Quality contract 'prevention of postoperative delirium in the care of elderly patients' study protocol: a non-randomised, pre-post, monocentric, prospective trial.

INTRODUCTION: Postoperative delirium (POD) is seen in approximately 15% of elderly patients and is related to poorer outcomes. In 2017, the Federal Joint Committee (Gemeinsamer Bundesausschuss) introduced a 'quality contract' (QC) as a new instrument to improve healthcare in Germany. One of the four areas for improvement of in-patient care is the 'Prevention of POD in the care of elderly patients' (QC-POD), as a means to reduce the risk of developing POD and its complications.The Institute for Quality Assurance and Transparency in Health Care identified gaps in the in-patient care of elderly patients related to the prevention, screening and treatment of POD, as required by consensus-based and evidence-based delirium guidelines. This paper introduces the QC-POD protocol, which aims to implement these guidelines into the clinical routine. There is an urgent need for well-structured, standardised and interdisciplinary pathways that enable the reliable screening and treatment of POD. Along with effective preventive measures, these concepts have a considerable potential to improve the care of elderly patients. METHODS AND ANALYSIS: The QC-POD study is a non-randomised, pre-post, monocentric, prospective trial with an interventional concept following a baseline control period. The QC-POD trial was initiated on 1 April 2020 between Charité-Universitätsmedizin Berlin and the German health insurance company BARMER and will end on 30 June 2023. INCLUSION CRITERIA: patients 70 years of age or older that are scheduled for a surgical procedure requiring anaesthesia and insurance with the QC partner (BARMER). Exclusion criteria included patients with a language barrier, moribund patients and those unwilling or unable to provide informed consent. The QC-POD protocol provides perioperative intervention at least two times per day, with delirium screening and non-pharmacological preventive measures. ETHICS AND DISSEMINATION: This protocol was approved by the ethics committee of the Charité-Universitätsmedizin, Berlin, Germany (EA1/054/20). The results will be published in a peer-reviewed scientific journal and presented at national and international conferences. TRIAL REGISTRATION NUMBER: NCT04355195.

Cerebral organoids containing an AUTS2 missense variant model microcephaly.

Variants in the AUTS2 gene are associated with a broad spectrum of neurological conditions characterized by intellectual disability, microcephaly, and congenital brain malformations. Here, we use a human cerebral organoid model to investigate the pathophysiology of a heterozygous de novo missense AUTS2 variant identified in a patient with multiple neurological impairments including primary microcephaly and profound intellectual disability. Proband cerebral organoids exhibit reduced growth, deficits in neural progenitor cell (NPC) proliferation and disrupted NPC polarity within ventricular zone-like regions compared to control cerebral organoids. We used CRISPR-Cas9-mediated gene editing to correct this variant and demonstrate rescue of impaired organoid growth and NPC proliferative deficits. Single-cell RNA sequencing revealed a marked reduction of G1/S transition gene expression and alterations in WNT-ß-catenin signalling within proband NPCs, uncovering a novel role for AUTS2 in NPCs during human cortical development. Collectively, these results underscore the value of cerebral organoids to investigate molecular mechanisms underlying AUTS2 syndrome.

Spatially resolved transcriptomics reveals genes associated with the vulnerability of middle temporal gyrus in Alzheimer's disease.

Human middle temporal gyrus (MTG) is a vulnerable brain region in early Alzheimer's disease (AD), but little is known about the molecular mechanisms underlying this regional vulnerability. Here we utilize the 10 × Visium platform to define the spatial transcriptomic profile in both AD and control (CT) MTG. We identify unique marker genes for cortical layers and the white matter, and layer-specific differentially expressed genes (DEGs) in human AD compared to CT. Deconvolution of the Visium spots showcases the significant difference in particular cell types among cortical layers and the white matter. Gene co-expression analyses reveal eight gene modules, four of which have significantly altered co-expression patterns in the presence of AD pathology. The co-expression patterns of hub genes and enriched pathways in the presence of AD pathology indicate an important role of cell-cell-communications among microglia, oligodendrocytes, astrocytes, and neurons, which may contribute to the cellular and regional vulnerability in early AD. Using single-molecule fluorescent in situ hybridization, we validated the cell-type-specific expression of three novel DEGs (e.g., KIF5A, PAQR6, and SLC1A3) and eleven previously reported DEGs associated with AD pathology (i.e., amyloid beta plaques and intraneuronal neurofibrillary tangles or neuropil threads) at the single cell level. Our results may contribute to the understanding of the complex architecture and neuronal and glial response to AD pathology of this vulnerable brain region.

Electrophysiological Maturation of Cerebral Organoids Correlates with Dynamic Morphological and Cellular Development.

Cerebral organoids (COs) are rapidly accelerating the rate of translational neuroscience based on their potential to model complex features of the developing human brain. Several studies have examined the electrophysiological and neural network features of COs; however, no study has comprehensively investigated the developmental trajectory of electrophysiological properties in whole-brain COs and correlated these properties with developmentally linked morphological and cellular features. Here, we profiled the neuroelectrical activities of COs over the span of 5 months with a multi-electrode array platform and observed the emergence and maturation of several electrophysiologic properties, including rapid firing rates and network bursting events. To complement these analyses, we characterized the complex molecular and cellular development that gives rise to these mature neuroelectrical properties with immunohistochemical and single-cell transcriptomic analyses. This integrated approach highlights the value of COs as an emerging model system of human brain development and neurological disease.

Convergence of human cellular models and genetics to study neural stem cell signaling to enhance central nervous system regeneration and repair.

Human central nervous system (CNS) regeneration is considered the holy grail of neuroscience research, and is one of the most pressing and difficult questions in biology and science. Despite more than 20 years of work in the field of neural stem cells (NSCs), the area remains in its infancy as our understanding of the fundamental mechanisms that can be leveraged to improve CNS regeneration in neurological diseases is still growing. Here, we focus on the recent lessons from lower organism CNS regeneration genetics and how such findings are starting to illuminate our understanding of NSC signaling pathways in humans. These findings will allow us to improve upon our knowledge of endogenous NSC function, the utility of exogenous NSCs, and the limitations of NSCs as therapeutic vehicles for providing relief from devastating human neurological diseases. We also discuss the limitations of activating NSC signaling for CNS repair in humans, especially the potential for tumor formation. Finally, we will review the recent advances in new culture techniques, including patient-derived cells and cerebral organoids to model the genetic regulation of signaling pathways controlling the function of NSCs during injury and disease states.

A survey of neuroimmune changes in pregnant and postpartum female rats.

During pregnancy and the postpartum period, the adult female brain is remarkably plastic exhibiting modifications of neurons, astrocytes and oligodendrocytes. However, little is known about how microglia, the brain's innate immune cells, are altered during this time. In the current studies, microglial density, number and morphological phenotype were analyzed within multiple regions of the maternal brain that are known to show neural plasticity during the peripartum period and/or regulate peripartum behavioral changes. Our results show a significant reduction in microglial density during late pregnancy and the early-mid postpartum period in the basolateral amygdala, medial prefrontal cortex, nucleus accumbens shell and dorsal hippocampus. In addition, microglia numbers were reduced postpartum in all four brain regions, and these reductions occurred primarily in microglia with a thin, ramified morphology. Across the various measures, microglia in the motor cortex were unaffected by reproductive status. The peripartum decrease in microglia may be a consequence of reduced proliferation as there were fewer numbers of proliferating microglia, and no changes in apoptotic microglia, in the postpartum hippocampus. Finally, hippocampal concentrations of the cytokines interleukin (IL)-6 and IL-10 were increased postpartum. Together, these data point to a shift in the maternal neuroimmune environment during the peripartum period that could contribute to neural and behavioral plasticity occurring during the transition to motherhood.