.0-600.0, in those with mucosal inflammation, median with IQR, P < 0.001). We were able to extract cut-off values for FC concentration with a high sensitivity and specificity for predicting clinical relapse (261 μg/g with AUC = 0.901, sensitivity 87.2%, specificity 85.3%, P < 0.001) or mucosal healing (174 μg/g with AUC = 0.956, sensitivity 91.9%, specificity 87.2%, P < 0.001). FC was better than CRP in predicting either outcome; nevertheless, having a pathological CRP (> 5 mg/L) in addition to the cut-offs for FC, significantly enhanced the specificity for predicting clinical relapse (95.1% from 85.3%) or endoscopic activity (100% from 87.2%)., Conclusion: Serial FC measurements may be useful in monitoring IBD patients in remission, as FC appears to be a reliable predictor of short-term relapse and endoscopic activity., Competing Interests: Conflict-of-interest statement: The authors have no conflict of interest to declare.