Different pain phenotypes are associated with anti-Caspr2 autoantibodies.

Autoantibodies against contactin-associated protein 2 (Caspr2) not only induce limbic autoimmune encephalitis but are also associated with pain conditions. Here, we analyzed clinical data on pain in a large cohort of patients included into the German Network for Research in Autoimmune Encephalitis. Out of 102 patients in our cohort, pain was a frequent symptom (36% of all patients), often severe (63.6% of the patients with pain) and/or even the major symptom (55.6% of the patients with pain). Pain phenotypes differed between patients. Cluster analysis revealed two major phenotypes including mostly distal-symmetric burning pain and widespread pain with myalgia and cramps. Almost all patients had IgG4 autoantibodies and some additional IgG1, 2, and/or 3 autoantibodies, but IgG subclasses, titers, and presence or absence of intrathecal synthesis were not associated with the occurrence of pain. However, certain pre-existing risk factors for chronic pain like diabetes mellitus, peripheral neuropathy, or preexisting chronic back pain tended to occur more frequently in patients with anti-Caspr2 autoantibodies and pain. Our data show that pain is a relevant symptom in patients with anti-Caspr2 autoantibodies and support the idea of decreased algesic thresholds leading to pain. Testing for anti-Caspr2 autoantibodies needs to be considered in patients with various pain phenotypes.

Comparison of Inflammatory Cytokine Levels in Hepatic and Jugular Veins of Patients with Cirrhosis.

Background: Systemic inflammation with elevated inflammatory cytokines is a hallmark in patients with cirrhosis and the main driver of decompensation. There is insufficient data on whether inflammatory cytokine levels differ between hepatic and jugular veins, which may have implications for further immunological studies. Methods: Blood from the hepatic and jugular veins of 40 patients with cirrhosis was collected during hepatic venous pressure gradient (HVPG) measurements. Serum levels of 13 inflammatory cytokines (IL-1ß, Int-α2, Int-γ, TNF-α, MCP-1, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-18, IL-23, and IL-33) were quantified by cytometric bead array. Results: Cytokine levels of IFN-α2, IFN-γ, TNF-α, IL-6, IL-8, IL-10, IL-17A, IL-18, IL-23, and IL-33 were significantly elevated in patients with decompensated cirrhosis compared to patients with compensated cirrhosis. When comparing patients with clinically significant portal hypertension (CSPH, HVPG ≥ 10 mmHg) to patients without CSPH, there were significantly enhanced serum levels of IL-6 and IL-18 in the former group. There was no significant difference between cytokine serum levels between blood obtained from the jugular versus hepatic veins. Even in subgroup analyses stratified for an early cirrhosis stage (Child-Pugh (CP) A) or more decompensated stages (CP B/C), cytokine levels were similar. Conclusion: Cytokine levels increase with decompensation and increasing portal hypertension in patients with cirrhosis. There is no relevant difference in cytokine levels between hepatic and jugular blood in patients with cirrhosis.

Validation of the CLIF-C OF Score and CLIF-C ACLF Score to Predict Transplant-Free Survival in Patients with Liver Cirrhosis and Concomitant Need for Intensive Care Unit Treatment.

Both the Chronic Liver Failure Consortium (CLIF-C) organ failure score (OFs) and the CLIF-C acute-on-chronic-liver failure (ACLF) score (ACLFs) were developed for risk stratification and to predict mortality in patients with liver cirrhosis and ACLF. However, studies validating the predictive ability of both scores in patients with liver cirrhosis and concomitant need for intensive care unit (ICU) treatment are scarce. The aim of the present study is to validate the predictive ability of the CLIF-C OFs and CLIF-C ACLFs regarding the rationale of ongoing ICU treatment and to investigate their predictive ability regarding 28-days (short-), 90-days (medium-), and 365-days (long-term) mortality in patients with liver cirrhosis treated in an ICU. Patients with liver cirrhosis and acute decompensation (AD) or ACLF and concomitant need for ICU treatment were retrospectively analyzed. Predictive factors for mortality, defined as transplant-free survival, were identified using multivariable regression analyses and the predictive ability of CLIF-C OFs, CLIF-C ACLFs, MELD score, and AD score (ADs) was assessed by determining the AUROC. Of 136 included patients, 19 patients presented with AD and 117 patients with ACLF at ICU admission. In multivariable regression analyses, CLIF-C OFs as well as CLIF-C ACLFs were independently associated with higher short-, medium-, and long-term mortality after adjusting for confounding variables. The predictive ability of the CLIF-C OFs in the total cohort in short-term was 0.687 (95% CI 0.599-0.774). In the subgroup of patients with ACLF, the respective AUROCs were 0.652 (95% CI 0.554-0.750) and 0.717 (95% CI 0.626-0.809) for the CLIF-C OFs and for the CLIF-C ACLFs, respectively. ADs performed well in the subgroup of patients without ACLF at ICU admission with an AUROC of 0.792 (95% CI 0.560-1.000). In the long-term, the AUROCs were 0.689 (95% Cl 0.581-0.796) and 0.675 (95% Cl 0.550-0.800) for CLIF-C OFs and CLIF-C ACLFs, respectively. The predictive ability of CLIF-C OFs and CLIF-C ACLFs was relatively low to predict short- and long-term mortality in patients with ACLF with concomitant need for ICU treatment. However, the CLIF-C ACLFs may have special merit in judging futility of further ICU treatment.

On-Chip Time-Domain Terahertz Spectroscopy of Superconducting Films below the Diffraction Limit.

Free-space time domain THz spectroscopy accesses electrodynamic responses in a frequency regime ideally matched to interacting condensed matter systems. However, THz spectroscopy is challenging when samples are physically smaller than the diffraction limit of ∼0.5 mm, as is typical, for example, in van der Waals materials and heterostructures. Here, we present an on-chip, time-domain THz spectrometer based on semiconducting photoconductive switches with a bandwidth of 200 to 750 GHz. We measure the optical conductivity of a 7.5-µm wide NbN film across the superconducting transition, demonstrating spectroscopic signatures of the superconducting gap in a sample smaller than 2% of the Rayleigh diffraction limit. Our spectrometer features an interchangeable sample architecture, making it ideal for probing superconductivity, magnetism, and charge order in strongly correlated van der Waals materials.

Elevated serum levels of glial fibrillary acidic protein are associated with covert hepatic encephalopathy in patients with cirrhosis.

Background & Aims: Blood biomarkers facilitating the diagnosis of covert hepatic encephalopathy (CHE) in patients with cirrhosis are lacking. Astrocyte swelling is a major component of hepatic encephalopathy. Thus, we hypothesised that glial fibrillary acidic protein (GFAP), the major intermediate filament of astrocytes, might facilitate early diagnosis and management. This study aimed to investigate the utility of serum GFAP (sGFAP) levels as a biomarker of CHE. Methods: In this bicentric study, 135 patients with cirrhosis, 21 patients with ongoing harmful alcohol use and cirrhosis, and 15 healthy controls were recruited. CHE was diagnosed using psychometric hepatic encephalopathy score. sGFAP levels were measured using a highly sensitive single-molecule array (SiMoA) immunoassay. Results: In total, 50 (37%) people presented with CHE at study inclusion. Participants with CHE displayed significantly higher sGFAP levels than those without CHE (median sGFAP, 163 pg/ml [IQR 136; 268] vs. 106 pg/ml [IQR 75; 153]; p <0.001) or healthy controls (p <0.001). sGFAP correlated with results in psychometric hepatic encephalopathy score (Spearman's ρ = -0.326, p <0.001), model for end-stage liver disease score (Spearman's ρ = 0.253, p = 0.003), ammonia (Spearman's ρ = 0.453, p = 0.002), and IL-6 serum levels (Spearman's ρ = 0.323, p = 0.006). Additionally, sGFAP levels were independently associated with the presence of CHE in multivariable logistic regression analysis (odds ratio 1.009; 95% CI 1.004-1.015; p <0.001). sGFAP levels did not differ between patients with alcohol-related cirrhosis vs. patients with non-alcohol-related cirrhosis or between patients with ongoing alcohol use vs. patients with discontinued alcohol use.Conclusions: sGFAP levels are associated with CHE in patients with cirrhosis. These results suggest that astrocyte injury may already occur in patients with cirrhosis and subclinical cognitive deficits and that sGFAP could be explored as a novel biomarker. Impact and implications: Blood biomarkers facilitating the diagnosis of covert hepatic encephalopathy (CHE) in patients with cirrhosis are lacking. In this study, we were able to demonstrate that sGFAP levels are associated with CHE in patients with cirrhosis. These results suggest that astrocyte injury may already occur in patients with cirrhosis and subclinical cognitive deficits and that sGFAP could be explored as a novel biomarker.

Clinical, serological and genetic predictors of response to immunotherapy in anti-IgLON5 disease.

Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited, and its efficacy remains controversial. In this study, we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological and genetic predictors of the immunotherapy response and long-term outcome. Patients were recruited from the GENERATE (German Network for Research on Autoimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined. We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder [at least one symptom present in 38% (20/53)]. At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless, 21% (11/53) still had an isolated brainstem syndrome and/or a characteristic sleep disorder only. About one third of patients [28% (15/53)] reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titre increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 [55% (24/44)] was associated with higher serum anti-IgLON5 IgG titres. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first 6 weeks was a predictor for therapy response. Sixty-eight per cent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome. In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response.

Systematic mutagenesis of TFIIH subunit p52/Tfb2 identifies residues required for XPB/Ssl2 subunit function and genetic interactions with TFB6.

TFIIH is an evolutionarily conserved complex that plays central roles in both RNA polymerase II (pol II) transcription and DNA repair. As an integral component of the pol II preinitiation complex, TFIIH regulates pol II enzyme activity in numerous ways. The TFIIH subunit XPB/Ssl2 is an ATP-dependent DNA translocase that stimulates promoter opening prior to transcription initiation. Crosslinking-mass spectrometry and cryo-EM results have shown a conserved interaction network involving XPB/Ssl2 and the C-terminal Hub region of the TFIIH p52/Tfb2 subunit, but the functional significance of specific residues is unclear. Here, we systematically mutagenized the HubA region of Tfb2 and screened for growth phenotypes in a TFB6 deletion background in Saccharomyces cerevisiae. We identified six lethal and 12 conditional mutants. Slow growth phenotypes of all but three conditional mutants were relieved in the presence of TFB6, thus identifying a functional interaction between Tfb2 HubA mutants and Tfb6, a protein that dissociates Ssl2 from TFIIH. Our biochemical analysis of Tfb2 mutants with severe growth phenotypes revealed defects in Ssl2 association, with similar results in human cells. Further characterization of these tfb2 mutant cells revealed defects in GAL gene induction, and reduced occupancy of TFIIH and pol II at GAL gene promoters, suggesting that functionally competent TFIIH is required for proper pol II recruitment to preinitiation complexes in vivo. Consistent with recent structural models of TFIIH, our results identify key residues in the p52/Tfb2 HubA domain that are required for stable incorporation of XPB/Ssl2 into TFIIH and for pol II transcription.

Suppressed serological vitamin A in patients with liver cirrhosis is associated with impaired liver function and clinical detoriation.

BACKGROUND: The liver is of critical importance for the homeostasis of metabolic and immunomodulatory properties as well as the storage of vitamins, especially vitamin A. In this prospective analysis, the incidence of serological vitamin A deficiency and the association with disease severity as well as clinical complications in patients with liver cirrhosis were investigated. METHOD: From May 2017 to May 2018, 159 patients with primarily alcohol-associated and non-alcoholic steatohepatitis (NASH)-associated preexisting liver cirrhosis were prospectively enrolled and vitamin A status was collected. Clinical complications and infections were followed and recorded over a period of 1-year follow-up. Selected findings were validated in an independent cohort of 44 patients. RESULTS: At study inclusion, 77% of patients showed decreased serological vitamin A. Suppressed vitamin A was more common in alcoholic (52 vs. 8%) and NASH-associated liver cirrhosis (16 vs. 9%) than in viral-associated liver cirrhosis. MELD score as well as Child-Pugh score were significantly associated with suppressed vitamin A ( P < 0.001). The association between the degree of vitamin A suppression and liver function was confirmed in univariate and multivariate regression analysis. After 1 year of follow-up, 57 patients died and 21 patients received a liver transplant. In addition, low vitamin A levels were more commonly observed in patients with severe ascites ( P = 0.001), hepatic encephalopathy ( P = 0.002) and hepatorenal syndromes ( P = 0.008). In addition, patients with reduced vitamin A showed an increased incidence of infections ( P = 0.02), especially respiratory infections ( P = 0.04). CONCLUSION: Suppressed serological Vitamin A is common in patients with liver cirrhosis and is associated with liver function. Clinical complications and infections are more frequent in patients with liver cirrhosis and vitamin A suppression.

Frailty as Tested by the Clinical Frailty Scale Is a Risk Factor for Hepatorenal Syndrome in Patients With Liver Cirrhosis.

INTRODUCTION: Frailty is common in patients with cirrhosis and increases the vulnerability to internal and external stressors. This study aimed to investigate the impact of frailty, as defined by the Clinical Frailty Scale (CFS), on the risk of acute kidney injury (AKI) and hepatorenal syndrome (HRS-AKI) in hospitalized patients with liver cirrhosis. METHODS: We analyzed data of 201 nonelectively hospitalized patients with cirrhosis and without higher-grade chronic kidney disease. Patient characteristics were captured within the first 24 hours of hospital admission, and frailty was assessed using the CFS. Patients were followed for the development of AKI and/or HRS-AKI during the hospital stay. RESULTS: In the total cohort, median CFS was 3 (interquartile range 3-4), and 34 (16.9%) patients were frail (CFS >4). During the hospital stay, 110 (54.7%) and 49 (24.3%) patients developed AKI or HRS-AKI, respectively. Patients with AKI or HRS-AKI had a significantly higher CFS than patients without kidney injury (P < 0.001 each). In multivariable analyses, a higher CFS was independently associated with the development of AKI (odds ratio [OR] 1.467, 95% confidence interval (CI) 1.065-2.021) in the total cohort and HRS-AKI (OR 1.809, 95% CI 1.263-2.591) in the subcohort of patients with a history of ascites. In addition, there was a strong association between frailty (OR 3.717, 95% CI 1.456-9.491) and HRS-AKI. DISCUSSION: Frailty in patients with cirrhosis is associated with AKI and HRS-AKI. In this context, CFS appears to be a reliable tool to identify patients at high risk for developing AKI or HRS-AKI on hospital admission.

Liver Frailty Index for Prediction of Short-Term Rehospitalization in Patients with Liver Cirrhosis.

Background: Stratifying patients with liver cirrhosis for risk of rehospitalization is challenging with established scoring systems for chronic liver disease. Frailty captures the physical characteristics of patients with cirrhosis. Its value for predicting short-term rehospitalizations in hospitalized patients remains to be defined. Methods: Eighty-three non-electively hospitalized patients with liver cirrhosis were analyzed in this study. Frailty was assessed during the last 48 h of hospital stay with the liver frailty index (LFI). Patients were followed for 30-day rehospitalization. Results: In total, 26 (31%) patients were rehospitalized within 30 days. The median LFI was 4.5, and 43 (52%) patients were identified as frail. Rehospitalized patients had a significant higher LFI compared to patients without a rehospitalization within 30 days. In multivariable analysis, LFI as a metric variable (OR 2.36, p = 0.02) and lower platelet count (OR 0.98, p < 0.01) were independently associated with rehospitalization. LFI and its subtest chair stands had the best discriminative ability to predict rehospitalization, with AUROCs of 0.66 and 0.67, respectively. An LFI cut-off of >4.62 discriminated best between patients with and without elevated risk for rehospitalization within 30 days. Conclusions: Measures of frailty could be useful to identify patients at higher risk for short-term rehospitalization.

Structured Early detection of Asymptomatic Liver Cirrhosis: Results of the population-based liver screening program SEAL.

BACKGROUND & AIMS: Detection of patients with early cirrhosis is of importance to prevent the occurrence of complications and improve prognosis. The SEAL program aimed at evaluating the usefulness of a structured screening procedure to detect cirrhosis as early as possible. METHODS: SEAL was a prospective cohort study with a control cohort from routine care data. Individuals participating in the general German health check-up after the age of 35 ("Check-up 35") at their primary care physicians were offered a questionnaire, liver function tests (aspartate and alanine aminotransferase [AST and ALT]), and follow-up. If AST/ALT levels were elevated, the AST-to-platelet ratio index (APRI) score was calculated, and patients with a score >0.5 were referred to a liver expert in secondary and/or tertiary care. RESULTS: A total of 11,859 participants were enrolled and available for final analysis. The control group comprised 349,570 participants of the regular Check-up 35. SEAL detected 488 individuals with elevated APRI scores (4.12%) and 45 incident cases of advanced fibrosis/cirrhosis. The standardized incidence of advanced fibrosis/cirrhosis in the screening program was slightly higher than in controls (3.83‰ vs. 3.36‰). The comparison of the chance of fibrosis/cirrhosis diagnosis in SEAL vs. in standard care was inconclusive (marginal odds ratio 1.141, one-sided 95% CI 0.801, +Inf). Of note, when patients with decompensated cirrhosis at initial diagnosis were excluded from both cohorts in a post hoc analysis, SEAL was associated with a 59% higher chance of early cirrhosis detection on average than routine care (marginal odds ratio 1.590, one-sided 95% CI 1.080, +Inf; SEAL 3.51‰, controls: 2.21‰). CONCLUSIONS: The implementation of a structured screening program may increase the early detection rate of cirrhosis in the general population. In this context, the SEAL pathway represents a feasible and potentially cost-effective screening program. REGISTRATION: DRKS00013460 LAY SUMMARY: Detection of patients with early liver cirrhosis is of importance to prevent the occurrence of complications and improve prognosis. This study demonstrates that the implementation of a structured screening program using easily obtainable measures of liver function may increase the early detection rate of cirrhosis in the general population. In this context, the 'SEAL' pathway represents a feasible and potentially cost-effective screening program.

Characteristics of bacterial infections and prevalence of multidrug-resistant bacteria in hospitalized patients with liver cirrhosis in Germany.

INTRODUCTION AND OBJECTIVES: Bacterial infections are associated with a dismal prognosis in patients with liver cirrhosis. Data on their prevalence and the associated pathogen spectra in Germany are scarce. This study aimed to evaluate the impact of bacterial infections on mortality in hospitalized patients with liver cirrhosis and to analyze the prevalence of multidrug-resistant (MDR) bacteria in a German tertiary care center. PATIENTS AND METHODS: Consecutive, non-electively hospitalized patients with liver cirrhosis were enrolled in this study between 03/2019-06/2021. All patients underwent clinical, laboratory and microbiological testing to detect potential bacterial infections. Patients were followed for 30 days regarding the composite endpoint of death or liver transplantation (mortality). RESULTS: In total, 239 patients were recruited (median MELD 18). Bacterial infection was detected in 81 patients (33.9%) at study inclusion. A total of 70 patients (29.3%) developed a hospital-acquired infection. When comparing community-acquired and hospital-acquired infections, the pathogen pattern shifted from a gram-negative to a more gram-positive spectrum and showed an increase of Staphylococcus spp.. MDR bacteria were detected in seven infected patients (5.8%). 34 patients reached the composite endpoint during 30-days follow-up. In multivariable logistic regression analysis, the presence of infection during hospitalization remained independently associated with higher mortality (OR 2.522, 95% CI 1.044 - 6.091, p = 0.040). CONCLUSIONS: This study demonstrates that bacterial infections are common in hospitalized patients with liver cirrhosis in Germany and are a major determinant of short-term mortality. Our data highlight the importance of regional differences in MDR bacteria and may guide physicians' decision-making regarding calculated antibiotic treatment.

Continued alcohol consumption and hepatic encephalopathy determine quality of life and psychosocial burden of caregivers in patients with liver cirrhosis.

BACKGROUND: Patients with liver cirrhosis suffer from significantly reduced health-related quality of life and are often dependent on support from caregivers. In this context, caregivers often suffer from impaired quality of life (QoL) as well as psychosocial burden (PB). The aim of the present study was to identify factors influencing QoL and PB of caregivers in order to improve the social care of patients and caregivers. METHODS: In this cross-sectional study, 106 patients with liver cirrhosis and their caregivers were included. (Health-related) QoL was surveyed in patients (CLDQ) and caregivers (SF-36) and PB was determined by Zarit Burden Interview. RESULTS: Alcohol related liver cirrhosis (55%) was the predominant etiology of liver cirrhosis and the median MELD of the cohort was 14. QoL did not differ between patients with and without alcohol-related liver cirrhosis (p = 0.6). In multivariable analysis, continued alcohol consumption (p = 0.020), a history of hepatic encephalopathy (HE) (p = 0.010), poorer QoL of patients (p = 0.030) and poorer QoL of caregivers (p = 0.005) were associated with a higher PB of caregivers. Factors independently associated with poorer QoL of caregivers were continued alcohol consumption (p = 0.003) and a higher PB of caregivers (p = 0.030). CONCLUSION: Caregivers of patients with liver cirrhosis suffer from impaired QoL and PB, especially in case of continued alcohol consumption or the occurrence of HE.

Validation of EncephalApp_Stroop as screening tool for the detection of minimal hepatic encephalopathy in German patients with liver cirrhosis.

BACKGROUND: In contrast to overt hepatic encephalopathy (OHE), the diagnosis of minimal HE (MHE) is challenging in patients with cirrhosis requiring elaborate, specialized testing. The EncephalApp_Stroop is a smartphone-based application established as screening tool for the diagnosis of MHE but has not yet been validated in a German cohort and country specific cut-offs are currently missing. METHODS: 93 patients with cirrhosis were enroled into this study. Psychometric hepatic encephalopathy score (PHES) was used to detect MHE, and a subset of the patients was tested with critical flicker frequency (CFF). All patients underwent testing with EncephalApp_Stroop. Cut-off thresholds for EncephalApp_Stroop were calculated according to Youden's Index and a separate cut-off was determined with focus on sensitivity. RESULTS: 24 (26%) patients had MHE according to PHES. EncephalApp_Stroop had a strong correlation with PHES (r=-0.76, p<0.001), while there was only a modest correlation with CFF (r=-0.51, <0.001). On time as well as on+off time discriminated best between patients with and without MHE with AUROCS of 0.87 for both measures. According to Youden's index, a cut-off of >224.7 s (sec) (on+off time) discriminated best between patients with and without MHE with a sensitivity of 71% and a specificity of 88%. The adjusted cut-off value for on+off time with focus on sensitivity (sensitivity:specificity weighed 2:1) was 185.1 s, yielding an optimized sensitivity of 92% and a negative predictive value of 96%. By using this cut-off as a pre-screening test in a stepwise diagnosis algorithm, elaborate testing with PHES could have been avoided in 49% of all patients. CONCLUSION: EncephalApp_Stroop may be useful in a stepwise diagnosis algorithm or even as a stand-alone screening tool to detect MHE in German patients with cirrhosis.

Evaluation of IL-6 for Stepwise Diagnosis of Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis.

Diagnosis of minimal hepatic encephalopathy (MHE) requires psychometric testing, which is time-consuming and often neglected in clinical practice. Elevated Interleukin-6 (IL-6) serum levels have been linked to MHE. The aim of this study was to investigate the usefulness of IL-6 as a biomarker in a stepwise diagnostic algorithm to detect MHE in patients with liver cirrhosis. A total of 197 prospectively recruited patients without clinical signs of hepatic encephalopathy (HE) served as the development cohort. Another independent cohort consisting of 52 patients served for validation purposes. Psychometric Hepatic Encephalopathy Score (PHES) was applied for the diagnosis of MHE. Fifty (25.4%) patients of the development cohort presented with MHE. Median IL-6 levels were more than twice as high in patients with MHE than in patients without HE (16 vs. 7 pg/mL; P < 0.001). On multivariable logistic regression analysis, higher IL-6 levels (odds ratio 1.036; 95% confidence interval [CI] 1.009-1.064; P = 0.008) remained independently associated with the presence of MHE. IL-6 levels ≥ 8pg/mL discriminated best between patients with and without MHE in receiver operating characteristic (ROC) analysis (area under the ROC 0.751). With a cutoff value of ≥7 pg/mL, further elaborate testing with PHES could be avoided in 38% of all patients with a sensitivity of 90% (95% CI 77%-96%) and a negative predictive value (NPV) of 93% (95% CI 84%-98%). This diagnostic accuracy was confirmed in the validation cohort (sensitivity 94%; NPV 93%). Conclusion: Using IL-6 serum levels as a biomarker in a stepwise diagnostic algorithm to detect MHE could substantially reduce the number of patients requiring testing with PHES and in turn the workload. IL-6 may have especially helped in patients who are unable to perform other screening tests.

Emergence of SARS-CoV-2 Delta Variant, Benin, May-July 2021.

Severe acute respiratory syndrome coronavirus 2 Delta variant epidemiology in Africa is unknown. We found Delta variant was introduced in Benin during April-May 2021 and became predominant within 2 months, after which a steep increase in reported coronavirus disease incidence occurred. Benin might require increased nonpharmaceutical interventions and vaccination coverage.

Elevated serum levels of methylglyoxal are associated with impaired liver function in patients with liver cirrhosis.

Methylglyoxal (MGO) is a highly reactive dicarbonyl species that forms advanced glycation end products (AGEs). The binding of these AGEs to their receptor (RAGE) causes and sustains severe inflammation. Systemic inflammation is postulated to be a major driver in the progression of liver cirrhosis. However, the role of circulating MGO levels in liver cirrhosis remains unknown. In this study, we investigated the serum levels of two dicarbonyl species, MGO and glyoxal (GO) using tandem mass spectrometry (HPLC-MS/MS) and evaluated their association with disease severity. A total of 51 inpatients and outpatients with liver cirrhosis of mixed etiology and different disease stages were included. Elevated MGO levels were seen in an advanced stage of liver cirrhosis (p < 0.001). High MGO levels remained independently associated with impaired liver function, as assessed by the model for end-stage liver disease (MELD) (ß = 0.448, p = 0.002) and acute decompensation (AD) (ß = 0.345, p = 0.005) scores. Furthermore, MGO was positively correlated with markers of systemic inflammation (IL-6, p = 0.004) and the development of ascites (p = 0.013). In contrast, no changes were seen in GO serum levels. Circulating levels of MGO are elevated in advanced stages of liver cirrhosis and are associated with impaired liver function and liver-related parameters.

Association Between Serum Levels of Neurofilament Light Chains and Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis.

INTRODUCTION: Serum biomarkers for the diagnosis of minimal hepatic encephalopathy (MHE) in patients with liver cirrhosis would be desirable. In this proof-of-concept study, we investigated the association between MHE and serum levels of neurofilament light chains (sNfL) in patients with liver cirrhosis. METHODS: sNfL were studied in patients with liver cirrhosis (with or without MHE) and controls (patients with ischemic stroke, transitory ischemic attack, and healthy individuals). MHE was diagnosed using the Psychometric Hepatic Encephalopathy Score. RESULTS: Patients with MHE showed higher sNfL than patients without MHE and controls. In multivariable analyses, higher sNfL were independently associated with the presence of MHE. sNfL had a reliable discriminative power for the detection of MHE with an area under the curve of 0.872. DISCUSSION: MHE is associated with higher sNfL.

Mutations Associated with SARS-CoV-2 Variants of Concern, Benin, Early 2021.

Intense transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Africa might promote emergence of variants. We describe 10 SARS-CoV-2 lineages in Benin during early 2021 that harbored mutations associated with variants of concern. Benin-derived SARS-CoV-2 strains were more efficiently neutralized by antibodies derived from vaccinees than patients, warranting accelerated vaccination in Africa.

Risk factors for poorer health literacy in patients with liver cirrhosis.

BACKGROUND: Health literacy is a concept that refers to patients' ability to manage their disease and the health system's ability to guarantee access to services. There is evidence that health literacy impacts the health outcomes of patients with chronic diseases, but detailed information on this topic in patients with liver cirrhosis is scarce. It was the aim of this study to identify risk factors for poorer health literacy in patients with liver cirrhosis. METHODS: 89 patients with liver cirrhosis were enrolled in this study and health literacy was measured using the Health Literacy Questionnaire (HLQ). Covert hepatic encephalopathy (CHE) was diagnosed clinically according to the West-Haven Criteria (HE grade 1) and the PHES (minimal HE). Depressive symptoms were assessed using the Hamilton Depression Rating Scale (HDRS). Based on the nine subscales of the HLQ, risk factors for poor health literacy were identified using linear regression models. RESULTS: Normalized HLQ scores ranged between 65-76%, while appraisal of health information had lowest score (65%) and ability to actively engage with healthcare providers had highest score (76%). Multivariable regression analyses revealed an association of poorer health literacy and liver function as determined by MELD score and complications of liver cirrhosis such as a history of ascites or CHE. Additionally, we identified modifiable or preventable factors such as depressive symptoms, a history of falls, and active smoking as risk factors for poorer health literacy. CONCLUSION: Multiple factors seem to impact on health literacy in patients with liver cirrhosis. Addressing modifiable and preventable factors may improve health literacy.