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Background:Synucleinopathies are disorders characterized by the abnormal accumulation of α-synuclein (aSyn). Synaptic compromise is observed in synucleinopathies parallel to aSyn aggregation and is accompanied by transcript deregulation.Objective:We sought to identify microRNAs associated with synaptic processes that may contribute to synaptic dysfunction and degeneration in synucleinopathies.Methods:We performed small RNA-sequencing of midbrain from 6-month-old transgenic mice expressing A30P mutant aSyn, followed by comparative expression analysis. We then used real-time quantitative polymerase chain reaction (qPCR) for validation. Functional analysis was performed in primary neurons by biochemical assays and imaging.Results:We found several deregulated biological processes linked to the synapse. miR-101a-3p was validated as a synaptic miRNA upregulated in aSyn Tg mice and in the cortex of dementia with Lewy bodies patients. Mice and primary cultured neurons overexpressing miR-101a-3p showed downregulation of postsynaptic proteins GABA Ab2 and SAPAP3 and altered dendritic morphology resembling synaptic plasticity impairments and/or synaptic damage. Interestingly, primary cultured neuron exposure to recombinant wild-type aSyn species efficiently increased miR-101a-3p levels. Finally, a dynamic role of miR-101a-3p in synapse plasticity was shown by identifying downregulation of miR-101a-3p in a condition of enhanced synaptic plasticity modelled in Wt animals housed in enriched environment.Conclusion:To conclude, we correlated pathologic aSyn with high levels of miR-101a-3p and a novel dynamic role of the miRNA in synaptic plasticity.

ImportanceDiagnostic incidence data for syndromes associated with frontotemporal lobar degeneration (FTLD) in multinational studies are urgent in light of upcoming therapeutic approaches.ObjectiveTo assess the incidence of FTLD across Europe.Design, Setting, and ParticipantsThe Frontotemporal Dementia Incidence European Research Study (FRONTIERS) was a retrospective cohort study conducted from June 1, 2018, to May 31, 2019, using a population-based registry from 13 tertiary FTLD research clinics from the UK, the Netherlands, Finland, Sweden, Spain, Bulgaria, Serbia, Germany, and Italy and including all new FTLD-associated cases during the study period, with a combined catchment population of 11 023 643 person-years. Included patients fulfilled criteria for the behavioral variant of frontotemporal dementia (BVFTD), the nonfluent variant or semantic variant of primary progressive aphasia (PPA), unspecified PPA, progressive supranuclear palsy, corticobasal syndrome, or frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS). Data were analyzed from July 19 to December 7, 2021.Main Outcomes and MeasuresRandom-intercept Poisson models were used to obtain estimates of the European FTLD incidence rate accounting for geographic heterogeneity.ResultsBased on 267 identified cases (mean [SD] patient age, 66.70 [9.02] years; 156 males [58.43%]), the estimated annual incidence rate for FTLD in Europe was 2.36 cases per 100 000 person-years (95% CI, 1.59-3.51 cases per 100 000 person-years). There was a progressive increase in FTLD incidence across age, reaching its peak at the age of 71 years, with 13.09 cases per 100 000 person-years (95% CI, 8.46-18.93 cases per 100 000 person-years) among men and 7.88 cases per 100 000 person-years (95% CI, 5.39-11.60 cases per 100 000 person-years) among women. Overall, the incidence was higher among men (2.84 cases per 100 000 person-years; 95% CI, 1.88-4.27 cases per 100 000 person-years) than among women (1.91 cases per 100 000 person-years; 95% CI, 1.26-2.91 cases per 100 000 person-years). BVFTD was the most common phenotype (107 cases [40.07%]), followed by PPA (76 [28.46%]) and extrapyramidal phenotypes (69 [25.84%]). FTD-ALS was the rarest phenotype (15 cases [5.62%]). A total of 95 patients with FTLD (35.58%) had a family history of dementia. The estimated number of new FTLD cases per year in Europe was 12 057.Conclusions and RelevanceThe findings suggest that FTLD-associated syndromes are more common than previously recognized, and diagnosis should be considered at any age. Improved knowledge of FTLD incidence may contribute to appropriate health and social care planning and in the design of future clinical trials.

European archives of oto-rhino-laryngology and head & neck (2023). doi:10.1007/s00405-023-07913-1, Published by Springer, Heidelberg

Funder: Alzheimer Society of Canada; Id: http://dx.doi.org/10.13039/501100000143, Funder: Weston Brain Institute; Id: http://dx.doi.org/10.13039/100012479, Funder: Fonds de Recherche du Québec ‐ Santé, Funder: Canadian Institutes of Health Research; Id: http://dx.doi.org/10.13039/501100000024, Funder: NIHR Rare Diseases Translational Research Collaboration, Funder: Deutsche Forschungsgemeinschaft; Id: http://dx.doi.org/10.13039/501100001659, Recent studies have reported early cerebellar and subcortical impact in the disease progression of genetic frontotemporal dementia (FTD) due to microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72). However, the cerebello-subcortical circuitry in FTD has been understudied despite its essential role in cognition and behaviors related to FTD symptomatology. The present study aims to investigate the association between cerebellar and subcortical atrophy, and neuropsychiatric symptoms across genetic mutations. Our study included 983 participants from the Genetic Frontotemporal dementia Initiative including mutation carriers and noncarrier first-degree relatives of known symptomatic carriers. Voxel-wise analysis of the thalamus, striatum, globus pallidus, amygdala, and the cerebellum was performed, and partial least squares analyses (PLS) were used to link morphometry and behavior. In presymptomatic C9orf72 expansion carriers, thalamic atrophy was found compared to noncarriers, suggesting the importance of this structure in FTD prodromes. PLS analyses demonstrated that the cerebello-subcortical circuitry is related to neuropsychiatric symptoms, with significant overlap in brain/behavior patterns, but also specificity for each genetic mutation group. The largest differences were in the cerebellar atrophy (larger extent in C9orf72 expansion group) and more prominent amygdalar volume reduction in the MAPT group. Brain scores in the C9orf72 expansion carriers and MAPT carriers demonstrated covariation patterns concordant with atrophy patterns detectable up to 20 years before expected symptom onset. Overall, these results demonstrated the important role of the subcortical structures in genetic FTD symptom expression, particularly the cerebellum in C9orf72 and the amygdala in MAPT carriers.

There is still limited mechanistic insight into how the interaction of individuals with their environment results in the emergence of individuality in behavior and brain structure. Nevertheless, the idea that personal activity shapes the brain is implicit in strategies for healthy cognitive aging as well as in the idea that individuality is reflected in the brain's connectome. We have shown that even isogenic mice kept in a shared enriched environment (ENR) developed divergent and stable social and exploratory trajectories. As these trajectories-measured as roaming entropy (RE)-positively correlated with adult hippocampal neurogenesis, we hypothesized that a feedback between behavioral activity and adult hippocampal neurogenesis might be a causal factor in brain individualization. We used cyclin D2 knockout mice with constitutively extremely low levels of adult hippocampal neurogenesis and their wild-type littermates. We housed them for 3 months in a novel ENR paradigm, consisting of 70 connected cages equipped with radio frequency identification antennae for longitudinal tracking. Cognitive performance was evaluated in the Morris Water Maze task (MWM). With immunohistochemistry we confirmed that adult neurogenesis correlated with RE in both genotypes and that D2 knockout mice had the expected impaired performance in the reversal phase of the MWM. But whereas the wild-type animals developed stable exploratory trajectories with increasing variance, correlating with adult neurogenesis, this individualizing phenotype was absent in D2 knockout mice. Here the behaviors started out more random and revealed less habituation and low variance. Together, these findings suggest that adult neurogenesis contributes to experience-dependent brain individualization.

According to current knowledge approximately 30-40% of all cases of dementia can be attributed to modifiable risk factors. As a result, dementia prevention and the concept of brain health are becoming increasingly relevant.The requirements for brain health services and their implementation are discussed and the Cologne Alzheimer Prevention Center (KAP) of the University Hospital Cologne is described as an example.In addition to a report on international brain health initiatives, the main activities of the KAP are presented. A program for individual risk profiling and risk communication is provided, which was piloted in the KAP in the context of the 'Individual risk profiling for Alzheimer's disease and dementia prevention (INSPIRATION)' study. The prevalence of risk factors in a cognitively healthy sample aged 50-86 years (n = 162) with interest in dementia prevention is presented.The most common risk factors were non-Mediterranean diet, obesity, subjective poor sleep quality and increased stress. Based on these results, preventive interventions can be developed that are adapted to the individual risk profile as a personalized medicine approach.Structures such as the KAP can provide individual risk factor assessment and personalized dementia prevention. The efficacy of this approach on dementia risk reduction needs to be evaluated.

Ancient Greek and Latin medical authors considered a flight into solitude a compelling sign of mental disturbance, frequently described as misanthropia, a word fraught with meaning beyond the medical discourse. The fictionalised character Timon of Athens, the quintessential misanthrope, can shed light on ancient cultural concepts of self-imposed isolation from human contact. To cope with the sense of unease this deviant behaviour induced, misanthropia was explained as ‘madness’, ridiculed in various genres of humour, morally condemned in philosophy, and ultimately demonized in Christian cosmology. These various attempts at containment echo in the medical works of the age, making it impossible to comprehend the concept of misanthropia in ancient medicine without taking full account of the cultural context.

Focal cortical dysplasias (FCDs) are malformations of cortical development and one of the most common pathologies causing pharmacoresistant focal epilepsy. Resective neurosurgery yields high success rates, especially if the full extent of the lesion is correctly identified and completely removed. The visual assessment of magnetic resonance imaging does not pinpoint the FCD in 30%-50% of cases, and half of all patients with FCD are not amenable to epilepsy surgery, partly because the FCD could not be sufficiently localized. Computational approaches to FCD detection are an active area of research, benefitting from advancements in computer vision. Automatic FCD detection is a significant challenge and one of the first clinical grounds where the application of artificial intelligence may translate into an advance for patients' health. The emergence of new methods from the combination of health and computer sciences creates novel challenges. Imaging data need to be organized into structured, well-annotated datasets and combined with other clinical information, such as histopathological subtypes or neuroimaging characteristics. Algorithmic output, that is, model prediction, requires a technically correct evaluation with adequate metrics that are understandable and usable for clinicians. Publication of code and data is necessary to make research accessible and reproducible. This critical review introduces the field of automatic FCD detection, explaining underlying medical and technical concepts, highlighting its challenges and current limitations, and providing a perspective for a novel research environment.

N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common subtype of autoimmune encephalitis characterized by a complex neuropsychiatric syndrome usually including memory impairment. Patients develop an intrathecal immune response against NMDARs with antibodies that presumably bind to the amino-terminal domain of the GluN1 subunit. The therapeutic response to immunotherapy is often delayed. Therefore, new therapeutic approaches for fast neutralization of NMDAR antibodies are needed. Here, we developed fusion constructs consisting of the Fc part of immunoglobulin G and the amino-terminal domains of either GluN1 or combinations of GluN1 with GluN2A or GluN2B. Surprisingly, both GluN1 and GluN2 subunits were required to generate high-affinity epitopes. The construct with both subunits efficiently prevented NMDAR binding of patient-derived monoclonal antibodies and of patient CSF containing high-titre NMDAR antibodies. Furthermore, it inhibited the internalization of NMDARs in rodent dissociated neurons and human induced pluripotent stem cell-derived neurons. Finally, the construct stabilized NMDAR currents recorded in rodent neurons and rescued memory defects in passive-transfer mouse models using intrahippocampal injections. Our results demonstrate that both GluN1 and GluN2B subunits contribute to the main immunogenic region of the NMDAR and provide a promising strategy for fast and specific treatment of NMDAR encephalitis, which could complement immunotherapy.

Mitochondria generate energy through oxidative phosphorylation (OXPHOS). The function of key OXPHOS proteins can be altered by variation in mitochondria-related genes, which may increase the risk of mental illness. We investigated the association of mitochondria-related genes and their genetic risk burden with cognitive performance.We leveraged cross-sectional data from 1320 individuals with a severe psychiatric disorder and 466 neurotypical individuals from the PsyCourse Study. The cognitive tests analyzed were the Trail-Making Test, Verbal Digit Span Test, Digit-Symbol Test, and Multiple Choice Vocabulary Intelligence Test. Association analyses between the cognitive tests, and single-nucleotide polymorphisms (SNPs) mapped to mitochondria-related genes, and their polygenic risk score (PRS) for schizophrenia (SCZ) were performed with PLINK 1.9 and R program.We found a significant association (FDR-adjusted p < 0.05) in the Cytochrome C Oxidase Assembly Factor 8 (COA8) gene locus of the OXPHOS pathway with the Verbal Digit Span (forward) test. Mitochondrial PRS was not significantly associated with any of the cognitive tests.Moderate statistical power due to relatively small sample size.COA8 encodes a poorly characterized mitochondrial protein involved in apoptosis. Here, this gene was associated with the Verbal Digit Span (forward) test, which evaluates short-term memory. Our results warrant replication and may lead to better understanding of cognitive impairment in mental disorders.

Journal of nephrology JN (2022). doi:10.1007/s40620-022-01454-2, Published by Springer, Milano

Gastric cancer (2022). doi:10.1007/s10120-022-01347-0, Published by Springer, Tokyo

Objective Previous meta-analytic data have demonstrated the propensity for mental morbidity among medical students (Rotenstein et al. JAMA. 2016;316(21):2214–36). However, there is a lack of research on medical students’ varying depression vulnerabilities and predictive factors. The present study aims to gain a better understanding of the development of mental health morbidity and its predictive factors among first-semester medical students. Methods In November 2020 and January 2021, 184 first-semester students from two medical schools were surveyed regarding depression (PHQ-9), self-efficacy, resilience, and cognitive self-regulation. Using latent profile analysis, we identified distinct depression development profiles. We applied a multinomial logistic regression analysis to determine how self-efficacy, resilience, and cognitive self-regulation and their changes predicted profile membership. Results Five profiles of depression development were identified: profile 1, no depression (53.8%); profile 2, mild depression (26.1%); profile 3, depression increase I (9.2%); profile 4, depression increase II (9.8%); and profile 5, persistent depression (1.1%). Students with initially high self-efficacy, resilience, and cognitive self-regulation levels were more likely to belong to the no depression profile. A decrease in self-efficacy and cognitive self-regulation was associated with both depression increase profiles (profiles 3 and 4), and a decrease in resilience was found to be a predictor of profile 4. Conclusion Students who enter medical school have varying states of mental health, and they differ in their vulnerability to developing depressive symptoms. The promotion of resilience, self-efficacy, and cognitive self-regulation strategies may be key in preventing students’ depression in the first semester of medical school.

Previous studies indicate that occupation might affect cognitive functioning in late life. As people in low- and middle-income countries often have to work until late life, we sought to investigate if there are cognitive benefits to working later into life and whether cognitive function deteriorates after exiting the labour force. We analysed longitudinal data from the Mexican Health and Aging Study (MHAS), a nationally representative sample of Mexican adults age 50+ (N = 7,375), that assessed cognitive functioning by verbal learning, delayed recall and visual scanning. Analyses were carried out using mixed-effects modelling corrected for the influence of gender, instrumental activities of daily living, diabetes, stroke, hypertension, depression, income and marital status. Results suggest that working actively, compared to exiting the workforce, was associated with cognitive performance only in context with occupation. Domestic workers had a faster decline in verbal learning (b = −0.02, p = 0.020) and delayed recall (b = −0.02, p = 0.036) if they continued working actively and people working in administration (b = 0.03, p = 0.007), sales (b = 0.02, p = 0.044) and educators (b = 0.03, p = 0.049) had a slower decline in visual scanning if they continued working in old age. Our findings indicate that continued participation in the labour force in old age does not necessarily come with cognitive benefits. Whether or not working actively in later life protects or even harms cognitive functioning is likely to depend on the type of job.

Die Vermeidung von Unfällen hat große Bedeutung, sowohl für die Betroffenen und ihre Familien als auch gesamtgesellschaftlich. Über 8 Millionen Menschen verletzten sich im Jahr 2011 durch Unfälle, so Schätzungen der Bundesanstalt für Arbeitsschutz und Arbeitsmedizin (BAuA 2011). Über 20.000 Personen wurden bei Unfällen getötet (StBA 2013). Neben unbeabsichtigten Verletzungen aufgrund von Unfällen können Verletzungen auch beabsichtigt sein, z. B. durch interpersonelle Gewalt (Angriff, Schlägerei) oder absichtliche Selbstverletzung. Für die medizinische Behandlung von Verletzungen werden jährlich knapp 5 % der gesamten Krankheitskosten aufgewendet (ICD-10: S00 – T98) (StBA 2010). Das Unfallgeschehen in Deutschland lässt sich auf der Basis amtlicher Statistiken nur unvollständig abbilden. Ein Grund dafür ist, dass bedeutsame Bereiche nicht systematisch erfasst werden, wie z. B. Unfälle zu Hause, Freizeitunfälle und Verkehrsunfälle ohne Beteiligung der Polizei. Repräsentative Befragungen liefern einen Überblick über das nichttödliche Unfallgeschehen und sind daher eine wichtige Ergänzung (RKI 2013).

This review on brain multiparametric quantitative MRI (MP-qMRI) focuses on the primary subset of quantitative MRI (qMRI) parameters that represent the mobile ("free") and bound ("motion-restricted") proton pools. Such primary parameters are the proton densities, relaxation times, and magnetization transfer parameters. Diffusion qMRI is also included because of its wide implementation in complete clinical MP-qMRI application. MP-qMRI advances were reviewed over the past 2 decades, with substantial progress observed toward accelerating image acquisition and increasing mapping accuracy. Areas that need further investigation and refinement are identified as follows

Purpose Intracranial rescue stent angioplasty is a bailout strategy for acute stroke patients in cases of unsuccessful endovascular thrombectomy due to underlying atherosclerotic stenosis. However, there is no consensus on a preprocedural and intraprocedural antiplatelet regimen. The aim of this single-centre study was to compare the safety and efficacy of emergency stenting in patients exhibiting intracranial atherosclerotic stenosis-related acute large-vessel occlusion with or without peri-interventional intravenous infusion of tirofiban. Materials and Methods We performed a retrospective analysis of 78 patients who were treated with rescuestent angioplasty between 2010 and 2019 due to acute ischaemic stroke. The patients were divided into 2 groups: those who received peri-interventional intravenous tirofiban and those who did not receive tirofiban. We compared clinical safety and functional outcomes in both treatment groups with symptomatic haemorrhage as the primary endpoint. Bivariate and multivariable logistic regression was performed to investigate the association between tirofiban and outcome measures. Results Thirty-seven patients were treated with intravenous tirofiban (47.4%), and 41 patients did not receive intravenous tirofiban (52.6%). Statistical analysis revealed no significant difference between the two groups in the rate of symptomatic haemorrhage (16.2% in the tirofiban group versus 14.6% in the control group, p = 0.847). The 3-month mortality (21.6% in the tirofiban group versus 17.1% in the control group, p = 0.611) and good functional outcomes according to the modified Rankin scale (45.9% versus 34.1%, p = 0.289) were comparable. Conclusion The results of our study suggest that the application of tirofiban for rescue stenting after failed mechanical thrombectomy is safe.

BackgroundEpidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties.ObjectiveWe used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors.MethodsWe used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses.ResultsWe confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31).ConclusionsWe show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Purpose In glioma patients, tumor development and multimodality therapy are associated with changes in health-related quality of life (HRQoL). It is largely unknown how different types and locations of tumor- and treatment-related brain lesions, as well as their relationship to white matter tracts and functional brain networks, affect HRQoL. Methods In 121 patients with pretreated gliomas of WHO CNS grades 3 or 4, structural MRI, O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET, resting-state functional MRI (rs-fMRI) and self-reported HRQoL questionnaires (EORTC QLQ-C30/BN20) were obtained. Resection cavities, T1-enhancing lesions, T2/FLAIR hyperintensities, and lesions with pathologically increased FET uptake were delineated. Effects of tumor lateralization, involvement of white matter tracts or resting-state network nodes by different types of lesions and within-network rs-fMRI connectivity were analyzed in terms of their interaction with HRQoL scores. Results Right hemisphere gliomas were associated with significantly less favorable outcomes in physical, role, emotional and social functioning, compared with left-sided tumors. Most functional HRQoL scores correlated significantly with right-sided white-matter tracts involvement by T2/FLAIR hyperintensities and with loss of within-network functional connectivity of right-sided nodes. Tumors of the left hemisphere caused significantly more communication deficits. Conclusion In pretreated high-grade gliomas, right hemisphere lesions are associated with reduced HRQoL scores in most functional domains except communication ability, compared to tumors of the left hemisphere. These relationships are mainly observed for T2/FLAIR lesions involving structural and functional networks in the right hemisphere. The data suggest that sparing the right hemisphere from treatment-related tissue damage may improve HRQoL in glioma patients.

Positron emission tomography is a highly sensitive molecular imaging modality, based on the coincident detection of annihilation photons after positron decay. The most used detector is based on dense, fast, and luminous scintillators read out by light sensors. This review covers the various detector concepts for clinical and preclinical systems.

ZUSAMMENFASSUNGHereditäre Ataxien werden aufgrund ihrer genetischen Grundlage zu Vorreitern einer zielgerichteten molekularen Präzisionsmedizin in der Neurologie. Neben diversen Small-molecule-Ansätzen werden erste Antisense-Oligonukleotid (ASO)-Therapiestudien erwartet. Dabei gestaltet sich jedoch die vorausgehende klinisch-genetische Aufarbeitung degenerativer Ataxie-Erkrankungen schwierig, angesichts einer zunehmenden, selbst für Experten oftmals kaum überschaubaren Anzahl neuer – teils häufiger, teils extremst seltener – genetischer Ataxie-Erkrankungen. Die vorliegende Arbeit gibt eine pragmatische Orientierung für Nichtataxie-Experten für die klinisch-genetische Aufarbeitung von Patienten mit degenerativer Ataxie. Nach einer allgemeinen Einführung zu besonderen Aspekten bei der Untersuchung und Anamnese bei Ataxie-Patienten werden vor allem Häufigkeit und Therapierelevanz der jeweiligen Ataxie-Typen berücksichtigt und ein praktisch orientierter genetischer diagnostischer Algorithmus vorgestellt.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is highly effective in controlling motor symptoms in patients with Parkinson's disease. However, correct selection of stimulation parameters is pivotal to treatment success and currently follows a time-consuming and demanding trial-and-error process. We aimed to assess treatment effects of stimulation parameters suggested by a recently published algorithm (StimFit) based on neuroimaging data.This double-blind, randomised, crossover, non-inferiority trial was carried out at Charité - Universitätsmedizin, Berlin, Germany, and enrolled patients with Parkinson's disease treated with directional octopolar electrodes targeted at the STN. All patients had undergone DBS programming according to our centre's standard of care (SoC) treatment before study recruitment. Based on perioperative imaging data, DBS electrodes were reconstructed and StimFit was applied to suggest optimal stimulation settings. Patients underwent motor assessments using the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS-III) during OFF-medication and in OFF-stimulation and ON-stimulation states under both conditions, StimFit and SoC parameter settings. Patients were randomly assigned (1:1) to receive either StimFit-programmed DBS first and SoC-programmed DBS second, or SoC-programmed DBS first and StimFit-programmed DBS second. The allocation schedule was generated using a computerised random number generator. Both the rater and patients were masked to the sequence of SoC and StimFit stimulation conditions. All patients who participated in the study were included in the analysis. The primary endpoint of this study was the absolute mean difference between MDS-UPDRS-III scores under StimFit and SoC stimulation, with a non-inferiority margin of 5 points. The study was registered at the German Register for Clinical Trials (DRKS00023115), and is complete.Between July 10, 2020, and Oct 28, 2021, 35 patients were enrolled in the study; 18 received StimFit followed by SoC stimulation, and 17 received SoC followed by StimFit stimulation. Mean MDS-UPDRS-III scores improved from 47·3 (SD 17·1) at OFF-stimulation baseline to 24·7 (SD 12·4) and 26·3 (SD 12·4) under SoC and StimFit stimulation, respectively. Mean difference between motor scores was -1·6 (SD 7·1; 95% CI -4·0 to 0·9; superiority test psuperiority=0·20; n=35), establishing non-inferiority of StimFit stimulation at a margin of -5 points (non-inferiority test pnon-inferiority=0·0038). In six patients (17%), initial programming of StimFit settings resulted in acute side-effects and amplitudes were reduced until side-effects disappeared.Automated data-driven algorithms can predict stimulation parameters that lead to motor symptom control comparable to SoC treatment. This approach could significantly decrease the time necessary to obtain optimal treatment parameters.Deutsche Forschungsgemeinschaft through NeuroCure Clinical Research Center and TRR 295.

Autoimmune encephalitis (AE) can be classified into antibody-defined subtypes, which can manifest with immunotherapy-responsive movement disorders sometimes mimicking non-inflammatory etiologies. In the elderly, anti-leucin-rich-glioma-inactivated-1 (LGI1) and contactin-associated-protein-like-2 (CASPR2) antibody-associated diseases compose a relevant fraction of AE. Patients with LGI1 autoantibodies are known to present with limbic encephalitis and additionally faciobrachial dystonic seizures (FBDS) may occur. However, the clinical spectrum of CASPR2 autoantibody-associated disorders is more diverse including limbic encephalitis, Morvan`s syndrome, peripheral nerve hyperexcitability syndrome, ataxia, pain and sleep disorders. Reports on unusual, sometimes isolated and immunotherapy-responsive movement disorders in CASPR2-autoantibody associated syndromes have caused substantial concern regarding necessity of autoantibody-testing in patients with movement disorders. Therefore, we aimed to systematically assess their prevalence and manifestation in patients with CASPR2 autoimmunity. This international, retrospective cohort study included patients with CASPR2 autoimmunity from participating expert centers in Europe. Patients with ataxia and/or movement disorders were analyzed in detail using questionnaires and video recordings. We recruited a comparator group with anti-leucin-rich-glioma-inactivated-1 (LGI1) encephalitis from the GENERATE network. Characteristics were compared according to serostatus. We identified 164 patients with CASPR2 autoantibodies. Of these, 149 (90.8%) had only CASPR2- and 15 (9.1%) both CASPR2- and LGI1-autoantibodies. Compared to 105 patients with LGI1 encephalitis, patients with CASPR2 autoantibodies more often had movement disorders and/or ataxia (35.6% versus 3.8%; p

(1) Background: Radial RARE-EPI MRI facilitates simultaneous T2 and T2* mapping (2in1-RARE-EPI). With modest undersampling (R = 2), the speed gain of 2in1-RARE-EPI relative to Multi-Spin-Echo and Multi-Gradient-Recalled-Echo references is limited. Further reduction in scan time is crucial for clinical studies investigating T2 and T2* as imaging biomarkers. We demonstrate the feasibility of further acceleration, utilizing compressed sensing (CS) reconstruction of highly undersampled 2in1-RARE-EPI. (2) Methods: Two-fold radially-undersampled 2in1-RARE-EPI data from phantoms, healthy volunteers (n = 3), and multiple sclerosis patients (n = 4) were used as references, and undersampled (Rextra = 1–12, effective undersampling Reff = 2–24). For each echo time, images were reconstructed using CS-reconstruction. For T2 (RARE module) and T2* mapping (EPI module), a linear least-square fit was applied to the images. T2 and T2* from CS-reconstruction of undersampled data were benchmarked against values from CS-reconstruction of the reference data. (3) Results: We demonstrate accelerated simultaneous T2 and T2* mapping using undersampled 2in1-RARE-EPI with CS-reconstruction is feasible. For Rextra = 6 (TA = 01:39 min), the overall MAPE was ≤8% (T2*) and ≤4% (T2); for Rextra = 12 (TA = 01:06 min), the overall MAPE was

Barrett’s esophagus is associated with an increased risk of adenocarcinoma. Thorough screening during endoscopic surveillance is crucial to improve patient prognosis. Detecting and characterizing dysplastic or neoplastic Barrett’s esophagus during routine endoscopy are challenging, even for expert endoscopists. Artificial intelligence-based clinical decision support systems have been developed to provide additional assistance to physicians performing diagnostic and therapeutic gastrointestinal endoscopy. In this article, we review the current role of artificial intelligence in the management of Barrett’s esophagus and elaborate on potential artificial intelligence in the future.

Background/Aims: Endoscopic submucosal dissection (ESD) has been established as a treatment modality for superficial esophageal squamous cell carcinoma (ESCC). Long-term follow-up data are lacking in Western countries. The aim of this study was to analyze long-term survival in a Western center.Methods: Patients undergoing ESD for ESCC were included. The analysis was performed retrospectively using a prospectively collected database.Results: R0 resection rate was 96.7% (59/61 lesions in 58 patients). Twenty-seven patients (46.6%) fulfilled the curative resection criteria (M1/M2) (group A), 11 patients (19.0%) had M3 lesions without lymphovascular invasion (LVI) (group B), and 20 patients (34.5%) had lesions with submucosal invasion or LVI (group C). Additional treatment was recommended after non-curative resection. It was not performed in 20/31 patients (64.5%), mainly because of comorbidities (75%). Twenty-nine out of 58 (50.0%) patients died during a mean follow-up of 3.7 years. Death was related to ESCC in 17.2% (5/29) of patients. The disease-specific survival rate after curative resection was 100%. Overall survival rates after 5 years were 61.5%, 63.6% and 28.1% for groups A, B, and C, respectively. The overall survival was significantly worse after non-curative resection (p=0.038).Conclusions: Non-curative resection is frequent after ESD for ESCC in Western patients. The long-term prognosis is limited and mainly determined by comorbidity. Early diagnosis and pre-interventional assessments need to be improved.

The purpose of this study was to implement a state-of-the-art convolutional neural network used to synthesize artificial T1-weighted (T1w) full-dose images from corresponding noncontrast and low-dose images (using various settings of input sequences) and test its performance on a patient population acquired prospectively.In this monocentric, institutional review board-approved study, a total of 138 participants were included who received an adapted imaging protocol with acquisition of a T1w low dose after administration of 10% of the standard dose and acquisition of a T1w full dose after administration of the remaining 90% of the standard dose of a gadolinium-containing contrast agent. A total of 83 participants formed the training sample (51.7 ± 16.5 years, 36 women), 25 the validation sample (55.3 ± 16.4 years, 11 women), and 30 the test sample (55.0 ± 15.0 years, 9 women). Four input settings were differentiated: only the T1w noncontrast and T1w low-dose images (standard setting), only the T1w noncontrast and T1w low-dose images with a prolonged postinjection time of 5 minutes (5-minute setting), multiple noncontrast sequences (T1w, T2w, diffusion) and the T1w low-dose images (extended setting), and only noncontrast sequences (T1w, T2w, diffusion) were used (zero-dose setting). For each setting, a deep neural network was trained to synthesize artificial T1w full-dose images, which were assessed on the test sample using an objective evaluation based on quantitative metrics and a subjective evaluation through a reader-based study. Three readers scored the overall image quality, the interchangeability in regard to the clinical conclusion compared with the true T1w full-dose sequence, the contrast enhancement of lesions, and their conformity to the respective references in the true T1w full dose.Quantitative analysis of the artificial T1w full-dose images of the standard setting provided a peak signal-to-noise ratio of 33.39 ± 0.62 (corresponding to an average improvement of the low-dose sequences of 5.2 dB) and a structural similarity index measure of 0.938 ± 0.005. In the 4-fold cross-validation, the extended setting yielded similar performance to the standard setting in terms of peak signal-to-noise ratio ( P = 0.20), but a slight improvement in structural similarity index measure ( P < 0.0001). For all settings, the reader study found comparable overall image quality between the original and artificial T1w full-dose images. The proportion of scans scored as fully or mostly interchangeable was 55%, 58%, 43%, and 3% and the average counts of false positives per case were 0.42 ± 0.83, 0.34 ± 0.71, 0.82 ± 1.15, and 2.00 ± 1.07 for the standard, 5-minute, extended, and zero-dose setting, respectively. Using a 5-point Likert scale (0 to 4, 0 being the worst), all settings of synthesized full-dose images showed significantly poorer contrast enhancement of lesions compared with the original full-dose sequence (difference of average degree of contrast enhancement-standard: -0.97 ± 0.83, P =

Background Impact of concomitant fractures on patients sustaining a proximal femur fracture remains unclear. Rising numbers and patient need for rehab is an important issue. The objective of our study was to investigate the impact of concomitant fractures, including all types of fractures, when treated operatively, for proximal femur fractures on the length of hospital stay, in-house mortality and complication rate. Methods Observational retrospective cohort single-center study including 85 of 1933 patients (4.4%) with a mean age of 80.5 years, who were operatively treated for a proximal femoral and a concomitant fracture between January 2016 and June 2020. A matched pair analysis based on age, sex, fracture type and anticoagulants was performed. Patient data, length of hospital stay, complications and mortality were evaluated. Results The most common fractures were osteoporosis-associated fractures of the distal forearm (n = 34) and the proximal humerus (n = 36). The group of concomitant fractures showed a higher CCI than the control group (5.87 vs. 5.7 points; p p N = 20), whilst only 7.1% of complications were recorded for concomitant fractures (p Conclusions A concomitant fracture to a hip fracture increases the length of hospital stay significantly but does not increase the complication rate or the in-house mortality. This might be due to the early mobilization, which is possible after early operative treatment of both fractures.

Background Atopic dermatitis (AD) is a heterogeneous, chronic inflammatory skin disease linked to skin microbiome dysbiosis with reduced bacterial diversity and elevated relative abundance of Staphylococcus aureus (S. aureus). Objectives We aimed to characterize the yet incompletely understood association between the skin microbiome and patients' demographic and clinical cofactors in relation to AD severity. Methods The skin microbiome in 48 adult moderate-to-severe AD patients was investigated using next-generation deep sequencing (16S rRNA gene, V1–V3 region) followed by denoising (DADA2) to obtain amplicon sequence variant (ASV) composition. Results In lesional skin, AD severity was associated with S. aureus relative abundance (rS = 0.53, p

Because human fetal ventral mesencephalic tissue grafts provide promising results in ameliorating Parkinson's disease-implicated motor dysfunctions, human fetal midbrain-derived dopamine neuronal precursor cells are considered good candidates for cell-based therapy for Parkinson's disease in that large quantities of cells can be supplied through a good manufacturing practice-compliant system.We conducted a prospective, phase I/IIa, dose-escalation, open-label 'first-in-human' clinical trial with fetal neural precursor cells to assess their safety and therapeutic efficacy in patients with idiopathic Parkinson's disease.Fifteen patients were assigned to receive three different doses of cells (4 × 106 , 12 × 106 , and 40 × 106 cells) and completed a 12-month follow-up. The primary outcome was safety, by measuring the presence of grade 3 or higher cells according to National Cancer Institute guidelines and any contaminated cells. Secondary outcomes assessed motor and neurocognitive function, as well as the level of dopamine transporters, by positron emission tomography-computed tomography.Although a pronation-supination and hand/arm movement performance was remarkably enhanced in all three groups (all P < 0.05), the medium- and high-dose-treated groups exhibited significant improvement in Unified Parkinson's Disease Rating Scale Part III only up to 26.16% and 40%, respectively, at 12 months after transplantation without any serious clinical complications or graft-induced dyskinesia in all patients. However, the motor improvements did not correlate with increase in the dopamine transporter on positron emission tomography images.Our results primarily demonstrate the safety and plausible dose-dependent efficacy of human fetal midbrain-derived dopamine neuronal precursor cells for idiopathic Parkinson's disease. © 2023 International Parkinson and Movement Disorder Society.

An unmet need exists for reliable plasma biomarkers of amyloid pathology, in the clinical laboratory setting, to streamline diagnosis of Alzheimer's disease (AD). For routine clinical use, a biomarker must provide robust and reliable results under pre-analytical sample handling conditions. We investigated the impact of different pre-analytical sample handling procedures on the levels of seven plasma biomarkers in development for potential routine use in AD. Using (1) fresh (never frozen) and (2) previously frozen plasma, we evaluated the effects of (A) storage time and temperature, (B) freeze/thaw (F/T) cycles, (C) anticoagulants, (D) tube transfer, and (E) plastic tube types. Blood samples were prospectively collected from patients with cognitive impairment undergoing investigation in a memory clinic. β-amyloid 1-40 (Aβ40), β-amyloid 1-42 (Aβ42), apolipoprotein E4, glial fibrillary acidic protein, neurofilament light chain, phosphorylated-tau (phospho-tau) 181, and phospho-tau-217 were measured using Elecsys® plasma prototype immunoassays. Recovery signals for each plasma biomarker and sample handling parameter were calculated. For all plasma biomarkers measured, pre-analytical effects were comparable between fresh (never frozen) and previously frozen samples. All plasma biomarkers tested were stable for ≤24 h at 4°C when stored as whole blood and ethylenediaminetetraacetic acid (EDTA) plasma. Recovery signals were acceptable for up to five tube transfers, or two F/T cycles, and in both polypropylene and low-density polyethylene tubes. For all plasma biomarkers except Aβ42 and Aβ40, analyte levels were largely comparable between EDTA, lithium heparin, and sodium citrate tubes. Aβ42 and Aβ40 were most sensitive to pre-analytical handling, and the effects could only be partially compensated by the Aβ42/Aβ40 ratio. We provide recommendations for an optimal sample handling protocol for analysis of plasma biomarkers for amyloid pathology AD, to improve the reproducibility of future studies on plasma biomarkers assays and for potential use in routine clinical practice.

(1) Background: Strong evidence supports the persuasive positive effects of exercise for cancer patients and survivors. Different approaches of exercise programs have been established; however, the special interests of young adults (YAs) with cancer have rarely been considered in exercise interventions. Therefore, the study YOUng EXercisers (YOUEX) aimed to investigate exercise preferences in YAs. (2) Methods: YOUEX was a three-arm, patient preference-based non-randomized, longitudinal, pre–post exercise intervention, offering three different exercise modules to YAs during or after acute therapy (Module 1: online supervised group-based (M1); Module 2: online unsupervised (M2); Module 3: in-person supervised (M3)). The intervention period was 12 weeks with another 12-week follow-up period, the modules could be changed or amended after 6 and 12 weeks. (3) Results: 92 YAs were allocated to the study. At baseline, 50 YAs (54%) chose M2, 32 YAs (35%) M1 and 10 YAs (11%) M3. The analysis revealed high acceptability and feasibility of the online exercise programs (M1, M2). There was a high impact of the COVID-19 pandemic on the execution of M3. YAs showed diverse preferences in module selection due to differences in, e.g., cancer therapy status or favored level of supervision. (4) Conclusions: YAs need personalized exercise programs that consider their individual interests and needs. Online exercise programs can be a promising addition to existing exercise opportunities. They are an effective way to increase physical activity levels in YAs. German Foundation of Young Adults with Cancer

Purpose Positron emission tomography (PET) with O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) is a well-established tool for non-invasive assessment of adult central nervous system (CNS) tumors. However, data on its diagnostic utility and impact on clinical management in children and adolescents are limited. Methods Twenty-one children and young adults (13 males; mean age, 8.6 ± 5.2 years; range, 1–19 at initial diagnosis) with either newly diagnosed (n = 5) or pretreated (n = 16) CNS tumors were retrospectively analyzed. All patients had previously undergone neuro-oncological work-up including cranial magnetic resonance imaging. In all cases, [18F]FET-PET was indicated in a multidisciplinary team conference. The impact of PET imaging on clinical decision-making was assessed. Histopathology (n = 12) and/or clinical and imaging follow-up (n = 9) served as the standard of reference. Results The addition of [18F]FET-PET to the available information had an impact on further patient management in 14 out of 21 subjects, with avoidance of invasive surgery or biopsy in four patients, biopsy guidance in four patients, change of further treatment in another five patients, and confirmation of diagnosis in one patient. Conclusion [18F]FET-PET may provide important additional information for treatment guidance in pediatric and adolescent patients with CNS tumors.

Impulse control disorders (ICD) in Parkinson’s disease (PD) frequently occur, not always as a direct consequence of dopaminergic medication. This study investigated premorbid personality traits and behavioural characteristics in non-demented PD patients with self-reported symptoms of ICD (PD-srICD). From a total of 200 non-demented PD patients who filled out questionnaires assessing symptoms and severity of ICD, those were classified as PD-srICD (n = 32) who reported current occurrence of at least one compulsive behaviour (gambling, sexual behaviour, buying behaviour, or eating). As a control group, 32 patients with no self-reported ICD symptoms were matched for levodopa equivalent daily dose. The demographic, clinical, and premorbid personality profiles were compared between both groups. Frequency of psychological characteristics indicating substance use disorder was evaluated in patients with PD-srICD. Patients with PD-srICD were more frequently male, younger at examination, had earlier PD onset, more depression, higher non-motor burden, less quality of life (p p = 0.03) and joyful experience of stress (p = 0.04) than patients in the control group. Of patients with PD-srICD, 90.6% reported at least one behavioural characteristic of substance use disorder, most frequently positive expectations following ICD behaviour and illusional beliefs about its behavioural control. Signs of addiction were common among patients with PD-srICD. Therefore, the profile of psychological characteristics in patients with PD-srICD resembled that of patients with substance use disorder. It can be concluded that dopamine replacement therapy (DRT) alone does not account for PD-srICD and that thorough psychological diagnostics are recommended.

Coronavirus disease-19 (COVID-19) is still affecting the lives of people round the globe and remains a major public health threat. The emergence of new variants more efficiently transmitted, more virulent and more capable of escaping naturally acquired and vaccine-induced immunity creates a long-term negative outlook for the management of the pandemic. The development of effective and viable prevention and treatment options to reduce viral transmission is of the utmost importance. The fruits of the European black elderberry and extracts thereof have been traditionally used to treat viral infections such as coughs, cold and flu. Specifically, its efficacy against the Influenza A virus has been shown in vitro as well as in human clinical trials. In the current project, we investigated the antiviral activity of a black elderberry extract, mainly containing anthocyanins and phenolic compounds, against SARS-CoV-2 and its variants of concern and explored the possible mode of action by performing time of addition experiments. The results revealed that the extract displayed a strong anti-SARS-CoV-2 activity against the Wuhan type as well as the variants of concern Alpha, Beta, Gamma, Delta and Omicron with a comparable antiviral activity. Based on cytotoxicity data, a 2-log theoretical therapeutic window was established. The data accumulated so far suggest that the viral replication cycle is inhibited at later stages, inasmuch as the replication process was affected after virus entry. Therefore, it would be legitimate to assume that black elderberry extract might have the potential to be an effective treatment option for SARS-CoV-2 infections.

BackgroundThe aim of this study is to examine the dosimetric influence of endorectal balloons (ERB) in rectal sparing in prostate cancer patients with implanted hydrogel rectum spacers treated with dose escalated/hypofractionated intensity modulated proton beam therapy (IMPT). MethodsTen patients with localised prostate cancer included in the ProRegPros study and treated at our centre were invastigated in this study. All patients underwent a placement of hydrogel rectum spacers before planning. Two planning CTs (with and without 120 cm3 fluid-filled ERB) were acquired for each patient. Dose prescription was set according to the used simultaneous integrated boost strategy with 72 Gray (Gy)/2.4 Gy/5 x weekly to prostate+1 cm of the seminal vesicle, and 60 Gy/2 Gy/5 x weekly to prostate+2 cm of the seminal vesicle. Planning with two lateral-opposed IMPT beams was performed in both CTs. Rectal dosimetry values including dose-volume statistics and normal tissue complication probability (NTCP) in both plans were compared (non-ERB plans vs. ERB plans).ResultsFor ERB plans compared to non-ERB, the reductions were 8.51 ± 5.25 Gy (RBE) (p= 0.000) and 15.76 ± 11.11Gy (P= 0.001) for the mean and the median rectal dose, respectively. No significant reductions in rectal volumes receiving high dose levels were found. The use of ERB resulted in significant reduction in rectal volume receiving 50 Gy (RBE), 40 Gy (RBE), 30 Gy (RBE), 20 Gy (RBE), and 10 Gy (RBE) with P values of 0.034, 0.008, 0.003, 0.001, and 0.001, respectively. For the anterior rectum, no differences between ERB and non-ERB plans were observed. For the posterior rectum, ERB reduced rectal volumes received 30 Gy (RBE), 20 Gy (RBE), and 10 Gy (RBE) with P values of 0.019, 0.003, and 0.001, respectively. No significant reductions in mean or median rectal toxicity (Late rectal bleeding ≥2, necrosis/stenosis, and Late rectal toxicity ≥ 3) were observed when using the ERB according to NTCP models.ConclusionThe ERB reduced rectal volumes exposed to intermediate/low dose levels. However, no significant reduction in rectal volumes receiving high/intermediate doses could be observed. No benefit but also no disadvantage of the ERB for late rectal toxicity was found according to available NTCP models.

The complement system plays a crucial role in host defense, homeostasis, and tissue regeneration and bridges the innate and the adaptive immune systems. Although the genetic variants in complement C2 (c.839_849+17del; p.(Met280Asnfs*5)) and C8B (c.1625C>T; p.(Thr542Ile)) are known individually, here, we report on a patient carrying their combination in a heterozygous form. The patient presented with a reduced general condition and suffers from a wide variety of autoimmune diseases. While no autoimmune disease-specific autoantibodies could be detected, genetic analysis revealed abnormalities in the two complement genes C2 and C8B. Therefore, we performed a comprehensive investigation of the innate immune system on a cellular and humoral level to define the functional consequences. We found slightly impaired functionality of neutrophils and monocytes regarding phagocytosis and reactive oxygen species generation and a diminished expression of the C5aR1. An extensive complement analysis revealed a declined activation potential for the alternative and classical pathway. Reconstitution with purified C2 and C8 into patient serum failed to normalize the dysfunction, whereas the addition of C3 improved the hemolytic activity. In clinical transfer, in vitro supplementation of the patient’s plasma with FFP as a complement source could fully restore full complement functionality. This study describes for the first time a combined heterozygous genetic variation in complement C2 and C8B which, however, cannot fully explain the overall dysfunctions and calls for further complement deficiency research and corresponding therapies.

Background: Extracellular vesicles (EV) are cell-derived vesicles released by all cells in health and disease. Accordingly, EVs are also released by cells in acute myeloid leukemia (AML), a hematologic malignancy characterized by uncontrolled growth of immature myeloid cells, and these EVs likely carry markers and molecular cargo reflecting the malignant transformation occurring in diseased cells. Monitoring antileukemic or proleukemic processes during disease development and treatment is essential. Therefore, EVs and EV-derived microRNA (miRNA) from AML samples were explored as biomarkers to distinguish disease-related patterns ex vivo or in vivo. Methodology: EVs were purified from serum of healthy (H) volunteers and AML patients by immunoaffinity. EV surface protein profiles were analyzed by multiplex bead-based flow cytometry (MBFCM) and total RNA was isolated from EVs prior to miRNA profiling via small RNA sequencing. Results: MBFCM revealed different surface protein patterns in H versus AML EVs. miRNA analysis showed individual as well as highly dysregulated patterns in H and AML samples. Conclusions: In this study, we provide a proof-of-concept for the discriminative potential of EV derived miRNA profiles as biomarkers in H versus AML samples. CA extern

Age-related cognitive decline varies greatly in healthy older adults, which may partly be explained by differences in the functional architecture of brain networks. Resting-state functional connectivity (RSFC) derived network parameters as widely used markers describing this architecture have even been successfully used to support diagnosis of neurodegenerative diseases. The current study aimed at examining whether these parameters may also be useful in classifying and predicting cognitive performance differences in the normally aging brain by using machine learning (ML). Classifiability and predictability of global and domain-specific cognitive performance differences from nodal and network-level RSFC strength measures were examined in healthy older adults from the 1000BRAINS study (age range: 55–85 years). ML performance was systematically evaluated across different analytic choices in a robust cross-validation scheme. Across these analyses, classification performance did not exceed 60% accuracy for global and domain-specific cognition. Prediction performance was equally low with high mean absolute errors (MAEs ≥ 0.75) and low to none explained variance (R2 ≤ 0.07) for different cognitive targets, feature sets, and pipeline configurations. Current results highlight limited potential of functional network parameters to serve as sole biomarker for cognitive aging and emphasize that predicting cognition from functional network patterns may be challenging.

Rationale: Pancreatic lineage specification follows the formation of tripotent pancreatic progenitors (PPs). Current protocols rebuilding PPs in vitro have an endocrine lineage bias and are mostly based on PDX1/NKX6-1 coexpression neglecting other markers decisive for PP heterogeneity and lineage potential. However, true tripotent PPs are of utmost interest to study also exocrine disorders such as pancreatic cancer and to simultaneously generate all three pancreatic lineages from the same ancestor. Methods: Here, we performed a comprehensive compound testing to advance the generation of multipotent progenitors, which were further characterized for their trilineage potential in vitro and in vivo. The heterogeneity and cell-cell communication across the PP subpopulations were analyzed via single-cell transcriptomics. Results: We introduce a novel PP differentiation platform based on a comprehensive compound screening with an advanced design of experiments computing tool to reduce impurities and to increase Glycoprotein-2 expression and subsequent trilineage potential. Superior PP tripotency was proven in vitro by the generation of acinar, endocrine, and ductal cells as well as in vivo upon orthotopic transplantation revealing all three lineages at fetal maturation level. GP2 expression levels at PP stage ascribed varying pancreatic lineage potential. Intermediate and high GP2 levels were superior in generating endocrine and duct-like organoids (PDLO). FACS-based purification of the GP2high PPs allowed the generation of pancreatic acinar-like organoids (PALO) with proper morphology and expression of digestive enzymes. scRNA-seq confirmed multipotent identity, positioned the GP2/PDX1/NKX6-1high population next to human fetal tip and trunk progenitors and identified novel ligand-receptor (LR) interactions in distinct PP subpopulations. LR validation experiments licensed midkine and VEGF signaling to increase markers labelling the single cell clusters with high GP2 expression. Conclusion: In this study, we guide human pluripotent stem cells into multipotent pancreatic progenitors. This common precursor population, which has the ability to mature into acinar, ductal and functional β-cells, serves as a basis for studying developmental processes and deciphering early cancer formation in a cell type-specific context. Using single-cell RNA sequencing and subsequent validation studies, we were able to dissect PP heterogeneity and specific cell-cell communication signals., publishedVersion

In recent years branched short-chain dicarboxylates (BSCD) such as itaconic acid gained increasing interest in both medicine and biotechnology. Their use as building blocks for plastics urges for developing microbial upcycling strategies to provide sustainable end-of-life solutions. Furthermore, many BSCD exhibit anti-bacterial properties or exert immunomodulatory effects in macrophages, indicating a medical relevance for this group of molecules. For both of these applications, a detailed understanding of the microbial metabolism of these compounds is essential. In this study, the metabolic pathway of BSCD degradation from Pseudomonas aeruginosa PAO1 was studied in detail by heterologously transferring it to Pseudomonas putida. Heterologous expression of the PA0878-0886 itaconate metabolism gene cluster enabled P. putida KT2440 to metabolize itaconate, (S)- and (R)-methylsuccinate, (S)-citramalate, and mesaconate. The functions of the so far uncharacterized genes PA0879 and PA0881 were revealed and proven to extend the substrate range of the core degradation pathway. Furthermore, the uncharacterized gene PA0880 was discovered to encode a 2-hydroxyparaconate (2-HP) lactonase that catalyzes the cleavage of the itaconate derivative 2-HP to itatartarate. Interestingly, 2-HP was found to inhibit growth of the engineered P. putida on itaconate. All in all, this study extends the substrate range of P. putida to include BSCD for bio-upcycling of high-performance polymers, and also identifies 2-HP as promising candidate for anti-microbial applications.

Purpose Characteristic features of amyloid-PET (A), tau-PET (T), and FDG-PET (N) can serve for the A/T/N classification of neurodegenerative diseases. Recent studies showed that the early, perfusion-weighted phases of amyloid- or tau-PET recordings serve to detect cerebrometabolic deficits equally to FDG-PET, therefore providing a surrogate of neuronal injury. As such, two channels of diagnostic information can be obtained in the setting of a single PET scan. However, there has hitherto been no comparison of early-phase amyloid- and tau-PET as surrogates for deficits in perfusion/metabolism. Therefore, we undertook to compare [18F]flutemetamol-amyloid-PET and [18F]PI-2620 tau-PET as “one-stop shop” dual purpose tracers for the detection of neurodegenerative disease. Methods We obtained early-phase PET recordings with [18F]PI-2620 (0.5–2.5 min p.i.) and [18F]flutemetamol (0–10 min p.i.) in 64 patients with suspected neurodegenerative disease. We contrasted global mean normalized images (SUVr) in the patients with a normal cohort of 15 volunteers without evidence of increased pathology to β-amyloid- and tau-PET examinations. Regional group differences of tracer uptake (z-scores) of 246 Brainnetome volumes of interest were calculated for both tracers, and the correlations of the z-scores were evaluated using Pearson’s correlation coefficient. Lobar compartments, regions with significant neuronal injury (z-scores Results The z-scores of perfusion-weighted images of both tracers showed high correlations across the brain, especially in the frontal and parietal lobes, which were the brain regions with pronounced perfusion deficit in the patient group (R = 0.83 ± 0.08; range, 0.61–0.95). Z-scores of individual patients correlated well by region (R = 0.57 ± 0.15; range, 0.16–0.90), notably when significant perfusion deficits were present (R = 0.66 ± 0.15; range, 0.28–0.90). Conclusion The early perfusion phases of [18F]PI-2620 tau- and [18F]flutemetamol-amyloid-PET are roughly equivalent indices of perfusion defect indicative of regional and lobar neuronal injury in patients with various neurodegenerative diseases. As such, either tracer may serve for two diagnostic channels by assessment of amyloid/tau status and neuronal activity.

Annals of hematology 102(2), 349-358 (2022). doi:10.1007/s00277-022-05080-7, Published by Springer, Berlin ; Heidelberg ; New York

Purpose This study aimed to evaluate the course of olfactory dysfunction [OD] due to upper respiratory tract infections [URTI] especially for COVID-19 [C19] in a multicentric design and to investigate possible predictors for the outcome. Methods In a multicentric study, patients (n = 147, of which 96 were women) with OD due to URTI, including C19 and non-C19 were evaluated at two visits with a standardized medical history and “Sniffin’ Sticks” extended psychophysical testing to examine the course and possible predictors for improvement of olfactory function. Results C19 patients showed better overall olfactory function (p p p = 0.20) except for a more pronounced improvement of odour threshold (p = 0.03) in C19. C19 patients with parosmia exhibited a higher probability of clinically relevant improvement of odour threshold, a better threshold in the second visit, and tended to have a better TDI-score at the second visit. Further possible predictors for an improving olfactory function were younger age, female gender, and had lower scores in olfactory tests at the first visit. Conclusions Patients with C19 and non-C19 URTI exhibit a similar improvement over 3–4 months except for the odour threshold, with a better TDI in both visits for C19. For C19 a better prognosis in terms of olfactory recovery was found for younger patients with parosmia and lower olfactory scores at the first visit. Still, for many patients with olfactory loss, an improvement that is experienced as complete may only occur over months and possibly years.

European journal of nuclear medicine and molecular imaging (2022). doi:10.1007/s00259-022-06066-3, Published by Springer-Verl., Heidelberg [u.a.]

Telemedicine is frequently used to provide remote neurological expertise for acute stroke workup and was associated with better functional outcomes when combined with a stroke unit system-of-care. We investigated whether such system-of-care yields additional benefits when implemented on top of neurological competence already available onsite.Quality improvement measures were implemented within a 'hub-and-spoke' teleneurology network in 11 hospitals already provided with onsite or telestroke expertise. Measures included dedicated units for neurological emergencies, standardization of procedures, multiprofessional training, and quality-of-care monitoring. Intervention effects were investigated in a controlled study enrolling patients insured at 3 participating statutory health insurances diagnosed with acute stroke or other neurological emergencies. Outcomes during the intervention period between November 2017 and February 2020 were compared with those pre-intervention between October 2014 and March 2017. To control for temporal trends, we compared outcomes of patients with respective diagnoses in 11 hospitals of the same region. Primary outcome was the composite of up-to-90-day death, new disability with the need of ambulatory or nursing home care, expressed by adjusted hazard ratio (aHR).We included 1,418 patients post-implementation (55% female, mean age 76.7 ± 12.8 year) and 2,306 patients pre-implementation (56%, 75.8 ± 13.0 year, respectively). The primary outcome occurred in 479/1,418 (33.8%) patients post-implementation and in 829/2,306 (35.9%) pre-implementation. The aHR for the primary outcome was 0.89 (95% confidence interval [CI]: 0.79-0.99, p = 0.04) with no improvement seen in non-participating hospitals between post- versus pre-implementation periods (aHR 1.04; 95% CI: 0.95-1.15).Implementation of a multicomponent system-of-care was associated with a lower risk of poor outcomes. ANN NEUROL 2022.

The chaperone protein BiP is the master regulator of the unfolded protein response in the endoplasmic reticulum. BiP chaperone activity is regulated by the post-translational modification AMPylation, exclusively provided by FICD. We investigated whether FICD variants identified in patients with motor neuron disease could interfere with BiP activity regulation. Methods Exome sequencing was performed to identify causative pathogenic variants associated with motor neuron diseases. Functional studies were conducted on fibroblasts from patients to explore the molecular mechanism of the disease. Results We identified biallelic variants in FICD causing a neurodegenerative disease of upper and lower motor neurons. Affected individuals harbor a specific missense variant, Arg374His, positioned in the catalytic motif of the enzyme and important for adenosine triphosphate binding. The mutated residue abolishes intramolecular interaction with the regulatory residue Glu234, essential to inhibit AMPylation and to promote de-AMPylation by FICD. Consequently, fibroblasts from patients with FICD variants have abnormally increased levels of AMPylated and thus inactivated BiP. Conclusion Loss of BiP chaperone activity in patients likely results in a chronic impairment of the protein quality control system in the endoplasmic reticulum. These findings will guide the development of therapeutic strategies for motoneuron and related diseases linked to proteotoxic stress.

Contains fulltext : 287484.pdf (Publisher’s version ) (Open Access) BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P