Cholestatic HCV Cryoglobulinemia: A New Clinical and Pathological Entity before and after Direct-Acting Antiviral Therapies-A Case-Control Study.

Twenty-nine patients with HCV infection (HCV+) and mixed cryoglobulinemia (MC+) were retrospectively selected and matched for age and sex with 31 HCV+ MC- patients. Biomarkers of cholestasis (direct bilirubin, alkaline phosphatase, and gamma-glutamyl transferase), HCV-RNA and genotype, and plasma cryoprecipitates were measured before and after virus eradication; liver histology and plasma cells (aggregation and distribution), observed blinded by two pathologists, were analyzed. Sixty participants (mean age: 56.5; range: 35-77, males: 50%) with HCV infection were enrolled. Cholestasis (≥2 pathologically increased cholestasis biomarkers) was significantly higher in the MC group (p = 0.02) and correlated with cryoglobulinemia (OR 6.52; p = 0.02). At liver histological assessment, plasma cells were significantly increased in the MC+ group (p = 0.004) and tended to form aggregates more than the control group (p = 0.05). At multivariate analysis with MC, age, HCV-RNA, HBV diabetes, and cirrhosis, cholestasis was only significantly correlated to MC (OR 8.30; p < 0.05). In 25% patients, MC persisted after virus eradication with new antiviral treatment. Our study identified for the first time an association between MC, cholestasis, and an increased number of intrahepatic plasma cells in chronic hepatitis C (CHC) patients before virus eradication. Future studies are required to understand how MC contributes to liver damage and how its persistence affects the patients' follow-up after antiviral therapies.

Prevalence of portal vein thrombosis in non-alcoholic fatty liver disease: a meta-analysis of observational studies.

Portal vein thrombosis (PVT) is a common complication of cirrhosis as a result of portal hypertension and modification in the hemostatic balance. Accumulating evidence now suggests that patients with non-alcoholic fatty liver disease (NAFLD), especially those with advanced forms, have an increased risk of PVT. Hence, we performed a meta-analysis of observational studies to estimate the overall prevalence of PVT in patients with NAFLD and its advanced forms compared with patients with advanced liver diseases from other etiologies. We systematically searched PubMed, Scopus and Web of Science databases from the inception date to December 30th 2022, using predefined keywords, to identify observational studies. Meta-analysis was performed using random-effects modeling. We included five observational studies for a total of 225,571 patients. Of these, 26,840 (11.9%) patients had NAFLD, whereas the PVT prevalence was 8.5% (n = 2,280). When compared with patients with advanced liver diseases from other etiologies, patients with NAFLD and its advanced forms had a higher risk of prevalent PVT (OR 1.34, 100% CI 1.07-1.67 p < 0,01). The between-study heterogeneity was substantial (I2 = 88%). This meta-analysis suggests that compared with patients with advanced liver diseases from other etiologies, patient with NAFLD and its advanced forms had a higher risk of prevalent PVT. Further research is required to understand the complex link between NAFLD/NASH and PVT development.

Bacterial infections as a risk factor for non-neoplastic portal vein thrombosis development in cirrhotic patients.

BACKGROUND: Portal vein thrombosis (PVT) and sepsis are common complications in patients with liver cirrhosis. Factors that lead to PVT are not completely understood. This study aimed to investigate the possible association between bacterial infections and the development of PVT in cirrhotic patients. PATIENTS AND METHODS: 202 consecutive cirrhotic patients without previous infections, followed at the Liver Unit in Verona Hospital, were enrolled from 2017 to 2021 (median follow-up 3.3 years). During the follow-up period, PVT was diagnosed by ultrasound, CT and/or MRI, and episodes of bacterial infections requiring hospitalization were recorded. Malignant PVT was an exclusion criterion. RESULTS: Of the 202 patients enrolled (68.3 % males, mean age 63.8 ± 11 years), 22 (10.8 %) developed PVT during the follow up. In patients with PVT, the prevalence of previous bacterial infections was significantly higher compared to patients without PVT (63.6% vs 31.1 %; p = 0.02). Cox regression analysis revealed that a history of bacterial infection was the only variable that demonstrated a significant association with the risk of de novo PVT occurrence (HR 4.04, 95 % CI: 1.68-9.65). CONCLUSION: in patients with liver cirrhosis bacterial infections are a predisposing factor for the following development of PVT. Further studies are needed to confirm this evidence.

Glomerular Hyperfiltration: A Marker of Fibrosis Severity in Metabolic Associated Steatotic Liver Disease in an Adult Population.

Glomerular hyperfiltration (GH) is an increase in the glomerular filtration rate, possibly progressing to chronic kidney disease (CKD). Metabolic-associated steatotic liver disease (MASLD) is linked to an increased risk of CKD, especially if fibrosis is present; however, the association between GH and MASLD has not been explored. To evaluate GH prevalence in MASLD and its possible correlation with liver fibrosis. 772 consecutive patients with ultrasound MASLD (mean age 47.3 ± 8.9 years, 67.1% males) were enrolled. GH was defined as estimated glomerular filtration rate (eGFR) greater than the upper quartile of values in the cohort. Liver stiffness measurement (LSM) by FibroScan ≥ 7.2 kPa suggested liver fibrosis. GH was present in 20% of patients, liver fibrosis in 30%. In total, 53.4% of the cohort was obese, 40.9% hypertensive, 36.3% diabetic and 70.8% dyslipidaemic. GH patients compared to non-GH were significantly younger (38.4 ± 8.3 vs. 49.5 ± 7.7, p < 0.001), with higher prevalence of LSM > 7.2 kPa (35.5% vs. 29%, p < 0.001), without any difference in metabolic comorbidities. In multivariate analysis, age (OR 0.85, CI 95% 0.82-0.87) and significant fibrosis (OR 1.83; CI 95%1.10-3.03) remained independently associated with GH, regardless of the presence of metabolic alterations and nephrotoxic drugs. GH, an early marker of renal damage, is highly prevalent in MASLD and is associated with hepatic fibrosis. GH may be considered an early marker of both liver and renal disease and its recognition could prompt the management of risk factors aimed at preventing the progression of both hepatic and renal disease.

Metabolic-associated fatty liver disease and liver fibrosis scores as COVID-19 outcome predictors: a machine-learning application.

Patients with COVID-19 and metabolic-dysfunction associated fatty liver disease (MAFLD) appear to be at higher risk for severe manifestations, especially in the youngest decades. Our aim was to examine whether patients with MAFLD and/or with increased liver fibrosis scores (FIB-4) are at risk for severe COVID-19 illness, using a machine learning (ML) model. Six hundred and seventy two patients were enrolled for SARS-CoV-2 pneumonia between February 2020 and May 2021. Steatosis was detected by ultrasound or computed tomography (CT). ML model valuated the risks of both in-hospital death and prolonged hospitalizations (> 28 days), considering MAFLD, blood hepatic profile (HP), and FIB-4 score. 49.6% had MAFLD. The accuracy in predicting in-hospital death was 0.709 for the HP alone and 0.721 for HP + FIB-4; in the 55-75 age subgroup, 0.842/0.855; in the MAFLD subgroup, 0.739/ 0.772; in the MAFLD 55-75 years, 0.825/0.833. Similar results were obtained when considering the accuracy in predicting prolonged hospitalization. In our cohort of COVID-19 patients, the presence of a worse HP and a higher FIB-4 correlated with a higher risk of death and prolonged hospitalization, regardless of the presence of MAFLD. These findings could improve the clinical risk stratification of patients diagnosed with SARS-CoV-2 pneumonia.

Interleukin-6: A New Marker of Advanced-Sarcopenic HCC Cirrhotic Patients.

Hepatocellular carcinoma (HCC) is the major cause of liver-related death worldwide. Interleukin 6 (IL-6) promotes the growth of the HCC microenvironment. The correlation between Child-Pugh (CP) and HCC stage and between HCC stage and sarcopenia is still not clear. Our aim was to investigate whether IL-6 is correlated with HCC stage and could represent a diagnostic marker for sarcopenia. Ninety-three HCC cirrhotic patients in different stages, according to BCLC-2022 (stages A, B, and C), were enrolled. Anthropometric and biochemical parameters, comprehensive of IL-6, were collected. The skeletal muscle index (SMI) was measured using dedicated software on computer tomography (CT) images. IL-6 level was higher in advanced (BCLC C) compared to the early-intermediate (BCLC A-B) stages (21.4 vs. 7.7 pg/mL, p < 0.005). On multivariate analysis, IL-6 levels were statistically dependent on the degree of liver disease severity (CP score) and HCC stages (p = 0.001 and p = 0.044, respectively). Sarcopenic patients presented lower BMI (24.7 ± 5.3 vs. 28.5 ± 7.0), higher PMN/lymphocyte ratio (2.9 ± 2.4 vs. 2.3 ± 1.2) and increased values of log (IL-6) (1.3 ± 0.6 vs. 1.1 ± 0.3). Univariate logistic regression between sarcopenia and log (IL-6) showed a significant odds ratio (OR 14.88, p = 0.044) with an AUC of 0.72. IL-6 appears to be an effective biomarker for the diagnosis of advanced cirrhotic HCC. In addition, IL-6 could be considered a marker of cirrhotic HCC-related sarcopenia, suggesting further investigation with BIA- or CT-dedicated software.

The multi-drug resistant organisms infections decrease during the antimicrobial stewardship era in cirrhotic patients: An Italian cohort study.

BACKGROUND AND PURPOSE: Bacterial infections represent a major cause of morbidity and mortality in cirrhotic patients. Our aim was to assess the incidence of bacterial infections, in particular due to multidrug-resistant organisms (MDROs) before and after the introduction of the antimicrobial stewardship program, "Stewardship Antimicrobial in VErona" (SAVE). In addition, we also analysed the liver complications and the crude mortality during the whole follow up. METHODS: We analysed 229 cirrhotic subjects without previous hospitalization for infections enrolled at the University Verona Hospital from 2017 to 2019 and followed up until December 2021 (mean follow-up 42.7 months). RESULTS: 101 infections were recorded and 31.7% were recurrent. The most frequent were sepsis (24.7%), pneumonia (19.8%), spontaneous bacterial peritonitis (17.8%). 14.9% of infections were sustained by MDROs. Liver complications occurred more frequently in infected patients, and in case of MDROs infections with a significantly higher MELD and Child-Pugh score. In Cox regression analysis, mortality was associated with age, diabetes and bacterial infections episodes (OR 3.30, CI 95%: (1.63-6.70). Despite an increase in total infections over the past three years, a decrease in the incidence rate in MDROs infections was documented concurrently with the introduction of SAVE (IRD 28.6; 95% CI: 4.6-52.5, p = 0.02). CONCLUSIONS: Our study confirms the burden of bacterial infections in cirrhotic patients, especially MDROs, and the strong interconnection with liver complications. The introduction of SAVE decreased MDROs infections. Cirrhotic patients require a closer clinical surveillance to identify colonized patients and avoid the horizontal spread of MDROs in this setting.

Bacterascites confers poor patient prognosis beyond MELD prediction.

Spontaneous bacterial peritonitis (SBP) is a well-recognized clinical entity with a poor prognosis. In comparison, the prevalence, microbiological flora, and prognostic significance of bacterascites (BA) (the presence of organism on culture but ascitic PMN <250 cells/mm³) is largely unknown. We, therefore, assessed the prognosis and predictors of outcome in patients with BA in comparison with those with SBP. Ascitic fluid cultures from consecutive patients with cirrhosis from 2008 to 2018 were reviewed retrospectively, and patients with SBP and BA were identified. Baseline demographic, laboratory, and microbiological data were collated and analyzed as prognostic indicators, and clinical outcomes were recorded. Patients were censored at the time of LT, death, or last follow-up. For this study 176 and 213 cases of SBP and BA, respectively, were identified and included. Patients with SBP had significantly higher Model for End-Stage Liver Disease (MELD) ( p =<0.01), peripheral blood WCC ( p < 0.01), and higher rates of Enterobacteriaceae ( p < 0.01) and multi-drug resistant pathogens ( p < 0.01). Survival at 1 and 3 months was lower in patients with SBP ( p < 0.01) when compared with BA but at 6 months and beyond, no significant difference remained. After the exclusion of deaths within 30 days of presentation, survival between SBP and BA was equivocal at all time points. Mortality was substantially higher across all MELD groupings for both SBP and BA when compared with the predicted mortality calculated by the MELD score alone. BA has a negative impact on patient survival above that predicted by the MELD score. It has similar impact to SBP on patient survival beyond 1 month suggesting it should be seen as a poor prognostic marker and prompt consideration of LT where appropriate. Further studies evaluating the role of secondary prophylaxis in this group are required.

Subclinical and clinical atherosclerosis in non-alcoholic fatty liver disease is associated with the presence of hypertension.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular (CV) risk. However, it is unclear whether NAFLD contributes independently to the development of CV disease. Our study aimed at assessing the differences in several indices of atherosclerosis, arterial stiffness and cardiac morphology among patients with isolated NAFLD, isolated hypertension (HT) or a combination of the two conditions. METHODS AND RESULTS: A total of 169 participants (mean age = 50.4 ± 10.2 yrs; males = 73.6%) were divided according to the presence of NAFLD and HT into three groups: only NAFLD (55 patients), only HT (49 patients), and NAFLD + HT (65 patients). Exclusion criteria were a BMI≥35 kg/m2 and a diagnosis of diabetes mellitus. Carotid ultrasonography was performed to measure markers of atherosclerosis and arterial stiffness. Cardiac remodeling was analyzed using echocardiography. The prevalence of subclinical and overt atherosclerosis was significantly higher in the NAFLD + HT patients as compared to the other two groups (atherosclerotic plaques: 43.1%, 10.9%, and 22.4% (p < 0.001) in NAFLD + HT, NAFLD, and HT groups, respectively). No differences were found among indices of arterial stiffening and cardiac remodeling across the three groups. In multivariate regression analysis, the coexistence of NAFLD and HT was an independent risk factor for overt atherosclerosis (OR = 4.88, CI 95% 1.14-20.93), while no association was found when either NAFLD or HT was considered alone. CONCLUSION: Overt atherosclerosis was significantly present only in NAFLD + HT patients, but not in patients with isolated NAFLD. This implies that the impact of NAFLD on vascular structure and function could depend on the coexistence of other major CV risk factors, such as HT.

Effects of direct-acting antiviral agents on lipid and glucose profile in HCV patients with type 2 diabetes: A real-life Italian experience.

OBJECTIVES: Hepatitis C virus (HCV) infection is associated with an increased risk of type 2 diabetes mellitus (T2DM) and cardiovascular diseases. The impact of HCV eradication on the metabolic profile in diabetic patients treated with direct-acting antiviral agents (DAAs) is not well defined. The aim of our study was to evaluate the effects of DAAs on a lipid and glucose profile in a cohort of diabetic patients with different liver fibrotic stages. METHODS: T2DM patients with active HCV infection were consecutively enrolled in this prospective trial. Glycolipidic status was assessed, before starting DAA treatment (T0) and at 12 months after the beginning of treatment (T1). Liver fibrotic stage was assessed by FibroScan. RESULTS: In all, 131 patients were enrolled and all of them achieved a sustained virologic response. At baseline, no significant differences were found in lipid and glucose profiles in subgroup analysis by liver fibrosis, HCV genotype, and cardiovascular risk factors. At T1, total cholesterol and low-density lipoprotein cholesterol, but not triglycerides, significantly increased irrespective of liver fibrotic stage and baseline anthropometric and clinical profiles, while glycated hemoglobin significantly decreased only in F4 patients. CONCLUSIONS: HCV eradication in diabetic patients is associated with a worsening lipid profile that could impact future cardiovascular risk. A careful global monitoring of cardiovascular risk factors in all diabetic patients after HCV eradication is needed.

Comparison of point-shear wave elastography (ElastPQ) and transient elastography (FibroScan) for liver fibrosis staging in patients with non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: ElastPQ is a point shear wave elastography technique used to non-invasively assess liver fibrosis. We compared liver stiffness measurements (LSM) by ElastPQ and fibroscan transient elastography (F-TE) in a cohort of patients with non-alcoholic fatty liver disease (NAFLD). We further evaluated the performance of ElastPQ in a subgroup of patients with available liver histology. MATERIALS AND METHODS: We included patients with NAFLD who presented in a dedicated multidisciplinary clinic. Anthropometric parameters, blood tests and elastography measurements were obtained using F-TE and ElastPQ as part of routine clinical care. RESULTS: We enrolled 671 patients with NAFLD, mean age 55.8 ± 13 years, body mass index (BMI) 31.5 ± 5.7 kg/m2 , 56.6% males, 41% diabetes, 53.7% hypertension, 68% dyslipidaemia. ElastPQ showed an excellent correlation with F-TE (Spearman's r = 0.80, p < .001), which was better for mild/moderate stages of fibrosis. Independent predictors of a >2 kPa discrepancy between the two techniques were a larger waist circumference and F-TE ≥10 kPa. In the subgroup of 159 patients with available histology, ElastPQ showed similar diagnostic accuracy with F-TE in staging liver fibrosis (ElastPQ area under the curves 0.84, 0.83, 0.86 and 0.95, for F ≥ 1, F ≥ 2, F ≥ 3 and F = 4 respectively). Optimal cut-off values of ElastPQ for individual fibrosis stages were lower than those of F-TE. CONCLUSIONS: ElastPQ shows an excellent correlation with F-TE in patients with NAFLD, which was better for lower LSM. The optimal cut-off values of ElastPQ are lower than those of F-TE for individual stages of fibrosis. ElastPQ has similar diagnostic accuracy to F-TE for all stages of fibrosis.

Relationship between common carotid distensibility/aortic stiffness and cardiac left ventricular morphology and function in a group of patients affected by chronic rheumatic diseases: an observational study.

OBJECTIVES: Chronic inflammatory arthritis (CIAs), including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) are characterised by high cardiovascular disease (CVD) risk, partly due to endothelial dysfunction and increased arterial stiffness of the carotid artery and aorta. The aim of the present study is to determine whether ultrasonography measures of carotid and aortic stiffness are correlated with left ventricular mass and function in patients affected by CIAs. METHODS: In this cross-sectional study, we consecutively enrolled outpatients diagnosed with CIAs with no overt CVD. For each participant we assessed disease characteristics, CVD risk factors, medications, including disease-modifying anti-rheumatic drugs (DMARDs), blood pressure, lipids and glucose levels. Carotid ultrasonography was performed in all patients using carotid distensibility (CD) and aortic stiffness index (AoSI) as measures of arterial stiffness. Participants underwent the same day a full echocardiographic study including assessment of left ventricular function and mass (LVM). RESULTS: The study population comprised 208 CIAs patients (mean age 57.4±11.4 y; females 63.9%), including 137 (65.9%) RA, 42 (20.2%) PsA and 29 (13.9%) AS patients. In multiple regression analysis, CD correlated with age (ß=-0.198, p<0.0001), mean arterial pressure (ß=-0.281, p<0.0001) and treatment with DMARDs (ß=-1.976, p=0.021), while AoSI was not associated with any anthropometric, haemodynamic or clinical covariates. CD was inversely related to LVM (r=-0.20, p=0.005), whereas AoSI was directly correlated with diastolic function of the left ventricle (E/E'; r=0.191, p=0.007). CONCLUSIONS: Our results underline the strict correlation between arterial stiffness and left ventricular mass and function in patients with CIAs.

Abnormal liver function tests predict transfer to intensive care unit and death in COVID-19.

BACKGROUND: The pandemic of coronavirus disease 2019 (COVID-19) has emerged as a relevant threat for humans worldwide. Abnormality in liver function tests (LFTs) has been commonly observed in patients with COVID-19, but there is controversy on its clinical significance. The aim of this study was to assess the prevalence, the characteristics and the clinical impact of abnormal LFTs in hospitalized, non-critically ill patients with COVID-19. METHODS: In this multicentre, retrospective study, we collected data about 565 inpatients with COVID-19. Data on LFTs were collected at admission and every 7 ± 2 days during the hospitalization. The primary outcome was a composite endpoint of death or transfer to intensive care unit (ICU). RESULTS: Upon admission 329 patients (58%) had LFTs abnormality. Patients with abnormal LFTs had more severe inflammation and higher degree of organ dysfunction than those without. During hospitalization, patients with abnormal LFTs had a higher rate of transfer to ICU (20% vs 8%; P < .001), acute kidney injury (22% vs 13%, P = .009), need for mechanical ventilation (14% vs 6%; P = .005) and mortality (21% vs 11%; P = .004) than those without. In multivariate analysis, patients with abnormal LFTs had a higher risk of the composite endpoint of death or transfer to ICU (OR = 3.53; P < .001). During the hospitalization, 86 patients developed de novo LFTs abnormality, which was associated with the use of tocilizumab, lopinavir/ritonavir and acetaminophen and not clearly associated with the composite endpoint. CONCLUSIONS: LFTs abnormality is common at admission in patients with COVID-19, is associated with systemic inflammation, organ dysfunction and is an independent predictor of transfer to ICU or death.

Beneficial effects of DAAs on cardiac function and structure in hepatitis C patients with low-moderate liver fibrosis.

Hepatitis C virus (HCV)-related chronic infection has been associated with a higher incidence of cardiovascular diseases. An altered morphology and function of both left and right heart have been described in HCV patients; however, the causality of the association is still debated. Ninety-eight nonobese and nondiabetic HCV patients (59.5 ± 12.0 years; males 52%) with Fibroscan-Transient Elastography assessed low-moderate liver fibrosis that achieved sustained viral response at 12 and 24 weeks after DAAs (direct-acting antivirals) participated. 56 were matched with 52 control subjects for age, sex and cardiovascular risk factors at baseline. A trans-thoracic echocardiography was performed in each subject at baseline (T0) and repeated in all HCV patients after eradication (6 months later eligibility, T1). TNF-α and IL-10 were measured at baseline and at T1. A concentric remodelling of the left heart in HCV participants was identified, whereas tricuspidal annular plane systolic excursion, right indexed atrial volume, right basal ventricular diameter, inferior vena cava diameter and pulmonary arterial pressure were higher in HCV participants compared to matched controls. After virus eradication, left indexed atrial volume and all right cardiac chambers measures were lower than baseline. A significant reduction of TNF-α was shown at T1, while IL-10 did not change. This study shows a concentric remodelling of the left ventricle and structural modifications in the right sections in HCV patients compared to controls. Virus eradication with DAAs was associated with a reduction of the main right atrioventricular parameters indicating a direct involvement of the HCV in cardiac changes.

Individual fatty acids in erythrocyte membranes are associated with several features of the metabolic syndrome in obese children.

PURPOSE: Obesity leads to the clustering of cardiovascular (CV) risk factors and the metabolic syndrome (MetS) also in children and is often accompanied by non-alcoholic fatty liver disease. Quality of dietary fat, beyond the quantity, can influence CV risk profile and, in particular, omega-3 fatty acids (FA) have been proposed as beneficial in this setting. The aim of the study was to evaluate the associations of individual CV risk factors, characterizing the MetS, with erythrocyte membrane FA, markers of average intake, in a group of 70 overweight/obese children. METHODS: We conducted an observational study. Erythrocyte membrane FA were measured by gas chromatography. Spearman correlation coefficients (rS) were calculated to evaluate associations between FA and features of the MetS. RESULTS: Mean content of Omega-3 FA was low (Omega-3 Index = 4.7 ± 0.8%). Not omega-3 FA but some omega-6 FA, especially arachidonic acid (AA), were inversely associated with several features of the MetS: AA resulted inversely correlated with waist circumference (rS = - 0.352), triglycerides (rS = - 0.379), fasting insulin (rS = - 0.337) and 24-h SBP (rS = - 0.313). Total amount of saturated FA (SFA) and specifically palmitic acid, correlated positively with waist circumference (rS = 0.354), triglycerides (rS = 0.400) and fasting insulin (rS = 0.287). Fatty Liver Index (FLI), a predictive score of steatosis based on GGT, triglycerides and anthropometric indexes, was positively correlated to palmitic acid (rS = 0.515) and inversely to AA (rS = - 0.472). CONCLUSIONS: Our data suggest that omega-6 FA, and especially AA, could be protective toward CV risk factors featuring the MetS and also to indexes of hepatic steatosis in obese children, whereas SFA seems to exert opposite effects.

Effects of Antiangiogenetic Drugs on Microcirculation and Macrocirculation in Patients with Advanced-Stage Renal Cancer.

Adverse cardiovascular effects, including hypertension, were described in patients with different cancers treated with tyrosine kinase inhibitors (TKI). The mechanism of TKI-related hypertension is still debated. The aim of this work was to study the effects of TKI on blood pressure (BP), searching for a relationship with possible causative factors in patients with metastatic renal cell carcinoma. We included 29 patients in a prospective, observational study; 22 were treated with a first-line drug (sunitinib), while seven participated in the second-line treatment (axitinib or cabozantinib). Patients were investigated at the beginning of antiangiogenic therapy (T0) and at one (T1), three (T2), and six months (T3) after treatment. Patients were evaluated by office blood pressure (BP) and ultrasonography to measure flow-mediated dilatation (FMD), and carotid artery distensibility (cDC) by echocardiography and nailfold capillaroscopy. Plasma endothelin-1 (p-ET-1), urine nitrates, and proteins were also measured. At T1, systolic BP, along with U proteins and p-ET-1, increased significantly. In patients with a clinically significant increase in BP (defined as either the need for an antihypertensive drug or systolic blood pressure (SBP) T1⁻T0 ≥10 and/or SBP ≥140 mmHg and/or diastolic blood pressure (DBP) T1⁻T0 ≥5 and/or DBP ≥90 mmHg), the urine nitrate concentration was lower at T0, whereas there were no differences in the p-ET-1 and U proteins. Seventeen participants showed changes in the capillaroscopic pattern at T1 with no association with BP increases. There were no differences in the FMD, cDC, and echocardiographic parameters. Our findings are consistent with those of previous studies about BP increases by TKI, and suggest a role of nitric oxide in BP maintenance in this population.

Criminal investigations: pupil pharmacological reactivity as method for assessing time since death is fallacious.

Determination of the time since death in the early postmortem period is one of the most critical issues to be faced by criminal investigators. One of the techniques is the evaluation of the pupil pharmacological reactivity. In the present work, we aim at identifying whether an objective and single method, based on pharmacological pupil reaction, is feasible or not. Between 2002 and 2003 calendar years, we observed 309 bodies, whose eyes have been each instilled apart, within 26 hours since death, with either a myotic substance or a mydriatic solution. Our results show that the real effectiveness of pupil pharmacological reactivity as method for assessing the time since death in early postmortem period is not only questionable but even highly misleading if not replaced by alternative objective physiological tests and appropriate professional judgments by the investigators.