Assembly of infectious Kaposi's sarcoma-associated herpesvirus progeny requires formation of a pORF19 pentamer.

Herpesviruses cause severe diseases particularly in immunocompromised patients. Both genome packaging and release from the capsid require a unique portal channel occupying one of the 12 capsid vertices. Here, we report the 2.6 Å crystal structure of the pentameric pORF19 of the γ-herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) resembling the portal cap that seals this portal channel. We also present the structure of its ß-herpesviral ortholog, revealing a striking structural similarity to its α- and γ-herpesviral counterparts despite apparent differences in capsid association. We demonstrate pORF19 pentamer formation in solution and provide insights into how pentamerization is triggered in infected cells. Mutagenesis in its lateral interfaces blocked pORF19 pentamerization and severely affected KSHV capsid assembly and production of infectious progeny. Our results pave the way to better understand the role of pORF19 in capsid assembly and identify a potential novel drug target for the treatment of herpesvirus-induced diseases.

Adherence in pediatric renal recipients and its effect on graft outcome, a single-center, retrospective study.

BACKGROUND: In recent years, treatment-adherence gained increasing attention in nearly every area of medicine including transplant medicine. Medication adherence following solid organ transplantation is known to be indispensable for a satisfactory allograft survival. METHODS: We examined 60 patients between the ages of four months and 20 years who underwent kidney transplantation at Hannover Medical School between January 2011 and August 2017. Age at transplantation varied from 4 months to 20 years. 12 patients (20%) already underwent their second solid organ transplantation. 5 patients (8.3%) had a combined kidney-liver-transplantation. We used two different methods for rating adherence: An objective one based on the coefficient of variation (CoV%) of immunosuppressant trough levels, and a subjective questionnaire answered by the patients themselves, their parents or legal custodians, the treating pediatrician, as well as by the attending psychologist. RESULTS: The CoV% in our study was by-trend higher in those patients who suffered from a biopsy-proven rejection (x̅CoV% = 35.7, σ CoV% = 30.1 in patients with rejection vs. x̅ CoV% = 26.0, σ CoV% = 10.5 in patients without rejection). Furthermore, the psychologist's assessment correlated significantly both with rejections as well as with the formation of de novo donor-specific antibodies (dnDSA) while the pediatrician's rating showed no correlation (Prejections  = 0.005 and PdnDSA  = 0.03 for psychologist's rating vs. Prejections  = 0.50 and PdnDSA  = 0.50 for pediatrician). CONCLUSIONS: Apart from underlining the importance of medication adherence, the present research stresses the role of a multi-disciplinary treatment approach to support pediatric renal transplant recipients and their families.

Low-dose steroids do make a difference: Independent risk factors for impaired linear growth after pediatric liver transplantation.

Growth failure persists after pediatric liver transplantation and impairs pediatric development and quality of life. Steroid dose minimization attempts to prevent growth impairment, yet long-term assessment in pediatric liver recipients is lacking. We identified risk factors for impaired linear growth after pediatric liver transplantation, with a special focus on low-dose steroid therapy. This is a single-center retrospective analysis of height development in pediatric liver recipients up to 5 years after transplantation. Risk factors for impaired linear growth (height Z-scores≤-2) at transplantation, after two (n = 347) and five years (n = 210) were identified by univariate and multivariate logistic regression. At transplantation, growth retardation was found in 52.2%, predominantly younger children. Height Z-scores improved from -2.23 to -1.40 (SE 0.11; 95%CI 0.74-1.16; p < .001) two years and -1.19 (SE 0.07;0.08-0.34; p = .017) five years post-transplant. Multivariate analysis showed previous growth impairment (OR=1.484; 95%-CI=1.107-1.988; p = .004), graft loss (49.006;2.232-1076; p = .006), and prolonged cold ischemic time (1.034;1.007-1.061; p = .011) as main long-term risk factors; steroid use was a significant predictor of 2-year but not 5-year growth impairment. In univariate analysis, impaired growth after 2 and 5 years was associated with continuous low-dose (2.5 mg/m2 BSA) steroid therapy (OR=3.323;1.578-6.996; p < .001/OR=8.352;1.089-64.07; p = .006)and graft loss (OR=2.513;1.395-4.525; p = .003/OR=3.378;1.815-7.576; p < .001). Furthermore, indication and era of transplantation affected growth. Our results show significant catch-up growth after pediatric liver transplantation, yet growth failure strongly affects particularly young liver recipients. The main influenceable long-term risk factor is pre-existing growth failure, emphasizing the importance of early aggressive nutritional therapy. Moreover, low-dose steroid therapy might impair growth and should therefore be critically questioned in long-term immunosuppression.

[Quality management in a postgraduate refresher course in otolaryngology]. / Qualitätssicherungssystem zur Bewertung eines HNO-Facharztrepetitoriums.

BACKGROUND: Residency training is often characterized by locally influenced training content and focus, which can lead to heterogeneous training outcomes. Refresher courses before the speciality certificate examinations can harmonize the situation. OBJECTIVE: The current publication aims to present a quality management system for evaluation of a postgraduate refresher course for otolaryngology residents. MATERIALS AND METHODS: The teaching sessions of a postgraduate course were evaluated using questionnaires. Descriptive statistics and multivariable binary logistic regression analysis were performed. To evaluate the factors leading to a negative perception of a teaching session, the focus was set on the worst 15% of all total ratings. An exemplary strength/weakness profile of a lecturer was created for individual feedback. RESULTS: Analysis of the evaluation results showed an overall average rating of 12.8 (±2.4) out of a maximum of 15 possible points. Multivariable regression determined the items "friendliness," "systematic structure," "own involvement," "prior knowledge," and "efficient teaching session" to be significant for a negative perception of a teaching session. Using the lecturer profile, the strengths and weaknesses of the individual lecturer can be shown in an objective manner. CONCLUSION: The developed questionnaire represents a good tool for quality management of a postgraduate refresher course for otolaryngology residents. This is achieved by regression analysis and creation of an individual lecturer profile, which provides an objective basis for improving the individual teaching session through detailed feedback to the lecturer.

Regression analyses of questionnaires in bedside teaching.

BACKGROUND: Students' ratings of bedside teaching courses are difficult to evaluate and to comprehend. Validated systematic analyses of influences on students' perception and valuation of bedside teaching can serve as the basis for targeted improvements. METHODS: Six hundred seventy-two observations were conducted in different surgical departments. Survey items covered the categories teacher's performance, student's self-perception and organizational structures. Relevant factors for the student overall rating were identified by multivariable linear regression after exclusion of variable correlations > 0.500. The main target for intervention was identified by the 15% worst overall ratings via multivariable logistic regression. RESULTS: According to the students the success of bedside teaching depended on their active participation and the teacher's explanations of pathophysiology. Further items are both relevant to the overall rating and a possible negative perception of the session. In comparison, negative perception of courses (worst 15%) is influenced by fewer variables than overall rating. Variables that appear in both calculations show slight differences in their weighing for their respective endpoints. CONCLUSION: Relevant factors for overall rating and negative perception in bedside teaching can be identified by regression analyses of survey data. Analyses provide the basis for targeted improvement.

Longterm calcineurin inhibitor therapy and brain function in patients after liver transplantation.

Calcineurin inhibitors (CNIs) frequently induce neurological complications early after orthotopic liver transplantation (OLT). We hypothesize that longterm CNI therapy after OLT causes dose-dependent cognitive dysfunction and alteration of brain structure. In this study, 85 OLT patients (20 with CNI-free, 35 with CNI low-dose, and 30 with standard-dose CNI immunosuppression) underwent psychometric testing and cerebral magnetic resonance imaging approximately 10 years after OLT to assess brain function and structural brain alterations. A total of 33 healthy patients adjusted for age, sex, and education served as controls. Patients receiving CNI showed a significantly worse visuospatial/constructional ability compared with controls (P ≤ 0.04). Furthermore, patients on low-dose CNI therapy had an overall impaired cognitive function compared with controls (P = 0.01). The tacrolimus total dose and mean trough level were negatively correlated to cognitive function. CNI doses had been adjusted in 91% of the patients in the low-dose and CNI-free groups in the past due to CNI-induced kidney damage. Patients treated with CNI showed significantly more white matter hyperintensities (WMH) than patients on CNI-free immunosuppression and controls (P < 0.05). Both the mean cyclosporine A and tacrolimus trough levels correlated significantly with WMH. In conclusion, longterm CNI therapy carries a risk of cognitive dysfunction especially in patients who already showed nephrotoxic side effects indicating an increased susceptibility of these patients against toxic CNI effects. This subgroup of patients might benefit from a change to CNI-free immunosuppression. Liver Transplantation 24 56-66 2018 AASLD.

Development and validation of a prognostic model for kidney function 1 year after combined pancreas and kidney transplantation using pre-transplant donor and recipient variables.

PURPOSE: The widening gap between demand and supply of organs for transplantation provides extraordinary challenges for ethical donor organ allocation rules. The transplant community is forced to define favorable recipient/donor combinations for simultaneous kidney-pancreas transplantation. The aim of this study is the development of a prognostic model for the prediction of kidney function 1 year after simultaneous pancreas and kidney transplantation using pre-transplant donor and recipient variables with subsequent internal and external validation. METHODS: Included were patients with end-stage renal failure due to diabetic nephropathy. Multivariable logistic regression modeling was applied for prognostic model design with retrospective data from Hannover Medical School, Germany (01.01.2000-31.12.2011) followed by prospective internal validation (01 Jan. 2012-31 Dec. 2015). Retrospective data from another German transplant center in Kiel was retrieved for external model validation via the initially derived logit link function. RESULTS: The developed prognostic model is able to predict kidney graft function 1 year after transplantation ≥ KDIGO stage III with high areas under the receiver operating characteristic curve in the development cohort (0.943) as well as the internal (0.807) and external validation cohorts (0.784). CONCLUSION: The proposed validated model is a valuable tool to optimize present allocation rules with the goal to prevent transplant futility. It might be used to support donor organ acceptance decisions for individual recipients.

Hangzhou criteria are more accurate than Milan criteria in predicting long-term survival after liver transplantation for HCC in Germany.

BACKGROUND: Milan criteria are used for patient selection in liver transplantation for hepatocellular carcinoma (HCC). Hangzhou criteria have been shown in China to enable access to liver transplantation for more patients when compared to Milan criteria without negative effects on long-term survival. The purpose of this study was to evaluate the Hangzhou criteria in a German cohort. METHODS: One hundred fifty-nine patients transplanted for HCC between 1975 and 2010 were investigated. Patients were categorized into four groups depending on the fulfillment of Milan and Hangzhou criteria. General and tumor baseline characteristics were compared. Overall and tumor-free survival rates were investigated with the Kaplan-Meier analysis. RESULTS: One-, 3-, 5-, and 10-year survival rates for patients fulfilling Milan criteria (n = 68) were 89.7, 83.7, 75.8, and 62.1%, respectively, versus 89.8, 82.2, 75.2, and 62.6% for patients fulfilling Hangzhou criteria (n = 109) (p = 0.833). When comparing patients exceeding Milan or Hangzhou criteria, survival rates were 75.3, 53.2, 48.1, and 41.1% versus 63.3, 31.4, 26.9, and 22.1%, respectively (p = 0.019). The comparison of tumor-free survival rates in patients fulfilling Milan or Hangzhou criteria was statistically not significant (p = 0.785), whereas the comparison of the groups exceeding the criteria showed significantly worse survival for patients outside Hangzhou criteria (p = 0.007). The proportion of patients fulfilling Hangzhou criteria (68.6%) was significantly larger as compared to the proportion fulfilling Milan criteria (42.8%) (p < 0.001). CONCLUSION: Hangzhou criteria are more accurate in predicting long-term survival after liver transplantation for HCC in Germany. Deployment of the Hangzhou criteria for patient selection could enlarge the pool of transplantable patients.

Prognostic factors for long-term survival after adult liver transplantation.

PURPOSE: Prognostic factors for survival ≥ 15 years and life years lost after liver transplantation are largely unknown. METHODS: One thousand six hundred thirty primary adult liver transplants between 1983 and 2014 were analyzed. Risk factors for survival were identified with multivariable Cox regression and subsequently tested for their relevance as prognostic factors for observed 15-year survival using multivariable logistic regression and c statistics. The difference of life expectancy between a matched national reference population and survival in patients with post-transplant survival ≥ 15 years was calculated. RESULTS: Survival of ≥ 15 years was observed in 361 patients (22%). Sixty-nine adults died after more than 15 years losing a median of 15 years of life expectancy. One of those patients lived longer while 292 patients still have the chance to survive longer than their normal life expectancy. The indication primary sclerosing cholangitis (PSC) and later eras of transplantation were identified as significant independent protective factors while recipient age > 36.8 years, graft loss due to initial non-function or thrombosis, the indications hepatocellular carcinoma (HCC), hepatitis-C-virus-related cirrhosis (HCV-cirrhosis) and all other indications, donor age > 53 years, the number of surgical complications, and operative durations > 4.5 h were identified as significant independent risk factors limiting survival. All of these factors except the duration of operation had also a significant independent influence on observed 15-year survival (AUROC = 0.739). CONCLUSIONS: Recipients can exceptionally live longer than their normal life expectancy. Older recipients and patients with the indications HCC, HCV-cirrhosis, or other indications except PSC, should be transplanted with younger donor organs.

Involvement of Angiopoietin-2 and Tie2 Receptor Phosphorylation in STEC-HUS Mediated by Escherichia coli O104:H4.

Escherichia coli O104:H4-associated hemolytic uremic syndrome (HUS) is characterized by Shiga toxin-induced vascular damage. As indicated by recent studies, dysregulation of the angiopoietin (Angpt)/Tie2 ligand receptor system may be crucial for endothelial dysfunction in HUS. Early Angpt-2 levels quantified in 48 adult HUS patients were predictive for a complicated clinical course, in particular for need of hemodialysis and mechanical ventilation as well as occurrence of seizures. In vitro challenge of human umbilical vein endothelial cells with patients' sera indicated an injurious mediator role of Angpt-2 opening future perspectives for mitigating endothelial activation in HUS.

Zinc-alpha2-glycoprotein in patients with acute and chronic kidney disease.

BACKGROUND: Zinc-alpha2-glycoprotein (AZGP1) is a secreted protein which is synthesized in a variety of cell types. AZGP1 has functionally been implicated in lipid metabolism, the regulation of cell cycling and cancer progression. Previous studies have shown increased circulating AZGP1 levels in patients with chronic kidney disease but AZGP1 has not been investigated in acute kidney injury (AKI). In this study, serum AZGP1 levels were measured in acute and chronic kidney disease to test for a correlation to renal function and other clinical parameters. METHODS: We performed ELISA based measurements of AZGP1 serum levels in 21 patients suffering from grade 3 AKI and in 20 chronic hemodialysis patients. In AKI patients, AZGP1 was first measured before initiation of acute renal replacement therapy and a second measurement was done during renal functional recovery. Sera of healthy blood donors served as controls. The association of AZGP1 with acute and chronic renal dysfunction was analysed, as well as the correlation with clinical parameters, body composition and biochemical variables. RESULTS: Levels of circulating AZGP1 were significantly elevated in AKI patients. High initial levels of AZGP1 correlated with extra-renal complications but not with parameters of renal function. At follow-up, AZGP1 levels were still increased but now correlated significantly with creatinine, eGFR and urea. Circulating AZGP1 in chronic hemodialysis patients was higher than in AKI patients. An association to parameters of lipid metabolism was not found. CONCLUSIONS: This study illustrates that circulating AZGP1 is not only elevated in chronic hemodialysis patients but also sharply increases during the early phase of AKI. The unexpected association with extra-renal complications during AKI needs further exploration as it might point to unknown biological effects of AZGP1.

Learning surgical knot tying and suturing technique - effects of different forms of training in a controlled randomized trial with dental students.

Objective: The acquisition of surgical skills requires motor learning. A special form of this is intermanual transfer by transferring motor skills from the nondominant hand (NDH) to the dominant hand (DH). The purpose of this study was to determine the learning gains that can be achieved for the DH by training with the DH, the NDH, and by non-surgical alternative training (AT). Methods: 124 preclinical (n=62) and clinical (n=62) dental students completed surgical knot tying and suturing technique training with the DH, with the NDH, and an AT in a controlled randomized trial. Results: A statistically significant learning gain in knot tying and suture technique with the DH was evident only after training with the DH when compared to training with the NDH (p<0.001 and p=0.004, respectively) and an AT (p=0.001 and p=0.010, respectively). Of those students who achieved a learning gain ≥4 OSATS points, 46.4% (n=32) benefited in their knot tying technique with the DH from training with the DH, 29.0% (n=20) from training with the NDH, and 24.6% (n=17) from an AT while 45.7% (n=32) benefited in their suturing technique with the DH from training with the DH, 31.4% (n=22) from training with the NDH, and 22, 9% (n=16) from an AT. Conclusions: Training with the DH enabled significantly better learning gains in the surgical knot tying and suturing techniques with the DH.

Microparticle generation and leucocyte death in Shiga toxin-mediated HUS.

BACKGROUND: Shiga toxin-induced haemolytic uraemic syndrome (STEC-HUS) is an acute multisystem disorder characterized by renal failure, neurological dysfunction, haemolysis and intravascular thrombosis. Circulating microparticles originating from a number of cell types including thrombocytes and leucocytes are elevated in paediatric patients. In vitro data also suggest modification of leucocyte death by Shiga toxin. Here, we investigated microparticle generation and leucocyte cell death in vivo in adult STEC-HUS patients during acute disease and recovery. METHODS: Multi-colour flow cytometry and immunofluorescence were used to assess microparticle concentration and provenience thrombocyte microparticle seeding to leucocytes and leucocyte cell death in adult STEC-HUS patients treated at a tertiary care centre during the STEC-HUS outbreak in Germany in 2011. RESULTS: Plasma microparticle concentrations of both platelet and leucocyte origin were elevated during acute STEC-HUS. Platelet microparticles (MP) were detected on a high proportion of monocytes and granulocytes. Among therapeutic interventions, plasma exchange reduced platelet marker expression on leucocytes, inhibition of complement had only moderate impact on the number of circulating MP and did not alter platelet microparticle binding to leucocytes. Numbers of apoptotic and necrotic monocytes and granulocytes were significantly increased in patients with STEC-HUS compared to healthy controls. Complement inhibition significantly increased the number of circulating apoptotic cells. Monocyte apoptosis on admission was significantly higher in patients subsequently assigned to plasma exchange or admitted to the intensive care unit. CONCLUSIONS: In STEC-HUS, elevated numbers of circulating MP and dead leucocytes were detected. Monocyte and granulocyte deaths are novel markers of acute STEC-HUS that may actively contribute to tissue destruction by liberation of pro-inflammatory enzymes and cytokines.

Implementation of a Mobile Application in Acute Stroke Care Documentation.

Acute stroke care is a time-critical process. Improving communication and documentation process may support a positive effect on medical outcome. To achieve this goal, a new system using a mobile application has been integrated into existing infrastructure at Hannover Medical School (MHH). Within a pilot project, this system has been brought into clinical daily routine in February 2022. Insights generated may support further applications in clinical use-cases.

Systematic review on potential brain dead donor estimations and conversion rates to actually realized organ donations.

INTRODUCTION: Accurate estimations of potential organ donors (POTDs) are required to improve transplant systems. This systematic review analyses current studies on national estimations of potential donors for transplantation as well as the practical and policy implications of detected differences. METHOD: A systematic review of literature published between 01.01.2010 and 01.04.2020 in PubMed was conducted. Data was extracted into a self-developed matrix, and further data retrieved on national population sizes, waiting lists and transplant activities. RESULTS: Six studies were included. Investigated populations, underlying data collections and eligibility criteria for POTDs varied widely. Estimated POTDs per million population (p.m.p.) ranged from 25.8 to 333.6, conversion rates from 3.2% to 47.5% leading to 41.2 to 86.4 transplanted organs p.m.p.. Patients on the waiting lists varied from 66.7 to 338.9 p.m.p., defining gaps between organ supply and demand in countries. Not all studies adhered to the definitions and processes of the critical pathway for deceased donation which is the latest international consensus statement on deceased organ donation. CONCLUSION: Differences in estimated POTDs and differences in supply and demand of donor organs between countries cannot be satisfactorily explained yet due to an obvious lack of evidence, consistent methodology, international consensus and robust underlying datasets. Future studies should be based on robust underlying data sets and aim for potential donor estimations that allow national comparisons due to the adherence to the international consensus on definitions, processes and methodology.

Recipient-Specific Risk Factors Impairing Patient and Graft Outcome after Pediatric Liver Transplantation-Analysis of 858 Transplantations in 38 Years.

(1) Background and Aim: Despite excellent long-term results in pediatric liver transplantation (pLTx), mortality and graft loss still are to be diminished. We aim to describe time-dependent changes and long-term outcome of a large single-center pLTx cohort and to identify independent recipient-related risk factors impairing patient and graft survival. (2) Methods: This is a retrospective single-center study analyzing all pediatric liver transplants from 1983-2020. Risk factors for mortality and graft loss were identified by univariable and multi-linear regression analysis. (3) Results: We analyzed 858 liver transplantations in 705 pediatric patients. Five-year patient/graft survival increased from 60.9%/48.0% (1983-1992) to 97.5%/86.5% (OR = 12.5; p < 0.0001/OR = 6.5; p < 0.0001) (2014-2020). Indications changed significantly over time, with a higher proportion of patients being transplanted for malignancies and metabolic disease and indications of PFIC and α1AT-deficiency declining. The era of transplantation (log7.378/9.657; p < 0.0001) and indication of acute liver failure (log = 1.944/2.667; HR = 2.015/1.772; p = 0.0114/0.002) impairs patient/graft survival significantly in the multivariate analysis. Furthermore, patient survival is worsened by re-transplantation (log = 1.755; HR = 1.744; p = 0.0176) and prolonged waiting times in high-urgency status (log = 2.588; HR = 1.073; p = 0.0026), whereas the indication of biliary atresia improved outcome (log = 1.502; HR = 0.575; p = 0.0315). Graft survival was additionally impaired by pre-existing portal vein thrombosis (log = 1.482; HR = 2.016; p = 0.0330). (4) Conclusions: Despite more complex indications, patient and graft survival after pLTx continue to improve.. Acute liver failure remains the indication with poorest outcome, and listing for high urgency liver transplantation should be considered carefully and early to keep waiting time on HU list short. Furthermore, pre-transplant portal vein thrombosis should be prevented whenever possible to improve graft survival.

Impact of immunosuppressive therapy on brain derived cytokines after liver transplantation.

BACKGROUND: While acute neurotoxic side effects of calcineurin inhibitors (CNI) are well-known, data upon long-term effects on brain structure and function are sparse. We hypothesize that long-term CNI therapy affects the neuroimmune system, thereby, increasing the risk of neurodegeneration. Here, we measured the impact of CNI therapy on plasma levels of brain- and T cell-derived cytokines in a cohort of patients after liver transplantation (LT). METHODS: Levels of T cell-mediated cytokines (e.g. Interferon-γ (IFN-γ)) and brain-derived cytokines (e.g. brain derived neurotrophic factor (BDNF), platelet derived growth factor (PDGF)) were measured by multiplex assays in plasma of 82 patients about 10 years after LT (17 with CNI free, 35 with CNI low dose, 30 with standard dose CNI immunosuppression) and 33 healthy controls. Data were related to psychometric test results and parameters of cerebral magnetic resonance imaging. RESULTS: IFN-γ levels were significantly higher in the CNI free LT patient group (p=0.027) compared to healthy controls. BDNF levels were significantly lower in LT patients treated with CNI (CNI low: p<0.001; CNI standard: p=0.016) compared to controls. PDGF levels were significantly lower in the CNI low dose group (p=0.004) and for PDGF-AB/BB also in the CNI standard dose group (p=0.029) compared to controls. BDNF and PDGF negatively correlated with cognitive function and brain volume (p<0.05) in the CNI low dose group. CONCLUSION: Our results imply that long-term treatment with CNI suppresses BDNF and PDGF expression, both crucial for neuronal signaling, cell survival and synaptic plasticity and thereby may lead to cognitive dysfunction and neurodegeneration.

Brain metabolic alterations in patients with long-term calcineurin inhibitor therapy after liver transplantation.

BACKGROUND: Calcineurin inhibitor (CNI) neurotoxicity after liver transplantation might be due to impairment of the cerebral metabolism. AIMS: To investigate CNI-related alterations of brain metabolite distributions and associations between cognitive function and brain metabolism in patients with long-term CNI treatment after liver transplantation. METHODS: Eighty-two patients (19 CNI free, 34 CNI low-dose and 29 standard-dose CNI immunosuppression) 10 years after liver transplantation and 32 adjusted healthy controls underwent nonlocalised brain phosphorus magnetic resonance spectroscopy (MRS) and single voxel proton MRS in the parietal white matter to estimate brain metabolite contents. The MRS results were correlated with psychometric data assessing cognitive function. RESULTS: Phosphorus metabolite concentrations with the exception of phosphocreatine (PCr) were reduced in patients compared to controls. Particularly, patients with low-dose CNI therapy showed a significant decrease in adenosine triphosphate (0.209 ± 0.012 vs 0.222 ± 0.010; P < 0.001) and a significant increase in PCr (0.344 ± 0.026 vs 0.321 ± 0.017; P < 0.001) compared to controls. Myo-Inositol in the CNI free group (2.719 ± 0.549 institutional unit [iu]) was significantly lower compared to controls (3.181 ± 0.425 iu; P = 0.02), patients on low-dose (3.130 ± 0.513 iu; P < 0.05) and standard-dose CNI therapy (3.207 ± 0.632 iu; P < 0.02). Glutamate and glutamine levels correlated negatively with cognitive function (Repeatable Battery for the Assessment of Neuropsychological Status Total Scale: R = -0.362, P = 0.029). CONCLUSION: Long-term CNI therapy after liver transplantation might be associated with alterations of brain metabolites.

Evaluation of published assessment tools for comorbidity in liver transplantation: a systematic review protocol.

INTRODUCTION: Liver transplantation is considered the best therapy option for end-stage liver disease. Different factors including recipient comorbidity at time of transplantation are supposed to have substantial impact on outcomes. Although several studies have focused on comorbidity assessment indices for liver transplant recipients, there is no systematic review available on the methodological details and prognostic accuracy of these instruments. The aim of this study is to systematically review recipient comorbidity assessment indices in the context of liver transplantation. METHODS AND ANALYSIS: PubMed, Embase, Web of Science and PsyINFO databases will be searched. Studies describing, using or evaluating specific assessment tools to predict the effect of comorbidity on clinical outcomes after liver transplantation will be included. The selection will be conducted independently by two reviewers. The study characteristics and methodological information on published comorbidity assessment tools will be extracted into a predefined structural table. This approach will be deployed to systematically extract information on the validity, reliability and practical feasibility of investigated comorbidity assessment tools for comparative evaluation. Narrative information synthesis will be conducted, and additional meta-analytical comparison will be performed, if appropriate. ETHICS AND DISSEMINATION: All data are collected from published literature. Thus, formal ethics review for the research is not required. The findings of this systematic review will be published in a peer-reviewed journal and presented at relevant conferences. The results of this systematic review will be highly relevant for further research on prognostic models, clinical decision making and optimisation of donor organ allocation. PROSPERO REGISTRATION NUMBER: CRD42017074609.

Decision modelling for economic evaluation of liver transplantation.

As the gap between a shortage of organs and the immense demand for liver grafts persists, every available donor liver needs to be optimized for utility, urgency and equity. To overcome this challenge, decision modelling might allow us to gather evidence from previous studies as well as compare the costs and consequences of alternative options. For public health policy and clinical intervention assessment, it is a potentially powerful tool. The most commonly used types of decision analytical models include decision trees, the Markov model, microsimulation, discrete event simulation and the system dynamic model. Analytic models could support decision makers in the field of liver transplantation when facing specific problems by synthesizing evidence, comprising all relevant options, generalizing results to other contexts, extending the time horizon and exploring the uncertainty. For modeling studies of economic evaluation for transplantation, understanding the current nature of the disease is crucial, as well as the selection of appropriate modelling techniques. The quality and availability of data is another key element for the selection and development of decision analytical models. In addition, good practice guidelines should be complied, which is important for standardization and comparability between economic outputs.