### Recent Submissions

• Journal Article

#### NanoSIMS observations of mouse retinal cells reveal strict metabolic controls on nitrogen turnover ﻿

BMC Molecular and Cell Biology. 2021 Jan 11;22(1):5
Background Most of the cells of the mammalian retina are terminally differentiated, and do not regenerate once fully developed. This implies that these cells have strict controls over their metabolic processes, including protein turnover. We report the use of metabolic labelling procedures and secondary ion mass spectrometry imaging to examine nitrogen turnover in retinal cells, with a focus on the outer nuclear layer, inner nuclear layer, and outer plexiform layer. Results We find that turnover can be observed in all cells imaged using NanoSIMS. However, the rate of turnover is not constant, but varies between different cellular types and cell regions. In the inner and outer nuclear layers, turnover rate is higher in the cytosol than in the nucleus of each cell. Turnover rates are also higher in the outer plexiform layer. An examination of retinal cells from mice that were isotopically labeled very early in embryonic development shows that proteins produced during this period can be found in all cells and cell regions up to 2 months after birth, even in regions of high turnover. Conclusions Our results indicate that turnover in retinal cells is a highly regulated process, with strict metabolic controls. We also observe that turnover is several-fold higher in the synaptic layer than in cell layers. Nevertheless, embryonic proteins can still be found in this layer 2 months after birth, suggesting that stable structures persist within the synapses, which remain to be determined.
• Journal Article

#### Risk assessment of acute kidney injury following cardiopulmonary bypass ﻿

Journal of Cardiothoracic Surgery. 2021 Jan 06;16(1):4
Abstract Background Acute kidney injury (AKI) is a frequent and serious complication of cardiac surgery, associated with a high incidence of morbidity and mortality. Although the RIFLE criteria serve as a prominent tool to identify patients at high risk of AKI, an optimized diagnosis model in clinical practice is desired. Methods Based on the SOP-criteria, 365 patients (10%) developed AKI following surgery and were subjected to RRT. In contrast, the incidence of AKI, defined according to the RIFLE criteria, was only 7% (n = 251 patients). Prominent risk factors identified by SOP were patients’ sex, valve and combined valve and bypass surgery, deep hypothermia, use of intra-aortic balloon pump (IABP) and previous coronary interventions. Ischemia, reperfusion, blood loss and surgery time also served as significant risk factors for patient evaluated by SOP. Results Risk assessment by RIFLE differed in as much as most patients with normothermia and those receiving only cardiovascular bypass developed AKI. However, patients’ sex and valve surgery did not serve as a risk factor. Conclusion Evaluation of patients by the RIFLE versus SOP criteria yielded different results with more AKI patients detected by SOP. Based on the present data, it is concluded that patients may not prone to AKI when surgery and ischemia time will be kept short, when blood loss is mitigated to a minimum and when surgery is performed under non-hypothermic conditions.
• Journal Article

#### Immunotherapy Targeting Amyloid-β Peptides in Alzheimer’s Disease ﻿

Exon Publications, 2020
Neurodegenerative diseases, in particular Alzheimer’s disease, represent significant unmet medical needs due to a lack of effective therapeutic treatment options and cause a substantial burden for health care systems. Accumulation of β-amyloid peptides within the brain is believed to be an initial trigger of the dis- ease process. In the last 20 years, immunotherapy has emerged as a promising target-directed strategy to develop efficient treatment options with disease-modi- fying potential. Unfortunately, either active vaccination against β-amyloid or its fragments, as well as passive immunization using monoclonal antibodies, have largely failed to show a clinical benefit in a variety of clinical trials. This chapter addresses progress and developments with regard to active and passive immuni- zation against Aβ and summarizes the current state of clinical trials.
• Journal Article

#### Case Report: Association of a Variant of Unknown Significance in the FIG4 Gene With Frontotemporal Dementia and Slowly Progressing Motoneuron Disease: A Case Report Depicting Common Challenges in Clinical and Genetic Diagnostics of Rare Neuropsychiatric and Neurologic Disorders ﻿

Frontiers in Neuroscience 2020; 14 p.1-5: Art. 559670
Background: Modern genetics have in many ways revolutionized clinical routine and have, for instance, shown that formerly distinct disease entities relate to common pathogenic mutations. One such example is the connection between dementia and amyotrophic lateral sclerosis (ALS) in a continuous disease spectrum affirmed by the discovery of shared mutations. Case Report: We describe a new variant in the FIG$_4$ gene in a patient with slowly progressing frontotemporal dementia (FTD) and probable primary lateral sclerosis (PLS). The patient initially showed depressive symptoms and global cognitive deficits. Severe difficulties with language and hallucinations became clearer as the disease progressed. Nuclear medicine imaging and cerebrospinal fluid (CSF) biomarkers were not specific for defined categories of dementia, but neuropsychological testing and clinical features finally led to an allocation of the syndrome to the non-fluent variant of primary progressive aphasia (nfv PPA). Because of increasing limb weakness and bulbar symptoms, motoneuron disease in the form of PLS was diagnosed, strongly supported by elevated CSF neurofilament and electrophysiologic assessments. The detected variant in the FIG$_4$ gene is described as pathogenic or likely pathogenic in common databases and reported once in the literature. While the phenotype of our patient fits the description of FIG$_4$-associated disease in literature, we consider the present variant as VUS in this case. Conclusion: We describe a variant in the FIG$_4$ gene in a patient with slowly progressing FTD and PLS. Mutations in the FIG$_4$ gene have been associated with ALS and PLS; however, this exact mutation was not reported in ALS or PLS patients before. The case illustrates generic diagnostic challenges in patients presenting with genetic variants that offer an explanation for otherwise uncommon symptom combinations but yet are of unknown significance.
• Journal Article

#### Lack of astrocytes hinders parenchymal oligodendrocyte precursor cells from reaching a myelinating state in osmolyte-induced demyelination ﻿

Acta Neuropathologica Communications 2020; 8(1) p.1-24: Art. 224
Abstract Demyelinated lesions in human pons observed after osmotic shifts in serum have been referred to as central pontine myelinolysis (CPM). Astrocytic damage, which is prominent in neuroinflammatory diseases like neuromyelitis optica (NMO) and multiple sclerosis (MS), is considered the primary event during formation of CPM lesions. Although more data on the effects of astrocyte-derived factors on oligodendrocyte precursor cells (OPCs) and remyelination are emerging, still little is known about remyelination of lesions with primary astrocytic loss. In autopsy tissue from patients with CPM as well as in an experimental model, we were able to characterize OPC activation and differentiation. Injections of the thymidine-analogue BrdU traced the maturation of OPCs activated in early astrocyte-depleted lesions. We observed rapid activation of the parenchymal NG2+ OPC reservoir in experimental astrocyte-depleted demyelinated lesions, leading to extensive OPC proliferation. One week after lesion initiation, most parenchyma-derived OPCs expressed breast carcinoma amplified sequence-1 (BCAS1), indicating the transition into a pre-myelinating state. Cells derived from this early parenchymal response often presented a dysfunctional morphology with condensed cytoplasm and few extending processes, and were only sparsely detected among myelin-producing or mature oligodendrocytes. Correspondingly, early stages of human CPM lesions also showed reduced astrocyte numbers and non-myelinating BCAS1+ oligodendrocytes with dysfunctional morphology. In the rat model, neural stem cells (NSCs) located in the subventricular zone (SVZ) were activated while the lesion was already partially repopulated with OPCs, giving rise to nestin+ progenitors that generated oligodendroglial lineage cells in the lesion, which was successively repopulated with astrocytes and remyelinated. These nestin+ stem cell-derived progenitors were absent in human CPM cases, which may have contributed to the inefficient lesion repair. The present study points to the importance of astrocyte-oligodendrocyte interactions for remyelination, highlighting the necessity to further determine the impact of astrocyte dysfunction on remyelination inefficiency in demyelinating disorders including MS.
• Journal Article

#### Associations of time-restricted eating with health-related quality of life and sleep in adults: a secondary analysis of two pre-post pilot studies ﻿

BMC Nutrition. 2020 Dec 17;6(1):76
Background Therapeutic fasting may improve health-related quality of life (HRQoL) and sleep but is not applicable for everyone. Time-restricted eating (TRE) offers a low threshold alternative but research on associations with HRQoL and sleep is rare. Methods We conducted a secondary analysis of two pilot studies in a pre-post design, which examined TRE in healthy employees at the Ulm University and in abdominal obese patients in a general practitioners office. Participants reported their HRQoL (EQ-5D visual analogue scale) before and after 3 months of restricting their daily eating to 8–9 h. They kept a diary to protocol timing of first and last meal, sleep quality (analogue scale) and duration. Pearson’s correlation coefficient was applied to test bivariate correlations between continuous variables and linear regression analyses were conducted to identify associated factors with the pre-post differences in HRQoL and the differences in sleep quality. Results Ninety-nine participants (aged aged 48.9 ± 1.1, 83.8% female) reached the fasting target of 15–16 h on average on 77.2 ± 18.7% of all recorded days. HRQoL increased by 7.8 ± 12.6 and sleep quality by 9.6 ± 13.9 points, but sleep duration was not extended. Regression analysis revealed mean fasting duration and baseline sleep quality as significant factors associated with changes in HRQoL. Improvements in sleep quality correlated with baseline sleep quality and HRQoL at follow-up but not with fasting. Changes in anthropometry did not correlate with the HRQoL or sleep quality. Conclusions TRE correlates with increased HRQoL and sleep quality independent from weight loss. TRE is easily applicable with or without medical supervision. The potential effects of TRE on health and sleep should be further investigated in larger randomized trials. Trial registration German Register for Clinical Trials (DRKS), DRKS-ID: DRKS00015057 . Registered 4 July 2018.
• Journal Article

#### Menoci: lightweight extensible web portal enhancing data management for biomedical research projects ﻿

BMC Bioinformatics. 2020 Dec 17;21(1):582
Background Biomedical research projects deal with data management requirements from multiple sources like funding agencies’ guidelines, publisher policies, discipline best practices, and their own users’ needs. We describe functional and quality requirements based on many years of experience implementing data management for the CRC 1002 and CRC 1190. A fully equipped data management software should improve documentation of experiments and materials, enable data storage and sharing according to the FAIR Guiding Principles while maximizing usability, information security, as well as software sustainability and reusability. Results We introduce the modular web portal software menoci for data collection, experiment documentation, data publication, sharing, and preservation in biomedical research projects. Menoci modules are based on the Drupal content management system which enables lightweight deployment and setup, and creates the possibility to combine research data management with a customisable project home page or collaboration platform. Conclusions Management of research data and digital research artefacts is transforming from individual researcher or groups best practices towards project- or organisation-wide service infrastructures. To enable and support this structural transformation process, a vital ecosystem of open source software tools is needed. Menoci is a contribution to this ecosystem of research data management tools that is specifically designed to support biomedical research projects.
• Journal Article

#### Muscle wasting as an independent predictor of survival in patients with chronic heart failure ﻿

Journal of Cachexia, Sarcopenia and Muscle 2020; 11(5) p.1242-1249
Background Skeletal muscle wasting is an extremely common feature in patients with heart failure, affecting approximately 20% of ambulatory patients with even higher values during acute decompensation. Its occurrence is associated with reduced exercise capacity, muscle strength, and quality of life. We sought to investigate if the presence of muscle wasting carries prognostic information. Methods Two hundred sixty‐eight ambulatory patients with heart failure (age 67.1 ± 10.9 years, New York Heart Association class 2.3 ± 0.6, left ventricular ejection fraction 39 ± 13.3%, and 21% female) were prospectively enrolled as part of the Studies Investigating Co‐morbidities Aggravating Heart Failure. Muscle wasting as assessed using dual‐energy X‐ray absorptiometry was present in 47 patients (17.5%). Results During a mean follow‐up of 67.2 ± 28.02 months, 95 patients (35.4%) died from any cause. After adjusting for age, New York Heart Association class, left ventricular ejection fraction, creatinine, N‐terminal pro‐B‐type natriuretic peptide, and iron deficiency, muscle wasting remained an independent predictor of death (hazard ratio 1.80, 95% confidence interval 1.01–3.19, P = 0.04). This effect was more pronounced in patients with heart failure with reduced than in heart failure with preserved ejection fraction. Conclusions Muscle wasting is an independent predictor of death in ambulatory patients with heart failure. Clinical trials are needed to identify treatment approaches to this co‐morbidity.
• Journal Article

#### Wheeze and cough measurements at night in children with respiratory symptoms ﻿

BMC Pediatrics 2020; 20(1) p.1-9: Art. 556
Abstract Background Nocturnal cough and wheeze are important symptoms when diagnosing any respiratory disease in a child, but objective measurements of these symptoms are not performed. Methods The aim of our study was to analyze the use of an automated detection system to assess breath sounds objectively in comparison to cough and wheeze questionnaires and to evaluate its feasibility in clinical practice. Results Forty-nine recordings of thirty-nine children were processed (asthma n = 13; cystic fibrosis n = 2; pneumonia n = 5; suspicion of habit cough n = 7; prolonged, recurrent or chronic cough n = 13), and cough and asthma scores were compared to the objective nocturnal recordings. Time for audio-validation of recordings took between 2 and 40 min (mean: 14.22 min, (SD): 10.72). Accuracy of the automated measurement was higher for cough than for wheezing sounds. Nocturnal cough readings but not wheeze readings correlated with some of the corresponding scores. Conclusion To our knowledge this is the first study using a new device to assess nocturnal cough and obstructive breath sounds objectively in children with a wide variety of respiratory diseases. The assessment proved user friendly. We obtained additional information on nighttime symptoms, which would otherwise have remained obscure. Further studies to assess possible diagnostic and therapeutic benefits of this device are needed.
• Journal Article

#### Efficacy of team-based collaborative care for distressed patients in secondary prevention of chronic coronary heart disease (TEACH): study protocol of a multicenter randomized controlled trial ﻿

BMC Cardiovascular Disorders 2020; 20(1) p.1-14: Art. 520
Abstract Background Coronary heart disease (CHD) is the leading cause of death and years of life lost worldwide. While effective treatments are available for both acute and chronic disease stages there are unmet needs for effective interventions to support patients in health behaviors required for secondary prevention. Psychosocial distress is a common comorbidity in patients with CHD and associated with substantially reduced health-related quality of life (HRQoL), poor health behavior, and low treatment adherence. Methods In a confirmatory, randomized, controlled, two-arm parallel group, multicenter behavioral intervention trial we will randomize 440 distressed CHD patients with at least one insufficiently controlled cardiac risk factor to either their physicians' usual care (UC) or UC plus 12-months of blended collaborative care (TeamCare = TC). Trained nurse care managers (NCM) will proactively support patients to identify individual sources of distress and risk behaviors, establish a stepwise treatment plan to improve self-help and healthy behavior, and actively monitor adherence and progress. Additional e-health resources are available to patients and their families. Intervention fidelity is ensured by a treatment manual, an electronic patient registry, and a specialist team regularly supervising NCM via videoconferences and recommending protocol and guideline-compliant treatment adjustments as indicated. Recommendations will be shared with patients and their physicians who remain in charge of patients’ care. Since HRQoL is a recommended outcome by both, several guidelines and patient preference we chose a ≥ 50% improvement over baseline on the HeartQoL questionnaire at 12 months as primary outcome. Our primary hypothesis is that significantly more patients receiving TC will meet the primary outcome criterion compared to the UC group. Secondary hypotheses will evaluate improvements in risk factors, psychosocial variables, health care utilization, and durability of intervention effects over 18–30 months of follow-up. Discussion TEACH is the first study of a blended collaborative care intervention simultaneously addressing distress and medical CHD risk factors conducted in cardiac patients in a European health care setting. If proven effective, its results can improve long-term chronic care of this vulnerable patient group and may be adapted for patients with other chronic conditions. Trial registration: German Clinical Trials Register, DRKS00020824, registered on 4 June, 2020; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00020824
• Journal Article

#### The evolution of the huntingtin-associated protein 40 (HAP40) in conjunction with huntingtin ﻿

BMC Evolutionary Biology 2020; 20(1) p.1-18: Art. 162
Abstract Background The huntingtin-associated protein 40 (HAP40) abundantly interacts with huntingtin (HTT), the protein that is altered in Huntington’s disease (HD). Therefore, we analysed the evolution of HAP40 and its interaction with HTT. Results We found that in amniotes HAP40 is encoded by a single-exon gene, whereas in all other organisms it is expressed from multi-exon genes. HAP40 co-occurs with HTT in unikonts, including filastereans such as Capsaspora owczarzaki and the amoebozoan Dictyostelium discoideum, but both proteins are absent from fungi. Outside unikonts, a few species, such as the free-living amoeboflagellate Naegleria gruberi, contain putative HTT and HAP40 orthologs. Biochemically we show that the interaction between HTT and HAP40 extends to fish, and bioinformatic analyses provide evidence for evolutionary conservation of this interaction. The closest homologue of HAP40 in current protein databases is the family of soluble N-ethylmaleimide-sensitive factor attachment proteins (SNAPs). Conclusion Our results indicate that the transition from a multi-exon to a single-exon gene appears to have taken place by retroposition during the divergence of amphibians and amniotes, followed by the loss of the parental multi-exon gene. Furthermore, it appears that the two proteins probably originated at the root of eukaryotes. Conservation of the interaction between HAP40 and HTT and their likely coevolution strongly indicate functional importance of this interaction.
• Journal Article

#### Type 2A von Willebrand disease and systemic sclerosis: Vonicog alfa reduced gastrointestinal bleeding ﻿

Research and Practice in Thrombosis and Haemostasis 2020; 4(7) p.1230-1234
Von Willebrand disease (VWD) is a bleeding disorder caused by qualitative or quantitative defects of von Willebrand factor (VWF). This case report of a patient with systemic sclerosis and gastrointestinal bleeding from angiodysplasias seeks to address the key clinical question of a useful diagnostic and therapeutic approach in this setting. The extent of vascular malformations and the frequency of bleeding episodes were unusually severe, and we reached a diagnosis of inherited type 2A VWD. After an insufficient effect of treatment with factor VIII (FVIII)/VWF, prophylactic administration of vonicog alfa, a recombinant VWF preparation without FVIII, was initiated. This therapy led to a substantial reduction of transfusion requirements and the improvement of angiodysplasias. In refractory gastrointestinal bleeding, hemostaseological evaluation is crucial, as inherited disorders of hemostasis may go unnoticed, especially in patients with underlying autoimmune diseases, where complications may be ascribed to the underlying disease.
• Journal Article

#### Low serum albumin is an independent risk factor in elderly patients with aggressive B‐cell lymphoma: Results from prospective trials of the German High‐Grade Non‐Hodgkin's Lymphoma Study Group ﻿

eJHaem 2020; 1(1) p.181-187
Serum albumin a well‐known risk factor predicting outcome in many solid tumors. We explore the role of low serum albumin (≤3.5 g/dL) as an independent risk factor in elderly patients with aggressive B‐cell lymphoma. Outcome of 429 patients treated with R‐CHOP‐14 in the RICOVER‐60 trial and available serum albumin were analyzed in this retrospective study. Of the 429 patients in the RICOVER‐60 trial, 137 (32%) had low and 292 (68%) had normal serum albumin levels (>3.5 g/dL). In the low albumin group, patients had significantly higher International Prognostic Index (IPI), bulky disease, extralymphatic involvement, and B‐symptoms. Event‐free survival (EFS) (P < .001), progression‐free survival (PFS) (P < .001), and overall survival (OS) (P < .001) were significantly inferior for patients with low compared to those with normal serum albumin. Multivariate analysis adjusted for IPI shows following Hazard ratios (HR) for low serum albumin: EFS (HR = 1.5; 95% confidance interval [CI] [1.1; 2.1], P = .009), PFS (HR = 1.7; 95% CI [1.2; 2.4], P = .001) and OS (HR = 1.6; 95% CI [1.1; 2.3], P = .006). Results were confirmed in 185 patients from the DENSE‐R‐CHOP‐14 and SMARTE‐R‐CHOP‐14 trials. In conclusion, low serum albumin is an independent risk factor in elderly patients with aggressive B‐cell lymphoma treated with R‐CHOP.
• Journal Article

#### Modulating the Heat Sensitivity of Prostate Cancer Cell Lines In Vitro: A New Impact for Focal Therapies ﻿

Biomedicines 2020; 8(12) p.1-15: Art. 585
Focal therapies such as high-intensity focused ultrasound (HiFU) are an emerging therapeutic option for prostate cancer (PCA). Thermal or mechanical effects mediate most therapies. Moreover, locally administered drugs such as bicalutamide or docetaxel are new focal therapeutic options. We assessed the impact of such focal medical treatments on cell viability and heat sensitivity by pre-treating PCA cell lines and then gradually exposing them to heat. The individual heat response of the cell lines tested differed largely. Vertebral-Cancer of the Prostate (VCaP) cells showed an increase in metabolic activity at 40–50 °C. Androgen receptor (AR)-negative PC3 cells showed an increase at 51.3 °C and were overall more resistant to higher temperatures. Pre-treatment of VCaP cells with testosterone (VCaPrev) leads to a more PC3-like kinetic of the heat response. Pre-treatment with finasteride and bicalutamide did not cause changes in heat sensitivity in any cell line. Mitoxantrone treatment, however, shifted heat-induced proliferation loss to lower temperature in VCaP cells. Further analysis via RNAseq identified a possible correlation of heat resistance with H3K27me3-dependent gene regulation, which could be related to an increase in the histone methyltransferase EZH2 and a possible neuroendocrine differentiation. Pre-treatment with mitoxantrone might be a perspective for HiFU treatment. Further studies are needed to evaluate possible combinations with Hsp90 or EZH2 inhibitors.
• Journal Article

#### Muscle mass, muscle strength, and functional capacity in patients with heart failure of Chagas disease and other aetiologies ﻿

ESC Heart Failure 2020; 7(5) p.3086-3094
Aims Patients with Chagas disease and heart failure (HF) have a poor prognosis similar to that of patients with ischaemic or dilated cardiomyopathy. However, the impact of body composition and muscle strength changes in these aetiologies is still unknown. We aimed to evaluate these parameters across aetiologies in two distinct cohort studies [TESTOsterone‐Heart Failure trial (TESTO‐HF; Brazil) and Studies Investigating Co‐morbidities Aggravating Heart Failure (SICA‐HF; Germany)]. Methods and results A total of 64 male patients with left ventricular ejection fraction ≤40% were matched for body mass index and New York Heart Association class, including 22 patients with Chagas disease (TESTO‐HF; Brazil), and 20 patients with dilated cardiomyopathy and 22 patients with ischaemic heart disease (SICA‐HF; Germany). Lean body mass (LBM), appendicular lean mass (ALM), and fat mass were assessed by dual energy X‐ray absorptiometry. Sarcopenia was defined as ALM divided by height in metres squared <7.0 kg/m$^2$ (ALM/height$^2$) and handgrip strength cut‐off for men according to the European Working Group on Sarcopenia in Older People. All patients performed maximal cardiopulmonary exercise testing. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Chagasic and ischaemic patients had lower total fat mass (16.3 ± 8.1 vs. 19.3 ± 8.0 vs. 27.6 ± 9.4 kg; P < 0.05) and reduced peak oxygen consumption (VO$_2$) (1.17 ± 0.36 vs. 1.15 ± 0.36 vs. 1.50 ± 0.45 L/min; P < 0.05) than patients with dilated cardiomyopathy, respectively. Chagasic patients showed a trend towards decreased LBM when compared with ischaemic patients (48.3 ± 7.6 vs. 54.2 ± 6.3 kg; P = 0.09). Chagasic patients showed lower handgrip strength (27 ± 8 vs. 37 ± 11 vs. 36 ± 14 kg; P < 0.05) and FBF (1.84 ± 0.54 vs. 2.75 ± 0.76 vs. 3.42 ± 1.21 mL/min/100 mL; P < 0.01) than ischaemic and dilated cardiomyopathy patients, respectively. There was no statistical difference in the distribution of sarcopenia between groups (P = 0.87). In addition, FBF correlated positively with LBM (r = 0.31; P = 0.012), ALM (r = 0.25; P = 0.046), and handgrip strength (r = 0.36; P = 0.004). In a logistic regression model using peak VO$_2$ as the dependent variable, haemoglobin (odds ratio, 1.506; 95% confidence interval, 1.043–2.177; P = 0.029) and ALM (odds ratio, 1.179; 95% confidence interval, 1.011–1.374; P = 0.035) were independent predictors for peak VO$_2$ adjusted by age, left ventricular ejection fraction, New York Heart Association, creatinine, and FBF. Conclusions Patients with Chagas disease and HF have decreased fat mass and exhibit reduced peripheral blood flow and impaired muscle strength compared with ischaemic HF patients. In addition, patients with Chagas disease and HF show a tendency to have greater reduction in total LBM, with ALM remaining an independent predictor of reduced functional capacity in these patients. The percentage of patients affected by sarcopenia was equal between groups.
• Journal Article

#### Sacubitrilat reduces pro‐arrhythmogenic sarcoplasmic reticulum Ca$^{2+}$ leak in human ventricular cardiomyocytes of patients with end‐stage heart failure ﻿

ESC Heart Failure 2020; 7(5) p.2992-3002
Aims Inhibition of neprilysin and angiotensin II receptor by sacubitril/valsartan (Val) (LCZ696) reduces mortality in heart failure (HF) patients compared with sole inhibition of renin–angiotensin system. Beneficial effects of increased natriuretic peptide levels upon neprilysin inhibition have been proposed, whereas direct effects of sacubitrilat (Sac) (LBQ657) on myocardial Ca$^{2+}$ cycling remain elusive. Methods and results Confocal microscopy (Fluo‐4 AM) was used to investigate pro‐arrhythmogenic sarcoplasmic reticulum (SR) Ca$^{2+}$ leak in freshly isolated murine and human ventricular cardiomyocytes (CMs) upon Sac (40 μmol/L)/Val (13 μmol/L) treatment. The concentrations of Sac and Val equalled plasma concentrations of LCZ696 treatment used in PARADIGM‐HF trial. Epifluorescence microscopy measurements (Fura‐2 AM) were performed to investigate effects on systolic Ca$^{2+}$2+ release, SR Ca$^{2+}$ load, and Ca$^{2+}$‐transient kinetics in freshly isolated murine ventricular CMs. The impact of Sac on myocardial contractility was evaluated using in toto‐isolated, isometrically twitching ventricular trabeculae from human hearts with end‐stage HF. Under basal conditions, the combination of Sac/Val did not influence diastolic Ca$^{2+}$‐spark frequency (CaSpF) nor pro‐arrhythmogenic SR Ca$^{2}$ leak in isolated murine ventricular CMs (n CMs/hearts = 80/7 vs. 100/7, P = 0.91/0.99). In contrast, Sac/Val treatment reduced CaSpF by 35 ± 9% and SR Ca$^{2+}$ leak by 45 ± 9% in CMs put under catecholaminergic stress (isoproterenol 30 nmol/L, n = 81/7 vs. 62/7, P < 0.001 each). This could be attributed to Sac, as sole Sac treatment also reduced both parameters by similar degrees (reduction of CaSpF by 57 ± 7% and SR Ca$^{2+}$ leak by 76 ± 5%; n = 101/4 vs. 108/4, P < 0.01 each), whereas sole Val treatment did not. Systolic Ca$^{2+}$ release, SR Ca$^{2+}$ load, and Ca$^{2+}$‐transient kinetics including SERCA activity (kSERCA) were not compromised by Sac in isolated murine CMs (n = 41/6 vs. 39/6). Importantly, the combination of Sac/Val and Sac alone also reduced diastolic CaSpF and SR Ca$^{2+}$ leak (reduction by 74 ± 7%) in human left ventricular CMs from patients with end‐stage HF (n = 71/8 vs. 78/8, P < 0.05 each). Myocardial contractility of human ventricular trabeculae was not acutely affected by Sac treatment as the developed force remained unchanged over a time course of 30 min (n trabeculae/hearts = 3/3 vs. 4/3). Conclusion This study demonstrates that neprilysin inhibitor Sac directly improves Ca$^{2+}$ homeostasis in human end‐stage HF by reducing pro‐arrhythmogenic SR Ca$^{2+}$ leak without acutely affecting systolic Ca$^{2+}$ release and inotropy. These effects might contribute to the mortality benefits observed in the PARADIGM‐HF trial.
• Journal Article

#### Fully Automated Cardiac Assessment for Diagnostic and Prognostic Stratification Following Myocardial Infarction ﻿

Journal of the American Heart Association 2020; 9(18) p.1-13: Art. e016612
Background Cardiovascular magnetic resonance imaging is considered the reference methodology for cardiac morphology and function but requires manual postprocessing. Whether novel artificial intelligence–based automated analyses deliver similar information for risk stratification is unknown. Therefore, this study aimed to investigate feasibility and prognostic implications of artificial intelligence–based, commercially available software analyses. Methods and Results Cardiovascular magnetic resonance data (n=1017 patients) from 2 myocardial infarction multicenter trials were included. Analyses of biventricular parameters including ejection fraction (EF) were manually and automatically assessed using conventional and artificial intelligence–based software. Obtained parameters entered regression analyses for prediction of major adverse cardiac events, defined as death, reinfarction, or congestive heart failure, within 1 year after the acute event. Both manual and uncorrected automated volumetric assessments showed similar impact on outcome in univariate analyses (left ventricular EF, manual: hazard ratio [HR], 0.93 [95% CI 0.91–0.95]; P<0.001; automated: HR, 0.94 [95% CI, 0.92–0.96]; P<0.001) and multivariable analyses (left ventricular EF, manual: HR, 0.95 [95% CI, 0.92–0.98]; P=0.001; automated: HR, 0.95 [95% CI, 0.92–0.98]; P=0.001). Manual correction of the automated contours did not lead to improved risk prediction (left ventricular EF, area under the curve: 0.67 automated versus 0.68 automated corrected; P=0.49). There was acceptable agreement (left ventricular EF: bias, 2.6%; 95% limits of agreement, −9.1% to 14.2%; intraclass correlation coefficient, 0.88 [95% CI, 0.77–0.93]) of manual and automated volumetric assessments. Conclusions User‐independent volumetric analyses performed by fully automated software are feasible, and results are equally predictive of major adverse cardiac events compared with conventional analyses in patients following myocardial infarction.
• Journal Article

#### Diagnosis and therapy of functional tremor a systematic review illustrated by a case report ﻿

Neurological Research and Practice. 2020 Dec 03;2(1):35
Background Diagnosis of functional movement disorders and specifically functional tremor (FT) (representing 50% of them) remains demanding. Additionally, due to heterogeneity of the disorders, structured concepts and guidelines for diagnosis and therapy are difficult to establish. Ascertaining the state of knowledge to derive instructions for operating procedures is the aim of this review. Main text Based on a standardized systematic literature research using the term “psychogenic tremor” in the MEDLINE database dating back ten years, 76 studies were evaluated. Conventional features of FT are variability of frequency and amplitude. Further, response to distraction by motor and cognitive tasks is a key diagnostic feature in differentiation between organic and functional origin. A variety of electrophysiological tests have been evaluated including surface electromyography and accelerometry to establish laboratory-supported criteria for diagnosing tremor. Also, finger tapping tests have been used to identify FT, showing positive potential as supplementary evidence. Imaging studies in general are mostly underpowered and imaging cannot be used on an individual basis. Therapeutic studies in FT often have a diagnostic component. Cognitive behavioral therapy should be the preferred psychological treatment independent of additional psychiatric symptoms. Other psychotherapeutic methods show lack of evidence concerning FT. Relaxation techniques and physiotherapy are an important additional feature, especially in children and adolescents. In regard to drug therapy, randomized and blinded trials are not available. A significant decrease in rating scales could be detected after active, not sham repetitive transcranial magnetic stimulation with a long-lasting effect. Also root magnetic stimulation seems to be effective. The clinical feature of tremor entrainment in FT can be used in combination with biofeedback as so-called tremor retrainment, using self-modulation of frequency and severity, to bring the movements under volitional control. Conclusion Diagnosis and treatment of FT is challenging and should include a combination of intensive clinical examination and targeted addition of standardized testing, especially electrophysiological methods. Often therapeutic effects have a diagnostic component. A multimodal strategy, considering psychological factors as a potential origin as well as maintaining effects seems to be most effective.
• Journal Article

#### Comprehensive 3D analysis of condylar morphology in adults with different skeletal patterns – a cross-sectional study ﻿

Head & Face Medicine 2020; 16(1) p.1-10: Art. 33
Abstract Background The correlation between individuals’ condylar morphology and their skeletal pattern is of great interest for treatment strategies ranging from orthodontic orthopaedics to orthognathic surgery. The objective of the present study was to investigate this relationship three-dimensionally. Methods A total of 111 adult patients (mean age = 27.0 ± 10.2 years) who underwent head computed tomography or cone beam computed tomography scans were included. Based on these data, 3D models of the skull and the condyles were calculated. The craniofacial skeleton was evaluated (1) transversally regarding skeletal symmetry (menton deviation), (2) sagittally regarding skeletal classes (Wits appraisal) and vertically regarding the inclination of the jaws (maxillomandibular plane angle). The condylar morphology was assessed (a) linearly by the condylar width, height and depth; (b) angularly by the antero-posterior and medio-lateral condylar inclination; and (c) volumetrically by the ratio of the condylar volume/mandibular volume (C/Mand). Results (1) Transversal: Asymmetric patients showed significantly higher discrepancies in the volumetric ratio C/Mand on the deviation and non-deviation side compared to symmetric patients. (2) Sagittal: Class III subjects demonstrated longer, more voluminous condyles with higher antero-posterior and medio-lateral inclination angles compared to Class II participants. (3) Vertical: Hyperdivergent subjects had smaller condyles with higher antero-posterior inclination angles than those of hypodivergent subjects. No interactions of skeletal class and vertical relationships regarding condylar morphology were observed. Conclusions This study demonstrates a clear correlation between pronounced skeletal patterns and condylar morphology in an adult population. The description of radiographic condyle characteristics in relation to the craniofacial morphology improves orthodontic treatment planning and could be helpful in the diagnosis of temporomandibular joint pathologies.
• Journal Article

#### “…This Has to Do With My Identity. And I Don't Want to Make it Totally Transparent.” Identity Relevance in the Attitudes of Affected People and Laypersons to the Handling of High-Throughput Genomic Data ﻿

Frontiers in Sociology 2020; 5 p.1-17: Art. 532357
With the establishment of genome sequencing, the influence of genomic information on self-understanding and identity construction has become increasingly important. New sequencing methods far exceed previous genetic tests in terms of scope and quantity. Despite theoretical approaches, however, there are few empirical findings on the identity-relevant influence of genomic information. The present study examines genomic information's identity-relevant influences and considers whether developments in the field of genome sequencing may generate problems that are not yet addressed by existing identity concepts based on traditional genetic tests. The study is based on 10 partially standardized interviews with personally affected persons and four focus groups with medical laypersons as representatives of the public, which were evaluated on the basis of qualitative content analysis. As a result, this paper presents five thematic areas with identity-relevant references within subjective attitudes toward the handling of genomic information, and also derives two basic identity concepts. The results indicate that the lay discourse is still strongly based on older debates about genetic testing and that the view on the complexity of genomic information established in the scientific context has thus far no influence on the perspectives either of those affected or laypersons.