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Low-grade endotoxemia by lipopolysaccharide (LPS) has been detected in COVID-19 and could favor thrombosis via eliciting a pro-inflammatory and pro-coagulant state. The aim of this study was to analyze the mechanism accounting for low-grade endotoxemia and its relationship with oxidative stress and clotting activation thrombosis in COVID-19. We measured serum levels of sNOX2-dp, zonulin, LPS, D-dimer, and albumin in 175 patients with COVID-19, classified as having or not acute respiratory distress syndrome (ARDS), and 50 healthy subjects. Baseline levels of sNOX2-dp, LPS, zonulin, D-dimer, albumin, and hs-CRP were significantly higher in COVID-19 compared to controls. In COVID-19 patients with ARDS, sNOX2-dp, LPS, zonulin, D-dimer, and hs-CRP were significantly higher compared to COVID-19 patients without ARDS. Conversely, concentration of albumin was lower in patients with ARDS compared with those without ARDS and inversely associated with LPS. In the COVID-19 cohort, the number of patients with ARDS progressively increased according to sNOX2-dp and LPS quartiles; a significant correlation between LPS and sNOX2-dp and LPS and D-dimer was detected in COVID-19. In a multivariable logistic regression model, LPS/albumin levels and D-dimer predicted thrombotic events. In COVID-19 patients, LPS is significantly associated with a hypercoagulation state and disease severity. In vitro, LPS can increase endothelial oxidative stress and coagulation biomarkers that were reduced by the treatment with albumin. In conclusion, impaired gut barrier permeability, increased NOX2 activation, and low serum albumin may account for low-grade endotoxemia and may be implicated in thrombotic events in COVID-19., Competing Interests: The authors declare no conflicts of interest.

The association between Inflammatory Bowel Disease (IBD) and Spondyloarthritis (SpA) has been known for years, as has the concept that IBD is associated with an altered intestinal bacterial composition, a condition known as "dysbiosis". Recently, a state of intestinal dysbiosis has also been found in SpA. Dysbiosis in the field of IBD has been well characterized so far, as well as in SpA. The aim of this review is to summarize what is known to date and to emphasize the similarities between the microbiota conditions in these two diseases: particularly, an altered distribution in the gut of Enterobacteriaceae , Streptococcus , Haemophilus , Clostridium , Akkermansia , Ruminococcus , Faecalibacterium Prausnitzii , Bacteroides Vulgatus , Dialister Invisus , and Bifidubacterium Adolescentis is common to both IBD and SpA. At the same time, little is known about intestinal dysbiosis in IBD-related SpA. Only a single recent study has found an increase in Escherichia and Shigella abundances and a decrease in Firmicutes, Ruminococcaceae, and Faecalibacterium abundances in an IBD-related SpA group. Based on what has been discovered so far about the altered distribution of bacteria that unite both pathologies, it is appropriate to carry out further studies aiming to improve the understanding of IBD-related SpA for the purpose of developing new therapeutic strategies.

Hepatic encephalopathy (HE) is a common complication of advanced liver disease and acute liver failure. It is a condition that features several neuropsychiatric symptoms that affect mortality, morbidity and the quality of patients' and caregivers' lives. An HE diagnosis is generally an exclusion diagnosis. Once the patient is admitted to the hospital, clinical examination, blood tests and eventually neuroimaging should be performed with the aim of ruling out other causes of acute brain dysfunction. Moreover, HE is recognized using various precipitants that can potentially promote its onset, alone or in combination, and must be identified. Once the diagnostic process is complete, a correct treatment should be started. The anti-HE treatment is based on a combination of the correction of precipitants; non-absorbable antibiotics, such as rifaximin; and non-absorbable disaccharides. Once the patient is discharged from the hospital, specific anti-HE therapy should be maintained in order to prevent other HE episodes.

Malnutrition is a tangible complication of cirrhosis with portal hypertension with a prevalence of up to 50%. In particular, sarcopenia and myosteatosis, defined as the alteration in muscle quantity and quality, have a negative impact on the main complications of liver disease and are associated with higher mortality in patients with cirrhosis. Recently, alterations in adipose tissue have also been described in cirrhotic patients and they seem to influence the course of liver disease. Several pieces of evidence indicate that a transjugular intrahepatic portosystemic shunt (TIPS), placed for the treatment of refractory portal hypertension, can lead to a modification of body composition consisting in the improvement of the skeletal muscle index, myosteatosis, and an increase in subcutaneous fat. These modifications of the nutritional status, even more pronounced in sarcopenic patients before TIPS, have been associated with an amelioration of cognitive impairment after TIPS as well as with an increase in the survival rate. The aim of this paper is to provide an overview of the effects of TIPS placement on nutritional status in cirrhosis focusing on its pathophysiological mechanisms and its relationship with liver-related outcomes.

Hepatic encephalopathy (HE) is a common complication in patients with advanced liver disease. It is a brain dysfunction characterized by neurological and psychiatric symptoms that significantly affects quality of life, morbidity and mortality of patients. HE has various precipitants that can potentially promote its onset, alone or in combination. Among the historically well-known precipitants, such as infections, gastrointestinal bleeding, dehydration, electrolyte disorders and constipation, recent studies have highlighted the role of malnutrition and portosystemic shunts as new precipitating factors of HE. The identification, management and correction of these factors are fundamental for effective HE treatment, in addition to pharmacological therapy with non-absorbable disaccharides and/or antibiotics.

Minimal hepatic encephalopathy (MHE) is a frequent complication of hepatic encephalopathy (HE) and can affect up to 80% of patients with liver cirrhosis. It is characterized by the lack of obvious clinical signs and the presence of alterations detectable using psychometric or electrophysiological testing focused on attention, working memory, psychomotor speed and visuospatial ability. Ideally, each patient should be tested for this condition because, despite the absence of symptoms, it has severe repercussions on daily life activities. It may be responsible for an inability to drive, sleep disturbances, risk of falls and inability to work. Some studies have highlighted its prognostically unfavorable role on mortality and risk of "overt" HE (OHE). Finally, MHE severely affects the lives of patients and caregivers, altering their quality of life and their socioeconomic status. Several treatments have been proposed for MHE treatment, including non-absorbable disaccharides, poorly absorbable antibiotics, such as rifaximin, probiotics and branched-chain amino acids, with promising results. For this reason, early diagnosis and intervention with appropriate measures is essential, with the aim of improving both performance on psychometric tests, as well as clinical aspects related to this condition.

Hepatic encephalopathy (HE) represents a common complication of liver cirrhosis. Protein-calorie malnutrition is frequently encountered in the cirrhotic patient and its most obvious clinical manifestation is sarcopenia. This condition represents a risk factor for HE occurrence because skeletal muscle acts as an alternative site for ammonium detoxification. Preventive intervention through an adequate assessment of nutritional status should be carried out at early stages of the disease and in a multidisciplinary team using both non-instrumental methods (food diary, anthropometric measurements, blood chemistry tests) and instrumental methods (bioimpedance testing, DEXA, CT, indirect calorimetry, dynamometry). Dietary recommendations for patients with HE do not differ from those for cirrhotic patient without HE. Daily caloric intake in the non-obese patient should be 30-40 Kcal/Kg/day with a protein intake of 1-1.5 g/Kg/day, especially of vegetable origin, through 4-6 meals daily. In patients with HE, it is also essential to monitor electrolyte balance, supplementing any micronutrient deficiencies such as sodium and zinc, as well as vitamin deficiencies because they can cause neurological symptoms similar to those of HE. In light of the critical role of nutritional status, this aspect should not be underestimated and should be included in the diagnostic-therapeutic algorithm of patients with HE.

In the last years the link between the presence of muscular alterations and hepatic encephalopathy (HE), both minimal and overt, has been deeply studied. The pathophysiological background supporting the relationship between muscle depletion, and HE is characterized by an imbalance between the capacity of muscle in ammonia metabolism and trafficking and the inability of the liver in removing ammonia through urea synthesis due to liver failure and/or the presence of porto-systemic shunts. This review will focus on the clinical burden, the physio pathological mechanisms understanding the liver muscle axis and principles of management of muscular alterations in cirrhosis.

Hepatic encephalopathy (HE) is one of the most frequent complications of cirrhosis. Several studies and case reports have shown that cognitive impairment may also be a tangible complication of portal hypertension secondary to chronic portal vein thrombosis and to porto-sinusoidal vascular disease (PSVD). In these conditions, representing the main causes of non-cirrhotic portal hypertension (NCPH) in the Western world, both overt and minimal/covert HE occurs in a non-neglectable proportion of patients, even lower than in cirrhosis, and it is mainly sustained by the presence of large porto-systemic shunt. In these patients, the liver function is usually preserved or only mildly altered, and the development of porto-systemic shunt is either spontaneous or iatrogenically frequent; HE is an example of type-B HE. To date, in the absence of strong evidence and large cooperative studies, for the diagnosis and the management of HE in NCPH, the same approach used for HE occurring in cirrhosis is applied. The aim of this paper is to provide an overview of type B hepatic encephalopathy, focusing on its pathophysiology, diagnostic tools and management in patients affected by porto-sinusoidal vascular disease and chronic portal vein thrombosis.

Cholangiocarcinoma is a group of malignancies with poor prognosis. Treatments for the management of advanced-stage cholangiocarcinoma are limited, and the 5-year survival rate is estimated to be approximately 5-15%, considering all tumor stages. There is a significant unmet need for effective new treatment approaches. The present review is provided with the aim of summarizing the current evidence and future perspectives concerning new therapeutic strategies for cholangiocarcinoma. The role of targeted therapies and immunotherapies is currently investigational in cholangiocarcinoma. These therapeutic options might improve survival outcomes, as shown by the promising results of several clinical trials illustrated in the present review. The co-presence of driver mutations and markers of susceptibility to immunotherapy may lead to rational combination strategies and clinical trial development. A better understanding of immunologically based therapeutic weapons is needed, which will lead to a form of a precision medicine strategy capable of alleviating the clinical aggressiveness and to improve the prognosis of cholangiocarcinoma.