Identification of hemodynamically stable patients with acute pulmonary embolism at high risk for death: external validation of different models.

BACKGROUND: The optimal strategy for identification of hemodynamically stable patients with acute pulmonary embolism (PE) at risk for death and clinical deterioration remains undefined. OBJECTIVES: We aimed to assess the performances of currently available models/scores for identifying hemodynamically stable patients with acute, symptomatic PE at risk of death and clinical deterioration. METHODS: This was a prospective multicenter cohort study including patients with acute PE (NCT03631810). Primary study outcome was in-hospital death within 30 days or clinical deterioration. Other outcomes were in-hospital death, death, and PE-related death, all at 30 days. We calculated positive and negative predictive values, c-statistics of European Society of Cardiology (ESC)-2014, ESC-2019, Pulmonary Embolism Thrombolysis (PEITHO), Bova, Thrombo-embolism lactate outcome study (TELOS), fatty acid binding protein, syncope and tachicardia (FAST), and National Early Warning Scale 2 (NEWS2) for the study outcomes. RESULTS: In 5036 hemodynamically stable patients with acute PE, positive predictive values for the evaluated models/scores were all below 10%, except for TELOS and NEWS2; negative predictive values were above 98% for all the models/scores, except for FAST and NEWS2. ESC-2014 and TELOS had good performances for in-hospital death or clinical deterioration (c-statistic of 0.700 and 0.722, respectively), in-hospital death (c-statistic of 0.713 and 0.723, respectively), and PE-related death (c-statistic of 0.712 and 0.777, respectively); PEITHO, Bova, and NEWS2 also had good performances for PE-related death (c-statistic of 0.738, 0.741, and 0.742, respectively). CONCLUSION: In hemodynamically stable patients with acute PE, the accuracy for identification of hemodynamically stable patients at risk for death and clinical deterioration varies across the available models/scores; TELOS seems to have the best performance. These data can inform management studies and clinical practice.

Risk and Management of Bleeding Complications with Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Venous Thromboembolism: a Narrative Review.

Atrial fibrillation (AF) and venous thromboembolism (VTE) are highly prevalent conditions with a significant healthcare burden, and represent the main indications for anticoagulation. Direct oral anticoagulants (DOACs) are the first choice treatment of AF/VTE, and have become the most prescribed class of anticoagulants globally, overtaking vitamin K antagonists (VKAs). Compared to VKAs, DOACs have a similar or better efficacy/safety profile, with reduced risk of intracerebral hemorrhage (ICH), while the risk of major bleeding and other bleeding harms may vary depending on the type of DOAC. We have critically reviewed available evidence from randomized controlled trials and observational studies regarding the risk of bleeding complications of DOACs compared to VKAs in patients with AF and VTE. Special patient populations (e.g., elderly, extreme body weights, chronic kidney disease) have specifically been addressed. Management of bleeding complications and possible resumption of anticoagulation, in particular after ICH and gastrointestinal bleeding, are also discussed. Finally, some suggestions are provided to choose the optimal DOAC to minimize adverse events according to individual patient characteristics and bleeding risk.

Juniperus oxycedrus L. ssp. Essential Oil Microneedles: A Promising Antimicrobial and Wound Healing Activity.

The use of essential oil (EO) in treating infected wounds is still challenging. A lot of effort has been made to make such an application more convenient. Recently, microneedles (MNDs) have been considered as a smart dermal delivery system to overcome the poor absorption and distribution, low bioavailability, and skin penetration of some drugs. The aim of our study is to evaluate the wound healing activity of juniper-EO-loaded MNDs (EO MNDs) against wounds with bacterial and fungal infection. The Polyvinylpyrrolidone (PVP) MNDs were prepared using the gel-filled mold technique and loaded with juniper EO. In vivo models were created and wounds on rats were infected with two clinically isolated bacterial strains Pseudomonas aeruginosa and Staphylococcus aureus. Furthermore, Candida albicans was used to mimic fungal infection and juniper EO MNDs were tested. The obtained results showed an improvement in wound healing which started from the third day after application of the juniper EO MNDs, and at the sixth day post-infection, the treated wounds were significantly smaller than untreated wounds. A complete healing was shown by the 12th day after infection. Furthermore, our cytotoxicity results showed a cytotoxic effect of juniper EO MNDs on epithelial cells, which explained the faster wound healing in rats. Our study showed that juniper EO MNDs represent a novel strategy in EO delivery with minimal invasion. Juniper EO MNDs demonstrated significant antimicrobial activity against both the bacterial strains Pseudomonas aeruginosa and Staphylococcus aureus and against one fungal strain, Candida albicans. Finally, application of juniper EO MNDs exerted promising activity in the treatment and healing of wound infection.

Liver Fibrosis Biomarkers Accurately Exclude Advanced Fibrosis and Are Associated with Higher Cardiovascular Risk Scores in Patients with NAFLD or Viral Chronic Liver Disease.

Liver fibrosis predicts liver-related and cardiovascular outcomes in chronic liver disease patients. We compared the diagnostic performance of various liver fibrosis biomarkers for identifying histological significant/advanced fibrosis. Additionally, the correlations of such liver fibrosis biomarkers with cardiovascular risk (CVR) scores were evaluated. 173 patients with viral hepatitis (157 HCV and 16 HBV) and 107 with a non-alcoholic fatty liver disease (NAFLD) were consecutively enrolled. Various liver fibrosis biomarkers: aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (ARR), AST to Platelet Ratio Index (APRI), Fibrosis-4 (FiB-4), Forns index, NAFLD fibrosis score (NFS), BARD (body mass index (BMI), AAR, Diabetes) score, and Hepamet fibrosis score (HFS), were used to identify significant/advanced fibrosis. CVR was assessed by using the SCORE, the Progetto CUORE, or the Framingham risk scoring systems. Liver fibrosis biomarkers performed better in predicting advanced rather than significant liver fibrosis in all patients, regardless of chronic liver disease aetiology. Forns index and HFS performed best in predicting advanced fibrosis in patients with viral chronic liver disease and NAFLD. Lower cut-offs of these liver fibrosis biomarkers had high negative predictive values for advanced fibrosis overall, as well as in patients with NAFLD or viral chronic liver disease. FIB-4, Forns index, NFS, and HFS were positively correlated with SCORE and Framingham risk scores. In conclusion, liver fibrosis biomarkers accurately exclude advanced fibrosis and positively correlate with CVR scores in patients with chronic liver disease.

Nonalcoholic fatty liver disease: Evolving paradigms.

In the last years new evidence has accumulated on nonalcoholic fatty liver disease (NAFLD) challenging the paradigms that had been holding the scene over the previous 30 years. NAFLD has such an epidemic prevalence as to make it impossible to screen general population looking for NAFLD cases. Conversely, focusing on those cohorts of individuals exposed to the highest risk of NAFLD could be a more rational approach. NAFLD, which can be diagnosed with either non-invasive strategies or through liver biopsy, is a pathogenically complex and clinically heterogeneous disease. The existence of metabolic as opposed to genetic-associated disease, notably including "lean NAFLD" has recently been recognized. Moreover, NAFLD is a systemic condition, featuring metabolic, cardiovascular and (hepatic/extra-hepatic) cancer risk. Among the clinico-laboratory features of NAFLD we discuss hyperuricemia, insulin resistance, atherosclerosis, gallstones, psoriasis and selected endocrine derangements. NAFLD is a precursor of type 2 diabetes (T2D) and metabolic syndrome and progressive liver disease develops in T2D patients in whom the course of disease is worsened by NAFLD. Finally, lifestyle changes and drug treatment options to be implemented in the individual patient are also critically discussed. In conclusion, this review emphasizes the new concepts on clinical and pathogenic heterogeneity of NAFLD, a systemic disorder with a multifactorial pathogenesis and protean clinical manifestations. It is highly prevalent in certain cohorts of individuals who are thus potentially amenable to selective screening strategies, intensive follow-up schedules for early identification of liver-related and extrahepatic complications and in whom earlier and more aggressive treatment schedules should be carried out whenever possible.

Ultrasonographic fatty liver indicator detects mild steatosis and correlates with metabolic/histological parameters in various liver diseases.

BACKGROUND AND AIMS: Fatty liver is a common feature of different types of liver diseases. The sensitivity and specificity of ultrasonography for diagnosing fatty liver are variable. A semi-quantitative ultrasound score, i.e., the ultrasonographic fatty liver indicator (US-FLI), is closely associated with metabolic/histological variables in patients with nonalcoholic fatty liver disease (NAFLD). The main aims of this study were to assess the diagnostic performance of US-FLI in detecting varying degrees of histological steatosis, and to examine the association of US-FLI with metabolic/histological parameters in 352 biopsied patients with various chronic liver diseases (173 with hepatitis C [HCV], 23 with hepatitis B [HBV], 123 with NAFLD and 33 with other etiologies). RESULTS: US-FLI accurately detected mild steatosis (minimum amount 10% on histology) with a cut-off value ≥2 (sensitivity 90.1%, specificity 90%), moderate steatosis (≥30%) with a cut-off value ≥3 (sensitivity 86.4%, specificity 92.5%) and severe steatosis (>66%) with a cut-off value ≥5 (sensitivity 88.5%, specificity 87%). US-FLI was correlated with steatosis percentage in each liver disease group as well as with lobular inflammation, ballooning, portal fibrosis, grading and staging in patients with NAFLD or HCV. US-FLI was also correlated with waist circumference, body mass index and insulin resistance both in the whole sample and in each liver disease group. CONCLUSIONS: US-FLI accurately identifies histological severity and is correlated with metabolic parameters in patients with various steatogenic liver diseases. US-FLI is an easy and versatile tool for the screening of steatosis and the metabolic health of these patients.

NAFLD as a Sexual Dimorphic Disease: Role of Gender and Reproductive Status in the Development and Progression of Nonalcoholic Fatty Liver Disease and Inherent Cardiovascular Risk.

Nonalcoholic fatty liver disease (NAFLD) spans steatosis through nonalcoholic steatohepatis, cirrhosis, and hepatocellular carcinoma (HCC) associated with striking systemic features and excess cardiovascular and liver-related mortality. The pathogenesis of NAFLD is complex and multifactorial. Endocrine derangements are closely linked with dysmetabolic traits. For example, in animal and human studies, female sex is protected from dysmetabolism thanks to young individuals' ability to partition fatty acids towards ketone body production rather than very low density lipoprotein (VLDL)-triacylglycerol, and to sex-specific browning of white adipose tissue. Ovarian senescence facilitates both the development of massive hepatic steatosis and the fibrotic progression of liver disease in an experimental overfed zebrafish model. Consistently, estrogen deficiency, by potentiating hepatic inflammatory changes, hastens the progression of disease in a dietary model of nonalcoholic steatohepatitis (NASH) developing in ovariectomized mice fed a high-fat diet. In humans, NAFLD more often affects men; and premenopausal women are equally protected from developing NAFLD as they are from cardiovascular disease. It would be expected that early menarche, definitely associated with estrogen activation, would produce protection against the risk of NAFLD. Nevertheless, it has been suggested that early menarche may confer an increased risk of NAFLD in adulthood, excess adiposity being the primary culprit of this association. Fertile age may be associated with more severe hepatocyte injury and inflammation, but also with a decreased risk of liver fibrosis compared to men and postmenopausal status. Later in life, ovarian senescence is strongly associated with severe steatosis and fibrosing NASH, which may occur in postmenopausal women. Estrogen deficiency is deemed to be responsible for these findings via the development of postmenopausal metabolic syndrome. Estrogen supplementation may at least theoretically protect from NAFLD development and progression, as suggested by some studies exploring the effect of hormonal replacement therapy on postmenopausal women, but the variable impact of different sex hormones in NAFLD (i.e., the pro-inflammatory effect of progesterone) should be carefully considered.

Sofosbuvir-based therapy cures hepatitis C virus infection after prior treatment failures in a patient with concurrent lymphoma.

We report on the first well-tolerated and successful use of sofosbuvir-based therapy in a patient in whom chronic infection with hepatitis C had preceded the development of B-cell non-Hodgkin's lymphoma. The patient had previously failed numerous attempts to clear the hepatitis C virus with traditional antiviral schedules. We demonstrate that sofosbuvir-based therapy resulted in cure of hepatitis C in a patient who had relapsed during combination therapy with an NS5A inhibitor, an NS3 protease inhibitor and ribavirin, as well as treatment failures to multiple courses of interferon-based therapy. This report also suggests that eradication of hepatitis C virus may result in the short-term prevention of B-cell non-Hodgkin's lymphoma relapse. The findings from our case require further validation in future cohorts of patients.