A comparison of semiparametric approaches to evaluate composite endpoints in heart failure trials.

In heart failure (HF) trials efficacy is usually assessed by a composite endpoint including cardiovascular death (CVD) and heart failure hospitalizations (HFHs), which has traditionally been evaluated with a time-to-first-event analysis based on a Cox model. As a considerable fraction of events is ignored that way, methods for recurrent events were suggested, among others the semiparametric proportional rates models by Lin, Wei, Yang, and Ying (LWYY model) and Mao and Lin (Mao-Lin model). In our work we apply least false parameter theory to explain the behavior of the composite treatment effect estimates resulting from the Cox model, the LWYY model, and the Mao-Lin model in clinically relevant scenarios parameterized through joint frailty models. These account for both different treatment effects on the two outcomes (CVD, HFHs) and the positive correlation between their risk rates. For the important setting of beneficial outcome-specific treatment effects we show that the correlation results in composite treatment effect estimates, which are decreasing with trial duration. The estimate from the Cox model is affected more by the attenuation than the estimates from the recurrent event models, which both demonstrate very similar behavior. Since the Mao-Lin model turns out to be less sensitive to harmful effects on mortality, we conclude that, among the three investigated approaches, the LWYY model is the most appropriate one for the composite endpoint in HF trials. Our investigations are motivated and compared with empirical results from the PARADIGM-HF trial (ClinicalTrials.gov identifier: NCT01035255), a large multicenter trial including 8399 chronic HF patients.

Does the revised intubating laryngeal tube (ILTS-D2) perform better than the intubating laryngeal mask (Fastrach)? - a randomised simulation research study.

BACKGROUND: The intubating laryngeal tube (ILTS-D™) and the intubating laryngeal mask (Fastrach™) are devices that facilitate both extraglottic application and blind tracheal intubation. A revised model of the iLTS-D (for scientific reasons called ILTS-D2) has been designed but not yet evaluated. Therefore, we compared the ILTS-D2 with the established Fastrach under controlled conditions in a prospective randomised controlled simulation research study. METHODS: After ethical approval, we randomised 126 medical students into two groups. Each participant received either Fastrach or ILTS-D2 to perform five consecutive ventilation attempts in a manikin. The primary endpoint was the time to ventilation in the last attempt of using the devices as extraglottic devices. Secondary endpoints were the time to tracheal intubation and the success rates. RESULTS: There was no relevant difference between the two devices in the time to ventilation in the last of five attempts (Fastrach: median 14 s [IQR: 12-15]; ILTS-D2: median 13 s [IQR: 12-15], p = 0.592). Secondary endpoints showed a 2 s faster blind tracheal intubation using the Fastrach than using the ILTS-D2 (Fastrach: median 14 s [IQR: 13-17]; ILTS-D2: median 16 s [IQR: 15-20] p < 0.001). For both devices, the success rates were 100% in the last attempt. CONCLUSIONS: Concerning extraglottic airway management, we could not detect a relevant difference between the revised ILTS-D2 and the Fastrach under laboratory conditions. We advocate for an evaluation of the ILTS-D2 in randomised controlled clinical trials. TRIAL REGISTRATION: Identifier at clinicaltrials.gov: NCT03542747. May 31, 2018.

Development and Validation of a Prognostic Score to Predict Covert Hepatic Encephalopathy in Patients With Cirrhosis.

OBJECTIVES: Diagnosis of covert hepatic encephalopathy (CHE) is challenging and often neglected in clinical practice. The aim of this study was to develop an easy-to-perform score to predict CHE in patients with cirrhosis. METHODS: For the development or validation cohort of the proposed clinical CHE score, 142 or 96 consecutive patients with cirrhosis were prospectively enrolled. The Psychometric Hepatic Encephalopathy Score was used to detect minimal hepatic encephalopathy. All patients were examined with the simplified animal naming test and were asked to complete the Chronic Liver Disease Questionnaire. We followed the TRIPOD guideline for development, validation, and reporting of the proposed score. RESULTS: The clinical covert hepatic encephalopathy score containing the variables-clinically detectable ascites, history of overt hepatic encephalopathy (OHE), albumin serum level, activity subdomain of the Chronic Liver Disease Questionnaire, and simplified animal naming test-discriminated best between patients with and without CHE. We generated 2 cutoff values for the identification of the high-, intermediate- (with need for additional specialized testing), and low-risk groups for CHE. By applying these cutoffs, the sensitivity, specificity, positive predictive value, and negative predictive value were 90%, 91%, 85%, and 94%, respectively. The AUC was 0.908 or 0.872 for the development or the validation cohort, respectively. Higher scores were further associated with poorer quality of life, and the high-risk group was predictive for first-time OHE within 180 days. CONCLUSIONS: We developed an easy-to-perform score to identify patients with cirrhosis at risk of CHE, which correlates with quality of life and risk of first-time OHE.

Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis.

BACKGROUND: The course of multiple sclerosis (MS) shows substantial inter-individual variability. The underlying determinants of disease severity likely involve genetic and environmental factors. OBJECTIVE: The aim of this study was to assess the impact of APOE and HLA polymorphisms as well as smoking and body mass index (BMI) in the very early MS course. METHODS: Untreated patients ( n = 263) with a recent diagnosis of relapsing-remitting (RR) MS or clinically isolated syndrome underwent standardized magnetic resonance imaging (MRI). Genotyping was performed for single-nucleotide polymorphisms (SNPs) rs3135388 tagging the HLA-DRB1*15:01 haplotype and rs7412 (Ɛ2) and rs429358 (Ɛ4) in APOE. Linear regression analyses were applied based on the three SNPs, smoking and BMI as exposures and MRI surrogate markers for disease severity as outcomes. RESULTS: Current smoking was associated with reduced gray matter fraction, lower brain parenchymal fraction and increased cerebrospinal fluid fraction in comparison to non-smoking, whereas no effect was observed on white matter fraction. BMI and the SNPs in HLA and APOE were not associated with structural MRI parameters. CONCLUSIONS: Smoking may have an unfavorable effect on the gray matter fraction as a potential measure of MS severity already in early MS. These findings may impact patients' counseling upon initial diagnosis of MS.

Clinical Predictors for Poor Quality of Life in Patients With Covert Hepatic Encephalopathy.

BACKGROUND: Current EASL/AASLD guidelines recommend treatment of covert hepatic encephalopathy (HE) only in symptomatic patients, for example, in those with impaired quality of life or with affected driving abilities. GOALS: Because testing for impaired quality of life is time consuming, the aim of the present study was to identify simple clinical predictors for poor quality of life in patients with covert HE (CHE). STUDY: In total, 139 cirrhotic in- and outpatients without a history of overt hepatic encephalopathy were enrolled. Diagnosis of HE grade 1 (HE1) was diagnosed clinically according to the West-Haven Criteria. Critical flicker frequency and the Psychometric Hepatic Encephalopathy Score were used to detect minimal HE (MHE). Chronic Liver Disease Questionnaire was used to assess health-related quality of life (HrQoL). RESULTS: CHE was detected in 51 (36.7%) patients. Multivariate analysis identified a history of falls in the previous year (P=0.003) and female gender (P=0.030) as independent predictors of reduced HRQoL in patients with CHE. Comparison of patients with and without a history of falls revealed relevant differences in the subdomains-abdominal symptoms, fatigue, systemic symptoms, emotional functions and worries. CONCLUSIONS: A history of falls and female gender are associated with impaired HRQoL in patients with CHE. These data indicate that a history of falls should be considered as a treatment indication in patients with CHE to improve HRQoL and ultimately prognosis.

Marginal hazard ratio estimates in joint frailty models for heart failure trials.

This work is motivated by clinical trials in chronic heart failure disease, where treatment has effects both on morbidity (assessed as recurrent non-fatal hospitalisations) and on mortality (assessed as cardiovascular death, CV death). Recently, a joint frailty proportional hazards model has been proposed for these kind of efficacy outcomes to account for a potential association between the risk rates for hospital admissions and CV death. However, more often clinical trial results are presented by treatment effect estimates that have been derived from marginal proportional hazards models, that is, a Cox model for mortality and an Andersen-Gill model for recurrent hospitalisations. We show how these marginal hazard ratios and their estimates depend on the association between the risk processes, when these are actually linked by shared or dependent frailty terms. First we derive the marginal hazard ratios as a function of time. Then, applying least false parameter theory, we show that the marginal hazard ratio estimate for the hospitalisation rate depends on study duration and on parameters of the underlying joint frailty model. In particular, we identify parameters, for example the treatment effect on mortality, that determine if the marginal hazard ratio estimate for hospitalisations is smaller, equal or larger than the conditional one. How this affects rejection probabilities is further investigated in simulation studies. Our findings can be used to interpret marginal hazard ratio estimates in heart failure trials and are illustrated by the results of the CHARM-Preserved trial (where CHARM is the 'Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity' programme).

Activity profiling of vacuolar processing enzymes reveals a role for VPE during oomycete infection.

Vacuolar processing enzymes (VPEs) are important cysteine proteases that are implicated in the maturation of seed storage proteins, and programmed cell death during plant-microbe interactions and development. Here, we introduce a specific, cell-permeable, activity-based probe for VPEs. This probe is highly specific for all four Arabidopsis VPEs, and labeling is activity-dependent, as illustrated by sensitivity for inhibitors, pH and reducing agents. We show that the probe can be used for in vivo imaging and displays multiple active isoforms of VPEs in various tissues and in both monocot and dicot plant species. Thus, VPE activity profiling is a robust, simple and powerful tool for plant research for a wide range of applications. Using VPE activity profiling, we discovered that VPE activity is increased during infection with the oomycete pathogen Hyaloperonospora arabidopsidis (Hpa). The enhanced VPE activity is host-derived and EDS1-independent. Sporulation of Hpa is reduced on vpe mutant plants, demonstrating a role for VPE during compatible interactions that is presumably independent of programmed cell death. Our data indicate that, as an obligate biotroph, Hpa takes advantage of increased VPE activity in the host, e.g. to mediate protein turnover and nutrient release.

Recovery of right ventricular function after intermediate-risk pulmonary embolism: results from the multicentre Pulmonary Embolism International Trial (PEITHO)-2.

BACKGROUND: Right ventricular (RV) function plays a critical role in the pathophysiology and acute prognosis of pulmonary embolism (PE). We analyzed the temporal changes of RV function in the cohort of a prospective multicentre study investigating if an early switch to oral anticoagulation in patients with intermediate-risk PE is effective and safe. METHODS: Echocardiographic and laboratory examinations were performed at baseline (PE diagnosis), 6 days and 6 months. Echocardiographic parameters were classified into categories representing RV size, RV free wall/tricuspid annulus motion, RV pressure overload and right atrial (RA)/central venous pressure. RESULTS: RV dysfunction based on any abnormal echocardiographic parameter was present in 84% of patients at baseline. RV dilatation was the most frequently abnormal finding (40.6%), followed by increased RA/central venous pressure (34.6%), RV pressure overload (32.1%), and reduced RV free wall/tricuspid annulus motion (20.9%). As early as day 6, RV size remained normal or improved in 260 patients (64.7%), RV free wall/tricuspid annulus motion in 301 (74.9%), RV pressure overload in 297 (73.9%), and RA/central venous pressure in 254 (63.2%). At day 180, the frequencies slightly increased. The median NT-proBNP level decreased from 1448 pg/ml at baseline to 256.5 on day 6 and 127 on day 180. CONCLUSION: In the majority of patients with acute intermediate-risk PE switched early to a direct oral anticoagulant, echocardiographic parameters of RV function normalised within 6 days and remained normal throughout the first 6 months. Almost one in four patients, however, continued to have evidence of RV dysfunction over the long term.

Derivation and validation of the nonalcoholic fatty liver disease cirrhosis score (NCS) to distinguish bridging fibrosis from cirrhosis.

Separation of bridging fibrosis from cirrhosis in non-alcoholic fatty liver disease (NAFLD) is critical to guide management. Therefore, it was the aim of this study to develop an easy-to-perform score distinguishing F3 and F4 fibrosis in NAFLD. A derivation cohort comprising 251 NAFLD patients with F3 or F4 was used to develop the NAFLD Cirrhosis Score (NCS). The NCS was validated in three independent cohorts with liver histology comprising 1666 participants from the STELLAR trials, 47 patients from China and 2058 patients from the European NAFLD Registry. A model including INR, gGT, ALT, platelets and age discriminated best between patients with bridging fibrosis and cirrhosis with an area under the curve (AUC) of 0.733 (95%CI 0.671-0.795). The diagnostic performance of the NCS was similar in the STELLAR studies (AUC 0.700; 95%CI 0.680-0.730) and a smaller cohort from China (AUC 0.727; 95%CI 0.533-0.921). In the European NAFLD Registry, spanning all histological fibrosis stages, the NCS exhibited an AUC of 0.798 (95%CI 0.766-0.830) to detect cirrhosis. We derived two NCS cut-off values (<64.5 and >79.17) to classify patients at low, intermediate, or high risk for the presence of cirrhosis. Using these cut-offs, further diagnostic workup could be avoided by ruling in or ruling out cirrhosis in approximately half of the patients. Furthermore, NCS identified patients at risk for progression to cirrhosis in the F3 cohort and liver-related outcomes in the F4 cohort. CONCLUSION: The NCS is a simple tool to improve the identification of compensated cirrhosis within the large group of advanced disease stage and provides prognostic information. Overall, the differentiation of F3 from F4 disease using standard laboratory remains difficult and does not exceed moderate accuracy.

Liver injury in patients with severe acute respiratory syndrome coronavirus-2 infection: a systematic review and meta-analysis.

OBJECTIVE: Coronavirus disease-19 (COVID-19) infection is a global health threat. To inform the liver community on the potential relevance of COVID-19, we performed a systematic review and meta-analysis of published data on liver injury in patients with COVID-19 infection. METHODS: We searched PubMed and Google Scholar through 22 March according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled data were analyzed by using random-effects meta-analyses. RESULTS: A total of 14 studies combining data from 2.871 patients were identified. The prevalence of pre-existing liver disease was reported at 3.1%. The pooled prevalence of elevated aspartate aminotransferase (AST) and alanine transaminase (ALT) levels were 26% [95% confidence interval (CI), 20-32%] and 19% (95% CI, 14-26%), respectively. Only two studies reported the prevalence of elevated liver function tests according to normal ward versus ICU and here the frequency of elevated levels of AST was 50% and 62% versus ALT 40.8% and thus quantitatively higher in ICU-treated patients. Mean levels of absolute AST levels were 33 U/L (95% CI, 30.21-36.09), while mean ALT levels were 31 U/L (95% CI, 27.52-34.57). Cholestatic liver function tests were only incompletely reported in 510 patients. Here, mean levels of alkaline phosphatase were 71 U/L across three studies, and mean levels of gamma-glutamyl transferase were 40.6 U/L across four studies. CONCLUSIONS: Emerging data on LFTs in COVID-19 are heterogeneous indicating mild LFTs involvement in every fourth to fifth patients with numerical more prevalent AST over ALT elevations. Prospective studies are needed to define the clinical relevance of liver injury in COVID-19.

Disturbed Glucose Metabolism and Left Ventricular Geometry in the General Population.

BACKGROUND: This study sought to investigate the prevalence and clinical outcome of left ventricular (LV) geometry in prediabetes and type 2 diabetes mellitus (T2DM) and the impact of glucose metabolism on the incidence of left ventricular hypertrophy (LVH). METHODS: 15,010 subjects (35-74 years) of the population-based Gutenberg Health Study were categorized into euglycemia, prediabetes, and T2DM according to clinical and metabolic (HbA1c) information. Clinical outcome was assessed via structured follow-up. RESULTS: The study comprised 12,121 individuals with euglycemia (81.6%), 1415 with prediabetes (9.5%), and 1316 with T2DM (8.9%). Prevalence of LVH increased from euglycemia (10.2%) over prediabetes (17.8%) to T2DM (23.8%). Prediabetes and T2DM were associated with increased LV mass index (prediabetes: ß1.3 (95% CI 0.78-1.81), p < 0.0001; T2DM: ß2.37 (95% CI 1.81; 2.92), p < 0.0001) independent of age, sex, and cardiovascular risk factors (CVRF). The frequency of LVH was related to the presence of T2DM (prevalence ratio (PR)T2DM 1.2 (95% CI 1.06-1.35), p = 0.0038). T2DM was related to mortality independent of age, sex, and CVRF regardless of LVH (hazard ratio (HR)T2DM-LVH 2.67 (95% CI 1.94-3.66), p < 0.0001; HRT2DM-noLVH 1.59 (95% CI 1.29-1.96), p < 0.0001), prediabetes was only associated with outcome in individuals with LVH independent of age and sex (HRprediabetes-LVH 1.51 (95% CI 1.01-2.25), p = 0.045). Neither T2DM nor prediabetes were predictors of incident LVH after adjustment for clinical covariates. CONCLUSIONS: Prediabetes and T2DM promote alterations of cardiac geometry. T2DM and particularly the coprevalence of T2DM with LVH substantially reduce life expectancy. These findings highlight the need for new therapeutic and screening approaches to prevent and detect cardiometabolic diseases at an early stage.

Early switch to oral anticoagulation in patients with acute intermediate-risk pulmonary embolism (PEITHO-2): a multinational, multicentre, single-arm, phase 4 trial.

BACKGROUND: Current guidelines recommend a risk-adjusted treatment strategy for the management of acute pulmonary embolism. This is a particular patient category for whom optimal treatment (anticoagulant treatment, reperfusion strategies, and duration of hospitalisation) is currently unknown. We investigated whether treatment of acute intermediate-risk pulmonary embolism with parenteral anticoagulation for a short period of 72 h, followed by a switch to a direct oral anticoagulant (dabigatran), is effective and safe. METHODS: We did a multinational, multicentre, single-arm, phase 4 trial at 42 hospitals in Austria, Belgium, France, Germany, Italy, Netherlands, Romania, Slovenia, and Spain. Adult patients (aged ≥18 years) with symptomatic intermediate-risk pulmonary embolism, with or without deep-vein thrombosis, were enrolled. Patients received parenteral low-molecular-weight or unfractionated heparin for 72 h after diagnosis of pulmonary embolism before switching to oral dabigatran 150 mg twice per day following a standard clinical assessment. The primary outcome was recurrent symptomatic venous thromboembolism or pulmonary embolism-related death within 6 months. The primary and safety outcomes were assessed in the intention-to-treat population. The study was terminated early, as advised by the data safety and monitoring board, following sample size adaptation after the predefined interim analysis on Dec 18, 2018. This trial is registered with the EU Clinical Trials Register (EudraCT 2015-001830-12) and ClinicalTrials.gov (NCT02596555). FINDINGS: Between Jan 1, 2016, and July 31, 2019, 1418 patients with pulmonary embolism were screened, of whom 402 were enrolled and were included in the intention-to-treat analysis (median age was 69·5 years [IQR 60·0-78·0); 192 [48%] were women and 210 [52%] were men). Median follow-up was 217 days (IQR 210-224) and 370 (92%) patients adhered to the protocol. The primary outcome occurred in seven (2% [upper bound of right-sided 95% CI 3]; p<0·0001 for rejecting the null hypothesis) patients, with all events occurring in those with intermediate-high-risk pulmonary embolism (seven [3%; upper bound of right-sided 95% CI 5] of 283). At 6 months, 11 (3% [95% CI 1-5]) of 402 patients had at least one major bleeding event and 16 (4% [2-6]) had at least one clinically relevant non-major bleeding event; the only fatal haemorrhage occurred in one (<1%) patient before the switch to dabigatran. INTERPRETATION: A strategy of early switch from heparin to dabigatran following standard clinical assessment was effective and safe in patients with intermediate-risk pulmonary embolism. Our results can help to refine guideline recommendations for the initial treatment of acute intermediate-risk pulmonary embolism, optimising the use of resources and avoiding extended hospitalisation. FUNDING: German Federal Ministry of Education and Research, University Medical Center Mainz, and Boehringer Ingelheim.

Computational issues in fitting joint frailty models for recurrent events with an associated terminal event.

BACKGROUND AND OBJECTIVE: Joint frailty regression models are intended for the analysis of recurrent event times in the presence of informative drop-outs. They have been proposed for clinical trials to estimate the effect of some treatment on the rate of recurrent heart failure hospitalisations in the presence of drop-outs due to cardiovascular death. Whereas a R-software-package for fitting joint frailty models is available, some technical issues have to be solved in order to use SASⓇ1 software, which is required in the regulatory environment of clinical trials. METHODS: First, we demonstrate how to solve these issues by deriving proper likelihood-decompositions, in particular for the case of non-normally distributed random terms. Second, we perform a simulation study to evaluate the accuracy of different software-implementations (in SAS and R) in terms of convergence behavior, bias of model parameter estimates and coverage probabilities of confidence intervals. Therefore we developed SAS macros that facilitate the analysis and simulation of joint frailty data. These are provided as supplementary material along with comprehensive manuals. RESULTS: Whereas estimates for regression coefficients are unbiased irrespective of the software, the bias of the remaining (nuisance) parameter estimates strongly depends on the software: SAS is shown to be much more efficient in avoiding bias compared to R. However, even in SAS a careful choice of the implementation is required to get reliable results, in particular for the joint gamma frailty model. By far the best performance is reached with a SAS-implementation that makes use of the probability integral transformation method. CONCLUSIONS: We have shown, that getting reliable results from joint frailty models is not straightforward and users should be aware about the computational options between and within software packages. Based on our simulation study, we elaborate recommendations on these options. In addition, our provided SAS macros may encourage statistical practitioners to apply these models in clinical trials with recurrent event data and potentially informative drop-outs.

Clinical Frailty Scale for risk stratification in patients with SARS-CoV-2 infection.

Predictive factors for adverse outcomes in patients with COVID-19 are urgently needed. Data related to the applicability of the Clinical Frailty Scale (CFS) for risk stratification in patients with COVID-19 are currently lacking. We investigated the ability of CFS to predict need for mechanical ventilation and the duration of hospital stays in European patients with COVID-19. In total, 42 patients with confirmed COVID-19 infection admitted to the University Medical Center Mainz between March 3 and April 15 2020 were included into this validation study and data were retrospectively analyzed. CFS was assessed at admission in all patients. Patients were followed for need for mechanical ventilation and time to hospital discharge. At admission, the median CFS was 3 (range: 1-7) and 14 (33.3%) patients were considered as at least pre-frail (CFS >3). 24 (57.1%) patients were discharged from hospital after a median time of 7 days (IQR 4-8). 12 (28.6%) patients developed acute respiratory distress syndrome and required mechanical ventilation. In multivariable Cox regression analyses, higher CFS scores (HR 1.659, 95% CI 1.090 to 2.525, p=0.018) were an independent predictor for a higher risk of mechanical ventilation after adjusting for age, Charlson Comorbidity Index and quick sepsis-related organ failure score. Additionally, lower CFS scores (HR 0.554, 95% CI 0.312 to 0.983, p=0.043) were associated with earlier discharge from hospital. In conclusion, this report demonstrates the usefulness of the CFS for risk stratification at hospital admission in patients with COVID-19.

Impact of non-selective ß-blockers on hepatic encephalopathy in patients with liver cirrhosis.

BACKGROUND: Non-selective ß-blockers (NSBB) are frequently used for the treatment of portal hypertension and gastroesophageal varices in patients with liver cirrhosis; however prospective studies investigating the potential association between NSBB use and hepatic encephalopathy (HE) are still scarce. We investigated the potential association between NSBB use and the presence of covert HE (CHE) as well as the development of overt HE (OHE). METHODS: 224 patients with liver cirrhosis were included into this cohort study at two German centers and followed for a median of 364 days. CHE was diagnosed by pathological results in the PHES. Predictors for the presence of CHE or the development of OHE were analyzed using logistic-regression or cox-regression models. RESULTS: 39% of patients were treated with NSBB and CHE was detected in 34% of patients at study inclusion. In logistic regression analysis, NSBB use, higher MELD score and a history of OHE were independently associated with the presence of CHE. Cumulative incidence of OHE was considerably higher in NSBB users than in non-users (p<0.001). In Cox-regression models NSBB use, presence of CHE, lower albumin and higher MELD score were independently associated with the development of OHE in the whole cohort as well as in the subgroup of patients with decompensated liver cirrhosis. NSBB use was independently associated with higher risk of mortality or need for liver transplantation in decompensated patients but not in the total cohort. CONCLUSION: NSBB use seems to be associated with the presence of CHE as well as the development of OHE in patients with decompensated liver cirrhosis.

Association between diabetes mellitus and hepatic encephalopathy in patients with cirrhosis.

BACKGROUND: Diabetes mellitus may lead to increased serum ammonia and systemic inflammation thereby promoting hepatic encephalopathy (HE). AIM: To investigate the potential association between diabetes mellitus/glycaemic control and the presence of covert HE as well as the development of overt HE in a prospective setting. METHODS: A total of 240 patients with liver cirrhosis were included into this prospective cohort study and followed for a median of 17 months. Covert HE was diagnosed by pathological results in the Portosystemic Hepatic Encephalopathy Score. Predictors for the presence of covert HE or the development of overt HE were analysed using logistic regression or Cox-regression models. RESULTS: At study inclusion, 65 patients (27.1%) presented with diabetes mellitus and covert HE was detected in 33.3%. Patients with diabetes mellitus had a more preserved liver function as compared to patients without diabetes mellitus (MELD 9 vs 10; P = 0.043). In regression analyses after adjustment for confounders, diabetes mellitus was independently associated with the presence of covert HE at study inclusion and the development of overt HE during follow-up. These associations were confirmed in separate propensity-score-weighted regression models. In subgroup analyses, patients with worse glycaemic control (HbA1c >= 6.5%) had a pronounced risk for covert HE (OR 2.264, 95% CI 1.002-5.118) and overt HE (HR 4.116, 95% CI 1.791-9.459). CONCLUSIONS: Diabetes mellitus may associate with higher risk for the presence of covert HE and the development of overt HE in patients with liver cirrhosis. Adequate glycaemic control may be a potential target to attenuate this important complication.

Outcome Prediction of Covert Hepatic Encephalopathy in Liver Cirrhosis: Comparison of Four Testing Strategies.

INTRODUCTION: Despite the negative impact of covert hepatic encephalopathy on the outcome of patients with liver cirrhosis, data regarding the ability of different testing strategies to predict overt hepatic encephalopathy (OHE) development and mortality are limited. This study aimed to compare the ability of Psychometric Hepatic Encephalopathy Score (PHES), critical flicker frequency (CFF), simplified animal naming test (S-ANT1), and clinical covert hepatic encephalopathy (CCHE) score to predict OHE development and mortality. METHODS: A total of 224 patients with liver cirrhosis were tested with different testing strategies and prospectively followed up regarding clinically relevant outcomes (OHE or death/liver transplantation). RESULTS: Prevalence of pathological results varied among the testing strategies: PHES 33.9%, CFF 17.9%, S-ANT1 41.5%, and CCHE score 33.9%. All testing strategies were independent predictors of OHE development after adjusting for model of end-stage liver disease (MELD) score and history of OHE. The predictive performances of PHES (area under the receiver operating characteristic curve, 0.742) and CCHE (area under the receiver operating characteristic curve, 0.785) regarding OHE development during the next 180 days were significantly better than those of CFF and S-ANT1. In multivariable analysis, pathological results in PHES, S-ANT1, and CCHE score were independently associated with higher mortality. CFF did not correlate with mortality in the whole cohort. In the subgroup of patients with a MELD score <15, pathological results in PHES, CFF, or CCHE score were independent predictors of higher mortality. DISCUSSION: PHES and CCHE score predict OHE development and mortality in patients with liver cirrhosis. In particular, in patients with low MELD score, both testing strategies could help to identify patients who might benefit from liver transplantation.

Sarcopenia as prognostic factor for survival after orthotopic liver transplantation.

BACKGROUND AND AIM: Body composition has emerged as a prognostic factor for end-stage liver disease. We therefore investigated muscle mass, body fat and other clinical-pathological variables as predictors of posttransplant survival. METHODS: A total of 368 patients, who underwent orthotopic liver transplantation (OLT) at our institution, were assessed prior to OLT and followed for a median of 9.0 years (range 2.0-10.0 years) after OLT. Psoas, erector spinae and the combined paraspinal muscle area, as well as the corresponding indices normalized by body-height squared, were quantified by a lumbar (L3) cross-sectional computed tomography. In addition, absolute body fat and bone density were estimated by the same computed tomography approach. RESULTS: Paraspinal muscle index (PSMI) (hazard ratio 0.955, P = 0.039) and hepatitis C (hazard rati 1.498, P = 0.038) were independently associated with post-OLT mortality. In contrast, body fat and bone density did not significantly affect post-OLT outcome (P > 0.05). The PSMI also predicted one-year posttransplant mortality with a receiver operating characteristics-area under the curve of 0.671 [95% confidence interval (CI) 0.589-0.753, P < 0.001) in male patients and outperformed individual psoas and erector spinae muscle group assessments in this regard. In male patients, a defined PSMI cutoff (<18.41 cm/m) was identified as suitable determinant for sarcopenia and posttransplant one-year mortality. In female OLT-recipients, however, sarcopenia was not predictive for patient survival und a women-specific cutoff could not be derived from this study. CONCLUSIONS: Taken together this analysis provides evidence, which PSMI is a relevant marker for muscle mass and that sarcopenia is an independent predictor of early post-OLT survival in male patients.

Is APOE ε4 associated with cognitive performance in early MS?

OBJECTIVE: To assess the impact of APOE polymorphisms on cognitive performance in patients newly diagnosed with clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS). METHODS: This multicenter cohort study included 552 untreated patients recently diagnosed with CIS or RRMS according to the 2005 revised McDonald criteria. The single nucleotide polymorphisms rs429358 (ε4) and rs7412 (ε2) of the APOE haplotype were assessed by allelic discrimination assays. Cognitive performance was evaluated using the 3-second paced auditory serial addition test and the Multiple Sclerosis Inventory Cognition (MUSIC). Sum scores were calculated to approximate the overall cognitive performance and memory-centered cognitive functions. The impact of the APOE carrier status on cognitive performance was assessed using multiple linear regression models, also including demographic, clinical, MRI, and lifestyle factors. RESULTS: APOE ε4 homozygosity was associated with lower overall cognitive performance, whereas no relevant association was observed for APOE ε4 heterozygosity or APOE ε2 carrier status. Furthermore, higher disability levels, MRI lesion load, and depressive symptoms were associated with lower cognitive performance. Patients consuming alcohol had higher test scores than patients not consuming alcohol. Female sex, lower disability, and alcohol consumption were associated with better performance in the memory-centered subtests of MUSIC, whereas no relevant association was observed for APOE carrier status. CONCLUSION: Along with parameters of a higher disease burden, APOE ε4 homozygosity was identified as a potential predictor of cognitive performance in this large cohort of patients with CIS and early RRMS.

Impact of cardiopulmonary resuscitation on a cannot intubate, cannot oxygenate condition: a randomised crossover simulation research study of the interaction between two algorithms.

OBJECTIVES: During a 'cannot intubate, cannot oxygenate' situation, asphyxia can lead to cardiac arrest. In this stressful situation, two complex algorithms facilitate decision-making to save a patient's life: difficult airway management and cardiopulmonary resuscitation. However, the extent to which competition between the two algorithms causes conflicts in the execution of pivotal treatment remains unknown. Due to the rare incidence of this situation and the very low feasibility of such an evaluation in clinical reality, we decided to perform a randomised crossover simulation research study. We propose that even experienced healthcare providers delay cricothyrotomy, a lifesaving approach, due to concurrent cardiopulmonary resuscitation in a 'cannot intubate, cannot oxygenate' situation. DESIGN: Due to the rare incidence and dynamics of such a situation, we conducted a randomised crossover simulation research study. SETTING: We collected data in our institutional simulation centre between November 2016 and November 2017. PARTICIPANTS: We included 40 experienced staff anaesthesiologists at our tertiary university hospital centre. INTERVENTION: The participants treated two simulated patients, both requiring cricothyrotomy: one patient required cardiopulmonary resuscitation due to asphyxia, and one patient did not require cardiopulmonary resuscitation. Cardiopulmonary resuscitation was the intervention. Participants were evaluated by video records. PRIMARY OUTCOME MEASURES: The difference in 'time to ventilation through cricothyrotomy' between the two situations was the primary outcome measure. RESULTS: The results of 40 participants were analysed. No carry-over effects were detected in the crossover design. During cardiopulmonary resuscitation, the median time to ventilation was 22 s (IQR 3-40.5) longer than that without cardiopulmonary resuscitation (p=0.028), including the decision-making time. CONCLUSION: Cricothyrotomy, which is the most crucial treatment for cardiac arrest in a 'cannot intubate, cannot oxygenate' situation, was delayed by concurrent cardiopulmonary resuscitation. If cardiopulmonary resuscitation delays cricothyrotomy, it should be interrupted to first focus on cricothyrotomy.