Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology.

BACKGROUND & AIMS: Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model. METHODS: In total, 776 patients who underwent elective TIPS (TIPS cohort) and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses. RESULTS: In the TIPS/non-TIPS cohorts, the etiology of liver disease was viral in 402/188, alcoholic in 185/130, and non-alcoholic steatohepatitis in 65/33; mean follow-up±SD was 25±9/19±21 months; and the number of deaths at 3-6-12 months was 57-102-142/31-47-99, respectively. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in the non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used to update the MELD. CONCLUSIONS: In this validation study, the performance of the MELD score was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for an update to the MELD score are proposed. LAY SUMMARY: While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model.

Efficacy of Albumin Treatment for Patients with Cirrhosis and Infections Unrelated to Spontaneous Bacterial Peritonitis.

BACKGROUND & AIMS: We performed a randomized trial to determine whether albumin should be administered to patients with infections unrelated to spontaneous bacterial peritonitis (SBP). METHODS: We performed a multicenter, open-label trial in which 118 patients with cirrhosis, non-SBP infections, and additional risk factors for poor outcome were randomly assigned to receive antibiotics plus albumin (study group; n = 61) or antibiotics alone (control group; n = 57). The primary outcome was in-hospital mortality; secondary outcomes were effect of albumin on disease course. RESULTS: There were no significant differences at baseline between groups in results from standard laboratory tests, serum markers of inflammation, circulatory dysfunction, or liver severity scores. However, the combined prevalence of acute on chronic liver failure (ACLF) and kidney dysfunction was significantly higher in the study group (44.3% vs 24.6% in the control group; P = .02), indicating greater baseline overall severity. There was no significant difference in the primary outcome between groups (13.1% in the study group vs 10.5% in the control group; P = .66). Circulatory and renal functions improved in only the study group. A significantly higher proportion of patients in the study group had resolution of ACLF (82.3% vs 33.3% in the control group; P = .03). A significantly lower proportion of patients in the study group developed nosocomial infections (6.6% vs 24.6% in the control group; P = .007). CONCLUSIONS: In a randomized trial of patients with advanced cirrhosis and non-SBP infections, in-hospital mortality was similar between those who received albumin plus antibiotics vs those who received only antibiotics (controls). However, patients given albumin were sicker at baseline and, during the follow-up period, a higher proportion had ACLF resolution and a lower proportion had nosocomial infections. ClinicalTrials.gov no: NCT02034279.

Effects of Albumin Treatment on Systemic and Portal Hemodynamics and Systemic Inflammation in Patients With Decompensated Cirrhosis.

BACKGROUND & AIMS: We investigated the effect of albumin treatment (20% solution) on hypoalbuminemia, cardiocirculatory dysfunction, portal hypertension, and systemic inflammation in patients with decompensated cirrhosis with and without bacterial infections. METHODS: We performed a prospective study to assess the effects of long-term (12 weeks) treatment with low doses (1 g/kg body weight every 2 weeks) and high doses (1.5 g/kg every week) of albumin on serum albumin, plasma renin, cardiocirculatory function, portal pressure, and plasma levels of cytokines, collecting data from 18 patients without bacterial infections (the Pilot-PRECIOSA study). We also assessed the effect of short-term (1 week) treatment with antibiotics alone vs the combination of albumin plus antibiotics (1.5 g/kg on day 1 and 1 g/kg on day 3) on plasma levels of cytokines in biobanked samples from 78 patients with bacterial infections included in a randomized controlled trial (INFECIR-2 study). RESULTS: Circulatory dysfunction and systemic inflammation were extremely unstable in many patients included in the Pilot-PRECIOSA study; these patients had intense and reversible peaks in plasma levels of renin and interleukin 6. Long-term high-dose albumin, but not low-dose albumin, was associated with normalization of serum level of albumin, improved stability of the circulation and left ventricular function, and reduced plasma levels of cytokines (interleukin 6, granulocyte colony-stimulating factor, interleukin 1 receptor antagonist, and vascular endothelial growth factor) without significant changes in portal pressure. The immune-modulatory effects of albumin observed in the Pilot-PRECIOSA study were confirmed in the INFECIR-2 study. In this study, patients given albumin had significant reductions in plasma levels of cytokines. CONCLUSIONS: In an analysis of data from 2 trials (Pilot-PRECIOSA study and INFECIR-2 study), we found that albumin treatment reduced systemic inflammation and cardiocirculatory dysfunction in patients with decompensated cirrhosis. These effects might be responsible for the beneficial effects of albumin therapy on outcomes of patients with decompensated cirrhosis. ClinicalTrials.gov, Numbers: NCT00968695 and NCT03451292.

The influence of nitrogen position on charge carrier mobility in enantiopure aza[6]helicene crystals.

The properties of an organic semiconductor are dependent on both the chemical structure of the molecule involved, and how it is arranged in the solid-state. It is challenging to extract the influence of each individual factor, as small changes in the molecular structure often dramatically change the crystal packing and hence solid-state structure. Here, we use calculations to explore the influence of the nitrogen position on the charge mobility of a chiral organic molecule when the crystal packing is kept constant. The transfer integrals for a series of enantiopure aza[6]helicene crystals sharing the same packing were analysed in order to identify the best supramolecular motifs to promote charge carrier mobility. The regioisomers considered differ only in the positioning of the nitrogen atom in the aromatic scaffold. The simulations showed that even this small change in the chemical structure has a strong effect on the charge transport in the crystal, leading to differences in charge mobility of up to one order of magnitude. Some aza[6]helicene isomers that were packed interlocked with each other showed high HOMO-HOMO integrals (up to 70 meV), whilst molecules arranged with translational symmetry generally afforded the highest LUMO-LUMO integrals (40-70 meV). As many of the results are not intuitively obvious, a computational approach provides additional insight into the design of new semiconducting organic materials.

Management of acute respiratory failure in interstitial lung diseases: overview and clinical insights.

BACKGROUND: Interstitial lung diseases (ILDs) are a heterogeneous group of diseases characterized by widespread fibrotic and inflammatory abnormalities of the lung. Respiratory failure is a common complication in advanced stages or following acute worsening of the underlying disease. Aim of this review is to evaluate the current evidence in determining the best management of acute respiratory failure (ARF) in ILDs. METHODS: A literature search was performed in the Medline/PubMed and EMBASE databases to identify studies that investigated the management of ARF in ILDs (the last search was conducted on November 2017). RESULTS: In managing ARF, it is important to establish an adequate diagnostic and therapeutic management depending on whether the patient has an underlying known chronic ILD or ARF is presenting in an unknown or de novo ILD. In the first case both primary causes, such as acute exacerbations of the disease, and secondary causes, including concomitant pulmonary infections, fluid overload and pulmonary embolism need to be investigated. In the second case, a diagnostic work-up that includes investigations in regards to ILD etiology, such as autoimmune screening and bronchoalveolar lavage, should be performed, and possible concomitant causes of ARF have to be ruled out. Oxygen supplementation and ventilatory support need to be titrated according to the severity of ARF and patients' therapeutic options. High-Flow Nasal oxygen might potentially be an alternative to conventional oxygen therapy in patients requiring both high flows and high oxygen concentrations to correct hypoxemia and control dyspnea, however the evidence is still scarce. Neither Non-Invasive Ventilation (NIV) nor Invasive Mechanical Ventilation (IMV) seem to change the poor outcomes associated to advanced stages of ILDs. However, in selected patients, such as those with less severe ARF, a NIV trial might help in the early recognition of NIV-responder patients, who may present a better short-term prognosis. More invasive techniques, including IMV and Extracorporeal Membrane Oxygenation, should be limited to patients listed for lung transplant or with reversible causes of ARF. CONCLUSIONS: Despite the overall poor prognosis of ARF in ILDs, a personalized approach may positively influence patients' management, possibly leading to improved outcomes. However, further studies are warranted.

The impact of infection by multidrug-resistant agents in patients with cirrhosis. A multicenter prospective study.

BACKGROUND & AIMS: Bacterial strains resistant to antibiotics are a serious clinical challenge. We assessed the antibiotic susceptibility of bacteria isolated from infections in patients with cirrhosis by a multicentre investigation. RESULTS: Three hundred and thirteen culture-positive infections (173 community acquired [CA] and 140 hospital acquired [HA]) were identified in 308 patients. Urinary tract infections, spontaneous bacterial peritonitis and bacteremias were the most frequent. Quinolone-resistant Gram-negative isolates were 48%, 44% were extended-spectrum beta-lactamase producers and 9% carbapenem resistant. In 83/313 culture-positive infections (27%), multidrug-resistant agents (MDRA) were isolated. This prevalence did not differ between CA and HA infections. MDRA were identified in 17 of 37 patients on quinolone prophylaxis, and in 46 of 166 not on prophylaxis (45% vs 27%; P<.03). In 287 cases an empiric antibiotic therapy was undertaken, in 37 (12.9%) this therapy failed. The in-hospital mortality rate of this subset of patients was significantly higher compared to patients who received an effective broad(er)-spectrum therapy (P=.038). During a 3-month follow-up, 56/203 culture-positive patients (27.6%) died, 24/63 who have had MDRA-related infections (38%) and 32/140 who have had antibiotic-susceptible infections (22.8%) (P=.025). Multivariate analysis disclosed MDRA infection, age, hepatocellular carcinoma, bilirubin, international normalized ratio and the occurrence of portal hypertension-related complications independent predictors of death. CONCLUSIONS: Infection by MDRA is frequent in patients with cirrhosis and the prognosis is severe, especially in patients unresponsive to empiric antibiotic therapy.

Antipsychotic prescription and mortality in hospitalized older persons.

BACKGROUND: Recent scientific reports have shown that older persons treated with antipsychotics for dementia-related behavioural symptoms have increased mortality. However, the impact of these drugs prescribed during hospitalization has rarely been assessed. We aimed to investigate whether antipsychotics are associated with an increased risk of mortality during hospitalization and at 3-month follow-up in elderly inpatients. METHODS: We analyzed data gathered during two waves (2010 and 2012) by the REPOSI (Registro Politerapie Società Italiana Medicina Interna). All new prescriptions of antipsychotic drugs during hospitalization, whether maintained or discontinued at discharge, were collected, and logistic regression models were used to analyze their association with in-hospital and 3-month mortality. Covariates were age, sex, the Short Blessed Test (SBT) score, and the Cumulative Illness Rating Scale. RESULTS: Among 2703 patients included in the study, 135 (5%) received new prescriptions for antipsychotic drugs. The most frequently prescribed antipsychotic during hospitalization and eventually maintained at discharge was haloperidol (38% and 36% of cases, respectively). Patients newly prescribed with antipsychotics were older and had a higher Cumulative Illness Rating Scale comorbidity index both at admission and at discharge compared to those who did not receive a prescription. Of those prescribed antipsychotics, 71% had an SBT score ≥10 (indicative of dementia), 12% had an SBT score of 5-9 (indicative of questionable dementia); and 17% had an SBT score <5 (indicative of normal cognition). In-hospital mortality was slightly higher in patients prescribed antipsychotic drugs (14.3% vs 9.4%; P = 0.109), but in multivariate analysis only male sex, older age, and higher SBT scores were significantly related to mortality during hospitalization. At 3-month follow-up, only male sex, older age, and higher SBT scores were associated with mortality. CONCLUSION: We found that the prescription of antipsychotic drugs during hospitalization was not associated with in-hospital or follow-up mortality. Short-term antipsychotic prescriptions (for acutely ill patients) may have a different effect than long-term, repeated prescriptions.

Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: A randomized trial.

UNLABELLED: Hepatorenal syndrome (HRS), a serious complication of cirrhosis, is associated with high mortality without treatment. Terlipressin with albumin is effective in the reversal of HRS. Where terlipressin is not available, as in the United States, midodrine and octreotide with albumin are used as an alternative treatment of HRS. The aim was to compare the effectiveness of terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of HRS in a randomized controlled trial. Twenty-seven patients were randomized to receive terlipressin with albumin (TERLI group) and 22 to receive midodrine and octreotide plus albumin (MID/OCT group). The TERLI group received terlipressin by intravenous infusion, initially 3 mg/24 hours, progressively increased to 12 mg/24 hours if there was no response. The MID/OCT group received midodrine orally at an initial dose of 7.5 mg thrice daily, with the dose increased to a maximum of 12.5 mg thrice daily, together with octreotide subcutaneously: initial dose 100 µg thrice daily and up to 200 µg thrice daily. Both groups received albumin intravenously 1 g/kg of body weight on day 1 and 20-40 g/day thereafter. There was a significantly higher rate of recovery of renal function in the TERLI group (19/27, 70.4%) compared to the MID/OCT group (6/21, 28.6%), P = 0.01. Improvement in renal function and lower baseline Model for End-Stage Liver Disease score were associated with better survival. CONCLUSION: Terlipressin plus albumin is significantly more effective than midodrine and octreotide plus albumin in improving renal function in patients with HRS.

E-learning in order to improve drug prescription for hospitalized older patients: a cluster-randomized controlled study.

AIMS: The aim of the study was to evaluate the effect of an e-learning educational program meant to foster the quality of drug prescription in hospitalized elderly patients. METHODS: Twenty geriatric and internal medicine wards were randomized to intervention (e-learning educational program) or control (basic geriatric pharmacology notions). Logistic regression analysis was used in order to assess the effect of the intervention on the use of potentially inappropriate medication (PIM, primary outcome) at hospital discharge. Secondary outcomes were a reduced prevalence of at least one potential drug-drug interaction (DDI) and potentially severe DDI at discharge. Mortality rate and incidence of re-hospitalizations were other secondary outcomes assessed at the 12-month follow-up. RESULTS: A total of 697 patients (347 in the intervention and 350 in the control arms) were enrolled. No difference in the prevalence of PIM at discharge was found between arms (OR 1.29 95%CI 0.87-1.91). We also found no decrease in the prevalence of DDI (OR 0.67 95%CI 0.34-1.28) and potentially severe DDI (OR 0.86 95%CI 0.63-1.15) at discharge, nor in mortality rates and incidence of re-hospitalization at 12-month follow-up. CONCLUSIONS: This e-learning educational program had no clear effect on the quality of drug prescription and clinical outcomes in hospitalized elderly patients. Given the high prevalence of PIMs and potential DDIs recorded in the frame of this study, other approaches should be developed in order to improve the quality of drug prescription in this population.

Therapy of the refractory ascites: Total paracentesis vs. TIPS.

This revision was aimed to report the evidences on the treatment of patients with cirrhosis and refractory ascites. Mainly, we wished to explore which of the predicting variables could be used to prefer large-volume paracentesis or TIPS.

Albumin treatment regimen for type 1 hepatorenal syndrome: a dose-response meta-analysis.

BACKGROUND: Recommended treatment for type 1 hepatorenal syndrome consists of albumin and vasoconstrictor. The optimal albumin dose remains poorly characterized. This meta-analysis aimed to determine the impact of albumin dose on treatment outcomes. METHODS: Clinical studies of type 1 hepatorenal syndrome treatment with albumin and vasoconstrictor were sought. Search terms included: hepatorenal syndrome; albumin; vasoconstrictor; terlipressin; midodrine; octreotide; noradrenaline; and norepinephrine. A meta-analysis was performed of hepatorenal syndrome reversal and survival in relation to albumin dose. RESULTS: Nineteen clinical studies with 574 total patients were included, comprising 8 randomized controlled trials, 8 prospective studies and 3 retrospective studies. The pooled percentage of patients achieving hepatorenal syndrome reversal was 49.5% (95% confidence interval, 40.0-59.1%). Increments of 100 g in cumulative albumin dose were accompanied by significantly increased survival (hazard ratio, 1.15; 95% confidence interval, 1.02-1.31; p = 0.023). A non-significant increase of similar magnitude in hepatorenal syndrome reversal was also observed (odds ratio, 1.15; 95% confidence interval, 0.97-1.37; p = 0.10). Expected survival rates at 30 days among patients receiving cumulative albumin doses of 200, 400 and 600 g were 43.2% (95% confidence interval, 36.4-51.3%), 51.4% (95% confidence interval, 46.3-57.1%) and 59.0% (95% confidence interval, 51.9-67.2), respectively. Neither survival nor hepatorenal syndrome reversal was significantly affected by vasoconstrictor dose or type, treatment duration, age, baseline serum creatinine, bilirubin or albumin, baseline mean arterial pressure, or study design, size or time period. CONCLUSIONS: This meta-analysis suggests a dose-response relationship between infused albumin and survival in patients with type 1 hepatorenal syndrome. The meta-analysis provides the best current evidence on the potential role of albumin dose selection in improving outcomes of treatment for type 1 HRS and furnishes guidance for the design of future dose-ranging studies.

Treatment of Spontaneous Bacterial Peritonitis.

Spontaneous bacterial peritonitis (SBP) is an infection of patients with cirrhosis and ascites. This peculiarity is due to the frequent intestinal translocation that allows bacteria to cross the intestinal barrier, colonizing the ascitic fluid. In cirrhosis, SBP is inferior only to urinary tract infections. It is prevalently sustained by Gram-negative bacteria such as Escherichia coli and Klebsiella. Risk factors for developing SBP are advanced age, refractory ascites, variceal bleeding, renal failure, low albumin levels (below 2.5 g/ml), bilirubin over 4 mg/dl, Child-Pugh class C and a previous diagnosis of SBP. Thus, this is an indication for a long-term antibiotic prophylaxis with norfloxacin. Renal failure - especially the hepatorenal syndrome - complicates SBP in about 20% of cases independently of the efficacy of the antibiotic therapy. The mortality of these patients is about 90%. Infusion of albumin significantly reduces the incidence of hepatorenal syndrome and consequently the risk of death. Long-term quinolonic prophylaxis as well as increased antibiotic therapies are causing the emergence of multidrug-resistant agents as frequent causes of SBP. In such cases, the antibiotic sensitivity to quinolones is low, and European recommendations suggest a second-line antibiotic therapy, including meropenem or piperacillin plus tazobactam. Collection of blood, urine and ascitic fluid for cultures is important for bacterial recognition, possibly before starting an empirical antibiotic therapy. Indeed, the probability of positive cultures rapidly vanishes when they are performed during already implemented antibiotic administration. It is important to know that a failure of the first-line therapy is associated with an increased probability of death.

Italian registry of patients with alpha-1 antitrypsin deficiency: general data and quality of life evaluation.

Alpha1-antitrypsin Deficiency (AATD) is a rare hereditary disorder with an estimated prevalence of about 1/5000 individuals in Italy. Deficient patients are at a higher risk of developing lung emphysema and chronic liver disease. The low estimated prevalence of AATD prompted the establishment of a registry with the aim of learning more about the natural history and the quality of care of these patients. The Italian registry for AATD was established in 1996. In this study, genetic and clinical findings of Italian AATD patients are presented. Moreover, we also evaluated the changes in health-related quality of life (HRQoL) in patients with COPD and AAT deficiency over a three-year period, in relation to augmentation therapy. In a period spanning 18 years (1996-2014) a total of 422 adult subjects with severe AATD were enrolled, namely 258 PI*ZZ, 74 PI*SZ, 4 PI*SS and 86 patients with at least one rare deficient allele. The 21.3% frequency for AATD patients with at least one deficient rare variant is the highest so far recorded in national registries of AATD. The registry data allow a detailed characterization of the natural course of the disease and the level of patient care, as well as confirm the usefulness of early AATD detection.

Albumin infusion improves outcomes of patients with spontaneous bacterial peritonitis: a meta-analysis of randomized trials.

BACKGROUND & AIMS: Renal impairment increases mortality among patients with spontaneous bacterial peritonitis (SBP), despite administration of non-nephrotoxic antibiotics. Albumin infusion has been reported to reduce renal impairment and mortality in patients with SBP. We performed a meta-analysis of randomized controlled trials (RCTs) to quantify the effect of albumin infusion on renal impairment and mortality in patients with SBP. METHODS: We searched MEDLINE, EMBASE, the Cochrane Library, and ClinicalTrials.gov for RCTs that evaluated albumin treatment for patients with SBP; we also performed searches by additional methods. Four trials of 288 total patients were included in our analysis. Data were quantitatively combined under a fixed-effects model. RESULTS: We found no evidence of statistically significant heterogeneity or publication bias among the studies analyzed. Albumin was compared with no albumin in 3 trials and with artificial colloid in 1 trial. All patients received antibiotics. The incidence of renal impairment in control groups was 44 of 144 (30.6%), compared with 12 of 144 (8.3%) in groups given albumin. The pooled odds ratio for a reduction in renal impairment after albumin infusion was 0.21 (95% confidence interval, 0.11-0.42). Odds ratios for renal impairment after albumin therapy ranged from 0.19-0.30 among the individual studies. Mortality among controls was 51 of 144 (35.4%), compared with 23 of 144 (16.0%) among patients who received albumin. The pooled odds ratio for decreased mortality after infusion of albumin was 0.34 (95% confidence interval, 0.19-0.60). Odds ratios for mortality in individual RCTs ranged from 0.16-0.55. CONCLUSIONS: In a meta-analysis of 4 RCTs (288 patients), albumin infusion prevented renal impairment and reduced mortality among patients with SBP.

Mortality risk according to different clinical characteristics of first episode of liver decompensation in cirrhotic patients: a nationwide, prospective, 3-year follow-up study in Italy.

OBJECTIVES: The occurrence of decompensation marks a crucial turning point in the course of cirrhosis. The purpose of this study was to assess the risk of mortality according to the clinical characteristics of first decompensation, considering also the impact of acute-on-chronic liver failure (AoCLF). METHODS: We conducted a prospective nationwide inception cohort study in Italy. Decompensation was defined by the presence of ascites, either overt or detected by ultrasonography (UD), gastroesophageal variceal bleeding (GEVB), and hepatic encephalopathy (HE). AoCLF was defined according to the Asian Pacific Association for the Study of the Liver criteria. Multivariable Cox proportional hazards regression was used to analyze the risk of failure (death or orthotopic liver transplantation (OLT)). RESULTS: A total of 490 consecutive cirrhotic patients (314 males, mean age 60.9±12.6 years) fulfilled the study criteria. AoCLF was identified in 59 patients (12.0%). Among the remaining 431 patients, ascites were found in 330 patients (76.6%): in 257 (77.8%) as overt ascites and in 73 (22.2%) as UD ascites. GEVB was observed in 77 patients (17.9%) and HE in 30 patients (7.0%). After a median follow-up of 33 months, 24 patients underwent OLT and 125 died. The cumulative incidence of failure (death or OLT) after 1, 2, and 3 years was, respectively, 28, 53, and 62% in patients with AoCLF; 10, 18, and 25% in patients with UD ascites; 17, 31, and 41% in patients with overt ascites; and 8, 12, and 24% in patients with GEVB (P<0.0001). CONCLUSIONS: AoCLF is responsible for a relevant proportion of first decompensation in cirrhotic patients and is associated with the poorest outcome. Patients with UD ascites do not have a negligible mortality rate and require clinical monitoring similar to that of patients with overt ascites.

Drug-drug interactions in a cohort of hospitalized elderly patients.

PURPOSE: The aim of this study is to assess the prevalence of patients exposed to potentially severe drug-drug interactions (DDIs) at hospital admission and discharge and the related risk of in-hospital mortality and adverse clinical events, readmission, and all-cause mortality at 3 months. METHODS: This cross-sectional, prospective study was held in 70 Italian internal medicine and geriatric wards. Potentially severe DDIs at hospital admission and discharge; risk of in-hospital mortality and of adverse clinical events, readmission, and all-cause mortality at 3-month follow-up. RESULTS: Among 2712 patients aged 65 years or older recruited at hospital admission, 1642 (60.5%) were exposed to at least one potential DDI and 512 (18.9%) to at least one potentially severe DDI. Among 2314 patients discharged, 1598 (69.1%) were exposed to at least one potential DDI and 1561 (24.2%) to at least one potentially severe DDI. Multivariate analysis found a significant association with an increased risk of mortality at 3 months in patients exposed to at least two potentially severe DDIs (Odds ratio 2.62; 95% confidence interval, 1.00-6.68; p = 0.05). Adverse clinical events were potentially related to severe DDIs in two patients who died in the hospital, in five readmitted, and one who died at 3 months after discharge. CONCLUSIONS: Hospitalization was associated with an increase in potentially severe DDIs. A significant association was found for mortality at 3 months after discharge in patients with at least two potentially severe DDIs. Careful monitoring for potentially severe DDIs, especially those created at discharge or recently generated, is important to minimize the risk of harm.

Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis.

OBJECTIVES: To propose an improvement on the current classification of renal dysfunction in cirrhosis. Clinicians caring for patients with cirrhosis recognize that the development of renal dysfunction is associated with significant morbidity and mortality. While most cases of renal dysfunction in cirrhosis are functional in nature, developed as a result of changes in haemodynamics, cardiac function, and renal auto-regulation, there is an increasing number of patients with cirrhosis and structural changes in their kidney as a cause of renal dysfunction. Therefore, there is a need for a newer classification to include both functional and structural renal diseases. DESIGN: A working party consisting of specialists from multiple disciplines conducted literature search and developed summary statements, incorporating the renal dysfunction classification used in nephrology. These were discussed and revised to produce this proposal. SETTING: Multi-disciplinary international meeting. PATIENTS: None. INTERVENTIONS: Literature search using keywords of cirrhosis, renal dysfunction, acute kidney injury (AKI), chronic kidney injury (CKD), and hepatorenal syndrome. RESULTS: Acute kidney injury will include all causes of acute deterioration of renal function as indicated by an increase in serum creatinine of >50% from baseline, or a rise in serum creatinine of ≥ 26.4 µmol/L (≥ 0.3 mg/dL) in < 48 hours. Chronic renal disease will be defined as an estimated glomerular filtration rate (GFR) of < 60 ml/min calculated using the Modification of Diet in Renal Disease 6 (MDRD6) formula, recognising that the MDRD6 formula is not perfect for the cirrhotic patients and this may change as improved means of estimating GFR becomes available. Acute on chronic kidney disease will be defined as AKI superimposed on existing chronic renal disease using the above definitions for AKI and CKD. CONCLUSIONS: Accepting this new classification will allow studies into the epidemiology, incidence, prevalence, natural history and the development of new treatments for these subtypes of renal dysfunction in cirrhosis.

Simvastatin Prevents Liver Microthrombosis and Sepsis Induced Coagulopathy in a Rat Model of Endotoxemia.

Background: Endotoxemia causes endothelial dysfunction and microthrombosis, which are pathogenic mechanisms of coagulopathy and organ failure during sepsis. Simvastatin has potential anti-thrombotic effects on liver endothelial cells. We investigated the hemostatic changes induced by lipopolysaccharide (LPS) and explored the protective effects of simvastatin against liver vascular microthrombosis. Methods and results: We compared male Wistar rats exposed to LPS (5 mg/kg one i.p. dose) or saline in two experimental protocols­placebo (vehicle) and simvastatin (25 mg/kg die, orally, for 3 days before LPS). Morphological studies were performed by light- and electron-microscopy analyses to show intravascular fibrin deposition, vascular endothelial structure and liver damage. Peripheral- and organ-hemostatic profiles were analyzed using whole blood viscoelastometry by ROTEM, liver biopsy and western-blot/immunohistochemistry of thrombomodulin (TM), as well as immunohistochemistry of the von Willebrand factor (VWF). LPS-induced fibrin deposition and liver vascular microthrombosis were combined with a loss of sinusoidal endothelial TM expression and VWF-release. These changes were associated with parenchymal eosinophilia and necrosis. ROTEM analyses displayed hypo-coagulability in the peripheral blood that correlated with the degree of intrahepatic fibrin deposition (p < 0.05). Simvastatin prevented LPS-induced fibrin deposition by preserving TM expression in sinusoidal cells and completely reverted the peripheral hypo-coagulability caused by endotoxemia. These changes were associated with a significant reduction of liver cell necrosis without any effect on eosinophilia. Conclusions: Simvastatin preserves the antithrombotic properties of sinusoidal endothelial cells disrupted by LPS, deserving pharmacological properties to contrast sepsis-associated coagulopathy and hepatic failure elicited by endotoxemia

Controlling anisotropic properties by manipulating the orientation of chiral small molecules.

Chiral π-conjugated molecules bring new functionality to technological applications and represent an exciting, rapidly expanding area of research. Their functional properties, such as the absorption and emission of circularly polarized light or the transport of spin-polarized electrons, are highly anisotropic. As a result, the orientation of chiral molecules critically determines the functionality and efficiency of chiral devices. Here we present a strategy to control the orientation of a small chiral molecule (2,2'-dicyano[6]helicene) by the use of organic and inorganic templating layers. Such templating layers can either force 2,2'-dicyano[6]helicene to adopt a face-on orientation and self-assemble into upright supramolecular columns oriented with their helical axis perpendicular to the substrate, or an edge-on orientation with parallel-lying supramolecular columns. Through such control, we show that low- and high-energy chiroptical responses can be independently 'turned on' or 'turned off'. The templating methodologies described here provide a simple way to engineer orientational control and, by association, anisotropic functional properties of chiral molecular systems for a range of emerging technologies.