Fluorescence confocal microscopy on liver specimens for full digitization of transplant pathology.

Fluorescence confocal microscopy (FCM) is a rapidly evolving tool that provides real-time virtual HE images of native tissue. Data about the potential of FCM as an alternative to frozen sections for the evaluation of donor liver specimens are lacking so far. The aim of the current study was to determine the value of FCM in liver specimens according to the criteria of the German Society for Organ Procurement. In this prospective study, conventional histology and FCM scans of 50 liver specimens (60% liver biopsies, 26% surgical specimens, and 14% donor samples) were evaluated according to the German Society for Organ Procurement. A comparison of FCM scans and conventional frozen sections revealed almost perfect levels of agreement for cholangitis (κ = 0.877), fibrosis (κ = 0.843), and malignancy (κ = 0.815). Substantial levels of agreement could be obtained for macrovesicular steatosis (κ = 0.775), inflammation (κ = 0.763), necrosis (κ = 0.643), and steatohepatitis (κ = 0.643). Levels of agreement were moderate for microvesicular steatosis (κ = 0.563). The strength of agreement between frozen sections and FCM was superior to the comparison of conventional HE and FCM imaging. We introduce FCM as a potential alternative to the frozen section that may represent a novel approach to liver transplant pathology where timely feedback is crucial and the deployment of human resources is becoming increasingly difficult.

Rostral Anterior Cingulate Cortex Oscillatory Power Indexes Treatment-Resistance to Multiple Therapies in Major Depressive Disorder.

INTRODUCTION: High rostral anterior cingulate cortex (rACC) activity is proposed as a nonspecific prognostic marker for treatment response in major depressive disorder, independent of treatment modality. However, other studies report a negative association between baseline high rACC activation and treatment response. Interestingly, these contradictory findings were also found when focusing on oscillatory markers, specifically rACC-theta power. An explanation could be that rACC-theta activity dynamically changes according to number of previous treatment attempts and thus is mediated by level of treatment-resistance. METHODS: Primarily, we analyzed differences in rACC- and frontal-theta activity in large national cross-sectional samples representing various levels of treatment-resistance and resistance to multimodal treatments in depressed patients (psychotherapy [n = 175], antidepressant medication [AD; n = 106], repetitive transcranial magnetic stimulation [rTMS; n = 196], and electroconvulsive therapy [ECT; n = 41]), and the respective difference between remitters and non-remitters. For exploratory purposes, we also investigated other frequency bands (delta, alpha, beta, gamma). RESULTS: rACC-theta activity was higher (p < 0.001) in the more resistant rTMS and ECT patients relative to the less resistant psychotherapy and AD patients (psychotherapy-rTMS: d = 0.315; AD-rTMS: d = 0.320; psychotherapy-ECT: d = 1.031; AD-ECT: d = 1.034), with no difference between psychotherapy and AD patients. This association was even more pronounced after controlling for frontal-theta. Post hoc analyses also yielded effects for delta, beta, and gamma bands. CONCLUSION: Our findings suggest that by factoring in degree of treatment-resistance during interpretation of the rACC-theta biomarker, its usefulness in treatment selection and prognosis could potentially be improved substantially in future real-world practice. Future research should however also investigate specificity of the theta band.

Vigilance Data in Organ Donation and Solid Organ Transplantation in Germany: Six Years of Experience 2016-2022.

The reporting of serious adverse events (SAE) and serious adverse reactions (SAR) is an essential part of an effective vigilance and surveillance system (V&S) in organ donation and transplantation. All SAE and SAR reported to the German organ procurement organization (DSO) between 2016 and 2022 were analyzed. In case of a possible transmission of a disease to one or more recipients, an assessment of imputability was done according to the grading system of the US Disease Transmission Advisory Committee (DTAC). 543 SAE and SAR cases were reported to the DSO and analyzed in detail. 53 of the 543 reports (9.8%) were proven or probable (P/P) transmissions of infectious diseases, malignancies or other diseases to 75 recipients. Infections were the most frequently reported P/P disease transmission occurrences (30/53, 57%). In case of disease transmission, the mortality of the recipients was high (17/75, 23%), especially when a malignant disease was transmitted (11/22, 50 %). Donor-Derived disease transmission is a rare event (53/8,519; 0.6 %), but when it occurs can lead to significant morbidity and mortality.

Common and differential neural mechanisms underlying mood disorders.

BACKGROUND: Despite homogenous clinical presentations between bipolar and unipolar disorders, there are distinct neurobiological differences. Chronicity of illness may be a factor impacting and sustaining certain neural features. The goal of this study was to investigate common and shared neural mechanisms underlying mood disorders, and possible sustained neural changes relating to illness chronicity by investigating a cohort of euthymic patients with bipolar disorder (BD), unipolar depression who had responded to treatment (treatment-sensitive depression, TSD), and a chronically treatment-resistant depressed (TRD) group. METHODS: One hundred and seventy-two participants (40 BD, 39 TSD, 40 TRD, and 53 age-gender-matched healthy controls) underwent resting-state fMRI scans. Seed-based and independent component analyses were performed to investigate group differences in resting-state connectivity between the four groups. RESULTS: All three clinical groups had significantly lower connectivity within the frontoparietal network (FPN) relative to controls. TRD and BD were significantly different from TSD (TRD, BD > TSD) but were not significantly different from each other. TRDs were also significantly different from both BD and TSD for salience network connectivity with the posterior cingulate (DMN) and the FPN with frontal pole (DMN). Additionally, the BD group exhibited greater DMN-FPN (sgACC-RDLPFC) connectivity relative to TRD, TSD, and controls, which was correlated with a previous number of depressive episodes, in the BD group only. CONCLUSIONS: BD demonstrated shared and differential connectivity features relative to symptomatic TRD and euthymic TSD groups. The increased sgACC-RDLPFC connectivity in BD and its correlation with a number of depressive episodes could be a neural feature associated with illness chronicity.

Investigating neural circuits of emotion regulation to distinguish euthymic patients with bipolar disorder and major depressive disorder.

BACKGROUND: Up to 40% of patients with bipolar disorder (BD) are initially diagnosed as having major depressive disorder (MDD), and emotional lability is a key aspect of both sets of mood disorders. However, it remains unknown whether differences in the regulation of emotions through cognitive reappraisal may serve to distinguish BD and MDD. Therefore, we examined this question in euthymic BD and MDD patients. METHODS: Thirty-eight euthymic BD, 33 euthymic MDD and 37 healthy control (HC) participants, matched for age, gender and depression severity, engaged in an emotion regulation (ER) cognitive reappraisal task during an fMRI scan were examined. Participants either reappraised (Think condition) or passively watched negative (Watch condition) or neutral (Neutral condition) pictures and rated their affect. Activation and connectivity analyses were used to examine group differences in reappraisal (Think vs Watch) and reactivity (Watch vs Neutral) conditions in ER-specific neural circuits. RESULTS: Irrespective of group, participants rated most negatively the images during the Watch condition relative to Think and Neutral conditions, and more negatively to Think relative to Neutral. Notably, BD participants exhibited reduced subgenual anterior cingulate activation (sgACC) relative to MDD during reappraisal, but exhibited greater sgACC activation relative to MDD during reactivity, whereas MDD participants elicited greater activation in right amygdala relative to BD during reactivity. We found no group differences in task-related connectivity. CONCLUSIONS: Euthymic BD and MDD patients engage differential brain regions to process and regulate emotional information. These differences could serve to distinguish the clinical groups and provide novel insights into the underlying pathophysiology of BD.

Meta-analysis of randomised controlled trials with N-acetylcysteine in the treatment of schizophrenia.

OBJECTIVE: There is accumulating evidence that adjunctive treatment with N-acetylcysteine may be effective for schizophrenia. This study aimed to conduct a comprehensive meta-analysis examining the efficacy of randomised control trials investigating N-acetylcysteine as an adjunct treatment for schizophrenia and the first to investigate cognition as an outcome. METHODS: We systematically reviewed Medline, EmCare, PsycINFO, Embase, CINAHL Complete, China Knowledge Resource Integrated Database and the Cochrane Clinical Trials online registry for randomised control trials of N-acetylcysteine for schizophrenia. We undertook pairwise meta-analyses of N-acetylcysteine vs placebo for psychosis symptoms and cognition. RESULTS: Seven studies, including n = 220 receiving N-acetylcysteine and n = 220 receiving placebo, met inclusion criteria for the pairwise meta-analyses. Positive and Negative Syndrome Scale negative and total scores were significantly improved in the N-acetylcysteine group after 24 weeks of treatment. The cognitive domain of working memory improved with N-acetylcysteine supplementation. CONCLUSION: Evidence supports the notion that N-acetylcysteine may be a useful adjunct to standard treatment for the improvement of schizophrenia symptoms, as well as the cognitive domain of working memory. Treatment effects were observed at the later time point (⩾24 weeks), suggesting that longer interventions are required for the success of N-acetylcysteine treatment.

[Brain Death and Treatment of (Potential) Organ Donors and Interactions with their Relatives]. / Hirntod und Umgang mit (potenziellen) Organspendern und Angehörigen.

In recent years, the diagnosis of irreversible brain function loss in severely brain-damaged patients has gained in importance. Brain death, defined as an irreversible loss of the overall function of the cerebrum, cerebellum and brain stem, is a prerequisite for organ removal in the context of organ donation. The article presents the legal and organizational framework.Brain death is determined on the basis of the latest update of the guidelines of the German Medical Chamber (Bundesärztekammer) using a three-step scheme and consists of clinical and instrumental examinations. After the final diagnosis of brain death, the phase of organ-preserving treatment for the potential organ donor begins. In the case of patients who themselves or their relatives have not agreed to organ donation, the intensive care therapy must be terminated promptly. The legal framework for the determination of brain death and for the removal of organs from potential organ donors is provided by the Transplantation Act. The German Foundation for Organ Transplantation (DSO) is responsible for the coordination of organ donations in Germany. The DSO supports hospitals in many ways during the organ donation process, but also in training courses for medical staff on organ donation. The main contact person of the DSO is the transplant officer in the hospitals. The care of the relatives of a potential organ donor is of great importance.

Progression of transthyretin (TTR) amyloidosis in donors and recipients after domino liver transplantation-a prospective single-center cohort study.

Liver transplantation (LT) is the first-line therapy in patients with transthyretin (TTR) amyloidosis and progressive familial amyloid polyneuropathy (FAP). Explanted organs from these patients can be used for domino liver transplantation (DLT). After DLT, de novo amyloidosis may develop in domino recipients (DR). Data were collected prospectively in a transplant database. Electroneurography by nerve conduction velocity (NCV), quantitative sensory testing, heart rate variability (HRV), sympathetic skin response, orthostatic reaction (tilt table test), transthoracic echocardiography, cardiac MRI and organ biopsy results were evaluated. The cohort included 24 FAP- (11 Val30Met, 13 nonVal30Met) and 23 DR-patients. DR symptoms referred to post-DLT only, while those of FAP patients were both pre- and post-transplantation. Symptoms of TTR-amyloidosis in Val30Met and Non-Val30Met patients pre- and post-LT were similarly distributed. Biopsy-proven de novo amyloidosis occurred in 4/23 DR after a mean observation of 10 years. Analysis for manifestations of amyloidosis only included patients with available 5-year follow-up data (n = 13 FAP, n = 12 DR). Compared to Val30Met FAP patients pre-LT, Val30Met DR patients had better NCV (P = 0.04) and HRV (P = 0.015). In the Non-Val30Met group no differences were found between DR and FAP patients pre-LT. TTR-amyloidosis symptoms showed no differences in FAP patients pre- and 5 years post-LT, irrespective of Val30Met status. In DR patients, de novo amyloidosis occurred earlier than expected. Therefore, recipients for DLT need to be carefully selected and followed.

[Updated S3-Guideline for Prophylaxis, Diagnosis and Treatment of Gallstones. German Society for Digestive and Metabolic Diseases (DGVS) and German Society for Surgery of the Alimentary Tract (DGAV) - AWMF Registry 021/008]. / Aktualisierte S3-Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie (DGAV) zur Prävention, Diagnostik und Behandlung von Gallensteinen.

This guideline provides evidence-based key recommendations for the prevention, diagnosis and therapy of gallstones and upgrades the 2007 version. The guideline was developed by an interdisciplinary team of gastroenterologists and surgeons, and patient support groups under the auspice of the German Society for Gastroenterology and Metabolic Diseases and the German Society for General Surgery and Surgery of the Alimentary Tract. The guideline used structural S3 consensus-based methodology and includes statements on clinical practice, medical education, prevention, quality assurance, outcome analysis, and integration of outpatient and inpatient care for patients with gallstone diseases.

Liver transplantation in Germany.

Liver transplantation (LT) is a well-accepted procedure for end-stage liver disease in Germany. In 2015, 1489 patients were admitted to the waiting list (including 1308 new admissions), with the leading etiologies being fibrosis and cirrhosis (n = 349), alcoholic liver disease (n = 302), and hepatobiliary malignancies (n = 220). Organ allocation in Germany is regulated within the Eurotransplant system based on urgency as expressed by the Model for End-Stage Liver Disease score. In 2015, only 894 LTs (n = 48 from living donors) were performed at 23 German transplant centers, reflecting a shortage of organs. Several factors may contribute to the low number of organ donations. The German transplant legislation only accepts donation after brain death (not cardiac death), whereas advances in neurosurgery and a more frequently requested "palliative care" approach render fewer patients suitable as potential donors. The legislation further requires the active consent of the donor or first-degree relatives before donation. Ongoing debates within the German transplant field address the optimal management of patients with alcoholic liver cirrhosis, hepatocellular carcinoma (HCC), and cholangiocarcinoma and measures to increase living donor transplantations. As a result of irregularities at mainly 4 German transplant centers that were exposed in 2012, guiding principles updated by the German authorities have since implemented strict rules (including internal and external auditing, the 8-eyes principle, mandatory repeated testing for alcohol consumption) to prohibit any manipulations in organ allocation. In conclusion, we will summarize important aspects on the management of LT in Germany, discuss legal and organizational aspects, and highlight challenges mainly related to the relative lack of organ donations, increasing numbers of extended criteria donors, and the peculiarities of the recipient patients. Liver Transplantation 22 1136-1142 2016 AASLD.

Volume-assisted estimation of liver function based on Gd-EOB-DTPA-enhanced MR relaxometry.

OBJECTIVES: To determine whether liver function as determined by indocyanine green (ICG) clearance can be estimated quantitatively from hepatic magnetic resonance (MR) relaxometry with gadoxetic acid (Gd-EOB-DTPA). METHODS: One hundred and seven patients underwent an ICG clearance test and Gd-EOB-DTPA-enhanced MRI, including MR relaxometry at 3 Tesla. A transverse 3D VIBE sequence with an inline T1 calculation was acquired prior to and 20 minutes post-Gd-EOB-DTPA administration. The reduction rate of T1 relaxation time (rrT1) between pre- and post-contrast images and the liver volume-assisted index of T1 reduction rate (LVrrT1) were evaluated. The plasma disappearance rate of ICG (ICG-PDR) was correlated with the liver volume (LV), rrT1 and LVrrT1, providing an MRI-based estimated ICG-PDR value (ICG-PDRest). RESULTS: Simple linear regression model showed a significant correlation of ICG-PDR with LV (r = 0.32; p = 0.001), T1post (r = 0.65; p < 0.001) and rrT1 (r = 0.86; p < 0.001). Assessment of LV and consecutive evaluation of multiple linear regression model revealed a stronger correlation of ICG-PDR with LVrrT1 (r = 0.92; p < 0.001), allowing for the calculation of ICG-PDRest. CONCLUSIONS: Liver function as determined using ICG-PDR can be estimated quantitatively from Gd-EOB-DTPA-enhanced MR relaxometry. Volume-assisted MR relaxometry has a stronger correlation with liver function than does MR relaxometry. KEY POINTS: • Measurement of T1 relaxation times in Gd-EOB-DTPA-enhanced MR imaging quantifies liver function. • Volume-assisted Gd-EOB-DTPA-enhanced MR relaxometry has stronger correlation with ICG-PDR than does Gd-EOB-DTPA-enhanced MR relaxometry. • Gd-EOB-DTPA-enhanced MR relaxometry may provide robust parameters for detecting and characterizing liver disease. • Gd-EOB-DTPA-enhanced MR relaxometry may be useful for monitoring liver disease progression. • Gd-EOB-DTPA-enhanced MR relaxometry has the potential to become a novel liver function index.

To biopsy or not to biopsy: evaluation of a large German cohort of patients with abnormal liver tests of unknown etiology.

BACKGROUND AND AIMS: Despite increasingly sensitive and accurate blood tests to detect liver disease, liver biopsy remains very useful in patients with atypical clinical features and abnormal liver tests of unknown etiology. The aim was to determine those elevated laboratory liver parameters that cause the clinician to order a biopsy, and whether laboratory tests are associated with pathological findings on histology. METHODS: 504 patients with unclear hepatopathy, admitted to the outpatient clinic of a university hospital between 2007 and 2010, were analyzed with respect to laboratory results, clinical data, and the results of liver biopsies. RESULTS: Aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH) levels above the normal range significantly increased the likelihood of recommending a liver biopsy by 81% [OR with 95% CI 1.81 (1.21-2.71), p = 0.004] and 159% [OR with 95% CI 2.59 (1.70-3.93), p < 0.001], respectively. AST values above normal were associated with fibrosis (63 vs. 40% for normal AST, p = 0.010). Elevated ferritin levels pointed to a higher incidence of steatosis (48 vs. 10% for normal ferritin, p < 0.001) and inflammation (87 vs. 62% for normal ferritin, p = 0.004). CONCLUSIONS: Our results indicate that elevated AST and GLDH were associated with a greater likelihood of recommending liver biopsy. Elevated AST and ferritin levels were associated with steatosis, inflammation and fibrosis on liver biopsies. Thus, AST and ferritin may be useful non-invasive predictors of liver pathology in patients with unclear hepatopathy.

[Challenges of automation in quantitative evaluation of liver biopsies : Automatic quantification of liver steatosis]. / Herausforderungen der Automation bei der quantitativen Auswertung von Leberbiopsien : Automatische Quantifizierung von Leberverfettung.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD), or non-alcoholic fatty liver disease (NAFLD), is a common disease that is diagnosed through manual evaluation of liver biopsies, an assessment that is subject to high interobserver variability (IBV). IBV can be reduced using automated methods. OBJECTIVES: Many existing computer-based methods do not accurately reflect what pathologists evaluate in practice. The goal is to demonstrate how these differences impact the prediction of hepatic steatosis. Additionally, IBV complicates algorithm validation. MATERIALS AND METHODS: Forty tissue sections were analyzed to detect steatosis, nuclei, and fibrosis. Data generated from automated image processing were used to predict steatosis grades. To investigate IBV, 18 liver biopsies were evaluated by multiple observers. RESULTS: Area-based approaches yielded more strongly correlated results than nucleus-based methods (⌀ Spearman rho [ρ] = 0.92 vs. 0.79). The inclusion of information regarding tissue composition reduced the average absolute error for both area- and nucleus-based predictions by 0.5% and 2.2%, respectively. Our final area-based algorithm, incorporating tissue structure information, achieved a high accuracy (80%) and strong correlation (⌀ Spearman ρ = 0.94) with manual evaluation. CONCLUSION: The automatic and deterministic evaluation of steatosis can be improved by integrating information about tissue composition and can serve to reduce the influence of IBV.

Familial amyloid polyneuropathy.

Familial amyloid polyneuropathy (FAP; also known as familiar amyloidosis and hereditary amyloidosis) is an autosomal dominant inherited disease due to mutations of the transthyretin (TTR) gene coding for the corresponding protein, consisting of 127 amino acids. The gene is located on chromosome 18q. More than 100 different mutations are known. Other mutant precursor proteins produced in the liver, such as apolipoprotein I and II, lysozyme and fibrinogen Aα, may be of etiological importance as well. Amyloidogenic mutations of the TTR gene lead to decreased stability of the corresponding protein and subsequently to extracellular deposition of amyloid in several tissues (peripheral and autonomic nerves, walls of the gastrointestinal tract, heart, etc.). The Val30Met mutation is the most prevalent cause of FAP worldwide. There are endemic regions in Portugal, Sweden and Japan. The onset of symptoms is usually between 25 and 35 years of age, but late-onset families are also known. The most common clinical symptoms are polyneuropathy of the lower limbs, rhythmological disturbances and diarrhea/obstipation. TTR amyloid is predominantly produced in the liver; only as few as 5% are synthesized in the retina and choroid plexus. Therefore, liver transplantation has become widely accepted as the ultimate curative treatment of this disease in order to prevent the ultimately fatal outcome and ameliorate disabling symptoms. Because of shortage of donor grafts, livers of FAP patients are used for domino liver transplantation. Last year, a new therapeutic option was approved by the European Medical Authority (EMA) for therapy of early-stage FAP. The first results of a multicenter-controlled trial have been published and show a benefit in patients with an early stage of disease regarding neurological symptoms as well as modified BMI. There are several other pharmacologic approaches that have been reported in the last years which may lead to stabilization of the TTR tetramer. Therefore, this might be the beginning of new therapeutic options with pharmacological therapies in patients with FAP.

Evaluation of domino liver transplantations in Germany.

A retrospective multicenter study has been conducted to evaluate domino liver transplantations (DLTs) in Germany. The study provides insight into survival and features having an impact on the assessment of neuropathy after DLT. In addition, a neurologic follow-up program with a scheme to estimate the likelihood of de novo amyloidosis is presented. A series of 61 DLTs at seven transplant centers in Germany was enrolled. The mean age of domino recipients at the time of transplantation was 58 years, 46 of them being men, and 15 being women. The median follow-up was 46 months. The overall 1-, 3-, and 5-year survival of domino recipients was 81.6%, 70.8% and 68.8%, respectively. Causes of death were primarily not related to familial amyloidosis. The main indication of DLT was hepatocellular carcinoma. Two of the reported domino recipients developed symptoms and signs of de novo amyloidosis within 10 years after transplantation. A total of 30 domino graft recipients (49.18%) presented with diabetes post transplantation. In conclusion, an advanced follow-up program is crucial to evaluate the risk of transmitting familial amyloidosis by DLT and to establish more strict selection criteria for domino recipients.

Disrupted auditory N1, theta power and coherence suppression to willed speech in people with schizophrenia.

The phenomenon of sensory self-suppression - also known as sensory attenuation - occurs when a person generates a perceptible stimulus (such as a sound) by performing an action (such as speaking). The sensorimotor control system is thought to actively predict and then suppress the vocal sound in the course of speaking, resulting in lowered cortical responsiveness when speaking than when passively listening to an identical sound. It has been hypothesized that auditory hallucinations in schizophrenia result from a reduction in self-suppression due to a disruption of predictive mechanisms required to anticipate and suppress a specific, self-generated sound. It has further been hypothesized that this suppression is evident primarily in theta band activity. Fifty-one people, half of whom had a diagnosis of schizophrenia, were asked to repeatedly utter a single syllable, which was played back to them concurrently over headphones while EEG was continuously recorded. In other conditions, recordings of the same spoken syllables were played back to participants while they passively listened, or were played back with their onsets preceded by a visual cue. All participants experienced these conditions with their voice artificially shifted in pitch and also with their unaltered voice. Suppression was measured using event-related potentials (N1 component), theta phase coherence and power. We found that suppression was generally reduced on all metrics in the patient sample, and when voice alteration was applied. We additionally observed reduced theta coherence and power in the patient sample across all conditions. Visual cueing affected theta coherence only. In aggregate, the results suggest that sensory self-suppression of theta power and coherence is disrupted in schizophrenia.